HK1189234A - Modified 2' and 3'-nucleoside prodrugs for treating flaviridae infections - Google Patents

Abstract

2' and/or 3' prodrugs of 1', 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

Modified 2 'and 3' -nucleoside prodrugs for treating flavivirus infections

This application is a divisional application of chinese patent application 03820501.7 entitled "modified 2 'and 3' -nucleoside prodrugs for the treatment of flavivirus infection", filed on 27/6/2003.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims U.S. provisional application No. 60/392,350 filed on 28/6/2002; U.S. provisional application No. 60/466,194 filed on 28/4/2003; and U.S. provisional application No. 60/470,949 filed on 14.5.2003, the disclosure of each of which is incorporated herein by reference.

Technical Field

The present invention relates to the field of medicinal chemistry, and in particular to 2 'and/or 3' prodrugs of 6-modified 1 ', 2', 3 'or 4' -branched pyrimidine nucleosides or 8-modified 1 ', 2', 3 'or 4' -branched purine nucleosides for the treatment of flavivirus infections, such as hepatitis c virus infections.

Background

Flaviviridae virus

Flaviviridae viruses contain at least 3 separate genera: pestiviruses (pestiviruses), which cause disease in cattle and pigs; flaviviruses (flaviviruses), which are the main causes of diseases such as dengue and yellow fever; and the hepaciviruses (hepaciviruses), the only member of which is Hepatitis C Virus (HCV). The flavivirus genus comprises more than 68 members, which can be divided into different groups according to serological relatedness (Calisher et al, J.Gen.Virol,1993,70, 37-43). Clinical symptoms vary, and include fever, encephalitis, and hemorrhagic fever (Fields Virology, eds: Fields, B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA,1996, Chapter 31, 931 and 959). Flaviviruses of global concern associated with human disease include dengue hemorrhagic fever virus (DHF), yellow fever virus, shock syndrome, and Japanese encephalitis virus (Halstead, S.B., Rev.Infect.DIS.,1984,6, 251-.

Pestiviruses include Bovine Viral Diarrhea Virus (BVDV), classical swine fever virus (CSFV, also known as hog cholera virus) and ovine Border Disease Virus (BDV) (Moennig, V. et al. adv. Vir. Res.1992,41, 53-98). Pestivirus infection of livestock (cattle, pigs and sheep) causes huge economic losses worldwide. BVDV causes disease of bovine mucosa and is of great economic importance to the livestock industry (Meyers, G., and Thiel, H. -J., Advances in Virus Research,1996,47,53-118; Moennig V., et al, adv. Vir. Res.1992,41, 53-98). Human pestiviruses have not been extensively identified as animal pestiviruses. However, serological investigations have shown that humans are at risk for a considerable number of pestiviruses.

Within the flaviviridae family, pestiviruses and hepaciviruses are closely related groups of viruses. Other closely related viruses in this family include the GB virus A, GB virus a analog, GB virus B, and GB virus C (also known as hepatitis G virus, HGV). The hepacivirus group (hepatitis C virus; HCV) includes a number of closely related but genotypically distinguishable viruses that infect humans. There are approximately 6 HCV genotypes and more than 50 subtypes. Due to the similarity between pestiviruses and hepaciviruses, and because hepaciviruses are difficult to grow efficiently in cell culture media, Bovine Viral Diarrhea Virus (BVDV) is often used as a surrogate to study HCV virus.

The genetic structures of pestiviruses and hepaciviruses are very similar. These positive-stranded RNA viruses have a single large Open Reading Frame (ORF) encoding all of the viral proteins necessary for viral replication. These proteins are expressed as a multimeric protein which is co-translated and post-translationally processed by cellular and virally encoded proteases to produce mature viral proteins. . The viral proteins responsible for replication of the viral genomic RNA are located approximately at the carboxy terminus. Two thirds of the open reading frames are designated as non-structural (NS) proteins. The genetic structure of the nonstructural protein portion of the ORF and processing of the polyprotein are very similar for pestiviruses and hepaciviruses. For both pestiviruses and hepaciviruses, the mature non-structural (NS) protein, comprising, in succession from the amino terminus of the non-structural protein coding region to the carboxy terminus of the ORF: p7, NS2, NS3, NS4A, NS4B, NS5A, and NS 5B.

The NS proteins of pestiviruses and hepaciviruses all have sequence domains with specific protein functional properties. For example, the NS3 protein in these two groups of viruses has amino Acid sequence motifs characteristic of serine proteases and helicases (Gorbalenya et al (1988) Nature333:22; Bazan and Fletterick (1989) Virology171:637-639; Gorbalenya et al (1989) Nucleic Acid Res.17.3889-3897). Similarly, the NS5B protein of pestiviruses and hepaciviruses has motifs for RNA-directed RNA polymerase properties (Koonin, E.V. and Dolja, V.V. (1993) Crit. Rev. biochem. molec. biol.28: 375-430).

The actual role and function of the NS proteins of pestiviruses and hepaciviruses in the viral life cycle are completely similar. In both cases, the NS3 serine protease is responsible for all proteolytic processing at the downstream position of the polyprotein precursor in the ORF (Wiskerchen and Collett (1991) Virology184:341-350; Bartenschlager et al (1993) J Virol.67:3835-3844; Eckart et al (1993) biochem.Biophys.Res.Comm.192:399-406; Grakoui et al (1993) J.Virol.67:2832-2843; Grakoui et al (1993) Proc.Natl.Acad.Sci.USA90:10583-10587; Hijikata et al (1993) J.Virol.67:4665-4675; Tome et al (1993) J.Virol.67: 4017-4026). The NS4 protein acts as a cofactor for the NS3 serine protease in both cases (Bartenschlager et al (1994) J.Virol.68:5045-5055; Faillea et al (1994) J.Virol.68:3753-3760; Lin et al (1994)68:8147-8157; Xu et al (1997) J.Virol.71: 5312-5322). The NS3 proteins of both genera also have helicase function (Kim et al (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). Finally, the NS5B protein of pestiviruses and hepaciviruses has the expected RNA-directed RNA polymerase activity (Behrens et al (1996) EMBO J.15:12-22; Lchmann et al (1997) J.Virol.71:8416-8428; Yuan et al (1997) biochem.Biophys.Res.Comm.232:231-235; Hagedorn, PCT WO97/12033; Zhong et al (1998) J.Virol.72.9365-9369).

Hepatitis C virus

Hepatitis C Virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J.hepatol.32:98-112,2000). HCV causes a slowly growing viral infection and is the main cause of cirrhosis and hepatocellular carcinoma (Di Bescheglie, A.M. and Bacon, B.R., scientific American, Oct:80-85, (1999); Boyer, N.et al J.Hepatol.32:98-112,2000). It is estimated that 1.7 million worldwide are infected with HCV (Boyer, N. et al. J.hepatol.32:98-112,2000). It is estimated that cirrhosis due to chronic hepatitis c virus infection causes death of 12,000 people by 8,000 cells annually in the united states, and HCV infection is the most prominent indication for liver transplantation.

HCV is known to cause at least 80% of post-transfusion hepatitis and a large proportion of sporadic acute hepatitis. Preliminary evidence also suggests that HCV is not associated with other hepatitis viruses, such as Hepatitis B Virus (HBV), in many cases of "primary" chronic hepatitis, "latent" cirrhosis, and possibly hepatocellular carcinoma. A small proportion of healthy people appear to be carriers of chronic HCV, with a diversity in geographic distribution and other epidemiological factors. Although only a preliminary message, the number may substantially exceed the number of carriers of HBV; it is not clear how many people have chronic liver disease with clinically insignificant symptoms (The Merck Manual, ch.69, p.901, 16) ^th ed.,(1992))。

HCV is an enveloped virus containing a sense single-stranded RNA genome of about 9.4 kb. The viral genome consists of a 5 'untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of about 3011 amino acids, and a short 3' UTR. The 5' UTR is the most prominent highly conserved part of the HCV genome and plays an important role in initiating and controlling the translation of polyproteins. Translation of the HCV genome is initiated by a capping independent mechanism known as internal ribosome entry. This mechanism involves the binding of ribosomes and RNA sequences at what is known as the Internal Ribosome Entry Site (IRES). An RNA pseudoknot structure has recently been identified as a basic structural element of HCV IRES. The viral structural proteins include a nucleocapsid core protein (C) and two enveloped glycoproteins, El and E2. HCV also encodes two proteases, a zinc-dependent metalloprotease encoded by the NS2-NS3 region and a serine protease encoded by the NS3 region. These proteases are necessary to cleave specific regions of the precursor polyprotein to form the mature peptide. The carboxy portion of the nonstructural protein 5, NS5B, contains an RNA-dependent RNA polymerase. The function of the remaining nonstructural proteins NS4A and NS4B and NS5A (amino moiety of nonstructural protein 5) remains unknown.

An important focus of current antiviral research is the development of improved methods for treating chronic HCV infection in humans (Di Bescheglie, A.M. and Bacon, B.R., Scientific American, Oct:80-85, (1999)).

Treatment of HCV infection with interferon

Interferons (IFNs) have been commercially available for the treatment of chronic hepatitis for the last decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit the replication of many viruses, including HCV, but when used alone to treat hepatitis C infection, IFNs can inhibit serum HCV-RNA to undetectable levels in some cases. In addition, IFN can normalize serum aminotransferase levels. Unfortunately, the effects of IFN are only temporary, with sustained responses being produced only in 8% -9% of patients infected with chronic HCV (Gary l.davis.gastroenterology118: S104-S114,2000). However, most patients have difficulty tolerating severe flu-like symptoms, weight loss, and fatigue weakness resulting from interferon therapy.

A number of patents disclose the use of interferon-based therapies to treat flaviviridae, including HCV. For example, U.S. patent No. 5,980,884 to Blatt et al discloses a method of treating a patient suffering from HCV with a consensus interferon. U.S. Pat. No. 5,942,223 to Bazer et al discloses anti-HCV therapy using ovine or bovine interferon-tau. U.S. patent No. 5,928,636 to Alber et al discloses a combination therapy of interleukin-12 and interferon alpha (IFN- α) for the treatment of infectious diseases including HCV. U.S. patent No. 5,849,696 to Chretien et al discloses the use of thymosins alone or in combination with interferons for the treatment of HCV. United states patent No. 5,830,455 to valdue et al discloses a combination therapy for HCV using interferon and a basal-only scavenger. U.S. patent No. 5,738,845 to Imakawa discloses the use of human interferon-Tau protein for the treatment of HCV. In addition, other interferon-based HCV therapies are disclosed in U.S. Pat. No. 5,676,942 to Testa et al, U.S. Pat. No. 5,372,808 to Blatt et al, and U.S. Pat. No. 5,849,696. There are also numerous patents disclosing pegylated forms of interferon, such as the following: U.S. Pat. Nos. 5,747,646,5,792,834 and 5,834,594 to Hoffmann-La Roche Inc; PCT patent publication Nos. WO99/32139 and WO99/32140 to Enzon; U.S. Pat. Nos. 5,738,846 and 5,711,944 to Schering, WO95/13090, and U.S. Pat. No. 5,908,621 to Glue et al.

Interferon alpha-2 a and interferon alpha-2 b are currently licensed as monotherapies for the treatment of HCV.-A (Roche) is a recombinant form of interferon alpha-2 a.(Roche) is a pegylated form of interferon alpha-2 a (i.e., polyethylene glycol modified).(Schering Corporation) recombinant forms of interferon alpha-2 b.(Schering corporation) is a pegylated form of interferon alpha-2 b.

Other forms of interferon alpha, as well as interferons beta, gamma, tau and omega, are currently in the clinical development phase of HCV therapy. For example, InterMune's INFERGEN (Interferon. Alpha. con-1), Viragen's OMNIFERON (Natural Interferon), Human Genome Sciences ' ALBUFERON, Ares-Serono's REBIF (Interferon. beta. -la), Biomedicine's omega Interferon, Amarillobiosciences ' Oral Interferon Alpha, and InterMune's Interferon gamma, Interferon tau, and Interferon gamma-lb are under investigation.

Ribavirin (Ribavirin)

Ribavirin (1- β -D-ribofuranosyl-1-1, 2, 4-triazole-3-carboxamide) is a synthetic, non-interferon-induced, broad-spectrum antiviral nucleoside analogue sold under the trade name Virazole (the Merck Index, 11 th edition: Budavari, S., Merck & Co., Inc., Rahway, NJ, PL304,1989). Ribavirin is disclosed and claimed in U.S. Pat. No. 3,798,209 and RE29,835. Ribavirin is structurally similar to guanosine and has in vitro activity against a variety of DNA and RNA viruses including the flaviviridae family (Gary l.davis.gastroenterology118: S104-S114,2000).

Ribavirin reduces serum aminotransferase levels to normal levels in 40% of patients, but it does not reduce serum levels of HCV-RNA (Gary l.davis.gastroenterology118: S104-S114,2000). Thus, ribavirin alone is not effective in reducing viral RNA levels. Additionally, ribavirin is quite toxic and known to induce anemia.

Ribavirin is not approved for the sole treatment of HCV, but is approved for the combined treatment of HCV with interferon alpha-2 a or interferon alpha-2 b.

Combination administration of interferon and ribavirin

The current standard for treating chronic hepatitis c is combination therapy with interferon-alpha and ribavirin. For the treatment of HCV infection with a combination therapy of interferon and ribavirin, it has been reported that this therapy is effective in the treatment of interferon naive patients (interferon negative patients) (Battaglia, A.M. et al, Ann. Pharmacother.34: 487-. Studies have shown that more hepatitis c patients respond more strongly to pegylated interferon- α/ribavirin combination therapy than to non-pegylated interferon- α combination therapy. However, as with monotherapy, considerable side effects are produced in combination therapy, including hemolysis, influenza-like symptoms, anemia, and fatigue (Gary L.Davis.gastroenterology118: S104-S114,2000).

By using(peg Interferon alpha-2 b) andcapsules for combination therapy (ribavirin, USP) are available from Schering Corporation.(Schering corporation) has also been approvedA (interferon alpha-2 b, recombinant, Schering corporation) was used in combination. Additionally, Roche' s(Pegylated interferon alpha-2 a) and(ribavirin) is also approved for the treatment of HCV. )))

PCT publications WO99/59621, WO00/37110, WO01/81359, WO02/32414and WO03/024461 from Schering Corporation disclose the use of pegylated interferon-alpha and ribavirin combination therapy for the treatment of HCV. PCT publication Nos. WO99/15194, WO99/64016, and WO00/24355 to Hoffmann-La Roche Inc. also disclose the use of pegylated interferon-alpha in combination with ribavirin for the treatment of HCV.

Other methods of treating flaviviridae infections

Development of new antiviral agents for flaviviridae infections, particularly hepatitis c virus, is currently ongoing. Specific inhibitors of HCV-derived enzymes such as proteases, helicases, and polymerase inhibitors are under development. In addition, inhibitors for inhibiting other steps of HCV replication are also under development, such as drugs that block the production of HCV antigens from RNA (IRES inhibitors), drugs that block the normal processing of HCV proteins (glycosylation inhibitors), drugs that block the entry of HCV into cells (by blocking its receptors), and non-specific cytoprotective agents that block cell damage due to viral infection. Further, molecular methods have also been developed for the treatment of hepatitis c, e.g., ribozymes, which specifically destroy enzymes of the viral RNA molecule; antisense oligonucleotides, which are small complementary fragments of DNA, are also under investigation that bind to viral RNA and inhibit viral replication. Many HCV therapies are discussed in Bymock et al, antibacterial Chemistry & chemotherapeutics, 11:2;79-95(2000) and De France Research et al, antibacterial Research,58:1-16 (2003).

Examples of classes of drugs that have been developed for the treatment of flavivirus infections include:

(1) protease inhibitors

There are being studied: substrate-based NS3protease Inhibitors (Attwood et al, antiviral peptides derivatives, PCT WO98/22496,1998; Attwood et al, antiviral chemistry and Chemotherapy, 1999,10,259-273; Attwood et al, prepatation and use of amino acid derivatives as anti-viral agents, German patent publication No. DE19914474; Tung et al, Inhibitors of serum proteins, particulate peptides Cviruses 3 NS3 proteins, PCT WO98/17679), including alpha-keto amides and hydrazinoureas, and Inhibitors that terminate electrophilic agents such as boronic acids or phosphonates (Llinas-Bret al, hepatitis C virus inhibitor peptides, PCT WO 99/07734).

In addition, there are studies on: non-substrate based NS3protease inhibitors, such as 2,4, 6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al, Biochemical and biophysical research Communications,1997,238,643-647; Sudo K. et al, analytical chemistry and chemistry, 1998,9,186), including RD3-4082 and RD3-4078, the former being substituted on the amide by a 14 carbon chain and the latter processing p-phenoxyphenyl.

Sch68631, a phenanthrenequinone, is an inhibitor of HCV protease (Chu M. et al, Tetrahedron Letters37:7229-7232, 1996). In another example given by the authors, Sch351633, isolated from Penicillium griseofulvum, was identified as a protease inhibitor (Chu M. et al, Bioorganic and Medicinal Chemistry Letters9: 1949) -1952). Nanomolar potency of the enzyme against HCV NS3 protease was obtained by designing selective inhibitors based on the macromolecular hirudin protease inhibitor c, Eglin c. Eglin c is isolated from leeches and is a potential inhibitor of several serine proteases such as streptomyces griseus (s.griseus) proteases a and B, alpha-chymotrypsin, chymotrypsin and subtilisin. Qasim M.A.et al, Biochemistry36:1598-1607, 1997.

Several U.S. patents disclose protease inhibitors for the treatment of HCV. For example, U.S. Pat. No. 6,004,933 to Spruce et al discloses a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2. U.S. patent No. 5,990,276 to Zhang et al discloses synthetic inhibitors of hepatitis c virus NS3 protease. The inhibitor is a subsequence of the NS3 protease substrate or is a substrate for the NS4A cofactor. The use of restriction enzymes for the treatment of HCV is disclosed in U.S. Pat. No. 5,538,865 to Reyes et al. Peptides that are inhibitors of the HCV NS3 serine protease are disclosed in WO02/008251 by Corvas International, Inc., and WO02/08187 and WO02/008256 by Schering corporation. HCV inhibitor tripeptides are disclosed in U.S. Pat. Nos. 6,534,523, 6,410,531 and 6,420,380 to Boehringer Ingelheim and WO02/060926 to Bristol Myers Squibb. Diaryl peptides as inhibitors of the HCV NS3 serine protease are disclosed in WO02/48172 from Schering Corporation. Imidazolinediones (Imidazoleindiones) as inhibitors of the HCV NS3 serine protease are disclosed in WO02/08198 from Schering Corporation and WO02/48157 from Bristol Myers Squibb. WO98/17679 to Vertex Pharmaceuticals and WO02/48116 to Bristol Myers Squibb also disclose HCV protease inhibitors.

(2) Thiazolidine (Thiazolidines) derivatives, showing a relevant inhibitory effect in reverse phase HPLC assays using NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al, Antiviral Research,1996,32,9-18), in particular the compound RD-1-6250 with fused cinnamoyl moiety substituted by long chain alkyl, as well as RD46205 and RD 46193;

(3) thiazolidines and benzanilides (benzanilides), identified by Kakiuchi N.et al, J.EBS letters421,217-220, Takeshita N.et al, Analytical Biochemistry,1997,247, 242-;

(4) phenanthrenequinones (phenan-threnequinone) which show antiprotease activity in SDS-PAGE and autoradiography assays, by isolation from fermentation culture broths of Streptomyces (Streptomyces sp) (Chu m. et al, Tetrahedron Letters,1996,37, 7229-;

(5) helicase inhibitors (e.g., Diana G.D., et al, Compounds, compositions and methods for treating of hepatitis C, U.S. Pat. No. 5,633,358; Diana G.D., et al, Piperidine derivatives, pharmaceutical compositions of therof and the hair use of the treatment of hepatitis C, PCT WO 97/36554);

(6) Nucleoside polymerase inhibitors and gliotoxins (Ferrari R. et al. Journal of Virology,1999,73,1649-1654), and the natural product cerulenin (Lohmann V. et al. Virology,1998,249, 108-118);

(7) an antisense phosphorothioate oligonucleotide (S-ODN) which is complementary to the sequence of the 5 'non-coding region (NCR) extending into the virus (Alt M. et al, Hepatology,1995,22,707-717), or the nucleoside 326-348 comprising the 3' end of the NCR and the nucleoside 371-388 (Alt M. et al, Archives of Virology,1997,142,589-599; Galderisi U. et al, Journal of cellular Physiology,1999,181, 251-257) located in the core coding region of HCV RNA;

(8) inhibitors of IRES-dependent translation (Ikeda N et al, Agent for the Prevention and treatment of hepatitis C, Japanese patent publication No. JP-08268890; Kai Y. et al, Prevention and treatment of viral diseases, Japanese patent publication No. JP-10101591);

(9) ribozymes such as nuclease-resistant ribozymes (Maccjak D.J. et al, Hepatology1999,30, abstract 995) and those disclosed in Barber et al, U.S. Pat. No. 6,043,077 and Draper et al, U.S. Pat. Nos. 5,869,253 and 5,610,054; and

(10) Nucleoside analogs have not been developed for use in treating flaviviridae virus infections.

Idenix Pharmaceuticals in International application publication Nos. WO01/90121 and WO01/92282 disclose the use of branched nucleosides to treat flaviviruses, including HCV, and pestiviruses. In particular, the method disclosed in the disclosure of Idenix for treating hepatitis C virus infections (flaviviruses and pestiviruses) in humans and other host animals comprises administering an effective amount of a biologically active 1 ', 2',3 'or 4' -branched β -D or β -L nucleoside or a pharmaceutically acceptable salt or derivative thereof, either alone or in combination with other antiviral agents, optionally with a pharmaceutically acceptable carrier. The pharmaceutically acceptable salt is selected from

Other patent applications disclosing the use of certain nucleoside analogs for the treatment of hepatitis c virus include: PCT/CA00/01316(WO01/32153; filed 11/3/2000) and PCT/CA01/00197(WO01/60315; filed 2/19/2001), both filed by BioChem Pharma, Inc. (now Shire BioChem, Inc.); PCT/US02/01531(WO02/057425; filed 1/18.2002) and PCT/US02/03086(WO02/057287; filed 1/18.2002) filed by Merck & Co., Inc., PCT/EP01/09633(WO02/18404; published 8/21.2001) filed by Roche, and PCT publication No. WO OIT9246 (filed 4/13.2001) by Pharmasset, Ltd, WO02/32920 (filed 10/18.2001) and WO 02/48165.

PCT publication No. WO99/43691 to Emory University, entitled "2 '-fluoronucleosides", discloses the use of certain 2' -fluoronucleosides to treat HCV.

Eldrup et al describe the structural activity relationship of 2' -modified nucleosides for the inhibition of HCV (Oral Session V, Hepatitis C Virus, Flaviviridae; 16)^th InternationalConference on Antiviral Research(April27,2003,Savannah,Ga.)）。

Bhat et al describe the synthesis and pharmacokinetic properties of nucleoside analogs as potential inhibitors of HCV RNA replication. The authors reported that 2' -modified nucleosides showed potential inhibitory activity in cell-based replicon assays (Oral Session V, Hepatitis C Virus, Flaviviridae; 16)^th International Conference on Antiviral Research(April27,2003,Savannah,Ga.);p A75）。。

Olsen et al also describe the effect of 2' -modified nucleosides on HCV RNA replication (Oral Session V, Hepatitis C Virus, Flaviviridae; 16)^th International Conference on AntiviralResearch(April27,2003,Savannah,Ga.)p A76)。

(11) Other various compounds include: 1-amino-alkylcyclohexane (Gold et al, U.S. Pat. No. 6,034,134), alkyl lipids (Chojkier et al, U.S. Pat. No. 5,922,757), vitamin E and other antioxidants (Chojkier et al, U.S. Pat. No. 5,922,757), squalene, amantadine, bile acids (Ozeki et al, U.S. Pat. No. 5,846,964), N- (phosphonoacetyl) -L-aspartic acid, (Diana et al, U.S. Pat. No. 5,830,905), benzenedicarboxamides (Diana et al, U.S. Pat. No. 5,633,388), polyadenylic acid derivatives (Wang et al, U.S. Pat. No. 5,496,546), 2',3' -dideoxyinosine (Yarchan et al, U.S. Pat. No. 5,026,687), benzimidazoles (Colacino et al, U.S. Pat. No. 5,891,874), plant extracts (Tsai et al, U.S. Pat. No. 5,837,257, Omer et al, U.S. Pat. No. 5,725,859, and U.S. Pat. No. 6,056,961), and piperidines (piperadiness) (Diana et al, U.S. Pat. No. 5,830,905).

(12) Other compounds currently in preclinical or clinical development for the treatment of hepatitis c virus include: Schering-Plough interleukin-10, InterneuIP-501 of ron, Merimebodib (VX-497) of Vertex, of Endo Labs Solvay(of amantadine), RPIIDun Pharma IDN-6556, XTL-002 for XTL, Chiron HCV/MF59, NABI(immunoglobulin of hepatitis C virus), of ICN/RIBAPHARMOf ICN/RIBAPHARMOf Sci Clone(thymosin alpha-1), thymosin of Sci Clone and pegylated interferon, of Maxim(histamine dihydrochloride), VX950/LY570310 by Vertex/EliLilly, ISIS14803 by Isis PHARMACEUTICAL/ELAN, IDN-6556 by Idun PHARMACEUTICALs Inc., JTK003 by AKROS Pharma, BILN-2061 by Boehringer Ingelheim, CellCept (mycophenolate mofetil) by Roche, T67 by Tularik, a beta-tubulin inhibitor, a therapeutic vaccine against E2 by Innogenetics, FK788 by Fujisawa Healthcare, Inc, Celb 1016(Siliphos, an oral silymarin-phosphothiophene, a (intracellular-phosphoenolate), an RNA replication inhibitor of Virosary, a therapeutic vaccine against Epsilone, a chemotherapeutic inhibitor of interferon, a chemotherapeutic vaccine for interferon, a chemotherapeutic treatment, a chemotherapeutic inhibitor of interferon, a chemotherapeutic vaccine for interferon, for chemotherapy for interferon, for chemotherapy for interferon, for tumors, Dication by Int, protease inhibitors by Agouron, protease inhibitors by Chiron/Meivir, antisense therapy by AVI BioPharma, antisense therapy by Hybridon, blood cleaners (hemopurifier) by Aethlon Medical, therapeutic vaccine by Merix, protease inhibitors by Bristol-Myers Squibb/Axys, Chron-VacC by Tripep, a therapeutic vaccine, UT231B by United Therapeutics, protease, helicase and polymerase inhibitors by Genelabs Technologies, IRES inhibitors by Immusol, R803 by Rigelpharmaceuticals, IRES by InterMuneOf (alpha con-1 interferon), Viragen(Natural interferons), of Human Genome SciencesOf Ares-Serono(beta-1 a interferon), omega interferon from BioMedicine, oral alpha interferon from Amarillo Biosciences, gamma interferon, tau interferon, and gamma-1 b interferon from intermone.

Nucleoside prodrugs have been previously described for use in the treatment of other types of hepatitis. WO00/09531 (filed 8/10.1999) and WO01/96353 (filed 6/5.2001) to IdenixPharmaceuticals disclose 2 '-deoxy- β -L-nucleosides, and their 3' -prodrugs for the treatment of HBV. U.S. Pat. No. 4,957,924 to Beaucham discloses various esters of acyclovir for therapeutic use.

Given that HCV infection has reached a worldwide epidemic and has a catastrophic impact on patients, there is an urgent need to provide new and effective pharmaceutical formulations for the treatment of hepatitis C that are less toxic to the host.

In addition, given the increasing risk of other flaviviridae infections, there is an urgent need to provide new and effective pharmaceutical formulations with low toxicity to the host.

Accordingly, it is an object of the present invention to provide compounds, methods and compositions for treating a host infected with hepatitis c virus.

It is another object of the present invention to provide a general method and composition for treating a patient infected with pestivirus, flavivirus or hepacivirus.

Disclosure of Invention

2 'and 3' -prodrugs of 1',2',3', or 4' -branched beta-D or beta-L nucleosides, or their pharmaceutically acceptable salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of Flaviviridae viral infections and other related conditions such as anti-Flaviviridae antibody-positive and Flaviviridae virus-positive conditions, HCV-induced chronic hepatitis, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or delay the development of clinical disease in individuals who are positive for anti-flaviviridae antibodies or flaviviridae antigens or who are at risk for flaviviridae.

A method for treating Flaviviridae virus infections in a host, including a human, is also disclosed, which comprises administering an effective amount of a 2 'and 3' -prodrug of a biologically active 1',2',3 'or 4' -branched β -D or β -L nucleoside or a pharmaceutically acceptable salt thereof, alone or in combination or in alternation with other anti-Flaviviridae virus agents, or optionally in a pharmaceutically acceptable carrier. The term 2 '-prodrug, as used herein, refers to a 1',2',3' or 4 '-branched β -D or β -L nucleoside having a biologically cleavable moiety at the 2' -position, including but not limited to an acyl group, which in one embodiment is a natural or synthetic D or L amino acid, preferably an L-amino acid. The term 3 '-prodrug, as used herein, refers to a 1',2',3' or 4 '-branched β -D or β -L nucleoside having a biologically cleavable moiety at the 3' -position, including but not limited to an acyl group, which in one embodiment is a natural or synthetic D or L amino acid, preferably an L-amino acid.

Pharmaceutically acceptable salts include tosylate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate and alpha-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, sulfonate, nitrate, bicarbonate, hydrobromide, hydroiodide, carbonate, and orthophosphate. A particularly preferred embodiment is the mono-or dihydrochloride salt.

In one embodiment, the 1',2',3', or 4' -branched β -D or β -L nucleoside includes a biologically cleavable moiety at the 2 'and/or 5' position. Preferred moieties are natural or synthetic D or L amino acid esters, including D or L-valinyl, but preferably L-amino acid esters, such as L-valinyl, and alkyl esters including acetyl. Thus, the invention specifically includes 2' -D or L-amino acid esters and 2',5' -D or L-diamino acid esters, preferably L-amino acid esters of 1',2',3' or 4' -branched β -D or β -L nucleosides having any desired purine or pyrimidine base, wherein the parent drug optionally has an EC of less than 15 micromolar₅₀More preferably less than 10 micromolar; 2' - (alkyl or aryl) esters or 2',5' -di (alkyl or aryl) esters of 1',2',3', or 4' -branched β -D or β -L nucleosides having any desired purine or pyrimidine base, wherein the parent drug optionally has an EC of less than 10 or 15 micromolar₅₀(ii) a And 2',5' -diesters of 1',2',3 'or 4' -branched β -D or β -L nucleosides, wherein (i) the 2 'ester is a natural or synthetic D or L-amino acid ester, but preferably the L-amino acid ester, and the 5' -ester is an alkyl or aryl ester; (ii) both esters are independently natural or synthetic D or L-amino acid esters, although preferably both are L-amino acid esters; (iii) both esters are independently alkyl or aryl esters; and (iv) the 2 'ester is independently an alkyl or aryl ester and the 5' -ester is a natural or synthetic D or L-amino acid ester, although preferably an L-amino acid ester, wherein the parent drug optionally has an EC of less than 10 or 15 micromolar ₅₀。

Examples of prodrugs falling within the present invention are the 2'-D or L-valine esters of β -D-2', 6-dimethyl-cytidine; 2 '-L-valine ester of β -D-2', 6-dimethyl-thymidine; 2 '-L-valine esters of β -D-2', 8-dimethyl-adenosine; 2 '-L-valine ester of β -D-2', 8-dimethyl-guanosine; 2 '-L-valine ester of β -D-2', 6-dimethyl-5-fluorocytidine; 2 '-L-valine ester of β -D-2', 6-dimethyl-uridine; 2 '-acetyl ester of β -D-2', 6-dimethyl-cytidine; 2 '-acetyl ester of β -D-2', 6-dimethyl-thymidine; 2 '-acetyl esters of beta-D-2', 8-dimethyl-adenosine, 2 '-acetyl esters of beta-D-2', 8-dimethyl-guanosine; 2 '-acetyl ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; and 2' -esters of β -D-2', 6-dimethyl- (cytidine, 5-fluorocytidine, uridine, or thymidine) or 2' -esters of β -D-2', 8-dimethyl- (guanosine, adenosine, or inosine), wherein (i) the 2' esters are amino acid esters; or (ii) the 2' ester is an alkyl or aryl ester.

Other examples of prodrugs falling within the invention are the 2',5' -L-divaline esters of β -D-2', 6-dimethyl-cytidine (dival-2', 6-diMe-L-dC); 2',5' -L-divaline ester of β -D-2', 6-dimethyl-thymidine; 2',5' -L-divaline ester of β -D-2', 8-dimethyl-adenosine; 2',5' -L-divaline ester of β -D-2', 8-dimethyl-guanosine; 2',5' -L-divaline ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; 2',5' -L-divaline ester of β -D-2', 6-dimethyl-uridine; 2',5' -diacetyl ester of β -D-2', 6-dimethyl-cytidine; 2',5' -diacetyl ester of β -D-2', 6-dimethyl-thymidine; 2',5' -diacetyl ester of β -D-2', 8-dimethyl-adenosine; 2',5' -diacetyl ester of β -D-2', 8-dimethyl-guanosine; 2',5' -diacetyl ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; and 2',5' -diester of β -D-2', 6-dimethyl- (cytidine, 5-fluorocytidine, uridine, or thymidine) or 2',5 '-diester of β -D-2', 8-dimethyl- (guanosine, adenosine, or inosine), wherein (i) the 2 'ester is an amino acid ester and the 5' -ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; or (iv) the 2 'ester is an alkyl or aryl ester and the 5' -ester is an amino acid ester.

In another embodiment, the 1',2',3', or 4' -branched β -D or β -L nucleoside 3' -prodrugs include a biologically cleavable moiety at the 3' and/or 5' position. Preferred moieties are natural or synthetic D or L amino acidsEsters, such as valinyl, but preferably L-amino acids, such as L-valinyl, and alkyl esters including acetyl. Thus, the invention specifically includes 3' -L-amino acid esters and 3',5' -L-diamino acid esters of 1',2',3' or 4' -branched β -D or β -L nucleosides having any desired purine or pyrimidine base, wherein the parent drug optionally has an EC of less than 15 micromolar₅₀And more preferably less than 10 micromolar; 3' - (alkyl or aryl) esters or 3',5' -L-di (alkyl or aryl) esters of 1',2',3', or 4' -branched beta-D or beta-L nucleosides having any desired purine or pyrimidine base, wherein the parent drug optionally has an EC of less than 10 or 15 micromolar₅₀(ii) a And a prodrug of a 3',5' -diester of a 1',2',3', or 4' -branched β -D or β -L nucleoside, wherein (i) the 3 'ester is a natural or synthetic D or L amino acid ester and the 5' -ester is an alkyl or aryl ester; (ii) both esters are natural or synthetic D or L-amino acid esters; (iii) the two esters are independently alkyl or aryl esters; and (iv) the 3 'ester is independently an alkyl or aryl ester and the 5' -ester is a natural or synthetic D or L-amino acid ester, wherein the parent drug optionally has an EC of less than 10 or 15 micromolar ₅₀。

Examples of prodrugs falling within the present invention are the 3 '-L-valine ester of β -D-2', 6-dimethyl-cytidine; 3 '-L-valine ester of β -D-2', 6-dimethyl-thymidine; 3 '-L-valine esters of β -D-2', 8-dimethyl-adenosine; 3 '-L-valine ester of β -D-2', 8-dimethyl-guanosine; 3 '-L-valine ester of β -D-2', 6-dimethyl-5 fluorocytidine; 3 '-L-valine ester of β -D-2', 6-dimethyl-uridine; 3 '-acetyl ester of β -D-2', 6-dimethyl-cytidine; 3 '-acetyl ester of β -D-2', 6-dimethyl-thymidine; 3 '-acetyl ester of β -D-2', 8-dimethyl-adenosine; 3 '-acetyl ester of β -D-2', 8-dimethyl-guanosine; 3 '-acetyl ester of β -D-2', 6-dimethyl-5 fluoro-cytidine; and 3' -esters of β -D-2', 6-dimethyl- (cytidine, 5-fluorocytidine, uridine, or thymidine) or 3' -esters of β -D-2', 8-dimethyl- (guanosine, adenosine, or inosine), wherein (i) the 3' ester is an amino acid ester; or (ii) the 3' ester is an alkyl or aryl ester.

Further examples of prodrugs falling within the present invention are the 3',5' -L-divaline esters of β -D-2', 6-dimethyl-cytidine (dival-2', 6-diMe-L-dC); 3',5' -L-divaline ester of β -D-2', 6-dimethyl-thymidine; 3',5' -L-divaline ester of β -D-2', 8-dimethyl-adenosine; 3',5' -L-divaline ester of β -D-2', 8-dimethyl-guanosine; 3',5' -L-divaline ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; 3',5' -L-divaline ester of β -D-2', 6-dimethyl-uridine; 3',5' -diacetyl ester of β -D-2', 6-dimethyl-cytidine; 3',5' -diacetyl ester of β -D-2', 6-dimethyl-thymidine; 3',5' -diacetyl ester of β -D-2', 8-dimethyl-adenosine; 3',5' -diacetyl ester of β -D-2', 8-dimethyl-guanosine; 3',5' -diacetyl ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; and 3',5' -diesters of β -D-2', 6-dimethyl- (cytidine, 5-fluorocytidine, uridine, or thymidine) or 3',5 '-diesters of β -D-2', 8-dimethyl- (guanosine, adenosine, or inosine), wherein (i) the 3 'esters are amino acid esters and the 5' -esters are alkyl or aryl esters; (ii) both esters are amino acid esters; (iii) the two esters are independently alkyl or aryl esters; or (iv) the 3 'ester is an alkyl or aryl ester and the 5' -ester is an amino acid ester.

In another embodiment, prodrugs of 1',2',3', or 4' -branched β -D or β -L nucleosides include a biologically cleavable moiety at the 2',3', and/or 5' position. Preferred moieties are natural or synthetic D or L amino acid esters, including D or L-valinyl, but preferably L-amino acid esters, such as L-valinyl, and alkyl esters including acetyl. Thus, the invention specifically includes 2',3' -L or D-diamino acid esters and 2',3',5' -L or D-triamino acid esters of 1',2',3' or 4' -branched β -D or β -L nucleosides, preferably L-amino acids having any desired purine or pyrimidine base, wherein the parent drug optionally has an EC of less than 15 micromolar₅₀More preferably less than 10 micromolar; 2',3' -di (alkyl or aryl) esters or 2',3',5' -L-tri (alkyl or aryl) esters of 1',2',3' or 4' -branched β -D or β -L nucleosides having any desired purine or pyrimidine base, wherein the parent drug optionally has an EC of less than 10 or 15 micromolar₅₀(ii) a And a 2',3' -diester of a 1',2',3 'or 4' -branched β -D or β -L nucleoside, wherein (i) the 2 'ester is an amino acid ester and the 3' -ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; and (iv) the 2 'ester is independently an alkyl or aryl ester and the 3' -ester is an amino acid ester, wherein the parent drug optionally has a molar content of less than 10 or 15 micromoles EC₅₀. Further, 2',3',5' -triesters of 1',2',3' or 4' -branched β -D or β -L nucleosides, wherein (i) all three esters are amino acid esters; (ii) all three esters are independently alkyl or aryl esters; (iii) the 2' ester is an amino acid ester, the 3' ester is an amino acid ester and the 5' -ester is an alkyl or aryl ester; (iv) (iv) the 2 'ester is an alkyl or aryl ester, the 3' ester is an alkyl or aryl ester and the 5 '-ester is an alkyl or aryl ester, (v) the 2' ester is an alkyl or aryl ester, the 3 'ester is an alkyl or aryl ester and the 5' -ester is an amino acid ester; (vi) the 2' ester is an alkyl or aryl ester, the 3' ester is an amino acid ester and the 5' -ester is an amino acid ester; (vii) the 2' ester is an alkyl or aryl ester, the 3' ester is an amino acid ester and the 5' -ester is an alkyl or aryl ester; and (viii) the 2' ester is an amino acid ester, the 3' ester is an alkyl or aryl ester and the 5' -ester is an amino acid ester; wherein the parent drug optionally has an EC of less than 10 or 15 micromolar₅₀。

Examples of prodrugs falling within the present invention include the 2',3' -L-divaline ester of β -D-2', 6-dimethyl-cytidine (dival-2', 6-diMe-L-dC); 2',3' -L-divaline ester of β -D-2', 6-dimethyl-thymidine; 2',3' -L-divaline esters of β -D-2', 8-dimethyl-adenosine; 2',3' -L-divaline ester of β -D-2', 8-dimethyl-guanosine; 2',3' -L-divaline ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; 2',3' -L-divaline ester of β -D-2', 6-dimethyl-uridine; 2',3' -diacetyl ester of β -D-2', 6-dimethyl-cytidine; 2',3' -diacetyl ester of β -D-2', 6-dimethyl-thymidine; 2',3' -diacetyl ester of β -D-2', 8-dimethyl-adenosine; 2',3' -diacetyl ester of β -D-2', 8-dimethyl-guanosine; 2',3' -diacetyl ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; and 2',3' -diester of β -D-2', 6-dimethyl- (cytidine, 5-fluorocytidine, uridine, or thymidine) or 2',3 '-diester of β -D-2', 8-dimethyl- (guanosine, adenosine, or inosine), wherein (i) the 2 'ester is an amino acid ester and the 3' -ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) the two esters are independently alkyl or aryl esters; or (iv) the 2 'ester is an alkyl or aryl ester and the 3' -ester is an amino acid ester.

Further examples of prodrugs falling within the present invention include the 2',3',5' -L-trivaline ester of β -D-2', 6-dimethyl-cytidine (trival-2', 6-diMe-L-dC); 2',3',5 '-L-trivaline ester of β -D-2', 6-dimethyl-thymidine; 2',3',5 '-L-trivaline esters of β -D-2', 8-dimethyl-adenosine; 2',3',5 '-L-trivaline ester of β -D-2', 8-dimethyl-guanosine; 2',3',5 '-L-trivaline ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; 2',3',5 '-L-trivaline ester of β -D-2', 6-dimethyl-uridine; 2',3',5 '-triacetyl ester of β -D-2', 6-dimethyl-cytidine; 2',3',5 '-triacetyl ester of β -D-2', 6-dimethyl-thymidine; 2',3',5 '-triacetyl ester of β -D-2', 8-dimethyl-adenosine; 2',3',5 '-triacetyl ester of β -D-2', 8-dimethyl-guanosine; 2',3',5 '-triacetyl ester of β -D-2', 6-dimethyl-5-fluoro-cytidine; and 2',3',5 '-triesters of β -D-2', 6-dimethyl- (cytidine, 5-fluorocytidine, uridine, or thymidine) and 2',3',5 '-triesters of β -D-2', 8-dimethyl- (guanosine, adenosine, or inosine), wherein (i) all three esters are amino acid esters; (ii) all three esters are independently alkyl or aryl esters; (iii) the 2' ester is an amino acid ester, the 3' ester is an amino acid ester and the 5' -ester is an alkyl or aryl ester; (iv) the 2' ester is an amino acid ester, the 3' ester is an alkyl or aryl ester and the 5' -ester is an alkyl or aryl ester; (v) the 2' ester is an alkyl or aryl ester, the 3' ester is an alkyl or aryl ester and the 5' -ester is an amino acid ester; (vi) the 2' ester is an alkyl or aryl ester, the 3' ester is an amino acid ester and the 5' -ester is an amino acid ester; (vii) the 2' ester is an alkyl or aryl ester, the 3' ester is an amino acid ester and the 5' -ester is an alkyl or aryl ester; and (viii) the 2' ester is an amino acid ester, the 3' ester is an alkyl or aryl ester and the 5' -ester is an amino acid ester.

In a first main embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹,R²and R³Independently H, phosphate (including mono-, di-or triphosphate and stable phosphate); straight, branched or cyclic alkyl (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate esters including alkyl or aralkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl is optionally substituted with one or more substituents as defined herein for aryl; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, lipids, including phospholipids; an amino acid; and amino acid residues, carbohydrates; a peptide; cholesterol; or other pharmaceutically acceptable leaving group, e.g. which, when administered in vivo, is capable of providing a compound wherein R ¹,R²And/or R³A compound that is independently H or phosphate (including mono-, di-, or triphosphate); wherein in one embodiment, R²And/or R³Is not a phosphate (including mono-, di-, or triphosphate or a stable phosphate prodrug);

wherein R is²And R³At least one of which is not hydrogen, and wherein:

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

X¹Is a linear, branched or cyclic optionally substituted alkyl radical, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵(ii) a And

X²is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵(ii) a And

wherein each Y³Independently hydrogen, fluorine, chlorine, bromine or iodine;

R⁴and R⁵Each independently is hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl), lower alkyl, alkenyl, alkynyl, or cycloalkyl.

In the embodiments described herein, R¹,R²And/or R³May be a pharmaceutically acceptable leaving group, e.g. which, when administered in vivo, provides a compound wherein R¹,R²And/or R³Independently H or phosphate (including mono-, di-or triphosphate).

In a second main embodiment, there is provided a compound of formula (II) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (II):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹，R²，R³，R⁴，R⁵，Y¹，Y³，X¹and X²As defined above.

In a third main embodiment, there is provided a compound of formula (III), (IV) or (V) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (III), (IV) or (V):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

The base is selected from:

R¹，R²，R³，R⁴and R⁵As defined above;

W¹，W²，W³and W⁴Each independently is N, CH, CF, CI, CBr, CCl, CCN, CCH₃，CCF₃，CCH₂CH₃，CC(O)NH₂，CC(O)NHR⁴，CC(O)N(R⁴)₂，CC(O)OH，CC(O)OR⁴Or CX³；

W^*Each independently is O, S, NH or NR⁴；

X is O, S, SO₂，CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂；

X is CH, CF, CY³Or CR⁴；

X²Is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵；

X³Each independently is a linear, branched or cyclic optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N₃，CN，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，OH，OR⁴-O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R) alkyl⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), chloro, bromo, fluoro, iodo, NH ₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂；

Y is independently selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCONH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

Wherein R is H, alkyl or acyl;

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

Y²Each independently of the other O, S, NH or NR⁴；

Y³Each independently is H, F, Cl, Br or I;

wherein if W¹，W²And W³Is N, for the base (B), W⁴Cannot be CH;

wherein if W^lIs N, and for bases (E), (F), (K), (L), (W) and (X), W⁴Cannot be CH;

R⁶each independently is optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH2)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)2，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl) ₂Or cyano;

R⁷are each independently OH, OR²Optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaryl ring with one or more O, S and/or N), -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO ₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

or, R⁶And R⁷A compound capable of binding to form a spiro ring selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); and

m is independently 0, 1 or 2.

In a fourth main embodiment, there is provided a compound of formula (VI) or (VII) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a virus of the flaviviridae family, comprising administering a therapeutically effective amount of a compound of formula (VI) or (VII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

base, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，Y，Y¹，Y²，Y³，W¹，W²，W³，W⁴，W^*，X，X*，X¹，X²And X³As defined above;

wherein, in one embodiment, R in formula (VI) is R only when X is carbon⁸is-OH or-NH₂(ii) a And wherein;

R⁸and R¹¹Each independently is hydrogen, optionally substituted alkyl (including lower alkyl), CH ₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Cyano, NH-acyl or N (acyl)₂；

R⁹And R¹⁰Each independently of the others is hydrogen, OH, OR²Optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaromatic with one or more O, S and/or N), -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH) ₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

m is each independently 0, 1 or 2; and

or, R⁶And R¹⁰，R⁷And R⁹，R⁸And R⁷Or R⁹And R¹¹Capable of combining to form a bridged compound selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); or

Or may be R⁶And R⁷Or R⁹And R¹⁰A compound capable of binding to form a spiro ring selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N).

In a fifth main embodiment, there is provided a compound of formula (VIII), (IX) or (X), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VIII), (IX) or (X):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹，R²，R³，R⁴，R⁵，X，Y³and X is as defined above;

base is a purine or pyrimidine base as defined herein;

R¹²each independently is substituted alkyl (including lower alkyl), CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴，-C(O)NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂；

R¹³Each independently is substituted alkyl (including lower alkyl), CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF ₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaromatic with one or more O, S and/or N), -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl) -, (CH₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴，-C(O)SH，-C(O)SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，-O(R⁴) -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), -NHR⁴，-NR⁴R⁵-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), SCN, OCN, NCO or fluorine;

or, R¹²And R¹³A compound capable of binding to form a spiro ring selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); and

m is independently 0, 1 or 2.

In a sixth main embodiment, there is provided a compound of formula (XI) or (XII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (XI) or (XII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

alternatively, the base is substituted with a base of formula (XI) and (XII); and

base, R¹，R²，R³，R⁴，R⁵，R¹²，R¹³，Y，Y¹，Y²，Y³，W^*，W¹，W²，W³，W⁴，X，X*，X¹，X²And X³As defined above;

wherein, in one embodiment, R in formula (XI) is only present when X is carbon⁸is-OH or-NH₂；

And

wherein:

R⁸and R¹¹Each independently is hydrogen, optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH) ₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Cyano, NH-acyl or N (acyl)₂；

R⁹And R¹⁰Each independently of the others is hydrogen, OH, OR²Optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaromatic with one or more O, S and/or N), -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R) ⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

m is each independently 0, 1 or 2; and

or, R⁸And R¹³，R⁹And R¹³，R⁹And R¹¹Or R¹⁰And R¹²Capable of combining to form a bridged compound selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); or

Or, R^l2And R¹³Or R⁹And R¹⁰Capable of combining to form a spiro compound selected from optionally substituted carbocycles (preferably 3-7 membered carbocycles) or optionally substituted heterocycles (preferably 3-7 membered heterocycles with one or more O, S and/or N).

In a particular aspect of the invention, there is provided a compound of formula (XI) or (XII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (XI) or (XII):

Or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R³selected from: h; mono-, di-, and triphosphate or stable phosphate prodrugs; an acyl group; a sulfonate ester; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group, which when administered in vitro provides wherein R³Independently H, or mono-, di-, and triphosphate;

x' is selected from one or more of the following groups: o, S, SO₂N, NH, NR and CH₂Wherein any of the aforementioned groups may be optionally substituted and may be in different positions to form a 3-7 membered ring;

r is H, alkyl or acyl; and

b represents a spiro compound selected from optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N);

the base is selected from:

and

wherein: r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl ₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

m is 0 or 1;

w is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In a second particular aspect of the invention, there is provided a compound of formula (XV), (XVI) or (XVII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, which method comprises administering a therapeutically effective amount of a compound of formula (XV), (XVI) or (XVII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

g and E are independently selected from: CH (CH)₃，CH₂OH，CH₂F，CH₂N₃，CH₂CN，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCONH₂，(CH₂)_mCONR₂，(CH₂)_mCONHR and N-acyl;

m is 0 or 1;

r is H, alkyl or acyl; and

r ', R' ', R' '', R '' '' and R³And the base group is as defined for formula (XIII).

Alternatively, for compounds of formula (XVII), no more than one of G and E can be further hydrogen.

In a third particular aspect of the invention, there is provided a compound of formula (XVIII) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, which method comprises administering a therapeutically effective amount of a compound of formula (XVIII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

m is selected from S, SO, and SO₂(ii) a And

R’，R’’，R’’’，R’'' and R³And the base group is as defined for formula (XIII).

In a fourth particular aspect of the invention, there is provided a compound of formula (XIX), (XX), (XXI) (XXII) or (XXIII) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, which method comprises administering a therapeutically effective amount of a compound of formula (XIX), (XX), (XXI) (XXII) or (XXIII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

a is selected from optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

Y is selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

X is selected from the group consisting of-OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂，(CH₂)_mCONHR, an optionally substituted 3-7 membered carbocyclic ring, and an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently or in combination as heteroatoms;

m is 0 or 1;

r is H, alkyl or acyl;

R₃is selected from H; mono-, di-, and triphosphate or stable phosphate prodrugs; substituted or unsubstituted alkyl; an acyl group; a sulfonate ester; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group, which when administered in vitro provides wherein R ³Independently H, or mono-, di-, and triphosphate; and

the base is a non-natural base selected from:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

m is 0 or 1;

w is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R ' ' '; and

Q₃，Q₄，Q₅and Q₆Independently is N or CH;

the limiting conditions are: in bases (g) and (i), R ', R' '' is not H, OH, or NH₂(ii) a And Q, T, V, Q₂，Q₅And Q₆Is not N.

In one embodiment, the amino acid residue has the formula C (O) C (R) ¹¹)(R¹²)(NR¹³R¹⁴) Wherein:

R¹¹is the side chain of an amino acid, wherein, when in proline, R¹¹May be optionally linked to R¹³Thereby forming a ring structure; or, R¹¹Is an alkyl, aryl, heteroaryl or heterocyclic moiety;

R¹²is hydrogen, alkyl (including lower alkyl) or aryl; and

R¹³and R¹⁴Independently hydrogen, acyl (including the linkage to R)¹¹Acyl derivatives of (a) or alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl).

In another preferred embodiment, R²And R³At least one of which is an amino acid residue, preferably L-valyl.

The beta-D-and beta-L-nucleosides of the present invention inhibit the activity of flaviviridae polymerase. Nucleosides can be screened for their ability to inhibit flavivirus polymerase activity in vitro by the screening methods specifically described herein. The range of activity can be readily determined by evaluating the compounds in the assays described herein or with other confirmatory assays.

In one embodiment, the effectiveness of an anti-flaviviridae compound may be determined based on the concentration of the compound necessary to reduce the number of viral plaques in vitro, up to 50% (i.e., the EC of the compound) according to the methods specifically set forth herein₅₀). In preferred embodiments the parent prodrug compound exhibits an EC of less than 25, 15, 10, 5, or 1 micromolar ₅₀. In a preferred embodiment, the compositions when used in accordance with the methods described in Ferrari et al, Jnl, of vir, 73:1649-1654, 1999; ishii et al, Hepatology,29:1227-1235,1999, Lohmann et al, Jnl.of Bio.chem.,274:10807-10815,1999, or Yamashita et al, Jnl.of Bio.chem.,273:15479The compounds show an EC of less than 15 or 10 micromolar when measured by the polymerase assay described in-15486,1998₅₀。

In another embodiment, combination and/or alternation therapy is provided. In combination therapy, an effective dose of two or more agents are administered together, while in alternating therapy, an effective dose of each agent is administered sequentially. The dosage will depend on the absorption, inactivation and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage will also vary with the severity of the condition to be alleviated. It will also be appreciated that for any particular patient, the particular dosage regimen and timing of administration will be readily adjusted according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

The present invention provides for the co-administration of at least two of the prodrugs described herein. The present invention further provides for the co-administration or alternation of at least one of the 2 'and 3' -prodrugs with another nucleoside exhibiting anti-flaviviridae activity, including, but not limited to, the parent drug of any of the prodrugs defined herein, i.e.,. beta. -D-2', 6-dimethyl-cytidine, beta-D-2', 6-dimethyl-thymidine, beta-D-2 ', 8-dimethyl-adenosine, beta-D-2', 8-dimethyl-guanosine, beta-D-2 ', 6-dimethyl-5-fluorocytidine and/or beta-D-2', 6-dimethyl-uridine. Alternatively, the 2 'or 3' -prodrugs or their prodrugs or pharmaceutically acceptable salts may have an EC of less than 10 or 15 micromolar with others ₅₀In combination or in alternation.

Non-limiting examples of antiviral agents that may be used in combination with the compounds disclosed herein include: 1) interferon and/or ribavirin; (2) a substrate-based NS3 protease inhibitor; (3) a non-substrate based inhibitor; (4) a thiazolidine derivative; (5) thiazolidine and benzanilide; (6) phenanthrenequinone; (7) an NS3 inhibitor; (8) HCV helicase inhibitors; (9) polymerase inhibitors, including RNA-dependent RNA-polymerase inhibitors; (10) antisense oligodeoxynucleotide; (11) inhibitors of IRES-dependent translation; (12) nuclease-resistant ribozymes; and (13) other compounds having activity against flaviviridae viruses. The invention further encompasses co-administration or alternation of the prodrug with immunomodulators or other pharmaceutically active modulators of viral replication, including biological materials such as proteins, peptides, oligonucleotides or gamma-globulins, including but not limited to interferons, interleukins or antisense oligonucleotides expressing or modulating genes of flaviviridae viral replication.

The invention further encompasses co-administration or alternation of the prodrug with immunomodulators or other pharmaceutically active modulators of viral replication, including biological materials such as proteins, peptides, oligonucleotides or gamma-globulins, including but not limited to interferons, interleukins or antisense oligonucleotides expressing or modulating genes of flaviviridae viral replication. Prodrugs

Specifically, the present invention provides the following:

(a) compounds of formulae (XIII) - (XXIII), or pharmaceutically acceptable salts or prodrugs thereof;

(b) a pharmaceutical composition comprising a compound of formulae (XIII) - (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, in combination with a pharmaceutically acceptable carrier or diluent;

(c) a pharmaceutical composition comprising a compound of formulae (XIII) - (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, and one or more other effective antiviral agents, optionally together with a pharmaceutically acceptable carrier or diluent;

(d) a pharmaceutical composition for treating a flaviviridae viral infection in a host, comprising a compound of formulae (I) - (XXIII), or a pharmaceutically acceptable salt thereof or prodrug thereof, and a pharmaceutically acceptable carrier or diluent;

(e) a pharmaceutical composition for the treatment of a flaviviridae viral infection in a host, comprising a compound of formulae (I) - (XXIII), or a pharmaceutically acceptable salt thereof or prodrug thereof, in combination with one or more other effective antiviral agents, optionally in combination with a pharmaceutically acceptable carrier or diluent;

(f) a method for treating a flaviviridae viral infection in a host, comprising a compound of (I) - (XXIII), or a pharmaceutically acceptable salt thereof or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent;

(g) a method for treating a flaviviridae viral infection in a host, comprising combining a compound of formulae (I) - (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent;

(h) Use of a compound of formulae (I) - (XXIII), or a pharmaceutically acceptable salt thereof or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent, in the treatment of a flaviviridae infection in a host;

(i) use of a compound of formulae (I) - (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent, in the treatment of a flaviviridae viral infection in a host;

(j) use of a compound of formulae (I) - (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, optionally together with a pharmaceutically acceptable carrier or diluent, in the manufacture of a medicament for the treatment of a flavivirus infection in a host; and

(k) use of a compound of formulae (I) - (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, with one or more other effective antiviral agents, optionally together with a pharmaceutically acceptable carrier or diluent, in the manufacture of a medicament for the treatment of a flavivirus infection in a host.

In an alternative embodiment, the parent nucleoside compound (i.e., a nucleoside without a 2 '-or 3' -cleavage moiety) of any 2 '-or 3' -prodrug is provided for use in the treatment of flaviviridae infections, particularly hepatitis c virus infections.

Drawings

FIG. 1 provides the structure of various non-limiting examples of nucleosides of the present invention, as well as the structure of other known nucleosides, specifically FIAU and ribavirin.

FIG. 2 provides non-limiting examples of reaction steps involved in esterifying a 1',2',3', or 4' -branched β -D or β -L nucleoside to obtain a 2' -prodrug, a prodrug. The same general procedure can be used to obtain 3' -prodrugs by selective protection of the 2' and 5' -hydroxy groups or protection of the 2',3' and 5' -hydroxy groups and selective deprotection of the 3' -hydroxy group.

FIG. 3 provides non-limiting examples of reaction steps involved in esterifying a 1',2',3', or 4' -branched β -D or β -L nucleoside to obtain a 3' -prodrug, including prodrugs.

FIG. 4 provides non-limiting examples of reaction steps involved in esterifying a 1',2',3', or 4' -branched β -D or β -L nucleoside to obtain a 2',3' -prodrug.

Detailed Description

Disclosed herein are compounds, methods and compositions for treating Flaviviridae virus infections in humans and other host animals. The methods comprise administering a therapeutically effective amount of a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside described herein, or a pharmaceutically acceptable salt, derivative or prodrug thereof, optionally in a pharmaceutically acceptable carrier, against a flaviviridae virus. The compounds of the present invention also have antiviral (i.e., anti-HCV) activity, or are metabolically produced to compounds having such activity. HCV is a member of the flaviviridae family. HCV has been placed into a new haplotype genus, the hepacivirus genus. Thus, in one embodiment, the flaviviridae virus is HCV. In another alternative embodiment, the flaviviridae virus is a flavivirus or pestivirus.

2 'and/or 3' -prodrugs of 1',2',3', or 4' -branched β -D or β -L nucleosides are acyl derivatives of secondary or tertiary alcohols in the alpha position to a secondary or tertiary carbon. Prodrugs are capable of differentially modulating the biological properties of molecules in vitro based on the steric hindrance of these prodrugs to the acyl derivatives of 5' -prodrugs, primary alcohols. It has been found that 2 'and/or 3' -prodrugs of 1',2',3 'or 4' -branched β -D or β -L nucleosides can provide drugs with increased half-lives and improved drug metabolic profiles.

The 2 'or 3' -prodrug in a preferred embodiment is a cleavable acyl group, most particularly an amino acid moiety, prepared from any naturally occurring and synthetic alpha, beta, gamma or delta amino acid, including, but not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid may be a derivative of alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, aspartyl, glutamyl, 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 -aspartyl, β -glutamyl, β -lysyl, β -arginyl or β -histidyl. In a specific embodiment, the moiety is a valine ester. A particularly preferred compound is the 3 '-valine ester of 2', 6-dimethyl-ribose-cytidine.

1',2',3 'or 4' -branched β -D or β -L nucleosides have low oral bioavailability in rodents and non-human primates as the natural base and HCl salt forms. It has been found that 1',2',3', or 4' -branched β -D or β -L nucleosides and other nucleosides or nucleoside analogs have significant competition in gastrointestinal absorption, or transport, and that other nucleosides or nucleoside analogs compete with 1',2',3', or 4' -branched β -D or β -L nucleosides in absorption. To improve oral bioavailability and reduce potential drug-drug interactions, 2',3' or 4' -branched β -D or β -L nucleoside 2' and 3' -prodrugs are obtained with higher oral bioavailability than the parent molecule and with reduced impact on bioavailability of other nucleosides or nucleoside analogs for co-administration.

The 2',3', and/or 5' -mono-, di-or tri-valine esters of the 1',2',3', or 4' -branched β -D or β -L nucleoside have a higher oral bioavailability than the parent 1',2',3', or 4' -branched β -D or β -L nucleoside, and reduced interaction with other nucleosides or nucleoside analogs when used in combination, as compared to the 1',2',3', or 4' -branched β -D or β -L nucleoside.

The 2',3', and/or 5' -mono, di, or tri-valine ester of a 1',2',3', or 4' -branched β -D or β -L nucleoside can be converted to the parent 1',2',3', or 4' -branched β -D or β -L nucleoside by deesterification in the gastrointestinal mucosa, blood, or liver. 2',3', and/or 5' -mono-, di-or tri-valine esters of 1',2',3', or 4' -branched β -D or β -L nucleosides are efficiently transported from the gastrointestinal lumen to the blood upon oral administration by amino acid transporter action in the gastrointestinal mucosa. This is why oral bioavailability is increased compared to the parent 1',2',3 'or 4' -branched β -D or β -L nucleosides, which are transported primarily by the action of amino acid transporters. At the same time, there is also a reduction in the competition between the 2',3', and/or 5' -mono-, di-or tri-valine ester of the ingested 1',2',3', or 4' -branched β -D or β -L nucleoside with other nucleosides or nucleoside analogs that are transported by the action of the nucleoside transporter and not by the action of the amino acid transporter. Since partial deesterification of the di-or tri-valine ester of the 1',2',3 'or 4' -branched β -D or β -L nucleoside occurs prior to complete absorption, the mono-or di-valine ester continues to be absorbed by transport through the action of the amino acid transporter. Thus, the desired better absorption or bioavailability can be maintained, as well as reduced competition with other nucleosides or nucleoside analogs taken into the blood.

In summary, the present invention includes the following features:

(a) 2 'and/or 3' -prodrugs of 1',2',3', or 4' -branched β -D or β -L nucleosides described herein, and pharmaceutically acceptable salts and compositions thereof;

(b) 2 'and/or 3' -prodrugs of 1',2',3', or 4' -branched β -D or β -L nucleosides described herein, and pharmaceutically acceptable salts and compositions thereof, are useful for treating and/or preventing flaviviridae infections, particularly in individuals diagnosed with or at risk of becoming infected with flaviviridae;

(c) 2 'and/or 3' -prodrugs of 1',2',3', or 4' -branched β -D or β -L nucleosides described herein, or pharmaceutically acceptable salts and compositions, are substantially absent of enantiomers of the nucleosides or are substantially isolated from other chemical entities;

(d) methods for preparing 2 'and/or 3' -prodrugs of 1',2',3', or 4' -branched β -D or β -L nucleosides, described in more detail below;

(e) a pharmaceutical formulation comprising a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or diluent;

(f) a pharmaceutical formulation comprising a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside or a pharmaceutically acceptable salt thereof, and one or more other effective anti-HCV agents, optionally in a pharmaceutically acceptable carrier or diluent;

(g) A pharmaceutical formulation comprising a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside or a pharmaceutically acceptable salt thereof, a parent different from the 1',2',3 'or 4' -branched β -D or β -L nucleoside, optionally in a pharmaceutically acceptable carrier or diluent;

(h) a method for treating and/or preventing a host infected with a virus of the flaviviridae family comprising administering an effective amount of a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside, or a pharmaceutically acceptable salt or composition thereof;

(i) a method for treating and/or preventing a host infected with a virus of the flaviviridae family comprising administering in combination and/or alternation an effective amount of a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside, or a pharmaceutically acceptable salt or composition thereof, with one or more effective anti-HCV agents;

(j) a method for treating and/or preventing a host infected with a virus of the flaviviridae family comprising administering an effective amount of a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside, or a pharmaceutically acceptable salt or composition thereof, that is different from the parent of the 1',2',3 'or 4' -branched β -D or β -L nucleoside;

(k) a method for treating and/or preventing a host infected with a virus of the flaviviridae family comprising administering an effective amount of a 2' and/or 3' -prodrug of β -D-2' -methyl-cytidine, or a pharmaceutically acceptable salt thereof or a combination thereof;

(l) A method for the treatment and/or prophylaxis of a host infected with a virus of the flaviviridae family comprising administering an effective amount of a 2 '-valinyl or acetyl ester of β -D-2' -methyl-cytidine, or a pharmaceutically acceptable salt thereof, or a combination thereof;

(m) 2 'and/or 3' -prodrugs of 1',2',3 'or 4' -branched β -D or β -L nucleosides, and pharmaceutically acceptable salts and compositions thereof for treating and/or preventing flaviviridae virus infections in a host;

(n) 2 'and/or 3' -prodrugs of 1',2',3 'or 4' -branched β -D or β -L nucleosides, pharmaceutically acceptable salts or compositions thereof, are administered in combination and/or alternation with one or more effective anti-HCV agents for the treatment and/or prevention of a flaviviridae viral infection in a host;

(o) a 2 'and/or 3' -prodrug of a 1',2',3', or 4' -branched β -D or β -L nucleoside, or a pharmaceutically acceptable salt or composition thereof, for treating and/or preventing a flaviviridae viral infection in a host, the parent being different from the 1',2',3', or 4' -branched β -D or β -L nucleoside;

(p) 2' and/or 3' -prodrugs of β -D-2' -methyl-cytidine, or pharmaceutically acceptable salts thereof, or compositions thereof, for use in the treatment and/or prevention of flaviviridae virus infections in a host;

(q) 2 '-valyl or acetyl ester of β -D-2' -methyl-cytidine, or a pharmaceutically acceptable salt thereof, or a combination thereof, for use in the treatment and/or prevention of a flaviviridae viral infection in a host;

(r) the use of 2 'and/or 3' -prodrugs of 1',2',3 'or 4' -branched β -D or β -L nucleosides, and pharmaceutically acceptable salts and compositions thereof, in the manufacture of a medicament for the treatment and/or prevention of a flaviviridae viral infection in a host;

(s) use of a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside, a pharmaceutically acceptable salt or composition thereof in combination and/or alternation with one or more effective anti-HCV agents in the manufacture of a medicament for the treatment and/or prevention of a flaviviridae viral infection in a host;

(t) use of a 2 'and/or 3' -prodrug of a 1',2',3 'or 4' -branched β -D or β -L nucleoside, or a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment and/or prevention of a flaviviridae viral infection in a host other than a 1',2',3 'or 4' -branched β -D or β -L nucleoside;

(u) use of a 2' and/or 3' -prodrug of β -D-2' -methyl-cytidine, or a pharmaceutically acceptable salt thereof, or a combination thereof, in the manufacture of a medicament for the treatment and/or prevention of a flaviviridae viral infection in a host; and

(v) use of β -D-2 '-methyl-cytidine 2' -valinyl or acetyl ester, or a pharmaceutically acceptable salt thereof, or a combination thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of a flaviviridae viral infection in a host.

A general discussion of Flaviviridae within the scope of the present invention is found in Fields Virology, eds: Fields, B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter31, 1996. In a particular embodiment of the invention, the flaviviridae virus is HCV. In an alternative embodiment of the invention, the flaviviridae virus is a flavivirus or pestivirus. Specific flaviviruses include, but are not limited to: absettarov, Alfuy, Apoi, Aroa, Bagaza, Pacific (Banzi), Bouboui, Bussuquaa, Cacipacore, Kaili Island (Carey Island), Dakarl bat (Dakar bat), Dengue1 (Dengue 1), Dengue2 (Dengue 2), Dengue3 (Dengue 3), Dengue4 (Dengue 4), Edge Hill, Entebbe bat (Entebb bat), Gadgets Guy, Hanzalova, Hypr, Ilheus, Israel turkey meningitidis (Israel turkey meningitidis), Japanese encephalitis (Jasweesee encephatis), Jugla, Hiragia Pacific virus (Jukukayaja), Kadamia, Kakukukutakura, Keuguie, Ke-kayakoea, Hayakayakuchi, Haematology, Hayata, Haemata, Haemargia, Haemargi-Kagakuyazae, Hakkai, Hakkaie, Hakkaike, Hakkai, Hakkaie, Hayae, Hayawarnakai, Hayae, Hayawarnakai, Hayae, Hayawarnakai, Haya, golden bat (phenom-Penh bat), Powassan (Powassan), Rio Bravo (Rio Bravo), rocheo (Rocio), Royal Farm (Royal Farm), Russian spring-summer encephalitis (Russian spring-summer encephalitis), sabaya (Saboya), sai louis encephalitis (st. louis encephalitis), Sal Vieja, San Perlita, saururey Reef, seipike river (Sepik), sokuluuk, Spondweni, stretford (Stratford), Tembusu (Tembusu), autumn eryoni (Tyuleniy), udada s (uganda s), suntout river (usu), weisselbronon (West brazzellon), West wen (West warrio (Yellow fever), Yellow river (Yellow fever) and greenka.

A general discussion of pestiviruses within the scope of the present invention is found in Fields Virology, eds.: Fields, B.N., Knipe, D.M., and Howley, P.M., Lippincott-Raven Publishers, Philadelphia, PA, Chapter33, 1996. Specific pestiviruses include, but are not limited to: bovine viral diarrhea virus ("BVDV"), classical swine fever virus ("CSFV", also known as hog cholera virus) and ovine border disease virus ("BDV").

I. Active compound

In a first broad embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹,R²and R³Independently H, phosphate (including mono-, di-or triphosphate and stable phosphate); straight, branched or cyclic alkyl (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate esters including alkyl or aralkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl is optionally substituted with one or more substituents as defined herein for aryl; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, lipids, including phospholipids; an amino acid; and amino acid residues, carbohydrates; a peptide; cholesterol; or other pharmaceutically acceptable leaving group, e.g. which, when administered in vivo, is capable of providing a compound wherein R ¹,R²And/or R³A compound that is independently H or phosphate (including mono-, di-, or triphosphate); wherein in one embodiment, R²And/or R³Is not a phosphate (including mono-, di-, or tri-phosphate or a stabilized phosphate prodrug);

wherein R is²And R³At least one of which is not hydrogen:

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

X¹Is a linear, branched or cyclic optionally substituted alkyl radical, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵；

X²Is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵(ii) a And

wherein each Y³Independently hydrogen, fluorine, chlorine, bromine or iodine;

R⁴and R⁵Each independently is hydrogen, acyl (including lower acyl), alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl), lower alkyl, alkenyl, alkynyl, or cycloalkyl.

In a preferred embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

R¹is H or phosphate (preferably H);

R²and R³Independently H, phosphate, acyl or an amino acid residue, wherein R²And R³At least one is an acyl group or an amino acid residue;

X¹is CH₃，CF₃Or CH₂CH₃；

X²Is H or NH₂(ii) a And

y is hydrogen, bromine, chlorine, fluorine, iodine, NH₂Or OH.

In a second main embodiment, there is provided a compound of formula (II) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (II):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹，R²，R³，R⁴，R⁵，Y¹，Y³，X¹and X²As defined above.

In a preferred embodiment, there is provided a compound of formula (II) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof. Wherein:

R¹Is H or phosphate (preferably H);

R²and R³Independently H, phosphate, acyl or an amino acid residue, wherein R²And R³At least one is an acyl group or an amino acid residue;

X¹is CH₃，CF₃Or CH₂CH₃；

X²Is H, F, Cl, Br, I or CH₃(ii) a And

y is hydrogen, bromine, chlorine, fluorine, iodine, NH₂Or OH.

In a third main embodiment, there is provided a compound of formula (III), (IV) or (V) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (III), (IV) or (V):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹，R²，R³，R⁴，R⁵，Y，Y¹and X²As defined above;

the base is selected from:

W¹，W²，W³and W⁴Each independently is N, CH, CF, CI, CBr, CCl, CCN, CCH₃，CCF₃，CCH₂CH₃，CC(O)NH₂，CC(O)NHR⁴，CC(O)N(R⁴)₂，CC(O)OH，CC(O)OR⁴Or CX³；

W^*Each independently is O, S, NH or NR⁴；

Wherein if W¹，W²And W³Is N, for the base (B), W⁴Cannot be CH;

wherein if W^lIs N, and for bases (E), (F), (K), (L), (W) and (X), W⁴Cannot be CH;

x is O, S, SO₂，CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂；

X^*Is CH, CF, CY³Or CR⁴；

X³Each independently is a linear, branched or cyclic optionally substituted alkyl (including lower alkyl), CH ₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N₃，CN，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，OH，OR⁴-O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R) alkyl⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), chloro, bromo, fluoro, iodo, NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂；

Y²Each independently is O, S, NH or NR⁴；

Y³Each independently is H, F, Cl, Br or I;

R⁶each independently is optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH ₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Or cyano;

R⁷are each independently OH, OR²Optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaromatic with one or more O, S and/or N), -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl) ₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

or, R⁶And R⁷A compound capable of binding to form a spiro ring selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); and

m is independently 0, 1 or 2.

In a first sub-embodiment, there is provided a compound of formula (III), (IV) or (V) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus comprising administering a therapeutically effective amount of a compound of formula (III), (IV) or (V) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

R^lIs H or phosphate (preferably H);

R²and R³Independently is H, phosphate, acyl or an amino acid residue, wherein R²And R³At least one is an acyl group or an amino acid residue;

W⁴is CX³；

X³Is CH₃，CF₃Or CH₂CH₃；

R⁶Is an alkyl group; and

x is O, S, SO₂Or CH₂。

In a second subembodiment, there is provided a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus comprising administering a therapeutically effective amount of a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

R^lis H or phosphate (preferably H);

R²and R³Independently is H, phosphate, acyl or an amino acid residue, wherein R²And R³At least one is an amino acid residue;

W⁴is CX³；

X³Is CH₃，CF₃Or CH₂CH₃；

R⁶Is an alkyl group; and

x is O, S, SO₂Or CH₂。

In a third sub-embodiment, there is provided a compound of formula (III), (IV) or (V) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus comprising administering a therapeutically effective amount of a compound of formula (III), (IV) or (V) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

R^lIs H or phosphate (preferably H);

R²and R³Independently is H, phosphate, acyl or an amino acid residue, wherein R²And R³At least one is an acyl group or an amino acid residue;

W⁴is CX³；

X³Is CH₃，CF₃Or CH₂CH₃；

R⁶Is an alkyl group; and

x is O.

In a more preferred sub-embodiment, there is provided a compound of formula (iv (a)) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a virus of the flaviviridae family comprising administering a therapeutically effective amount of a compound of formula (iv (a):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

base is defined herein; optionally substituted with an amine or cyclopropyl (e.g., 2-amino, 2, 6-diamino or cyclopropyl guanosine);

R⁷is halogen (F, Cl, Br or I), but preferably F;

R¹is H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹Or R²Independently H or phosphate. In one embodiment, R²Is not a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); and

R²is a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; carbohydrate compound(ii) a A peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R¹Or R²Independently H or phosphate. In one embodiment, R²Is not a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug);

in a fourth main embodiment, there is provided a compound of formula (VI) or (VII) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a virus of the flaviviridae family, comprising administering a therapeutically effective amount of a compound of formula (VI) or (VII):

Or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

base, R¹，R⁴，R⁵，R⁶，R⁷，Y，Y¹，Y²，Y³，W^*，W¹，W²，W³，W⁴，X，X*，X¹，X²And X³As defined above;

wherein, in one embodiment, R in formula (VI) is R only when X is carbon⁸is-OH or-NH₂；

And

wherein;

R⁸and R¹¹Each independently is hydrogen, optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (includingHalogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Cyano, NH-acyl or N (acyl)₂；

R⁹And R¹⁰Each independently of the others is hydrogen, OH, OR²Optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted alkynyl Substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaromatic with one or more O, S and/or N), -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

m is each independently 0, 1 or 2; and

Or, R⁶And R¹⁰，R⁷And R⁹，R⁸And R⁷Or R⁹And R¹¹Capable of combining to form a bridged compound selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); or

Or, R⁶And R⁷Or R⁹And R¹⁰A compound capable of binding to form a spiro ring selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N).

In a particularly preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is O, S, SO or SO₂(ii) a And/or

·R⁶Each independently is optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁷Each independently is-OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO ₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R⁹Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R¹⁰Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

and

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

Their tautomers.

In a particularly preferred alternative embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is O, S, SO or SO₂(ii) a And/or

·R⁶And R⁷(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁹Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO ₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-to 7-membered carbocyclic ring, and optionally substituted with O, S and/orN independently or in combination as a heteroatom 3-7 membered heterocycle; and/or

·R¹⁰Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl,o-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF ₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In another particularly preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is O, S, SO or SO₂(ii) a And/or

·R⁶Each independently is optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynylSubstituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁷Each independently is-OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO ₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R⁹And R¹⁰(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl ₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In another particularly preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is O, S, SO or SO₂(ii) a And/or

·R⁶And R⁷(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁹And R¹⁰(ii) bind to form a spiro compound selected from: an optionally substituted 3-7 membered spirocarbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms as heteroatoms, independently or in combination with others; and/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅And Q₆Independently is N or CH; and

their tautomers.

In a particularly preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂(ii) a And/or

·R⁶Each independently is optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁷Each independently of the others, -OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl,Br，I，CN，NC，SCN，OCN，NCO，NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R⁹Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R¹⁰Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In a particularly preferred alternative embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

X is CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂(ii) a And/or

·R⁶And R⁷(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁹Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R¹⁰Each independently is hydrogen, optionally substituted lower alkyl, optionally substitutedSubstituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-arylRadicals, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In another particularly preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

X is CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂(ii) a And/or

·R⁶Each independently is optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁷Each independently is-OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R⁹And R¹⁰Combined to form a spiro compound, optionallyFrom: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In another particularly preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

X is CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂(ii) a And/or

·R⁶And R⁷(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁹And R¹⁰(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH ₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In a particularly preferred embodiment, there is provided a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is CH, CF, CY³Or CR⁴(ii) a And/or

·R⁶Each independently is optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁷Each independently is-OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO ₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R⁹Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R¹⁰Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

wherein R is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In a particularly preferred alternative embodiment, there is provided a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is CH, CF, CY³Or CR⁴(ii) a And/or

·R⁶And R⁷(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁹Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -OH, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO ₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R¹⁰Each independently is hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF ₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

r is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In another particularly preferred embodiment, there is provided a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is CH, CF, CY³Or CR⁴(ii) a And/or

·R⁶Each independently is optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂Or (CH)₂)_mCONHR⁴(ii) a And/or

·R⁷Each independently is-OH, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO ₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R⁴，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴Optionally substituted 3-7 membered carbocycle, and optionally substituted 3-7 membered heterocycle having O, S and/or N independently or in combination as heteroatoms; and/or

·R⁹And R¹⁰(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl ₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN，-C-COOH，-C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

r is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In another particularly preferred embodiment, there is provided a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, wherein:

x is CH, CF, CY³Or CR⁴(ii) a And/or

·R⁶And R⁷(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁹And R¹⁰(ii) bind to form a spiro compound selected from: optionally substituted 3-7 membered spiro carbocyclic ring or heterocyclic compound having one or more N, O and/or S atoms, said heteroatoms being selected individually or together with other heteroatoms; and/or

·R⁸And R¹¹Are each independently H, CH₃，CH₂OH，CH₂F，CH₂N₃，(CH₂)_mCOOH，(CH₂)_m COOR⁴，(CH₂)_mCONH₂，(CH₂)_mCON(R⁴)₂，(CH₂)_mCONHR⁴And an N-acyl group; and/or

M is each independently 0 or 1; and/or

The base is selected from one of the following:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

W is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

r is H, alkyl or acyl;

Q₃，Q₄，Q₅And Q₆Independently is N or CH; and

their tautomers.

In a first sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R¹A compound that is independently H or phosphate; (2) r⁶Is an alkyl group; (3) r⁷And R⁹Independently is OR²Alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂Amino, lower alkylamino or di (lower alkyl) amino; (4) r⁸And R¹⁰Independently is H, alkyl (including lower alkyl), chloro, bromo, or iodo; (5) x is O, S, SO₂Or CH₂；(6)W⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a second sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate)A root, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO₂Amino, lower alkylamino, or di (lower alkyl) amino; (3) r⁷And R⁹Independently is OR²；(4)R⁸And R¹⁰Independently is H, alkyl (including lower alkyl), chloro, bromo, or iodo; (5) x is O, S, SO₂Or CH₂；(6)W⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a third sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is alkyl, alkenyl, alkynylBr-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂Amino, lower alkylamino, or di (lower alkyl) amino; (3) r⁷And R⁹Independently is OR²Alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (4) r⁸And R¹⁰Is H; (5) x is O, S, SO₂Or CH 2; (6) w⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a fourth sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO₂Amino, lower alkylamino, or di (lower alkyl) amino; (3) r⁷And R⁹Independently is OR²Alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (4) r⁸And R¹⁰Independently is H, alkyl (including lower alkyl), chloro, bromoOr iodine; (5) x is O; (6) w⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a fifth subembodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, and also a method for treating a host infected with a flavivirus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is an alkyl group; (3) r⁷And R⁹Independently is OR¹；(4)R⁸And R¹⁰Independently H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) x is O, S, SO₂Or CH₂；(6)W⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a sixth sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, and also a method for treating a host infected with a flavivirus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower)Acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is an alkyl group; (3) r⁷And R⁹Independently is OR²Alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (4) r⁸And R¹⁰Is H; (5) x is O, S, SO₂Or CH₂；(6)W⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a seventh sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is an alkyl group; (3) r⁷And R⁹Independently is OR²Alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine,bromine, iodine, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (4) r⁸And R¹⁰Independently is H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) x is O; (6) w⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In an eighth sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (3) r⁷And R⁹Independently is OR²；(4)R⁸And R¹⁰Is hydrogen; (6) x is O, S, SO₂Or CH₂；(6)W⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a ninth subembodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a patient infected with yellow feverA method of treating a host of a virus of the virus family comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; an amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ¹A compound that is independently H or phosphate; (2) r⁶Is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (3) r⁷And R⁹Independently is OR²；(4)R⁸And R¹⁰Independently is H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) x is O; (6) w⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a tenth subembodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein: (1) r¹Independently H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate esters include alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as defined herein for aryl; lipids, including phospholipids; An amino acid; a carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R¹A compound that is independently H or phosphate; (2) r⁶Is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (3) r⁷And R⁹Independently is OR²Alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO₂Amino, lower alkylamino, or di (lower alkyl) amino; (4) r⁸And R¹⁰Is hydrogen; (5) x is O; (6) w⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a tenth embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently is H or phosphate; (2) r ⁶Is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂Amino, lower alkylamino or di (lower alkyl) amino; (3) r⁷And R⁹Independently is OR²；(4)R⁸And R¹⁰Is hydrogen; (5) x is O, S, SO₂Or CH₂；(6)W⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a twelfth subembodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a viral infection with a Flaviviridae virusA method of treating a disease or disorder comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer, or polymorph thereof, wherein: (1) r¹Independently is H or phosphate; (2) r⁶Is an alkyl group; (3) r⁷And R⁹Independently is OR²；(4)R⁸And R¹⁰Is hydrogen; (5) x is O, S, SO₂Or CH₂；(6)W⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a thirteenth subembodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein: (1) r ¹Independently is H or phosphate; (2) r⁶Is an alkyl group; (3) r⁷And R⁹Independently is OR²；(4)R⁸And R¹⁰Independently is H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) x is O; (6) w⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a fourteenth sub-embodiment is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein: (1) r¹Independently is H or phosphate; (2) r⁶Is an alkyl group; (3) r⁷And R⁹Independently is OR²Alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO₂Amino, lower alkylamino, or di (lower alkyl) aminoA group; (4) r⁸And R¹⁰Is hydrogen; (5) x is O; (6) w⁴Is CX³(ii) a And (7) X³Is CH₃，CF₃Or CH₂CH₃。

In a more preferred sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, wherein:

(1) The base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methylguanine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methylcytosine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyl thymidine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyluracil; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyladenine; (2) r¹Is a phosphate radical; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is an ethyl group; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is a propyl group; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is a butyl group; (4) r⁷And R ⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷Is hydrogen and R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is O;

(1) the base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is S;

(1) the base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is SO₂；

(1) The base is 8-methyladenine; (2) r¹Is hydrogen; (3) r⁶Is methyl; (4) r⁷And R⁹Is a hydroxyl group; (5) r⁸And R¹⁰Is hydrogen; and (6) X is CH₂；

In a fifth main embodiment, there is provided a compound of formula (VIII), (IX) or (X), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (VIII), (IX) or (X):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹，R²，R³，R⁴，R⁵，Y³x and X are as defined above;

base is a purine or pyrimidine base as defined herein;

R¹²each independently is substituted alkyl (including lower alkyl), CH ₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴，-C(O)NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂；

R¹³Each independently is substituted alkyl (including lower alkyl), CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaromatic with one or more O, S and/or N), -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (Low)Alkyl grade)₂，-C(O)OH，-C(O)OR⁴，-C(O)SH，-C(O)SR⁴-C (O) S (lower alkyl), -C (O) NH ₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，-O(R⁴) -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), -NHR⁴，-NR⁴R⁵-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), SCN, OCN, NCO or fluorine;

or, R¹²And R¹³A compound capable of binding to form a spiro ring selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); and

m is independently 0, 1 or 2.

In a sixth main embodiment, there is provided a compound of formula (XI) or (XII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a virus of the flaviviridae family comprising administering a therapeutically effective amount of a compound of formula (XI) or (XII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

base groups R, R¹，R²，R³，R⁴，R⁵，R¹²，R¹³，Y，Y¹，Y²，Y³，W^*，W¹，W²，W³，W⁴，X，X*，X²And X³As defined above;

wherein, in one embodiment, R in formula (XI) is only present when X is carbon ⁸is-OH or-NH₂；

And wherein;

R⁸and R¹¹Each independently is hydrogen, optionally substituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Cyano, NH-acyl or N (acyl)₂；

R⁹And R¹⁰Each independently of the others is hydrogen, OH, OR²Optionally takingSubstituted alkyl (including lower alkyl), CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl (including halogenated lower alkyl), CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocycle), optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N), optionally substituted heteroaryl (preferably 3-7 membered heteroaromatic with one or more O, S and/or N), -CH ₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

m is each independently 0, 1 or 2; and

or, R⁸And R¹³，R⁹And R¹³，R⁹And R¹¹Or R¹⁰And R¹²Capable of combining to form a bridged compound selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); or

Or, R^l2And R¹³Or R⁹And R¹⁰Capable of combining to form a spiro compound selected from optionally substituted carbocycles (preferably 3-7 membered carbocycles) or optionally substituted heterocycles (preferably 3-7 membered heterocycles with one or more O, S and/or N).

In a particular aspect of the invention, there is provided a compound of formula (XIII) or (XIV), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a virus of the flaviviridae family, comprising administering a therapeutically effective amount of a compound of formula (XIII) or (XIV):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R₃is selected from H; mono-, di-, and triphosphate or stable phosphate prodrugs; an acyl group; a sulfonate ester; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R₃Independently H, or mono-, di-, and triphosphate;

x' is selected from one or more of O, S, SO₂N, NH, NR and CH₂Wherein any one of the aforementioned groups may be optionally substituted and may be in different positions to form a 3-7 membered ring;

R is H, alkyl or acyl;

b represents a spiro compound selected from optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably 3-7 membered heterocycle with one or more O, S and/or N); and

the base is selected from:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

m is 0 or 1;

w is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

r is H, alkyl or acyl;

Q₃，Q₄，Q₅and Q₆Independently is N or CH; and

their tautomers.

In a second particular aspect of the invention, there is provided a compound of formula (XV), (XVI) or (XVII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (XV), (XVI) or (XVII):

Or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

g and E are independently selected from CH₃，CH₂OH，CH₂F，CH₂N₃，CH₂CN，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCONH₂，(CH₂)_mCONR₂，(CH₂)_mCONHR and N-acyl;

r is H, alkyl or acyl; and

m is 0 or 1;

R³and bases are as defined for formula (XIII).

Alternatively, for compounds of formula (XVII), up to one of G and E may further be hydrogen.

In a third particular aspect of the invention, there is provided a compound of formula (XVIII) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (XVIII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

m is selected from S, SO, and SO₂(ii) a And

R₃and bases are as defined for formula (XIII).

In a fourth particular aspect of the invention, there is provided a compound of formula (XIX), (XX), (XXI) (XXII) or (XXIII) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (XIX), (XXI) (XXII) or (XXIII):

Or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

a is selected from optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

Y is selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

X is selected from the group consisting of-OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCONH₂，(CH₂)_mCONR₂，(CH₂)_mCONHR, an optionally substituted 3-7 membered carbocyclic ring, and an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently or in combination as heteroatoms;

m is 0 or 1;

R₃is selected from H; mono-, di-, and triphosphate or stable phosphate prodrugs; substituted or unsubstituted alkyl; an acyl group; a sulfonate ester; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R ³Independently H, or mono-, di-, and triphosphate; and

the base is a non-natural base selected from:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl,s-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

m is 0 or 1;

w is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R ' ' '; and

Q₃，Q₄，Q₅and Q₆Independently is N or CH;

with the proviso that in the bases (g) and (i) R ', R ' ' ' ' is not H, OH, or NH₂(ii) a And Q, T, V, Q₂，Q₅And Q₆Is not N.

In another preferred embodiment, there is provided a compound of formula (IX) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomer, tautomer or polymorph thereof, and also a method for treating a host infected with a flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (IX):

Or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer, or polymorph thereof, wherein:

R¹，R²and R³Independently is H; phosphate radical; linear, branched or cyclic alkyl; an acyl group; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; a sulfonate ester; benzyl, wherein the phenyl is optionally substituted with one or more substituents; an alkylsulfonyl group; an arylsulfonyl group; an aralkylsulfonyl group; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; or a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound wherein R¹，R²And/or R³A compound that is independently H or phosphate;

x is O, S, SO₂Or CH₂；

Base is a purine or pyrimidine base;

R¹²is C (Y)³)³；

Y³Independently is H, F, Cl, Br or I; and

R¹³is fluorine.

In one sub-embodiment X is O, and Y³Is H. In another sub-embodiment, when X is O and Y³When is H, R¹，R²And R³Is also H.

Stereochemistry

It will be appreciated that nucleosides of the present invention have multiple chiral centers and can exist and be isolated in optically active and racemic forms. Some compounds have polymorphism. It is to be understood that the present invention encompasses any racemate, optically active form, diastereomer, polymorph, or stereoisomer of the compounds of the present invention, or mixtures thereof, which have utility as described herein. It is well known in the art how to prepare optically active forms (e.g., by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

In particular, because the 1 'and 4' carbons of nucleosides are chiral, their non-hydrogen substituents (base and CHOR, respectively) can be either cis (on the same side) or trans (on the opposite side) with respect to the sugar ring system. Thus, the four optical isomers are represented in the following configuration (when the sugar moiety is oriented in the horizontal plane, such that the oxygen atom is located behind): cis (two groups located "above", corresponding to the configuration of the naturally occurring β -D nucleoside), cis (two groups located "below", corresponding to the configuration of the naturally occurring β -L nucleoside), trans (C2 'substituent located "above" and C4' substituent located "below"), and trans (C2 'substituent located "below" and C4' substituent located "above"). A "D-nucleoside" is a cis nucleoside in its natural configuration and an "L-nucleoside" is a cis nucleoside in its non-naturally occurring configuration.

Likewise, most amino acids are also chiral (designated as L or D, where the L enantiomer is the naturally occurring configuration) and can exist as separate enantiomers.

Examples of methods for obtaining optically active starting materials are well known in the art and include at least the following:

i)mechanical resolution method of crystalIn this technique, individual enantiomers of macroscopic crystals are separated manually. This technique can be used if crystals of the separated enantiomers are present, i.e., the starting material is an agglomerate, and the crystals are visually distinguishable;

ii)Simultaneous crystallization processIn this technique, the individual enantiomers are crystallized separately from the racemic solution, only if the latter is a coagulum in the solid state;

iii)enzyme resolution methodIn this synthesis technique, the racemate is partially or totally separated by the difference in the reaction rate of the enantiomers with the enzyme;

iv)enzyme asymmetric synthesis method-in this synthesis technique, at least one step in the synthesis process uses an enzymatic reaction to obtain a synthetic precursor of the desired enantiomer, isomerically pure or enriched;

v)chemical asymmetric synthesis methodIn this synthesis technique, the synthesis of the desired enantiomer from a chiral precursor under conditions that produce asymmetry (i.e. chirality) in the product is achieved by the use of chiral catalysts or chiral auxiliaries;

vi)diastereomer resolution processIn this technique, the racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization according to more distinct structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;

vii)first and second order asymmetric transformation methodIn this technique, the diastereomers in the racemate reach equilibrium, so that the predominant diastereomer in solution is produced from the desired enantiomer, or the predominant crystallization of the diastereomer in the desired enantiomer disturbs the equilibrium, so that eventually all the starting materials are converted essentially from the desired enantiomer into the crystalline diastereomer, after which the desired enantiomer is released from the diastereomer;

viii)Kinetic resolution methodThis technique refers to the use of reactions of enantiomers with chiral, non-racemic reagents or catalysts with different reaction rates under kinetic conditions to obtain partial or complete resolution of the racemate (or further resolution of partially resolved compounds);

ix)enantiospecific synthesis starting from non-racemic precursorsIn this synthesis technique, the desired enantiomer is obtained starting from achiral starting materials and its stereochemical integrity is not or only minimally compromised during the synthesis.

x)Chiral liquid chromatographyIn this technique, the enantiomers of the racemate are separated in the liquid mobile phase according to their different interactions with the stationary phase. The stationary phase may be made of chiral starting materials or the mobile phase may contain additional chiral starting materials to induce different interactionsActing;

xi)chiral gas chromatographyIn this technique, the racemate is volatilized and the enantiomers are separated by different interactions of the racemate and the enantiomers in the gas mobile phase with the fixed, non-racemic chiral absorption phase;

xii)chiral solvent extraction process-in this technique, the separation of enantiomers by selective dissolution of one enantiomer in a specific chiral solvent;

xiii)Chiral membrane through resolution methodIn this technique, the racemate is brought into contact with a thin barrier membrane. The separation membrane usually separates two miscible liquids, one containing the racemate, and this separation is carried out by using a driving force such as a concentration difference or a pressure difference to promote selective passage through the separation membrane. The separation results in a non-racemic chiral body since the membrane exploits the property of allowing only one enantiomer of the racemate to pass through.

III. definition

The term "alkyl" as used herein, unless otherwise indicated, refers to a saturated straight, branched or cyclic primary, secondary or tertiary hydrocarbon group of generally 1 to 10 carbon atoms, including specifically methyl, CF₃，CCl₃，CFCl₂，CF₂Cl, ethyl, CH₂CF₃，CF₂CF₃Propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2, 2-dimethylbutyl, and 2, 3-dimethylbutyl. The term includes substituted and unsubstituted alkyl groups, and particularly includes haloalkyl groups, and more particularly fluorinated alkyl groups. Non-limiting examples of moieties which may be used to substitute alkyl are selected from halogen (fluorine, chlorine, bromine or iodine), hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, which are either unprotected or protected as desired, as is known in the art Known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, second edition,1991, which is hereby incorporated by reference.

The term "lower alkyl" as used herein, unless otherwise indicated, refers to a saturated straight, branched or suitably cyclic (e.g., cyclopropyl) alkyl group, typically 1 to 4 carbon atoms, including both substituted and unsubstituted.

The term "alkylamino" or "arylamino" refers to an amino group having one or two alkyl or aryl substituents, respectively. In the present application, unless otherwise specified, when alkyl is a suitable substituent, lower alkyl is preferred. Likewise, when alkyl or lower alkyl is a suitable substituent, unsubstituted alkyl or lower alkyl is preferred.

Unless otherwise defined, the term "protected" as used herein refers to a group added to an oxygen, nitrogen or phosphorus atom to prevent further reaction thereof or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

The term "aryl" as used herein, unless otherwise indicated, refers to phenyl, biphenyl or naphthyl, preferably phenyl. The term includes both substituted and unsubstituted. The aryl group may be substituted with any of the groups described including, but not limited to, one or more groups selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as needed, as known to those skilled in the art, for example, as taught in Greene, et al, protective groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The term "alkaryl" or "alkylaryl" refers to an alkyl group having one aryl substituent. The term aralkyl or arylalkyl refers to an aryl group having one alkyl substituent.

The term "halo" as used herein includes chloro, bromo, iodo and fluoro.

The term "purine" or "pyrimidine" base includes, but is not limited to, adenine, N⁶-alkylpurine, N⁶Acylpurines (in which the acyl group is C (O) (alkyl, aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinyl purine, N⁶-acetylene type purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-alkylaminopurine, N⁶Thio alkyl purine, N²-alkylpurine, N²-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine including 6-azacytosine, 2-and/or 4-mercaptopyrimidine, uracil, 5-halouracil including 5-fluorouracil, C⁵Alkyl pyrimidines, C⁵-benzylpyrimidine, C⁵-halogenopyrimidines, C⁵-vinyl pyrimidine, C⁵-acetylene type pyrimidines, C⁵Acyl pyrimidines, C⁵-hydroxyalkylpurine, C⁵- (acyl) aminopyrimidines, C⁵-cyanopyrimidine, C⁵-iodopyrimidine, C⁶-iodopyrimidine, C⁵-Br-vinyl pyrimidine C ⁶-Br-vinyl pyrimidine C⁵-nitropyrimidine, C⁵-amino-pyrimidine, N²-alkylpurine, N²-alkyl-6-thiopurine, 5-azacytidine, 5-azauracil, triazolopyridine, imidazopyridine, pyrrolopyrimidine, and pyrazolopyrimidine. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2, 6-diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen on the base may be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

The term "acyl" or "O-linked ester" refers to a group having the formula c (O) R ', wherein R' is a straight, branched, or cyclic alkyl (including lower alkyl), amino acid, aryl including phenyl, alkaryl, aralkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including optionally chloro, bromo, fluoro, iodo, C ₁To C₄Alkyl or C₁To C₄Alkoxy substituted phenyl, sulfonates such as alkyl or aralkylsulfonyl including methanesulfonyl, mono-, di-or triphosphate, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, aralkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. The aryl group in the ester preferably comprises a phenyl group. Specifically, the acyl group includes acetyl group, trifluoroacetyl group, methylacetyl group, cyclopropylacetyl group, cyclopropylcarboxyl group, propionyl group, butyryl group, hexanoyl group, heptanoyl group, octanoyl group, neo-heptanoyl group, phenylacetyl group, 2-acetoxy-2-phenylacetyl group, diphenylacetyl group, α -methoxy- α -trifluoromethyl-phenylacetyl group, bromoacetyl group, 2-nitro-phenylacetyl group, 4-chloro-phenylacetyl group, 2-chloro-2, 2-diphenylacetyl group, 2-chloro-2-phenylacetyl group, pivaloyl group, chlorodifluoroacetyl group, perfluoroacetyl group, fluoroacetyl group, bromodifluoroacetyl group, methoxyacetyl group, 2-thienylacetyl group, chlorosulfonylacetyl group, 3-methoxyphenylacetyl group, phenoxyacetyl, tert-butylacetyl, trichloroacetyl, monochloroacetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodecafluoro-heptanoyl, 7-chlorododecafluoro-heptanoyl, 7-chloro-dodecadifluoro-heptanoyl, 7H-dodecafluoro-heptanoyl, nonafluoro-3, 6-dioxa-heptanoyl, nonanfluoro-3, 6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxy, 3, 6-dichloro-2-methoxy-benzoyl, 4- (1, 2, 2-tetrafluoro-ethoxy) -benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearoyl, 3-cyclopentyl-propionyl, 1-benzene-carboxylic acid -yl, O-acetylmandeloyl, pivaloylacetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2, 6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexylcarboxyl, 4-methylbenzoyl, chloromethyl isoxazolylcarbonyl, perfluorocyclohexylcarboxyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinocarbonyl, 4-phenylbenzoyl. When the term acyl is used, it refers to the following specifically and independently: acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, diphenylacetyl, α -trifluoromethyl-phenylacetyl, bromoacetyl, 4-chloro-phenylacetyl, 2-chloro-2, 2-diphenylacetyl, 2-chloro-2-phenylacetyl, pivaloyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiopheneacetyl, t-butylacetyl, trichloroacetyl, monochloroacetyl, dichloroacetyl, methoxybenzoyl, 2-bromo-propionyl, decanoyl, n-pentadecanoyl, stearoyl, 3-cyclopentyl-propionyl, 1-benzene-carboxy, pivaloylacetyl, 1-adamantane-carboxy, cyclohexane-carboxy, 2, 6-pyridinedicarboxy, cyclopropane-carboxy, cyclobutane-carboxy, 4-methylbenzoyl, crotonyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 4-phenylbenzoyl.

The term "amino acid" includes naturally occurring and synthetic alpha, beta, gamma or delta amino acids, including, but not limited to, the amino acids found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine. In a preferred embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid may be a derivative of alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, aspartyl, glutamyl, 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 -aspartyl, β -glutamyl, β -lysyl, β -arginyl or β -histidyl. Tables 1-24 list examples used in the present invention. When the term amino acid is used, it is considered to be the following specific and independent respectively: esters of alpha, beta, gamma or delta glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine in the D and L configurations.

As used herein, the term "substantially free of" or "substantially absent" means that at least 85% or 90%, preferably 95%, 98%,99% or 100% by weight of the designated enantiomer of the nucleoside is included in the nucleoside composition. In a preferred embodiment, in the methods and compounds of the present invention, the compounds are substantially free of enantiomers.

Similarly, the term "isolated" refers to a nucleoside composition that includes at least 85%, 90%, 95%, 98%,99% or 100% by weight of the nucleoside, with the remainder comprising other chemicals or enantiomers.

The term "host" as used herein refers to a unicellular or multicellular organism in which a virus can replicate, including cell lines and animals, preferably humans. Alternatively, the host may carry a portion of the flavivirus genome, the replication or function of which may be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with all or a portion of the flavivirus genome, and animals, particularly primates (including chimpanzees) and humans. In most animals, the host is a human patient for which the invention is useful. However, in certain indications, veterinarians may also apply the invention (e.g. for chimpanzees).

The term "pharmaceutically acceptable salt or prodrug" is used throughout to describe any pharmaceutically acceptable form of the nucleoside compound (e.g., ester, phosphate, ester salt or related group) which, upon administration of all of these forms to a patient, provides the nucleoside compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Among other acids well known in the pharmaceutical arts, suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium. Pharmaceutically acceptable prodrugs refer to compounds that are metabolized, e.g., hydrolyzed or oxidized, in the host to form the compounds of the invention. Typical examples of prodrugs include compounds having a biologically labile protecting group in a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The compounds of the present invention have antiviral activity against flaviviridae viruses, or are metabolized to produce compounds having such activity.

IV prodrugs and derivatives

In the recipient to be administered, the active compound may be administered in the form of any salt or prodrug to provide, directly or indirectly, the parent compound, or a compound which is active itself. Non-limiting examples are pharmaceutically acceptable salts (or referred to as "physiologically acceptable salts"), and compounds that are alkylated, acylated or otherwise modified at the 5' position or at the purine or pyrimidine base (a type of "pharmaceutically acceptable prodrug"). Further, the modification can affect the biological activity of the compound, in some instances increasing the activity over the parent compound. The compounds can be readily evaluated by preparing the salts or prodrugs and testing them against viruses according to the methods described herein or other methods known to those skilled in the art.

A. Pharmaceutically acceptable salts

In some instances, it is suitable to administer a compound in the form of a pharmaceutically acceptable salt when the compound is sufficiently basic or acidic to form a stable, non-toxic acid or base salt. Examples of pharmaceutically acceptable salts are organic acid addition salts formed by addition of an acid which form a physiologically acceptable anion, such as tosylate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α -ketoglutarate, α -glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate and salicylate. Suitable inorganic salts may also be formed, including sulfates, nitrates, bicarbonates, carbonates, hydrobromides and phosphoric acid. In a preferred embodiment, the salt is a mono-or di-hydrochloride salt.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a compound having sufficient basicity, such as an amine, with a suitable acid to provide a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids may also be obtained. In one embodiment, the salt is the hydrochloride salt of the compound. In another embodiment, the pharmaceutically acceptable salt is the dihydrochloride salt.

B. Nucleotide prodrug compositions

The nucleosides described herein can be administered in the form of nucleotide prodrugs to increase the activity, bioavailability, stability, or otherwise alter the properties of the nucleosides. Many nucleotide prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the mono-, di-or triphosphate of the nucleoside reduces its polarity and enters the cell. Examples of substituents which can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates including sugars, 1, 2-diacylglycerol and alcohols. Many are described in R.Jones and N.Bischofenger, Antiviral Research,1995,27: 1-17. Any of which may be used in combination with the nucleosides disclosed herein to achieve the desired effect.

In an alternative embodiment, the nucleoside is provided in the form of a phosphonate or a SATE derivative.

The active nucleoside may also be provided in the form of a 2',3' and/or 5 '-phosphoether ester or a 2',3 'and/or 5' -ether ester. Non-limiting examples are described in references (which are hereby incorporated by reference) including the following: kucera, l.s., n.i. er, e.leak, a.raben, model e.k., d.l.w., and c.piantadosi.1990, "new membrane-interacting ether-lipid analogs (Novel membrane-interactive viral infection HIV-1production and induced defective virus formation) that inhibit HIV-1 infection from producing and inducing defective virus formation" AIDS res.hum.retro viruses.6:. ion 501; pinatadosi, c, j.marasco c.j., s.l.morris-Natschke, k.l.meyer, f.gummus, j.r.surles, k.s.ishaq, l.s.kucera, n.i yer, c.a.wallen, s.pinatadosi, and e.j.model.1991, "Synthesis and evaluation of novel etherlipid nucleoside conjugates with anti-HIV activity" (j.med.chem.34: 1408.1414; lipid prodrugs of "dimyristoyl glycerol 3' -deoxythymine diphosphate, 3' -deoxythymine" of human immunodeficiency virus type1replication inhibition in CEM and HT4-6C cells (great handheld inhibition of human immunodeficiency virus type1replication CEM and HT4-6C cells by3' -deoxythymidine diphosphate of ionic products of formula 3, deoxythymidine) ", antibiotic chemistry 2025.2029, antibiotic chemistry 3836; hosetler, k.y., l.m.stuhmiller, h.b.lenting, h.van den bosch, and d.d.richman,1990 "Synthesis of phospholipid analogs of azidothymine and other antiviral nucleosides has anti-retroviral activity (Synthesis and antiviral activity of phospholipid analogs of azido thymine and other antiviral nucleosides)" j.biol.chem.265: 61127. Non-limiting examples of suitable lipophilic substituents or lipophilic agents disclosed in U.S. patents that can be covalently bound to a nucleoside, preferably at the 2',3' and/or 5' -OH position of the nucleoside, include: U.S. Pat. No. 5,149,794 (22/9/1992, Yatvin et al); no. 5,194,654 (3.16.1993, Hostetler et al); no. 5,223,263 (6.29.1993, Hostetler et al); 5,256,641 (26/10/1993, Yatvin et al); no. 5,411,947 (5.2.1995, Hostetler et al); no. 5,463,092 (10.31.1995, Hostetler et al); 5,543,389 (1996, 8/6/Yatvin et al); 5,543,390 (1996, 8/6/Yatvin et al); 5,543,391 (1996, 8/6/Yatvin et al); and 5,554,728 (1996, 9/10/Basava, etc.), all of which are incorporated herein by reference. Applications in foreign patents disclosing lipophilic substituents or lipophilic agents that may be attached to the nucleosides of the present invention include: WO89/02733, WO90/00555, WO 91/1697, WO91/18914, WO93/00910, WO94/26273, WO96/15132, EP0350287, EP93917054.4 and WO 91/19721.

Aryl esters, particularly phenyl esters, are also provided. Non-limiting examples are disclosed in DeLambertet et al, j.med.chem.37:498 (1994). Also provided are phenyl esters containing carboxylic acid esters ortho-linked to a phosphate ester. Khamnei and Torrence, J.Med.chem.;39: 4109-. In particular, benzyl esters are provided which yield the parent compound, in some instances using substituents in the ortho or para positions to accelerate hydrolysis. Examples of such prodrugs are described in Mitchellet et al, j.chem.soc.perkin trans.i2345 (1992); brook, et al, WO 91/19721; and andGlazier et al, WO 91/19721.

Cyclic and acyclic phosphonates are also provided. Non-limiting examples are disclosed in Hunstonet et al, J.Med.chem.27: 440-. In addition, cyclic 3',5' -phosphate esters are also provided. Non-limiting examples are disclosed in Meier et al, J.Med.chem.22:811-815 (1979). Cyclic 1',3' -propyl phosphonates and phosphates, such as one containing a fused aryl ring, i.e., a cyclosaligenyl ester, are also provided (Meier et al, bioorg. Med. chem. Lett.7:99-104 (1997)). Cyclic 1',3' -propyl esters are also provided for the preparation of unsubstituted monophosphates (Farquhar et al, J.Med.Chem.26:1153(1983); Farquhar et al, J.Med.Chem.28:1358 (1985)). In addition, cyclic 1',3' -propyl esters substituted at C-1' with a pivaloyloxy (pivaloyloxy) methoxy group are provided (Freed et al, biochem. Pharmac.38:3193(1989); Biller et al, U.S. Pat. No.5,157, 027).

Cyclic phosphoramidate cleavage by an oxidative mechanism is known in vivo. Thus, in one embodiment of the present invention, various substituted 1',3' propyl cyclic phosphoramidates are provided. Non-limiting examples are disclosed in Zon, Progress in Med. chem.19,1205 (1982). In addition, a number of 2 '-and 3' -substituted pro-esters are provided. 2' -substituents include methyl, dimethyl, bromo, trifluoromethyl, chloro, hydroxy, and methoxy; the 3' -substituent includes phenyl, methyl, trifluoromethyl, ethyl, propyl, isopropyl, and cyclohexyl. Various 1' -substituted analogs are also provided.

Also provided are cyclic ester compounds containing phosphorus. Non-limiting examples are described below:

di-and triesters of [1] phosphoric acid, reported in Nifanteyev et Al, phosphorous, Sulfur silicon and Related elements,113:1(1996), Wijnberg et Al, EP-180276 Al;

2 trivalent phosphoric acid ester. Kryuchkov et al, Izv. Akad. Nauk SSSR, Ser. Khim.6:1244 (1987). Some of the claimed compounds for the asymmetric synthesis of levodopa precursors. Sylvain et al, DE3512781a 1;

3 phosphoramidates. Shih et al, fill. inst.chem.acad.sin,41:9 (1994); edmundson et al, J.chem.Res.Synop.5:122 (1989); and

4 phosphoric acid ester. Neidlein et al, heterocycles 35:1185(1993).

Further, non-limiting examples of U.S. and international patent applications that disclose suitable cyclic phosphoramidate prodrugs include: U.S. Pat. No. 6,312,662 to Erion et al, Metabasis Therapeutics, Inc., WO99/45016, WO00/52015, WO01/47935, and WO 01/18013. In particular, prodrugs are provided, represented by the formula:

wherein:

v and Z are linked together by an additional 3 to 5 atoms to form a cyclic group containing 5 to 7 atoms, optionally containing 1 heteroatom, substituted with a hydroxyl, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy group attached to a carbon atom three atoms away from the two oxygen atoms attached to the phosphorus atom; or

V and Z are linked together by an additional 3 to 5 atoms to form a cyclic group, optionally containing 1 heteroatom, which is fused to an aryl group in the beta and gamma positions to the oxygen attached to the phosphorus atom;

v and W are linked together by an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted by a substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy, which is attached to one of said carbon atoms that is three atoms away from the oxygen atom attached to the phosphorus atom;

Z and W are linked together by an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

w and W' are linked together by an additional 2 to 5 atoms to form a cyclic group, optionally containing 0 to 2 heteroatoms, and V should be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

z is selected from-CHR²OH，-CHR²OC(O)R³，-CHR²OC(S)R³，-CHR²OC(S)OR³，-CHR²OC(O)SR³，-CHR²OCO₂R³，-OR²，-SR²，-CHR²N₃，-CH₂Aryl, -CH (aryl) OH, -CH (CH = CR)² ₂)OH，-CH(C.ident.CR²)OH，-R²，-NR² ₂，-OCOR³，-OCO₂R³，-SCOR³，-SCO₂R³，-NHCOR²，-NHCO₂R³，-CH₂NH aryl, - (CH)₂)_p–OR¹²And- (CH)₂)_P-SR¹²；

P is an integer 2 or 3;

the limiting conditions are:

a) V, Z, W, W' are not all-H; and

b) when Z is-R²When at least one of V, M and W' is not-H, alkyl, aralkyl, or alicyclic;

·R²is selected from R³and-H;

·R³selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;

·R¹²selected from-H and lower acyl;

m is a biologically active agent which is linked to the phosphorus atom in formula I via the 2',3' and/or 5' -hydroxyl group.

V. combination or alternation therapy

The active compounds of the present invention may be administered in combination or alternation with other anti-flavivirus or pestivirus agents, or in particular anti-HCV agents, to treat any of the conditions described herein. In combination therapy, an effective dose of two or more agents are administered together, while in alternating or sequential therapy, an effective dose of each agent is administered sequentially or sequentially. The dosage will depend on the absorption, inactivation and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage will also vary with the severity of the condition to be alleviated. It should also be understood that for any particular patient, specific administration is given The regimen and schedule of administration should be adjusted at any time, according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition. In a preferred embodiment, having an EC of 10 to 15. mu.M or preferably less than 1 to 5. mu.M₅₀Are desirable.

It has been recognized that after prolonged treatment with antiviral agents, drug resistant variants of flavivirus, pestivirus or HCV may occur. The most common drug resistance is due to mutations in the genes encoding the enzymes that replicate the virus. The efficacy of a drug against viral infections can be prolonged, increased or restored by administering the compound in combination or alternation with a second or third antiviral compound that induces a mutation different from that induced by the primary drug. Alternatively, the pharmacokinetics, biodistribution or other parameters of the drug may be altered by such combination or alternation therapy. In general, combination therapy is generally preferred over alternation therapy because it simultaneously exerts multiple stress effects on the virus.

Any of the antiviral agents described in the background of the invention may be used in combination therapy or alternation therapy with the compounds described in the specification.

Non-limiting examples include:

1) protease inhibitors

Examples include substrate-based NS3protease inhibitors (Attwo 9/22496, 1998; Attwoood et al, antibiotic Chemistry and Chemistry 1999,10, 259-273; Attwoood et al, Preparation and use of amino acid derivatives as anti-viral agents, German patent publication No. DE 19914474; turbine et al, inhibitors of serine proteases, especially Hepatitis C virus NS3 proteases), PCO 98/79), including alpha-ketoamides and hydrazinium ureas (hydrabam 176176176176176176176), and electrophilic inhibitors such as inhibitors of electrophilic peptides, such as Hepatitis C inhibitors (PCT peptide inhibitors), and Hepatitis C inhibitors (PCT 07734); non-substrate based NS3protease inhibitors such as 2,4, 6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al, Biochemical and Biophysical Research Communications,1997,238, 643-647; Sudo K. et al, analytical Chemistry and Chemistry, 1998,9,186) include RD3-4082 and RD3-4078, the former being substituted on the amide by a 14 carbon chain and the latter processing the p-phenoxyphenyl group. (ii) a And Sch68631, a phenanthrenequinone, is an inhibitor of HCV protease (Chu M.et al., Tetrahedron Letters37:7229-7232, 1996).

Sch351633, isolated from Penicillium griseofulvum, was identified as a protease inhibitor (Chu M. et al, Bioorganic and Medicinal Chemistry Letters9: 1949-. Eglin c is isolated from leeches and is a potential inhibitor of several serine proteases such as streptomyces griseus (s.griseus) proteases a and B, alpha-chymotrypsin, chymotrypsin and subtilisin. Qasim M.A.et al, Biochemistry36:1598-1607, 1997.

U.S. patents disclosing protease inhibitors for the treatment of HCV include, for example, U.S. patent No. 6,004,933 to Spruce et al, which discloses a class of cysteine protease inhibitors for the inhibition of HCV endopeptidase 2; U.S. patent No. 5,990,276 to Zhang et al discloses synthetic inhibitors of hepatitis c virus NS3 protease; U.S. patent No. 5,538,865 to Reyes et al; WO02/008251 by Corvas International, Inc., and WO02/08187 and WO02/008256 by Schering Corporation. HCV inhibitor peptides are disclosed in U.S. Pat. Nos. 6,534,523, 6,410,531 and 6,420,380 to Boehringer Ingelheim and WO02/060926 to Bristol Myers Squibb. Diaryl peptides as inhibitors of the HCV NS3 serine protease are disclosed in WO02/48172 from Schering Corporation. Imidazolinediones (Imidazoleindiones) as inhibitors of the HCV NS3 serine protease are disclosed in WO02/08198 from Schering corporation and WO02/48157 from Bristol Myers Squibb. WO98/17679 to Vertex Pharmaceuticals and WO02/48116 to Bristol Myers Squibb also disclose HCV protease inhibitors.

2) Thiazolidine (Thiazolidines) derivatives, showing a relevant inhibitory effect in reverse phase HPLC assays using NS3/4A fusion protein and NS5A/5B substrate (Sudo K. et al, Antiviral Research,1996,32,9-18), in particular the compound RD-1-6250 with fused cinnamoyl moiety substituted by long chain alkyl, as well as RD46205 and RD 46193;

3) thiazolidines and benzanilides (benzanilides), identified by Kakiuchi N.et al, J.EBS letters421,217-220, Takeshita N.et al, Analytical Biochemistry,1997,247, 242-;

4) phenanthrenequinones (phenan-threnequinone) which show antiprotease activity in SDS-PAGE and autoradiography assays, by isolation from fermentation culture broths of Streptomyces (Streptomyces sp) (Chu m. et al, Tetrahedron Letters,1996,37, 7229-;

5) helicase inhibitors (e.g., Diana g.d. et al, Compounds, compositions and methods for the treatment of hepatitis C, U.S. patent No. 5,633,358; diana g.d., et al, Piperidine derivatives, pharmaceutical compositions of and the hair using the treatment of hepatis C, PCT WO 97/36554); )

6) Nucleoside polymerase inhibitors and gliotoxins (Ferrari R. et al. Journal of Virology,1999,73,1649-1654), and the natural product cerulenin (Lohmann V. et al. Virology,1998,249, 108-118);

7) an antisense phosphorothioate oligonucleotide (S-ODN) which is complementary to the sequence of the 5 'non-coding region (NCR) extending into the virus (Alt M. et al, Hepatology,1995,22,707-717), or the nucleoside 326-348 comprising the 3' end of the NCR and the nucleoside 371-388 (Alt M. et al, Archives of Virology,1997,142,589-599; Galderisi U. et al, Journal of cellular physiology,1999,181, 251-257)) located in the core coding region of HCV RNA; )

8) Inhibitors of IRES-dependent translation (Ikeda N et al, Agent for the Prevention and treatment of hepatitis C, Japanese patent publication No. JP-08268890; Kai Y. et al, Prevention and treatment of viral diseases, Japanese patent publication No. JP-10101591);

9) ribozymes such as nuclease-resistant ribozymes (Maccjak D.J. et al, Hepatology1999,30, abstract 995) and those disclosed in Barber et al, U.S. Pat. No. 6,043,077 and Draper et al, U.S. Pat. Nos. 5,869,253 and 5,610,054; and

10) Nucleoside analogs have also been developed for the treatment of flaviviridae virus infections.

11) Any of the compounds described in International application Nos. WO01/90121 and WO01/92282 to Idenix Pharmaceuticals;

12) other patent applications disclosing the use of certain nucleoside analogs for the treatment of hepatitis c virus include: PCT/CA00/01316(WO01/32153; filed 11/3/2000) and PCT/CA01/00197(WO01/60315; filed 2/19/2001), both filed by BioChem Pharma, Inc. (now Shire BioChem, Inc.); PCT/US02/01531(WO02/057425; filed 1/18.2002) and PCT/US02/03086(WO02/057287; filed 1/18.2002) filed by Merck & Co., Inc., PCT/EP01/09633(WO02/18404; published 8/21.2001) filed by Roche, and PCT publication No. WO OIT9246 (filed 4/13.2001) by Pharmasset, Ltd, WO02/32920 (filed 10/18.2001) and WO 02/48165.

13) PCT publication No. WO99/43691 to Emory University, entitled "2 '-fluoronucleosides", discloses the use of certain 2' -fluoronucleosides to treat HCV.

14) Other various compounds include: 1-amino-alkylcyclohexane (Gold et al, U.S. Pat. No. 6,034,134), alkyl lipids (Chojkier et al, U.S. Pat. No. 5,922,757), vitamin E and other antioxidants (Chojkier et al, U.S. Pat. No. 5,922,757), squalene, amantadine, bile acids (Ozeki et al, U.S. Pat. No. 5,846,964), N- (phosphonoacetyl) -L-aspartic acid, (Diana et al, U.S. Pat. No. 5,830,905), benzenedicarboxamides (Diana et al, U.S. Pat. No. 5,633,388), polyadenylic acid derivatives (Wang et al, U.S. Pat. No. 5,496,546), 2',3' -dideoxyinosine (Yarchan et al, U.S. Pat. No. 5,026,687), benzimidazoles (Colacino et al, U.S. Pat. No. 5,891,874), plant extracts (Tsai et al, U.S. Pat. No. 5,837,257, Omer et al, U.S. Pat. No. 5,725,859, and U.S. Pat. No. 6,056,961), and piperidines (piperadiness) (Diana et al, U.S. Pat. No. 5,830,905).

15) Other compounds currently in preclinical or clinical development for the treatment of hepatitis c virus, including: interleukin-10 from Schering-Plough, IP-501 from Interneuron, Merimebodib (VX-497) from Vertex, of Endo Labs Solvay(of amantadine), RPIIDun Pharma IDN-6556, XTL-002 for XTL, Chiron HCV/MF59, NABI(immunoglobulin of hepatitis C virus), of ICN/RIBAPHARMOf ICN/RIBAPHARMOf Sci Clone(thymosin alpha-1), thymosin of Sci Clone and pegylated interferon, of Maxim(histamine dihydrochloride), VX950/LY570310 by Vertex/EliLilly, ISIS14803 by Isis PHARMACEUTICAL/ELAN, IDN-6556 by Idun PHARMACEUTICALs Inc., JTK003 by AKROS Pharma, BILN-2061 by Boehringer Ingelheim, CellCept (mycophenolate mofetil) by Roche, T67 by Tularik, a beta-tubulin inhibitor, a therapeutic vaccine against E2 by Innogenetics, FK788 by Fujisawa Healthcare, Inc, Celb 1016(Siliphos, an oral silymarin-phosphothiophene, a (intracellular-phosphoenolate), an RNA replication inhibitor of Virosary, a therapeutic vaccine against Epsilone, a chemotherapeutic inhibitor of interferon, a chemotherapeutic vaccine for interferon, a chemotherapeutic treatment, a chemotherapeutic inhibitor of interferon, a chemotherapeutic vaccine for interferon, for chemotherapy for interferon, for chemotherapy for interferon, for tumors, dication by Int, protease inhibitors by Agouron, protease inhibitors by Chiron/Meivir, antisense therapy by AVI BioPharma, antisense therapy by Hybridon, blood cleaners (hemopurifier) by Aethlon Medical, therapeutic vaccine by Merix, protease inhibitors by Bristol-Myers Squibb/Axys, Chron-VacC by Tripep, a therapeutic vaccine, UT231B by United Therapeutics, protease, helicase and polymerase inhibitors by Genelabs Technologies, IRES inhibitors by Immusol, R803 by Rigelpharmaceuticals, IRES by InterMune (Interferon. alpha. con-1), of Viragen(Natural interferons), of Human Genome SciencesOf Ares-Serono(beta-1 a Interferon), omega of BiomedicineInterferon, oral interferon alpha from Amarillo Biosciences, InterMune's interferon gamma, interferon tau and interferon gamma-1 b.

VI pharmaceutical composition

Hosts, including humans, infected with pestiviruses, flaviviruses, HCV or other organisms having any other condition described herein or which replicate by RNA-dependent RNA viral polymerase can be treated, or for the purpose of treating any condition described herein, by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof, in the presence of a pharmaceutically acceptable carrier or diluent. The active substance may be administered in liquid or solid form by any suitable route, e.g. orally, parenterally, intravenously, transdermally, subcutaneously or topically.

For pestivirus, flavivirus or HCV infection, the preferred dose of the compound is about 1 to 50mg per kg body weight per day, preferably 1 to 20mg, more usually 0.1 to about 100mg per kg body weight per day. Lower doses are preferred, for example doses of 0.5-100mg, 0.5-50mg, 0.5-10mg or 0.5-5mg per kg body weight per day. Even lower doses are effective, and thus the range may include 0.1-0.5mg per kg body weight per day. The effective dosage range of pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be released. If the salt or prodrug itself is active, the effective dose can be estimated as described above using the weight of the salt or prodrug or by other methods known to those skilled in the art.

The compounds may be conveniently administered in any suitable dosage unit, including but not limited to, those containing 7 to 3000mg, preferably 70 to 1400mg, of active compound per dosage unit. Oral dosages of 50-1000mg are generally convenient, including dosages in the range of 50, 100, 200, 250, 300, 400, 500, 600, 700, 800, 900 or 1000mg in one or more. Lower doses, e.g., 10-100 or 1-50mg, are preferred. The desired dose may also be 0.1-50mg or 0.1-20mg or 0.1-10.0 mg. Furthermore, in the case of administration by non-oral routes, such as by injection or inhalation, lower doses may be used.

It is desirable to administer the active ingredient in such a way that the peak plasma concentration of the active compound is from about 0.2 to about 70 μ M, preferably from about 1.0 to about 10 μ M. This aim can be achieved, for example, by intravenous injection of a 0.1-5% solution of the active ingredient, optionally in saline solution, or as a bolus for administration of the active ingredient.

The concentration of the active compound in the pharmaceutical composition depends on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage will also vary with the severity of the condition to be alleviated. It is also to be understood that for any particular patient, the particular dosage regimen will be adjusted at any time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the foregoing concentration ranges are exemplary only and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered in a single dose or it may be divided into several small doses to be administered at different time intervals.

The preferred mode of administration of the active compound is oral. Oral compositions typically include an inert diluent or an edible carrier. It can be made into gelatin capsule, or compressed into tablet. For oral administration, the active compound may be mixed with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binders, and/or adjuvants may also be added to the composition.

Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, the unit dosage form may contain various other materials which modify the physical form of the dosage form, such as sugar-coated tablets, shellacs, or other enteric coatings.

The compounds may also be administered as components of elixirs (elixir), suspensions, syrups, wafers (wafer), chewing gums and the like. Syrups may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The compounds or pharmaceutically acceptable prodrugs or salts thereof may also be mixed with other active agents that do not affect their desired effect, or with agents that supplement the desired effect, such as antibiotics, antifungal agents, anti-inflammatory agents, or other antiviral agents, including other nucleoside compounds. Solutions or suspensions for parenteral, intradermal, subcutaneous or topical use may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for adjusting the osmotic pressure, such as sodium chloride or glucose. The parent formulation may be presented in ampoules, disposable syringes or multiple dose glass or plastic vials.

If administered by intravenous injection, the preferred carrier is physiological saline or Phosphate Buffered Saline (PBS).

In a preferred embodiment, the active compound is formulated with carriers that will protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Methods of preparing such formulations will be apparent to those skilled in the art. Such materials are available from Alza corporation.

Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred pharmaceutically acceptable carriers. Such formulations may be prepared according to methods known to those skilled in the art, such as those described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome preparations are prepared by dissolving appropriate lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation and formation of a dry lipid film on the surface of the container. Subsequently, an aqueous solution of the active or monophosphate, diphosphate and/or triphosphate derivative thereof is added to the vessel. The container is then rotated by hand to detach the lipid material from the surface of the container and disperse the lipid aggregates, thereby forming a liposomal suspension.

VII preparation of active Compounds

The nucleosides of the present invention can be synthesized by any method known in the art. Specifically, the synthesis of nucleosides of the present invention can be accomplished by alkylation of appropriately modified sugars followed by glycosylation or glycosylation of the nucleoside followed by alkylation. The following non-limiting embodiments illustrate some of the conventional methods for obtaining nucleosides of the present invention.

General Synthesis of A.1' -C-branched nucleosides

1' -C-branched ribonucleosides of the structure:

wherein, the base group, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹，R¹⁰，Y，W¹，W²，W³，X，X¹，X²And X³As defined herein.

1) Obtained by modification of lactones

The key raw material of the method is appropriately substituted lactone. The lactones are commercially available or can be prepared by any known method, including standard epimerization, substitution, and cyclization techniques. According to methods well known to those skilled in the art, such as in Greene et al.Protective Groups in Organic SynthesisThe lactone may optionally be protected with a suitable protecting group, preferably an acyl or silyl group, as taught in John Wiley and Sons, Second Edition, 1991. The protected lactone is then reacted with a suitable coupling reagent, such as an organometallic carbon nucleophile (e.g., Grignard reagent, organolithium, lithium dialkylcopper or R in TBAF ⁶-SiMe₃) Coupled in a suitable aprotic solvent at a suitable temperature to give the 1' -alkylated sugar.

Then according to methods well known to those skilled in the art, e.g. as in TownsendChemistry of Nucleosides and NucleotidesCoupling of optionally activated sugars to the bases is taught in Plenum Press, 1994. For example, the coupling of the acylated sugar to the silylated base can be carried out in a suitable solvent at a suitable temperature using a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate.

Subsequently, according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisThe nucleosides can be deprotected as taught in John Wiley and Sons, Second Edition,1991, the lactones can be optionally protected with suitable protecting groups, preferably acyl or silyl groups.

In a specific embodiment, 1' -C-branched ribonucleosides are desirable. Scheme 1 shows the synthesis of ribonucleosides. Alternatively, deoxyribonucleosides are also desirable. To obtain these nucleosides, one can follow the general knowledge of those skilled in the artKnown methods are described, for example, in Greene et al.Protective Groups in Organic SynthesisThe ribonucleosides formed are optionally protected and then the 2' -OH is reduced with a suitable reducing agent as taught in John Wiley and Sons, Second Edition, 1991. Optionally, activating the 2' -hydroxyl group to facilitate its reduction; i.e. by a Barton reduction reaction.

Scheme 1

Other methods for preparing 2, 1' -C-branched nucleosides

The key starting material for this process is an appropriately substituted hexose. The hexoses are commercially available or can be prepared by any known method, including standard epimerization (e.g., base treatment), substitution, and coupling techniques. The hexose may be selectively protected to give the appropriate hexafuranose. As in TownsendChemistry of Nucleosides and NucleotidesAs taught in Plenum Press, 1994.

The 1' -hydroxy group may optionally be activated as a suitable leaving group, such as acyl or halogen by acylation or halogenation activation, respectively. Then, by methods well known to those skilled in the art, e.g., as in TownsendChemistry of Nucleosides and NucleotidesOptionally activated sugars were coupled to the bases as taught in Plenum Press, 1994. For example, the coupling of the acylated sugar to the silylated base can be carried out in a suitable solvent at a suitable temperature using a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate. Alternatively, the halo sugar is coupled to the silylated base in the presence of trimethylsilyl triflate.

If the 1' -CH₂-OH is protected, then it can be selectively deprotected according to methods well known in the art. Primary hydroxyl function to be produced To give various C-branched nucleosides. For example. The primary hydroxyl group is reduced to a methyl group with a suitable reducing agent. Alternatively, the hydroxyl group is activated prior to reduction to facilitate its reduction, i.e., by a Barton reduction reaction. In another embodiment, the primary hydroxyl group is first oxidized to the aldehyde and then reacted with a carbon nucleophile (such as a Grignard reagent, organolithium, lithium dialkylcopper or R in TBAF⁶-SiMe₃) Coupling in a suitable aprotic solvent at a suitable temperature.

In a specific embodiment, 1' -C-branched ribonucleosides are desirable. Scheme 2 shows the synthesis of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. To obtain these nucleosides, methods well known to those skilled in the art can be followed, as in Greene et al.Protective Groups in Organic SynthesisThe ribonucleosides formed are optionally protected and then the 2' -OH is reduced with a suitable reducing agent as taught in John Wiley and Sons, Second Edition, 1991. Optionally, activating the 2' -hydroxyl group to facilitate its reduction; i.e. by a Barton reduction reaction.

Scheme 2

Furthermore, the corresponding L-enantiomer of the compound of the present invention can be prepared according to the same conventional method (1 or 2) using the corresponding L-sugar or nucleoside L-enantiomer as a starting material.

Conventional synthesis of B.2' -C-branched nucleosides

2' -C-branched ribonucleosides of the structure:

wherein, the base group, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹，R¹⁰，Y，W¹，W²，W³，X，X¹，X²And X³As defined herein.

1. Glycosylating a nucleobase (nucleobase) with a suitably modified sugar

The key starting material for this process is a suitably substituted sugar with 2'-OH and 2' -H with a suitable Leaving Group (LG), such as an acyl or halogen substitution. The sugars are commercially available or can be prepared by any known method, including standard epimerization, substitution, oxidation, and reduction techniques. The substituted sugar is then oxidized with a suitable oxidizing agent at a suitable temperature in a compatible solvent to provide a 2' -modified sugar. Possible oxidizing agents are Jones ' reagent (mixture of chromic and sulfuric acids), Collins ' reagent (bipyridine Cr (VI) oxide), Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate (acid dichromate), potassium permanganate, MnO₂Ruthenium tetroxide, phase transfer catalysts, e.g. chromic acid or polymer-supported potassium permanganate, Cl₂-pyridine, H₂O₂Ammonium molybdate, NaBrO₂-CAN, NaOCl in HOAc solution, copper chromite, copper oxide, raney nickel, palladium acetate, melvin-pointdoff-waley reagent (Meerwin-Pondorf-Verley) (aluminum tert-butoxide and another ketone) and N-bromosuccinimide.

Followed by organometallic carbon nucleophiles (e.g. Grignard reagents, organolithium, lithium dialkylcopper or R in TBAF)⁶-SiMe₃) Coupled with the ketone in a suitable aprotic solvent at a suitable temperature to produce a 2' -alkylated sugar. Then according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisOptionally, as taught in John Wiley and Sons, Second Edition,1991The alkylated sugar is preferably protected with an acyl or silyl protecting group.

Followed by a procedure well known to those skilled in the art, e.g. as in TownsendChemistry of Nucleosides and NucleotidesOptional sugar coupling to the bases is taught in Plenum Press, 1994. For example, the coupling of the acylated sugar to the silylated base can be carried out in a suitable solvent at a suitable temperature using a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate. Alternatively, the halo sugar is coupled to the silylated base in the presence of trimethylsilyl triflate.

Subsequently, according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisDeprotection of nucleosides is taught in John Wiley and Sons, Second Edition, 1991.

In one embodiment, 2' -C-branched ribonucleosides are desirable. Scheme 3 shows the synthesis of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. To obtain these nucleosides, methods well known to those skilled in the art can be followed, as in Greene et al.Protective Groups in Organic SynthesisThe ribonucleosides formed are optionally protected and then the 2' -OH is reduced with a suitable reducing agent as taught in John Wiley and Sons, Second Edition, 1991. Optionally, activating the 2' -hydroxyl group to facilitate its reduction; i.e. by a Barton reduction reaction.

Scheme 3

2. Modification of preformed nucleosides

The key starting material for this process is an appropriately substituted nucleoside with 2'-OH and 2' -H. The coreGlycosides are commercially available or can be prepared by any known method, including standard coupling techniques. Then according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisThe nucleoside is optionally protected with a suitable protecting group, preferably an acyl or silyl group, as taught in John Wiley and Sons, Second Edition, 1991.

The appropriately protected nucleoside is then oxidized at an appropriate temperature in a compatible solvent using an appropriate oxidizing agent to provide the 2' -modified sugar. Possible oxidizing agents are Jones ' reagent (mixture of chromic and sulfuric acids), Coriolis's reagent (bipyridine Cr (VI) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate (acid dichromate), potassium permanganate, MnO ₂Ruthenium tetroxide, phase transfer catalysts, e.g. chromic acid or polymer-supported potassium permanganate, Cl₂-pyridine, H₂O₂Ammonium molybdate, NaBrO₂-CAN, NaOCl in HOAc solution, copper chromite, copper oxide, raney nickel, palladium acetate, melvin-pointdoff-waley reagent (Meerwin-Pondorf-Verley) (aluminum tert-butoxide and another ketone) and N-bromosuccinimide.

Subsequently, according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisDeprotection of nucleosides is taught in John Wiley and Sons, Second Edition, 1991.

In one embodiment, 2' -C-branched ribonucleosides are desirable. Scheme 4 shows the synthesis of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. To obtain these nucleosides, methods well known to those skilled in the art can be followed, as in Greene et al.Protective Groups in Organic SynthesisThe ribonucleosides formed are optionally protected and then the 2' -OH is reduced with a suitable reducing agent as taught in John Wiley and Sons, Second Edition, 1991. Optionally, activating the 2' -hydroxyl groupTo facilitate its reduction; i.e. by a Barton reduction reaction.

Scheme 4

In another embodiment of the invention, the L-enantiomer is desired. Thus, the corresponding L-enantiomer of the compound of the present invention can be prepared according to the same conventional methods as previously described, using the corresponding L-sugar or nucleoside L-enantiomer as a starting material.

General Synthesis of C.3' -C-branched nucleosides

3' -C-branched ribonucleosides of the structure:

wherein, the base group, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹，R¹⁰，Y，W¹，W²，W³，X，X¹，X²And X³As defined herein.

1. Nucleobase glycosylation with appropriately modified sugars

The key starting material for this process is a suitably substituted sugar with 3'-OH and 3' -H with a suitable Leaving Group (LG), such as an acyl or halogen substitution. The sugars are commercially available or can be prepared by any known method, including standard epimerization, substitution, oxidation, and reduction techniques. The substituted sugar is then oxidized with a suitable oxidizing agent at a suitable temperature in a compatible solvent to give the 3' -modified sugar. Possible oxidizing agents are Jones reagent (A), (B), (CMixture of chromic and sulfuric acids), corin (Collins) reagent (bipyridine cr (vi) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO₂Ruthenium tetroxide, phase transfer catalysts, e.g. chromic acid or polymer-supported potassium permanganate, Cl₂-pyridine, H₂O₂Ammonium molybdate, NaBrO₂-CAN, NaOCl in HOAc solution, copper chromite, copper oxide, raney nickel, palladium acetate, melvin-pomdow-waley (Meerwin-Pondorf-Verley) reagents (aluminium tert-butoxide and another ketone) and N-bromosuccinimide.

Followed by organometallic carbon nucleophiles (e.g. Grignard reagents, organolithium, lithium dialkylcopper or R in TBAF)⁶-SiMe₃) Coupling with the ketone in a suitable aprotic solvent at a suitable temperature produces a 3' -C-branched sugar. Then according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisThe alkylated sugar is optionally protected with a suitable protecting group, preferably an acyl or silyl group, as taught in John Wiley and Sons, Second Edition, 1991.

Followed by a procedure well known to those skilled in the art, e.g. as in TownsendChemistry of Nucleosides and NucleotidesOptionally protected sugars were coupled to the bases as taught in Plenum Press, 1994. For example, the coupling of the acylated sugar to the silylated base can be carried out in a suitable solvent at a suitable temperature using a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate. Alternatively, the halo sugar is coupled to the silylated base in the presence of trimethylsilyl triflate.

Thereafter, according to methods well known to those skilled in the art, such as in Greene et al.Protective Groups in Organic SynthesisDeprotection of nucleosides is taught in John Wiley and Sons, Second Edition, 1991.

In one embodiment, 3' -C-branched ribonucleosides are desirable. Scheme 5 shows the synthesis of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. To obtain these nucleosides, methods well known to those skilled in the art can be followed, as in Greene et al.Protective Groups in Organic SynthesisThe ribonucleosides formed are optionally protected and then the 2' -OH is reduced with a suitable reducing agent as taught in John Wiley and Sons, Second Edition, 1991. Optionally, activating the 2' -hydroxyl group to facilitate its reduction; i.e. by a Barton reduction reaction.

Scheme 5

2. Modification of preformed nucleosides

The key starting material for this process is an appropriately substituted nucleoside with 3'-OH and 3' -H. The nucleosides are commercially available or can be prepared by any known method, including standard coupling techniques. Then according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisThe nucleoside is optionally protected with a suitable protecting group, preferably an acyl or silyl group, as taught in John Wiley and Sons, Second Edition, 1991.

The appropriately protected nucleoside is then oxidized at an appropriate temperature in a compatible solvent using an appropriate oxidizing agent to provide the 2' -modified sugar. Possible oxidizing agents are Jones ' reagent (mixture of chromic and sulfuric acids), Coriolis's reagent (bipyridine Cr (VI) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate (acid dichromate), potassium permanganate, MnO ₂Ruthenium tetroxide, phase transfer catalysts, e.g. chromic acid or polymer-supported potassium permanganate, Cl₂-pyridine, H₂O₂Ammonium molybdate, NaBrO₂-CAN, NaOCl in HOAc solution, copper chromite, copper oxide, raney nickel, palladium acetate, milvin-pomdoff-volley reagent (aluminum tert-butoxide and another ketone) and N-bromosuccinimide.

Thereafter, according to methods well known to those skilled in the art, such as in Greene et al.Protective Groups in Organic SynthesisDeprotection of nucleosides is taught in John Wiley and Sons, Second Edition, 1991.

In one embodiment, 3' -C-branched ribonucleosides are desirable. Scheme 6 shows the synthesis of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. To obtain these nucleosides, methods well known to those skilled in the art can be followed, as in Greene et al.Protective Groups in Organic SynthesisThe ribonucleosides formed are optionally protected and then the 2' -OH is reduced with a suitable reducing agent as taught in John Wiley and Sons, Second Edition, 1991. Optionally, activating the 2' -hydroxyl group to facilitate its reduction; i.e. by a Barton reduction reaction.

Scheme 6

In another embodiment of the invention, the L-enantiomer is desired. Thus, the corresponding L-enantiomer of the compound of the present invention can be prepared according to the same conventional methods as previously described, using the corresponding L-sugar or nucleoside L-enantiomer as a starting material.

General synthetic method of D.4' -C-branched nucleoside

4' -C-branched ribonucleosides of the structure:

wherein, the base group, R¹，R²，R³，R⁴，R⁵，R⁶，R⁷，R⁸，R⁹，R¹⁰，Y，W¹，W²，W³，X，X¹，X²And X³As defined herein.

1. Obtained by modification of glutaraldehyde (pentadialdo) -furanose

The key raw material of the method is appropriately substituted glutaraldehyde (pentadialdo) -furanose. The glutaraldehyde (pentadialdo) -furanose is commercially available or can be prepared by any known method, including standard epimerization, substitution, and cyclization techniques.

In a preferred embodiment, the glutaraldehyde (pentanaldo) -furanose is prepared from an appropriately substituted hexose. The hexoses are commercially available or can be prepared by any known method, including standard epimerization (e.g., base treatment), substitution, and coupling techniques. The hexose may be in the form of a furanose, or may be cyclized by any method known in the art, such as in TownsendChemistry of Nucleosides and NucleotidesPreferably, the hexose is protected by selectivity to give the appropriate hexafuranose, as taught in Plenum Press, 1994.

The 4 '-hydroxymethyl group of the hexafuranose is then oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to give the 4' -aldehyde-modified sugar. Possible oxidizing agents are Swern reagent, Jones reagent (mixture of chromic and sulfuric acids), Coriolis reagent (bipyridine Cr (VI) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate (acid dichromate), potassium permanganate, MnO ₂Ruthenium tetroxide, phase transfer catalysts, e.g. chromic acid or polymer-supported potassium permanganate, Cl₂-pyridine,H₂O₂Ammonium molybdate, NaBrO₂HOAc solution of CAN, NaOCl, copper chromite, copper oxide, Raney nickel, palladium acetate, Milvin-Pontdoff-Wallace reagent (aluminum tert-butoxide and another ketone) and N-bromosuccinimide, although H is preferably used in the benzene/pyridine mixture at room temperature₃PO₄DMSO and DCC.

Thereafter, according to methods well known to those skilled in the art, such as in Greene et al.Protective Groups in Organic SynthesisThe glutaraldehyde (pentalado) -furanose may be optionally protected with a suitable protecting group, preferably an acyl or silyl group, as taught by John Wiley and Sons, Second Edition, 1991. The protected glutaraldehyde (pentadialdo) -furanose can then be coupled with a suitable electrophilic alkyl, halo-alkyl (i.e., CF 3), alkenyl or alkynyl (i.e., allyl) group in the presence of a base such as sodium hydroxide to give a 4' -alkylated sugar. Alternatively, the protected glutaraldehyde (pentadialdo) -furanose can be coupled with the corresponding carbonyl group, such as formaldehyde, in the presence of a base, such as sodium hydroxide, followed by reduction with a suitable reducing agent in a suitable polar solvent, such as dioxane, at a suitable temperature to give the 4' -alkylated sugar. In one embodiment, the reduction is performed using phoc(s) Cl, DMAP, preferably in acetonitrile at room temperature, followed by a reflux treatment of ACCN and TMSS in toluene.

Followed by a procedure well known to those skilled in the art, e.g. as in TownsendChemistry of Nucleosides and NucleotidesOptionally activated sugars were coupled to the bases as taught in Plenum Press, 1994. For example, the coupling of the acylated sugar to the silylated base can be carried out in a suitable solvent at a suitable temperature using a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate.

Thereafter, according to methods well known to those skilled in the art, such as in Greene et al.Protective Groups in Organic Synthesis,John Wiley and Deprotection of nucleosides is taught in Sons, Second Edition, 1991.

In one embodiment, a 4' -C-branched ribonucleoside is desirable. Scheme 6 shows the synthesis of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. To obtain these nucleosides, methods well known to those skilled in the art can be followed, as in Greene et al.Protective Groups in Organic SynthesisThe ribonucleosides formed are optionally protected and then the 2' -OH is reduced with a suitable reducing agent as taught in John Wiley and Sons, Second Edition, 1991. Optionally, activating the 2' -hydroxyl group to facilitate its reduction; i.e. by a Barton reduction reaction.

In another embodiment of the invention, the L-enantiomer is desired. Thus, the corresponding L-enantiomer of the compound of the invention can be prepared according to the same general method as previously described, using the corresponding L-glutaraldehyde (pentanedioldo) -furanose as starting material.

Conventional methods for the synthesis of E.2 'and/or 3' -prodrugs

The key starting material for this process is an appropriately substituted 1',2',3 'or 4' -branched β -D or β -L nucleoside. The branched nucleosides are commercially available or can be prepared by any known method, including the techniques disclosed herein. Then according to methods well known to those skilled in the art, as in Greene et al.Protective Groups in Organic SynthesisThe branched nucleoside is optionally protected with a suitable protecting group, preferably a silyl group, as taught in John Wiley and Sons, Second Edition, 1991. The protected branched nucleoside may then be coupled with a suitable acyl donor, such as an acid chloride and/or anhydride, in a suitable protic or aprotic solvent at a suitable temperature to provide a 2 'and/or 3' prodrug of the 1',2',3 'or 4' -branched β -D or β -L nucleoside. Alternatively, the protected branched nucleoside may be reacted with an appropriate acyl group, such as a carboxylic acid, such as an alkanoic acid and/or ammonia, in a suitable aprotic solvent, optionally at a suitable temperature, optionally with a suitable coupling agentCoupling of the amino acid residues to give 2 'and/or 3' prodrugs of 1',2',3 'or 4' -branched β -D or β -L nucleosides. Possible coupling agents are any reagents that facilitate coupling, including, but not limited to, Mitsunobu reagents with triphenylphosphine or various carbodiimides (e.g., diisopropyl azodicarboxylate and diethyl azodicarboxylate).

For example, simple amino-ethanol can be esterified using an acid chloride in a refluxing acetonitrile-benzene mixture (see scheme 7: Synthetic Communications,1978,8(5), 327-333; incorporated herein by reference). Alternatively, the esterification is carried out using an anhydride, as described in J am. chem. Soc.,1999,121(24),5661-5664, which is incorporated herein by reference. See fig. 2, 3 and 4.

Scheme 7

The following examples illustrate the invention by way of example. It will be understood by those of ordinary skill in the art that these examples are not intended to limit the invention and that changes in detail may be made without departing from the spirit and scope of the invention.

Example 1: preparation of 1' -C-methylriboadenine by 6-amino-9- (1-deoxy-beta-D-furanosylulose) purine

The melting point was determined on a Mel-temp II apparatus and was uncorrected. On a Bruker400AMX spectrometer, 400MHz¹H NMR and 100MHz¹³C NMR, NMR spectrum was recorded using TMS as an internal standard. Chemical shifts (δ) are expressed in parts per million (ppm) and signals are expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or bs (broad singlet). The Infrared (IR) spectra were measured on a Nicolet510P fourier transform infrared (FT-IR) spectrometer. Mass spectra were recorded on a Micromass Autospec high resolution mass spectrometer. In Uniplates (silicon) available from Analtech Co Gel) was analyzed by Thin Layer Chromatography (TLC). Flash column chromatography was performed using silica gel-60 (220-440 mesh) or using silica gel G (TLC grade,>440 mesh) was subjected to vacuum flash chromatography. Ultraviolet (UV) spectra were obtained from a Beckman DU650 spectrophotometer. Elemental analysis was performed in Atlantic Microlab, Inc., Norcross, GA or Galbraith Laboratories, Inc., Knoxville, TN. High Performance Liquid Chromatography (HPLC) analysis was performed using a Waters HPLC system (Millipore Corporation, Milord, Mass.) equipped with a Model600 controller, a Model996 photodiode array probe, and a Model717plus autosampler. Millennium2010 software was used for system control, data acquisition and processing. A chiral polarimeter (chiral polarimeter) Perkin-Elmer Model241MC polarimeter (Wilton, CT) was used to determine optical rotation.

Synthesis of 1' -C-methyl ribose-8-methyl adenine

The target compound may also be prepared according to the published methods (J.Farkas, and F.Sorm, "nucleic components and the same algorithms. XCIV. Synthesis of6-amino-9- (1-deoxy-beta-D-psicofurannosyl) purine" Collection. Czech. chem. Commun.1967,32,2663-266;J.Farkas",Collect.Czech.Chem.Commun.1966,311535) preparation. (scheme 8).

Scheme 8

In a similar manner, but with the appropriate sugar and purine bases, nucleosides of the following formula XXIV can be prepared:

Wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Alternatively, using the appropriate sugar and pyrimidine bases, nucleosides of the following formula XXV can be prepared:

wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXVI can be prepared:

wherein R is¹，R²，R³，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXVII can be prepared:

wherein R is¹，R²，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXVIII can be prepared:

wherein R is¹，R²，R⁶X and base areAs defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXIX can be prepared:

wherein R is¹，R⁶，R⁷，R⁸，X，R⁹，R¹⁰And base is as defined herein.

Example 2: preparation of 2' -C-methylribose-8-methyladenine

The target compound may be prepared according to the disclosed methods (r.e. harry-O 'kuru, j.m. smith, and m.s.wolfe, "a short, flexible route aware 2' -C-branched ketones", j.org.chem.1997,621754-1759). (scheme 9).

Scheme 9

(a)Dess-Martin periodinane；(b)MeMgBr/TiCl₄；(c)BzCl,DMAP,Et₃N; (d) bis (trimethylsilyl) acetamide, N⁶-benzoyladenine, TMSOTf; (e) NH (NH) ₃/MeOH

The 3 '-prodrugs of the 2' -branched nucleosides can be prepared according to published methods (synthetic Communications,1978,8(5), 327-56333; J.Am.chem.Soc.,1999,121(24), 5661-5664). Alternatively, the 2' -branched nucleoside can be esterified without protection (scheme 9 b). Carbonyldiimidazole (377mg,2.33mmol) was added to a solution of 15ml of N- (tert-butoxycarbonyl) -L-valine (507mg,2.33mmol) in dry tetrahydrofuran. The mixture was stirred at 20 ℃ for 1 hour and at 50 ℃ for 10 minutes, then added to a solution of 4-amino-L- (3, 4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -1H-pyrimidin-2-one (500mg,1.95mmol), 4- (dimethylamino) pyridine (25mg,0.195mmol), triethylamine (5mL) in anhydrous N, N-dimethylformamide (10mL) and also stirred at 50 ℃. The reaction mixture was stirred at 50 ℃ for 1 hour, followed by detection by HPLC. HPLC analysis indicated that, in addition to the by-products, 52% of the product was the desired ester and 17% of the product was the starting material. The 3' -OH of the 4-amino-1- (3, 4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl) -1H-pyrimidin-2-one tends to react selectively when coupled with BOC-valine (BOC-Val).

In a similar manner, but with the appropriate sugar and purine bases, nucleosides of the following formula XXX can be prepared:

Wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Alternatively, using appropriate sugar and pyrimidine bases, nucleosides of the following formula XXXI can be prepared:

wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXII can be prepared:

wherein R is¹，R²，R³，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXIII can be prepared:

wherein R is¹，R²，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXIV can be prepared:

wherein R is¹，R²，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXV may be prepared:

wherein R is¹，R⁶，R⁷，R⁹，R¹⁰And X and base are as defined herein.

Example 3: preparation of 3' -C-methyl ribose-8-methyl adenine

The target compound may be prepared according to published methods (r.f. nutt, m.j.dickinson, f.w.holly, and e.walton, "Branched-chain sugar nucleotides.iii.3' -C-methyaddine", j.org.chem.1968,331789-1795) (scheme 10).

Scheme 10

(a)RuO₂/NaIO₄；(b)MeMgBr/TiCl₄；(c)HCl/MeOH/H₂O; (d) BzCl/pyrimidine; (e) AcBr, HBr/AcOH; (f) mercuric chloride-6-benzoylaminopurine; (g) NH (NH) ₃/MeOH。

In a similar manner, but with the appropriate sugar and purine bases, nucleosides of the following formula XXXVI can be prepared:

wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Alternatively, nucleosides of the following formula XXXVII can be prepared using appropriate sugar and pyrimidine bases:

wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Alternatively, nucleosides of the following formula XXXVIII can be prepared using appropriate sugar and pyrimidine or purine bases:

wherein R is¹，R²，R³，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXIX can be prepared:

wherein R is¹，R²，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXX can be prepared:

wherein R is¹，R²，R⁶And X and base are as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXXI can be prepared:

wherein R is¹，R⁶，R⁷，R⁸，R⁹And X and base are as defined herein.

Example 4: preparation of 1-O-methyl-2, 3-O-isopropylidene-beta-D-ribofuranose- (1)

The target compounds may be prepared according to published methods (Leonard, N.J.; Carraway, K.L. "5-Amino-5-deoxyriboside derivatives. Synthesis and use in the preparation of" reversed "nucleosides" J.Heterocycl.Chem.1966,3485 and 489).

50.0g (0.34mole) of a dried solution of D-ribose in 1.0L of acetone, 100mL2, 2-dimethoxypropane, 200mL of methanol containing 20mL of methanol saturated with hydrogen chloride at 0 ℃ were stirred at room temperature overnight. The resulting solution was neutralized with pyrimidine and evaporated under reduced pressure. The resulting oil was partitioned between 400mL water and 400mL dichloromethane. The aqueous layer was extracted twice with dichloromethane (400 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [ eluent: gradient (stepwise gradient) methanol in dichloromethane (1-2%)]Pure 1(52.1g,75%) was obtained as a yellow syrup. H¹-NMR(CDCl₃)：δ5.00(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(br s,1H,OH-5),1.51(s,3H CH₃),1.34(s,3H CH₃);MS(matrix GT):FAB>0m/z173(M-OCH3)⁺。

Example 5: preparation of 1-O-methyl-2, 3-O-isopropylidene-beta-D-glutaraldehyde-ribofuranose- (2)

The target compounds can be prepared according to the Methods disclosed (Jones, G.H.; Moffatt, J.G.G.Oxidation of carbohydrates by the sulphoxide-Carbohydrate and related methods.Oxidation with a bicyclic Carbohydrate-DMSO, dispropyrocarbohydrate-DMSO, acetic anhydride-DMSO, and phosphono-oxide-DMSO: in Methods in Carbohydrate Chemistry; Whisler, R.L.and Moffatt, J.L.Eds; Academic Press: New York,1972; 315-322).

Compound 1 was co-evaporated twice with anhydrous pyrimidine. Dicyclohexylcarbodiimide (DCC,137.8g,0.67mol) was added to a solution of 1(68.2g,0.33mole) in dry benzene (670mL), DMSO (500mL) and pyrimidine (13.4 mL). To generate a solution, cool to 0 ℃ and add a solution of anhydrous crystalline orthophosphoric acid (16.4g,0.167mmol) in anhydrous DMSO (30 mL). The mixture was stirred at 0 ℃ for 1.5 h and at room temperature for 18 h under an argon atmosphere, diluted with ethyl acetate (1000 mL).A solution of oxalic acid dihydrate (63.1g,038mol) in DMSO (30mL) was added, the reaction mixture was stirred at room temperature for 1 hour, and then the precipitated Dicyclohexylurea (DCU) was removed by filtration. The filtrate was concentrated under reduced pressure to a volume of about 600mL and neutralized with a saturated aqueous solution of sodium bicarbonate (400 mL). Brine (200mL) was added, and the organic layer was extracted with ethyl acetate (4X 1000 mL). The combined organic layers were concentrated to a volume of about 2000mL, washed with a saturated aqueous solution of sodium bicarbonate (2 × 700mL) and brine (2 × 700mL) before being dried over sodium sulfate and evaporated under reduced pressure. A small portion of the crude residue was purified by column chromatography over silica gel [ eluent: chloroform/diethyl ether, 8: 2%]The structure of 2 was obtained as a pale yellow solid.¹H-NMR(CDCl₃):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=6.0Hz),4.51(s,1H,H-4),3.48(s,1H,OCH₃),1.56(s,3H CH₃),1.36(s,3H CH₃);MS(matrix GT):FAB>0m/z203(M+H)⁺,171(M-OCH₃)⁺。

Example 6: preparation of 4-C-hydroxymethyl-1-O-methyl-2, 3-O-isopropylidene-beta-D-ribofuranose- (3)

The target compound may be synthesized of9- [4-C- (hydroxymethyl) -a-L-thio-pentafuranosyl ] according to the published methods (Leland, D.L.; Kotick, M.P.; Studies on4-C- (hydroxymethyl) pentafuranoses]adenine”Carbohydr.Res.1974,38,C9-C11;Jones,G.H.;Taniguchi,M.;Tegg,D.;Moffatt,J.G.“4'-substituted nucleosides。5.Hydroxylation of nucleoside5'-aldehydes”J.Org.Chem.1979,44,1309-1317;Gunic,E.;Girardet,J.-L.;Pietrzkowski,Z.;Esler,C.;Wang,G.“Synthesis and cytotoxicity of4'-C-and5'-C-substitutedToyocamycins”Bioorg.Med.Chem2001,9, 163-.

To the crude material (2) obtained above and 37% formaldehyde (167mL) in dioxane (830mL) was added sodium hydroxide (2N,300 mL). The mixture was stirred at room temperature for 4 hours and by addition of Dowex50W X2 (H)⁺Type) is neutralized. After filtration of the resin, washing with methanol, the combined filtrates were concentrated to dryness and co-evaporated several times with absolute ethanol. By filteringPrecipitating the sodium formate with anhydrous ethanol, concentrating the filtrate, drying, and purifying the residue with silica gel column chromatography [ eluent: methanol in chloroform (0-4%) with stepwise gradient)]Pure 3(42.2g,54% from 1) was obtained, which was recrystallized from cyclohexylamine. Mp =94-95(dec.) (lit.94-96.5;97-98: Refs:3,4),¹H-NMR(DMSO-d₆) 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-6)_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,OCH₃),1.48(s,3H CH3),1.05(s,3H CH₃);MS(matrixGT):FAB>0m/z469(2M+H)⁺,235(M+H)⁺,203(M-OCH₃)⁺FAB<0m/z233(M-H)^-。

Example 7: preparation of 6-O-monomethoxytrityl-4-C-hydroxymethyl-1-O-methyl-2, 3-O-isopropylidene-beta-D-ribofuranose- (4)

The target compounds can be prepared according to the methods disclosed (Gunic, E.; Girardet, J. -L.; Pietrzkowski, Z.; Esler, C.; Wang, G. "Synthesis and cytotoxicity of4'-C-and5' -C-substitated Toyocamycins" Bioorg.Med.Chem2001,9, 163-.

To a solution of 3(41.0g,175mmol) in pyrimidine (700ml) was added a portion of di-p-methoxytrityl chloride (60.5g,178mmol) at +4 ℃. The reaction mixture was stirred at room temperature for 3 hours. After addition of methanol, the reaction mixture was concentrated (200ml), followed by dissolution with ethyl acetate (2L). The organic layer was washed with 5% aqueous sodium bicarbonate, water and dried over sodium sulfate, followed by evaporation to dryness. Purifying by silica gel column chromatography [ eluent: ethyl acetate/hexane 15/85]Pure 4(63.0g,68%) was obtained as syrup.¹H-NMR(CDCl₃) Delta 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)_5-OH=5.5Hz,J5-5'=10.5Hz),3.79(s,6H,OCH3),3.54(dd,1H,H-5',J_5'-OH=4.9Hz,J_5'-5=10.5Hz),3.31(s,3H,OCH₃),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 CH₃),1.15(s,3H CH₃);MS(matrix GT):FAB>0m/z303(DMTr)⁺。

Example 8: preparation of 5-O-benzoyl-4-C-hydroxymethyl-1-O-methyl-2, 3-O-isopropylidene-beta-D-ribose-furanose- (5)

The target compounds can be prepared according to the methods disclosed (Gunic, E.; Girardet, J. -L.; Pietrzkowski, Z.; Esler, C.; Wang, G. "Synthesis and cytotoxicity of4'-C-and5' -C-substitated Toyocamycins"Bioorg.Med.Chem2001,9, 163-.

To a solution of 4(2.51g,4.68mmol) in anhydrous pyrimidine (37 mL) under argon was added benzoyl chloride (1.09mL,9.36mmol) and the reaction mixture was stirred at room temperature for 13 h. Then, the reaction mixture was cooled to 0 ℃ and quenched with ice water (100 mL). The aqueous layer was extracted with dichloromethane (3 □ 200 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2X 150mL), water (1X 150mL), then dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 80% acetic acid (70.2mL), and the mixture was stirred at room temperature for 3 hours and concentrated to dryness. Purifying by silica gel column chromatography [ eluent: chloroform ] ]Pure 5(1.40g,88%) was obtained as syrup.¹H-NMR(CDCl₃):δ8.1-7.4(m,5H,C₆H₅CO),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-1H-2, H-3, H-2, H-5, H-2_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 CH₃),1.38(s,3H CH₃);MS(matrix GT):FAB>0m/z677(2M+H)⁺,339(M+H)⁺,307(M-OCH₃)⁺,105(C₆H₅CO)⁺FAB<0m/z121(C₆H₅CO₂)^-。

Example 9: preparation of 5-O-benzoyl-4-C-methyl-1-O-methyl-2, 3-O-isopropylidene-beta-D-ribofuranose- (6)

The target compounds can be prepared according to the methods disclosed (Gunic, E.; Girardet, J. -L.; Pietrzkowski, Z.; Esler, C.; Wang, G. "Synthesis and cytotoxicity of4'-C-and5' -C-substitated Toyocamycins"Bioorg.Med.Chem2001,9, 163-.

A solution of 5(37.6g,0.111mol), 4-dimethylaminopyridine (DMAP,40.7g,0.333mol) and phenoxythiocarbonylchloride in dry acetonitrile (1000mL) was stirred at room temperature for 1h and concentrated to dryness. The residue was dissolved in dichloromethane (500mL) and washed with 0.2M hydrochloric acid (2 × 500mL) and water (500mL) before drying over sodium sulfate, evaporation under reduced pressure and co-evaporation several times with anhydrous toluene. The crude extract was dissolved in dry toluene (880mL) and tris (trimethylsilyl) silane (TMSS,42.9mL,0.139mol), followed by the addition of 1,1' -azobis (cyclohexylaminonitrile) (ACCN,6.8g,27.8 mmol). The reaction mixture was stirred at reflux for 45 minutes, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography over silica gel [ eluent: stepwise gradient of ethyl ether in petroleum ether (5-20%) ]Pure 6(26.4g,74%) was obtained as a yellow syrup.¹H-NMR(DMSO-d6):δ8.0-7.5(m,5H,C₆H₅CO),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-3, J, H_5-5'=11.1Hz),4.10(d,1H,H-5',J_5'-5=11.1Hz),3.17(s,1H,OCH₃),1.38(s,3H CH₃),1.30(s,3H CH₃),1.25(s,3H CH₃);MS(matrix GT):FAB>0m/z291(M-OCH₃)⁺,105(C₆H₅CO)⁺FAB<0m/z121(C₆H₅CO₂)^-。

Example 10: preparation of 5-O-benzoyl-4-C-methyl-1, 2, 3-O-acetyl-alpha, beta-D-ribofuranose- (7)

Compound 6(22.5g,70mmol) was suspended in 80% anhydrous acetic acid solution (250 mL). The solution was heated at 100 ℃ for 3 hours. The solution was then halved in volume and co-evaporated with absolute ethanol and pyrimidine. The oily residue was dissolved in pyrimidine (280mL) and then cooled to 0 ℃. Acetic anhydride (80mL) and 4-dimethylamino-pyrimidine pyridine (500mg) were added. The reaction mixture was stirred at room temperature for 3 hours, followed by concentration under reduced pressure. The residue was dissolved with ethyl acetate (1L), followed by washing with a saturated aqueous solution of sodium hydrogencarbonate, 1M hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel [ eluent: stepwise gradient of ether in petroleum ether (30-40%) ], yielding pure 7(16.2g,60%) as a pale yellow syrup. A small portion of the starting material was repurified [ same eluent: system ] by silica gel column chromatography to separate the alpha and beta anomers.

α anomer:¹H-NMR(DMSO-d₆):δ8.1-7.5(m,5H,C₆H₅CO),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 =18.7Hz),2.15(s,3H, CH) ₃C0₂),2.11(s,3H,CH₃C0₂),2.07(s,3H,CH₃C0₂),1.37(s,3H,CH₃);MS(matrix GT):FAB>0m/z335(M-CH₃C0₂ ^-)⁺,275(M-CH₃C0₂ ^-+H)⁺,105(C₆H₅CO)⁺,43(CH₃CO)⁺FAB<0m/z121(C₆H₅CO₂)^-,59(CH₃CO₂)^-。

Beta anomer:¹H-NMR(DMSO-d₆):δ8.1-7.5(m,5H,C₆H₅CO),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'=11.7HZ),4.19(d,1H,H-5',J_5'-5=11.7Hz),2.10(s,3H,CH₃C0₂),2.06(s,3H,CH₃C0₂),2.02(s,3H,CH₃C0₂),1.30(s,3H,CH₃);MS(matrix GT):FAB>0m/z335(M-CH₃C0₂ ^-)⁺,275(M-CH₃C0₂ ^-+H)⁺,105(C₆H₅CO)⁺,43(CH₃CO)⁺FAB<0m/z121(C₆H₅CO₂)^-,59(CH₃CO₂)^-。

example 11: preparation of O-6-diphenylcarbamoyl-N²-isobutyryl-9- (2, 3-di-O-acetyl-5-O-benzoyl-4-C-methyl- β -D-ribofuranyl) -8-methylguanine- (18)

To O-6-diphenylcarbamoyl-8-methyl-N²To a suspension of isobutyrylguanine in anhydrous toluene (20mL) was added N, O-bis (trimethylsilyl) acetamide (1.92ML,7.9 mmol). The reaction mixture was heated at reflux for 1 hour. Compound 7(1.55g,3.93mmol) was dissolved in toluene (10mL) followed by the addition of trimethylsilyl trifluoro-methanesulfonate (TMSTF) (915mL,4.72 mmol). The mixture was heated at reflux for 30 minutes. The solution was then cooled to room temperature and neutralized with 5% aqueous sodium bicarbonate. The reaction mixture was diluted with ethyl acetate (200 mL). The organic phase was washed with 5% aqueous sodium bicarbonate (150mL) and water (2 × 150 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography over silica gel [ eluent: stepwise gradient of diethyl ether in petroleum ether (70-90%)]18 was obtained.

Example 12: preparation of 9- (4-C-methyl-. beta. -D-ribofuranyl) -8-methylguanine- (19)

The target compound may be prepared according to the published methods from 18 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4' -C-methyl nucleosides" Biosci.Biotechnol.Biochem1993,57, 1433-1438).

A solution of 18 in methanolic ammonia (presaturated at-10 ℃ C.) (20mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (60mL) and water (60 mL). The aqueous layer was washed with dichloromethane (2X 60mL) and concentrated under reduced pressure. The residue was purified by RP18 column chromatography [ eluent: water/acetonitrile 95/5], to afford 19.

Example 13: 9- (2, 3-di-O-acetyl-5-O-benzoyl-4-C-methyl-beta-D-ribofuranosyl) -8-methyladenine- (20)

A solution of 7(1.10g,2.79mmol) in dry acetonitrile (50ml) was treated with 8-methyladenine and tin tetrachloride (SnCl)₄660 μ L,5.58mmol) and stirred at room temperature overnight. The solution was concentrated under reduced pressure and diluted with chloroform (100mL), followed by treatment with a saturated aqueous solution of cold sodium bicarbonate (100 mL). The mixture was filtered through celite, and the precipitated material was washed with hot chloroform. Mixing filtrates, adding water (100 m)l) and brine (100ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel [ eluent: stepwise gradient of methanol in dichloromethane (3-5%)]And 20 was obtained.

Example 14: preparation of 9- (4-C-methyl-. beta. -D-ribofuranyl) -8-methyladenine- (21)

The target compound may be prepared according to the published methods from 20 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4' -C-methyl nucleosides" Biosci.Biotechnol.Biochem1993,57, 1433-1438).

A solution of 20 methanol in ammonia (presaturated at-10 ℃ C.) (50mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (100mL) and water (100 mL). The aqueous layer was washed with dichloromethane (2 × 100mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [ eluent: a stepwise gradient of methanol in ethyl acetate (10-30%) ], giving 21.

In a similar manner, but with the appropriate sugar and purine bases, nucleosides of the following formula XXXXII can be prepared:

wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Example 15: preparation of 1- (5-O-benzoyl-4-C-methyl-2, 3-O-acetyl-. beta. -D-ribofuranyl) -6-methyluracil- (8)

The suspension of 6-methyluracil was treated with hexamethyldisilane (HMDS,21mL) and a catalytic amount of ammonium sulfate at reflux for 17 hours. After cooling to room temperature, the mixture was evaporated under reduced pressure to give a residue as a colorless oil, which was diluted with anhydrous 1, 2-dichloroethane (7.5 mL). To the resulting solution was added a solution of 7(0.99g,2.51mmol) in dry 1, 2-dichloroethane (14mL), followed by trimethylsilyl triflate (TMSTf,0.97mL,5.02 mmol). The solution was stirred at room temperature for 2.5 hours under argon, then diluted with chloroform (150mL), washed with the same volume of saturated aqueous solution of sodium bicarbonate and finally with water (2X100 mL). The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography over silica gel [ eluent: stepwise gradient of methanol in chloroform (0-2%) ], obtaining pure 8.

Example 16: preparation of 1- (4-C-methyl-. beta. -D-ribofuranyl) -6-methyluracil- (9)

The target compound may be prepared according to the published method from 8 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4' -C-methyl nucleosides"Biosci.Biotechnol.Biochem1993,57, 1433-1438).

A methanolic ammonia solution of 8 (presaturated at-10 ℃ C.) (27mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (40mL) and water (40 mL). The aqueous layer was washed with dichloromethane (2X 40mL), concentrated under reduced pressure, and co-evaporated several times with absolute ethanol. Recrystallization from an absolute ethanol/methanol mixture gave 9.

Example 17: preparation of 1- (5-O-benzoyl-4-C-methyl-2, 3-O-acetyl-beta-D-ribofuranyl) -4-thioxo-6-methyl-uracil- (10)

Lawesson's reagent (926mg,2.29mmol) was added to a solution of 8 in dry 1, 2-dichloroethane (65mL) under argon, and the reaction mixture was stirred at reflux overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel [ eluent (1-2%) stepwise gradient of methanol in chloroform ], affording 10.

Example 18: preparation of 1- (4-C-methyl-. beta. -D-ribofuranyl) -4-thioxo-6-methyluracil- (11)

10 aqueous methanolic ammonia (presaturated at-10 ℃ C.) (27mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (40mL) and water (40 mL). The aqueous layer was washed with dichloromethane (2X 40mL) and concentrated under reduced pressure. The crude extract was purified by column chromatography over silica gel [ eluent (5-7%) stepwise gradient of methanol in dichloromethane ], to give 11, which was lyophilized.

Example 19: preparation of 1- (4-C-methyl-. beta. -D-ribofuranyl) -6-methylcytosine, hydrochloride form- (12)

Compound 11 was treated with methanolic ammonia in water (presaturated at-10 deg.C) (12mL) in a stainless steel pressure tank at 100 deg.C for 3 hours, followed by cooling to room temperature. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (40mL) and water (40 mL). The aqueous layer was washed with dichloromethane (2X 40mL) and concentrated under reduced pressure. The crude extract was purified by silica gel column chromatography [ eluent: dichloromethane/methanol/ammonium hydroxide 65:30:5 ]. The collected fractions were evaporated under reduced pressure in anhydrous ethanol (6.3 mL). To the solution was added a 2N hydrochloric acid solution (1.5mL), followed by stirring the mixture before being concentrated under reduced pressure. This process was repeated twice, precipitating 12 from absolute ethanol.

Example 20: preparation of 1- (5-O-benzoyl-4-C-methyl-2, 3-O-acetyl-. beta. -D-ribofuranyl) -6-methyl-thymine- (13)

A suspension of 6-methyl thymine was treated with hexamethyldisilane (HMDS,17mL) and a catalytic amount of ammonium sulfate at reflux overnight. After cooling to room temperature, the mixture was evaporated under reduced pressure to give a residue as a colorless oil which was diluted with anhydrous 1, 2-dichloroethane solution (6 mL). To the resulting solution was added a solution of 7(1.0g,2.53mmol) in dry 1, 2-dichloroethane (14mL), followed by trimethylsilyl triflate (TMSTf,0.98mL,5.06 mmol). The solution was stirred at room temperature under an argon atmosphere for 5 hours, then diluted with chloroform (150mL), saturated with the same volume of sodium bicarbonate solution and finally washed with water (2X 100 mL). The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The resulting crude extract was purified by silica gel column chromatography [ eluent: 2% methanol in chloroform ] to obtain pure 13.

Example 21: preparation of 1- (4-C-methyl-. beta. -D-ribofuranyl) -6-methylthymine- (14)

The target compound may be prepared according to the published methods from 13 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4' -C-methyl nucleosides"Biosci.Biotechnol.Biochem1993,57, 1433-1438).

13 of methanol in aqueous ammonia (presaturated at-10 ℃) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (60mL) and water (60 mL). The aqueous layer was washed with dichloromethane (2X 60mL), concentrated under reduced pressure, and co-evaporated several times with anhydrous ethanol. Recrystallization from methanol gave 14.

Example 22: preparation of 1- (5,2, 3-tri-O-acetyl-4-C-methyl-beta-D-ribofuranyl) -6-methyl-thymine- (15)

A solution of 14 in anhydrous pyrimidine (7.4mL) was treated with acetic anhydride (1.2mL) and stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel [ eluent (0-5%) stepwise gradient of methanol in dichloromethane ], affording 15.

Example 23: preparation of 1- (5,2, 3-tri-O-acetyl-4-C-methyl-beta-D-ribofuranyl) -4-thioxo-6-methyl-thymine- (16)

Lawesson's reagent (119mg,0.29mmol) was added to a solution of 15 in dry 1, 2-dichloroethane (11mL) under argon, and the reaction mixture was stirred at reflux overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel [ eluent (1-2%) stepwise gradient of methanol in chloroform ], affording 16.

Example 24: preparation of 1- (4-C-methyl-beta-D-ribofuranyl) -5-methyl-6-methylcytosine- (17), hydrochloride form

Compound 16 was treated with methanolic ammonia solution (presaturated at-10 ℃ C.) for 3 hours at 100 ℃ in a stainless steel pressure tank, followed by cooling to room temperature. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane (30mL) and water (30 mL). The aqueous layer was washed with dichloromethane (2X 30mL) and concentrated under reduced pressure. The crude extract was purified by column chromatography on silica gel [ eluent: 20% methanol in dichloromethane ], to give 17. This compound was dissolved in EtOH100(1.5mL), treated with 2N hydrochloric acid solution (0.3mL), and the mixture was stirred before being concentrated under reduced pressure. This process was repeated twice, precipitating 17 from absolute ethanol.

Alternatively, nucleosides of the following formula XXXIII can be prepared using appropriate sugar and pyrimidine bases:

wherein R is¹，R²，R³，X¹，X²And Y is as defined herein.

Alternatively, using appropriate sugar and pyrimidine or purine bases, nucleosides of the following formula XXXXIV can be prepared:

wherein R is¹，R²，R³，R⁶And X and base are as defined herein.

Alternatively, nucleosides of the following formula XXXXV can be prepared using appropriate sugar and pyrimidine or purine bases:

wherein R is¹，R²，R⁶And X and base are as defined herein.

Alternatively, nucleosides of the following formula XXXXVI can be prepared using appropriate sugar and pyrimidine or purine bases:

wherein R is¹，R²，R⁶And X and base are as defined herein.

Alternatively, nucleosides of the following formula XXXXVI can be prepared using appropriate sugar and pyrimidine or purine bases:

wherein R is¹，R⁶，R⁷，R⁸，R⁹，R¹⁰And X and base are as defined herein.

Biological assay method

A number of assay methods can be used to determine the antiviral ability of a test compound. Some of these biological assays are described in the examples below.

Example 25: anti-flavivirus or pestivirus activity

The compounds may exhibit activity against flavivirus or pestivirus by inhibiting flavivirus or pestivirus polymerase, by inhibiting other enzymes required in the replication cycle, or by other means.

Determination of phosphorylation of nucleosides to active triphosphates

To determine the metabolic mechanism of the compounds in cells, HepG2 cells obtained from the American type culture Collection (Rockville, Md.) and grown at 225cm²In minimal essential medium supplemented with non-essential amino acids and 1% penicillin-streptomycin in tissue culture flasks, the medium was changed every 3 days and cells were passaged once a week. After detachment of adherent monolayers by contacting with 30ml trypsin-EDTA for 10 min and washing 3 times with medium, the combined HepG2 cells were removed at 2.5X 10 per well⁶The concentration of each cell was inoculated in a 6-well plate and incubated with 10. mu.M³H]The labeled active compound (500dpm/pmol) is contacted for a certain time. These cells were maintained at 37 ℃ in 5% CO₂In the environment. At selected time points, cells were washed 3 times with ice-cold Phosphate Buffered Saline (PBS). The intracellular active compounds and their metabolites were extracted by incubating the cell sediment with 60% methanol at-20 ℃ overnight, followed by extraction with 20. mu.L of cold methanol in an ice bath for 1 hour. The extracts were then combined, dried under gentle brushing of filtered air flow, and stored at-20 ℃ until HPLC analysis.

Bioavailability assay in macaques

At 1 week prior to study initiation, rhesus macaques were surgically implanted with indwelling (chronic) venous catheters and subcutaneous Venous Access (VAP) for blood collection and physical examination, including hematology and serum chemistry evaluations, and body weights recorded. Each monkey (total 6) contains the active compound of about 250. mu. Ci per administration³H]I.e. at a concentration of 5mg/ml at a dose of 10 mg/kg. The administration was by intravenous bolus injection (3 monkeys, IV), or by oral gavage (3 monkeys, PO). Each dosing syringe is weighed prior to each dose to determine the amount of formulation administered. At designated time intervals (approximately 18-0 hours before dosing, 0-4, 4-8 and 8-12 hours after dosing), urine samples were collected and processed through a pan catch. Also, at designated time intervals (0.25, 0.5, 1, 2, 3, 6, 8, 12 and 24 hours before, after administration), blood samples were collected via the indwelling venous catheter and VAP or peripheral blood where the indwelling venous catheter approach was not feasible. Analysis of the blood and urine samples gave the peak concentration (C)_max) Time to peak concentration (T)_max) )), area under the curve (AUC), dose concentration half-life (T) _1/2) Clearance (CL), steady state volume and distribution (V)_ss) And bioavailability (F).

Bone marrow toxicity assay

From normal healthy volunteersHuman bone marrow cells are collected and isolated by single centrifugation of gradient nuclei as described by Sommadossi J-P, Carlisle R.in "sensitivity of3' -azido-3' -deoxythymidine and9- (1, 3-dihydroxy-2-prolymethyl) guanine for normal human hepatotoxicity reagent cells" analytical Agents and Chemotherapy1987;31:452-454; and Sommadossi J-P, Schinazi RF, Chu CK, Xie M-Y in "diagnosis of cytology of the (-) -and (+) -anticancer 2',3' -dideoxy-3' -thiocytidine in normal human marrow cells" 19244. simple centrifugation of gradient nuclei as described by Sommadossi J-P, Carlisse R.. CFU-GM and BFU-E assays of the cultures were performed using the double layer soft agar or methylcellulose method. The drug was diluted with tissue culture medium and filtered. At 37 deg.C, in a humidified atmosphere, with 5% CO₂After 14-18 days in air, colonies of more than 50 cells were counted using an inverted microscope. Results are expressed as percent inhibition of colony formation in the presence of drug compared to solvent control cultures.

Mitochondrial toxicity assay

HepG2cells were cultured in 12-well plates using the method described above, and HepG2cells were contacted with various concentrations of drugs according to the teaching of Pan-ZhouX-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usimer VM in "Difference differences of anti nuclear bacteria reactions on mitochondial functions in HepG2 cells" antibodies. Agents Chemothers.2000; 44: 496-503. After 4 days of drug exposure, the lactic acid level in the culture was determined using the Boehringer lactate assay kit. Lactate levels were normalized to the number of cells determined by a hemocytometer.

Cytotoxicity assays

Cells were treated at 5X 10³-5×10⁴The amount per well was inoculated in growth medium of 96-well culture plates, humidified CO at 37 deg.C₂(5%) incubation overnight in ambient. New growth medium containing serial dilutions of the drug was then added. After 4 days of incubation, the cultures were fixed with 50% TCA and stained with sulforhodamine B. At 550The optical density was measured at nm. Cytotoxic concentrations are expressed as the concentration required to reduce cell number by 50% (CC)₅₀）。

Cytoprotective assay (CPA)

The assay was carried out essentially according to the method described in Baginski, S.G., Pevear, D.C., SEIPEL, M.A., Sun, S.C.C., Benetates, C.A., Chunduru, S.K., Rice, C.M., and M.S. in "Mechanism of a pestivirus anti viral compound" PNAS USA2000,97(14), 7981-. MDBK cells (ATCC) were seeded in 96-well culture plates (4000 cells per well) 24 hours prior to use. After infection with BVDV (NADL strain, ATCC) at a multiplicity of infection (MOI) of 0.02 plaque-forming units per cell, serial dilutions of test compound were added to infected and uninfected cells, with a final concentration of DMSO in culture of 0.5%. Each dilution was done in quadruplicate. Cell density and inoculated virus were adjusted to ensure continued cell growth throughout the experiment and to achieve more than 90% virus-induced cell destruction in the untreated control group four days after infection. Four days later, plates were fixed with 50% TCA and stained with rhodamine. The optical density of each well was read using a plate reader at 550 nm. 50% Effective Concentration (EC) ₅₀) Values are defined as the concentration of compound that reduces the cytotoxic effect of the virus by 50%.

Plaque number reduction assay

The effective concentration of each compound was measured by a plaque number reduction assay on two identical 24-well plates. The cell monolayer was infected with 100PFU virus per well. Then, a MEM series of dilutions of the test compound supplemented with 2% inactivated serum and 0.75% methylcellulose was added to the monolayers. The cultures were further incubated at 37 ℃ for 3 days, followed by fixation with 50% ethanol and 0.8% crystal violet, washing and air drying. Plaques were then counted to determine the concentration required to achieve 90% viral inhibition.

Yield reduction assay

The concentration of each compound required to reduce viral load by 6-log was tested by yield reduction assay on duplicate 24-well plates. The assay was performed according to the method described in Baginski, S.G., Pevear, D.C., Seipel, M.S., Sun, S.C.C., Benetates, C.A., Chunduru, S.K., Rice, C.M., and M.S.Collett, in "Mechanism of action of a pestivirus anti viral consistent" PNAS USA2000,97(14), 7981-. Briefly, MDBK cells were seeded in 24-well culture plates (2 × 105 cells per well) 24 hours before infection with BVDV (NADL strain) at a multiplicity of infection (MOI) of 0.1 PFU per cell. Serial dilutions of test compounds were added to the cells at a final DMSO concentration of 0.5% in the growth medium. Each dilution was done in triplicate. After three days, the cell cultures were lysed by three freeze-thaw cycles (cell monolayer and supernatant) and virus yield was quantified by plaque assay. Briefly, MDBK cells were seeded in 6-well plates (5 × 105 cells per well) 24 hours prior to use. Cells were inoculated with 0.2ml of test lysate for 1 hour, washed and plated with growth medium solution of 0.5% agarose. After three days, the cell monolayer was fixed with 3.5% formaldehyde and stained with 1% crystal violet (w/v, solution in 50% ethanol) to visualize plaques. Plaques were counted and the concentration of 6-log reduction in viral load was determined.

Example 26: in vitro antiviral Activity

In vitro antiviral activity was tested in the following cell lines: MT-4 infected with HIV, Vero76, African green monkey kidney cells infected with SARS, BHK infected with bovine viral diarrhea virus, SB-1 infected with Sabin1, CVB-2, CVB-3, CVB-4, and CVA-9 infected with Coxsackie viruses B-2, B-3, B-4, and A-9, and REO-1 infected with double-stranded RNA virus. Note that: BVDV = bovine viral diarrhea virus, YFV = yellow fever virus, DENV = dengue virus, WNV = west nile virus, CVB-2= coxsackie B-2 virus, SB-1= Sabin1 type poliovirus, and REO = double stranded RNA reovirus.

beta-D-2' -C-methyl-7-methyl-6-phenyl-3, 3a,5,8 a-tetrahydro-1, 3,4,5,7 a-penta-aza-s-indacen-8- CC of Ketone (Compound F) ₅₀ And EC ₅₀ Test results

beta-D-2' -C-methyl-7-methyl-6-phenyl-3, 3a,5,8 a-tetrahydro-1, 3,4,5,7 a-penta-aza-s-indacen-8- CC of Ketone (Compound F) ₅₀ Test results

The applicant has described the invention with reference to preferred embodiments. However, it will be apparent to those skilled in the art from the foregoing detailed description that various changes and modifications can be made.

Claims (10)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹,R²and R³Independently is H, phosphate; linear, branched or cyclic alkyl; an acyl group; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substitutedAryl of (a), sulfonate ester; benzyl, wherein the phenyl is optionally substituted with one or more substituents; an alkylsulfonyl group; an arylsulfonyl group; an aralkylsulfonyl group; a lipid; an amino acid; amino acid residues; a carbohydrate; peptides, cholesterol; or other pharmaceutically acceptable leaving group capable of providing wherein R when administered in vivo¹,R²And/or R³A compound that is independently H or phosphate;

wherein R is²And R³At least one of which is not hydrogen; and

wherein:

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

X¹Is a linear, branched or cyclic optionally substituted alkyl radical, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵(ii) a And

X²is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵(ii) a And

wherein each Y³Independently is H, F, Cl, Br or I; and

R⁴and R⁵Each independently is hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl.

2. A compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹,R²and R³Independently is H, phosphate; straight, branched or cyclic alkyl, acyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate; benzyl, wherein the phenyl is optionally substituted with one or more substituents; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, lipid, amino acid; amino acid residues, carbohydrates; peptides, cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing wherein R¹,R²And/or R³A compound that is independently H or phosphate;

wherein R is²And R³At least one of which is not hydrogen; and

wherein:

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

X¹Is a linear, branched or cyclic optionally substituted alkyl radical, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substitutedAlkynyl, COOH, COOR ⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵(ii) a And

X²is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵(ii) a And

wherein each Y³Independently is H, F, Cl, Br or I; and

R⁴and R⁵Each independently is hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl.

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

or a pharmaceutically acceptable salt thereof, wherein:

R¹,R²and R³Independently is H, phosphate; straight, branched or cyclic alkyl, acyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate; benzyl, wherein the phenyl is optionally substituted with one or more substituents; an alkylsulfonyl group; an arylsulfonyl group; an aralkylsulfonyl group; a lipid; an amino acid; amino acidsA residue; a carbohydrate; peptides, cholesterol; or other pharmaceutically acceptable leaving group capable of providing wherein R when administered in vivo ¹,R²And/or R³A compound that is independently H or phosphate;

wherein R is²And R³At least one of which is not hydrogen; and

wherein:

the base is selected from:

R⁴and R⁵Each independently is hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl;

W¹，W²，W³and W⁴Each independently is N, CH, CF, CI, CBr, CCl, CCN, CCH₃，CCF₃，CCH₂CH₃，CC(O)NH₂，CC(O)NHR⁴，CC(O)N(R⁴)₂，CC(O)OH，CC(O)OR⁴Or CX³；

W^*Each independently is O, S, NH or NR⁴；

X is O, S, SO₂，CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂；

X is CH, CF, CY³Or CR⁴；

X²Is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵；

X³Each independently being a linear, branched or cyclic optionally substituted alkyl group, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substitutedAlkynyl, haloalkynyl, N₃，CN，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，OH，OR⁴-O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R) alkyl ⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), chloro, bromo, fluoro, iodo, NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂；

Y is independently selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCONH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

R is H, alkyl or acyl;

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

Y²Each independently of the other O, S, NH or NR⁴(ii) a And

Y³each independently is H, F, Cl, Br or I;

wherein if W¹，W²And W³Is N, for the Base (Base) (B), W⁴Cannot be CH;

wherein, ifW^lIs N, W for the bases (Base) (E), (F), (K), (L), (W) and (X)⁴Cannot be CH;

R⁶each independently is optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH2)_mC(O)OH，-(CH2)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)2，-(CH₂)_mC (O) N (lower alkyl) ₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Or cyano;

R⁷are each independently OH, OR²Optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl) ₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen;

or, R⁶And R⁷(ii) capable of combining to form a spiro compound selected from an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring; and is

m is independently 0, 1 or 2.

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

or a pharmaceutically acceptable salt thereof,

wherein:

R¹is H; phosphate radical; straight, branched or cyclic alkyl, acyl, CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; a sulfonate ester; benzyl, wherein the phenyl is optionally substituted with one or more substituents; an alkylsulfonyl group; an arylsulfonyl group; an aralkylsulfonyl group; a lipid; an amino acid; amino acid residues; a carbohydrate; peptides, cholesterol; or other pharmaceutically acceptable leaving group capable of providing wherein R when administered in vivo¹A compound that is H or phosphate; and the number of the first and second electrodes,

wherein:

the Base (Base) is selected from:

R⁴and R⁵Each independently is hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl;

W¹，W²，W³and W⁴Each independently is N, CH, CF, CI, CBr, CCl, CCN, CCH ₃，CCF₃，CCH₂CH₃，CC(O)NH₂，CC(O)NHR⁴，CC(O)N(R⁴)₂，CC(O)OH，CC(O)OR⁴Or CX³；

W^*Each independently of the other O, S, NH or NR⁴；

X is O, S, SO₂，CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂；

X is CH, CF, CY³Or CR⁴；

X²Is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵；

X³Each independently being a linear, branched or cyclic optionally substituted alkyl group, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N₃，CN，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，OH，OR⁴-O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R) alkyl⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), chloro, bromo, fluoro, iodo, NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl) ₂；

Y is independently H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCONH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

R is H, alkyl or acyl;

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

Y²Each independently of the other O, S, NH or NR⁴(ii) a And

Y³each independently is H, F, Cl, Br or I;

wherein if W¹，W²And W³Is N, for the Base (Base) (B), W⁴Cannot be CH;

wherein if W^lIs N, W for the bases (Base) (E), (F), (K), (L), (W) and (X)⁴Cannot be CH;

R⁶each independently is optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH2)_mC(O)OH，-(CH2)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)2，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Or cyano;

R⁷are each independently OH, OR²Optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH ₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkane)A radical, -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen;

or, R⁶And R⁷A compound capable of binding to form a spiro ring selected from: an optionally substituted carbocycle or an optionally substituted heterocycle;

R⁸and R¹¹Each independently is hydrogen, optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH ₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Cyano, NH-acyl or N (acyl)₂；

R⁹And R¹⁰Each independently of the others is hydrogen, OH, OR²Optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R) ⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen;

m is each independently 0, 1 or 2; and

or, R⁶And R¹⁰，R⁷And R⁹，R⁸And R⁷Or R⁹And R¹¹Capable of combining to form a bridged compound selected from: optionally substituted carbocycle or optionally substituted heterocycle, or, R⁶And R⁷Or R⁹And R¹⁰A compound capable of binding to form a spiro ring selected from: optionally substituted carbocycle or optionally substituted heterocycle.

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

or a pharmaceutically acceptable salt thereof, wherein:

R¹,R²and R³Independently is H, phosphate; straight, branched or cyclic alkyl, acyl, CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; a sulfonate ester; benzyl radical, in which the phenyl radical representsOptionally substituted by one or more substituents; alkylsulfonyl, arylsulfonyl; an aralkylsulfonyl group; a lipid; an amino acid; amino acid residues; a carbohydrate; peptides, cholesterol; or other pharmaceutically acceptable leaving group capable of providing wherein R when administered in vivo ¹,R²And/or R³A compound that is independently H or phosphate;

wherein R is²And R³At least one of which is not hydrogen; and

x is O, S, SO₂，CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂；

X is CH, CF, CY³Or CR⁴；

Y³Each independently is H, F, Cl, Br or I;

R⁴and R⁵Each independently is hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl;

base is a purine or pyrimidine Base;

R¹²each independently is substituted alkyl, CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴，-C(O)NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂；

R¹³Each independently is substituted alkyl, CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH ₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴，-C(O)SH，-C(O)SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，-O(R⁴) -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), -NHR⁴，-NR⁴R⁵-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), SCN, OCN, NCO or fluorine;

or, R¹²And R¹³A compound capable of binding to form a spiro ring selected from: an optionally substituted carbocycle or an optionally substituted heterocycle; and

m is independently 0, 1 or 2.

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

or a pharmaceutically acceptable salt thereof, wherein:

R¹is H, phosphate; straight, branched or cyclic alkyl, acyl, CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; a sulfonate ester; benzyl, wherein the phenyl is optionally substituted with one or more substituents; an alkylsulfonyl group; an arylsulfonyl group; an aralkylsulfonyl group; a lipid; an amino acid; amino acid residues; a carbohydrate; peptides, cholesterol; or other pharmaceutically acceptable leaving group capable of providing wherein R when administered in vivo ¹A compound that is H or phosphate;

the Base (Base) is selected from:

W¹，W²，W³and W⁴Each independently is N, CH, CF, CI, CBr, CCl, CCN, CCH₃，CCF₃，CCH₂CH₃，CC(O)NH₂，CC(O)NHR⁴，CC(O)N(R⁴)₂，CC(O)OH，CC(O)OR⁴Or CX³；

W^*Each independently of the other O, S, NH or NR⁴；

X is O, S, SO₂，CH₂，CH₂OH，CHF，CF₂，C(Y³)₂，CHCN，C(CN)₂，CHR⁴Or C (R)⁴)₂；

X is CH, CF, CY³Or CR⁴；

X²Is H, straight-chain, branched-chain or cyclic optionally substituted alkyl, CH₃，CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃，CH₂OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR⁴COO-alkyl, COO-aryl, CO-O alkoxyalkyl, CONH₂，CONHR⁴，CON(R⁴)₂Chlorine, bromine, fluorine, iodine, CN, N₃，OH，OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁵；

X³Each independently being a linear, branched or cyclic optionally substituted alkyl group, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N₃，CN，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，OH，OR⁴-O (acyl), -O (lower acyl), -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R) alkyl⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), chloro, bromo, fluoro, iodo, NH ₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl))₂；

Y is independently H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCONH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

R is H, alkyl or acyl;

Y¹is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR⁴，NH₂，NHR⁴，NR⁴R⁵SH or SR⁴；

Y²Each independently is O, S, NH or NR⁴(ii) a And

Y³each independently is H, F, Cl, Br or I;

wherein if W¹，W²And W³Is N, for the Base (Base) (B), W⁴Cannot be CH;

wherein if W^lIs N, W for the bases (Base) (E), (F), (K), (L), (W) and (X)⁴Cannot be CH;

R⁴and R⁵Each independently is hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl;

R¹²each independently is substituted alkyl, CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴，-C(O)NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R) ⁴)₂-C (O) N (lower alkyl)₂；

R¹³Each independently is substituted alkyl, CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower)Alkyl radical)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴，-C(O)SH，-C(O)SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂，-O(R⁴) -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), -NHR⁴，-NR⁴R⁵-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), SCN, OCN, NCO or fluorine; and

or, R¹²And R¹³A compound capable of binding to form a spiro ring selected from: an optionally substituted carbocycle or an optionally substituted heterocycle;

R⁸and R¹¹Each independently is hydrogen, optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF ₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，-(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，-C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl)₂Cyano, NH-acyl or N (acyl)₂；

R⁹And R¹⁰Each independently of the others is hydrogen, OH, OR²Optionally substituted alkyl, CH₃，CH₂CN，CH₂N₃，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂OH, haloalkyl, CF₃，C(Y³)₃2-Br-ethyl, CH₂F，CH₂Cl，CH₂CF₃，CF₂CF₃，C(Y³)₂C(Y³)₃Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH₂C(O)OH，-CH₂C(O)OR⁴，-CH₂C (O) O (lower alkyl), -CH₂C(O)SH，-CH₂C(O)SR⁴，-CH₂C (O) S (lower alkyl), -CH₂C(O)NH₂，-CH₂C(O)NHR⁴，-CH₂C (O) NH (lower alkyl), -CH₂C(O)N(R⁴)₂，-CH₂C (O) N (lower alkyl)₂，(CH₂)_mC(O)OH，-(CH₂)_mC(O)OR⁴，-(CH₂)_mC (O) O (lower alkyl), - (CH)₂)_mC(O)SH，-(CH₂)_mC(O)SR⁴，-(CH₂)_mC (O) S (lower alkyl), - (CH)₂)_mC(O)NH₂，-(CH₂)_mC(O)NHR⁴，-(CH₂)_mC (O) NH (lower alkyl), - (CH)₂)_mC(O)N(R⁴)₂，-(CH₂)_mC (O) N (lower alkyl)₂，C(O)OH，-C(O)OR⁴-C (O) O (lower alkyl), -C (O) SH, -C (O) SR⁴-C (O) S (lower alkyl), -C (O) NH₂，-C(O)NHR⁴-C (O) NH (lower alkyl), -C (O) N (R)⁴)₂-C (O) N (lower alkyl) ₂-O (acyl), -O (lower acyl), -O (R)⁴) -O (alkyl), -O (lower alkyl), -O (alkenyl), -O (alkynyl), -O (aralkyl), -O (cycloalkyl), -S (acyl), -S (lower acyl), -S (R)⁴) -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO₂，NH₂-NH (lower alkyl), -NHR⁴，-NR⁴R⁵-NH (acyl), -N (lower alkyl)₂-NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl)₂Azido, cyano, SCN, OCN, NCO or halogen;

m is each independently 0, 1 or 2; and

or, R⁸And R¹³，R⁹And R¹³，R⁹And R¹¹Or R¹⁰And R¹²Capable of combining to form a bridged compound selected from: an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring, or

Or, R¹²And R¹³Or R⁹And R¹⁰Capable of combining to form a spiro compound selected from an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.

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

or a pharmaceutically acceptable salt thereof, wherein:

R³h, H is selected; mono-, di-, and triphosphate or stable phosphate prodrugs; an acyl group; a sulfonate ester; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group capable of providing R thereof when administered in vivo ³Independently H, or mono-, di-, and triphosphate;

b represents a spiro compound selected from an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring;

the Base (Base) is selected from:

and

wherein

R ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

m is 0 or 1;

w is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R;

r is H, alkyl or acyl; and

Q₃，Q₄，Q₅and Q₆Independently is N or CH.

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

or

Or a pharmaceutically acceptable salt thereof, wherein:

A is selected from optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

Y is selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂And (CH)₂)_mCONHR；

R is H, alkyl or acyl;

x is selected from the group consisting of-OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂，NH₂，N₃NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aryl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂Alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH₂OH，CH₂NH₂，CH₂NHCH₃，CH₂N(CH₃)₂，CH₂F，CH₂Cl，CH₂N₃，CH₂CN，CH₂CF₃，CF₃，CF₂CF₃，CH₂CO₂R，(CH₂)_mCOOH，(CH₂)_mCOOR，(CH₂)_mCO-NH₂，(CH₂)_mCONR₂，(CH₂)_mCONHR, an optionally substituted 3-7 membered carbocyclic ring, and an optionally substituted 3-7 membered heterocyclic ring having O, S and/or N independently or in combination as heteroatoms;

m is 0 or 1;

R₃is selected from H; mono-, di-, and triphosphate or stable phosphate prodrugs; substituted or unsubstituted alkyl; an acyl group; a sulfonate ester; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group capable of providing wherein R when administered in vivo ₃Independently H, or mono-, di-, and triphosphateA compound; and

the base is a non-natural base selected from:

wherein:

r ', R' ', R' '' and R '' '' are each independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH-alkyl, and optionally substituted alkyl, substituted or unsubstituted alkynyl, cycloalkyl, Br-vinyl, -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl₂NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂，CO₂Alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃，CH₂OH，(CH₂)_mOH，(CH₂)_mNH₂，(CH₂)_mCOOH，(CH₂)_mCN，(CH₂)_mNO₂And (CH)₂)_mCONH₂；

m is 0 or 1;

w is C-R' or N;

t and V are independently CH or N;

q is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C-CONH₂Or N;

Q₁and Q₂Independently is N or C-R ' ' '; and

Q₃，Q₄，Q₅and Q₆Independently is N or CH;

the limiting conditions are: in bases (g) and (i), R ', R' '' is not H, OH, or NH₂(ii) a And Q, T, V, Q₂，Q₅And Q₆Is not N.

9. A compound of formula (IX):

or a pharmaceutically acceptable salt thereof, wherein:

R¹,R²and R ³Independently is H, phosphate; straight, branched or cyclic alkyl, acyl, CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; a sulfonate ester; benzyl, wherein the phenyl is optionally substituted with one or more substituents; an alkylsulfonyl group; an arylsulfonyl group; an aralkylsulfonyl group; a lipid; an amino acid; amino acid residues; a carbohydrate; peptides, cholesterol; or other pharmaceutically acceptable leaving group capable of providing wherein R when administered in vivo¹,R²And/or R³A compound that is independently H or phosphate;

x is O, S, SO₂Or CH₂；

Base is a purine or pyrimidine Base;

R¹²is C (Y)³)₃；

Y³Independently is H, F, Cl, Br or I; and

R¹³is fluorine.

10. The compound of claim 9, wherein X is O, Y³Is H.