CN101172992A

CN101172992A - Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae infections

Info

Publication number: CN101172992A
Application number: CNA2007101933010A
Authority: CN
Inventors: 让-皮埃尔·索马多西; 波罗·拉科拉; 理查德·斯托勒; 吉勒·戈瑟兰
Original assignee: Centre National de la Recherche Scientifique CNRS; Universita degli Studi di Cagliari; Idenix Cayman Ltd
Current assignee: Univ. Montpellier II; Centre National de la Recherche Scientifique CNRS; Universita degli Studi di Cagliari; Idenix Pharmaceuticals LLC
Priority date: 2002-06-28
Filing date: 2003-06-27
Publication date: 2008-05-07
Also published as: CN1761677A; ZA200410249B

Abstract

2' and/or 3' prodrugs of l', 2', 3' or 4'-branchednucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

Description

Be used for the treatment of flaviviridae infections modification 2 ' and 3 '-nucleoside prodrugs

The application submitted on June 27th, 2003, and denomination of invention is divided an application for the Chinese patent application 03820501.7 of " 2 ' and the 3 '-nucleoside prodrugs that is used for the treatment of the modification of flaviviridae infections ".

The cross reference of related application

The application requires the U.S. Provisional Application submitted on June 28th, 2002 the 60/392nd, No. 350; No. the 60/466th, 194, the U.S. Provisional Application of submitting on April 28th, 2003; With the right of priority of No. the 60/470th, 949, the U.S. Provisional Application of submitting on May 14th, 2003, wherein every piece of disclosed content is incorporated herein by reference in the lump at this.

Invention field

The present invention relates to the pharmaceutical chemistry field, in particular to being used for the treatment of flaviviridae infections, as the 6-of infection with hepatitis C virus modify 1 ', 2 ', 3 ' or 4 '-side chain pyrimidine nucleoside or 8-modify 1 ', 2 ' and/or 3 ' prodrug of 2 ', 3 ' or 4 '-side chain purine nucleoside.

Background of invention

Flaviviridae

Flaviviridae comprises at least 3 isolating genus: pestivirus (pestiviruses), and it causes the disease in ox and the pig; Flavivirus (flaviviruses), its be disease such as singapore hemorrhagic fever and yellow jack main diseases because of; And hepatovirus (hepaciviruses), its unique member is hepatitis C virus (HCV).Flavivirus comprises more than 68 members, can according to the serology dependency with they be divided into different groups (Calisher etc., J.Gen.Virol, 1993,70,37-43).Clinical symptom has nothing in common with each other, and comprises heating, encephalitis and hemorrhagic fever (Fields Virology, editor: Fields, B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, 1996 the 31st chapters, 931-959).The flavivirus that cause global concern relevant with human diseases comprises singapore hemorrhagic fever hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome and japanese encephalitis virus (Halstead, S.B., Rev.Infect.DIS., 1984,6,25 1-264; Halstead, S.B., Science, 239:476-481,1988; Monath, T.P., New Eng.J.Med., 1988,319,641-643).

Pestivirus comprise bovine viral diarrhea virus (BVDV), Pestivirus suis (CSFV is also referred to as hog cholera virus) and sheep border disease virus (BDV) (Moennig .Adv.Vir.Res.1992 such as V., 41,53-98).The pestivirus infection of domestic animal (ox, pig and sheep) causes worldwide tremendous economic loss.BVDV causes the ox membrane disease, has great economic implications (Meyers, G. and Thiel, H.-J., Advances in Virus Research, 1996,47,53-118 for tame farm; Moennig V., etc., Adv.Vir.Res.1992,41,53-98).People's pestivirus is not also identified as the animal pestivirus widely.But serological investigation shows that the mankind are subjected to the threat of considerable pestivirus.

In flaviviridae, pestivirus and hepatovirus are closely-related virus groups.Other closely-related virus comprises that GB virus of A, GB virus of A analogue, GB virus B and GB virus C (are also referred to as hepatitis G virus, HGV) in this section.Hepatovirus group (hepatitis C virus; HCV) comprise many closely related but viruses of the recognizable infected person of genotype.Nearly 6 kinds of HCV genotype and surpass 50 kinds of hypotypes.Because the similarity between pestivirus and the hepatovirus, and because hepatovirus is difficult in growth effectively in the cell culture medium, bovine viral diarrhea virus (BVDV) often is used as substitute and studies HCV virus.

The gene structure of pestivirus and hepatovirus is quite similar.These positive chain RNA virus have a single big open reading frame (ORF) and encode all for the essential viral protein of virus replication.These albumen are expressed as a kind of polyprotein, and it is carried out common translation and translation post-treatment by the proteolytic enzyme of the proteolytic enzyme of cell and encoding viral, thereby produces sophisticated viral protein.。The viral protein that responsible virus genome RNA duplicates approximately is positioned at C-terminal.2/3rds open reading frame is named as non-structure (NS) albumen.For pestivirus and hepatovirus, the gene structure of the Nonstructural Protein of ORF part and the processing of polyprotein are closely similar.For pestivirus and hepatovirus for the two, sophisticated non-structure (NS) albumen, the C-terminal from the N-terminal of Nonstructural Protein coding region to ORF comprises continuously: p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B.

The NS albumen of pestivirus and hepatovirus all has the sequence domains of specific protein functional performance.For example, the NS3 albumen in this two papova have serine protease and helicase characteristic the aminoacid sequence motif (Gorbalenya etc. (1988) Nature 333:22; Bazan and Fletterick (1989) Virology 171:637-639; Gorbalenya etc. (1989) NucleicAcid Res.17.3889-3897).Similarly, the NS5B albumen of pestivirus and hepatovirus has the motif (Koonin, E.V. and Dolja, V.V. (1993) Crit.Rev.Biochem.Molec.Biol.28:375-430) of the RNA polymerase characteristic of RNA guidance.

Actual role and the function of the NS albumen of pestivirus and hepatovirus in viral life cycle is on all four.In both, the NS3 serine protease is responsible for all proteolysis processing (Wiskerchen and Collett (1991) Virology 184:341-350 of polyprotein precursor downstream position in ORF; Bartenschlager etc. (1993) JVirol.67:3835-3844; Eckart etc. (1993) Biochem.Biophys.Res.Comm.192:399-406; Grakoui etc. (1993) J.Virol.67:2832-2843; Grakoui etc. (1993) Proc.Natl.Acad.Sci.USA 90:10583-10587; Hijikata etc. (1993) J.Virol.67:4665-4675; Tome etc. (1993) J.Virol.67:4017-4026).NS4 albumen in both all as the cofactor of NS3 serine protease (Bartenschlager etc. (1994) J.Virol.68:5045-5055; Failla etc. (1994) J.Virol.68:3753-3760; Lin etc. (1994) 68:8147-8157; Xu etc. (1997) J.Virol.71:5312-5322).The NS3 albumen of two kinds of Tobamovirus also all also have helicase function (Kim etc. (1995) Biochem.Biophys.Res.Comm.215:160-166; Jin and Peterson (1995) Arch.Biochem.Biophys., 323:47-53; Warrener and Collett (1995) J.Virol. 69:1720-1726).At last, the NS5B albumen of pestivirus and hepatovirus have the rna polymerase activity that the RNA of expection instructs (Behrens etc. (1996) EMBO J.15:12-22; Lchmann etc. (1997) J. Virol.71:8416-8428; Yuan etc. (1997) Biochem.Biophys.Res.Comm.232:231-235; Hagedom, PCT WO 97/12033; Zhong etc. (1998) J.Virol.72.9365-9369).

Hepatitis C virus

Hepatitis C virus (HCV) is the main cause of disease (Boyer .J.Hepatol.32:98-112 such as N., 2000) of chronic hepatopathy in the world wide.HCV has caused the virus infection of slow growth and has been that the main diseases of liver cirrhosis and hepatocellular carcinoma is because of (DiBesceglie, A.M. and Bacon, B.R., Scientific American, Oct:80-85, (1999); Boyer .J.Hepatol.32:98-112 such as N., 2000).Estimating worldwide has 1.7 hundred million to infect HCV (Boyer .J.Hepatol.32:98-112 such as N., 2000).Estimate annual because the liver cirrhosis that chronic hcv infection causes causes 8 in the U.S., 000-12,000 people's death, and the HCV infection is topmost indication for liver transplantation.

Known HCV causes at least 80% post-transfusion hepatitis and most sporadic acute hepatitis.Prima Facie Evidence also show HCV many " primary " chronic hepatitis, " latent send out a property " liver cirrhosis and may case in hepatocellular carcinoma in other hepatitis virus, irrelevant as hepatitis B virus (HBV).It seems that a fraction of healthy population be the carrier of chronic hcv, has in the regional distribution and the variation of other epidemiologic factor.Though only be a preliminary message, its number may surpass the carrier of HBV in fact; It is unclear that have actually how many people suffer from the unconspicuous chronic hepatopathy of clinical symptom (TheMerck Manual, ch.69, p.901,16 ^ThEd., (1992)).

HCV is a kind of genomic envelope virus of the adopted single stranded RNA of having of about 9.4kb that contains.Viral genome is made up of the open reading frame of the length of a 5 ' non-translational region (UTR), about 3011 the amino acid whose polyprotein precursors of coding and 3 ' UTR of a weak point.5 ' UTR is the genomic topmost high conservative part of HCV and for starting and the translation of control polyprotein plays an important role.The genomic translation of HCV starts by being known as the cap independence mechanism that adds that internal ribosome enters.This mechanism comprises that rrna and RNA sequence are being known as upward combination of internal ribosome entry site (IRES).RNA false knot structure is recently determined to be the basic structure element of HCV IRES.Virus structural protein comprises that a kind of nucleocapsid core protein (C) and two kinds have envelope glycoprotein, E1 and E2.The HCV two kinds of proteolytic enzyme of also encoding, the serine protease of encoding in the metalloprotease that depends on zinc of a kind of NS2-NS3 district coding and a kind of NS3 district.For the specific region of shearing the precursor polyprotein formed mature peptide, these proteolytic enzyme were essential.Nonstructural Protein 5, NS5B, carboxy moiety contain the RNA polymerase that RNA relies on.The function of remaining Nonstructural Protein NS4A and NS4B and NS5A (the amino part of Nonstructural Protein 5) is still unknown.

An important focus of current antiviral research is the method (DiBesceglie, A.M. and Bacon, B.R., Scientific American, Oct:80-85, (1999)) that is to develop chronic HCV infection in the treatment human body of improvement.

Infect with interferon therapy HCV

Over past ten years, Interferon, rabbit (IFNs) can obtain to be used for the treatment of chronic hepatitis by commercial sources.IFN is the glycoprotein that produces by immunocyte response virus infection.IFNs suppresses duplicating of many viruses, comprises HCV, but when being used for the treatment of hepatitis C separately and infecting, and IFN can suppress serum HCV-RNA to can't detected level in some case.In addition, IFN can make serum transamination enzyme level normalizing.Unfortunately, the effect of IFN only is temporary, the response that continues only in 8%～9% infection produce (Gary L.Davis.Gastroenterology 118:S104-S114,2000) among the patient of chronic hcv.But serious flu-like symptoms, body weight that Most patients is difficult to stand because of interferon therapy causes reduce and fatigue and weak.

Many patents all disclose uses the flaviviridae that comprises HCV based on the therapy for treating of Interferon, rabbit.For example, people's such as Blatt United States Patent (USP) discloses the method for enduring the patient of HCV torment with the composite interference extract for treating to the fullest extent for the 5th, 980, No. 884.People's such as Bazer United States Patent (USP) discloses the whose anti-HCV therapy of using sheep or Bov IFN-τ for the 5th, 942, No. 223.People's such as Alber United States Patent (USP) the 5th, 928,636 discloses interleukin 12 and interferon alpha (IFN-α) conjoint therapy that is used for the treatment of by the communicable disease that comprises HCV.People's such as Chretien United States Patent (USP) discloses independent use thymosin for the 5th, 849, No. 696 or has been used in combination with Interferon, rabbit treats HCV.People's such as Valtuena United States Patent (USP) discloses the HCV conjoint therapy that uses Interferon, rabbit and have only basic scavenging agent for the 5th, 830, No. 455.The United States Patent (USP) of Imakawa discloses end user's Interferon, rabbit-Tau protein for treatment HCV for the 5th, 738, No. 845.Other the HCV therapy based on Interferon, rabbit is disclosed in No. the 5th, 849,696, people's such as people's such as Testa No. the 5th, 676,942, United States Patent (USP), Blatt No. the 5th, 372,808, United States Patent (USP) and United States Patent (USP) in addition.The Interferon, rabbit of Pegylation form that also had many patent disclosures, these patents are as the United States Patent (USP) the 5th, 747,646,5,792,834 and 5,834 of Hoffmann-La Roche Inc, No. 594; The publication number of Enzon is the PCT patent of WO 99/32139 and WO99/32140; WO 95/13090 United States Patent (USP) the 5th, 738,846 and 5,711 of Schering, No. 944, and No. the 5th, 908,621, people's such as Glue United States Patent (USP).

The present licensed independent therapy of Intederon Alpha-2a and Interferon Alpha-2b as treatment HCV.ROFERON -A (Roche) is the recombinant forms of Intederon Alpha-2a.PEGASYS  (Roche) is the Pegylation form (being polyethyleneglycol modified) of Intederon Alpha-2a.The recombinant forms of INTRON  A (Schering Corporation) Interferon Alpha-2b.PEG-INTRON  (Schering Corporation) is the Pegylation form of Interferon Alpha-2b.

Other form of interferon alpha and Interferon, rabbit beta, gamma, τ and ω also are in the clinical development stage of HCV treatment at present.For example, the INFERGEN of InterMune (interferon alpha con-1), the OMNIFERON of Viragen (natural interferon), the ALBUFERON of Human Genome Sciences, the REBIF of Ares-Serono (interferon beta-1a), the omega interferon of BioMedicine, the Oral Interferon Alpha of Amarillo Biosciences, and the interferon-gamma of InterMune, interferon-tau and gamma interferon 1-b are all among research.

Ribavirin (Ribavirin)

Ribavirin (1-β-D-ribose furyl-1-1,2,4-triazole-3-methane amide) is the antiviral nucleoside analogue of a kind of synthetic, non-interferon-induced, wide spectrum, with trade name Virazole (The Merck Index, the 11st edition, editor: Budavari, S., Merck﹠amp; Co., Inc., Rahway, NJ, PL304,1989) sell.United States Patent (USP) the 3rd, 798, No. 209 and RE 29,835 open and claimed ribavirins.Be similar to guanosine on the ribavirin structure, and have antagonism and comprise the multiple DNA of flaviviridae and the external activity of RNA viruses (Gary L.Davis.Gastroenterology 118:S104-S114,2000).

Ribavirin reduces serum transamination enzyme level to normal level in 40% patient, but it does not reduce the serum level (Gary L.Davis.Gastroenterology 118:S104-S114,2000) of HCV-RNA.Therefore, ribavirin is individually dosed can't effectively reduce the viral RNA level.In addition, ribavirin has suitable toxicity and knownly can bring out anemia.

Ribavirin is not granted to be used for treating separately HCV, but is approved for and Intederon Alpha-2a or Interferon Alpha-2b combination therapy HCV.

The Combined Preparation of Interferon, rabbit and ribavirin

The standard of current treatment chronic hepatitis C is the conjoint therapy of interferon-alpha and ribavirin.The conjoint therapy treatment HCV that adopts Interferon, rabbit and ribavirin is infected, existing this therapy effective (Battaglia when the treatment Interferon, rabbit is come into being patient (interferon naivepatients) that reports, A.M.et al., Ann.Pharmacother.34:487-494,2000), in addition, there is the patient's of histology disease treatment for treatment, this therapy also is effective (Berenguer .Antivir.Ther.3 such as M. (Suppl.3): 125-136,1998).Studies show that more hepatitis C patients is strong with the response of the interferon-' alpha ' conjoint therapy of non-Pegylation to the response ratio of the interferon-' alpha '/ribavirin conjoint therapy of Pegylation pair.But identical with independent therapy is, in conjoint therapy, produces sizable side effect, and this comprises haemolysis, flu-like symptoms, anemia and tired (GaryL.Davis.Gastroenterology 118:S104-S114,2000).

(ribavirin, USP) capsule of conjoint therapy can be obtained by Schering Corporation to adopt PEG-INTRON  (peg Interferon Alpha-2b) and REBETOL .REBETOL  (Schering Corporation) also goes through and INTRON  A (Interferon Alpha-2b, recombinant chou, Schering Corporation) unites use.In addition, Roche ' s PEGASYS  (pegylated interferon alfa-2a) also be approved for treatment HCV with COPEGUS  (ribavirin).)))

The PCT publication number of Schering Corporation is WO 99/59621, WO 00/37110, WO 01/81359, discloses use pegylated interferon alfa and ribavirin conjoint therapy treatment HCV in the patent application of WO02/32414 and WO 03/024461.The PCT publication number of Hoffmann-La Roche Inc is WO 99/15194, and WO 99/64016, also discloses use pegylated interferon alfa and ribavirin conjoint therapy treatment HCV in the patent application of and WO00/24355.

Other method of treatment flaviviridae infections

Be used at present the exploitation of the new anti-virus formulation of flaviviridae infections, particularly hepatitis C virus.The specific inhibitor and the AG14361 that are derived from the enzyme of HCV such as proteolytic enzyme, helicase are just under development.In addition; the inhibitor that is used to suppress other step that HCV duplicates is also under development; for example block the medicine that produces HCV antigen (IRES inhibitor) from RNA; the medicine (glycosylation inhibitor) that stops HCV albumen normal process, blocking-up HCV enter the medicine and the non-specific cell protective material that stops the cell injury that causes owing to virus infection of the medicine (by blocking its acceptor) of cell.Further, the molecules method also is developed and is used for the treatment of hepatitis C, for example, and ribozyme, the enzyme of its energy specificity break virus RNA molecule; Antisense oligonucleotide, it is the little complementary fragment of DNA, can and suppress virus replication in conjunction with viral RNA, also under study for action.Many HCV therapies are discussed in Bymock etc., Antiviral Chemistry ﹠amp; Chemotherapy, 11:2; .Antiviral Research such as 79-95 (2000) and De Francesco are among the 58:1-16 (2003).

The example of the classification of the medicine that is used for the treatment of flaviviridae infections that has been developed comprises:

(1) proteinase inhibitor

That is studying has: based on NS3 proteinase inhibitor (Attwood etc., Antiviral peptide derivatives, the PCT WO 98/22496,1998 of substrate; Attwood etc., Antiviral Chemistry and Chemotherapy, 1999,10,259-273; Attwood etc., Preparation and use of amino acid derivatives as anti-viral agents, German patent publication No. .DE 19914474; .Inhibitors of serine proteases such as Tung, particularly hepatitis C virusNS3 protease, PCT WO 98/17679), comprise alpha-keto amide and diazanyl urea (hydrazinoureas), with the inhibitor (Llinas-Brunet etc. that can stop electrophilic reagent such as boric acid or phosphonate, the hepatitis C virus inhibitors peptide analogs, PCT WO99/07734).

In addition, also having in research: based on the NS3 proteinase inhibitor of non-substrate, as 2,4,6-trihydroxy--3-nitro-benzamide derivatives (Sudo K. etc., Biochemical and Biophysical Research Communications, 1997,238,643-647; .Antiviral Chemistry and Chemotherapy such as Sudo K., 1998,9,186), comprising RD3-4082 and RD3-4078, the former is replaced by 14 carbochains on acid amides, and the latter processes Phenoxyphenyl.

Sch 68631, a kind of phenanthrenequione, be a kind of HCV proteolytic enzyme inhibitor (Chu M. etc., Tetrahedron Letters 37:7229-7232,1996).In another example that provides by this author, Sch 351633, separation is from Penicillium griseofulvum (Penicilliumgriseofulvum), be confirmed to be a kind of proteinase inhibitor (Chu M. etc., Bioorganic and Medicinal ChemistryLetters 9:1949-1952).By based on macromole eglin c, the selective depressant of Eglin c design can obtain receiving the enzyme of anti-HCV NS3 proteolytic enzyme of usefulness of rubbing.Eglin c separates from leech, is several serine proteases such as streptomyces griseus (S.Griseus) protease A and B, Chymetin, Chymotrypsin and subtilisin potential inhibitor.Qasim M.A.et al.，Biochemistry 36：1598-1607，1997。

Some U.S. Patent Publications be used for the treatment of the proteinase inhibitor of HCV.For example, the United States Patent (USP) of Spruce etc. discloses the cystatin that a class is used to suppress HCV endopeptidase 2 for the 6th, 004, No. 933.The synthetic inhibitor that the United States Patent (USP) of Zhang etc. discloses hepatitis C virus NS proteolytic enzyme the 5th, 990, No. 276.This inhibitor is a kind of subsequence of NS3 protease substrate or a kind of substrate of NS4A cofactor.Use restriction enzyme enzyme treatment HCV to be disclosed in No. the 5th, 538,865, the United States Patent (USP) of Reyes etc.Peptide as HCV NS3 serpin is disclosed in CorvasInternational, among the WO 02/008251 of Inc and the WO 02/08187 of Schering Corporation and the WO 02/008256.HCV inhibitor tripeptides is disclosed in No. the 6th, 534,523, the United States Patent (USP) of Boehringer Ingelheim, among the WO 02/060926 of 6,410, No. 531 and 6,420, No. 380 and Bristol Myers Squibb.Diaryl peptides as HCV NS3 serpin is disclosed among the WO 02/48172 of Schering Corporation.Be disclosed in as the imidazolinedione (Imidazoleidinones) of HCV NS3 serpin among the WO 02/48157 of the WO 02/08198 of Schering Corporation and Bristol Myers Squibb.The WO 98/17679 of Vertex Phamaceuticals and the WO 02/48116 of BristolMyers Squibb also disclose the HCV proteinase inhibitor.

(2) thiazolidine (Thiazolidines) derivative, in measuring, the reversed-phase HPLC that adopts NS3/4A fusion rotein and NS5A/5B substrate to carry out shown relevant restraining effect (Sudo K. etc., Antiviral Research, 1996,32,9-18), particularly have the compound R D-1-6250 of the cinnyl that is replaced by the chain alkyl part of fusion,, and RD4 6205 and RD46193;

(3) thiazolidine and N-benzanilide (benzanilides) .J.EBS Letters 421 such as Kakiuchi N., 217-220 are seen in its affirmation; Takeshita N. etc., Ahalytical Biochemistry, 1997,247,242-246;

(4) phenanthrenequione (phenan-threnequinone), it shows to have the protease inhibitor activity in SDS-PAGE and autoradiograph method mensuration, separate (Chu M. etc. by fermentation culture meat soup from streptomycete (Streptomyces sp.), TetrahedronLetters, 1996,37,7229-7232), Sch 68631 and Sch 351633, separation is from grey Penicillium notatum (Penicilliumgriseofulvum), in flicker approximate test (SPA), demonstrate activity (Chu M. etc., Bioorganic and MedicinalChemistry Letters 9,1949-1952);

(5) helicase inhibitor (for example, Diana G.D. etc., Compounds, compositions and methods for treatmentof hepatitis C, United States Patent (USP) the 5th, 633, No. 358; Diana G.D. etc., Piperidine derivatives, pharmaceuticalcompositions there of and their use in the treatment of hepatitis C, PCT WO 9,7/3 65 54);

(6) nucleoside polymerase inhibitor and gliotoxin (.Journal of Virology such as Ferrari R., 1999,73,1649-1654) and the natural product cerulenin (Lohmann V. etc., Virology, 1998,249,108-118);

(7) antisense phosphorothioate ester oligonucleotide (S-ODN) its with extend into virus 5 ' non-coding region (NCR) (Alt M. etc., Hepatology, 1995,22,707-717), or comprise 3 ' the nucleosides 326-348 that holds of NCR and nucleosides 371-388 (the Alt M. etc. that are positioned at the core encoder district of HCV RNA, Archives of Virology, 1997,142,589-599; Galderisi U. etc., Journal of Cellular Physiology, 1999,181, sequence complementation 251-257);

(8) depend on the inhibitor Ikeda N etc. of the translation of IRES, Agent for the prevention and treatment ofhepatitis C, (being used to prevent and treat the medicament A of hepatitis C), Japanese patent application publication No. JP-08268890; Kai Y. etc., Prevention and treatment of viral diseases, (prevention of virus disease and treatment), Japanese patent application publication No. JP-10101591);

(9) ribozyme, as the nuclease-resistant ribozyme (Maccjak D.J. etc., Hepatology 1999,30, summary 995) and the United States Patent (USP) the 5th, 869 of those No. the 6th, 043,077, United States Patent (USP)s that are disclosed in Barber etc. and Draper etc., No. 253 and 5,610, the content in No. 054; With

(10) nucleoside analog is not developed yet and is used for the treatment of flaviviridae infections.

Idenix Pharmaceuticals is to disclose the nucleosides treatment Flavivirus (comprising HCV) and the pestivirus of using branching among WO 01/90121 and the WO 01/92282 in International Publication No..Particularly, the disclosed method that is used for the treatment of at human and the intravital infection with hepatitis C virus of other host animal (Flavivirus and pestivirus) in the open text of Idenix, this method comprises 1 ' of the biologically active of implementing significant quantity, 2 ', 3 ' or 4 '-β-D or β-L nucleosides or its pharmacologically acceptable salt or derivatives thereof of side chain, embodiment be implement separately or with other anti-virus formulation Combined Preparation, also optionally adopt pharmaceutically acceptable carrier.Pharmacologically acceptable salt is optional

Other announcement use the patent application of some nucleoside analogs treatment hepatitis C virus to comprise: BioChemPharma, (be Shire Biochem now, Inc.) (WO 01/32153 for the PCT/CA00/01316 of Ti Jiaoing for Inc.; Submitted on November 3rd, 2000) and PCT/CA01/00197 (WO 01/60315; Submit to February 19 calendar year 2001); Merck﹠amp; Co., (WO 02/057425 for the PCT/US02/01531 of Inc. submission; On January 18th, 2002 submitted to) and PCT/US02/03086 (WO02/057287; On January 18th, 2002 submitted to), (WO 02/18404 for the PCT/EP01/09633 that Roche submits to; August 21 calendar year 2001 is open), and Pharmasset, the PCT publication number WO OIT9246 of Ltd (submission on April 13 calendar year 2001), WO02/32920 (submission on October 18 calendar year 2001) and WO 02/48165.

The PCT publication number WO 99/43691 of Emory University, title use for " 2 '-fluoro nucleosides " disclose some 2 '-fluoro nucleosides treatment HCV.

People such as Eldrup have described structure-activity relationship (Oral Session V, Hepatitis C Virus, the Flaviviridae of the nucleosides that is used to suppress 2 of HCV '-modification; 16 ^ThInternational Conference on Antiviral Research (April27,2003, Savannah, Ga.)).

People such as Bhat have described the synthetic and pharmacokinetic properties as the nucleoside analog of possible HCV rna replicon inhibitor.The author reported 2 '-nucleosides modified demonstrates potential and suppresses active (OralSession V, Hepatitis C Virus, Flaviviridae in the replicon test based on cell; 16 ^ThInternational Conference on Antiviral Research (April 27,2003, Savannah, Ga.); P A75).。

People such as Olsen have also described 2 '-modified nucleoside is to effect (Oral Session V, Hepatitis CVirus, the Flaviviridae of HCV rna replicon; 16 ^ThInternational Conference on Antiviral Research (April 27,2003, Savannah, Ga.) p A76).

(11) other all cpds comprises: 1-amino-alkylcyclohexane (No. the 6th, 034,134, United States Patent (USP) such as Gold); alkyl lipid (No. the 5th, 922,757, United States Patent (USP) such as Chojkier); vitamin-E and other antioxidant (United States Patent (USP) the 5th such as Chojkier; 922, No. 757), shark alkene; amantadine; bile acide (United States Patent (USP) the 5th such as Ozeki; 846, No. 964), N-(phosphono ethanoyl)-L-aspartic acid; (United States Patent (USP) the 5th such as Diana; 830, No. 905), benzene two carboxamides (United States Patent (USP) the 5th such as Diana; 633; No. 388), polyadenylic acid derivative (United States Patent (USP) the 5th, 496 such as Wang; No. 546); 2 ', 3 '-didanosine (United States Patent (USP) the 5th, 026 such as Yarchoan; No. 687); benzoglyoxaline (No. the 5th, 891,874, United States Patent (USP) such as Colacino); plant extract (United States Patent (USP) the 5th such as Tsai; 837, No. 257, United States Patent (USP)s such as Omer the 5th; 725; No. 859 and United States Patent (USP) the 6th, 056; No. 961); and piperidines (piperidenes) (No. the 5th, 830,905, United States Patent (USP) such as Diana).

(12) current be in clinical before or clinical development in other compound that is used for the treatment of hepatitis C virus comprise: the interleukin 10 of Schering-Plough, the IP-501 of Interneuron, the Merimebodib of Vertex (VX-497), the AMANTADINE  (amantadine) of Endo Labs Solvay, the HEPTAZYME  of RPI, the IDN-6556 of Idun Pharma, the XTL-002 of XTL, the HCV/MF59 of Chiron, the CIVACIR  of NABI (hepatitis C virus immunoglobulin (Ig)), the LEVOVIRIN  of ICN/RIBAPHARM, the VIRAMIDINE  of ICN/RIBAPHARM, the ZADAXIN  (thymosin alpha 1) of SciClone, the thymosin of Sci Clone and Peg-Intron, the CEPLENE  (Peremin) of Maxim, the VX 950/LY 570310 of Vertex/Eli Lilly, the ISIS 14803 of IsisPHARMACEUTICAL/ELAN, the IDN-6556 of Idun Pharmaceuticals Inc., the JTK 003 of AKROSPharma, the BILN-2061 of Boehringer Ingelheim, the CellCept of Roche (mycophenolic acid morpholine ethyl ester), the T67 of Tularik, a kind of 'beta '-tubulin inhibitor, the treatment vaccine of Innogenetics at E2, FujisawaHealthcare, the FK788 of Inc, IdB 1016 (Siliphos, oral silymarin-phosphoric acid sleepwell phytosome (oralsilybin-phosphatdylcholine phytosome)), the rna replicon inhibitor (VP50406) of ViroPharma/Wyeth, the treatment vaccine of Intercell, the treatment vaccine of Epimmune/Genencor, the IRES inhibitor of Anadys, the ANA 245 of Anadys and ANA 246, the immunotherapy of Avant (Therapore), the proteinase inhibitor of Corvas/Schering, the helicase inhibitor of Vertex, the fusion inhibitor of Trimeris, the T cell therapy of CellExSys, the AG14361 of Biocryst, the targeted rna chemistry of PTC Therapeutics, Immtech, the dication of Int (Dication), the proteinase inhibitor of Agouron, the proteinase inhibitor of Chiron/Medivir, the antisense therapy of AVI BioPharma, the antisense therapy of Hybridon, the blood clean agent (hemopurifier) of Aethlon Medical, the treatment vaccine of Merix, the proteinase inhibitor of Bristol-MyersSquibb/Axys, the Chron-VacC of Tripep, a kind of treatment vaccine, the UT 231B of United Therapeutics, the proteolytic enzyme of Genelabs Technologies, helicase and AG14361, the IRES inhibitor of Immusol, the R803 of Rigel Pharmaceuticals, the INFERGEN  of InterMune (α con-1 Interferon, rabbit), the OMNIFERON  (natural interferon) of Viragen, the ALBUFERON  of Human Genome Sciences, the REBIF  of Ares-Serono (β-1a Interferon, rabbit), the ω of BioMedicine)-Interferon, rabbit, the oral alpha-interferon of Amarillo Biosciences, the gamma-interferon of InterMune, τ-Interferon, rabbit and γ-1b Interferon, rabbit.

Previous the hepatitis that nucleoside prodrugs is used for the treatment of other type described.The WO00/09531 of Idenix Pharmaceuticals (submission on August 10th, 1999) and WO 01/96353 (submission on June 5 calendar year 2001) disclose 2 '-deoxidation-β-L-nucleosides, and their treatment that is used for HBV 3 '-prodrug.The United States Patent (USP) of Beaucham discloses the ester of the acycloguanosine of various treatment usefulness for the 4th, 957, No. 924.

Considering that HCV infects has reached worldwide popularity degree, and the patient is caused tragic influence, therefore is badly in need of providing new and effectively and to the pharmaceutical preparation of the hypotoxic treatment hepatitis C of host.

In addition, consider the harm of day by day rising of other flaviviridae infections, be badly in need of providing new and effectively and to the hypotoxic pharmaceutical preparation of host.

Therefore, an object of the present invention is to provide a kind of compound, method and composition that is used for the treatment of the host of infection with hepatitis C virus.

Another object of the present invention provides a kind of universal method and composition that is used for the treatment of the patient of pestivirus, Flavivirus or hepatovirus virus infection.

Summary of the invention

1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and 3 '-prodrug, or their pharmacologically acceptable salt or the pharmaceutically acceptable prescription that contains these compounds are useful on chronic hepatitis, liver cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis and the fatigue of the prevention symptom relevant with other with the treatment flaviviridae infections such as anti-flavivirus coe virus antibody positive and flaviviridae male symptom, HCV initiation.These compounds or prescription also can be used for preventing or postponing the development of individuality clinical disease by pre-defense sector, and this individuality is that anti-flavivirus coe virus antibody or flaviviridae antigen positive or its are in the individuality in the threat of flavivirus.

A kind of being used for comprises that the host method of people's treatment flaviviridae infections also is disclosed, it comprise use significant quantity have 1 of biologic activity ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and 3 '-prodrug or their pharmacologically acceptable salt, individually dosed or Combined Preparation or replace administration with other anti-flavivirus coe virus preparation, or optionally be used in administration in pharmaceutically acceptable carrier.As used herein term 2 '-prodrug, refer to 2 '-position have biologically can shear 1 of position ', 2 '; 3 ' or 4 '-side chain β-D or β-L nucleosides, include but not limited to acyl group, in one embodiment; be natural or synthetic D or L amino acid, preferred L-amino acid.As used herein term 3 '-prodrug, refer to 3 '-position have biologically can shear 1 of position ', 2 '; 3 ' or 4 '-side chain β-D or β-L nucleosides, include but not limited to acyl group, in one embodiment; be natural or synthetic D or L amino acid, preferred L-amino acid.

Pharmacologically acceptable salt comprises tosylate, mesylate, acetate, Citrate trianion, malonate, tartrate, succinate, benzoate, ascorbate salt, alpha-ketoglutarate and α-Phosphoric acid glycerol esters, formate, fumarate, propionic salt, glycollate, lactic acid salt, pyruvate salt, oxalate, maleate, salicylate, vitriol, sulfonate, nitrate, supercarbonate, hydrobromate, hydrobromide, hydriodide, carbonate, and orthophosphoric acid salt.A particularly preferred embodiment is list or dihydrochloride.

In one embodiment, 1 ', 2 ', but 3 ' or 4 '-side chain β-D or β-L nucleosides be included in 2 ' and/or the biology cutting out section of 5 ' position.Preferred part is natural or synthetic D or L amino acid ester, comprises that D or L-are valyl, but preferred L-amino acid ester, valyl and alkyl ester comprises ethanoyl as L-.Therefore, the present invention comprises 2 especially '-D or L-amino acid ester and 2 ', 5 '-D or L-diamino acid esters, preferably have 1 of any desired purine or pyrimidine bases ', 2 ', 3 ' or 4 '-the L-amino acid ester of side chain β-D or β-L nucleosides, wherein parent drug is optional has less than 15 little EC that rub ₅₀, be more preferably less than 10 little rubbing; Have 1 of any desired purine or pyrimidine bases ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 '-(alkyl or aryl) ester or 2 ', 5 '-two (alkyl or aryl) ester, wherein parent drug is optional has less than 10 or 15 little EC that rub ₅₀With 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 5 '-prodrug of diester, wherein (i) 2 ' ester is natural or synthetic D or L-amino acid ester, but preferred L-amino acid ester and 5 '-ester is the alkyl or aryl ester; (ii) two kinds of esters all are natural or synthetic D or L-amino acid ester independently, although preferred both is the L-amino acid ester; (iii) two kinds of esters all are the alkyl or aryl ester independently; (iv) 2 ' ester be independently a kind of alkyl or aryl ester and 5 '-ester is natural or synthetic D or L-amino acid ester, although L-amino acid ester preferably, wherein parent drug is optional has less than 10 or 15 little EC that rub ₅₀

The example that falls into prodrug of the present invention is β-D-2 ', 2 of 6-dimethyl-cytidine '-D or L-L-valine ester; β-D-2 ', 2 of 6-dimethyl-thymidine '-the L-L-valine ester; β-D-2 ', 2 of 8-dimethyl-adenosine '-the L-L-valine ester; β-D-2 ', 2 of 8-dimethyl-guanosine '-the L-L-valine ester; β-D-2 ', 6-dimethyl-5-fluoro cytidine '-the L-L-valine ester; β-D-2 ', 2 of 6-dimethyl-uridine '-the L-L-valine ester; β-D-2 ', 2 of 6-dimethyl-cytidine '-acetonyl ester; β-D-2 ', 2 of 6-dimethyl-thymidine '-acetonyl ester; β-D-2 ', 2 of 8-dimethyl-adenosine '-acetonyl ester; β-D-2 ', 2 of 8-dimethyl-guanosine '-acetonyl ester; β-D-2 ', 2 of 6-dimethyl-5-fluoro-cytidine '-acetonyl ester; And β-D-2 ', 2 of 6-dimethyl-(cytidine, 5-fluoro cytidine, uridine or thymidine) '-ester or β-D-2 ', 2 of 8-dimethyl-(guanosine, adenosine or inosine) '-ester, wherein (i) 2 ' ester is an amino acid ester; Or (ii) 2 ' ester is the alkyl or aryl ester.

Other examples that fall into prodrug of the present invention are β-D-2 ', 6-dimethyl-cytidine (dival-2 ', 6-diMe-L-dC) 2 ', 5 '-L-two L-valine esters; β-D-2 ', 2 of 6-dimethyl-thymidine ', 5 '-L-two L-valine esters; β-D-2 ', 2 of 8-dimethyl-adenosine ', 5 '-L-two L-valine esters; β-D-2 ', 2 of 8-dimethyl-guanosine ', 5 '-L-two L-valine esters; β-D-2 ', 2 of 6-dimethyl-5-fluoro-cytidine ', 5 '-L-two L-valine esters; β-D-2 ', 2 of 6-dimethyl-uridine ', 5 '-L-two L-valine esters; β-D-2 ', 2 of 6-dimethyl-cytidine ', 5 '-the diacetyl ester; β-D-2 ', 2 of 6-dimethyl-thymidine ', 5 '-the diacetyl ester; β-D-2 ', 2 of 8-dimethyl-adenosine ', 5 '-the diacetyl ester; β-D-2 ', 2 of 8-dimethyl-guanosine ', 5 '-the diacetyl ester; β-D-2 ', 2 of 6-dimethyl-5-fluoro-cytidine ', 5 '-the diacetyl ester; And β-D-2 ', 6-dimethyl-(cytidine, 5-fluoro cytidine, uridine or thymidine) 2 ', 5 '-diester or β-D-2 ', 8-dimethyl-(guanosine, adenosine or inosine) 2 ', 5 '-diester, wherein (i) 2 ' ester be amino acid ester and 5 '-ester is the alkyl or aryl ester; (ii) two kinds of esters all are amino acid esters; (iii) two kinds of esters all are the alkyl or aryl ester independently; Or (iv) 2 ' ester be a kind of alkyl or aryl ester and 5 '-ester is a kind of amino acid ester.

In another embodiment, 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 3 '-prodrug is included in 3 ' and/or 5 ' position on the part that can shear of biology.Preferred part is natural or synthetic D or L amino acid ester, and as valyl, but preferred L-amino acid, valyl and alkyl ester comprises ethanoyl as L-.Therefore, the present invention comprise especially have 1 of any desired purine or pyrimidine bases ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides '-L-amino acid ester and 3 ', 5 '-L-diamino acid esters, wherein parent drug is optional has less than 15 little EC that rub ₅₀Be more preferably less than 10 little rubbing; Have 1 of any desired purine or pyrimidine bases ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 3 '-(alkyl or aryl) ester or 3 ', 5 '-L-two (alkyl or aryl) ester, wherein parent drug is optional has less than 10 or 15 little EC that rub ₅₀With 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 3 ', 5 '-prodrug of diester, wherein (i) 3 ' ester be natural or synthetic D or L amino acid ester and 5 '-ester is the alkyl or aryl ester; (ii) two kinds of esters all are natural or synthetic D or L-amino acid ester; (iii) two kinds of esters are the alkyl or aryl ester independently; (iv) 3 ' ester be independently a kind of alkyl or aryl ester and 5 '-ester is a kind of natural or synthetic D or L-amino acid ester, wherein parent drug is optional has less than 10 or 15 little EC that rub ₅₀

The example that falls into prodrug of the present invention is β-D-2 ', 6-dimethyl-cytidine '-the L-L-valine ester; β-D-2 ', 6-dimethyl-thymidine '-the L-L-valine ester; β-D-2 ', 8-dimethyl-adenosine '-the L-L-valine ester; β-D-2 ', 3 of 8-dimethyl-guanosine '-the L-L-valine ester; β-D-2 ', 6-dimethyl-5 fluoro cytidine '-the L-L-valine ester; β-D-2 ', 6-dimethyl-uridine '-the L-L-valine ester; β-D-2 ', 3 of 6-dimethyl-cytidine '-acetonyl ester; β-D-2 ', 3 of 6-dimethyl-thymidine '-acetonyl ester; β-D-2 ', 3 of 8-dimethyl-adenosine '-acetonyl ester; β-D-2 ', 3 of 8-dimethyl-guanosine '-acetonyl ester; β-D-2 ', 3 of 6-dimethyl-5 fluoro-cytidine '-acetonyl ester; And β-D-2 ', 3 of 6-dimethyl-(cytidine, 5-fluoro cytidine, uridine or thymidine) '-ester or β-D-2 ', 3 of 8-dimethyl-(guanosine, adenosine or inosine) '-ester, wherein (i) 3 ' ester is a kind of amino acid ester; Or (ii) 3 ' ester is a kind of alkyl or aryl ester.

The other example that falls into prodrug of the present invention is β-D-2 ', 6-dimethyl-cytidine (dival-2 ', 6-diMe-L-dC) 3 ', 5 '-L-two L-valine esters; β-D-2 ', 3 of 6-dimethyl-thymidine ', 5 '-L-two L-valine esters; β-D-2 ', 3 of 8-dimethyl-adenosine ', 5 '-L-two L-valine esters; β-D-2 ', 3 of 8-dimethyl-guanosine ', 5 '-L-two L-valine esters; β-D-2 ', 3 of 6-dimethyl-5-fluoro-cytidine ', 5 '-L-two L-valine esters; β-D-2 ', 3 of 6-dimethyl-uridine ', 5 '-L-two L-valine esters; β-D-2 ', 3 of 6-dimethyl-cytidine ', 5 '-the diacetyl ester; β-D-2 ', 3 of 6-dimethyl-thymidine ', 5 '-the diacetyl ester; β-D-2 ', 3 of 8-dimethyl-adenosine ', 5 '-the diacetyl ester; β-D-2 ', 3 of 8-dimethyl-guanosine ', 5 '-the diacetyl ester; β-D-2 ', 3 of 6-dimethyl-5-fluoro-cytidine ', 5 '-the diacetyl ester; And β-D-2 ', 6-dimethyl-(cytidine, 5-fluoro cytidine, uridine or thymidine) 3 ', 5 '-diester or β-D-2 ', 8-dimethyl-(guanosine, adenosine or inosine) 3 ', 5 '-diester, wherein (i) 3 ' ester be amino acid ester and 5 '-ester is the alkyl or aryl ester; (ii) two kinds of esters all are amino acid esters; (iii) two kinds of esters are the alkyl or aryl ester independently; Or (iv) 3 ' ester be alkyl or aryl ester and 5 '-ester is an amino acid ester.

In another embodiment, 1 ', 2 ', 3 ' or 4 '-prodrug of side chain β-D or β-L nucleosides is included in 2 ', 3 ' and/or 5 ' position on the part that can shear of biology.Preferred part is natural or synthetic D or L amino acid ester, comprises that D or L-are valyl, but preferred L-amino acid ester, and valyl and alkyl ester comprises ethanoyl as L-.Therefore, the present invention comprises 1 especially ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 '-L or D-diamino acid esters and 2 ', 3 ', 5 '-L or D-triamino acid esters, the L-amino acid that preferably has any desired purine or pyrimidine bases, wherein parent drug is optional has less than 15 little EC that rub ₅₀, be more preferably less than 10 little rubbing; Have 1 of any desired purine or pyrimidine bases ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 '-two (alkyl or aryl) esters or 2 ', 3 ', 5 '-L-three (alkyl or aryl) ester, wherein parent drug is optional has less than 10 or 15 little EC that rub ₅₀With 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 '-prodrug of diester, wherein (i) 2 ' ester be amino acid ester and 3 '-ester is the alkyl or aryl ester; (ii) two kinds of esters all are amino acid esters; (iii) two kinds of esters all are the alkyl or aryl ester independently; (iv) 2 ' ester be independently alkyl or aryl ester and 3 '-ester is an amino acid ester, wherein parent drug is optional has less than 10 or 15 little EC that rub ₅₀Further, 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 ', 5 '-three esters, wherein three kinds of all esters of (i) all are amino acid esters; Three kinds of (ii) all esters are the alkyl or aryl ester independently; (iii) 2 ' ester is an amino acid ester, 3 ' ester be amino acid ester and 5 '-ester is the alkyl or aryl ester; (iv) 2 ' ester is an amino acid ester, 3 ' ester be alkyl or aryl ester and 5 '-ester is the alkyl or aryl ester; (v) 2 ' ester is the alkyl or aryl ester, 3 ' ester be alkyl or aryl ester and 5 '-ester is an amino acid ester; (vi) 2 ' ester is the alkyl or aryl ester, 3 ' ester be amino acid ester and 5 '-ester is an amino acid ester; (vii) 2 ' ester is the alkyl or aryl ester, 3 ' ester be amino acid ester and 5 '-ester is the alkyl or aryl ester; (viii) 2 ' ester is an amino acid ester, 3 ' ester be alkyl or aryl ester and 5 '-ester is an amino acid ester; Wherein parent drug is optional has less than 10 or 15 little EC that rub ₅₀

The example that falls into prodrug of the present invention comprises β-D-2 ', 2 of 6-dimethyl-cytidine ', 3 '-L-two L-valine esters (dival-2 ', 6-diMe-L-dC); β-D-2 ', 2 of 6-dimethyl-thymidine ', 3 '-L-two L-valine esters; β-D-2 ', 2 of 8-dimethyl-adenosine ', 3 '-L-two L-valine esters; β-D-2 ', 2 of 8-dimethyl-guanosine ', 3 '-L-two L-valine esters; β-D-2 ', 2 of 6-dimethyl-5-fluoro-cytidine ', 3 '-L-two L-valine esters; β-D-2 ', 2 of 6-dimethyl-uridine ', 3 '-L-two L-valine esters; β-D-2 ', 2 of 6-dimethyl-cytidine ', 3 '-the diacetyl ester; β-D-2 ', 2 of 6-dimethyl-thymidine ', 3 '-the diacetyl ester; β-D-2 ', 2 of 8-dimethyl-adenosine ', 3 '-the diacetyl ester; β-D-2 ', 2 of 8-dimethyl-guanosine ', 3 '-the diacetyl ester; β-D-2 ', 2 of 6-dimethyl-5-fluoro-cytidine ', 3 '-the diacetyl ester; And β-D-2 ', 6-dimethyl-(cytidine, 5-fluoro cytidine, uridine or thymidine) 2 ', 3 '-diester or β-D-2 ', 8-dimethyl-(guanosine, adenosine or inosine) 2 ', 3 '-diester, wherein (i) 2 ' ester be amino acid ester and 3 '-ester is the alkyl or aryl ester; (ii) two kinds of esters all are amino acid esters; (iii) two kinds of esters are the alkyl or aryl ester independently; Or (iv) 2 ' ester be alkyl or aryl ester and 3 '-ester is an amino acid ester.

The other example that falls into prodrug of the present invention comprises β-D-2 ', 2 of 6-dimethyl-cytidine ', 3 ', 5 '-L-three L-valine esters (trival-2 ', 6-diMe-L-dC); β-D-2 ', 2 of 6-dimethyl-thymidine ', 3 ', 5 '-L-three L-valine esters; β-D-2 ', 2 of 8-dimethyl-adenosine ', 3 ', 5 '-L-three L-valine esters; β-D-2 ', 2 of 8-dimethyl-guanosine ', 3 ', 5 '-L-three L-valine esters; β-D-2 ', 2 of 6-dimethyl-5-fluoro-cytidine ', 3 ', 5 '-L-three L-valine esters; β-D-2 ', 2 of 6-dimethyl-uridine ', 3 ', 5 '-L-three L-valine esters; β-D-2 ', 2 of 6-dimethyl-cytidine ', 3 ', 5 '-the triacetyl ester; β-D-2 ', 2 of 6-dimethyl-thymidine ', 3 ', 5 '-the triacetyl ester; β-D-2 ', 2 of 8-dimethyl-adenosine ', 3 ', 5 '-the triacetyl ester; β-D-2 ', 2 of 8-dimethyl-guanosine ', 3 ', 5 '-the triacetyl ester; β-D-2 ', 2 of 6-dimethyl-5-fluoro-cytidine ', 3 ', 5 '-the triacetyl ester; And β-D-2 ', 2 of 6-dimethyl-(cytidine, 5-fluoro cytidine, uridine or thymidine) ', 3 ', 5 '-three ester and β-D-2 ', 2 of 8-dimethyl-(guanosine, adenosine or inosine) ', 3 ', 5 '-three esters, wherein (i) all three kinds of esters all are amino acid esters; (ii) all three kinds of esters are the alkyl or aryl ester independently; (iii) 2 ' ester is an amino acid ester, 3 ' ester be amino acid ester and 5 '-ester is the alkyl or aryl ester; (iv) 2 ' ester is an amino acid ester, 3 ' ester be alkyl or aryl ester and 5 '-ester is the alkyl or aryl ester; (v) 2 ' ester is the alkyl or aryl ester, 3 ' ester be alkyl or aryl ester and 5 '-ester is an amino acid ester; (vi) 2 ' ester is the alkyl or aryl ester, 3 ' ester be amino acid ester and 5 '-ester is an amino acid ester; (vii) 2 ' ester is the alkyl or aryl ester, 3 ' ester be amino acid ester and 5 '-ester is the alkyl or aryl ester; (viii) 2 ' ester is an amino acid ester, 3 ' ester be alkyl or aryl ester and 5 '-ester is an amino acid ester.

In first main embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (I) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, and this method comprises the compound of the formula (I) of using effective therapeutic dose:

Or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, wherein:

R ¹, R ²And R ³Be H independently, phosphate radical (comprise list, two or triphosphate and stable phosphate radical); Straight chain, side chain or cycloalkyl (comprising low alkyl group); Acyl group (comprising lower acyl); The CO-alkyl, CO-aryl, CO-alkoxyalkyl, the CO-aryloxy alkyl, the aryl that CO-replaces, sulphonate comprises that alkyl or aralkyl alkylsulfonyl comprise methylsulfonyl and benzyl, wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Alkyl sulphonyl, aryl sulfonyl, the aralkyl alkylsulfonyl, lipid comprises phosphatide; Amino acid; And amino-acid residue, carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, for example when using in the body, it can provide wherein R ¹, R ²And/or R ³Be independently H or phosphate radical (comprise list, two or triphosphate) compound; Wherein in one embodiment, R ²And/or R ³Be not phosphate radical (comprise list, two or triphosphate or a kind of stable phosphate radical prodrug);

R wherein ²And R ³One of at least be not hydrogen and wherein:

Y ¹Be hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁴

X ¹Be straight chain, the optional alkyl that replaces of side chain or ring-type, CH ₃, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂C1, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, CH ₂OH, the optional alkenyl that replaces, the optional alkynyl that replaces, COOH, COOR ⁴, COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH ₂, CONHR ⁴, CON (R ⁴) ₂, chlorine, bromine, fluorine, iodine, CN, N ₃, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁵With

X ²Be H, straight chain, the optional alkyl that replaces of side chain or ring-type, CH ₃, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, CH ₂OH, the optional alkenyl that replaces, the optional alkynyl that replaces, COOH, COOR ⁴, COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH ₂, CONHR ⁴, CON (R ⁴) ₂, chlorine, bromine, fluorine, iodine, CN, N ₃, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁵With

Each Y wherein ³Be hydrogen independently, fluorine, chlorine, bromine or iodine;

R ⁴And R ⁵Be respectively hydrogen independently, acyl group (comprising lower acyl), alkyl (including but not limited to methyl, ethyl, propyl group and cyclopropyl), low alkyl group, alkenyl, alkynyl or cycloalkyl.

Be in the embodiment of this description R ¹, R ²And/or R ³Can be pharmaceutically acceptable leavings group, for example when using in the body, it can provide wherein R ¹, R ²And/or R ³Be independently H or phosphate radical (comprise list, two or triphosphate) compound.

In second main embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (II) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, and this method comprises the compound of the formula (II) of using effective therapeutic dose:

R ¹, R ², R ³, R ⁴, R ⁵, Y ¹, Y ³, X ¹And X ²Definition as above.

In the 3rd main embodiment, formula (III) is provided, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, this method comprises the formula (III) of using effective therapeutic dose, (IV) or compound (V):

Base (Base) is selected from:

R ¹, R ², R ³, R ⁴And R ⁵Definition as above;

W ¹, W ², W ³And W ⁴Be respectively N independently, CH, CF, CI, CBr, CCl, CCN, CCH ₃, CCF ₃, CCH ₂CH ₃, CC (O) NH ₂, CC (O) NHR ⁴, CC (O) N (R ⁴) ₂, CC (O) OH, CC (O) OR ⁴Or CX ³

W ^*Be respectively O, S, NH or NR independently ⁴

X is O, S, SO ₂, CH ₂, CH ₂OH, CHF, CF ₂, C (Y ³) ₂, CHCN, C (CN) ₂, CHR ⁴Or C (R ⁴) ₂

X ^*Be CH, CF, CY ³Or CR ⁴

X ²Be H, straight chain, the optional alkyl that replaces of side chain or ring-type, CH ₃, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, CH ₂OH, the optional alkenyl that replaces, the optional alkynyl that replaces, COOH, COOR ⁴, COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH ₂, CONHR ⁴, CON (R ⁴) ₂, chlorine, bromine, fluorine, iodine, CN, N ₃, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁵

X ³Be respectively straight chain independently, the optional alkyl (comprising low alkyl group) that replaces of side chain or ring-type, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl, N ₃, CN ,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂, OH, OR ⁴,-O (acyl group) ,-O (lower acyl) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), chlorine, bromine, fluorine, iodine, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂

Y is independently selected from H respectively, the optional low alkyl group that replaces, cycloalkyl, alkenyl, alkynyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCONH ₂, (CH ₂) _mCONR ₂And (CH ₂) _mCONHR;

Wherein R is H, alkyl or acyl group;

Y ²Difference is O, S, NH or NR independently ⁴

Y ³Be respectively H independently, F, Cl, Br or I;

If W wherein ¹, W ²And W ³Be N, for base (Base) (B) for, W ⁴Can not be CH;

If W wherein ¹Be N, for base (Base) (E), (F), (K), (L), (W) and (X), W ⁴Can not be CH;

R ⁶Be respectively the optional alkyl (comprising low alkyl group) that replaces independently, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH2) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) 2 or cyano group;

R ⁷Be respectively OH independently, OR ², the optional alkyl (comprising low alkyl group) that replaces, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃The optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, the halo alkynyl, the optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7), the optional heterocycle that replaces (preferably has one or more O, the 3-7 unit heterocycle of S and/or N), the optional heteroaryl that replaces (preferably having one or more O, the 3-7 unit hetero-aromatic ring of S and/or N) ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (acyl group) ,-O (lower acyl) ,-O (R ⁴) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), NO ₂, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂, azido-, cyano group, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

Perhaps, R ⁶And R ⁷Can be in conjunction with forming spirocyclic compound, it is selected from: optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N); With

M is respectively 0,1 or 2 independently.

In the 4th main embodiment, formula (VI) or compound (VII) or pharmacologically acceptable salt or prodrug are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, and this method comprises formula (VI) or the compound (VII) of using effective therapeutic dose:

Base (Base), R, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, Y, Y ¹, Y ², Y ³, W ¹, W ², W ³, W ⁴, W ^*, X, X ^*, X ¹, X ²And X ³Definition as above;

Wherein, in one embodiment, only when X is carbon, the R in the formula (VI) ⁸Be-OH or-NH ₂Wherein,

R ⁸And R ¹¹Be respectively hydrogen independently, the optional alkyl (comprising low alkyl group) that replaces, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂, cyano group, NH-acyl group or N (acyl group) ₂

R ⁹And R ¹⁰Be respectively hydrogen independently, OH, OR ², the optional alkyl (comprising low alkyl group) that replaces, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃The optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, the halo alkynyl, the optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7), the optional heterocycle that replaces (preferably has one or more O, the 3-7 unit heterocycle of S and/or N), the optional heteroaryl (preferably having one or more O, the 3-7 membered aromatic heterocycle of S and/or N) that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂, (CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂, C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (acyl group) ,-O (lower acyl) ,-O (R ⁴) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), NO ₂, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂, azido-, cyano group, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

M is respectively 0,1 or 2 independently; With

Perhaps, R ⁶And R ¹⁰, R ⁷And R ⁹, R ⁸And R ⁷Or R ⁹And R ¹¹Can be selected from conjunction with forming the bridging compound: optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N); Or

Also can be R ⁶And R ⁷Or R ⁹And R ¹⁰Can be selected from conjunction with forming spirocyclic compound: optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N).

In the 5th main embodiment, formula (VIII) is provided, (IX) or compound (X) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, this method comprises the formula (VIII) of using effective therapeutic dose, (IX) or compound (X):

R ¹, R ², R ³, R ⁴, R ⁵, X, Y ³And X ^*Definition as above;

Base ^*(Base ^*) be purine or pyrimidine bases in this definition;

R ¹²Be respectively the alkyl (comprising low alkyl group) that replaces independently, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the alkenyl of replacement, halogenated alkenyl (but not being the Br-vinyl), the alkynyl of replacement, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂

R ¹³Be respectively the alkyl (comprising low alkyl group) that replaces independently, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃The alkenyl that replaces, halogenated alkenyl (but not being the Br-vinyl), the alkynyl of replacement, halo alkynyl, the optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7), the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N), the optional heteroaryl that replaces (preferably has one or more O, the 3-7 membered aromatic heterocycle of S and/or N) ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (R ⁴) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl) ,-NHR ⁴,-NR ⁴R ⁵,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl), SCN, OCN, NCO or fluorine;

Perhaps, R ¹²And R ¹³Can be in conjunction with forming spirocyclic compound, it is selected from: optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N); With

M is respectively 0,1 or 2 independently.

In the 6th main embodiment, formula (XI) or compound (XII) or pharmacologically acceptable salt or prodrug are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, and this method comprises formula (XI) or the compound (XII) of using effective therapeutic dose:

Selectively, base ^*(Base ^*) by formula (XI) and the base (Base) (XII) replace; With

Base (Base), base ^*(Base ^*), R, R ¹, R ², R ³, R ⁴, R ⁵, R ¹², R ¹³, Y, Y ¹, Y ², Y ³, W ^*, W ¹, W ², W ³, W ⁴, X, X ^*, X ¹, X ²And X ³Definition as above;

Wherein, in one embodiment, only when X is carbon, the R in the formula (XI) ⁸Be-OH or-NH ₂

With

Wherein:

R ⁹And R ¹⁰Be respectively hydrogen independently, OH, OR ², the optional alkyl (comprising low alkyl group) that replaces, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃The optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, the halo alkynyl, the optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7), the optional heterocycle that replaces (preferably has one or more O, the 3-7 unit heterocycle of S and/or N), the optional heteroaryl (preferably having one or more O, the 3-7 membered aromatic heterocycle of S and/or N) that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂, (CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂, C (O) OH ,-C (O) OR ₄,-C (O) O (low alkyl group) ,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (acyl group) ,-O (lower acyl) ,-O (R ⁴) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), NO ₂, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂, azido-, cyano group, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

M is respectively 0,1 or 2 independently; With

Perhaps, R ⁸And R ¹³, R ⁹And R ¹³, R ⁹And R ¹¹Or R ¹⁰And R ¹²Can be selected from conjunction with forming the bridging compound: optional carbocyclic ring that replaces (preferred 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or many O, the first heterocycle of the 3-7 of S and/or N); Or

Perhaps, R ¹²And R ¹³Or R ⁹And R ¹⁰Can be selected from optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N) in conjunction with forming spirocyclic compound.

In aspect one of the present invention is concrete, formula (XI) or compound (XII) or pharmacologically acceptable salt or prodrug are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, and this method comprises formula (XI) or the compound (XII) of using effective therapeutic dose:

R ³Be selected from: H; Single, two and triphosphate or stable phosphate radical prodrug; Acyl group; Sulphonate; The optional alkyl sulphonyl that replaces; The optional aryl sulfonyl that replaces; Lipid; Amino acid; Carbohydrate; Peptide; Cholesterol; With pharmaceutically acceptable leavings group, when external using, it can provide wherein R ³Be H independently, or single, two and the compound of triphosphate;

X " be selected from following one or more group: O, S, SO, SO ₂, N, NH, NR and CH ₂, wherein any one aforementioned group of mentioning all can be optionally substituted, and can be that different positions is encircled to form 3-7 unit;

R is H, alkyl or acyl group; With

B represents spirocyclic compound, is selected from optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N);

Base (Base) is selected from:

With

Wherein: R ', R ", R  and R " " be independently selected from H respectively; OH, replacement or unsubstituted alkyl, alkenyl replacement or unsubstituted; alkynyl replacement or unsubstituted, cycloalkyl, Br-vinyl ;-O-alkyl, O-alkenyl, O-alkynyl; O-aryl, O-aralkyl ,-O-acyl group; O-cycloalkyl, NH ₂, NH-alkyl, N-dialkyl group, NH-acyl group, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl group, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH ₂, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, OH, CF ₃, CH ₂OH, (CH ₂) _mOH, (CH ₂) _mNH ₂, (CH ₂) _mCOOH, (CH ₂) _mCN, (CH ₂) _mNO ₂(CH ₂) _mCONH ₂

M is 0 or 1;

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In aspect second of the present invention is concrete, formula (XV) is provided, (XVI) or compound (XVII) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, this method comprises the formula (XV) of using effective therapeutic dose, (XVI) or compound (XVII):

G and E are independently selected from: CH ₃, CH ₂OH, CH ₂F, CH ₂N ₃, CH ₂CN, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCONH ₂, (CH ₂) _mCONR ₂, (CH ₂) _mCONHR and N-acyl group;

M is 0 or 1;

R is H, alkyl or acyl group; With

R ', R ", R , R " " and R ³And base (Base) defines suc as formula (XIII).

Perhaps, for formula (XVII) compound, G and E at the most one can be hydrogen further.

In aspect the 3rd of the present invention is concrete, compound or the pharmacologically acceptable salt or the prodrug of formula (XVIII) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, and this method comprises the compound of the formula (XVIII) of using effective therapeutic dose:

M is selected from S, SO, and SO ₂With

R ', R ", R , R " " and R ³And base (Base) defines suc as formula (XIII).

In aspect the 4th of the present invention is concrete, formula (XIX) is provided, (XX), (XXI) (XXII) or compound (XXIII) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, this method comprises the formula (XIX) of using effective therapeutic dose, (XX), (XXI) (XXII) or compound (XXIII):

A is selected from the optional low alkyl group that replaces, cycloalkyl, alkenyl, alkynyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂(CH ₂) _mCONHR;

Y is selected from H, the optional low alkyl group that replaces, cycloalkyl, alkenyl, alkynyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂(CH ₂) _mCONHR;

X is selected from-OH, the optional alkyl that replaces, and cycloalkyl, alkenyl, alkynyl ,-O-alkyl ,-O-alkenyl ,-O-alkynyl ,-O-aryl ,-O-aralkyl ,-O-cycloalkyl-, O-acyl group, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO ₂, NH ₂, N ₃, NH-acyl group, NH-alkyl, N-dialkyl group, NH-alkenyl, NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-aralkyl, S-acyl group, S-cycloalkyl, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂, (CH ₂) _mCONHR, the optional 3-7 unit's carbocyclic ring that replaces and optional replace have an O, S and/or N independence or unite heterocycle as heteroatomic 3-7 unit;

M is 0 or 1;

R is H, alkyl or acyl group;

R ₃Be selected from H; Single, two and triphosphate or stable phosphate radical prodrug; That replace or unsubstituted alkyl; Acyl group; Sulphonate; The optional alkyl sulphonyl that replaces; The optional aryl sulfonyl that replaces; Lipid; Amino acid; Carbohydrate; Peptide; Cholesterol; With pharmaceutically acceptable leavings group, when external using, it can provide wherein R ³Be H independently, or single, two and the compound of triphosphate; With

The natural base of base (Base) right and wrong is selected from:

Wherein:

R ', R ", R  and R " " be independently selected from H respectively, OH, replacement or unsubstituted alkyl, alkenyl replacement or unsubstituted; alkynyl replacement or unsubstituted, cycloalkyl, Br-vinyl ,-O-alkyl, O-alkenyl, O-alkynyl; O-aryl, O-aralkyl ,-O-acyl group, O-cycloalkyl, NH ₂, NH-alkyl, N-dialkyl group, NH-acyl group, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl group, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH ₂, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, OH, CF ₃, CH ₂OH, (CH ₂) _mOH, (CH ₂) _mNH ₂, (CH ₂) _mCOOH, (CH ₂) _mCN, (CH ₂) _mNO ₂(CH ₂) _mCONH ₂

M is 0 or 1;

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently " "; With

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently;

Restrictive condition is: in base (g) with (i), and R ', R " " not H, OH, or NH ₂And Q, T, V, Q ₂, Q ₅And Q ₆Not N.

In one embodiment, amino-acid residue has molecular formula C (O) C (R ¹¹) (R ¹²) (NR ¹³R ¹⁴), wherein:

R ¹¹Be amino acid whose side chain, wherein, when in proline(Pro), R ¹¹Can choose wantonly and be connected to R ¹³And the formation ring texture; Perhaps, R ¹¹Be alkyl, aryl, heteroaryl or heterocyclic moiety;

R ¹²Be hydrogen, alkyl (comprising low alkyl group) or aryl; With

R ¹³And R ¹⁴Be hydrogen independently, acyl group (comprises and is connected to R ¹¹Acyl derivative) or alkyl (including but not limited to methyl, ethyl, propyl group, and cyclopropyl).

In another preferred embodiment, R ²And R ³One of at least be amino-acid residue, L-valyl preferably.

β-D-of the present invention and β-L-nucleosides can suppress the activity of flaviviridae polysaccharase.By at this special screening method of setting forth, can screen nucleosides according to the ability that whether has vitro inhibition flavivirus polymerase activity.By in test described here or test, assessing compound, can easily determine field of activity with other conclusive evidences.

In one embodiment, the validity of anti-flavivirus coe virus compound can according in this special method of setting forth, reach 50% (that is EC of compound, according to measuring at the compound concentration of external essential minimizing virus plaque quantity ₅₀).The parent of preceding drug compound has shown less than 25,15,10,5 in preferred embodiments, or 1 little EC that rubs ₅₀In preferred embodiments, when according to being described in Ferrari etc., Jnl.of Vir., 73:1649-1654,1999; Ishii etc., Hepatology, 29:1227-1235,1999; Lohmann etc., Jnl.of Bio.Chem., 274:10807-10815,1999; Or Yamashita etc., Jnl.of Bio.Chem., 273:15479-15486, when the polymerase assay of describing in 1998 is measured, compound exhibits less than 15 or 10 little EC that rub ₅₀

In another embodiment, associating and/or alternating treatment are provided.In combination therapy, the medicament of two or more of effective dose is used together, and in alternating treatment, each medicament of effective dose is used continuously.Dosage depends on absorption, inactivation and the excretion rate of this medicine, depends on that also other well known to a person skilled in the art factor.It should be noted that dosage also should change to some extent along with the severity of disease that will alleviate.Be also to be understood that simultaneously for any specific patient, specific dosage regimen and administration time arrangement should according to the needs of individuality and use or supervise the said composition administration personnel professional judgement and adjust at any time.

The invention provides the Combined Preparation of at least two kinds of prodrugs described here.The present invention further provides at least a described 2 ' and 3 '-prodrug shows the active nucleosides Combined Preparation of anti-flavivirus coe virus or replaces administration with another kind, this nucleosides includes but not limited to the parent drug at any prodrug of this definition, promptly. β-D-2 ', 6-dimethyl-cytidine, β-D-2 ', 6-dimethyl-thymidine, β-D-2 ', 8-dimethyl-adenosine, β-D-2 ', 8-dimethyl-guanosine, β-D-2 ', 6-dimethyl-5-fluoro cytidine and/or β-D-2 ', 6-dimethyl-uridine.Perhaps, 2 ' or 3 '-prodrug or their prodrug or pharmacologically acceptable salt can have less than 10 or 15 little EC that rub with other ₅₀Anti-flavivirus agent Combined Preparation or alternately administration.

The limiting examples of antiviral agent that can be used to and be disclosed in this compound Combined Preparation comprises: 1) Interferon, rabbit and/or ribavirin; (2) based on the NS3 proteinase inhibitor of substrate; (3) non-inhibitor based on substrate; (4) tetrahydrothiazole derivates; (5) thiazolidine and N-benzanilide; (6) phenanthrenequione; (7) NS3 inhibitor; (8) HCV helicase inhibitor; (9) AG14361 comprises the RNA-AG14361 that RNA relies on; (10) oligomeric deoxynucleotide; (11) inhibitor of the translation of IRES dependence; (12) nuclease-resistant ribozyme; (13) other has the active compound of anti-flavivirus coe virus.The present invention further comprises prodrug and immunomodulator or other activity modulators of virus replication pharmaceutically, comprise biomaterial such as albumen, peptide, oligonucleotide or gamma globulin include but not limited to the antisense oligonucleotide Combined Preparation or the alternately administration of the gene that Interferon, rabbit, interleukin-or expression or adjusting flaviviridae duplicate.

The present invention further comprises prodrug and immunomodulator or other activity modulators of virus replication pharmaceutically, comprise biomaterial such as albumen, peptide, oligonucleotide or gamma globulin include but not limited to the antisense oligonucleotide Combined Preparation or the alternately administration of the gene that Interferon, rabbit, interleukin-or expression or adjusting flaviviridae duplicate.Prodrug

Particularly, the invention provides as follows:

(a) compound of formula (XIII)-(XXIII), or its pharmacologically acceptable salt or their prodrug;

(b) pharmaceutical composition comprises the compound of formula (XIII)-(XXIII), or its pharmacologically acceptable salt or their prodrug, with a kind of pharmaceutically acceptable carrier or thinner;

(c) pharmaceutical composition comprises the compound of formula (XIII)-(XXIII), or its pharmacologically acceptable salt or their prodrug, with one or more other effective antiviral agent, and optional and pharmaceutically acceptable carrier or thinner;

(d) be used for the treatment of the pharmaceutical composition of flaviviridae infections among the host, comprise the compound of formula (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug and pharmaceutically acceptable carrier or thinner;

(e) be used for the treatment of the pharmaceutical composition of flaviviridae infections among the host, comprise the compound of formula (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug, with one or more other effective antiviral agent, optional and pharmaceutically acceptable carrier or thinner;

(f) be used for the treatment of the method for flaviviridae infections among the host, comprise the compound of (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug, optional and pharmaceutically acceptable carrier or thinner;

(g) be used for the treatment of the method for flaviviridae infections among the host, comprise the compound of formula (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug, with one or more other effective antiviral agent, optional and pharmaceutically acceptable carrier or thinner;

(h) compound of formula (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug, optional and pharmaceutically acceptable carrier or thinner purposes in the flaviviridae infections in the treatment host;

(i) compound of formula (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug, with one or more other effective antiviral agent, optional with pharmaceutically acceptable carrier or thinner the purposes in the flaviviridae infections in the treatment host;

(j) compound of formula (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug, optional and a kind of pharmaceutically acceptable carrier or thinner are used for the treatment of purposes in the medicine of flaviviridae infections among the host in preparation; With

(k) compound of formula (I)-(XXIII), or its pharmacologically acceptable salt or their prodrug, with one or more other effective antiviral agent, optional and a kind of pharmaceutically acceptable carrier or thinner are used for the treatment of purposes in the medicine of flaviviridae infections among the host in preparation.

Can select in the embodiment at one, any 2 '-or 3 '-the parent nucleoside compound of prodrug (that is, do not have 2 '-or 3 '-nucleosides of cutting out section) be provided for treatment flaviviridae infections, particularly infection with hepatitis C virus.

Description of drawings

Fig. 1 provides the structure of the nucleosides of the various limiting examples of the present invention, and the structure of other known nucleosides also is provided, and particularly is FIAU and ribavirin.

Fig. 2 provide esterification 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides with obtain 2 '-limiting examples of the reactions steps that comprises in the prodrug, prodrug.By selective protection 2 ' and 5 '-hydroxyl or protect 2 ', 3 ' and 5 '-hydroxyl and selectivity deprotection 3 '-hydroxyl, same ordinary method can be used to obtain 3 '-prodrug.

Fig. 3 provide esterification 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides with obtain 3 '-limiting examples of the reactions steps that comprises in the prodrug, comprise prodrug.

Fig. 4 provide esterification 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides with obtain 2 ', 3 '-the limiting examples prodrug of the reactions steps that comprises in the prodrug.

Embodiment

The present invention discloses compound, the method and composition that is used for the treatment of flaviviridae infections in people or other host animal at this.Described method comprise use the effective therapeutic dose of anti-flavivirus coe virus described herein 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or pharmacologically acceptable salt, derivative or their prodrug are chosen wantonly in pharmaceutically acceptable carrier.Activity that compound of the present invention also has antiviral (promptly anti-HCV), or produce by metabolism and to have this active compound.HCV is a member of flaviviridae.HCV has been put in the new monotypic genus, hepatovirus.Therefore, in one embodiment, described flaviviridae is HCV.Select in the embodiment at another, described flaviviridae is flavivirus or pestivirus.

1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug is secondary alcohol or the tertiary alcohol acyl derivative in the α position of secondary carbon or tertiary carbon.Based on these prodrugs to 5 '-steric hindrance of the acyl derivative of prodrug, primary alconol, these prodrugs of prodrug are in the external biological nature that can differentially regulate molecule.Have been found that 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-medicine that prodrug can provide the drug metabolism of transformation period with increase and improvement to distribute.

In a preferred embodiment 2 ' or 3 '-prodrug is the acyl group that can shear, amino acid moiety most particularly, it prepares from any natural existence and synthetic α, beta, gamma or δ amino acid; include but not limited to glycine, L-Ala, Xie Ansuan; leucine, Isoleucine, methionine(Met), phenylalanine; tryptophane, proline(Pro), Serine, Threonine; halfcystine, tyrosine, l-asparagine, glutamine; aspartic acid, L-glutamic acid, Methionin, arginine and Histidine.In a preferred embodiment, described amino acid is the L-configuration.Perhaps, described amino acid can be alanyl, valyl, leucyl; isoleucyl-, prolyl, phenylalanyl, tryptophyl; methionyl, glycyl, seryl, threonyl; cysteinyl, tyrosyl, asparaginyl, glutaminyl; aspartoyl, glutamy, lysyl; arginyl, histidyl-, β-alanyl; β-valyl, β-leucyl, β-isoleucyl-; β-prolyl, β-phenylalanyl, β-tryptophyl; β-methionyl, β-glycyl, β-seryl; β-threonyl, β-cysteinyl, β-tyrosyl; β-asparaginyl, β-glutaminyl, β 3-aspartoyl; β-glutamy, β-lysyl, the derivative of β-arginyl or β-histidyl-.In a specific embodiments, described part is a L-valine ester.Particularly preferred compound is 2 ', 3 of 6-dimethyl-ribose-cytidine '-L-valine ester.

1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides have low oral administration biaavailability with natural base and HCl salt form in rodent and non-human primate.Have been found that 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides and other nucleosides or nucleoside analog absorb at intestines and stomach, or has tangible competition in the transhipment, with other nucleosides or nucleoside analog and 1 ', 2 ', 3 ' or 4 '-side chain β-D or the competition on absorbing of β-L nucleosides.Interact for improving oral administration biaavailability and reducing between the potential drug-drug, obtained 1 of the influence that reduces than the higher oral administration biaavailability of parent molecule with to the bioavailability of other nucleosides that is used for Combined Preparation or nucleoside analog ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and 3 '-prodrug.

With 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides compare, 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 ', and/or 5 '-single, two or three L-valine esters have than parent 1 ', 2 ', 3 ' or 4 '-the higher oral administration biaavailability of side chain β-D or β-L nucleosides and when being used to Combined Preparation and the interaction that reduces of other nucleosides or nucleoside analog.

By in stomach mucous membrane, blood or liver, taking off esterification, 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 ', and/or 5 '-single, two or three L-valine esters can be changed into parent 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides.By the amino acid carrier effect in intestines and stomach mucous membrane transportation, 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 ', and/or 5 '-single, two or three L-valine esters can be transported in the blood from the stomach chamber after oral effectively.Here it is with main mother 1 by amino acid carrier effect transportation ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides compare the reason that oral administration biaavailability increases.Simultaneously, also reduced 1 of picked-up ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ', 3 ', and/or 5 '-single, two or three L-valine esters and other do not pass through the nucleosides of amino acid carrier effect transportation or the competition between the nucleoside analog by nucleosides carrier effect transportation.Because 1 ', 2 ', 3 ' or 4 '-two or three L-valine esters of side chain β-D or β-L nucleosides partly take off esterification occur in absorb fully before, therefore single or two L-valine esters continue to be absorbed by amino acid carrier effect transportation.Therefore, can keep better absorption or the bioavailability expected, and reduce and other being shotly be taken into nucleosides in the blood or the competition between the nucleoside analog.

Generally speaking, the present invention includes following feature:

(a) described herein 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug and pharmacologically acceptable salt and their composition;

(b) described herein 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, be used for the treatment of with the composition of pharmacologically acceptable salt and they and/or the prevention of flavivirus coe virus infects, particularly be diagnosed as by flaviviridae infections or be in the individuality that becomes by in the risk of infection with hepatitis C virus;

(c) described herein 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or there is not the enantiomorph of described nucleosides in fact in pharmacologically acceptable salt and composition, or separate with other chemical entity in fact;

(d) preparation 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-method of prodrug, more detailed description as after;

(e) formula of medicine, comprise 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or its pharmacologically acceptable salt and a kind of pharmaceutically acceptable carrier or thinner;

(f) formula of medicine, comprise 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug or its pharmacologically acceptable salt, with one or more other effective anti-HCV agent, choose wantonly in pharmaceutically acceptable carrier or thinner;

(g) formula of medicine, comprise 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug or its pharmacologically acceptable salt, with 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-different parent of L nucleosides, choose wantonly in pharmaceutically acceptable carrier or thinner;

(h) be used for the treatment of and/or preventing infection has the host's of flaviviridae method, comprise use 1 of significant quantity ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or its pharmacologically acceptable salt or composition;

(i) be used for the treatment of and/or preventing infection has the host's of flaviviridae method, comprise 1 of significant quantity ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or its pharmacologically acceptable salt or composition and one or more effective anti-HCV agent Combined Preparation and/or alternately administration;

(j) be used for the treatment of and/or preventing infection has the host's of flaviviridae method, comprise use 1 of significant quantity ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or its pharmacologically acceptable salt or composition and 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-different parent of L nucleosides;

(k) be used for the treatment of and/or preventing infection has the host's of flaviviridae method, comprise 2 of β-D-2 '-methyl-cytidine of using significant quantity ' and/or 3 '-prodrug, or its pharmacologically acceptable salt or their composition;

(l) be used for the treatment of and/or preventing infection has the host's of flaviviridae method, comprise 2 of β-D-2 '-methyl-cytidine of using significant quantity '-valyl or acetonyl ester, or its pharmacologically acceptable salt or their composition;

(m) 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug and pharmacologically acceptable salt and their composition be used for the treatment of and/or prevent flaviviridae infections among the host;

(n) 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, its pharmacologically acceptable salt or composition and one or more effective anti-HCV agent Combined Preparation and/or alternately be administered for the flaviviridae infections that treats and/or prevents among the host;

(o) 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or its pharmacy acceptable salt or composition and 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-different parent of L nucleosides be used for the treatment of and/or prevent flaviviridae infections among the host;

(p) 2 of β-D-2 '-methyl-cytidine ' and/or 3 '-prodrug, or its pharmacologically acceptable salt or their composition are used for the treatment of and/or prevent flaviviridae infections among the host;

(q) 2 of β-D-2 '-methyl-cytidine '-valyl or acetonyl ester, or its pharmacologically acceptable salt or their composition are used for the treatment of and/or prevent flaviviridae infections among the host;

(r) 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug and pharmacologically acceptable salt and their composition be used for the treatment of and/or prevent purposes in the medicine of the flaviviridae infections among the host in preparation;

(s) 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, its pharmacologically acceptable salt or composition and one or more effective anti-HCV agent Combined Preparation and/or alternately administration be used for the treatment of and/or prevent purposes in the medicine of the flaviviridae infections among the host in preparation;

(t) 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides 2 ' and/or 3 '-prodrug, or its pharmacologically acceptable salt or composition and 1 ', 2 ', 3 ' or 4 '-the different parent of side chain β-D or β-L nucleosides is used for the treatment of and/or prevents purposes in the medicine of the flaviviridae infections among the host in preparation;

(u) 2 of β-D-2 '-methyl-cytidine ' and/or 3 '-prodrug, or its pharmacologically acceptable salt or their composition are used for the treatment of and/or prevent purposes in the medicine of the flaviviridae infections among the host in preparation; With

(v) β-D-2 '-methyl-cytidine 2 '-valyl or acetonyl ester, or its pharmacologically acceptable salt or their composition are used for the treatment of and/or prevent purposes in the medicine of the flaviviridae infections among the host in preparation.

General discussion to the flaviviridae in the scope of the invention sees Fields Virology, editor: Fields, B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 31,1996.In specific embodiments of the present invention, described flaviviridae is HCV.Can select in the embodiment one of the present invention, described flaviviridae is flavivirus or pestivirus.Specific flavivirus comprises, but be not limited to: Absettarov, Alfuy, Apoi, Aroa, Bagaza, spot neat (Banzi), Bouboui, Bussuquara, Cacipacore, island, Kerry (Carey Island), Dakar bat (Dakar bat), 1 type singapore hemorrhagic fever (Dengue 1), 2 type singapore hemorrhagic fever (Dengue 2), 3 type singapore hemorrhagic fever (Dengue 3), 4 type singapore hemorrhagic fever (Dengue 4), Edge Hill, Entebbe bat (Entebbe bat), Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel's turkey meningoencephalitis (Israel turkey meningoencephalitis), Japanese encephalitis (Japanese encephalitis), Jugra, Jutiapa (Jutiapa), Kadam, Karshi, Kedougou, Ke Kebeila (Kokobera), Ku Tange (Koutango), Kumlinge, Kun Jin (Kunjin), kyassnur forest disease (Kyasanur Forest disease), Langat, ramaninjana (Louping ill), Meaban, Mo Duoke (Modoc), Montana leukoencephalitis (Montana myotis leukoencephalitis), Murray Valley encephalitis (Murray valley encephalitis), Naranjal, Le Gexi (Negishi), En Taye (Ntaya), Omsk hemorrhagic fever (Omsk hemorrhagic fever), golden-rimmed bat (Phnom-Penh bat), Bo Wasang (Powassan), lining Ao Bulawo (Rio Bravo), sieve Theo (Rocio), imperial family farm (Royal Farm), RSSE (Russian spring-summer encephalitis), Sa Boya (Saboya), SLE (St.Louis encephalitis), Sal Vieja, San Perlita, Saumarez Reef, a plug gram river (Sepik), Sokuluk, Spondweni, Stratford (Stratford), Tan Busu (Tembusu), Qiu Lieni (Tyuleniy), Uganda S (Uganda S), Usu Tu He (Usutu), Wei Saiersibulong (Wesselsbron), West Nile (WestNile), Yaounde (Yaounde), yellow jack (Yellow fever) and neat card (Zika).

General discussion to the pestivirus in the scope of the invention sees Fields Virology, editor: Fields, and B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter 33,1996.Specific pestivirus includes, but are not limited to: bovine viral diarrhea virus (" BVDV "), Pestivirus suis (" CSFV " is also referred to as hog cholera virus) and sheep border disease virus (" BDV ").

I. active compound

In first main embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (I) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the compound of the formula (I) of using effective therapeutic dose:

R ¹, R ²And R ³Be H independently, phosphate radical (comprise list, two or triphosphate and stable phosphate radical); Straight chain, side chain or cycloalkyl (comprising low alkyl group); Acyl group (comprising lower acyl); The CO-alkyl, CO-aryl, CO-alkoxyalkyl, the CO-aryloxy alkyl, the aryl that CO-replaces, sulphonate comprises that alkyl or aralkyl alkylsulfonyl comprise methylsulfonyl and benzyl, wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Alkyl sulphonyl, aryl sulfonyl, the aralkyl alkylsulfonyl, lipid comprises phosphatide; Amino acid; And amino-acid residue, carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, for example when using in the body, it can provide wherein R ¹, R ²And/or R ³Be independently H or phosphate radical (comprise list, two or triphosphate) compound; Wherein in one embodiment, R ²And/or R ³Be not phosphate radical (comprise list, two or triphosphate or stable phosphate radical prodrug);

R wherein ²And R ³One of at least be not hydrogen:

X ¹Be straight chain, the optional alkyl that replaces of side chain or ring-type, CH ₃, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, CH ₂OH, the optional alkenyl that replaces, the optional alkynyl that replaces, COOH, COOR ⁴, COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH ₂, CONHR ⁴, CON (R ⁴) ₂, chlorine, bromine, fluorine, iodine, CN, N ₃, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁵

Preferred a branch in the embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (I) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (I) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

R ¹Be H or phosphate radical (preferred H);

R ²And R ³H independently, phosphate radical, acyl group or amino-acid residue, wherein R ²And R ³One of at least be acyl group or amino-acid residue;

X ¹Be CH ₃, CF ₃Or CH ₂CH ₃

X ²Be H or NH ₂With

Y is a hydrogen, bromine, chlorine, fluorine, iodine, NH ₂Or OH.

In second main embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (II) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the compound of the formula (II) of using effective therapeutic dose:

R ¹, R ², R ³, R ⁴, R ⁵, Y ¹, Y ³, X ¹And X ²Definition as above.

Preferred a branch in the embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (II) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (II) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form.Wherein:

R ¹Be H or phosphate radical (preferred H);

X ¹Be CH ₃, CF ₃Or CH ₂CH ₃

X ²Be H, F, Cl, Br, I or CH ₃With

Y is a hydrogen, bromine, chlorine, fluorine, iodine, NH ₂Or OH.

In the 3rd main embodiment, formula (III) is provided, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, comprise the formula (III) of using effective therapeutic dose, (IV) or compound (V):

R ¹, R ², R ³, R ⁴, R ⁵, Y, Y ¹And X ²Definition as above;

Base (Base) is selected from:

W ^*Be respectively O, S, NH or NR independently ⁴

Wherein, if W ¹, W ²And W ³Be N, for base (Base) (B) for, W ⁴Can not be CH;

Wherein, if W ¹Be N, for base (Base) (E), (F), (K), (L), (W) and (X), W ⁴Can not be CH;

X ^*Be CH, CF, CY ³Or CR ⁴

Y ²Be respectively O, S, NH or NR independently ⁴

Y ³Be respectively H independently, F, Cl, Br or I;

R ⁶Be respectively the optional alkyl (comprising low alkyl group) that replaces independently, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂Or cyano group;

R ⁷Be respectively OH independently, OR ², the optional alkyl (comprising low alkyl group) that replaces, CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃The optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, the halo alkynyl, the optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7), the optional heterocycle that replaces (preferably has one or more O, the 3-7 unit heterocycle of S and/or N), the optional heteroaryl (preferably having one or more O, the 3-7 membered aromatic heterocycle of S and/or N) that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) 2 ,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (acyl group) ,-O (lower acyl) ,-O (R ⁴) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), NO ₂, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂, azido-, cyano group, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

Perhaps, R ⁶And R ⁷Can be selected from conjunction with forming spirocyclic compound: optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N); With

M is respectively 0,1 or 2 independently.

In first minute embodiment, formula (III) is provided, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the formula (III) of using effective therapeutic dose, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, wherein:

R ¹Be H or phosphate radical (preferred H);

R ²And R ³Be H independently, phosphate radical, acyl group or amino-acid residue, wherein R ²And R ³One of at least be acyl group or amino-acid residue;

W ⁴Be CX ³

X ³Be CH ₃, CF ₃Or CH ₂CH ₃

R ⁶It is alkyl; With

X is O, S, SO ₂Or CH ₂

In second branch embodiment, formula (III) is provided, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the formula (III) of using effective therapeutic dose, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, wherein:

R ¹Be H or phosphate radical (preferred H);

R ²And R ³Be H independently, phosphate radical, acyl group or amino-acid residue, wherein R ²And R ³One of at least be amino-acid residue;

W ⁴Be CX ³

X ³Be CH ₃, CF ₃Or CH ₂CH ₃

R ⁶It is alkyl; With

X is O, S, SO ₂Or CH ₂

In the 3rd branch embodiment, formula (III) is provided, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the formula (III) of using effective therapeutic dose, (IV) or compound (V) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, wherein:

R ¹Be H or phosphate radical (preferred H);

W ⁴Be CX ³

X ³Be CH ₃, CF ₃Or CH ₂CH ₃

R ⁶Alkyl; With

X is O.

In a preferred minute embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (IV (a)) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the compound of the formula (IV (a)) of using effective therapeutic dose:

Base (Base) is defined in this; Optional by amine or cyclopropyl (as, 2-amino, 2,6-diamino or cyclopropyl guanosine) replace;

R ⁷Be halogen (F, Cl, Br or I), but preferred F;

R ¹Be H; Phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug); Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Or R ²Be H or phosphate radical independently.In one embodiment, R ²It or not phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug); With

R ²It is phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug); Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Or R ²Be H or phosphate radical independently.In one embodiment, R ²It or not phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug);

In the 4th main embodiment, formula (VI) or compound (VII) or pharmacologically acceptable salt or prodrug are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised formula (VI) or the compound (VII) of using effective therapeutic dose:

Base (Base), R, R ¹, R ⁴, R ⁵, R ⁶, R ⁷, Y, Y ¹, Y ², Y ³, W ^*, W ¹, W ², W ³, W ⁴, X, X ^*, X ¹, X ²And X ³Definition as above;

Wherein, in one embodiment, only when X is carbon, the R in the formula (VI) ⁸Be-OH or-NH ₂

With

Wherein,

R ⁹And R ¹⁰Be respectively hydrogen independently, OH, OR ², the alkyl of optional replacement (comprising low alkyl group), CH ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl (comprising junior alkyl halides), CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃The optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, the halo alkynyl, the optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7), the optional heterocycle that replaces (preferably has one or more O, the 3-7 unit heterocycle of S and/or N), the optional heteroaryl (preferably having one or more O, the 3-7 membered aromatic heterocycle of S and/or N) that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂, (CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂, C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (acyl group) ,-O (lower acyl) ,-O (R ⁴) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), NO ₂, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂, azido-, cyano group, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

M is respectively 0,1 or 2 independently; With

Perhaps, R ⁶And R ⁷Or R ⁹And R ¹⁰Can be selected from conjunction with forming spirocyclic compound: optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N).

In a concrete preferred embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

X is O, S, SO or SO ₂And/or

R ⁶Be respectively the optional low alkyl group that replaces independently, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R ⁴, (CH ₂) _mCOOH, (CH ₂) _mCOOR ⁴, (CH ₂) _mCONH ₂, (CH ₂) _mCON (R ⁴) ₂, or (CH ₂) _mCONHR ⁴And/or

R ⁷Be-OH the optional low alkyl group that replaces, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces ,-O-alkyl ,-O-alkenyl respectively independently;-O-alkynyl ,-O-aralkyl ,-O-cycloalkyl-, O-acyl group, F, Cl, Br; I, CN, NC, SCN, OCN, NCO, NO ₂, NH ₂, N ₃, NH-acyl group, NH-alkyl, N-dialkyl group, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl group, S-cycloalkyl, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R ⁴, (CH ₂) _mCOOH, (CH ₂) _mCOOR ⁴, (CH ₂) _mCONH ₂, (CH ₂) _mCON (R ⁴) ₂, (CH ₂) _mCONHR ⁴, the optional 3-7 unit's carbocyclic ring that replaces and optional replace have an O, S and/or N independence or unite heterocycle as heteroatoms 3-7 unit; And/or

R ⁹Be respectively hydrogen independently, the optional low alkyl group that replaces, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces ,-OH ,-O-alkyl ,-O-alkenyl;-O-alkynyl ,-O-aralkyl ,-O-cycloalkyl-, O-acyl group, F, Cl, Br; I, CN, NC, SCN, OCN, NCO, NO ₂, NH ₂, N ₃, NH-acyl group, NH-alkyl, N-dialkyl group, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl group, S-cycloalkyl, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R ⁴, (CH ₂) _mCOOH, (CH ₂) _mCOOR ⁴, (CH ₂) _mCONH ₂, (CH ₂) _mCON (R ⁴) ₂, (CH ₂) _mCONHR ⁴, the optional 3-7 unit's carbocyclic ring that replaces and optional replace have an O, S and/or N independence or unite heterocycle as heteroatoms 3-7 unit; And/or

R ¹⁰Be respectively hydrogen independently, the optional low alkyl group that replaces, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R ⁴, (CH ₂) _mCOOH, (CH ₂) _mCOOR ⁴, (CH ₂) _mCONH ₂, (CH ₂) _mCON (R ⁴) ₂Or (CH ₂) _mCONHR ⁴And/or

R ⁸And R ¹¹Be respectively H independently, CH ₃, CH ₂OH, CH ₂F, CH ₂N ₃, (CH ₂) _mCOOH, (CH ₂) _mCOOR ⁴, (CH ₂) _mCONH ₂, (CH ₂) _mCON (R ⁴) ₂, (CH ₂) _mCONHR ⁴With the N-acyl group; And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In a concrete preferred selectable embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

X is O, S, SO or SO ₂And/or

R ⁶And R ⁷In conjunction with forming spirocyclic compound, be selected from: choose the 3-7 unit's spiral shell shape carbocyclic ring that replaces wantonly or have one or more N, the heterogeneous ring compound of O and/or S atom, described heteroatoms are chosen separately or are selected jointly with other heteroatoms; And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In another concrete preferred embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

X is O, S, SO or SO ₂And/or

R ⁹And R ¹⁰In conjunction with forming spirocyclic compound, be selected from: choose the 3-7 unit's spiral shell shape carbocyclic ring that replaces wantonly or have one or more N, the heterogeneous ring compound of O and/or S atom, described heteroatoms are chosen separately or are selected jointly with other heteroatoms; And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

X is O, S, SO or SO ₂And/or

R ⁹And R ¹⁰In conjunction with forming spirocyclic compound, be selected from: choose the 3-7 unit's spiral shell shape carbocyclic ring that replaces wantonly or have one or more N, the heterogeneous ring compound of O and/or S atom, described heteroatoms are united independently or with other as heteroatoms; And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

X is CH ₂, CH ₂OH, CHF, CF ₂, C (Y ³) ₂, CHCN, C (CN) ₂, CHR ⁴Or C (R ⁴) ₂And/or

R ⁹Be respectively hydrogen independently, the optional low alkyl group that replaces, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces ,-OH ,-O-alkyl ,-O-alkenyl;-O-alkynyl ,-O-aralkyl ,-O-cycloalkyl-, O-acyl group, F, Cl, Br; I, CN, NC, SCN, OCN, NCO, NO ₂, NH ₂, N ₃, NH-acyl group, NH-alkyl, N-dialkyl group, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl group, S-cycloalkyl, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R ₄, (CH ₂) _mCOOH, (CH ₂) _mCOOR ⁴, (CH ₂) _mCONH ₂, (CH ₂) _mCON (R ⁴) ₂, (CH ₂) _mCONHR ⁴, the optional 3-7 unit's carbocyclic ring that replaces and optional replace have an O, S and/or N independence or unite heterocycle as heteroatoms 3-7 unit; And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

R ⁷Be-OH the optional low alkyl group that replaces, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces ,-O-alkyl ,-O-alkenyl respectively independently;-O-alkynyl ,-O-aralkyl ,-O-cycloalkyl-, O-acyl group, F, Cl, Br; I, CN, NC, SCN, OCN, NCO, NO ₂, NH ₂, N ₃, NH-acyl group, NH-alkyl, N-dialkyl group, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl group, S-cycloalkyl, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂p ⁴, (CH ₂) _mCOOH, (CH ₂) _mCOOR ⁴, (CH ₂) _mCONH ₂, (CH ₂) _mCON (R ⁴) ₂, (CH ₂) _mCONHR ⁴, the optional 3-7 unit's carbocyclic ring that replaces and optional replace have an O, S and/or N independence or unite heterocycle as heteroatoms 3-7 unit; And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂Or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In a concrete preferred embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VII) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VII) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

X ^*Be CH, CF, CY ³Or CR ⁴And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

Wherein R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In a concrete preferred selectable embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VII) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VII) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

X ^*Be CH, CF, CY ³Or CR ⁴And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In another concrete preferred embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VII) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VII) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

X ^*Be CH, CF, CY ³Or CR ⁴And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

X ^*Be CH, CF, CY ³Or CR ⁴And/or

M is respectively 0 or 1 independently; And/or

It is one of following that base (Base) is selected from:

Wherein:

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In first minute embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶It is alkyl; (3) R ⁷And R ⁹Be OR independently ², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (4) R ⁸And R ¹⁰Be H independently, alkyl (comprising low alkyl group), chlorine, bromine, or iodine; (5) X is O, S, SO ₂Or CH ₂(6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In second branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶Be alkyl, alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂, amino, low-grade alkyl amino, or two (low alkyl group) amino; (3) R ⁷And R ⁹Be OR independently ²(4) R ⁸And R ¹⁰Be H independently, alkyl (comprising low alkyl group), chlorine, bromine, or iodine; (5) X is O, S, SO ₂Or CH ₂(6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 3rd branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶Be alkyl, alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂, amino, low-grade alkyl amino, or two (low alkyl group) amino; (3) R ⁷And R ⁹Be OR independently ², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (4) R ⁸And R ¹⁰Be H; (5) X is O, S, SO ₂Or CH2; (6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 4th branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶Be alkyl, alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂, amino, low-grade alkyl amino, or two (low alkyl group) amino; (3) R ⁷And R ⁹Be OR independently ², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (4) R ⁸And R ¹⁰Be H independently, alkyl (comprising low alkyl group), chlorine, bromine, or iodine; (5) X is O; (6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 5th branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flavivirus is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶It is alkyl; (3) R ⁷And R ⁹Be OR independently ¹(4) R ⁸And R ¹⁰H independently, alkyl (comprising low alkyl group), chlorine, bromine or iodine; (5) X is O, S, SO ₂Or CH ₂(6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 6th branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flavivirus is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶It is alkyl; (3) R ⁷And R ⁹Be OR independently ², alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (4) R ⁸And R ¹⁰Be H; (5) X is O, S, SO ₂Or CH ₂(6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 7th branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶It is alkyl; (3) R ⁷And R ⁹Be OR independently ², alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ², amino, low-grade alkyl amino or two (low alkyl group) amino; (4) R ⁸And R ¹⁰Be H independently, alkyl (comprising low alkyl group), chlorine, bromine or iodine; (5) X is O; (6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 8th branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶Be alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (3) R ⁷And R ⁹Be OR independently ²(4) R ⁸And R ¹⁰Be hydrogen; (6) X is O, S, SO ₂Or CH ₂(6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 9th branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶Be alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (3) R ⁷And R ⁹Be OR independently ²(4) R ⁸And R ¹⁰Be H independently, alkyl (comprising low alkyl group), chlorine, bromine or iodine; (5) X is O; (6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the tenth branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical (comprising single phosphate radical, gen-diphosphate, triphosphate, or stable phosphate radical prodrug) independently; Acyl group (comprising lower acyl); Alkyl (comprising low alkyl group); Sulphonate comprises that the alkyl or aryl alkyl sulphonyl comprises methylsulfonyl and benzyl, and wherein phenyl is optional by one or more and substituting group replacement identical in this definition to aryl; Lipid comprises phosphatide; Amino acid; Carbohydrate; Peptide; Cholesterol; Or other pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ¹Be the compound of H or phosphate radical independently; (2) R ⁶Be alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (3) R ⁷And R ⁹Be OR independently ², alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂, amino, low-grade alkyl amino, or two (low alkyl group) amino; (4) R ⁸And R ¹⁰Be hydrogen; (5) X is O; (6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 11 branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical independently; (2) R ⁶Be alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂, amino, low-grade alkyl amino or two (low alkyl group) amino; (3) R ⁷And R ⁹Be OR independently ²(4) R ⁸And R ¹⁰Be hydrogen; (5) X is O, S, SO ₂Or CH ₂(6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 12 branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical independently; (2) R ⁶It is alkyl; (3) R ⁷And R ⁹Be OR independently ²(4) R ⁸And R ¹⁰Be hydrogen; (5) X is O, S, SO ₂Or CH ₂(6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In the 13 branch embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical independently; (2) R ⁶It is alkyl; (3) R ⁷And R ⁹Be OR independently ²(4) R ⁸And R ¹⁰Be H independently, alkyl (comprising low alkyl group), chlorine, bromine or iodine; (5) X is O; (6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

Compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided in the 14 branch embodiment, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein: (1) R ¹Be H or phosphate radical independently; (2) R ⁶It is alkyl; (3) R ⁷And R ⁹Be OR independently ², alkyl (comprising low alkyl group), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂, amino, low-grade alkyl amino, or two (low alkyl group) amino; (4) R ⁸And R ¹⁰Be hydrogen; (5) X is O; (6) W ⁴Be CX ³(7) X ³Be CH ₃, CF ₃Or CH ₂CH ₃

In preferred minute embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (VI) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, the compound or pharmacologically acceptable salt or the prodrug that comprise the formula (VI) of using effective therapeutic dose, or their steric isomer, tautomer or polymorphic form, wherein:

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methyl guanine; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methylcystein; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methylthymidine; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-6-Methyl Uracil; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methyladenine; (2) R ¹It is phosphate radical; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is ethyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is propyl group; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is butyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷Be hydrogen and R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is O;

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is S;

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is SO ₂

(1) base (Base) is the 8-methyladenine; (2) R ¹Be hydrogen; (3) R ⁶It is methyl; (4) R ⁷And R ⁹It is hydroxyl; (5) R ⁸And R ¹⁰Be hydrogen; (6) X is CH ₂

In the 5th main embodiment, formula (VIII) is provided, (IX) or compound (X) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, comprise the formula (VIII) of using effective therapeutic dose, (IX) or compound (X):

R ¹, R ², R ³, R ⁴, R ⁵, Y ³, X and X ^*Definition as above;

Base ^*(Base ^*) be purine or pyrimidine bases in this definition;

Perhaps, R ¹²And R ¹³Can be selected from conjunction with forming spirocyclic compound: optional carbocyclic ring that replaces (preferably 3-7 unit carbocyclic ring) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N); With

M is respectively 0,1 or 2 independently.

In the 6th main embodiment, formula (XI) or compound (XII) or pharmacologically acceptable salt or prodrug are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised formula (XI) or the compound (XII) of using effective therapeutic dose:

Base ^*(Base ^*), R, R ¹, R ², R ³, R ⁴, R ⁵, R ¹², R ¹³, Y, Y ¹, Y ², Y ³, W ^*, W ¹, W ², W ³, W ⁴, X, X ^*, X ²And X ³Definition as above;

Wherein,

M is respectively 0,1 or 2 independently; With

In particular aspects of the present invention, formula (XIII) or compound (XIV) or pharmacologically acceptable salt or prodrug are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised formula (XIII) or the compound (XIV) of using effective therapeutic dose:

R ₃Be selected from H; Single, two and triphosphate or stable phosphate radical prodrug; Acyl group; Sulphonate; The optional alkyl sulphonyl that replaces; The optional aryl sulfonyl that replaces; Lipid; Amino acid; Carbohydrate; Peptide; Cholesterol; With pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ₃Be H independently, or single, two and the compound of triphosphate;

X " be selected from one or more O, S, SO, SO ₂, N, NH, NR and CH ₂, wherein any one aforementioned group of mentioning can be optionally substituted, and can be in different positions to form 3-7 unit ring;

R is H, alkyl or acyl group;

B represents spirocyclic compound, is selected from optional carbocyclic ring that replaces (the first carbocyclic ring of preferred 3-7) or the optional heterocycle that replaces (preferably having one or more O, the 3-7 unit heterocycle of S and/or N); With

Base (Base) is selected from:

Wherein:

M is 0 or 1;

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

R is H, alkyl or acyl group;

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently; With

Their tautomer.

In second particular aspects of the present invention, formula (XV) is provided, (XVI) or compound (XVII) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, comprise the formula (XV) of using effective therapeutic dose, (XVI) or compound (XVII):

G and E are independently selected from CH ₃, CH ₂OH, CH ₂F, CH ₂N ₃, CH ₂CN, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCONH ₂, (CH ₂) _mCONR ₂, (CH ₂) _mCONHR and N-acyl group;

R is H, alkyl or acyl group; With

M is 0 or 1;

R ³And base (Base) is formula (XIII) definition.

Perhaps, for formula (XVII) compound, G and E at the most one can further be hydrogen.

In the 3rd particular aspects of the present invention, compound or the pharmacologically acceptable salt or the prodrug of formula (XVIII) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the compound of the formula (XVIII) of using effective therapeutic dose:

M is selected from S, SO, and SO ₂With

R ₃And base (Base) is formula (XIII) definition.

In the 4th particular aspects of the present invention, formula (XIX) is provided, (XX), (XXI) (XXII) or compound (XXIII) or pharmacologically acceptable salt or prodrug, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the formula (XIX) of using effective therapeutic dose, (XXI) (XXII) or compound (XXIII):

A is selected from the optional low alkyl group that replaces, cycloalkyl, alkenyl, alkynyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂And (CH ₂) _mCONHR;

Y is selected from H, the optional low alkyl group that replaces, cycloalkyl, alkenyl, alkynyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂And (CH ₂) _mCONHR;

X is selected from-OH, the optional alkyl that replaces, and cycloalkyl, alkenyl, alkynyl ,-O-alkyl ,-O-alkenyl ,-O-alkynyl ,-O-aryl ,-O-aralkyl ,-O-cycloalkyl-, O-acyl group, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO ₂, NH ₂, N ₃, NH-acyl group, NH-alkyl, N-dialkyl group, NH-alkenyl, NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-aralkyl, S-acyl group, S-cycloalkyl, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCONH ₂, (CH ₂) _mCONR ₂, (CH ₂) _mCONHR, the optional 3-7 unit's carbocyclic ring that replaces and optional replace have an O, S and/or N independence or unite heterocycle as heteroatomic 3-7 unit;

M is 0 or 1;

R ₃Be selected from H; Single, two and triphosphate or stable phosphate radical prodrug; That replace or unsubstituted alkyl; Acyl group; Sulphonate; The optional alkyl sulphonyl that replaces; The optional aryl sulfonyl that replaces; Lipid; Amino acid; Carbohydrate; Peptide; Cholesterol; With pharmaceutically acceptable leavings group, when using in the body, it can provide wherein R ³Be H independently, or single, two and the compound of triphosphate; With

The natural base of base (Base) right and wrong is selected from:

Wherein:

R ', R ", R , and R " " be independently selected from H respectively, OH, replacement or unsubstituted alkyl; alkenyl replacement or unsubstituted, alkynyl replacement or unsubstituted, cycloalkyl, Br-vinyl ,-O-alkyl, O-alkenyl; O-alkynyl, O-aryl, O-aralkyl ,-O-acyl group, O-cycloalkyl, NH ₂, NH-alkyl, N-dialkyl group, NH-acyl group, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl group, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH ₂, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, OH, CF ₃, CH ₂OH, (CH ₂) _mOH, (CH ₂) _mNH ₂, (CH ₂) _mCOOH, (CH ₂) _mCN, (CH ₂) _mNO ₂(CH ₂) _mCONH ₂

M is 0 or 1;

W is C-R " or N;

T and V are CH or N independently;

Q is CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently " "; With

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently;

Restrictive condition is in base (g) with (i), R ', R " " not H, OH, or NH ₂And Q, T, V, Q ₂, Q ₅And Q ₆Not N.

In a further preferred embodiment, compound or the pharmacologically acceptable salt or the prodrug of formula (IX) are provided, or their steric isomer, tautomer or polymorphic form, a kind of method that infects the host that flaviviridae is arranged that is used for the treatment of also is provided, has comprised the compound of the formula (IX) of using effective therapeutic dose:

R ¹, R ²And R ³Be H independently; Phosphate radical; Straight chain, side chain or cyclic alkyl; Acyl group; The CO-alkyl; The CO-aryl; The CO-alkoxyalkyl; The CO-aryloxy alkyl; The aryl that CO-replaces; Sulphonate; Benzyl, wherein phenyl is optional is replaced by one or more substituting group; Alkyl sulphonyl; Aryl sulfonyl; The aralkyl alkylsulfonyl; Lipid; Amino acid; Carbohydrate; Peptide; Cholesterol; Or a kind of pharmaceutically acceptable leavings group, in the time of in being applied to body, it can provide wherein R ¹, R ²And/or R ³Be the compound of H or phosphate radical independently;

X is O, S, SO ₂Or CH ₂

Base ^*(Base ^*) be purine or pyrimidine bases;

R ¹²Be C (Y ³) ³

Y ³Be H independently, F, Cl, Br or I; With

R ¹³It is fluorine.

X is O in a branch embodiment, and Y ³Be H.In another minute embodiment, when X is O and Y ³When being H, R ¹, R ²And R ³Also be H.

II. stereochemistry

Should recognize that nucleosides of the present invention has a plurality of chiral centres and also can exist with separated with optically active form and racemic modification form.Some compounds have polytropism.Be understood that the present invention comprises any racemic modification, optically active form, diastereomer, polymorphic form or the steric isomer of The compounds of this invention, or their mixture, they all have purposes described herein.How to prepare optically active form (for example, by the recrystallization technology resolution of racemates,, synthesize, or pass through to use the chromatographic separation of chiral stationary phase) as everyone knows by chirality by synthetic from the opticity starting raw material in this area.

Particularly because nucleosides 1 ' and 4 ' carbon be chirality, as for sugared loop systems, their non-hydrogen substituting group (being base and CHOR respectively) can be cis (at homonymy) or trans (at offside).Therefore, four optical isomers are expressed as configuration (when sugar moieties is oriented to horizontal plane, make Sauerstoffatom be positioned at the back): (two groups are positioned at " top " to cis, configuration corresponding to naturally occurring β-D nucleosides), (two groups are positioned at " below " to cis, configuration corresponding to naturally occurring β-L nucleosides), trans (C2 ' substituting group is positioned at " top " and C4 ' substituting group is positioned at " below ") and trans (C2 ' substituting group is positioned at " below " and C4 ' substituting group is positioned at " top ")." D-nucleosides " is that cis nucleosides and " L-nucleosides " are the cis nucleosides in the configuration that non-natural exists in native configurations.

Similarly, most of amino acid also are chiralitys (be appointed as L or D, wherein the L enantiomorph is naturally occurring configuration) and can exist with isolating enantiomorph.

The example that obtains the method for opticity raw material is well known in the art, and comprises following at least method:

I) Crystalline machinery Split MethodOne in this technology, by the naked eyes visible crystals of the independent enantiomorph of artificial separation.If the crystal of isolating enantiomorph exists,, that is, raw material is that agglomerate and crystal visually can be distinguished, and then can use this technology;

Ii) The while crystallization processOne in this technology, and each enantiomorph is crystallization from racemic modification solution respectively, only the latter under the situation that under the solid state is concrement just by may;

Iii) The enzyme Split MethodOne in this synthetic technology, the speed of response by enantiomorph and enzyme different, partly or entirely separation of racemic body;

Iv) Enzyme asymmetric synthesis methodOne in this synthetic technology, and at least one step in the building-up process uses enzyme reaction to obtain the synthetic precursor of the enantiomorph of isomery expectation pure or enrichment;

V) Chemistry asymmetric synthesis methodOne in this synthetic technology, reaches under the condition that produces asymmetric (that is chirality) in product from the synthetic enantiomorph of expecting of chiral precurser by using chiral catalyst or chiral auxiliary(reagent);

Vi) The diastereomer Split Method-to deposit in this technology, racemic compound and mapping pure reagent (chiral auxiliary(reagent)) reaction change each enantiomorph into diastereomer.The diastereomer that produces then according to the more distinct textural difference that has by chromatogram or crystallization and separated, subsequently chiral auxiliary(reagent) is removed to obtain the enantiomorph of expectation;

Vii) The asymmetric conversion method of firsts and seconds-in this technology, diastereomer in the racemoid reaches balance, thereby produce dominant diastereomer the solution from the enantiomorph of expectation, perhaps, the expectation enantiomorph in diastereomer the crystallization perturbation that is dominant this balance, make last all raw materials all change the crystalline diastereomer into from the enantiomorph of expectation basically, then, the enantiomorph of expectation discharges from diastereomer;

Viii) The kinetic resolution method-this technology is meant, utilizes under dynamic conditions, and enantiomorph and chirality, non-racemic reagent or catalyst reaction have differential responses speed, obtains the fractionation partially or completely (or to partly further fractionation of the compound of fractionation) to racemic modification;

Ix) From the initial mapping specificity synthesis method of non-racemize precursor-in this synthetic technology, from the enantiomorph of achirality raw material acquisition expectation, and in building-up process, its stereochemistry integrity is not subjected to or only is subjected to the harm of minimum level.

X) The chirality liquid phase chromatography-in this technology, the enantiomorph of racemic modification has different interaction and separated according to them and stationary phase at liquid-flow in mutually.This stationary phase can be made or this moving phase can contain extra chiral raw material to induce different interactions by chiral raw material;

Xi) Chiral gas chromatography-in this technology, by racemic modification and enantiomorph gas flow mutually in contain the non-racemize chirality of fixed and absorb and have different interactions mutually, racemic modification volatilization and enantiomorph are separated;

Xii) The chiral solvent extraction process-in this technology, the technology of enantiomer separation by a kind of enantiomorph of selective dissolution in a kind of specific chiral solvent;

Xiii) Chiral film runs through Split Method-in this technology, racemic modification is contacted with thin barrier film.This barrier film separates two kinds of mutually soluble liquidss usually, a kind of this racemic modification that contains, and this separation utilizes motivating forces such as concentration difference or pressure difference to impel the barrier film selectivity by carrying out.Because the characteristic that this film has utilized the enantiomorph that only allows a kind of racemic modification to pass through has produced non-racemize chirality body thereby separate.

III. definition

Except that indicating in addition, term " alkyl " is meant saturated straight chain, side chain or cyclic primary, the second month in a season or the tertiary hydrocarbon base that is generally 1-10 carbon atom as used herein, specifically comprises methyl, CF ₃, CCl ₃, CFCl ₂, CF ₂Cl, ethyl, CH ₂CF ₃, CF ₂CF ₃, propyl group, sec.-propyl, cyclopropyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, cyclopentyl, isopentyl, neo-pentyl, hexyl, isohexyl, cyclohexyl, cyclohexyl methyl, 3-methyl amyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.That this term comprises replacement and unsubstituted alkyl and comprise haloalkyl especially and fluorinated alkyl more particularly.The limiting examples that can be used to the part of substituted alkyl is selected from halogen (fluorine, chlorine, bromine or iodine); hydroxyl, amino, alkylamino; arylamino, alkoxyl group, aryloxy; nitro, cyano group, sulfonic acid; sulfate radical, phosphonic acids, phosphate radical or phosphonate radical; itself or unprotected, or protect as required, this is known to those skilled in the art; for example, at Greene, et al.; Protective Groups in Organic Synthesis; John Wiley and Sons, Second Edition, 1991; middle instruct such is incorporated herein by reference in the lump at this.

Except that indicating in addition, as used herein term " low alkyl group " be meant the saturated straight chain that is generally 1-4 carbon atom, side chain or or the ring-type that is fit to (as, cyclopropyl) alkyl, comprise replacement and unsubstituted two kinds of situations.

Term " alkylamino " or " arylamino " refer to have respectively the substituent amino of one or two alkyl or aryl.In this application, except that special stipulation, when alkyl is the substituting group that is fit to, preferred low alkyl group.Similarly, when alkyl or low alkyl group are the substituting groups that is fit to, preferred unsubstituted alkyl or low alkyl group.

Unless otherwise defined, term " protection " refers to the group that adds on oxygen, nitrogen or phosphorus atom as used herein, with the further reaction that stops it or be used for other purpose.Known various oxygen of the technician in organic synthesis field and nitrogen-protecting group group.

Except that indicating in addition, term " aryl " refers to phenyl as used herein, xenyl or naphthyl, preferred phenyl.This term comprises replacement and unsubstituted two kinds of situations.Described aryl can be replaced by any group that is described, and includes but not limited to that one or more is selected from halogen (fluorine, chlorine; bromine or iodine), hydroxyl, amino; alkylamino, arylamino, alkoxyl group; aryloxy, nitro, cyano group; sulfonic acid, sulfate radical, phosphonic acids; phosphate radical or phosphonate radical, itself or unprotected, perhaps protect as required; this is known to those skilled in the art, for example, and Greene; et al.; Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition; 1991, middle instruction like that.

Term " alkaryl " or " alkylaryl " refer to have the alkyl of an aryl substituent.Term aralkyl or arylalkyl refer to have the aryl of an alkyl substituent.

Term " halo " comprises chlorine as used herein, bromine, iodine and fluorine.

Term " purine " or " pyrimidine " base include, but are not limited to VITAMIN B4, N ⁶-alkyl purine, N ⁶(wherein acyl group is C (O) (alkyl, aryl, an alkylaryl, or arylalkyl) to-acyl group purine, N ⁶Benzyl purine, N ⁶-halo purine, N ⁶-vinyl purine, N ⁶-acetylene type purine, N ⁶-acyl group purine, N ⁶-hydroxyalkyl purine, N ⁶-alkylamino purine, N ⁶-alkylthio purine, N ²-alkyl purine, N ²-alkyl-6-thio-purine, thymus pyrimidine, cytosine(Cyt), 5-fluoro cytosine(Cyt), 5-methylcytosine, the 6-aza-pyrimidine comprises 6-azepine cytosine(Cyt), 2-and/or 4-mercaptopyrimidine, uridylic, 5-halo uridylic comprises the 5-fluorouracil, C ⁵-alkyl pyrimidine, C ⁵-benzyl pyrimidines, C ⁵-halogenated pyrimidine, C ⁵-vinyl pyrimidine, C ⁵-acetylene type pyrimidine, C ⁵-acyl group pyrimidine, C ⁵-hydroxyalkyl purine, C ⁵-(acyl) aminopyrimidine, C ⁵-cyanopyrimidine, C ⁵-iodo-pyrimidine, C ⁶-iodo-pyrimidine, C ⁵-Br-vinyl pyrimidine, C ⁶-Br-vinyl pyrimidine, C ⁵-nitro-pyrimidine, C ⁵-amino-pyrimidine, N ²-alkyl purine, N ²-alkyl-6-thio-purine, 5-azacytidine base, 5-azauracil base, Triazolopyridine base, imidazopyridyl, pyrrolo-pyrimidine radicals and pyrazolopyrimidine base.Purine bases include, but not limited to guanine, VITAMIN B4, xanthoglobulin, 2,6-diaminopurine and 6-chloro-purine.Necessary or when needing, can protect sense oxygen and nitrogen on the base.The well-known suitable blocking group of those skilled in the art comprises three silyls, dimethyl hexyl silyl, t-butyldimethylsilyl; t-butyldiphenylsilyl, trityl, alkyl and acyl group; as ethanoyl and propionyl, methylsulfonyl, and p-toluenesulfonyl.

Term " acyl group " or " ester that O-connects " refer to have the group of formula C (O) R ', wherein R ' is a straight chain, side chain, or cycloalkyl (comprising low alkyl group), amino acid, aryl comprises phenyl, alkaryl, aralkyl comprises benzyl, and alkoxyalkyl comprises methoxymethyl, aryloxy alkyl such as phenoxymethyl; Or the alkyl (comprising low alkyl group) that replaces, aryl comprises optional by chlorine, bromine, fluorine, iodine, C ₁To C ₄Alkyl or C ₁To C ₄The phenyl that alkoxyl group replaces; sulphonate such as alkyl or aralkyl alkylsulfonyl comprise methylsulfonyl; single; two or triguaiacyl phosphate, trityl or mono methoxy-trityl, the benzyl of replacement; alkaryl; aralkyl comprises benzyl, and alkoxyalkyl comprises methoxymethyl, aryloxy alkyl such as phenoxymethyl.Aryl in the described ester preferably comprises phenyl.Particularly, acyl group comprises ethanoyl, three fluoro ethanoyl; methyl acetyl, cyclopropyl ethanoyl, cyclopropyl carboxyl; propionyl, butyryl radicals, caproyl; oenanthyl, capryloyl is new-oenanthyl; phenylacetyl, 2-acetoxyl-2-phenylacetyl, two phenylacetyl; α-methoxyl group-α-trifluoromethyl-phenylacetyl, bromo ethanoyl, 2-nitro-phenylacetyl; 4-chloro-phenylacetyl, 2-chloro-2,2-two phenylacetyl; 2-chloro-2-phenylacetyl, pivaloyl, chlorine two fluoro ethanoyl; the perfluoro ethanoyl, fluoro ethanoyl, bromine two fluoro ethanoyl; the methoxyl group ethanoyl; the 2-thiophene acetyl, chlorosulfonyl ethanoyl, 3-anisole ethanoyl; the phenoxy group ethanoyl; the tert-butyl ethanoyl, three chloro ethanoyl, monochloro-ethanoyl; the dichloro-ethanoyl; 7H-12 fluoro-oenanthyl, perfluor-oenanthyl, 7H-12-fluoro oenanthyl; 7-chlorine 12 fluoro-oenanthyl; 7-chloro-12 fluoro-oenanthyl, 7H-12 fluoro oenanthyl, 7H-12 fluoro oenanthyl; nine fluoro-3; 6-two oxa-s-oenanthyl, the ninth of the ten Heavenly Stems, fluoro-3,6-two oxa-oenanthyl; the perfluoro oenanthyl; anisoyl, methyl 3-amino-5-phenyl thiophene-2-carboxyl, 3; 6-two chloro-2-methoxyl group-benzoyls; 4-(1,1,2; 2-tetrafluoro-oxyethyl group)-benzoyl; 2-bromo-propionyl, omega-amino-capryloyl, decanoyl; positive five decanoyl; stearyl-, 3-cyclopentyl-propionyl, 1-benzene-carboxyl; O-ethanoyl Semen Armeniacae Amarum acyl group; the valeryl ethanoyl, 1-diamantane-carboxyl, hexanaphthene-carboxyl; 2; 6-pyridine dicarboxyl, cyclopropane-carboxyl, tetramethylene-carboxyl; perfluoro cyclohexyl carboxyl; the 4-methyl benzoyl, chloromethyl isoxazolyl carbonyl, perfluoro cyclohexyl carboxyl; crotonyl; 1-methyl isophthalic acid H-indazole-3-carbonyl, 2-propenyl, isovaleryl; 1-tetramethyleneimine carbonyl, 4-phenyl benzoyl.When the term acyl group was used, it referred to following concrete and content independently: ethanoyl, three fluoro ethanoyl; methyl acetyl, cyclopropyl ethanoyl, propionyl; butyryl radicals, caproyl, oenanthyl; capryloyl, new-oenanthyl, phenylacetyl; two phenylacetyl, α-trifluoromethyl-phenylacetyl, bromo ethanoyl; 4-chloro-phenylacetyl, 2-chloro-2,2-two phenylacetyl; 2-chloro-2-phenylacetyl, pivaloyl, chlorine two fluoro ethanoyl; the perfluoro ethanoyl, fluoro ethanoyl, bromine two fluoro ethanoyl; the 2-thiophene acetyl, tert-butyl ethanoyl, tribromo-acetyl base; monochloro-ethanoyl; the dichloro-ethanoyl, anisoyl, 2-bromo-propionyl; decanoyl; decanoyl just-five, stearyl-, 3-cyclopentyl-propionyl; 1-benzene-carboxyl; the valeryl ethanoyl, 1-diamantane-carboxyl, hexanaphthene-carboxyl; 2; the 6-pyrrole is than pyridine dicarboxyl, cyclopropane-carboxyl, tetramethylene-carboxyl; the 4-methyl benzoyl; crotonyl, 1-methyl isophthalic acid H-indazole-3-carbonyl, 2-propenyl; isovaleryl, 4-phenyl benzoyl.

Term " amino acid " comprises natural existence and synthetic α, β, γ or δ amino acid, includes but not limited to the amino acid of finding in albumen, i.e. glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, methionine(Met), phenylalanine, tryptophane, proline(Pro), Serine, Threonine, halfcystine, tyrosine, l-asparagine, glutamine, aspartic acid, L-glutamic acid, Methionin, arginine and Histidine.In a preferred embodiment, described amino acid is the L-configuration.Perhaps, described amino acid can be alanyl, valyl, leucyl; isoleucyl-, prolyl, phenylalanyl, tryptophyl; methionyl, glycyl, seryl, threonyl; cysteinyl, tyrosyl, asparaginyl, glutaminyl; aspartoyl, glutamy, lysyl; arginyl, histidyl-, β-alanyl; β-valyl, β-leucyl, β-isoleucyl-; β-prolyl, β-phenylalanyl, β-tryptophyl; β-methionyl, β-glycyl, β-seryl; β-threonyl, β-cysteinyl, β-tyrosyl; β-asparaginyl, β-glutaminyl, β-aspartoyl; β-glutamy, β-lysyl, the derivative of β-arginyl or β-histidyl-.Table 1-24 has listed example employed among the present invention.When term amino acid was used, it is considered to was respectively following α, β, γ or δ glycine concrete and independently content: D and L configuration, L-Ala, Xie Ansuan, leucine, Isoleucine, methionine(Met), phenylalanine, tryptophane, proline(Pro), Serine, Threonine, halfcystine, tyrosine, l-asparagine, glutamine, aspartic acid, L-glutamic acid, Methionin, the ester of arginine and Histidine.

Term " is substantially devoid of " or " not existing basically " refers to comprise that weight ratio is at least 85% or 90% in nucleotide composition, the appointment enantiomorph of preferred 95%, 98%, 99% or 100% described nucleosides as used herein.In a preferred embodiment, in method of the present invention and the compound, compound is gone up substantially and is not contained enantiomorph.

Similarly, term " isolating " refers to comprise that weight ratio is at least 85%, 90% in nucleotide composition, 95%, 98%, 99% or 100% described nucleosides, and remaining material comprises other chemical substances or enantiomorph.

" host " refers to the reproducible therein unicellular or multicellular organisms of virus, comprises clone and animal, preferred people term as used herein.Perhaps, described host's portability part flavivirus genome, it duplicates or function can be changed by compound of the present invention.The cell that the term host specifically refers to infect, with genomic all or part of cells transfected of flavivirus and animal, particularly be primates (comprising chimpanzee) and people.When application was of the present invention in most of animals, described host was people patient.Yet in some indication, the animal doctor also can use the present invention's (as being used for chimpanzee).

The term " pharmacologically acceptable salt or prodrug " that uses is in full described any pharmaceutically acceptable form of nucleoside compound (as ester, phosphoric acid ester, ester salt or relevant group), after above-mentioned all these forms is applied to the patient, provide described nucleoside compound.Pharmacologically acceptable salt comprises that those are derived from pharmaceutically acceptable inorganic or organic bases and sour salt.In well-known other acid of numerous pharmacy fields, the salt that is fit to comprises that those are derived from basic metal such as potassium and sodium, the salt of alkaline-earth metal such as calcium and magnesium.Pharmaceutically acceptable prodrug refer in host by metabolism as be hydrolyzed or oxidation to form the compound of The compounds of this invention.The functional moieties that the representative instance of prodrug is included in described active compound has the compound of biology unstable protection group.Prodrug comprises can be oxidized, reduction, amination, deaminizating, hydroxylation, dehydroxylation, hydrolysis, dehydration, alkylation, take off the compound that alkyl, acidylate, deacylated tRNA base, phosphorylation, dephosphorylation produce active compound.Compound of the present invention has the antiviral activity of anti-flavivirus coe virus, or is had this active compound by metabolism with generation.

IV. prodrug and derivative

In the receptor who is applied, described active compound can be used with the form of any salt or prodrug so that described parent compound directly or indirectly to be provided, or itself has active compound.Non-limiting instance be pharmacologically acceptable salt (perhaps referring to " acceptable salt on the physiology ") and on 5 ' position or on purine or pyrimidine bases by alkylation, acidylate or have the compound of other modification (a kind of " pharmaceutically acceptable prodrug " type).Further, described modification can influence the biologic activity of this compound, can increase active in some instances than parent compound.By preparing described salt or prodrug and testing according to method described here or other method known to those skilled in the art that it is antiviral, this compound can be easily evaluated.

A. pharmacologically acceptable salt

In some instances, when compound has enough alkalescence or acid when forming stable nontoxic acid or alkali salt, be fit to use this compound with the form of pharmacologically acceptable salt.The example of pharmacologically acceptable salt is by adding the organic acid addition salt that acid forms, acceptable negatively charged ion, for example tosylate on its formation physiology, methanesulfonate, acetate moiety, citrate, malonate, tartrate anion, amber acid radical, benzoate anion, xitix root, α-Tong Jiwuersuan root, α-Phosphoric acid glycerol esters root, formate, fumarate, propionate, ethanol acid group, lactate, acetone acid group, oxalate, maleate and salicylate.Also can form suitable inorganic salt, comprise vitriol, nitrate, supercarbonate, carbonate, hydrobromate and phosphoric acid.In an embodiment preferred, described salt is list or dihydrochloride.

Adopt standard method well-known in the art, for example, can obtain pharmacologically acceptable salt by making compound such as amine and physiologically acceptable anionic suitable acid-respons being provided with enough alkalescence.Also can obtain the basic metal (for example, sodium, potassium or lithium) or alkaline-earth metal (for example calcium) salt of carboxylic acid.In one embodiment, described salt is the hydrochloride of this compound.In another embodiment, described pharmacologically acceptable salt is a dihydrochloride.

B. Nucleotide prodrug composition

Nucleosides described here can be used with activity, bioavailability, stability that increases nucleosides or the character that changes described nucleosides by other modes by the Nucleotide prodrug forms.Known have many Nucleotide prodrug parts.Generally speaking, to described nucleosides single, two or triguaiacyl phosphate carry out alkylation, acidylate or other lipotropy and modify and can reduce its polarity and enter cell.The substituent example that can replace one or more hydrogen at phosphonate moiety is that alkyl, aryl, steroide, carbohydrate comprise sugar, 1,2-DG and alcohols.Many at R.Jones and N.Bischoferger, Antiviral Research, 1995, be described among the 27:1-17.Wherein anyly all can unite use to obtain desired effects with nucleosides disclosed herein.

Can select in the embodiment at one, described nucleosides provides with the form of phosphonic acid ester or SATE derivative.

Described active nucleosides also can be with 2 ', 3 ' and/or 5 '-phosphoric acid ether ether fat or 2 ', 3 ' and/or 5 '-form of ether fat provides.Limiting examples is described comprising in the following reference (it is incorporated herein by reference in the lump at this): Kucera, L.S., N.Iyer, E.Leake, A.Raben, Modest E.K., D.L.W., and C.Piantadosi.1990. " suppress HIV-1 and infect the ether fat analogue new and membrane interaction (Novel membrane-interactive etherlipod analogs that inhibit infectious HIV-1 production and induce defective virus formation) that produces and induce defective virus to form " AIDSRes.Hum.Retro Viruses.6:491-501; Piantadosi, C., J.Marasco C.J., S.L.Morris-Natschke, K.L.Meyer, F.Gumus, J.R.Surles, K.S.Ishaq, L.S.Kucera, N.Iyer, C.A.Wallen, S.Piantadosi, and E.J.Modest.1991. " synthetic and assessment (Synthesis andevaluation of novel ether lipid nucleoside conjugates for anti-HIV activity) " J.Med.Chem.34:1408.1414 with new ether fat nucleosides conjugates of HIV (human immunodeficiency virus)-resistant activity; Hosteller, K.Y., D.D.Richman, D.A.Carson, L.M.Stuhmiller, G.M.T.van Wijk, with H.van den Bosch.1992. " two mnyristoyl base glycerols 3 '-the deoxythymidine bisphosphate; 3 '-lipid prodrug of deoxythymidine increase greatly the restraining effect that the human immunodeficiency virus type 1 duplicates in CEM and HT4-6C cell (Greatlyenhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6Ccells by 3 '-deoxythymine diphosphate dimyristoylglycerol; a lipid produg of 3 ;-deoxythymine) ", Antimicrob.Agents Chemother..36:2025.2029; Hosetler, K.Y., L.M.Stuhmiller, H.B.Lenting, H.van den Bosch, and D.D.Richman, 1990. " but synthetic anti-retroviral activity (Synthesis and antiretroviral activity of phospholipid analogs ofazidothymine and other antiviral nucleosides) of the phospholipid analogues of azido-thymus pyrimidine and other anti-viral nucleosides " J.Biol.Chem.265:61127.The disclosed nucleosides that is covalently bound in the United States Patent (USP), preferably 2 of nucleosides ', 3 ' and/or 5 '-the suitable lipophilic substituent of OH position or the limiting examples of lipotropy preparation comprise: United States Patent (USP) the 5th, 149, No. 794 (on September 22nd, 1992, Yatvin etc.); The 5th, 194, No. 654 (on March 16th, 1993, Hostetler etc.); The 5th, 223, No. 263 (on June 29th, 1993, Hostetler etc.); The 5th, 256, No. 641 (on October 26th, 1993, Yatvin etc.); The 5th, 411, No. 947 (May 2 nineteen ninety-five, Hostetler etc.); The 5th, 463, No. 092 (October 31 nineteen ninety-five, Hostetler etc.); The 5th, 543, No. 389 (on August 6th, 1996, Yatvin etc.); The 5th, 543, No. 390 (on August 6th, 1996, Yatvin etc.); The 5th, 543, No. 391 (on August 6th, 1996, Yatvin etc.); With the 5th, 554, No. 728 (on September 10th, 1996, Basava etc.), all contents are incorporated herein by reference in the lump at this.Disclosing the lipophilic substituent that can be connected with nucleosides of the present invention or the application of lipotropy preparation in the foreign patent comprises: WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, and WO 94/26273, WO96/15132, EP 0 350 287, EP 93917054.4 and WO 91/19721.

Aryl ester, particularly phenylester also are provided.Limiting examples is disclosed in DeLambertet al., J.Med.Chem.37:498 (1994).Also provide the ortho position to be connected to the phenylester that contains carboxylicesters of phosphoric acid ester.Khamnei and Torrence，J.Med.Chem.；39：4109-4115(1996)。Particularly, provide benzyl ester, it produces described parent compound, use at the ortho position in some instances or the substituting group of contraposition to quicken hydrolysis.The case description of this class prodrug is in Mitchellet al., and J.Chem.Soc.Perkin Trans.I 2345 (1992); Brook, et al., WO 91/19721; And Glazier et al. is among the WO91/19721.

Ring-type and non-annularity phosphonic acid ester also are provided.Limiting examples is disclosed in Hunstonet al., and J.Med.Chem.27:440-444 (1984) and Starrett et al. are among the J.Med.Chem.37:1857-1864 (1994).In addition, also provide ring-type 3 ', 5 '-phosphoric acid ester.Limiting examples is disclosed in Meier et al., among the J.Med.Chem.22:811-815 (1979).Also provide ring-type 1 ', 3 '-propyl phosphonous acid ester and phosphoric acid ester, as a kind of fused-aryl ring that contains, i.e. (Meier etal., the Bioorg.Med.Chem.Lett.7:99-104 (1997)) of cyclosaligenyl ester.Also provide the ring-type 1 for preparing unsubstituted phosplate ', 3 '-propyl diester (Farquhar et al., J.Med.Chem.26:1153 (1983); Farquhar et al., J.Med.Chem.28:1358 (1985)).In addition, provide on C-1 ' ring-type 1 that replaced by new pentane acyloxy (pivaloyloxy) methoxyl group ', 3 '-propyl diester (Freed et al., Biochem.Pharmac.38:3193 (1989); Biller et al., U.S.Pat.No.5,157,027).

Known in vivo by the excision of oxidation mechanism cyclic amino phosphoric acid ester.Therefore, in one embodiment of the invention, provide 1 of various replacement ', 3 ' propyl group cyclic amino phosphoric acid ester.Limiting examples is disclosed in Zon, and Progress in Med.Chem.19 is in 1205 (1982).In addition, provide many 2 '-and 3 '-the preceding ester that replaces.2 '-substituting group comprises methyl, dimethyl, bromine, trifluoromethyl, chlorine, hydroxyl, and methoxyl group; 3 '-substituting group comprises phenyl, methyl, and trifluoromethyl, ethyl, propyl group, different-propyl group, and cyclohexyl.Also provide various 1 '-analogue that replaces.

Phosphorated cyclic ester compound also is provided.Limiting examples is described in as follows:

[1] two of phosphoric acid and three esters are reported in Nifantyev et al., Phosphorus, Sulfur Silicon and RelatedEelements, 113:1 (1996); Wijnberg et al., EP-180276 A1;

[2] three valent phosphors acid esters.Kryuchkov et al.，Izv.Akad.Nauk SSSR，Ser.Khim.6：1244(1987)。Some are required the compound that is used for asymmetric synthesis levodopa precursor protected.Sylvain et al.，DE3512781 A1；

[3] phosphoramidate.Shih et al., Bull.Inst.Chem.Acad.Sin, 41:9 (1994); Edmundson et al., J.Chem.Res.Synop.5:122 (1989); With

[4] phosphoric acid ester.Neidlein et al.，Hetreocycles 35：1185(1993).

Further, disclosing the U.S. of the cyclic amino phosphoric acid ester prodrug that is fit to and the limiting examples of international patent application comprises: Metabasis Therapeutics, No. the 6th, 312,662, the United States Patent (USP) of the Erion of Inc etc.; WO 99/45016; WO00/52015; WO 01/47935; With WO 01/18013.Especially, provide as shown in the formula the prodrug of representing:

Wherein:

By an extra 3-5 atom V and Z are joined together to form the cyclic group that contains 5-7 atom, choose wantonly and contain 1 heteroatoms, it is connected the hydroxyl on the carbon atom, acyloxy, alkoxyl group carbonyl oxygen base, or aryloxy carbonyl oxygen base replaces, and this carbon atom and two Sauerstoffatoms that are connected to phosphorus atom have the distance of three atoms; Or

By an extra 3-5 atom V and Z are joined together to form cyclic group, optionally contain 1 heteroatoms, it is fused on the aryl of the β of the oxygen that is connected in phosphorus atom and γ position;

By 3 extra carbon atoms V and W are joined together to form the optional cyclic group that contains 6 carbon atoms that replaces, and quilt is selected from hydroxyl, acyloxy, alkoxyl group carbonyl oxygen base, alkylthio carbonyl oxygen base and aryloxy carbonyl oxy substituents replace, this substituting group is connected in the described carbon atom one, and this carbon atom and the Sauerstoffatom that is connected to phosphorus atom have the distance of three atoms;

By an extra 3-5 atom Z and W are joined together to form cyclic group, optional contain a heteroatoms, and V should be aryl, the aryl of replacement, heteroaryl, or the heteroaryl that replaces;

By an extra 2-5 atom W and W ' are joined together to form cyclic group, optional contain 0-2 heteroatoms, and V should be aryl, the aryl of replacement, heteroaryl, or the heteroaryl of replacement;

Z is selected from-CHR ²OH ,-CHR ²OC (O) R ³,-CHR ²OC (S) R ³,-CHR ²OC (S) OR ³,-CHR ²OC (O) SR ³,-CHR ²OCO ₂R ³,-OR ²,-SR ²,-CHR ²N ₃,-CH ₂Aryl ,-CH (aryl) OH ,-CH (CH=CR ² ₂) OH ,-CH (C.ident.CR ²) OH ,-R ²,-NR ² ₂,-OCOR ³,-OCO ₂R ³,-SCOR ³,-SCO ₂R ³,-NHCOR ²,-NHCO ₂R ³,-CH ₂The NH aryl ,-(CH ₂) _p-OR ¹²And-(CH ₂) _p-SR ¹²

P is

integer

2 or 3;

Restrictive condition is:

A) V, Z, W, W ' are not-H entirely; With

B) as Z be-R ²The time, V, M and W ' one of at least are not-H alkyl, aralkyl, or alicyclic radical;

R ²Be selected from R ³With-H;

R ³Be selected from alkyl, aryl, alicyclic radical, and aralkyl;

R ¹²Be selected from-H and lower acyl;

M is the biologic activity agent, its by 2 ', 3 ' and/or 5 '-hydroxyl is connected on the phosphorus atom among the formula I.

V. combination therapy or alternating treatment

Active compound of the present invention can with other anti-flavivirus or seasonal febrile diseases toxic agent or particularly be anti-HCV agent Combined Preparation or alternately administration to treat any illness described here.In combination therapy, two or more medicaments of effective dose are used together, and in alternately or continuously treating, every kind of medicament of effective dose is used continuously or sequentially.Dosage depends on absorption, inactivation and the excretion rate of this medicine, depends on that also other well known to a person skilled in the art factor.It should be noted that dosage also should change to some extent along with the severity of disease that will alleviate.Be also to be understood that simultaneously for any specific patient, specific dosage regimen and administration time table should according to the needs of individuality and use or supervise the said composition administration personnel professional judgement and adjust at any time.In a preferred embodiment, have 10-15 μ M or preferred EC less than 1-5 μ M ₅₀Whose anti-HCV (or anti-pestivirus or anti-flavivirus) compound be desired.

Have realized that and after for some time, the resistance variant of flavivirus, pestivirus or HCV can occur with the antiviral agent extended treatment.The most general resistance is because due to the gene of enzyme of coding virus replication undergos mutation.By with described compound and second kind or the associating of the third antiviral compound or alternately administration, can prolong, increase or recover the usefulness of medicine anti-virus infection, can induce and the different sudden change of main drug-induced sudden change with the third antiviral compound for described second kind.Perhaps, by this type of combination therapy or alternating treatment, can change pharmacokinetics, bio distribution or other parameter of described medicine.Generally speaking, with respect to alternating treatment, usually preferred combination therapy is because combination therapy produces the multiple stress effect simultaneously to described virus.

Any antiviral agent of describing in background of the present invention can be used for combination therapy or alternating treatment with the compound of describing in specification sheets.

Limiting examples comprises:

1) proteinase inhibitor

Example comprises NS3 proteinase inhibitor (Attwoodet al, Antiviral peptide derivatives (antiviral peptide derivative), the PCT WO 98/22496,1998 based on substrate; Attwoodet al., Antiviral Chemistry and Chemotherapy1999,10,259-273; Attwoodet al., Preparation and use of amino acid derivatives as anti-viralagents (preparation and use are as a kind of amino acid derivative of antiviral agent), German patent publication No. DE 19914474; Tunget al., Inhibitiors of serine proteases, particularly hepatitis C virus NS3 protease (serine protease, the inhibitor of hepatitis C virus NS proteolytic enzyme particularly), PCT WO 98/17679), comprise alpha-keto amide and diazanyl urea (hydrazinoureas), with the inhibitor that can stop electrophilic reagent such as boric acid or phosphonate (Llinas-Brunet et al, HepatitisC inhibitor peptide analogues (hepatitis C virus inhibitors peptide analogs), PCT WO 99/07734); Based on the NS3 proteinase inhibitor of non-substrate as 2,4,6-trihydroxy--3-nitro-benzamide derivatives (Sudo K.et al, Biochemicaland Biophysical Research Communications, 1997,238,643-647; Sudo K.et al., AntiviralChemistry and Chemotherapy, 1998,9,186), comprising RD3-4082 and RD3-4078, the former is replaced by 14 carbochains on acid amides, and the latter processes Phenoxyphenyl. With Sch 68631, a kind of phenanthrenequione is a kind of inhibitor (Chu M.et al., Tetrahedron Letters 37:7229-7232,1996) of HCV proteolytic enzyme.

Sch 351633, separate from Penicillium griseofulvum (Penicillium griseofulvum), be confirmed to be a kind of proteinase inhibitor (Chu M. etc., Bioorganic and Medicinal Chemistry Letters 9:1949-1952).Eglin c separates from leech, is several serine proteases such as streptomyces griseus (S.Griseus) protease A and B, Chymetin, Chymotrypsin and subtilisin potential inhibitor.Qasim M.A.et al.，Biochemistry 36：1598-1607，1997。

The United States Patent (USP) that discloses the proteinase inhibitor that is used for the treatment of HCV comprises, for example, the United States Patent (USP) of Spruce etc. discloses the cystatin that a class is used to suppress HCV endopeptidase 2 for the 6th, 004, No. 933; The synthetic inhibitor that the United States Patent (USP) of Zhang etc. discloses hepatitis C virus NS proteolytic enzyme the 5th, 990, No. 276; No. the 5th, 538,865, the United States Patent (USP) of Reyes etc.; Corvas International, the WO 02/008251 of Inc and the WO02/08187 of Schering Corporation and WO 02/008256.HCV inhibitor peptide is disclosed in No. the 6th, 534,523, the United States Patent (USP) of Boehringer Ingelheim, among the WO 02/060926 of 6,410, No. 531 and 6,420, No. 380 and Bristol Myers Squibb.Diaryl peptides as the HCVNS3 serpin is disclosed among the WO 02/48172 of Schering Corporation.Be disclosed in as the imidazolinedione (Imidazoleidinones) of HCV NS3 serpin among the WO 02/48157 of the WO 02,/08 198 of Schering Corporation and Bristol Myers Squibb.The WO 02/48116 of the WO98/17679 of Vertex Pharmaceuticals and Bristol Myers Squibb also discloses the HCV proteinase inhibitor.

2) thiazolidine (Thiazolidines) derivative, in measuring, the reversed-phase HPLC that adopts NS3/4A fusion rotein and NS5A/5B substrate to carry out shown relevant restraining effect (Sudo K. etc., Antiviral Research, 1996,32,9-18), particularly have the compound R D-1-6250 of the cinnyl that is replaced by the chain alkyl part of fusion,, and RD4 6205 and RD46193;

3) thiazolidine and N-benzanilide (benzanilides) .J.EBS Letters 421 such as Kakiuchi N., 217-220 are seen in its affirmation; Takeshita N. etc., Analytieal Biochemistry, 1997,247,242-246;

4) phenanthrenequione (phenan-threnequinone), it shows to have the protease inhibitor activity in SDS-PAGE and autoradiograph method mensuration, by separate from the fermentation culture meat soup of streptomycete (Streptomyces sp.) (Chu M. etc., TetrahedronLetters, 1996,37,7229-7232), Sch 68631 and Sch 351633, separation is from grey Penicillium notatum (Penicilliumgriseofulvum), in flicker approximate test (SPA), demonstrate activity (Chu M. etc., Bioorganic and MedicinalChemistry Letters 9,1949-1952);

5) helicase inhibitor (for example, Diana G.D. etc., Compounds, compositions and methods fortreatment of hepatitis C, United States Patent (USP) the 5th, 633, No. 358; Diana G.D. etc., Piperidine derivatives, pharmaceutical compositions thereof and their use in the treatment of hepatitis C, PCT WO97/36554); )

6) nucleoside polymerase inhibitor and gliotoxin (.Journal of Virology such as Ferrari R., 1999,73,1649-1654) and the natural product cerulenin (Lohmann V. etc., Virology, 1998,249,108-118);

7) antisense phosphorothioate ester oligonucleotide (S-ODN) its with extend into virus 5 ' non-coding region (NCR) (Alt M. etc., Hepatology, 1995,22,707-717), or comprise 3 ' the nucleosides 326-348 that holds of NCR and nucleosides 371-388 (the Alt M. etc. that are positioned at the core encoder district of HCV RNA, Archives of Virology, 1997,142,589-599; Galderisi U. etc., Journal of Cellular Physiology, 1999,181,251-257)) sequence complementation; )

8) depend on inhibitor (Ikeda N etc., Agent for the prevention and treatment ofhepatitis C, (being used to prevent and treat the medicament of hepatitis C), the Japanese patent application publication No. JP-08268890 of the translation of IRES; Kai Y. etc., Prevention and treatment of viral diseases, (prevention of virus disease and treatment), Japanese patent application publication No. JP-10101591);

9) ribozyme, as the nuclease-resistant ribozyme (Maccjak D.J. etc., Hepatology 1999,30, summary 995) and the United States Patent (USP) the 5th, 869 of those No. the 6th, 043,077, United States Patent (USP)s that are disclosed in Barber etc. and Draper etc., No. 253 and 5,610, the content in No. 054; With

10) nucleoside analog also is developed and is used for the treatment of flaviviridae infections.

11) any compound of in the international application no WO 01/90121 of Idenix Pharmaceuticals and WO 01/92282, describing;

12) other announcement use the patent application of some nucleoside analogs treatment hepatitis C virus to comprise: BioChemPharma, (be Shire Biochem now, Inc.) (WO 01/32153 for the PCT/CA00/01316 of Ti Jiaoing for Inc.; Submitted on November 3rd, 2000) and PCT/CA01/00197 (WO 01/60315; Submit to February 19 calendar year 2001); Merck﹠amp; Co., (WO 02/057425 for the PCT/US02/01531 of Inc. submission; On January 18th, 2002 submitted to) and PCT/US02/03086 (WO02/057287; On January 18th, 2002 submitted to), (WO 02/18404 for the PCT/EP01/09633 that Roche submits to; August 21 calendar year 2001 is open), and Pharmasset, the PCT publication number WO OIT9246 of Ltd (submission on April 13 calendar year 2001), WO02/32920 (submission on October 18 calendar year 2001) and WO 02/48165.

13) the PCT publication number WO 99/43691 of Emory University, title use for " 2 '-fluoro nucleosides " disclose some 2 '-fluoro nucleosides treatment HCV.

14) other all cpds comprises: 1-amino-alkylcyclohexane (No. the 6th, 034,134, United States Patent (USP) such as Gold); alkyl lipid (No. the 5th, 922,757, United States Patent (USP) such as Chojkier); vitamin-E and other antioxidant (United States Patent (USP) the 5th such as Chojkier; 922, No. 757), shark alkene; amantadine; bile acide (United States Patent (USP) the 5th such as Ozeki; 846, No. 964), N-(phosphono ethanoyl)-L-aspartic acid; (United States Patent (USP) the 5th such as Diana; 830, No. 905), benzene two carboxamides (United States Patent (USP) the 5th such as Diana; 633; No. 388), polyadenylic acid derivative (United States Patent (USP) the 5th, 496 such as Wang; No. 546); 2 ', 3 '-didanosine (United States Patent (USP) the 5th, 026 such as Yarchoan; No. 687); benzoglyoxaline (No. the 5th, 891,874, United States Patent (USP) such as Colacino); plant extract (United States Patent (USP) the 5th such as Tsai; 837, No. 257, United States Patent (USP)s such as Omer the 5th; 725; No. 859 and United States Patent (USP) the 6th, 056; No. 961); and piperidines (piperidenes) (No. the 5th, 830,905, United States Patent (USP) such as Diana).

15) current be in clinical before or clinical development in other compound that is used for the treatment of hepatitis C virus, comprise: the interleukin 10 of Schering-Plough, the IP-501 of Interneuron, the Merimebodib of Vertex (VX-497), the AMANTADINE  (amantadine) of Endo Labs Solvay, the HEPTAZYME  of RPI, the IDN-6556 of Idun Pharma, the XTL-002 of XTL, the HCV/MF59 of Chiron, the CIVACIR  of NABI (hepatitis C virus immunoglobulin (Ig)), the LEVOVIRIN  of ICN/RIBAPHARM, the VIRAMIDINE  of ICN/RIBAPHARM, the ZADAXIN  (thymosin alpha 1) of Sci Clone, the thymosin of Sci Clone and Peg-Intron, the CEPLENE  (Peremin) of Maxim, the VX 950/LY 570310 of Vertex/Eli Lilly, the ISIS 14803 of IsisPHARMACEUTICAL/ELAN, the IDN-6556 of Idun Pharmaceuticals Inc., the JTK 003 of AKROSPharma, the BILN-2061 of Boehringer Ingelheim, the CellCept of Roche (mycophenolic acid morpholine ethyl ester), the T67 of Tularik, a kind of 'beta '-tubulin inhibitor, the treatment vaccine of Innogenetics at E2, FujisawaHealthcare, the FK788 of Inc, IdB 1016 (Siliphos, oral silymarin-phosphoric acid sleepwell phytosome (oralsilybin-phosphatdylcholine phytosome)), the rna replicon inhibitor (VP50406) of ViroPharma/Wyeth, the treatment vaccine of Intercell, the treatment vaccine of Epimmune/Genencor, the IRES inhibitor of Anadys, the ANA 245 of Anadys and ANA 246, the immunotherapy of Avant (Therapore), the proteinase inhibitor of Corvas/Schering, the helicase inhibitor of Vertex, the fusion inhibitor of Trimeris, the T cell therapy of CellExSys, the AG14361 of Biocryst, the targeted rna chemistry of PTC Therapeutics, Immtech, the dication of Int (Dication), the proteinase inhibitor of Agouron, the proteinase inhibitor of Chiron/Medivir, the antisense therapy of AVI BioPharma, the antisense therapy of Hybridon, the blood clean agent (hemopurifier) of Aethlon Medical, the treatment vaccine of Merix, the proteinase inhibitor of Bristol-MyersSquibb/Axys, the Chron-VacC of Tripep, a kind of treatment vaccine, the UT 231B of United Therapeutics, the proteolytic enzyme of Genelabs Technologies, helicase and AG14361, the IRES inhibitor of Immusol, the R803 of Rigel Pharmaceuticals, the INFERGEN  of InterMune (interferon alpha con-1), the OMNIFERON  (natural interferon) of Viragen, the ALBUFERON  of Human Genome Sciences, the REBIF  of Ares-Serono (β-1a Interferon, rabbit), ω-Interferon, rabbit of BioMedicine, the oral alpha-interferon of Amarillo Biosciences, the gamma-interferon of InterMune, τ-Interferon, rabbit and γ-1b Interferon, rabbit.

VI. pharmaceutical composition

By under the condition of pharmaceutically acceptable carrier or thinner existence, using active compound or the pharmaceutically acceptable prodrug or their salt of significant quantity to the patient, can treat by pestivirus, flavivirus, HCV or have any other illness described here or the host of other organism infection of duplicating by the RNA viruses polysaccharase that RNA relies on comprises the people, or reach the purpose of any illness described here of treatment.Described active substance can be by any suitable approach, and for example, per os, parenteral, vein, through skin, subcutaneous or local are used with the liquid or solid form.

For pestivirus, flavivirus or HCV infect, and the preferred dose of described compound is about per kilogram of body weight 1-50mg every day, and preferred 1-20mg is more typically the about 100mg of patient's per kilogram of body weight 0.1-every day.Preferred lower dosage, for example per kilogram of body weight 0.5-100mg every day, 0.5-50mg, 0.5-10mg or 0.5-5mg dosage.Even lower dosage also is effectively, so this scope can comprise per kilogram of body weight 0.1-0.5mg every day.The effective dosage ranges of pharmacologically acceptable salt and prodrug can be calculated the pharmacologically acceptable salt prodrug based on the weight of parent nucleosides to be discharged.If described salt or prodrug itself have active words, can estimate effective dose as the weight of salt as described in the above-mentioned usefulness or prodrug or by additive method well known by persons skilled in the art so.

Described compound can be used by any suitable dose unit easily, includes but not limited to contain 7-3000mg in every dose unit, preferred 70-1400mg active compound.The oral dosage of 50-1000mg is very convenient usually, comprises with 50,100 200,250,300,400,500,600,700,800,900 or one or more dosage of 1000mg.Preferred lower dosage, for example 10-100 or 1-50mg.The dosage of expection also can be 0.1-50mg or 0.1-20mg or 0.1-10.0mg.In addition, by non-oral route, under situation, can use lower dosage by injection or suction.

It is desirable to the activeconstituents used in following mode, even the plasma peak concentration of this active compound is about 0.2-70 μ M, preferably about 1.0-10 μ M.This target can be by the solution as intravenous injection 0.1-5% activeconstituents, and optional is salts solution, or reaches with the pill of using activeconstituents.

The concentration of active compound depends on absorption, inactivation and the excretion rate of this medicine in the pharmaceutical composition, depends on that also other well known to a person skilled in the art factor.It should be noted that dosage also should change to some extent along with the severity of disease that will alleviate.Should also be appreciated that simultaneously; for any specific patient; specific dosage regimen should according to the needs of individuality and use or supervise the said composition administration personnel professional judgement and adjust at any time; and aforesaid concentration range only is exemplary, and is not intended to limit the scope or the enforcement of composition required for protection.Can be disposable employed described activeconstituents, also it can be divided into several low doses and use with the different timed intervals.

The preferred modes of described active compound is an oral administration.Oral compositions generally includes inert diluent or edible carrier.It can be packed in the gelatine capsule, also it can be pressed into tablet.Be used for oral administration when treatment, can be with active compound with mixed with excipients and with tablet, lozenge or capsule form use.Also can add pharmaceutically compatible tackiness agent and/or adjuvant in the composition.

Tablet, pill, capsule, lozenge etc. can contain the compound of any following ingredients or similarity: tackiness agent such as Microcrystalline Cellulose, tragacanth or gelatin; Vehicle such as starch or lactose, disintegrating agent such as alginic acid, Primogel or W-Gum; Lubricant such as Magnesium Stearate or Sterotes; Glidant such as colloid silica; Sweeting agent such as sucrose or asccharin; Or seasonings such as spearmint oil, wintergreen oil or orange class seasonings (orange flavoring).When described unit dosage is capsule, except that the above-mentioned type material, also can contain liquid vehicle such as fatty oil.In addition, unit dosage also can contain various other materials that change the physical form of this formulation, for example steamed bun stuffed with sugar clothing, shellac or other enteric coating agent.

Also can be with described compound as component applied such as elixir (elixir), suspension agent, syrup, disk (wafer), Chewing gums.Except that described activeconstituents, syrup can contain as the sucrose of sweeting agent and some sanitas, dyes and dyestuffs and seasonings.

Described compound or its pharmaceutically acceptable prodrug or salt and other can not influenced yet they expectation function active substance or mix with the material that can replenish this expectation function, these materials such as microbiotic, anti-mycotic agent, anti-inflammatory agent or other antiviral agents comprise other nucleoside compound.Be used for parenteral, intracutaneous, solution or suspension subcutaneous or local use and can comprise following component: sterile diluent such as water for injection, salt brine solution, fixed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetics; Antiseptic-germicide such as benzylalcohol or methyl p-hydroxybenzoate; Antioxidant is as xitix or sodium bisulfite; Sequestrant such as ethylenediamine tetraacetic acid (EDTA); Buffer reagent such as acetate, Citrate trianion or phosphoric acid salt, and be used to regulate the reagent that soaks into pressure, as sodium-chlor or glucose.The parent preparation can be packed in the glass or plastic jar of ampoule, disposable syringe or multiple doses.

If by intravenous administration, preferred carrier is physiological saline or phosphate buffered saline buffer (PBS).

In a preferred embodiment, described active compound is prepared as preparation with the carrier that can protect this compound not eliminate fast in the body, these carriers such as controlled release preparation comprise implant and micro-capsule delivery system.Can adopt biodegradable and biocompatible polymkeric substance, as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, poe and poly(lactic acid).To those skilled in the art, the method for preparing this type of preparation is conspicuous.Above-mentioned substance can be available from AlzaCorporation.

Liposome suspension agent (liposome that comprises the monoclonal antibody with virus antigen of target infected cell) also is preferred pharmaceutically acceptable carrier.Can be according to method known to those skilled in the art, as be described in United States Patent (USP) the 4th, 522, the method for No. 811 (being incorporated herein by reference in the lump in full at this) prepares such preparation.For example, by suitable lipid (as stearyl phosphatide thanomin, stearyl phosphatidylcholine, arachadoyl phosphatidylcholine and cholesterol) is dissolved in the inorganic solvent, evaporation and form the exsiccant lipid membrane with the preparation Liposomal formulation then at vessel surface.The aqueous solution that in container, adds described activity or its phosplate, bisphosphate and/or triguaiacyl phosphate derivative subsequently.Then rotate container by hand and make lipid matter and vessel surface disengaging and the lipid aggregate is disperseed, form the liposome suspension agent thus.

VII. the preparation method of active compound

Can synthesize nucleosides of the present invention by any method known in the art.Particularly, the alkylation of the sugar by making suitable modification, then glycosylation or make nucleosides glycosylation alkylation more earlier can be finished the synthetic of nucleosides of the present invention.Following non-limiting embodiments has been illustrated some ordinary methods that obtain nucleosides of the present invention.

A.1 ' the conventional synthetic method of C-branched nucleosides

By one of following ordinary method, can be prepared as follows 1 of structure '-C-side chain ribonucleoside:

Wherein, base (Base), R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, Y, W ¹, W ², W ³, X, X ¹, X ²And X ³As defined herein.

1) by interior ester modified acquisition

The critical materials of this method is the lactone that suitably replaces.Described lactone can be bought acquisition, also can comprise standard epimerization, replacement and cyclization reaction preparation by any known method.According to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, in 1991 instruction like that, can choose protection wantonly to described lactone with suitable blocking group, preferred acyl group or silyl.Make the lactone of described protection and suitable coupling reagent then, as organic metal carbon nucleophile (as Grignard reagent, organolithium, dialkyl group copper lithium or the R in TBAF ⁶-SiMe ₃), in suitable aprotic solvent, coupling under suitable temperature, obtain 1 '-alkylation sugar.

Then according to the well-known method of those skilled in the art, as at Townsend Chemistry of Nucleosides and NucleotidesPlenum Press, in 1994 instruction like that, the sugared coupling that makes optional activation is on base (BASE).For example, in appropriate solvent, under the temperature that is fit to, adopt Lewis acid, as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate, the sugared coupling that acidylates is on silylated base.

Subsequently, according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, in 1991 instruction like that, instruction is such in can appointing described lactone with suitable blocking group, preferred acyl group or silyl, and nucleosides is carried out deprotection.

In a specific embodiment, 1 '-C-side chain ribonucleoside is an ideal.Flow process 1 has been showed the synthetic method of ribonucleoside.Perhaps, dezyribonucleoside also is an ideal.For obtaining these nucleosides, can be according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, the ribonucleoside that forms is chosen wantonly protection, use then suitable reductive agent reductase 12 '-OH.Randomly, to described 2 '-hydroxyl activates to help its reduction; Promptly by the Barton reduction reaction.

Flow process 1

2.1 the preparation method of other of '-C-branched nucleosides

The critical materials of this method is the hexose that suitably replaces.Described hexose can be bought acquisition, also can comprise standard epimerization (as alkaline purification), replacement and the preparation of coupling technology by any known method.Can carry out selective protection to obtain six suitable furanoses to described hexose.As at Townsend Chemistry of Nucleosides and Nucleotides, PlenumPress, in 1994 instruction like that.

Can be with 1 '-the hydroxyl optional activation is suitable leavings group, as being acyl group or halogen by acidylate or halogenation activation respectively.Then, by the well-known method of those skilled in the art, as at Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, in 1994 instruction like that, the sugared coupling that makes optional activation is on base (BASE).For example, in appropriate solvent, under the temperature that is fit to, adopt Lewis acid, as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate, the sugared coupling that acidylates is on silylated base.Perhaps, in the presence of trimethylsilyl triflate, make the halogeno-sugar coupling on silylated base.

If described 1 '-CH ₂-OH is protected, can carry out the selectivity deprotection to it according to method well-known in the art so.The primary hydroxyl that produces is functionalized to obtain various C-branched nucleosides.For example.Reductive agent with suitable is reduced to methyl with primary hydroxyl.Perhaps, before reduction, hydroxyl is activated to help its reduction, promptly by the Barton reduction reaction.In another embodiment, at first primary hydroxyl is oxidized to aldehyde, makes itself and carbon nucleophile then (as Grignard reagent, organolithium, dialkyl group copper lithium or the R in TBAF ⁶-SiMe ₃) in suitable aprotic solvent, coupling under suitable temperature.

In a specific embodiment, 1 '-C-side chain ribonucleoside is an ideal.Flow process 2 has been showed the synthetic method of ribonucleoside.Perhaps, dezyribonucleoside is an ideal.For obtaining these nucleosides, can be according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, the ribonucleoside that forms is chosen wantonly protection, use then suitable reductive agent reductase 12 '-OH.Randomly, to described 2 '-hydroxyl activates to help its reduction; Promptly by the Barton reduction reaction.

Flow process 2

In addition,, adopt corresponding L-sugar or nucleosides L-enantiomorph, can prepare the corresponding L-enantiomorph of The compounds of this invention as raw material according to identical ordinary method (1 or 2).

B.2 '-the conventional synthetic method of C-branched nucleosides

By one of following ordinary method, can be prepared as follows 2 of structure '-C-side chain ribonucleoside:

1. the sugar with suitable modification obtains the glycosylation of nuclear alkali (nucleobase)

The critical materials of this method is to have a suitable leavings group (LG), as acyl group or halogen replace have 2 '-sugar of the suitable replacement of OH and 2 '-H.Described sugar can be bought acquisition, also can comprise standard epimerization, replacement, oxidation and reduction technique preparation by any known method.Then,, adopt suitable oxygenant that the sugar of this replacement is carried out oxidation under the suitable temperature, in compatible solvent, obtain 2 '-sugar of modification.Possible oxygenant is Jones reagent (chromic acid and vitriolic mixture), section woods (Collins) reagent (two pyridine Cr (VI) oxide compounds), CoreyShi reagent (chloro chromic acid pyridine), dichromic acid pyridine, acid dichromate (acid dichromate), potassium permanganate, MnO ₂, ruthenium tetroxide, phase-transfer catalyst, as potassium permanganate, the Cl of chromic acid or polymkeric substance load ₂-pyridine, H ₂O ₂-ammonium molybdate, NaBrO ₂The HOAc solution of-CAN, NaOCl, copper chromite, cupric oxide, Raney nickel, acid chloride, Meerwein-Pang doffer-Wo Lai reagent (Meerwin-Pondorf-Verley) (trimethyl carbinol aluminium and another kind of ketone) and N-bromosuccinimide.

Then make the organo-metallic carbon nucleophile (as Grignard reagent, organolithium, dialkyl group copper lithium or the R in TBAF ⁶-SiMe ₃) with described ketone in suitable aprotic solvent, coupling under suitable temperature, produce 2 '-alkylation sugar.Then according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, JohnWiley and Sons, Second Edition, in 1991 instruction like that, optional with suitable blocking group, preferably this alkylating sugar is protected with acyl group or silyl.

Subsequently according to the well-known method of those skilled in the art, as at Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, in 1994 instruction like that, make optional sugared coupling not on base (BASE).For example, in appropriate solvent, under the temperature that is fit to, adopt Lewis acid, as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate, the sugared coupling that acidylates is on silylated base.Perhaps, in the presence of trimethylsilyl triflate, make the halogeno-sugar coupling on silylated base.

Subsequently, according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, in 1991 instruction like that, nucleosides is carried out deprotection.

In a specific embodiments, 2 '-C-side chain ribonucleoside is an ideal.Flow process 3 has been showed the synthetic method of ribonucleoside.Perhaps, dezyribonucleoside is an ideal.For obtaining these nucleosides, can be according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, the ribonucleoside that forms is chosen wantonly protection, use then suitable reductive agent reductase 12 '-OH.Randomly, to described 2 '-hydroxyl activates to help its reduction; Promptly by the Barton reduction reaction.

Flow process 3

2. the modification of preformed nucleosides

The critical materials of this method be have 2 '-nucleosides of the suitable replacement of OH and 2 '-H.Described nucleosides can be bought acquisition, also can pass through any currently known methods, comprises the preparation of standard coupling technology.Then according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, optional with suitable blocking group, preferably this nucleosides is protected with acyl group or silyl.

Under suitable temperature, in compatible solvent, adopt suitable oxygenant that the nucleosides of this due care is carried out oxidation subsequently, obtain 2 '-sugar of modification.Possible oxygenant is Jones reagent (chromic acid and vitriolic mixture), Collin's reagent (two pyridine Cr (VI) oxide compounds), ConreyShi reagent (chloro chromic acid pyridine), dichromic acid pyridine, acid dichromate (acid dichromate), potassium permanganate, MnO ₂, ruthenium tetroxide, phase-transfer catalyst, as potassium permanganate, the Cl of chromic acid or polymkeric substance load ₂-pyridine, H ₂O ₂-ammonium molybdate, NaBrO ₂The HOAc solution of-CAN, NaOCl, copper chromite, cupric oxide, Raney nickel, acid chloride, Meerwein-Pang doffer-Wo Lai reagent (Meerwin-Pondorf-Verley) (trimethyl carbinol aluminium and another kind of ketone) and N-bromosuccinimide.

In a specific embodiments, 2 '-C-side chain ribonucleoside is an ideal.Flow process 4 has been showed the synthetic method of ribonucleoside.Perhaps, dezyribonucleoside is an ideal.For obtaining these nucleosides, can be according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, the ribonucleoside that forms is chosen wantonly protection, use then suitable reductive agent reductase 12 '-OH.Randomly, to described 2 '-hydroxyl activates to help its reduction; Promptly by the Barton reduction reaction.

Flow process 4

In another embodiment of the invention, the L-enantiomorph is an ideal.Therefore,, adopt corresponding L-sugar or nucleosides L-enantiomorph, can prepare the corresponding L-enantiomorph of The compounds of this invention as starting raw material according to ordinary method as hereinbefore.

C.3 '-routine of C-branched nucleosides is synthetic

By one of following ordinary method, can be prepared as follows 3 of structure '-C-side chain ribonucleoside:

1. examine the alkali glycosylation with the sugar of suitable modification

The critical materials of this method is to have a suitable leavings group (LG), as acyl group or halogen replace have 3 '-sugar of the suitable replacement of OH and 3 '-H.Described sugar can be bought acquisition, also can comprise standard epimerization, replacement, oxidation and reduction technique preparation by any known method.Then,, adopt suitable oxygenant that the sugar of this replacement is carried out oxidation under the suitable temperature, in compatible solvent, obtain 3 '-sugar of modification.Possible oxygenant is Jones reagent (chromic acid and vitriolic mixture), section woods (Collins) reagent (two pyridine Cr (VI) oxide compounds), ConreyShi reagent (chloro chromic acid pyridine), dichromic acid pyridine, acid dichromate (acid dichromate), potassium permanganate, MnO ₂, ruthenium tetroxide, phase-transfer catalyst, as potassium permanganate, the Cl of chromic acid or polymkeric substance load ₂-pyridine, H ₂O ₂-ammonium molybdate, NaBrO ₂The HOAc solution of-CAN, NaOCl, copper chromite, cupric oxide, Raney nickel, acid chloride, Meerwein-Pang doffer-Wo Lai (Meerwin-Pondorf-Verley) reagent (trimethyl carbinol aluminium and another kind of ketone) and N-bromosuccinimide.

Then make the organo-metallic carbon nucleophile (as Grignard reagent, organolithium, dialkyl group copper lithium or the R in TBAF ⁶-SiMe ₃) with described ketone in suitable aprotic solvent, coupling under suitable temperature, produce '-C-side chain sugar.Then according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, JohnWiley and Sons, Second Edition, in 1991 instruction like that, optional with suitable blocking group, preferably this alkylating sugar is protected with acyl group or silyl.

Subsequently according to the well-known method of those skilled in the art, as at Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, in 1994 instruction like that, the sugared coupling that makes optional protection is on base (BASE).For example, in appropriate solvent, under the temperature that is fit to, adopt Lewis acid, as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate, the sugared coupling that acidylates is on silylated base.Perhaps, in the presence of trimethylsilyl triflate, make the halogeno-sugar coupling on silylated base.

After this, according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, in 1991 instruction like that, nucleosides is carried out deprotection.

In a specific embodiments, 3 '-C-side chain ribonucleoside is an ideal.Flow process 5 has been showed the synthetic method of ribonucleoside.Perhaps, dezyribonucleoside is an ideal.For obtaining these nucleosides, can be according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, the ribonucleoside that forms is chosen wantonly protection, use then suitable reductive agent reductase 12 '-OH.Randomly, to described 2 '-hydroxyl activates to help its reduction; Promptly by the Barton reduction reaction.

Flow process 5

2. the modification of preformed nucleosides

The critical materials of this method be have 3 '-nucleosides of the suitable replacement of OH and 3 '-H.Described nucleosides can be bought acquisition, also can pass through any currently known methods, comprises the preparation of standard coupling technology.Then according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, optional with suitable blocking group, preferably this nucleosides is protected with acyl group or silyl.

Under suitable temperature, in compatible solvent, adopt suitable oxygenant that the nucleosides of this due care is carried out oxidation subsequently, obtain 2 '-sugar of modification.Possible oxygenant is Jones reagent (chromic acid and vitriolic mixture), Collin's reagent (two pyridine Cr (VI) oxide compounds), ConreyShi reagent (chloro chromic acid pyridine), dichromic acid pyridine, acid dichromate (acid dichromate), potassium permanganate, MnO ₂, ruthenium tetroxide, phase-transfer catalyst, as potassium permanganate, the Cl of chromic acid or polymkeric substance load ₂-pyrrole is than pyridine, H ₂O ₂-ammonium molybdate, NaBrO ₂The HOAc solution of-CAN, NaOCl, copper chromite, cupric oxide, Raney nickel, acid chloride, Meerwein-Pang doffer-Wo Lai reagent (trimethyl carbinol aluminium and another kind of ketone) and N-bromosuccinimide.

In a specific embodiments, 3 '-C-side chain ribonucleoside is an ideal.Flow process 6 has been showed the synthetic method of ribonucleoside.Perhaps, dezyribonucleoside is an ideal.For obtaining these nucleosides, can be according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, the ribonucleoside that forms is chosen wantonly protection, use then suitable reductive agent reductase 12 '-OH.Randomly, to described 2 '-hydroxyl activates to help its reduction; Promptly by the Barton reduction reaction.

Flow process 6

D.4 '-the conventional synthetic method of C-branched nucleosides

By one of following ordinary method, can be prepared as follows 4 of structure '-C-side chain ribonucleoside:

1. obtain by glutaraldehyde (pentodialdo)-furanose modification

The critical materials of this method is glutaraldehyde (the pentodialdo)-furanose that suitably replaces.Described glutaraldehyde (pentodialdo)-furanose can be bought acquisition, also can comprise standard epimerization, replacement and cyclization reaction preparation by any known method.

In a preferred embodiment, described glutaraldehyde (pentodialdo)-furanose preparation is from the hexose that suitably replaces.Described hexose can be bought acquisition, also can comprise standard epimerization (as alkaline purification), replacement and the preparation of coupling technology by any known method.Described hexose can be a furanose form, also can be by any methods known in the art by cyclisation, and as at Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, in 1994 instruction like that, preferably by the described hexose of selective protection, to obtain six suitable furanoses.

Subsequently under suitable temperature, in compatible solvent, adopt suitable oxygenant to 4 of six furanoses '-methylol carries out oxidation, obtain 4 '-sugar of aldehyde-modification.Possible oxygenant is Swern reagent, Jones reagent (chromic acid and vitriolic mixture), Collin's reagent (two pyridine Cr (VI) oxide compounds), ConreyShi reagent (chloro chromic acid pyridine), dichromic acid pyridine, acid dichromate (acid dichromate), potassium permanganate, MnO ₂, ruthenium tetroxide, phase-transfer catalyst, as potassium permanganate, the Cl of chromic acid or polymkeric substance load ₂-pyridine, H ₂O ₂-ammonium molybdate, NaBrO ₂The HOAc solution of-CAN, NaOCl, copper chromite, cupric oxide, Raney nickel, acid chloride, Meerwein-Pang doffer-Wo Lai reagent (trimethyl carbinol aluminium and another kind of ketone) and N-bromosuccinimide, although at room temperature, in benzene/pyridine mixtures the preferred H that uses ₃PO ₄, DMSO and DCC.

After this, according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, in 1991 instruction like that, can be with suitable blocking group, preferably acyl group or silyl be chosen protection wantonly to described glutaraldehyde (pentodialdo)-furanose.Then exist under the condition of alkali; as sodium hydroxide; described protected glutaraldehyde (pentodialdo)-furanose can with the electrophilic alkyl, halo-alkyl (being CF3), alkenyl or alkynyl (the being allyl group) coupling that are fit to, obtain 4 '-alkylating sugar.Perhaps; exist under the condition of alkali; as sodium hydroxide; described protected glutaraldehyde (pentodialdo)-furanose can be with corresponding carbonyl, as the formaldehyde coupling; then under suitable polar solvent, as diox, under suitable temperature; it can be by the reduction of suitable reductive agent, obtain 4 '-alkylating sugar.In one embodiment, use PhOC (S) Cl, DMAP, preferably at room temperature in acetonitrile, then, reduce by ACCN and TMSS reflow treatment in toluene.

Subsequently according to the well-known method of those skilled in the art, as at Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, in 1994 instruction like that, the sugared coupling that makes optional activation is on base (BASE).For example, in appropriate solvent, under the temperature that is fit to, adopt Lewis acid, as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate, the sugared coupling that acidylates is on silylated base.

In a specific embodiments, 4 '-C-side chain ribonucleoside is an ideal.Flow process 6 has been showed the synthetic method of ribonucleoside.Perhaps, dezyribonucleoside is an ideal.For obtaining these nucleosides, can be according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, in 1991 instruction like that, the ribonucleoside that forms is chosen wantonly protection, use then suitable reductive agent reductase 12 '-OH.Optional, to described 2 '-hydroxyl activates to help its reduction; Promptly by the Barton reduction reaction.

In another embodiment of the invention, the L-enantiomorph is an ideal.Therefore,, adopt corresponding L-glutaraldehyde (pentodialdo)-furanose, can prepare the corresponding L-enantiomorph of The compounds of this invention as starting raw material according to ordinary method as hereinbefore.

E.2 ' and/or 3 '-the conventional synthetic method of prodrug

The crucial starting raw material of this method be suitably replace 1 ', 2 ', 3 ' or 4 '-side chain β-D or β-L nucleosides.Described branched nucleosides can be bought acquisition, also can comprise technology preparation disclosed herein by any known method.Then according to the well-known method of those skilled in the art, as at Greene et al. Protective Groups in Organic Synthesis, JohnWiley and Sons, Second Edition, in 1991 instruction like that, optional with suitable blocking group, preferably this branched nucleosides is protected with silyl.Then in suitable proton or aprotic solvent, under the temperature that is fit to; described protected branched nucleosides can with the acry radical donor that is fit to, as acyl chlorides and/or the coupling of acyl acid anhydride, obtain 1 '; 2 ', 3 ' or 4 '-2 ' and/or 3 ' prodrug of side chain β-D or β-L nucleosides.Perhaps; then in suitable aprotic solvent, under suitable temperature; optional with a kind of suitable coupler; the branched nucleosides of described protection can with suitable acyl group; as carboxylic acid, as paraffinic acid and/or amino-acid residue coupling, obtain 1 '; 2 ', 3 ' or 4 '-2 ' and/or 3 ' prodrug of side chain β-D or β-L nucleosides.Possible coupler is any reagent that helps coupling, includes but not limited to, has the Mitsunobu reagent (as di-isopropyl azodicarboxylate and azoethane dicarboxylic ester) of triphenylphosphine or various carbodiimides.

For example, in the acetonitrile-benzol mixture that refluxes, use chloride of acid can the simple amino-ethanol of esterification (referring to following flow process 7:Synthetic Communications, 1978,8 (5), 327-333; Be incorporated herein by reference in the lump at this).Perhaps, use a kind of acid anhydride to carry out esterification, it is at J Am.Chem.Soc., and 1999,121 (24), described in the 5661-5664, it is incorporated herein by reference in the lump at this.Referring to Fig. 2,3 and 4.

Flow process 7

The following example is illustrated the present invention by the mode of example.For those of ordinary skills, being understood that these embodiment can not limit the present invention and need not to deviate from the spirit and scope of the present invention can obtain in detail variation.

Embodiment 1: by 6-amino-9-(1-deoxidation-β-D-furans psicose base (psicofuranosyl)) purine preparation 1 '-C-methylribose VITAMIN B4

Measure fusing point on Mel-temp II equipment, this fusing point is uncorrected.On Bruker 400 AMX spectrometers, with 400 MHz's ¹H NMR and 100MHz's ¹³C NMR composes as internal labeling record NMR with TMS.Chemical shift (δ) is expressed as PPM (ppm), and signal indication is s (unimodal), d (bimodal), t (triplet), q (quartet), m (multiplet), or bs (wide unimodal).Change mensuration infrared (IR) spectrum on infrared (FT-IR) spectrograph at Nicolet 510P fourier.On Micromass Autospec high resolution mass spectrometer, write down mass spectrum.On Uniplates (silica gel), carry out thin-layer chromatography (TLC) analysis available from Analtech Co.Use silica gel-60 (220-440 order) carries out rapid column chromatography or uses silica gel G (TLC rank,＞440 orders) to carry out the vacuum flash chromatography.Obtain ultraviolet (UV) spectrum by Beckman DU 650 spectrophotometers.At Atlantic Microlab, Inc., Norcross, GA or Galbraith Laboratories, Inc., Knoxville carries out ultimate analysis among the TN.(Millipore Corporation, Milord MA) carry out high performance liquid chromatography (HPLC) analysis with the Waters HPLC system that Model 600 controllers, Model 996 photoelectron diode array detectors and Model 717 plus automatic samplers are housed.Millennium 2010 softwares are used to system's control, data acquisition and processing (DAP).A kind of chirality polarization (chiralyserpolarimetric) detector, (Wilton CT) is used to measure specific rotation to Perkin-Elmer Model 241MC polariscope.

Synthetic 1 '-C-methylribose-8-methyladenine

Described target compound also can be according to disclosed method (J.Farkas, and F.Sorm, " Nucleic acid componentsand their analogues.XCIV.Synthesis of 6-amino-9-(purine of 1-deoxy-β-D-psicofurannosyl) " Collect.Czech.Chem.Commun.1967 32, 2663-266; J.Farkas ", Collect.Czech.Chem.Commun.1966, 31, 1535) and preparation.(flow process 8).

Flow process 8

In similar method, but adopt suitable sugar and purine bases, can prepare the nucleosides of following formula XXIV:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y by being defined at this.

Perhaps, use suitable sugar and pyrimidine bases, can prepare the nucleosides of following formula XXV:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXVI:

Wherein, R ¹, R ², R ³, R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXVII:

Wherein, R ¹, R ², R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXVIII:

Wherein, R ¹, R ², R ⁶, X and base (Base) are in this definition.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXIX:

Wherein, R ¹, R ⁶, R ⁷, R ⁸, X, R ⁹, R ¹⁰And base (Base) is by being defined at this.

Embodiment 2: preparation 2 '-C-methylribose-8-methyladenine

Described target compound can according to disclosed method (R.E.Harry-O ' kuru, J.M.Smith, and M.S.Wolfe, " Ashort, flexible route toward 2 '-C-branched ribonucleosides ", J.Org.Chem.1997, 62, 1754-1759) preparation.(flow process 9).

Flow process 9

(a) Dess-Martin periodinane; (b) MeMgBr/TiCl ₄(c) BzCl, DMAP, Et ₃N; (d) two (trimethyl silyl) ethanamide, N ⁶-benzoyl VITAMIN B4, TMSOTf; (e) NH ₃/ MeOH

Described 2 '-branched nucleosides 3 '-prodrug can be according to disclosed method (Syntetic Communications, 1978,8 (5), 327-333; J.Am.Chem.Soc., 1999,121 (24), 5661-5664) preparation.Perhaps, described 2 '-branched nucleosides can be by not protection ground esterification (flow process 9b).(377mg, (507mg is in anhydrous tetrahydrofuran solution 2.33mmol) 2.33mmol) to join N-(uncle-butoxy carbonyl)-L-Xie Ansuan of 15ml for the phosphinylidyne diimidazole.Described mixture stirred 1 hour down at 20 ℃, stirred 10 minutes down at 50 ℃, then join 4-amino-L-(3,4-dihydroxyl-5-methylol-3-methyl-tetrahydrochysene-furans-2-yl)-1H-pyrimid-2-one (500mg, 1.95mmol), 4-(dimethylamino) pyridine (25mg, 0.195mmol), the anhydrous N of triethylamine (5mL), in the dinethylformamide solution (10mL), also stir down at 50 ℃.Described reaction mixture stirred 1 hour down at 50 ℃, then detected with HPLC.The HPLC analytical table understands that 52% product is required ester except that by product, and 17% product is a starting raw material.When with BOC-Xie Ansuan (BOC-Val) coupling, 3 of described 4-amino-1-(3,4-dihydroxyl-5-methylol-3-methyl-tetrahydrochysene-furans-2-yl)-1H-pyrimid-2-one '-OH trends towards selective reaction.

In similar method, but adopt suitable sugar and purine bases, can prepare the nucleosides of following formula XXX:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y by being defined at this.

Perhaps, use suitable sugar and pyrimidine bases, can prepare the nucleosides of following formula XXXI:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y be in this definition.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXII:

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXIII:

Wherein, R ¹, R ², R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXIV:

Wherein, R ¹, R ², R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXV:

Wherein, R ¹, R ⁶, R ⁷, R ⁹, R ¹⁰, X and base (Base) are by being defined at this.

Embodiment 3: preparation 3 '-C-methylribose-8-methyladenine

Described target compound can according to disclosed method (R.F.Nutt, M.J.Dickinson, F.W.Holly, and E.Walton, " Branched-chain sugar nucleosides.III.3 ' C-methyladenine ", J.Org.Chem.1968, 33, 1789-1795) preparation (flow process 10).

Flow process 10

(a) RuO ₂/ NaIO ₄(b) MeMgBr/TiCl ₄(c) HCl/MeOH/H ₂O; (d) BzCl/ pyrimidine; (e) AcBr, HBr/AcOH; (f) chloromercuri-6-benzoyl aminopurine; (g) NH ₃/ MeOH.

With similar method, but adopt suitable sugar and purine bases, can prepare the nucleosides of following formula XXXVI:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y by being defined at this.

Perhaps, use suitable sugar and pyrimidine bases, can prepare the nucleosides of following formula XXXVII:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXVIII:

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXIX:

Wherein, R ¹, R ², R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXX:

Wherein, R ¹, R ², R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXXI:

Wherein, R ¹, R ⁶, R ⁷, R ⁸, R ⁹, X and base (Base) are by being defined at this.

Embodiment 4: preparation 1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose-(1)

Described target compound can be according to disclosed method (Leonard, N.J.; Carraway, K.L. " 5-Amino-5-deoxyribose derivatives.Synthese and use in the preparation of " reversed " nucleosides " J.Heterocycl.Chem.1966,3,485-489) preparation.

At room temperature stir down at 0 ℃ and spend the night 50.0g (0.34mole) solution, the 100mL 2 of exsiccant D-ribose in 1.0L acetone, 2-Propanal dimethyl acetal, 200mL contain 20mL with the methyl alcohol of the saturated methyl alcohol of hydrogenchloride.The solution that produces neutralizes and reduction vaporization with pyrimidine.The oil that produces distributes between 400mL water and 400mL methylene dichloride.Water layer methylene dichloride (400mL) extracting twice.The organic extract liquid that merges is through dried over sodium sulfate and reduction vaporization.Resistates obtains 1 pure (52.1g, 75%) of brown sugar pulpous state by purification by silica gel column chromatography [elutriant: stepwise gradient (stepwise gradient) be dissolved in methyl alcohol (1-2%) in the methylene dichloride].H ¹-NMR (CDCl ₃): δ 5.00 (s, 1H, H-1), 4.86 (d, 1H, H-2, J _2-3=5.9Hz), 4.61 (d, 1H, H-3, J _3-2=5.9Hz), 4.46 (t, 1H, H-4, J _4-5=2.7Hz), 3.77-3.61 (M, 2H, H-5 and H-5 '), 3.46 (s, 1H, OCH ₃), 3.0-2.4 (brs, 1H, OH-5), 1.51 (s, 3H CH ₃), 1.34 (s, 3H CH ₃); MS (matrix GT): FAB＞0m/z 173 (M-OCH3) ⁺

Embodiment 5: preparation 1-O-methyl-2,3-O-isopropylidene-β-D-glutaraldehyde-ribofuranose-(2)

Described target compound can be according to disclosed method (Jones, G.H.; Moffatt, J.G.Oxidation of carbohydratesby the sulfoxide-carbodiimide and related methods. Oxidation withdicyclohexhylcarbodiimide-DMSO, diisopropylcarbodiimide-DMSO, acetic anhydride-DMSO, and phosphorus pentoxide-DMSO:in Methods in Carbohydrate Chemistry; Whisler, R.L.andMoffatt, J.L.Eds; Academic Press:New York, 1972; 315-322) preparation.

Twice of compound 1 usefulness Anhydrous Pyridine coevaporation.((68.2g is in the solution of dry-out benzene 0.33mole) (670mL), DMSO (500mL) and pyrimidine (13.4mL) 0.67mol) to join 1 for DCC, 137.8g for dicyclohexylcarbodiimide.For producing solution, be cooled to 0 ℃, add and contain anhydrous crystal ortho-phosphoric acid (16.4g, anhydrous DMSO (30mL) solution 0.167mmol).Under argon atmosphere, this mixture stirred 1.5 hours down and at room temperature stirred 18 hours at 0 ℃, with ethyl acetate (1000mL) dilution.(at room temperature stirred reaction mixture is 1 hour, removes by filter sedimentary dicyclohexylurea (DCU) then for 63.1g, DMSO 038mol) (30mL) solution to add oxalic acid dihydrate.Filtrate decompression is concentrated into about 600mL volume and neutralizes with saturated aqueous solution of sodium bicarbonate (400mL).Add salt solution (200mL) and (4 * 1000mL) extract organic layers with ethyl acetate.The organic layer that merges is concentrated into about 2000mL volume, before dried over sodium sulfate and reduction vaporization, with saturated aqueous solution of sodium bicarbonate (2 * 700mL) and salt solution (2 * 700mL) wash.The a fraction of residue of slightly carrying is by purification by silica gel column chromatography [elutriant: chloroform/ether, 8: 2], obtains 2 structure of light yellow solid shape. ¹H-NMR(CDCl ₃)：δ9.61(s，1H，H-5)，5.12(s，1H，H-1)，5.08(d，1H，H-2，J _2-3＝5.9Hz)，4.53(d，1H，H-3，J _3-2＝6.0 Hz)，4.51(s，1H，H-4)，3.48(s，1H，OCH ₃)，1.56(s，3H CH ₃)，1.36(s，3H CH ₃)；MS(matrix GT)：FAB＞0m/z203(M+H) ⁺，171(M-OCH ₃) ⁺。

Embodiment 6: preparation 4-C-methylol-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose-(3)

Described target compound can be according to disclosed method (Leland, D.L.; Kotick, M.P. " Studies on4-C-(hydroxymethyl) pentofuranoses. Synthesis of9-[4-C-(hydroxymethyl)-a-L-threo-pentofuranosyl] adenine " Carbohydr.Res.1974,38, C9-C11; Jones, G.H.; Taniguchi, M.; Tegg, D.; Moffatt, J.G. " 4 '-substituted nucleosides.5.Hydroxylationof nucleoside 5 '-aldehydes " J.Org.Chem.1979,44,1309-1317; Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. " Synthesis and cytotoxicity of 4 '-C-and 5 '-C-substitutedToyocamycins " Bioorg.Med.Chem.2001,9,163-170) preparation.

Interpolation sodium hydroxide in the dioxane solution (830mL) of slightly carrying raw material (2) and 37% formaldehyde (167mL) of above-mentioned acquisition (2N, 300mL).Mixture at room temperature stirs 4 hours also by adding Dowex 50 W X 2 (H ⁺Type) neutralizes.Behind the resin filter, use methanol wash, then the filtrate concentrate drying that merges and with the dehydrated alcohol coevaporation for several times.By removing by filter the sodium formiate that precipitation produces in the dehydrated alcohol, the filtrate concentrate drying, residue obtains 3 pure (42.2g by purification by silica gel column chromatography [elutriant: the methyl alcohol that is dissolved in chloroform (0-4%) of stepwise gradient], 54% from 1), it is recrystallize from hexahydroaniline.Mp=94-95 (dec.) (lit.94-96.5; 97-98:Refs:3,4), ¹H-NMR (DMSO-d ₆): δ 4.65 (s, 1H, H-1), 4.44-4.37 (m, 3H, H-2, H-3 and OH-6), 4.27 (t, 1H, OH-5, J=5.6Hz, J=6.0Hz), 3.42-3.34 (m, 2H, H-5 and H-6) 3.29 (dd, 1H, H-5 ', J _{5 '-OH}=5.4Hz, J5-5 '=11.4Hz), 3.11 (dd, 1H, H-6 ', J _{6 '-OH}=5.7Hz, J6-6 '=10.9Hz), 3.03 (s, 3H, OCH ₃), 1.48 (s, 3H CH3), 1.05 (s, 3H CH ₃); MS (matrix GT): FAB＞0m/z 469 (2M+H) ⁺, 235 (M+H) ⁺, 203 (M-OCH ₃) ⁺FAB＜0m/z233 (M-H) ^-

Embodiment 7: preparation 6-O-mono methoxy trityl-4-C-methylol-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose-(4)

Described target compound can be according to disclosed method (Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. " Synthesis and cytotoxicity of 4 '-C-and 5 '-C-substituted Toyocamycins " Bioorg.Med. Chem.2001,9,163-170) preparation.

Under+4 ℃, to 3 (add among the 41.0g, pyrimidine solution (700ml) 175mmol) the part dimethoxy trityl chloride (60.5g, 178mmol).Reaction mixture at room temperature stirred 3 hours.After adding methyl alcohol, this reaction mixture is concentrated (200ml), then with ethyl acetate (2 L) dissolving.Organic layer is with 5% sodium bicarbonate aqueous solution, water washing and through dried over sodium sulfate, then evaporate to dryness.By silica gel column chromatography pure [elutriant: ethyl acetate/hexane 15/85], obtain melicera 4 pure (63.0g, 68%). ¹H-NMR (CDCl ₃): δ 7.5-6.9 (m, 13H, MMTr), 4.89 (s, 1H, H-1), 4.72-4.62 (m, 3H, H-2, H-3 and OH-5), 3.82 (dd, 1H, H-5, J _5-OH=5.5Hz, J5-5 '=10.5Hz), 3.79 (s, 6H, OCH3), 3.54 (dd, lH, H-5 ', J _{5 '-OH}=4.9Hz, J _{5 '-5}=10.5Hz), 3.31 (s, 3H, OCH ₃), 3.24 (d, 1H, H-6, J _{6 '-6}=9.2Hz), 3.13 (d, 1H, H-6 ', J _{6 '-6}=9.2Hz), 1.24 (s, 3H CH ₃), 1.15 (s, 3H CH ₃); MS (matrix GT): FAB＞0 m/z 303 (DMTr) ⁺

Embodiment 8: preparation 5-O-benzoyl-4-C-methylol-1-O-methyl-2,3-O-isopropylidene-β-D-ribose-furanose-(5)

Under argon atmospher, ((1.09mL, 9.36mmol), reaction mixture at room temperature stirred 13 hours to add Benzoyl chloride among the 2.51g, Anhydrous Pyridine solution (37mL) 4.68mmol) to 4.Then being cooled to 0 ℃ also stops reaction with frozen water (100mL).Water layer extracts with methylene dichloride (3 200mL).The organic layer that merges with saturated aqueous solution of sodium bicarbonate (2 * 150mL), (1 * 150mL) washing is then through dried over sodium sulfate and reduction vaporization for water.Residue dissolves in 80% acetate (70.2mL), and mixture at room temperature stirred 3 hours and concentrate drying.By purification by silica gel column chromatography [elutriant: chloroform], obtain melicera 5 pure (1.40g, 88%). ¹H-NMR (CDCl ₃): δ 8.1-7.4 (m, 5H, C ₆H ₅CO), 5.08 (s, 1H, H-1), 4.77 (dd, 2H, H-2 and H-3, J=6.1Hz, J=8.2Hz), 4.51 (q, 2H, H-5 and H-5 ', J=11.5Hz, J _{5-5 '}=23.8Hz), 3.91 (t, 2H, H-6 and H-6 ', J=12.3Hz), 4.38 (s, 1H, OCH ₃), 2.2-1.8 (brs, 1H, OH-6), 1.57 (s, 3H CH ₃), 1.38 (s, 3H CH ₃); MS (matrix GT): FAB＞0 m/z 677 (2M+H) ⁺, 339 (M+H) ⁺, 307 (M-OCH ₃) ⁺, 105 (C ₆H ₅CO) ⁺FAB＜0 m/z, 121 (C ₆H ₅CO ₂) ^-

Embodiment 9: preparation 5-O-benzoyl-4-C-methyl isophthalic acid-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose-(6)

At room temperature stir 5 (37.6g, 0.111mol), the 4-Dimethylamino pyridine (DMAP, 40.7g, 0.333mol) and anhydrous acetonitrile (1000mL) of phenoxy group thiono acyl chlorides 1 hour and concentrate drying.Residue is dissolved in the methylene dichloride (500mL), then through dried over sodium sulfate, reduction vaporization and with the dry toluene coevaporation for several times before, with 0.2 M hydrochloric acid (2 * 500mL) and water (500mL) wash.Crude extract be dissolved in dry toluene (880mL) and three (trimethyl silyl) silane (TMSS, 42.9mL, 0.139mol) in, then add 1,1 '-azo two (hexahydroaniline nitrile) (ACCN, 6.8g, 27.8mmol).Reaction mixture refluxed stirred 45 minutes, then was cooled to room temperature and concentrating under reduced pressure.The residue that generates obtains yellow melicera 6 pure (26.4g, 74%) by purification by silica gel column chromatography [elutriant: the ether that is dissolved in sherwood oil (5-20%) of stepwise gradient]. ¹H-NMR (DMSO-d6): δ 8.0-7.5 (m, 5H, C ₆H ₅CO), 4.85 (s, 1H, H-1), 4.63 (dd, 2H, H-2 and H-3, J=6.1Hz, J=11.6Hz), 4.24 (d, 1H, H-5, J _{5-5 '}=11.1Hz), 4.10 (d, 1H, H-5 ', J _{5 '-5}=11.1Hz), 3.17 (s, 1H, OCH ₃), 1.38 (s, 3H CH ₃), 1.30 (s, 3H CH ₃), 1.25 (s, 3H CH ₃); MS (matrix GT): FAB＞0 m/z, 291 (M-OCH ₃) ⁺, 105 (C ₆H ₅CO) ⁺FAB＜0 m/z, 121 (C ₆H ₅CO ₂) ^-

Embodiment 10: preparation 5-O-benzoyl-4-C-methyl isophthalic acid, 2,3-O-ethanoyl-α, β-D-ribofuranose-(7)

(22.5g 70mmol) is suspended in the 80% anhydrous acetic acid solution (250mL) compound 6.Solution heated 3 hours down at 100 ℃.Liquor capacity is reduced by half and with dehydrated alcohol and pyrimidine coevaporation.The buttery residue is dissolved in the pyrimidine (280mL), then is cooled to 0 ℃.Add diacetyl oxide (80mL) and 4-dimethylamino-pyrimidine pyridine (500mg).Reaction mixture at room temperature stirred 3 hours, then concentrating under reduced pressure.Residue is with ethyl acetate (1L) dissolving, then with saturated aqueous solution of sodium bicarbonate, 1M hydrochloric acid and water washing.Organic layer is through dried over sodium sulfate and reduction vaporization.Residue obtains 7 pure (16.2g, 60%) of buff syrup shape by purification by silica gel column chromatography [elutriant: stepwise gradient be dissolved in ether (30-40%) in the sherwood oil].The raw material of small portion is by silica gel column chromatography repurity [identical elutriant: system], to separate α and β anomer.

The α anomer: ¹H-NMR (DMSO-d ₆): δ 8.1-7.5 (m, 5H, C ₆H ₅CO), 6.34 (pt, 1H, H-1, J=2.4Hz, J=2.1Hz), 5.49 (m, 2H, H-2 and H-3), 4.33 (q, 2H, H-5 and H-5 ', J=11.6Hz, J=18.7 Hz), 2.15 (s, 3H, CH ₃CO ₂), 2.11 (s, 3H, CH ₃CO ₂), 2.07 (s, 3H, CH ₃CO ₂), 1.37 (s, 3H, CH ₃); MS (matrix GT): FAB＞0m/z335 (M-CH ₃CO ₂ ^-) ⁺, 275 (M-CH ₃CO ₂ ^-+ H) ⁺, 105 (C ₆H ₅CO) ⁺, 43 (CH ₃CO) ⁺FAB＜0 m/z121 (C ₆H ₅CO ₂) ^-, 59 (CH ₃CO ₂) ^-

The β anomer: ¹H-NMR (DMSO-d ₆): δ 8.1-7.5 (m, 5H, C ₆H ₅CO), 5.99 (s, 1H, H-1), 5.46 (d, 1H, H-2, J _2-3=5.3HZ), 5.30 (d, 1H, H-2, J _2-3=5.3Hz), 4.39 (d, 1H, H-5, J _{5-5 '}=11.7 HZ), 4.19 (d, 1H, H-5 ', J _{5 '-5}=11.7Hz), 2.10 (s, 3H, CH ₃CO ₂), 2.06 (s, 3H, CH ₃CO ₂), 2.02 (s, 3H, CH ₃CO ₂), 1.30 (s, 3H, CH ₃); MS (matrix GT): FAB＞0 m/z335 (M-CH ₃CO ₂ ^-) ⁺, 275 (M-CH ₃CO ₂ ^-+ H) ⁺, 105 (C ₆H ₅CO) ⁺, 43 (CH ₃CO) ⁺FAB＜0 m/z, 121 (C ₆H ₅CO ₂) ^-, 59 (CH ₃CO ₂) ^-

Embodiment 11: preparation O-6-diphenylamino formyl radical-N ²-isobutyryl-9-(2,3-two-O-ethanoyl-5-O-benzoyl-4-C-methyl-β-D-ribose furyl)-8-methyl guanine-(18)

To O-6-diphenylamino formyl radical-8-methyl-N ²Add N in the dry toluene suspension (20mL) of-isobutyryl guanine, and two (trimethyl silyl) ethanamides of O-(1.92ML, 7.9mmol).Reaction mixture refluxed heating 1 hour.Compound 7 (1.55g 3.93mmol) is dissolved in the toluene (10mL), then add trimethyl silyl three fluoro-methanesulfonates (TMSTF) (915mL, 4.72mmol).Mixture reflux 30 minutes.Then solution is cooled to room temperature and neutralizes with 5% sodium bicarbonate aqueous solution.With ethyl acetate (200mL) diluted reaction mixture.Organic phase is with (2 * 150mL) washings of 5% sodium bicarbonate aqueous solution (150mL) and water.Organic layer is through dried over sodium sulfate and evaporate to dryness.Residue obtains 18 by purification by silica gel column chromatography [elutriant: stepwise gradient be dissolved in ether (70-90%) in the sherwood oil].

Embodiment 12: preparation 9-(4-C-methyl-β-D-ribose furyl)-8-methyl guanine-(19)

Described target compound can be according to from 18 disclosed method (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. " Synthesis of 4 '-C-methylnucleosides " Biosci.Biotechnol.Biochem.1993,57,1433-1438) preparation.

18 methanol aqueous ammonia solution (-10 ℃ of following presaturations) (20mL) stirring at room temperature spends the night.Solvent evaporated under reduced pressure, residue are distributed between methylene dichloride (60mL) and water (60mL).(2 * 60mL) wash concentrating under reduced pressure to water layer with methylene dichloride.Residue obtains 19 by RP18 column chromatography purification [elutriant: water/acetonitrile 95/5].

Embodiment 13:9-(2,3-two-O-ethanoyl-5-O-benzoyl-4-C-methyl-β-D-ribose furyl)-8-methyladenine-(20)

7 (1.10g, anhydrous acetonitrile 2.79mmol) (50ml) solution 8-methyladenine and tin tetrachloride (SnCl ₄, 660 μ L 5.58mmol) handle, and at room temperature stir and spend the night.Decompression concentrated solution, and with chloroform (100mL) dilution, then handle with cold saturated aqueous solution of sodium bicarbonate (100ml).Mixture filters through C salt, then with hot chloroform washing precipitation object.Merging filtrate, water (100ml) and salt solution (100ml) washing, through dried over sodium sulfate, reduction vaporization.Residue obtains 20 by purification by silica gel column chromatography [elutriant: stepwise gradient is dissolved in the methyl alcohol (3-5%) in the methylene dichloride].

Embodiment 14: preparation 9-(4-C-methyl-β-D-ribose furyl)-8-methyladenine-(21)

Described target compound can be according to from 20 disclosed method (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. " Synthesis of 4 ' C-methylnucleosides " Biosci.Biotechnol.Biochem.1993,57,1433-1438) preparation.

20 methanol aqueous ammonia solution (-10 ℃ of following presaturations) (50mL) stirring at room temperature spends the night.Solvent evaporated under reduced pressure, residue are distributed between methylene dichloride (100mL) and water (100mL).(2 * 100mL) wash concentrating under reduced pressure to water layer with methylene dichloride.Residue obtains 21 by purification by silica gel column chromatography [elutriant: stepwise gradient be dissolved in methyl alcohol (10-30%) in the ethyl acetate].

In a similar method, but adopt suitable sugar and purine bases, can prepare the nucleosides of following formula XXXXII:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y by being defined at this.

Embodiment 15: preparation 1-(5-O-benzoyl-4-C-methyl-2,3-O-ethanoyl-β-D-ribose furyl)-6-6-Methyl Uracil-(8)

The suspension of 6-6-Methyl Uracil with hexamethyldisilane (HMDS, 21mL) and the ammonium sulfate reflow treatment of catalytic amount 17 hours.After being cooled to room temperature, the mixture reduction vaporization obtains the residue of colorless oil, and residue is with anhydrous 1, and 2-ethylene dichloride (7.5mL) dilutes.In the solution that generates, add 7 (0.99g, 2.51mmol) anhydrous 1,2-ethylene dichloride (14mL) solution, then add trimethylsilyl triflate (TMSTf, 0.97mL, 5.02mmol).Under argon atmospher, solution at room temperature stirred 2.5 hours, then with chloroform (150mL) dilution, with the saturated aqueous solution of sodium bicarbonate and (2 * 100mL) washings of last water of same volume.Organic phase is followed reduction vaporization through dried over sodium sulfate.The residue that generates is by purification by silica gel column chromatography [elutriant: stepwise gradient be dissolved in methyl alcohol (0-2%) in the chloroform], obtains pure 8.

Embodiment 16: preparation 1-(4-C-methyl-β-D-ribose furyl)-6-6-Methyl Uracil-(9)

Described target compound can be according to from 8 disclosed method (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. " Synthesis of 4 '-C-methylnucleosides " Biosci.Biotechnol.Biochem.1993,57,1433-1438) preparation.

8 methanol aqueous ammonia solution (-10 ℃ of following presaturations) (27mL) stirring at room temperature spends the night.Solvent evaporated under reduced pressure, residue are distributed between methylene dichloride (40mL) and water (40mL).(2 * 40mL) washings, concentrating under reduced pressure is with dehydrated alcohol coevaporation several with methylene dichloride for water layer.Recrystallization from dehydrated alcohol/carbinol mixture obtains 9.

Embodiment 17: preparation 1-(5-O-benzoyl-4-C-methyl-2,3-O-ethanoyl-β-D-ribose furyl)-4-sulfo--6-methyl-uridylic-(10)

Under argon atmospher, with LawessonShi reagent (926mg, 2.29mmol) join 8 anhydrous 1, in the 2-dichloroethane solution (65mL), then reaction mixture refluxed stirs and spends the night.Solvent evaporated under reduced pressure, residue obtains 10 by purification by silica gel column chromatography [elutriant: (1-2%) the methyl alcohol chloroformic solution of stepwise gradient].

Embodiment 18: preparation 1-(4-C-methyl-β-D-ribose furyl)-4-sulfo--6-6-Methyl Uracil-(11)

10 methanol aqueous ammonia solution (-10 ℃ of following presaturations) (27mL) stirring at room temperature spends the night.Solvent evaporated under reduced pressure, residue are distributed between methylene dichloride (40mL) and water (40mL).(2 * 40mL) wash concentrating under reduced pressure to water layer with methylene dichloride.Crude extract obtains 11, freeze-drying by purification by silica gel column chromatography [elutriant: (5-7%) the methanol dichloromethane solution of stepwise gradient].

Embodiment 19: preparation 1-(4-C-methyl-β-D-ribose furyl)-6-methylcystein, salt acid type-(12)

Under 100 ℃, in the stainless steel pressure jar, compound 11 usefulness methanol aqueous ammonia solution (-10 ℃ of following presaturations) (12mL) were handled 3 hours, then were cooled to room temperature.Solvent evaporated under reduced pressure, residue are distributed between methylene dichloride (40mL) and water (40mL).(2 * 40mL) wash concentrating under reduced pressure to water layer with methylene dichloride.Crude extract is by purification by silica gel column chromatography [elutriant: methylene chloride/ammonium hydroxide 65: 30: 5].Fraction reduction vaporization in dehydrated alcohol (6.3mL) of collecting.In solution, add 2N hydrochloric acid soln (1.5mL), then stir the mixture before concentrating being depressurized.Repeat this process twice, from dehydrated alcohol, precipitate 12.

Embodiment 20: preparation 1-(5-O-benzoyl-4-C-methyl-2,3-O-ethanoyl-β-D-ribose furyl)-6-methyl thymus pyrimidine-(13)

(HMDS's suspension of 6-methyl thymus pyrimidine 17mL) spends the night with the ammonium sulfate reflow treatment of catalytic amount with hexamethyldisilane.After being cooled to room temperature, the mixture reduction vaporization obtains the residue of colorless oil, and this residue is with anhydrous 1, and 2-dichloroethane solution (6mL) dilutes.In the solution that generates, add 7 (1.0g, 2.53mmol) anhydrous 1,2-dichloroethane solution (14mL), then add trimethylsilyl triflate (TMSTf, 0.98mL, 5.06mmol).Under argon atmosphere, solution at room temperature stirred 5 hours, then with chloroform (150mL) dilution, with the saturated solution of sodium bicarbonate and (2 * 100mL) washings of last water of same volume.Organic phase is followed reduction vaporization through dried over sodium sulfate.The crude extract that produces is by purification by silica gel column chromatography [elutriant: the chloroformic solution of 2% methyl alcohol], obtains pure 13.

Embodiment 21: preparation 1-(4-C-methyl-β-D-ribose furyl)-6-methyl thymus pyrimidine-(14)

Described target compound can be according to from 13 disclosed method (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. " Synthesis of 4 '-C-methylnucleosides " Biosci.Biotechnol.Biochem.1993,57,1433-1438) preparation.

13 methanol aqueous ammonia solution (presaturation under-10C) at room temperature stirs and spends the night.Solvent evaporated under reduced pressure, residue are distributed between methylene dichloride (60mL) and water (60mL).Water layer with methylene dichloride (2 * 60mL) washings, concentrating under reduced pressure, and with the dehydrated alcohol coevaporation for several times.Recrystallization from methyl alcohol obtains 14.

Embodiment 22: preparation 1-(5,2,3-three-O-ethanoyl-4-C-methyl-β-D-ribose furyl)-6-methyl thymus pyrimidine-(15)

14 Anhydrous Pyridine solution (7.4mL) is handled with diacetyl oxide (1.2mL), and at room temperature stirs 3 hours.Solvent evaporated under reduced pressure, residue obtains 15 by purification by silica gel column chromatography [elutriant: (0-5%) the methanol dichloromethane solution of stepwise gradient].

Embodiment 23: preparation 1-(5,2,3-three-O-ethanoyl-4-C-methyl-β-D-ribose furyl)-4-sulfo--6-methyl thymus pyrimidine-(16)

Under argon atmospher, with LawessonShi reagent (119mg, 0.29mmol) join 15 anhydrous 1, in the 2-dichloroethane solution (11mL), then reaction mixture refluxed stirs and spends the night.Solvent evaporated under reduced pressure, residue obtains 16 by purification by silica gel column chromatography [elutriant: (1-2%) the methyl alcohol chloroformic solution of stepwise gradient].

Embodiment 24: preparation 1-(4-C-methyl-β-D-ribose furyl)-5-methyl-6-methylcystein-(17), salt acid type

Under 100 ℃, in the stainless steel pressure jar, compound 16 usefulness methanol aqueous ammonia solution (-10 ℃ of following presaturations) were handled 3 hours, then were cooled to room temperature.Solvent evaporated under reduced pressure, residue are distributed between methylene dichloride (30mL) and water (30mL).(2 * 30mL) wash concentrating under reduced pressure to water layer with methylene dichloride.Crude extract obtains 17 by purification by silica gel column chromatography [elutriant: 20% methanol dichloromethane solution].This compound dissolves in EtOH 100 (1.5mL), handle with 2N hydrochloric acid soln (0.3mL), be depressurized concentrate before, stir the mixture.Repeat this process twice, from dehydrated alcohol, precipitate 17.

Perhaps, use suitable sugar and pyrimidine bases, can prepare the nucleosides of following formula XXXXIII:

Wherein, R ¹, R ², R ³, X ¹, X ²With Y by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXXIV:

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXXV:

Wherein, R ¹, R ², R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXXVI:

Wherein, R ¹, R ², R ⁶, X and base (Base) are by being defined at this.

Perhaps, use suitable sugar and pyrimidine or purine bases, can prepare the nucleosides of following formula XXXXVII:

Wherein, R ¹, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, X and base (Base) are by being defined at this.

VIII. biology measuring method

Many measuring methods can be used to measure the antiviral ability of test-compound.Some of them biology measuring method has been described in the following example.

Embodiment 25: anti-flavivirus or pestivirus activity

Compound by suppress flavivirus or pestivirus polysaccharase, by other enzymes of need in the replicative cycle suppressing or by other approach, can show the activity of anti-flavivirus or pestivirus.

Nucleoside phosphorylase turns to the mensuration of active triguaiacyl phosphate

For measuring the metabolic mechanism of described compound in cell, (this cell is grown in 225cm for Rockville, HepG2 cell MD) from American Type Culture Collection in acquisition ²In the MEM that is supplemented with non-essential amino acid and 1% penicillin-Streptomycin sulphate in the tissue culture flasks, changed a subculture also weekly once in per 3 days with passage.Contacting 10 minutes with 30ml trypsinase-EDTA and with substratum continuous washing 3 times, after adherent monolayer cell breaks away from, with the HepG2 cell that merges with every hole 2.5 * 10 ⁶The concentration of individual cell is inoculated in 6 well culture plates, with 10 μ M[ ³H] active compound (500dpm/pmol) the contact certain hour of mark.These cells are remained in 37 ℃, 5%CO ₂In the environment.In selected time point, with ice-cold phosphate buffered saline buffer (PBS) washed cell 3 times.With the cell deposition thing with 60% methyl alcohol-20 ℃ of following overnight incubation, then in ice bath, extracted 1 hour with 20 μ L cold methanols, thereby extract intracellular reactive compound and metabolite thereof.The united extraction thing brushes drying down gently at filtered air stream then, is stored in-20 ℃ and carries out the HPLC analysis.

Bioavailability in macaque is measured

In research preceding 1 week of beginning, underwent operative is implanted into indwelling (chronic) ductus venosus and venae subcutaneae inlet (VAP) to the macaque body, is beneficial to blood collecting and carries out a medical examination, and comprises hematology and serum chemistry evaluation, the record body weight.Give to contain approximately in each monkey (totally 6 s') the active compound at every turn 250 μ Ci [ ³H], promptly give with the dosage of 10mg/kg concentration with 5mg/ml.The administration of process vein fast injection (3 monkeys, IV), or a process mouthful gavage administration (3 monkeys, PO).Before each administration, every administration injection device is being weighed, with the amount of the preparation determining to give.Designated time intervals (greatly before administration behind 18-0 hour, administration 0-4,4-8 and 8-12 hour), collect urine sample and handle by dish collector (pan catch).Equally, in designated time intervals (before administration, administration after 0.25,0.5,1,2,3,6,8,12 and 24 hour), by described indwelling venous catheter and VAP or under the infeasible situation of indwelling venous catheter method, collect blood sample by peripheral blood.Blood sample and urine sample are analyzed, obtained peak concentration (C _Max), reach the time (T of peak concentration _Max)))), area under curve (AUC), dose concentration transformation period (T _1/2), clearance rate (CL), stable state volume and distribution (V _Ss) and bioavailability (F).

Bone marrow toxicity is measured

By normal health volunteer collector medullary cell, according to Sommadossi J-P, Carlisle R. is at " Toxicity of3 '-azido-3 '-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl) guanine for normal humanhematopoietic progenitor cells in vitro " Antimicrobial Agents and Chemotherapy 1987; 31:452-454; With Sommadossi J-P, Schinazi RF, Chu CK, Xie M-Y " Comparison of cytotoxicity ofthe (-)-and (+)-enantiomer of 2 ', 3 '-dideoxy-3 '-thiacytidine in normal humanbone marrow protenitorcells " Biochemical Pharmacology 1992; Method described in the 44:1921-1925 is by Ficoll-Hypaque gradient centrifugation separating monocytic cell.The CFU-GM and the BFU-E that adopt double-deck soft agar or methylcellulose gum method to carry out culture measure.With tissue culture medium's dilution medicine and filtration.In 37 ℃, at the 5%CO that contains of humidifying ₂Air ambient in after 14-18 days, adopt inverted microscope to counting more than the bacterium colony of 50 cells.The result is expressed as with the solvent control culture and compares, and bacterium colony forms and suppresses per-cent in the presence of medicine.

Mitochondrial toxicity is measured

Adopt aforesaid method, in 12 well culture plates, cultivate the HepG2 cell, and according to Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer VM is at " Differential effects of antiretroviral nucleoside analogs onmitochondrial function in HepG2 cells " Antimicrob.Agents Chemother.2000; The instruction of 44:496-503 contacts the HepG2 cell with the medicine of various concentration.After contacting 4 days with medicine, adopt Boehringre lactic acid to measure lactate level in the kit measurement culture.The cell number of measuring according to hematimeter is with lactate level normalization method.

Cytotoxic assay

With cell with 5 * 10 ³-5 * 10 ⁴The amount in/hole is inoculated in the grown cultures liquid of 96 well culture plates, at 37 ℃, the CO of humidifying ₂(5%) overnight incubation in the environment.The new grown cultures liquid that adds the serial dilutions that contains medicine then.After hatching 4 days, use the 50%TCA fixed culture, with the dyeing of sulfo-rhodamine B.Measure optical density(OD) at the 550nm place.Cytotoxicity concentration is represented (CC cell number is reduced 50% required concentration ₅₀).

Cytoprotective is measured (CPA)

Basically according to Baginski, S.G.; Pevear, D.C.; SEIPEL, M.; Sun, S.C.C.; Benetatos, C.A.; Chundum, S.K.; Rice, C.M. and M.S. are at " Mechanism of action of a pestivirus antiviralcompound " PNAS USA 2000,97 (14), and the method described in the 7981-7986 is carried out this mensuration.24 hours before use, MDBK cell (ATCC) is inoculated in (4000 cells in every hole) in 96 well culture plates.With the infection multiplicity (MOI) of 0.02 plaque forming unit of each cell with BVDV (the NADL strain, ATCC) infect after, in the cell that infects and do not infect, add the serial dilutions of test-compound, the final concentration of DMSO in nutrient solution is 0.5%.Every kind of diluent is quadruplicate.Regulate the virus of cell density and inoculation, guaranteeing cell continued growth in entire test, and after infecting four days, in untreated control group, reach the cytoclasis of 90% above virus induction.After four days,, and dye with rhodamine with the fixing culture plate of 50%TCA.At the 550nm place, adopt and read the optical density(OD) that the plate instrument is read each hole.With 50% effective concentration (EC ₅₀) value defined is to make the cytotoxic effect of virus reduce by 50% compound concentrations.

The plaque number reduces to be measured

On identical two 24 well culture plates, reduce the effective concentration of measuring the detection all cpds by the plaque number.Infect with 100PFU virus pair cell individual layer in every hole.Then, in described individual layer, add the MEM serial dilutions of test-compound, be supplemented with 2% inactivated serum and 0.75% methylcellulose gum among the described MEM.Culture was further hatched 3 days in 37 ℃, then fix with 50% ethanol and 0.8% Viola crystallina, washing is also air-dry.Then plaque is counted to measure and obtain the needed concentration of 90% virus inhibition.

Output reduces to be measured

On identical two 24 well culture plates, reduce mensuration by output and detect the various required compound concentrations of viral loads minimizing 6-log that make.This is measured according to Baginski, S.G.; Pevear, D.C.; Seipel, M.; Sun, S.C.C.; Benetatos, C.A.; Chunduru, S.K.; Rice, C.M. and M.S.Collett are at " Mechanism of action of a pestivirusantiviral compound " PNAS USA 2000,97 (14), and the method described in the 7981-7986 is measured, and only carries out small change.In brief, infected 24 hours before with BVDV (NADL strain) in infection multiplicity (MOI), with MDBK cell inoculation in 24 well culture plates (2 * 105 cells in every hole) with 0.1 PFU of each cell.Add the serial dilutions of test-compound in cell, the final concentration of DMSO in grown cultures liquid is 0.5%.Every kind of diluent is triplicate.After three days, make cell culture cracking (cell monolayer and supernatant), measure by plaque viral yield is carried out quantitatively by three freeze-thaw cycle.In brief, 24 hours before use, with MDBK cell inoculation on 6 well culture plates (5 * 105 cells in every hole).Tried the lysate inoculating cell 1 hour with 0.2ml, washing and with the grown cultures based sols of 0.5% agarose shop layer.After three days,, dye to observe plaque with 1% Viola crystallina (w/v, the solution in 50% ethanol) with 3.5% formaldehyde fixed cell monolayer.The counting plaque is measured the concentration that viral load reduces 6-log.

Embodiment 26: the extracorporeal antivirus effect activity

The MT-4 that antiviral activity: HIV infects outside the test body in following clone; Vero 76, the African green monkey kidney cell that SARS infects; Bovine viral diarrhea virus infected B HK; The SB-1 that poliovirus Sabin 1 type infects; Coxsackie B virus-2, B-3, the CVB-2 that B-4 and A-9 infect, CVB-3, CVB-4, and CVA-9; REO-1 with the diplornavirus infection.Note: BVDV=bovine viral diarrhea virus; The YFV=yellow fever virus; The DENV=dengue fever virus; The WNV=west Nile virus; CVB-2=coxsackie B-2 virus; SB-1=Sabin 1 type poliovirus; With REO=double-stranded RNA reovirus.

β-D-2 '-C-methyl-7-methyl-6-phenyl-3,3a, 5,8a-tetrahydrochysene-1,3,4,5, the CC of 7a-penta-azepine-s-indacen-8-ketone (compound F 17-hydroxy-corticosterone) ₅₀And EC ₅₀Test result

	CC ₅₀	CC ₅₀	CC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀
	CC ₅₀	CC ₅₀	CC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀	EC ₅₀	Compound	MT-4	Vero 76	BHK	Sb-1	CVB-2	CVB-3	CVB-4	CVA- 9	REO-1
F	＞100	＞100	＞100	43	37	49	39	60	2	Compound	MT-4	Vero 76	BHK	Sb-1	CVB-2	CVB-3	CVB-4	CVA- 9	REO-1

β-D-2 '-C-methyl-7-methyl-6-phenyl-3,3a, 5,8a-tetrahydrochysene-1,3,4,5, the CC of 7a-penta-azepine-s-indacen-8-ketone (compound F 17-hydroxy-corticosterone) ₅₀Test result

	CC ₅₀
	CC ₅₀								Compound	BVDV	YFV	DENV	2	WNV	CVB-2	Sb-1	REO
F	＞100	10	2.5	1.3	1	37	43	2	Compound	BVDV	YFV	DENV	2	WNV	CVB-2	Sb-1	REO

Invention has been described with reference to embodiment preferred for aforementioned application people.But to those skilled in the art, it also is conspicuous can being carried out various variations and be changed by the aforementioned detailed description that the present invention is carried out.

Claims

1. the compound of formula (I):

Or its pharmacologically acceptable salt,

Wherein:

R ¹, R ²And R ³Be aryl, sulphonate, the benzyl of H, phosphoric acid ester, straight chain, side chain or cycloalkyl, acyl group, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, CO-replacement independently; wherein; phenyl is optional to be replaced by one or more substituents; this substituent comprises following: alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, lipid, amino acid, amino-acid residue, carbohydrate, peptide, cholesterol or pharmaceutically acceptable leavings group; when using in the body; described leavings group can provide a kind of compound; wherein, R ¹, R ²And/or R ³Be H or phosphoric acid ester independently;

Wherein, R ²And R ³Among at least one is not a hydrogen; With

Wherein:

X ¹Be optional alkyl, the CH that replaces of straight chain, side chain or ring-type ₃, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, CH ₂OH, the optional alkenyl that replaces, optional alkynyl, COOH, the COOR that replaces ⁴, COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH ₂, CONHR ⁴, CON (R ⁴) ₂, chlorine, bromine, fluorine, iodine, CN, N ₃, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁵With

X ²Be optional alkyl, the CH that replaces of H, straight chain, side chain or ring-type ₃, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, CH ₂OH, the optional alkenyl that replaces, optional alkynyl, COOH, the COOR that replaces ⁴, COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH ₂, CONHR ⁴, CON (R ⁴) ₂, chlorine, bromine, fluorine, iodine, CN, N ₃, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁵With

Wherein, each Y ³Be H, F, Cl, Br or I independently; With

R ⁴And R ⁵Be respectively hydrogen, acyl group, alkyl, low alkyl group, alkenyl, alkynyl or cycloalkyl independently.

2. the compound of formula (II):

Or its pharmacologically acceptable salt,

Wherein:

R ¹, R ²And R ³Be aryl, sulphonate, the benzyl of H, phosphoric acid ester, straight chain, side chain or cycloalkyl, acyl group, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, CO-replacement independently; wherein; phenyl is optional to be replaced by one or more substituent; this substituent comprises following: alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, lipid, amino acid, amino-acid residue, carbohydrate, peptide, cholesterol or pharmaceutically acceptable leavings group; when using in the body; it can provide a kind of compound; wherein, R ¹, R ²And/or R ³Be H or phosphoric acid ester independently;

Wherein, R ²And R ³Among at least one is not a hydrogen; With

Wherein:

Wherein, each Y ³Be H, F, Cl, Br or I independently; With

Each R ⁴And R ⁵Be hydrogen, acyl group, alkyl, low alkyl group, alkenyl, alkynyl or cycloalkyl independently.

3. formula (III), (IV) or compound (V):

Or their pharmacologically acceptable salt, wherein:

R ¹, R ²And R ³Be aryl, sulphonate, the benzyl of H, phosphoric acid ester, straight chain, side chain or cycloalkyl, acyl group, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, CO-replacement independently; wherein; phenyl is optional to be replaced by one or more substituent; this substituent comprises following: alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, lipid, amino acid, amino-acid residue, carbohydrate, peptide, cholesterol or pharmaceutically acceptable leavings group; when using in the body; described leavings group can provide a kind of compound; wherein, R ¹, R ²And/or R ³Be H or phosphoric acid ester independently;

R wherein ²And R ³Among at least one is not a hydrogen; With

Wherein:

Base is selected from the group of being made up of following:

Each R ⁴And R ⁵Be hydrogen, acyl group, alkyl, low alkyl group, alkenyl, alkynyl or cycloalkyl independently;

Each W ¹, W ², W ³And W ⁴Be N, CH, CF, CI, CBr, CCl, CCN, CCH independently ₃, CCF ₃, CCH ₂CH ₃, CC (O) NH ₂, CC (O) NHR ⁴, CC (O) N (R ⁴) ₂, CC (O) OH, CC (O) OR ⁴Or CX ³

Each W ^*Be O, S, NH or NR independently ⁴

X ^*Be CH, CF, CY ³Or CR ⁴

X ²Be optional alkyl, the CH that replaces of H, straight chain, side chain or ring-type ₃, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, CH ₂OH, the optional alkenyl that replaces, optional alkynyl, COOH, the COOR that replaces ⁴, COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH ₂, CONHR ⁴, CON (R ⁴) ₂, chlorine, bromine, fluorine, iodine, CN, N ₃, OH, OR ⁴, NH ₂, NHR ⁴, NR ⁴R ⁵, SH or SR ⁵

Each X ³Be optional alkyl, the CH that replaces of straight chain, side chain or ring-type independently ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, optional alkynyl, halo alkynyl, the N that replaces ₃, CN ,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂, OH, OR ⁴,-O (acyl group) ,-O (lower acyl) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), chlorine, bromine, fluorine, iodine, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) or-N (acyl group) ₂

Each Y is independently selected from by H, optional low alkyl group, cycloalkyl, alkenyl, alkynyl, the CH that replaces ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCONH ₂, (CH ₂) _mCONR ₂(CH ₂) _mThe group that CONHR forms;

R is H, alkyl or acyl group;

Each Y ²Be O, S, NH or NR independently ⁴With

Each Y ³Be H, F, Cl, Br or I independently;

Wherein, if W ¹, W ²And W ³Be N, for base (B), W ⁴Can not be CH;

Wherein, if W ¹Be N, for base (E), (F), (K), (L), (W) with (X), W ⁴Can not be CH;

Each R ⁶Be optional alkyl, the CH that replaces independently ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂Or cyano group;

Each R ⁷Be OH, OR independently ², optional alkyl, the CH that replaces ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl, the optional carbocyclic ring that replaces, the optional heterocycle that replaces, the optional heteroaryl that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (acyl group) ,-O (lower acyl) ,-O (R ⁴) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), NO ₂, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂, azido-, cyano group, SCN, OCN, NCO or halogen;

Perhaps, R ⁶And R ⁷Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming spirocyclic compound; And

Each m is 0,1 or 2 independently.

4. formula (VI) or compound (VII):

Or their pharmacologically acceptable salt,

Wherein:

R ¹Be aryl, sulphonate, the benzyl of H, phosphoric acid ester, straight chain, side chain or cycloalkyl, acyl group, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, CO-replacement; wherein; phenyl is optional to be replaced by one or more substituting groups; this substituting group comprises following: alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, lipid, amino acid, amino-acid residue, carbohydrate, peptide, cholesterol or pharmaceutically acceptable leavings group; when using in the body; described leavings group can provide a kind of compound; wherein, R ¹Be H or phosphoric acid ester; And,

Wherein:

Base is selected from the group of being made up of following:

Each W ¹, W ², W ³And W ⁴Be N independently, CH, CF, CI, CBr, CCl, CCN, CCH ₃, CCF ₃, CCH ₂CH ₃, CC (O) NH ₂, CC (O) NHR ⁴, CC (O) N (R ⁴) ₂, CC (O) OH, CC (O) OR ⁴Or CX ³

Each W ^*Be O, S, NH or NR independently ⁴

X ^*Be CH, CF, CY ³Or CR ⁴

R is H, alkyl or acyl group;

Each Y ²Be O, S, NH or NR independently ⁴With

Each Y ³Be H, F, Cl, Br or I independently;

Wherein, if W ¹, W ²And W ³Be N, for base (B), W ⁴Can not be CH;

Each R ⁶Be optional alkyl, the CH that replaces independently ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH2) _mC (O) OH ,-(CH2) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) 2 ,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂Or cyano group;

Perhaps, R ⁶And R ⁷Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming spirocyclic compound;

Each R ⁸And R ¹¹Be hydrogen, optional alkyl, the CH that replaces independently ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂, cyano group, NH-acyl group or N (acyl group) ₂

Each R ⁹And R ¹⁰Be hydrogen, OH, OR independently ², optional alkyl, the CH that replaces ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl, the optional carbocyclic ring that replaces, the optional heterocycle that replaces, the optional heteroaryl that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂, (CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂, C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (acyl group) ,-O (lower acyl) ,-O (R ⁴) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), NO ₂, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR ⁴R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂, azido-, cyano group, SCN, OCN, NCO or halogen;

Each m is 0,1 or 2 independently; With

Perhaps, R ⁶And R ¹⁰, R ⁷And R ⁹, R ⁸And R ⁷Or R ⁹And R ¹¹Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming the bridging compound, perhaps, R ⁶And R ⁷Or R ⁹And R ¹⁰Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming spirocyclic compound.

5. formula (VIII), IX) or compound (X):

Or their pharmacologically acceptable salt, wherein:

R ¹, R ²And R ³Be aryl, sulphonate, the benzyl of H, phosphoric acid ester, straight chain, side chain or cycloalkyl, acyl group, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, CO-replacement independently; wherein phenyl is optional is replaced by one or more substituent; this substituent comprises following: alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, lipid, amino acid, amino-acid residue, carbohydrate, peptide, cholesterol or pharmaceutically acceptable leavings group; when using in the body; described leavings group can provide a kind of compound; wherein, R ¹, R ²And/or R ³Be H or phosphoric acid ester independently;

Wherein, R ²And R ³Among at least one is not a hydrogen; With

X ^*Be CH, CF, CY ³Or CR ⁴

Each Y ³Be H, F, Cl, Br or I independently;

Base ^*Be purine or pyrimidine bases;

Each R ¹²Be alkyl, the CH that replaces independently ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, replace alkenyl, halogenated alkenyl (but not being the Br-vinyl), the alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂

Each R ¹³Be alkyl, the CH that replaces independently ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, replace alkenyl, halogenated alkenyl (but not being the Br-vinyl), the alkynyl that replaces, halo alkynyl, the optional carbocyclic ring that replaces, the optional heterocycle that replaces, the optional heteroaryl that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mCO) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (R ⁴) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl) ,-NHR ⁴,-NR ⁴R ⁵,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl), SCN, OCN, NCO or fluorine;

Perhaps, R ¹²And R ¹³Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming spirocyclic compound; With

Each m is 0,1 or 2 independently.

6. formula (XI) or compound (XII):

Or their pharmacologically acceptable salt, wherein:

R ¹Be aryl, sulphonate, the benzyl of H, phosphoric acid ester, straight chain, side chain or cycloalkyl, acyl group, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy alkyl, CO-replacement; wherein; phenyl is optional to be replaced by one or more substituent; this substituent comprises following: alkyl sulphonyl, aryl sulfonyl, aralkyl alkylsulfonyl, lipid, amino acid, amino-acid residue, carbohydrate, peptide, cholesterol or pharmaceutically acceptable leavings group; when using in the body; described leavings group can provide a kind of compound; wherein, R ¹Be H or phosphoric acid ester;

Base is selected from the group of being made up of following:

Each W ¹, W ², W ³And W ⁴Be N, CH, CF, CI, CBr, CCl, CCN, CCH independently ₃, CC _F3, CCH ₂CH ₃, CC (O) NH ₂, CC (O) NHR ⁴, CC (O) N (R ⁴) ₂, CC (O) OH, CC (O) OR ⁴Or CX ³

Each W ^*Be O, S, NH or NR independently ⁴

X ^*Be CH, CF, CY ³Or CR ⁴

Each X ³Be optional alkyl, the CH that replaces of straight chain, side chain or ring-type independently ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, optional alkynyl, halo alkynyl, the N that replaces ₃, CN ,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂, OH, OR ⁴,-O (acyl group) ,-O (lower acyl) ,-O (alkyl) ,-O (low alkyl group) ,-O (alkenyl) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl), chlorine, bromine, fluorine, iodine, NH ₂,-NH (low alkyl group) ,-NHR ⁴,-NR4R ⁵,-NH (acyl group) ,-N (low alkyl group) ₂,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl) ,-N (acyl group) ₂

Each Y is selected from by H, optional low alkyl group, cycloalkyl, alkenyl, alkynyl, the CH that replaces ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCONH ₂, (CH ₂) _mCONR ₂(CH ₂) _mThe group that CONHR forms;

R is H, alkyl or acyl group;

Each Y ²Be O, S, NH or NR independently ⁴With

Each Y ³Be H, F, Cl, Br or I independently;

Wherein, if W ¹, W ²And W ³Be N, for base (B), W ⁴Can not be CH;

Each R ¹³Be alkyl, the CH that replaces independently ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂Cl, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, replace alkenyl, halogenated alkenyl (but not being the Br-vinyl), the alkynyl that replaces, halo alkynyl, the optional carbocyclic ring that replaces, the optional heterocycle that replaces, the optional heteroaryl that replaces ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) SH ,-CH ₂C (O) SR ⁴,-CH ₂C (O) S (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) SH ,-(CH ₂) _mC (O) SR ⁴,-(CH ₂) _mC (O) S (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) SH ,-C (O) SR ⁴,-C (O) S (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂,-O (R ⁴) ,-O (alkynyl) ,-O (aralkyl) ,-O (cycloalkyl) ,-S (acyl group) ,-S (lower acyl) ,-S (R ⁴) ,-S (low alkyl group) ,-S (alkenyl) ,-S (alkynyl) ,-S (aralkyl) ,-S (cycloalkyl) ,-NHR ⁴,-NR ⁴R ⁵,-NH (alkenyl) ,-NH (alkynyl) ,-NH (aralkyl) ,-NH (cycloalkyl), SCN, OCN, NCO or fluorine; With

Perhaps, R ¹²And R ¹³Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming spirocyclic compound;

Each R ⁸And R ¹¹Be hydrogen, optional alkyl, the CH that replaces independently ₃, CH ₂CN, CH ₂N ₃, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂OH, haloalkyl, CF ₃, C (Y ³) ₃, 2-Br-ethyl, CH ₂F, CH ₂CI, CH ₂CF ₃, CF ₂CF ₃, C (Y ³) ₂C (Y ³) ₃, the optional alkenyl that replaces, halogenated alkenyl, Br-vinyl, the optional alkynyl that replaces, halo alkynyl ,-CH ₂C (O) OH ,-CH ₂C (O) OR ⁴,-CH ₂C (O) O (low alkyl group) ,-CH ₂C (O) NH ₂,-CH ₂C (O) NHR ⁴,-CH ₂C (O) NH (low alkyl group) ,-CH ₂C (O) N (R ⁴) ₂,-CH ₂C (O) N (low alkyl group) ₂,-(CH ₂) _mC (O) OH ,-(CH ₂) _mC (O) OR ⁴,-(CH ₂) _mC (O) O (low alkyl group) ,-(CH ₂) _mC (O) NH ₂,-(CH ₂) _mC (O) NHR ⁴,-(CH ₂) _mC (O) NH (low alkyl group) ,-(CH ₂) _mC (O) N (R ⁴) ₂,-(CH ₂) _mC (O) N (low alkyl group) ₂,-C (O) OH ,-C (O) OR ⁴,-C (O) O (low alkyl group) ,-C (O) NH ₂,-C (O) NHR ⁴,-C (O) NH (low alkyl group) ,-C (O) N (R ⁴) ₂,-C (O) N (low alkyl group) ₂, cyano group, NH-acyl group or N (acyl group) ₂

Each m is 0,1 or 2 independently; With

Perhaps, R ⁸And R ¹³, R ⁹And R ¹³, R ⁹And R ¹¹Or R ¹⁰And R ¹²Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming the bridging compound; Or

Perhaps, R ¹²And R ¹³Or R ⁹And R ¹⁰Can be selected from the group of forming by optional carbocyclic ring that replaces or the optional heterocycle that replaces in conjunction with forming spirocyclic compound.

7. formula (XIII) or compound (XIV):

Or their pharmacologically acceptable salt, wherein:

R ³Be to be selected from by H, list, two and triguaiacyl phosphate or stable phosphoric acid ester prodrug, acyl group, sulphonate, the optional alkyl sulphonyl that replaces, optional aryl sulfonyl, lipid, amino acid, carbohydrate, peptide, cholesterol and the pharmaceutically acceptable leavings group that replaces; when using in the body; described leavings group can provide a kind of compound; wherein, R ³Be independently H or single, two and triguaiacyl phosphate;

B represents a kind of spirocyclic compound, is selected from the group of being made up of optional carbocyclic ring that replaces or the optional heterocycle that replaces;

Base is selected from the group of being made up of following:

With

Wherein,

Each R ', R ", R  and R " " be independently be selected from by H, OH, replacement or unsubstituted alkyl, replacement or unsubstituted alkenyl, replacement or unsubstituted alkynyl, cycloalkyl, Br-vinyl ,-O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl ,-O-acyl group, O-cycloalkyl, NH ₂, NH-alkyl, N-dialkyl group, NH-acyl group, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl group, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH ₂, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, OH, CF ₃, CH ₂OH, (CH ₂) _mOH, (CH ₂) _mNH ₂, (CH ₂) _mCOOH, (CH ₂) _mCN, (CH ₂) _mNO ₂(CH ₂) _mCONH ₂The group of forming;

M is 0 or 1;

W is C-R " or N;

T and V are CH or N independently;

Q be CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂, or N;

Q ₁And Q ₂Be N or C-R independently;

R is H, alkyl or acyl group; With

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently.

8. formula (XIX), (XX), (XXI), (XXII) or compound (XXIII):

Or their pharmacologically acceptable salt, wherein:

A is selected from low alkyl group, cycloalkyl, alkenyl, alkynyl, the CH that is replaced by optional ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂(CH ₂) _mThe group that CONHR forms;

Y is selected from by H, optional low alkyl group, cycloalkyl, alkenyl, alkynyl, the CH that replaces ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂(CH ₂) _mThe group that CONHR forms;

R is H, alkyl or acyl group;

X be selected from by-OH, the optional alkyl that replaces, cycloalkyl, alkenyl, alkynyl ,-the O-alkyl ,-the O-alkenyl ,-the O-alkynyl ,-the O-aryl ,-the O-aralkyl ,-the O-cycloalkyl-, O-acyl group, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO ₂, NH ₂, N ₃, NH-acyl group, NH-alkyl, N-dialkyl group, NH-alkenyl, NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-aralkyl, S-acyl group, S-cycloalkyl, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH, CH ₂NH ₂, CH ₂NHCH ₃, CH ₂N (CH ₃) ₂, CH ₂F, CH ₂Cl, CH ₂N ₃, CH ₂CN, CH ₂CF ₃, CF ₃, CF ₂CF ₃, CH ₂CO ₂R, (CH ₂) _mCOOH, (CH ₂) _mCOOR, (CH ₂) _mCO-NH ₂, (CH ₂) _mCONR ₂, (CH ₂) _mCONHR, 3-7 unit's carbocyclic ring of choosing replacement wantonly and optional having O, S and/or N independence or uniting first heterocycle of replacing as heteroatomic 3-7;

M is 0 or 1;

R ₃Be be selected from by H, list, two and triguaiacyl phosphate or stable phosphoric acid ester prodrug, replacement or unsubstituted alkyl, acyl group, sulphonate, the optional alkyl sulphonyl that replaces, optional aryl sulfonyl, lipid, amino acid, carbohydrate, peptide, cholesterol and the pharmaceutically acceptable leavings group that replaces; when using in the body; described leavings group can provide a kind of compound; wherein, R ₃Be independently H or single, two and triguaiacyl phosphate; With

The natural base of base right and wrong is selected from the group of being made up of following:

Wherein:

Each R ', R ", R  and R " " be independently selected from by H, OH, replacement or unsubstituted alkyl, replacement or unsubstituted alkenyl, replacement or unsubstituted alkynyl, cycloalkyl, Br-vinyl ,-O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl ,-O-acyl group, O-cycloalkyl, NH ₂, NH-alkyl, N-dialkyl group, NH-acyl group, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl group, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH ₂, CO ₂-alkyl, CONH-alkyl, CON-dialkyl group, OH, CF ₃, CH ₂OH, (CH ₂) _mOH, (CH ₂) _mNH ₂, (CH ₂) _mCOOH, (CH ₂) _mCN, (CH ₂) _mNO ₂(CH ₂) _mCONH ₂The group of forming;

M is 0 or 1;

W is C-R " or N;

T and V are CH or N independently;

Q be CH ,-CCl ,-CBr ,-CF ,-CI ,-CCN ,-C-COOH ,-C-CONH ₂Or N;

Q ₁And Q ₂Be N or C-R independently " "; With

Q ₃, Q ₄, Q ₅And Q ₆Be N or CH independently;

Restrictive condition is, in base (g) with (i), and R ', R " " not H, OH or NH ₂With Q, T, V, Q ₂, Q ₅And Q ₆Not N.

9. the compound of formula (IX):

Or its pharmacologically acceptable salt, wherein:

X is O, S, SO ₂Or CH ₂

Base ^*Be purine or pyrimidine bases;

R ¹²Be C (Y ³) ₃

Y ³Be H, F, Cl, Br or I independently; With

R ¹³It is fluorine.

10. the compound of claim 9, wherein, X is O, and Y ³Be H.

11. the compound of claim 10, wherein, R ¹, R ²And R ³Be H.

12. treat the method that infects the host that flaviviridae is arranged, comprise claim 1-11 significant quantity each administered compound or its pharmacologically acceptable salt for one kind.

13. the method for claim 12, wherein, described virus is hepatitis C virus.

14. the method for claim 12, wherein, described compound or pharmaceutically acceptable salt thereof and second kind of antiviral agent Combined Preparation or alternately administration.

15. the method for claim 14, wherein, described second kind of antiviral agent is selected from by Interferon, rabbit, ribavirin, interleukin-, NS3 proteinase inhibitor, cystatin, phenanthrenequione, tetrahydrothiazole derivates, thiazolidine, N-benzanilide, phenanthrenequione, helicase inhibitor, AG14361, nucleotide analog, gliotoxin, cerulenin, antisense phosphorothioate ester oligodeoxynucleotide, the inhibitor of translation that depends on IRES and the group that ribozyme is formed.

16. the method for claim 15, wherein, described second kind of antiviral agent is Interferon, rabbit.

17. the method for claim 16, wherein, another kind of antiviral agent is selected from by α-2a Interferon, rabbit, alphacon-1 Interferon, rabbit, natural interferon, albuferon, β-1a Interferon, rabbit, ω-Interferon, rabbit, alpha-interferon, gamma-interferon, τ-Interferon, rabbit, the δ-Interferon, rabbit of Pegylation and the group that γ-the 1b Interferon, rabbit is formed.

18. the method for claim 12, wherein, described compound or pharmaceutically acceptable salt thereof is a dosage unit form.

19. the method for claim 18, wherein, described dose unit contains the described compound of 50-1000mg or 0.1-50mg.

20. the method for claim 18, wherein, described dose unit is tablet or capsule.

21. the method for claim 12, wherein, the host is the people.

22. the method for claim 12, wherein, described compound or pharmaceutically acceptable salt thereof is pure basically form.

23. the method for claim 12, wherein, the weight of described compound or pharmaceutically acceptable salt thereof at least 90% is β-D-isomer.

24. the method for claim 12, wherein, the weight of described compound or pharmaceutically acceptable salt thereof at least 95% is β-D-isomer.

25. the method for claim 12, wherein, described compound is a pharmaceutical acceptable salt, be selected from by benzene sulfonate, mesylate, acetate, Citrate trianion, malonate, tartrate, succinate, benzoate, vitamins C, alpha-ketoglutarate, alpha-phosphate glycerine, formate, fumarate, propionic salt, glycol hydrochlorate, lactic acid salt, pyruvate salt, oxalate, maleate, salicylate, vitriol, nitrate, supercarbonate, carbonate, hydrobromate, hydrochloride, dihydrochloride and phosphoric acid salt.

26. the method for claim 25, wherein, described pharmacologically acceptable salt is a hydrochloride.

27. pharmaceutical composition, comprise each compound or pharmaceutically acceptable salt thereof of claim 1-11, wherein, described compound or pharmaceutically acceptable salt thereof contains promising significant quantity for the treatment of flaviviridae infections, and described compound or pharmaceutically acceptable salt thereof is contained in pharmaceutically acceptable carrier.

28. the pharmaceutical composition of claim 27, wherein, described carrier is suitable for oral administration.

29. the pharmaceutical composition of claim 27, significant quantity inclusion compound or its pharmacologically acceptable salt, wherein, described pharmaceutical composition can be treated and be infected the host that west Nile virus, yellow fever virus, dengue fever virus or BVDV are arranged.

30. the composition of claim 27, wherein, flaviviridae is a hepatitis C virus.

31. the pharmaceutical composition of claim 29, wherein, described compound or pharmaceutically acceptable salt thereof is a dosage unit form.

32. the composition of claim 31, wherein, described dose unit contains the described compound or pharmaceutically acceptable salt thereof of 0.1-50mg or 50-1000mg.

33. the composition of claim 31, wherein, described dose unit is tablet or capsule.

34. the pharmaceutical composition of claim 27 further comprises second kind of antiviral agent.

35. the pharmaceutical composition of claim 34, wherein, described second kind of antiviral agent is selected from by Interferon, rabbit, ribavirin, interleukin-, NS3 proteinase inhibitor, cystatin, phenanthrenequione, tetrahydrothiazole derivates, thiazolidine, N-benzanilide, phenanthrenequione, helicase inhibitor, AG14361, nucleotide analog, gliotoxin, cerulenin, antisense phosphorothioate ester oligodeoxynucleotide, the inhibitor of translation that depends on IRES and the group that ribozyme is formed.

36. the pharmaceutical composition of claim 35, wherein, described second kind of antiviral agent is Interferon, rabbit.

37. the pharmaceutical composition of claim 36, wherein, described second kind of antiviral agent is selected from by α-2a Interferon, rabbit, alphacon-1 Interferon, rabbit, natural interferon, albuferon, β-1a Interferon, rabbit, ω-Interferon, rabbit, alpha-interferon, gamma-interferon, τ-Interferon, rabbit, the δ-Interferon, rabbit of Pegylation and the group that γ-the 1b Interferon, rabbit is formed.

38. the pharmaceutical composition of claim 27, wherein, described compound or pharmaceutically acceptable salt thereof is pure basically form.

39. the pharmaceutical composition of claim 27, wherein, the weight of described compound or pharmaceutically acceptable salt thereof at least 90% is β-D-isomer.

40. the pharmaceutical composition of claim 27, wherein, the weight of described compound or pharmaceutically acceptable salt thereof at least 95% is β-D-isomer.

41. the pharmaceutical composition of claim 27 further comprises the pharmaceutically acceptable carrier that is suitable for oral, parenteral, suction or intravenously administrable.

42. the pharmaceutical composition of claim 27, wherein, described pharmacologically acceptable salt be selected from by benzene sulfonate, mesylate, acetate, Citrate trianion, malonate, tartrate, succinate, benzoate, vitamins C, alpha-ketoglutarate, alpha-phosphate glycerine, formate, fumarate, propionic salt, glycol hydrochlorate, lactic acid salt, pyruvate salt, oxalate, maleate, salicylate, the group formed of vitriol, nitrate, supercarbonate, carbonate, hydrobromate, hydrochloride, dihydrochloride and phosphoric acid salt.

43. the pharmaceutical composition of claim 42, wherein, described pharmacologically acceptable salt is a hydrochloride.

44. claim 1-11 each be used for the treatment of the compound or pharmaceutically acceptable salt thereof that infects the host that flaviviridae is arranged.

45. the compound of claim 44, wherein, described virus is hepatitis C virus.

46. the compound of claim 44, wherein, described host is the people.

47. each compound or pharmaceutically acceptable salt thereof of claim 1-11 is used for the treatment of purposes in the medicine that infects the host that flaviviridae is arranged in preparation.

48. the purposes of claim 44, wherein, described virus is hepatitis C virus.

49. the purposes of claim 44, wherein, described host is the people.