CN1761677A - Modified 2' and 3'-nucleoside prodrugs for the treatment of flavivirus infection - Google Patents

Abstract

2 'and/or 3' -prodrugs of 1 ', 2', 3 'or 4' -branched nucleosides are described, as well as their pharmaceutically acceptable salts and derivatives. These prodrugs are useful in the prevention and treatment of flaviviridae infections, including HCV infections, and other related conditions. Compounds and compositions of the prodrugs of the invention are described. Also provided are methods and uses comprising administering an effective amount of the prodrugs of the invention, or their pharmaceutically acceptable salts or derivatives. These drugs can optionally be administered in combination or alternation with other antiviral agents to prevent or treat flavivirus infections and other related conditions.

Description

Modified 2' and 3'-nucleoside prodrugs for the treatment of flavivirus infection

Cross References to Related Applications

This application claims U.S. Provisional Application No. 60/392,350, filed June 28, 2002; U.S. Provisional Application No. 60/466,194, filed April 28, 2003; and U.S. Provisional Application No. 60/470,949, the disclosure of each of which is hereby incorporated by reference.

field of invention

The present invention relates to the field of medicinal chemistry, in particular, to 6-modified 1', 2', 3' or 4'-branched pyrimidine nucleosides or 8- 2' and/or 3' prodrugs of modified 1', 2', 3' or 4'-branched purine nucleosides.

Background of the invention

Flaviviridae

The Flaviviridae family of viruses comprises at least three separate genera: pestiviruses, which cause disease in cattle and pigs; flaviviruses, which are major causes of diseases such as dengue and yellow fever; and hepatic Viruses (hepaciviruses), the only member of which is the 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, 931-959 ). 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, 251-264; Halstead, S.B., Science, 239:476-481, 1988; Monath, T.P., New Eng. J. Med., 1988, 319, 641-643).

Pestiviruses include bovine viral diarrhea virus (BVDV), swine fever virus (CSFV, also known as hog cholera virus) and sheep border disease virus (BDV) (Moennig, V. et al. Adv. Vir. Res. 1992, 41 , 53-98). Pestivirus infections of domestic animals (cattle, pigs and sheep) cause huge economic losses worldwide. BVDV causes bovine mucosal disease 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 characterized as extensively as animal pestiviruses. However, serological investigations have shown that humans are threatened by a considerable number of pestiviruses.

Within the Flaviviridae family, Pestiviruses and Hepaviruses are closely related groups of viruses. Other closely related viruses in this family include GB virus A, GB virus A analogs, GB virus B and GB virus C (also known as hepatitis G virus, HGV). The hepadnavirus group (hepatitis C virus; HCV) includes many closely related but genotype-distinguished viruses that infect humans. There are about six HCV genotypes and more than 50 subtypes. Because of the similarities between pestiviruses and hepaviruses, and because hepaviruses are difficult to grow efficiently in cell culture media, bovine viral diarrhea virus (BVDV) is often used as a surrogate to study HCV viruses.

The genetic structures of pestiviruses and hepaviruses are very similar. These positive-strand RNA viruses possess a single large open reading frame (ORF) encoding all viral proteins essential for viral replication. These proteins are expressed as a polyprotein that is co-translationally and post-translationally processed by cellular and virally encoded proteases to produce mature viral proteins. . The viral proteins responsible for viral genomic RNA replication are located approximately at the carboxyl terminus. Two-thirds of the open reading frames were named nonstructural (NS) proteins. The gene structure of the nonstructural protein portion of the ORF and the processing of polyproteins are very similar for pestiviruses and hepadoviruses. For both Pestiviruses and Hepadoviruses, the mature nonstructural (NS) proteins consist consecutively from the amino terminus of the nonstructural protein coding region to the carboxy terminus of the ORF: p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B.

Both Pestivirus and Hepavirus NS proteins have sequence domains specific to the functional properties of the protein. For example, the NS3 protein in these two groups of viruses has an amino acid sequence motif (Gorbalenya et al. (1988) Nature 333:22; Bazan and Fletterick (1989) Virology 171:637-639; Gorbalenya et al. .(1989) Nucleic Acid Res. 17.3889-3897). Similarly, the NS5B proteins of Pestivirus and Hepadovirus have motifs characteristic of RNA-guided RNA polymerases (Koonin, E.V. and Dolja, V.V. (1993) Crit. Rev. Biochem. Molec. Biol. 28: 375-430 ).

The actual roles and functions of the NS proteins of pestiviruses and hepadoviruses in the viral life cycle are completely similar. In both, the NS3 serine protease is responsible for all proteolytic processing at positions downstream of the polyprotein precursor in the ORF (Wiskerchen and Collett (1991) Virology 184:341-350; Bartenschlager et al. (1993) JVirol.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. USA 90: 10583-10587; Hijikata et al. (1993) J. Virol. 67: 4665-4675; Tome et al. (1993) J. Virol. 67: 4017-4026). The NS4 protein acts in both as a cofactor for the NS3 serine protease (Bartenschlager et al. (1994) J. Virol. 68: 5045-5055; Failla 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 virus genera also have the function of helicase (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 proteins of pestiviruses and hepadoviruses have the expected RNA-guided 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 WO 97/12033; 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 slow-growing viral infection and is a major cause of cirrhosis and hepatocellular carcinoma (DiBesceglie, A.M. and Bacon, B.R., Scientific American, Oct: 80-85, (1999); Boyer, N. et al. J. Hepatol .32:98-112, 2000). An estimated 170 million people are infected with HCV worldwide (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). Cirrhosis due to chronic hepatitis C virus infection is estimated to cause 8,000-12,000 deaths per year in the United States, and HCV infection is the leading indication for liver transplantation.

HCV is known to cause at least 80% of post-transfusion hepatitis and most of the sporadic acute hepatitis. Preliminary evidence also indicates that HCV is not associated with other hepatitis viruses, such as hepatitis B virus (HBV), in many cases of "primary" chronic hepatitis, "occult" cirrhosis, and possibly hepatocellular carcinoma. A small proportion of the healthy population appears to be chronic HCV carriers, with diversity in geographic distribution and other epidemiological factors. Although only preliminary information, the number may substantially exceed the number of HBV carriers; it is not clear how many people have chronic liver disease without clinical symptoms (The Merck Manual, ch.69, p.901, 16 ^th ed., (1992)).

HCV is an enveloped virus with a sense, single-stranded RNA genome of approximately 9.4 kb. The viral genome consists of a 5' untranslated region (UTR), a long open reading frame encoding a polyprotein precursor of approximately 3011 amino acids, and a short 3' UTR. The 5'UTR is the most important 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 has recently been determined to be a fundamental structural element of the HCV IRES. Viral structural proteins include a nucleocapsid core protein (C) and two enveloped glycoproteins, E1 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 for cleaving specific regions of the precursor polyprotein to form mature peptides. The carboxyl portion of nonstructural protein 5, NS5B, contains an RNA-dependent RNA polymerase. The function of the remaining nonstructural proteins NS4A and NS4B and NS5A (the amino portion of nonstructural protein 5) remains unknown.

An important focus of current antiviral research is on the development of improved methods of treating chronic HCV infection in humans (DiBesceglie, 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 past decade. IFN is a glycoprotein 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, IFN can suppress serum HCV-RNA to undetectable levels in some cases. In addition, IFN normalized serum aminotransferase levels. Unfortunately, the effects of IFN are only transient, with sustained responses occurring in only 8%-9% of patients infected with chronic HCV (Gary L. Davis. Gastroenterology 118:S104-S114, 2000). However, the severe flu-like symptoms, weight loss, and fatigue that result from interferon therapy are difficult for most patients to tolerate.

Numerous patents disclose the use of interferon-based therapies for the treatment of Flaviviridae, including HCV. For example, US Patent No. 5,980,884 to Blatt et al. discloses a method of treating patients afflicted with HCV with consensus interferon. US Patent No. 5,942,223 to Bazer et al. discloses anti-HCV therapy using ovine or bovine interferon-T. US Patent No. 5,928,636 to Alber et al. discloses interleukin-12 and interferon alpha (IFN-alpha) combination therapy for the treatment of infectious diseases including HCV. US Patent No. 5,849,696 to Chretien et al. discloses the use of thymosin alone or in combination with interferon for the treatment of HCV. US Patent No. 5,830,455 to Valtuena et al. discloses HCV combination therapy using interferon and radical-only scavengers. US Patent No. 5,738,845 to Imakawa discloses the use of human interferon-Tau protein in the treatment of HCV. Additionally, other interferon-based HCV therapies are disclosed in US Patent No. 5,676,942 to Testa et al., US Patent No. 5,372,808 to Blatt et al., and US Patent No. 5,849,696. There are also a number of patents disclosing pegylated forms of interferon such as: U.S. Patent Nos. 5,747,646, 5,792,834 and 5,834,594 to Hoffmann-LaRoche Inc; PCT patents WO 99/32139 and WO 99/32140 to Enzon WO 95/13090 U.S. Patent Nos. 5,738,846 and 5,711,944 to Schering, and U.S. Patent No. 5,908,621 to Glue et al.

Interferon alpha-2a and interferon alpha-2b are currently licensed as monotherapy for the treatment of HCV. ROFERON(R)-A (Roche) is a recombinant form of interferon alpha-2a. PEGASYS(R) (Roche) is a pegylated (ie, polyethylene glycol modified) form of interferon alpha-2a. INTRON(R) A (Schering Corporation) Recombinant form of interferon alpha-2b. PEG-INTRON(R) (Schering Corporation) is a pegylated form of interferon alpha-2b.

Other forms of interferon alpha, as well as interferon beta, gamma, tau and omega, are currently in clinical development for HCV treatment. For example, INFERGEN (interferon α con-1) from InterMune, OMNIFERON (natural interferon) from Viragen, ALBUFERON from Human Genome Sciences, REBIF (interferon β-1a) from Ares-Serono, omega interferon from BioMedicine, omega interferon from Amarillo Biosciences Oral Interferon Alpha, as well as InterMune's interferon gamma, interferon tau and interferon gamma-1b are all under investigation.

Ribavirin

Ribavirin (1-β-D-ribofuryl-1-1,2,4-triazole-3-carboxamide) is a synthetic, non-interferon-induced, broad-spectrum antiviral nuclear Glycoside analogues, sold under the trade name Virazole (The Merck Index, 11th Edition, Editors: Budavari, S., Merck & Co., Inc., Rahway, NJ, PL304, 1989). U.S. Patent No. 3,798,209 and RE 29,835 disclose and claim ribavirin. Ribavirin is structurally similar to guanosine and has in vitro activity against a variety of DNA and RNA viruses, including Flaviviridae (Gary L. Davis. Gastroenterology 118: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. Gastroenterology 118:S104-S114, 2000). Therefore, ribavirin administered alone was not effective in reducing viral RNA levels. In addition, ribavirin is quite toxic and known to induce anemia.

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

Combination of interferon and ribavirin

The current standard of care for chronic hepatitis C is a combination therapy of interferon-alpha and ribavirin. For the treatment of HCV infection with combination therapy of interferon and ribavirin, it has been reported that this therapy is effective in the treatment of interferon naive patients (Battaglia, A.M.et al., Ann.Pharmacother.34: 487 -494, 2000), in addition, this therapy is also effective for the treatment of patients with histological diseases (Berenguer, M. et al. Antivir. Ther. 3 (Suppl. 3): 125-136, 1998). Studies have shown that more patients with hepatitis C respond better to pegylated interferon-alpha/ribavirin combination therapy than to non-pegylated interferon-alpha. However, as with monotherapy, in combination therapy, considerable side effects occur, including hemolysis, influenza-like symptoms, anemia, and fatigue (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).

Capsules for combination therapy with PEG-INTRON(R) (peg interferon alfa-2b) and REBETOL(R) (ribavirin, USP) are available from Schering Corporation. REBETOL® (Schering Corporation) is also approved for use in combination with INTRON® A (interferon alpha-2b, recombinant, Schering Corporation). Additionally, Roche's PEGASYS(R) (pegylated interferon alfa-2a) and COPEGUS(R) (ribavirin) are also approved for the treatment of HCV. )))

Schering Corporation's PCT Publication Nos. WO 99/59621, WO 00/37110, WO 01/81359, WO 02/32414 and WO 03/024461 disclose the use of pegylated interferon alfa and ribavirin Combination therapy for HCV. Hoffmann-La Roche Inc's PCT Publication Nos. WO 99/15194, WO 99/64016, and WO00/24355 also disclose the use of pegylated interferon alfa and ribavirin combination therapy for the treatment of HCV.

Other methods of treating infection with Flaviviridae viruses

The development of new antiviral agents for Flaviviridae viral infections, particularly hepatitis C virus, is currently under development. Specific inhibitors of HCV-derived enzymes such as proteases, helicases, and polymerase inhibitors are under development. In addition, inhibitors for other steps in HCV replication are in development, such as drugs that block the production of HCV antigens from RNA (IRES inhibitors), drugs that prevent the normal processing of HCV proteins (glycosylation inhibitors), drugs that block Drugs that block HCV's entry into cells (by blocking its receptors) and non-specific cytoprotectants that prevent cell damage due to viral infection. Further, molecular approaches have also been developed for the treatment of hepatitis C, for example, ribozymes, which are enzymes that specifically destroy viral RNA molecules; antisense oligonucleotides, which are small complementary fragments of DNA that bind Viral RNA and inhibition of viral replication are also under study. A number of HCV therapies are discussed in Bymock et al., Antiviral Chemistry & Chemotherapy, 11:2; 79-95 (2000) and De Francesco et al. Antiviral Research, 58:1-16 (2003).

Examples of classes of drugs that have been developed to treat flavivirus infections include:

(1) Protease inhibitors

Under investigation are: substrate-based NS3 protease inhibitors (Attwood et al., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy, 1999, 10, 259-273; Attwood et al., Preparation and use of amino acid derivatives as anti-viral agents, German Patent Publication No. DE 19914474; Tung et al. hydrazinoureas), and inhibitors capable of terminating electrophiles such as boronic acids or phosphonates (Llinas-Brunet et al., Hepatitis C Virus Inhibitor Peptide Analogs, PCT WO99/07734).

Also under study are: non-substrate-based NS3 protease 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. Antiviral Chemistry and Chemotherapy, 1998, 9, 186), including RD3-4082 and RD3-4078, the former is substituted by a 14-carbon chain on the amide, and the latter processes p-phenoxy phenyl.

Sch 68631, a phenanthrenequinone, is an inhibitor of HCV protease (Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996). In another example given by this author, Sch 351633, isolated from Penicillium griseofulvum, was identified as a protease inhibitor (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952). Through a selective inhibitor designed based on the macromolecular leech protease inhibitor c, Eglin c, an enzyme against HCV NS3 protease with nanomolar potency can be obtained. Eglin c, isolated from leeches, is a potential inhibitor of several serine proteases such as Streptomyces griseus (S. Griseus) proteases A and B, α-chymotrypsin, chymotrypsin, and subtilisin. Qasim M.A. et al., Biochemistry 36:1598-1607, 1997.

Several US patents disclose protease inhibitors for the treatment of HCV. For example, US Patent No. 6,004,933 to Spruce et al. discloses a class of cysteine protease inhibitors useful for inhibiting HCV endopeptidase 2. US Patent No. 5,990,276 to Zhang et al. discloses synthetic inhibitors of the hepatitis C virus NS3 protease. The inhibitor is a subsequence of an NS3 protease substrate or a substrate of an NS4A cofactor. The use of restriction enzymes to treat HCV is disclosed in US Patent No. 5,538,865 to Reyes et al. Peptides that are HCV NS3 serine protease inhibitors are disclosed in WO 02/008251 of Corvas International, Inc and WO 02/08187 and WO 02/008256 of Schering Corporation. HCV inhibitor tripeptides are disclosed in US Patent Nos. 6,534,523, 6,410,531 and 6,420,380 to Boehringer Ingelheim and WO 02/060926 to Bristol Myers Squibb. Diaryl peptides as HCV NS3 serine protease inhibitors are disclosed in WO 02/48172 by Schering Corporation. Imidazoleidinones as HCV NS3 serine protease inhibitors are disclosed in WO 02/08198 to Schering Corporation and WO 02/48157 to Bristol Myers Squibb. HCV protease inhibitors are also disclosed in WO 98/17679 to Vertex Pharmaceuticals and WO 02/48116 to Bristol Myers Squibb.

(2) Thiazolidine (Thiazolidines) derivatives showed relevant inhibitory effects in reversed-phase HPLC assays using NS3/4A fusion proteins and NS5A/5B substrates (Sudo K. et al., Antiviral Research, 1996, 32, 9-18), especially the compound RD-1-6250 with a fused cinnamoyl moiety substituted by a long-chain alkyl group, and RD4 6205 and RD46193;

(3) Thiazolidines and N-benzanilides, which are identified in Kakiuchi N. et al. J. EBS Letters 421, 217-220; Takeshita N. et al., Analytical Biochemistry, 1997, 247, 242-246 ;

(4) phenanthrenequinone (phenan-threnequinone), which is shown to have anti-protease activity in SDS-PAGE and autoradiography assay, is isolated from the fermentation broth of Streptomyces sp. (Chu M. et al. , Tetrahedron Letters, 1996,37,7229-7232), Sch 68631 and Sch 351633, isolated from Penicillium griseofulvum (Penicillium griseofulvum), showed activity in scintillation approximation assay (SPA) (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9 , 1949-1952);

(5) Helicase inhibitors (for example, Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Patent No. 5,633,358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions therefore and their use in the treatment of hepatitis C , PCT WO 97/36554);

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

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

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

(9) Ribozymes such as nuclease-resistant ribozymes (Maccjak D.J. et al., Hepatology 1999, 30, Abstract 995) and those disclosed in U.S. Patent No. 6,043,077 by Barber et al. and U.S. Patent Nos. 5,869,253 and 5,610,054 by Draper et al. the content of ; and

(10) Nucleoside analogues are also not being developed for the treatment of Flaviviridae virus infections.

Idenix Pharmaceuticals in International Application Publication Nos. WO 01/90121 and WO 01/92282 discloses the use of branched nucleosides for the treatment of flaviviruses (including HCV) and pestiviruses. Specifically, the method disclosed in the Idenix publication for the treatment of hepatitis C virus infection (flavivirus and pestivirus) in humans and other host animals comprising administering an effective amount of a biologically active 1', 2', 3' or 4'-branched β-D or β-L nucleosides or pharmaceutically acceptable salts or derivatives thereof, the embodiment is implemented alone or in combination with other antiviral agents , and a pharmaceutically acceptable carrier can also be optionally used. Pharmaceutically acceptable salt optional

Other patent applications disclosing the use of certain nucleoside analogs to treat hepatitis C virus include: PCT/CA00/01316 filed by BioChemPharma, Inc. (now Shire Biochem, Inc.) (WO 01/32153; Nov. 2000 filed 3 February) and PCT/CA01/00197 (WO 01/60315; filed 19 February 2001); PCT/US02/01531 filed by Merck & Co., Inc. (WO 02/057425; filed January 2002 18) and PCT/US02/03086 (WO02/057287; filed 18 January 2002), PCT/EP01/09633 filed by Roche (WO 02/18404; published 21 August 2001), and Pharmasset, Ltd's PCT Publication Nos. WO OIT9246 (filed 13 April 2001), WO 02/32920 (filed 18 October 2001) and WO 02/48165.

PCT Publication No. WO 99/43691 by Emory University, entitled "2'-Fluoronucleosides," discloses the use of certain 2'-fluoronucleosides for the treatment of HCV.

Eldrup et al. describe the structure-activity relationship of 2'-modified nucleosides for the inhibition of HCV (Oral Session V, Hepatitis C Virus, Flaviviridae; ^16th International Conference 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 (OralSession V, Hepatitis C Virus, Flaviviridae; ^16th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga. .); p A75). .

Olsen et al. electronically describe the effect of 2'-modified nucleosides on HCV RNA replication (Oral Session V, Hepatitis CVirus, Flaviviridae; ^16th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.) p A76).

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

(12) Other compounds currently in preclinical or clinical development for the treatment of hepatitis C virus include: Interleukin-10 from Schering-Plough, IP-501 from Interneuron, Merimebodib (VX-497) from Vertex, Endo AMANTADINE® (amantadine) from Labs Solvay, HEPTAZYME® from RPI, IDN-6556 from Idun Pharma, XTL-002 from XTL, HCV/MF59 from Chiron, CIVACIR® (hepatitis C virus immunoglobulin) from NABI, ICN /RIBAPHARM's LEVOVIRIN®, ICN/RIBAPHARM's VIRAMIDINE®, SciClone's ZADAXIN® (thymosin alpha-1), SciClone's thymosin and pegylated interferon, Maxim's CEPLENE® (histamine dihydrochloride), Vertex /VX 950/LY 570310 from Eli Lilly, ISIS 14803 from IsisPHARMACEUTICAL/ELAN, IDN-6556 from Idun Pharmaceuticals Inc., JTK 003 from AKROSPharma, BILN-2061 from Boehringer Ingelheim, CellCept (mycophenolate mofetil) from Roche , Tularik's T67, a β-tubulin inhibitor, Innogenetics' therapeutic vaccine against E2, Fujisawa Healthcare, Inc's FK788, IdB 1016 (Siliphos, oral silymarin-phosphatdylcholine phytosome (oralsilybin-phosphatdylcholine phytosome)) , ViroPharma/Wyeth's RNA Replication Inhibitor (VP50406), Intercell's Therapeutic Vaccine, Epimmune/Genencor's Therapeutic Vaccine, Anadys' IRES Inhibitor, Anadys' ANA 245 and ANA 246, Avant's Immunotherapy (Therapore), Corvas/Schering Protease Inhibitors from Vertex, Helicase Inhibitors from Vertex, Fusion Inhibitors from Trimeris, T Cell Therapies from CellExSys, Polymerase Inhibitors from Biocryst, Targeted RNA Chemistry from PTC Therapeutics, Immtech, Dicaion from Int, Agouron's Protease Inhibitor, Chiron/Medivir's Protease Inhibitor, AVI BioPharma's Antisense Therapy, Hybridon's Antisense Therapy, Aethlon Medical's Blood Cleaner (hemopurifier), Merix's Therapeutic Vaccine, Bristol-Myers Squibb/Axys' Protease Inhibitor Chron-VacC from Tripep, a therapeutic vaccine, UT 231B from United Therapeutics, protease, helicase and polymerase inhibitors from Genelabs Technologies, IRES inhibitor from Immusol, R803 from Rigel Pharmaceuticals, INFERGEN® (αcon -1 interferon), Viragen's OMNIFERON® (natural interferon), Human Genome Sciences' ALBUFERON®, Ares-Serono's REBIF® (beta-1a interferon), BioMedicine's omega-interferon, Amarillo Biosciences' oral α- Interferon, InterMune's gamma-interferon, tau-interferon and gamma-1b interferon.

Nucleoside prodrugs have been described previously for the treatment of other types of hepatitis. WO 00/09531 (filed August 10, 1999) and WO 01/96353 (filed June 5, 2001) of Idenix Pharmaceuticals disclose 2'-deoxy-β-L-nucleosides, and their use in HBV Therapeutic 3'-prodrugs. US Patent No. 4,957,924 to Beaucham discloses various esters of acyclovir for therapeutic use.

Considering that HCV infection has reached a worldwide epidemic level and caused tragic impact on patients, there is an urgent need to provide new and effective pharmaceutical agents for the treatment of hepatitis C with low toxicity to the host.

In addition, in view of the increasing risk of infection by other Flaviviridae viruses, there is an urgent need to provide new and effective pharmaceutical agents with low toxicity to the host.

Accordingly, it is an object of the present invention to provide compounds, methods and compositions useful in the treatment of a hepatitis C virus infected host.

Another object of the present invention is to provide a general method and composition for treating patients infected with pestiviruses, flaviviruses or hepadnaviruses.

Contents of the invention

2' and 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides, or their pharmaceutically acceptable salts or pharmaceutically acceptable compounds containing these compounds The formula is used in the prevention and treatment of Flaviviridae virus infection and other related symptoms, such as anti-Flaviridae virus antibody positive and Flaviviridae virus positive symptoms, chronic hepatitis caused by HCV, liver cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent It is useful for chronic 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-Flaviridae antibodies or Flaviviridae antigens or who are at risk of flaviviruses.

A method for treating a Flaviviridae virus infection in a host including humans is also disclosed, comprising administering an effective amount of a biologically active 1', 2', 3' or 4'-branched β-D or 2' and 3'-prodrugs of β-L nucleosides or their pharmaceutically acceptable salts, administered alone or in combination or alternately administered with other anti-Flaviridae virus preparations, or optionally used in pharmaceutically acceptable administered in the 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 site at the 2'-position, Including but not limited to acyl, in one embodiment, 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 site at the 3'-position, Including but not limited to acyl, in one embodiment, a natural or synthetic D or L amino acid, preferably an L-amino acid.

Pharmaceutically acceptable salts include tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate and alpha-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate, sulfate, sulfonate, Nitrates, bicarbonates, hydrobromides, hydrobromides, hydroiodides, carbonates, and orthophosphates. A particularly preferred embodiment is the mono- or dihydrochloride.

In one embodiment, the 1', 2', 3' or 4'-branched β-D or β-L nucleosides include biologically cleavable moieties at the 2' and/or 5' positions. Preferred moieties are natural or synthetic D or L amino acid esters, including D or L-valyl, but preferably L-amino acid esters, such as L-valyl 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 1', 2', 3' with any desired purine or pyrimidine base or L-amino acid esters of 4′-branched β-D or β-L nucleosides, wherein the parent drug optionally has an EC ₅₀ of less than 15 micromolar, more preferably less than 10 micromolar; with any desired purine or pyrimidine base 2'-(alkyl or aryl) esters of 1', 2', 3' or 4'-branched β-D or β-L nucleosides or 2', 5'-bis(alkyl or aryl) base) ester, wherein the parent drug optionally has an _EC50 of less than 10 or 15 micromolar; and 2', 5' of 1', 2', 3' or 4'-branched β-D or β-L nucleosides -prodrugs of diesters, wherein (i) the 2'-ester is a natural or synthetic D or L-amino acid ester, but preferably an L-amino acid ester, and the 5'-ester is an alkyl or aryl ester; (ii) both 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) 2 The '-ester is independently an alkyl or aryl ester and the 5'-ester is a natural or synthetic D or L-amino acid ester, although L-amino acid esters are preferred, where the parent drug optionally has less than 10 or 15 micromolar The _EC50 .

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

Other examples of prodrugs falling within the present invention are 2',5'-L-di Valine ester; 2′,5′-L-divaline ester of β-D-2′,6-dimethyl-thymidine; β-D-2′,8-Dimethyl-adenosine 2',5'-L-Divaline ester; 2',5'-L-Divaline ester of β-D-2',8-dimethyl-guanosine; β-D-2 ', 2',5'-L-divaline ester of 6-dimethyl-5-fluoro-cytidine; 2',5 of β-D-2',6-dimethyl-uridine '-L-Divaline ester; ',5'-diacetyl ester of β-D-2',6-dimethyl-cytidine; β-D-2',6-dimethyl-thymidine 2',5'-diacetyl ester of β-D-2',8-dimethyl-adenosine 2',5'-diacetyl ester; β-D-2',8-dimethyl- 2′,5′-diacetyl ester of guanosine; 2′,5′-diacetyl ester of β-D-2′,6-dimethyl-5-fluoro-cytidine; and β-D-2 2',5'-diester of ',6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or β-D-2',8-dimethyl-(bird glycoside, 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 an ester; (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'-prodrug includes a biologically cleavable Cut the part. Preferred moieties are natural or synthetic D or L amino acid esters, such as valyl, but preferably L-amino acids, such as L-valyl, and alkyl esters including acetyl. Thus, the present invention specifically includes 3'-L-amino acid esters of 1', 2', 3' or 4'-branched β-D or β-L nucleosides and 3' with any desired purine or pyrimidine base. ', 5'-L-diamino acid ester, wherein the parent drug optionally has an _EC50 of less than 15 micromolar and more preferably less than 10 micromolar; 1', 2', 3' with any desired purine or pyrimidine base or 3'-(alkyl or aryl) esters or 3',5'-L-di(alkyl or aryl) esters of 4'-branched β-D or β-L nucleosides, wherein the parent drug is either Prodrugs selected to have an EC ₅₀ of less than 10 or 15 micromolar; and 3', 5'-diesters of 1', 2', 3' or 4'-branched β-D or β-L nucleosides, 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 _EC50 of less than 10 or 15 micromolar.

Examples of prodrugs falling within the present invention are the 3'-L-valine ester of β-D-2',6-dimethyl-cytidine; β-D-2',6-dimethyl-thymidine 3′-L-valine ester of glycoside; 3′-L-valine ester of β-D-2′,8-dimethyl-adenosine; β-D-2′,8-dimethyl - 3'-L-valine ester of guanosine; 3'-L-valine ester of β-D-2',6-dimethyl-5-fluorocytidine; β-D-2', 3′-L-valine ester of 6-dimethyl-uridine; 3′-acetyl ester of β-D-2′,6-dimethyl-cytidine; β-D-2′,6- 3′-acetyl ester of dimethyl-thymidine; 3′-acetyl ester of β-D-2′,8-dimethyl-adenosine; β-D-2′,8-dimethyl-guanosine 3'-acetyl ester of β-D-2', 3'-acetyl ester of 6-dimethyl-5-fluoro-cytidine; and β-D-2', 6-dimethyl-(cytidine , 5-fluorocytidine, uridine or thymidine) 3'-ester or β-D-2',8-dimethyl-(guanosine, adenosine or inosine) 3'-ester, 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 ester; 3',5'-L-divaline ester of β-D-2',6-dimethyl-thymidine; β-D-2',8-dimethyl-adeno glycoside 3',5'-L-divaline ester; β-D-2',8-dimethyl-guanosine 3',5'-L-divaline ester; β-D- 3',5'-L-divalinate of 2',6-dimethyl-5-fluoro-cytidine; 3' of β-D-2',6-dimethyl-uridine, 5′-L-Divaline ester; 3′,5′-diacetyl ester of β-D-2′,6-dimethyl-cytidine; β-D-2′,6-Dimethyl- 3′,5′-diacetyl ester of thymidine; 3′,5′-diacetyl ester of β-D-2′,8-dimethyl-adenosine; β-D-2′,8-dimethyl 3′,5′-diacetyl ester of yl-guanosine; 3′,5′-diacetyl ester of β-D-2′,6-dimethyl-5-fluoro-cytidine; and β-D -3',5'-diester of 2',6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or β-D-2',8-dimethyl- 3′,5′-diesters of (guanosine, adenosine or inosine), wherein (i) the 3′-ester is an amino acid ester and the 5′-ester is an alkyl or aryl ester; (ii) both esters are is an amino acid ester; (iii) both 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, the prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides include biologically accessible cut part. Preferred moieties are natural or synthetic D or L amino acid esters, including D or L-valyl, but preferably L-amino acid esters, such as L-valyl, and alkyl esters including acetyl. Thus, the present invention specifically includes 2', 3'-L or D-diamino acid esters and 2', 3' , 5'-L or D-triamino acid ester, preferably an L-amino acid with any desired purine or pyrimidine base, wherein the parent drug optionally has an EC ₅₀ of less than 15 micromolar, more preferably less than 10 micromolar; with any 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside 2′, 3′-di(alkyl or aryl) ester or 2′ of the desired purine or pyrimidine base , 3′, 5′-L-tri(alkyl or aryl) ester, wherein the parent drug optionally has an EC ₅₀ of less than 10 or 15 micromolar; and 1′, 2′, 3′ or 4′-branched Prodrugs of 2',3'-diesters of β-D or β-L nucleosides, wherein (i) the 2'-ester is an amino acid ester and the 3'-ester is an alkyl or aryl ester; (ii) both Both esters are amino acid esters; (iii) both esters are independently alkyl or aryl esters; and (iv) the 2'-esters are independently alkyl or aryl esters and the 3'-esters are amino acid esters, wherein the parent The drug optionally has an _EC50 of less than 10 or 15 micromolar. 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) 2'-esters are amino acid esters, 3'-esters are alkyl or aryl esters and 5'-esters are alkyl or aryl esters; (v) 2'-esters are alkyl or aryl esters, 3'-esters are alkyl or aryl esters, 3'-esters are 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 amino acid ester; the 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 5'-Esters are amino acid esters; wherein the parent drug optionally has an _EC50 of less than 10 or 15 micromolar.

Examples of prodrugs falling within the present invention include 2',3'-L-divaline ester of β-D-2',6-dimethyl-cytidine (dival-2',6-diMe-L -dC); β-D-2′, 2′, 3′-L-divaline ester of 6-dimethyl-thymidine; β-D-2′, 8-dimethyl-adenosine 2′,3′-L-Divaline ester; 2′,3′-L-Divaline ester of β-D-2′,8-dimethyl-guanosine; β-D-2′ , 2′,3′-L-divaline ester of 6-dimethyl-5-fluoro-cytidine; β-D-2′, 2′,3′ of 6-dimethyl-uridine -L-Divaline ester; 2',3'-diacetyl ester of β-D-2',6-dimethyl-cytidine; β-D-2',6-dimethyl-thymidine 2',3'-diacetyl ester of β-D-2',8-dimethyl-adenosine 2',3'-diacetyl ester; β-D-2',8-dimethyl- 2′,3′-Diacetyl ester of guanosine; 2′,3′-diacetyl ester of β-D-2′,6-dimethyl-5-fluoro-cytidine; and β-D-2 2',3'-diester of ',6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or β-D-2',8-dimethyl-(bird glycoside, 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 an ester; (iii) both 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.

Additional examples of prodrugs falling within the present invention include 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; β-D-2',8- 2′,3′,5′-L-trivaline ester of dimethyl-adenosine; 2′,3′,5′-L of β-D-2′,8-dimethyl-guanosine - Trivaline ester; 2',3',5'-L-trivaline ester of β-D-2',6-dimethyl-5-fluoro-cytidine; β-D-2 ', 2',3',5'-L-trivaline ester of 6-dimethyl-uridine; 2',3' of β-D-2',6-dimethyl-cytidine, 5′-triacetyl ester; 2′,3′,5′-triacetyl ester of β-D-2′,6-dimethyl-thymidine; β-D-2′,8-dimethyl-adeno 2',3',5'-triacetyl ester of glycoside; 2',3',5'-triacetyl ester of β-D-2',8-dimethyl-guanosine; β-D-2' , 2′,3′,5′-triacetyl ester of 6-dimethyl-5-fluoro-cytidine; and β-D-2′,6-dimethyl-(cytidine, 5-fluoro 2′,3′,5′-triester of cytidine, uridine or thymidine) and 2′,3′ of β-D-2′,8-dimethyl-(guanosine, adenosine or inosine) ',5'-triesters, wherein (i) all three esters are amino acid esters; (ii) all three esters are independently alkyl or aryl esters; (iii) the 2' esters are amino acid esters, and the 3' The 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) 2'-esters are alkyl or aryl esters, 3'-esters are alkyl or aryl esters and 5'-esters are amino acid esters; (vi) 2'-esters are alkyl or aryl esters, 3'-esters are 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) 2 '-esters are amino acid esters, 3'-esters are alkyl or aryl esters and 5'-esters are amino acid esters.

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

R ¹ , R ² and R ³ are independently H, phosphate (including mono, di or triphosphate and stable phosphate); straight chain, branched or cyclic alkyl (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate including alkyl or aralkylsulfonyl including Methanesulfonyl and benzyl, wherein phenyl is optionally substituted by one or more of the same substituents as defined herein for aryl; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, lipid , including ^{phospholipids} ; amino acids; and amino acid residues ^, carbohydrates; ^peptides ; Compounds independently H or phosphate (including mono, di or triphosphate); wherein in one embodiment, R ^and /or ^R are not phosphate (including mono, di or triphosphate or a stable phosphate radical prodrug);

wherein at least one of ^R2 and ^R3 is not hydrogen, and wherein:

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

X ¹ is linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO- Aryl, CO-O alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; and

X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; and

wherein each ^Y3 is independently hydrogen, fluorine, chlorine, bromine or iodine;

R and ^R are independently 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, R ¹ , R ² and/or R ³ may be a pharmaceutically acceptable leaving group, for example, which, when administered in vivo, provides wherein R ¹ , R ² and/or R ³ Compounds that are independently 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, or a stereoisomer, tautomer or polymorph thereof, there is also provided a A method for treating a host infected with a Flaviviridae virus comprising administering a therapeutically effective amount of a compound of formula (II):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ , Y ³ , X ¹ and X ² are as defined above.

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

Or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein: the base (Base) is selected from:

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above;

W ¹ , W ² , W ³ and W ⁴ are independently N, CH, CF, CI, CBr, CCl, CCN, CCH ₃ , CCF ₃ , CCH ₂ CH ₃ , CC(O)NH ₂ , CC(O )NHR ⁴ , CC(O)N(R ⁴ ) ₂ , CC(O)OH, CC(O)OR ⁴ or CX ³ ;

W ^* is independently O, S, NH or NR ⁴ ;

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

X ^* is CH, CF, CY ³ or CR ⁴ ;

X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ;

X ³ are independently linear, branched or cyclic optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkyne group, N ₃ , CN, -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , OH, OR ⁴ , -O(acyl), -O (lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl) , -S (acyl), -S (lower acyl), -S (R ⁴ ), -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl ), -S (cycloalkyl), chlorine, bromine, fluorine, iodine, NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl Base) ₂ , -NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), -N (acyl) ₂ ;

Y are independently selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR;

wherein R is H, alkyl or acyl;

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

Y ² are independently O, S, NH or NR ⁴ ;

^Y3 are independently H, F, Cl, Br or I;

Wherein if W ¹ , W ² and W ³ are N, for the base (Base) (B), W ⁴ cannot be CH;

Wherein if W ¹ is N, for bases (Base)(E), (F), (K), (L), (W) and (X), W ⁴ cannot be CH;

R ⁶ are independently optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halo-lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH ₂ C(O )OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH2) _m C(O)OH , -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) 2, -(CH ₂ ) _m C(O )N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH (lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N (lower alkyl) ₂ or cyano;

R ⁷ are independently OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N( CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, any 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 group (preferably a 3-7 membered heteroaromatic ring with one or more O, S and/or N), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O )O(lower alkyl),-CH ₂ C(O)SH,-CH ₂ C(O)SR ⁴ ,-CH ₂ C(O)S(lower alkyl),-CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH (lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N (lower alkane base) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -( CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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 , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl ), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

Alternatively, R ⁶ and R ⁷ can combine to form a spirocyclic compound selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably with one or more O, S and/or 3-7 membered heterocycles of N); and

m is 0, 1 or 2 each independently.

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

Base, R, R ¹ , R ² , R ³ , R ⁴ , R 5 , R ⁶ , R ⁷ , Y, Y 1 , Y ² , ^{Y 3} , W ¹ , W ^{2 ,} W ³ , W ⁴ , W ^* , X, X ^* , ^X1 , ^X2 and ^X3 are as defined above;

wherein, in one embodiment, R ⁸ in formula (VI) is -OH or -NH ₂ only when X is carbon; and wherein;

R ⁸ and R ¹¹ are independently hydrogen, optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N( CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , cyano, NH- Acyl or N(acyl) ₂ ;

R ⁹ and R ¹⁰ are independently hydrogen, OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halo-lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, halo Alkynyl, 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), any Optionally substituted heteroaryl (preferably a 3-7 membered aromatic heterocyclic ring with one or more O, S and/or N), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , - CH ₂ C(O)O (lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S (lower alkyl), -CH ₂ C (O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O) )N(lower alkyl) ₂ , (CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S (lower alkyl), -(CH ₂ ) _m C( O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O )SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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(alk base), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S (lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl) , NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH(aralkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine );

m is each independently 0, 1 or 2; and

Alternatively, R ⁶ and R ¹⁰ , R ⁷ and R ⁹ , R ⁸ and R ⁷ or R ⁹ and R ¹¹ can combine to form a bridged compound, selected from: optionally substituted carbocycles (preferably 3-7 membered carbocycles) or an optionally substituted heterocycle (preferably a 3-7 membered heterocycle with one or more O, S and/or N); or

It can also be that R ⁶ and R ⁷ or R ⁹ and R ¹⁰ can combine to form a spiro compound, selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably with one or multiple O, S and/or N 3-7 membered heterocycles).

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

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

Base ^* (Base ^* ) is a purine or pyrimidine base as defined herein;

R ¹² are independently substituted alkyl (including lower alkyl), CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkane group (including halogenated lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ² C(O)NHR ⁴ , -CH ₂ C(O)NH( lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ² ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH (lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N (lower alkyl base) ² , -C(O)OH, -C(O)OR ⁴ , -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C( O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ ;

R ¹³ are independently substituted alkyl (including lower alkyl), CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkane group (including halogenated lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ² CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted 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 with one or more O, S and/or N 3-7 membered aromatic heterocycle), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C (O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O) NHR ⁴ , -(CH ₂ ) _m C(O)NH (lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N (lower alkyl) Alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C( O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , -O(R ⁴ ), -O(alkynyl), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (arylalkyl), -S (cycloalkyl), -NHR ⁴ , -NR ⁴ R ⁵ , - NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), SCN, OCN, NCO or fluorine;

Alternatively, R ¹² and R ¹³ can combine to form a spiro compound selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably with one or more O, S and/or 3-7 membered heterocycles of N); and

m is 0, 1 or 2 each independently.

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein: alternatively, base ^* (Base ^* ) is represented by formulas (XI) and (XII) Base (Base) substitution in; and Base (Base), Base ^* (Base ^* ), R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹² , R ¹³ , Y, Y ¹ , Y ² , Y ³ , W ^* , W ¹ , W ² , W ³ , W ⁴ , X, X ^* , X ¹ , X ² and X ³ are as defined above;

wherein, in one embodiment, R ⁸ in formula (XI) is -OH or -NH ₂ only when X is carbon; and

in:

R ⁸ and R ¹¹ are independently hydrogen, optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N( CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , cyano, NH- Acyl or N(acyl) ₂ ;

R ⁹ and R ¹⁰ are independently hydrogen, OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halo-lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, halo Alkynyl, 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), any Optionally substituted heteroaryl (preferably a 3-7 membered aromatic heterocyclic ring with one or more O, S and/or N), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , - CH ₂ C(O)O (lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S (lower alkyl), -CH ₂ C (O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O) )N(lower alkyl) ₂ , (CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S (lower alkyl), -(CH ₂ ) _m C( O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O )SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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(alk base), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S (lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl) , NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH(aralkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine );

m is each independently 0, 1 or 2; and

Alternatively, R ⁸ and R ¹³ , R ⁹ and R ¹³ , R ⁹ and R ¹¹ or R ¹⁰ and R ¹² can combine to form a bridged compound, selected from: optionally substituted carbocycles (preferably 3-7 membered carbocycles) or an optionally substituted heterocycle (preferably a 3-7 membered heterocycle with one or more O, S and/or N); or

Alternatively, R ¹² and R ¹³ or R ⁹ and R ¹⁰ can combine to form a spiro compound, selected from optionally substituted carbocycles (preferably 3-7 membered carbocycles) or optionally substituted heterocycles (preferably with one or more O, S and/or N 3-7 membered heterocycle).

In a specific aspect of the present invention, a compound or pharmaceutically acceptable salt or prodrug of formula (XI) or (XII), or their stereoisomers, tautomers or polymorphs, is also provided Provided is a method for treating a host infected with a Flaviviridae virus, the method comprising administering a therapeutically effective amount of a compound of formula (XI) or (XII):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

^R3 is selected from: H; mono-, di-, and triphosphates or stable phosphate prodrugs; acyl groups; sulfonate esters; optionally substituted alkylsulfonyl groups; optionally substituted arylsulfonyl groups; lipids; amino acid; carbohydrate; ^peptide ; cholesterol;

X" is selected from one or more of the following groups: O, S, SO, SO ₂ , N, NH, NR and CH ₂ , any of the aforementioned groups can be optionally substituted, and can be different position to form a 3-7 membered ring;

R is H, alkyl or acyl; and

B represents 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) ring);

Base (Base) is selected from:

Wherein: R', R", R' and R"" are 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 ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH, (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

G and E are independently selected from: CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , CH ₂ CN, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ₂ , (CH ₂ ) _m CONHR and N-acyl;

m is 0 or 1;

R is H, alkyl or acyl; and

R', R ", R'', R "" and R ³ and the base (Base) are as defined in formula (XIII).

Alternatively, for compounds of formula (XVII), at most one of G and E can further be hydrogen.

In a third specific aspect of the present invention, there is provided a compound of formula (XVIII) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a A method for treating a host infected with a Flaviviridae virus, the method comprising administering a therapeutically effective amount of a compound of formula (XVIII):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

M is selected from S, SO, and _SO2 ; and

R', R ", R'', R "" and R ³ and the base (Base) are as defined in formula (XIII).

In a fourth specific aspect of the present invention, there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (XIX), (XX), (XXI) (XXII) or (XXIII), or their stereoisomers, Tautomers or polymorphs also provide a method for treating a host infected with a Flaviviridae virus, the method comprising administering a therapeutically effective amount of formula (XIX), (XX), (XXI) Compounds of (XXII) or (XXIII):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

A is selected from optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ and (CH ₂ ) _m CONHR;

Y is selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F , CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ and (CH ₂ ) _m CONHR;

X is selected from -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, NO ₂ , NH ₂ , N ₃ , NH-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, CO ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ , (CH ₂ ) _m CONHR, optionally substituted 3-7 membered carbocyclic rings, and optionally substituted 3-7 membered carbocycles having O, S and/or N independently or in combination as heteroatoms Heterocycle;

m is 0 or 1;

R is H, alkyl or acyl;

_R3 is selected from H; mono-, di-, and triphosphates or stable phosphate prodrugs; substituted or unsubstituted alkyl; acyl; sulfonate; optionally substituted alkylsulfonyl; optionally substituted Arylsulfonyl; Lipid; Amino acid; Carbohydrate; ^Peptide ; Cholesterol; triphosphate compounds; and

Base (Base) is an unnatural base selected from:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

Q ₁ and Q ₂ are independently N or CR""; and

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH;

The provisos are: in bases (g) and (i), R', R"" are not H, OH, or _NH2 ; and Q, T, V, _Q2 , _Q5 and _Q6 are not N.

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

R ¹¹ is the side chain of an amino acid, wherein, when in proline, R ¹¹ can optionally be linked to R ¹³ to form a ring structure; alternatively, R ¹¹ is an alkyl, aryl, heteroaryl or heterocyclic moiety ;

^R is hydrogen, alkyl (including lower alkyl) or aryl; and

R ¹³ and R ¹⁴ are independently hydrogen, acyl (including acyl derivatives attached to R ¹¹ ) or alkyl (including but not limited to methyl, ethyl, propyl, and cyclopropyl).

In another preferred embodiment, at least one of ^R2 and ^R3 is an amino acid residue, preferably L-valyl.

The β-D- and β-L-nucleosides of the present invention can inhibit the activity of Flaviviridae virus polymerase. Nucleosides can be screened for their ability to inhibit flavivirus polymerase activity in vitro by the screening methods specifically described herein. The extent of activity can be readily determined by evaluating compounds in the assays described herein or by other validated assays.

In one embodiment, the effectiveness of a compound against Flaviviridae viruses can be determined in terms of the concentration of the compound in vitro necessary to reduce the number of viral plaques to achieve 50% (i.e., the compound's _EC50 ). In preferred embodiments the parent prodrug compound exhibits an _EC50 of less than 25, 15, 10, 5, or 1 micromolar. In a preferred embodiment, when 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 Vir. Bio.Chem., 274:10807-10815,1999; or Yamashita et al., Jnl.of Bio.Chem., 273:15479-15486, when the polymerase assay measurement described in 1998, compound shows less than 15 or 10 micromolar The _EC50 .

In another embodiment, combination and/or alternation therapy is provided. In combination therapy, effective doses of two or more agents are administered together, while in alternation therapy, effective doses of each agent are administered sequentially. Dosage depends on the rate of absorption, inactivation, and excretion of the drug, as well as other factors well known to those skilled in the art. It should be noted that dosage will also vary with the severity of the condition to be alleviated. It is also understood that for any particular patient, the particular dosing regimen and dosing schedule should be adjusted from time to time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.

The invention provides for the administration of at least two prodrugs described herein in combination. The present invention further provides that at least one of the 2' and 3'-prodrugs is administered in combination or alternately with another nucleoside exhibiting activity against Flaviviridae viruses, including but not limited to The parent drug of any prodrug as defined herein, i.e. β-D-2′, 6-dimethyl-cytidine, β-D-2′, 6-dimethyl-thymidine, β-D-2′ , 8-Dimethyl-adenosine, β-D-2′, 8-dimethyl-guanosine, β-D-2′, 6-dimethyl-5-fluorocytidine and/or β- D-2',6-Dimethyl-uridine. Alternatively, the 2' or 3'-prodrugs or their prodrugs or pharmaceutically acceptable salts may be co-administered or alternated with other anti-flaviviral agents having an _EC50 of less than 10 or 15 micromolar.

Non-limiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include: 1) interferon and/or ribavirin; (2) substrate-based NS3 protease inhibitors; (3) ) non-substrate-based inhibitors; (4) thiazolidine derivatives; (5) thiazolidine and N-benzanilides; (6) phenanthrenequinone; (7) NS3 inhibitors; (8) HCV helicase (9) polymerase inhibitors, including RNA-dependent RNA-polymerase inhibitors; (10) antisense oligodeoxynucleotides; (11) inhibitors of IRES-dependent translation; (12) anti-nucleic acid Enzyme ribozymes; and (13) other compounds having activity against viruses of the Flaviviridae family. The present invention further includes combining prodrugs with immunomodulators or other pharmaceutically active regulators 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 regulating genes of Flaviviridae virus replication are administered in combination or alternately.

The present invention further includes combining prodrugs with immunomodulators or other pharmaceutically active regulators 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 regulating genes of Flaviviridae virus replication are administered in combination or alternately. Prodrug

Specifically, the present invention provides the following:

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

(b) a pharmaceutical composition comprising a compound of formula (XIII)-(XXIII), or a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or diluent;

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

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

(e) a pharmaceutical composition for treating Flaviviridae virus infection in a host, comprising a compound of formula (I)-(XXIII), or a pharmaceutically acceptable salt thereof or their prodrug, and one or more other effective Antiviral agent, optionally with a pharmaceutically acceptable carrier or diluent;

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

(g) a method for treating a Flaviviridae virus infection in a host, comprising a compound of formula (I)-(XXIII), or a pharmaceutically acceptable salt thereof or a prodrug thereof, and one or more other effective anti-disease Toxic agent, optionally with a pharmaceutically acceptable carrier or diluent;

(h) compounds of formula (I)-(XXIII), or pharmaceutically acceptable salts thereof or their prodrugs, optionally together with pharmaceutically acceptable carriers or diluents in the treatment of Flaviviridae virus infections in hosts;

(i) compounds of formula (I)-(XXIII), or pharmaceutically acceptable salts thereof or their prodrugs, and one or more other effective antiviral agents, optionally with pharmaceutically acceptable carriers or diluents during treatment Use in Flaviviridae virus infection in a host;

(j) compounds of formula (I)-(XXIII), or pharmaceutically acceptable salts thereof or their prodrugs, optionally with a pharmaceutically acceptable carrier or diluent in the preparation of a medicament for treating flavivirus infection in a host in the use; and

(k) compounds of formula (I)-(XXIII), or pharmaceutically acceptable salts thereof or their prodrugs, and one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent Use in the preparation of a medicament for treating flavivirus infection in a host.

In an alternative embodiment, the parent nucleoside compound of any 2'- or 3'-prodrug (i.e., a nucleoside without a 2'- or 3'-cleavage moiety) is provided for use in the treatment of Flaviviridae viruses Infections, especially hepatitis C virus infection.

Description of drawings

Figure 1 provides the structures of various non-limiting examples of nucleosides of the invention, as well as other known nucleoside structures, specifically FIAU and ribavirin.

Figure 2 provides a non-limiting example of the reaction steps involved in esterifying 1', 2', 3' or 4'-branched β-D or β-L nucleosides to obtain 2'-prodrugs, prodrugs . The same conventional methods can be used to obtain 3'-prodrugs by selectively protecting the 2' and 5'-hydroxyl groups or protecting the 2', 3' and 5'-hydroxyl groups and selectively deprotecting the 3'-hydroxyl groups.

Figure 3 provides a non-limiting example of the reaction steps involved in esterifying 1', 2', 3' or 4'-branched β-D or β-L nucleosides to obtain 3'-prodrugs, including medicine.

Figure 4 provides a non-limiting example of the reaction steps involved in esterifying 1', 2', 3' or 4'-branched β-D or β-L nucleosides to obtain 2', 3'-prodrugs prodrug.

Detailed ways

Compounds, methods and compositions for treating Flaviviridae infections in humans or other host animals are disclosed herein. The method comprises administering an anti-Flaviridae therapeutically effective amount of the 2' and/or 3' of the 1', 2', 3' or 4'-branched β-D or β-L nucleosides described herein - Prodrugs, or pharmaceutically acceptable salts, derivatives or prodrugs thereof, optionally in a pharmaceutically acceptable carrier. The compounds of the present invention also possess antiviral (ie, anti-HCV) activity, or are metabolized to produce compounds having such activity. HCV is a member of the Flaviviridae family. HCV has been placed in a new monotypic genus, Hepavirus. Thus, in one embodiment, the Flaviviridae is HCV. In another alternative embodiment, said Flaviviridae virus is a Flavivirus or a Pestivirus.

2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides are secondary or tertiary alcohols alpha to the secondary or tertiary carbon Acyl derivatives. Based on the steric hindrance of these prodrugs to the 5'-prodrugs, acyl derivatives of primary alcohols, these prodrugs can differentially modulate the biological properties of the molecules in vitro. 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides have been found to provide drugs with increased half-life and improved metabolic profile of the drug .

In a preferred embodiment the 2' or 3'-prodrug 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, said amino acid is in the L-configuration. Alternatively, the amino acid may be alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, Threonyl, Cysteinyl, Tyrosyl, Asparaginyl, Glutaminyl, Aspartyl, Glutamyl, Lysyl, Arginyl, Histidyl, Beta-Alanyl, β-Valyl, β-Leucyl, β-Isoleucyl, β-Prolyl, β-Phenylalanyl, β-Tryptophanyl, β-Methionyl, β-Glycyl , β-seryl, β-threonyl, β-cysteinyl, β-tyrosyl, β-asparaginyl, β-glutamyl, β-aspartyl, β-glutamyl Derivatives of aminoacyl, β-lysyl, β-arginyl or β-histidyl. In a specific embodiment, said 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 with low oral bioavailability in rodents and nonhuman primates as natural bases and HCl salts . 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 other nucleosides. Glycosides or nucleoside analogs compete with 1', 2', 3' or 4'-branched β-D or β-L nucleosides for uptake. Higher oral bioavailability than the parent molecule and bioavailability to other nucleosides or nucleoside analogs for co-administration are achieved to improve oral bioavailability and reduce potential drug-drug interactions Reduced effect of 1′, 2′, 3′ or 4′-branched 2′- and 3′-prodrugs of β-D or β-L nucleosides.

1', 2', 3' or 4'-branched β-D or β-L nucleosides compared to 1', 2', 3' or 4'-branched β-D or β-L nucleosides The 2′, 3′, and/or 5′-mono, di, or trivaline esters have higher Oral bioavailability, and reduced interactions with other nucleosides or nucleoside analogs when used in combination.

2', 3', and/or 5'- Mono-, di- or tri-valine esters can be converted to the parent 1', 2', 3' or 4'-branched β-D or β-L nucleosides. 2', 3', and/or 5'-single , two or three valine esters can be effectively transported from the gastrointestinal cavity to the blood after oral administration. This is the reason for the increased oral bioavailability compared to the parent 1', 2', 3' or 4'-branched β-D or β-L nucleosides transported mainly by the action of amino acid transporters. Also, reduced uptake of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides with 2′, 3′, and/or 5′-mono, di, or trivalline Competition between esters and other nucleosides or nucleoside analogs that are transported by nucleoside transporters but not by amino acid transporters. Since partial deesterification of di- or trivaline esters of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides occurs prior to complete absorption, mono- or divaline Esters continue to be absorbed through the action of amino acid transporters. Thus, the desired better absorption or bioavailability, and reduced competition with other nucleosides or nucleoside analogs that are taken into the blood can be maintained.

In a word, 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 their Compositions;

(b) 2' and/or 3'-prodrugs of the 1', 2', 3' or 4'-branched β-D or β-L nucleosides described herein, and pharmaceutically acceptable salts and their Compositions for the treatment and/or prevention of Flaviviridae infection, particularly in individuals diagnosed as being infected with or at risk of becoming infected with Hepatitis C virus;

(c) 2' and/or 3'-prodrugs of the 1', 2', 3' or 4'-branched β-D or β-L nucleosides described herein, or pharmaceutically acceptable salts and combinations substances substantially free of enantiomers of said nucleosides, or substantially separated 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) Pharmaceutical formulations comprising 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides, or pharmaceutically acceptable salts thereof and a A pharmaceutically acceptable carrier or diluent;

(f) pharmaceutical formulations comprising 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides or pharmaceutically acceptable salts thereof, and a or multiple other effective anti-HCV agents, optionally in a pharmaceutically acceptable carrier or diluent;

(g) Pharmaceutical formulations comprising 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides or pharmaceutically acceptable salts thereof, in combination with 1 ', 2', 3' or 4'-branched chain β-D or β-L nucleoside different parent, optionally in a pharmaceutically acceptable carrier or diluent;

(h) a method for treating and/or preventing a host infected with a Flaviviridae virus, comprising administering an effective amount of 1′, 2′, 3′ or 4′-branched chain β-D or β-L nucleosides 2' and/or 3'-prodrugs, or pharmaceutically acceptable salts or compositions thereof;

(i) a method for treating and/or preventing a host infected with a Flaviviridae virus, comprising effective amounts of 1', 2', 3' or 4'-branched chain β-D or β-L nucleosides ' and/or 3'-prodrugs, or pharmaceutically acceptable salts or compositions thereof, are administered in combination and/or alternately with one or more effective anti-HCV agents;

(j) a method for treating and/or preventing a host infected with a Flaviviridae virus, comprising administering an effective amount of 1', 2', 3' or 4'-branched chain β-D or β-L nucleosides 2' and/or 3'-prodrugs, or pharmaceutically acceptable salts or compositions thereof, are different from 1', 2', 3' or 4'-branched β-D or β-L nucleosides;

(k) a method for treating and/or preventing a host infected with a Flaviviridae virus comprising administering an effective amount of 2' and/or 3'-prodrugs of β-D-2'-methyl-cytidine, Or its pharmaceutically acceptable salt or their composition;

(l) a method for treating and/or preventing a host infected with a Flaviviridae virus comprising administering an effective amount of 2'-valyl or acetyl ester of β-D-2'-methyl-cytidine, or Its pharmaceutically acceptable salt or their combination;

(m) 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched chain β-D or β-L nucleosides, and pharmaceutically acceptable salts and their compositions for use in Treating and/or preventing infection with a Flaviviridae virus 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 and one or more Two effective anti-HCV agents are administered in combination and/or alternately for the treatment and/or prevention of Flaviviridae infection in a host;

(o) 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched chain β-D or β-L nucleosides, or pharmaceutically acceptable salts or compositions thereof with 1', 2', 3' or 4'-branched β-D or β-L nucleoside-different parent for use in the treatment and/or prevention of Flaviviridae infection in a host;

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

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

(r) 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched chain β-D or β-L nucleosides, and pharmaceutically acceptable salts and their compositions in the preparation Use in a medicament for treating and/or preventing infection with a Flaviviridae virus in a host;

(s) 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides, pharmaceutically acceptable salts or compositions thereof and one or more Use of two effective anti-HCV agents for joint administration and/or alternate administration in the preparation of a medicament for treating and/or preventing Flaviviridae virus infection in a host;

(t) 2' and/or 3'-prodrugs of 1', 2', 3' or 4'-branched chain β-D or β-L nucleosides, or pharmaceutically acceptable salts or compositions thereof with 1' , 2′, 3′ or 4′-branched β-D or β-L nucleoside different parent in the preparation of the purposes of the medicament for treating and/or preventing the infection of Flaviviridae virus in the host;

(u) 2' and/or 3'-prodrugs of β-D-2'-methyl-cytidine, or pharmaceutically acceptable salts thereof or their compositions are prepared for treating and/or preventing host Use in medicine for Flaviviridae viral infections; and

(v) β-D-2'-methyl-cytidine 2'-valyl or acetyl ester, or a pharmaceutically acceptable salt thereof or a composition thereof is used in the preparation of treatment and/or prevention of flaviviruses in a host Use in medicine for virus infection.

A general discussion of the Flaviviridae family 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, Chapter 31, 1996. In a particular embodiment of the invention, said Flaviviridae virus is HCV. In an alternative embodiment of the invention, said Flaviviridae virus is a Flavivirus or a Pestivirus. Specific flaviviruses include, but are not limited to: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, 1 Dengue 1, Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango ), Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc, Montana myotis leukoencephalitis), Murray valley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya ), St.Louis encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spondweni, Stratford, Tembusu , Tyuleniy, Uganda S, Usutu, Wesselsbron, West Nile, Yaounde, yellow fever (Yellow fever) and Zika.

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, Chapter 33, 1996. Specific pestiviruses include, but are not limited to: bovine viral diarrhea virus ("BVDV"), swine fever virus ("CSFV", also known as swine cholera virus), and bovine border disease virus ("BDV").

I. Active compounds

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

R ¹ , R ² and R ³ are independently H, phosphate (including mono, di or triphosphate and stable phosphate); straight chain, branched or cyclic alkyl (including lower alkyl); acyl (including lower acyl); CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonate including alkyl or aralkylsulfonyl including Methanesulfonyl and benzyl, wherein phenyl is optionally substituted by one or more of the same substituents as defined herein for aryl; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, lipid , including ^{phospholipids} ; amino acids; and amino acid residues ^, carbohydrates; ^peptides ; Compounds independently H or phosphate (including mono, di or triphosphate); wherein in one embodiment R ^and /or ^R are not phosphate (including mono, di or triphosphate or stabilized phosphoric acid root prodrug);

wherein at least one of ^R2 and ^R3 is not hydrogen:

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

X ¹ is linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO- Aryl, CO-O alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ;

X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; and

wherein each ^Y3 is independently hydrogen, fluorine, chlorine, bromine or iodine;

R and ^R are independently 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 sub-embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and also provides a 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 their stereoisomers, tautomers or polymorphs Types, of which:

R ¹ is H or phosphate (preferably H);

^R2 and ^R3 are independently H, phosphate, acyl or amino acid residue, wherein at least one of ^R2 and ^R3 is an acyl group or an amino acid residue;

X ¹ is CH ₃ , CF ₃ or CH ₂ CH ₃ ;

^X2 is H or _NH2 ; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, _NH2 or OH.

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ , Y ³ , X ¹ and X ² are as defined above.

In a preferred sub-embodiment, there is provided a compound of formula (II) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a compound for use in 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 their stereoisomers, tautomers or polymorphs Models. in:

R ¹ is H or phosphate (preferably H);

^R2 and ^R3 are independently H, phosphate, acyl or amino acid residue, wherein at least one of ^R2 and ^R3 is an acyl group or an amino acid residue;

X ¹ is CH ₃ , CF ₃ or CH ₂ CH ₃ ;

^X2 is H, F, Cl, Br, I or _CH3 ; and

Y is hydrogen, bromine, chlorine, fluorine, iodine, _NH2 or OH.

In a third major embodiment there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (III), (IV) or (V), or a stereoisomer, tautomer or polymorph thereof Also provides a method for treating a host infected with a Flaviviridae virus, comprising administering an effective therapeutic amount of a compound of formula (III), (IV) or (V):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein: R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, Y ¹ and X ² is as defined above; Base (Base) is selected from:

W ¹ , W ² , W ³ and W ⁴ are independently N, CH, CF, CI, CBr, CCl, CCN, CCH ₃ , CCF ₃ , CCH ₂ CH ₃ , CC(O)NH ₂ , CC(O )NHR ⁴ , CC(O)N(R ⁴ ) ₂ , CC(O)OH, CC(O)OR ⁴ or CX ³ ;

W ^* is independently O, S, NH or NR ⁴ ;

Wherein, if W ¹ , W ² and W ³ are N, for the base (Base) (B), W ⁴ cannot be CH;

Wherein, if W ¹ is N, for bases (Base)(E), (F), (K), (L), (W) and (X), W ⁴ cannot be CH;

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

X ^* is CH, CF, CY ³ or CR ⁴ ;

X ³ are independently linear, branched or cyclic optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkyne group, N ₃ , CN, -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , OH, OR ⁴ , -O(acyl), -O (lower acyl), -O(alkyl), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl) , -S (acyl), -S (lower acyl), -S (R ⁴ ), -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (aralkyl ), -S (cycloalkyl), chlorine, bromine, fluorine, iodine, NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl Base) ₂ , -NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), -N (acyl) ₂ ;

Y ² are independently O, S, NH or NR ⁴ ;

^Y3 are independently H, F, Cl, Br or I;

R ⁶ are independently optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halo-lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH ₂ C(O )OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O) OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C( O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O) NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ or cyano;

R ⁷ are independently OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N( CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, any 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 group (preferably a 3-7 membered aromatic heterocyclic ring with one or more O, S and/or N), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O )O(lower alkyl),-CH ₂ C(O)SH,-CH ₂ C(O)SR ⁴ ,-CH ₂ C(O)S(lower alkyl),-CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH (lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N (lower alkane base) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -( CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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 , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl ), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

Alternatively, R ⁶ and R ⁷ can combine to form a spiro compound, selected from: optionally substituted carbocycles (preferably 3-7 membered carbocycles) or optionally substituted heterocycles (preferably with one or more O, S and /or 3-7 membered heterocycles of N); and

m is 0, 1 or 2 each independently.

In a first sub-embodiment there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (III), (IV) or (V), or a stereoisomer, tautomer or polymorph thereof Form thing, also provides a kind of method that is used for the treatment of the host that is infected with Flaviviridae virus, comprises the formula (III), (IV) or (V) compound or pharmaceutically acceptable salt or prodrug of administering therapeutically effective amount , or their stereoisomers, tautomers or polymorphs, wherein:

R ¹ is H or phosphate (preferably H);

^R2 and ^R3 are independently H, phosphate, acyl or an amino acid residue, wherein at least one of ^R2 and ^R3 is an acyl group or an amino acid residue;

W ⁴ is CX ³ ;

X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ ;

^R6 is alkyl; and

X is O, S, _SO2 or _CH2 .

In a second sub-embodiment there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (III), (IV) or (V), or a stereoisomer, tautomer or polymorph thereof Form thing, also provides a kind of method that is used for the treatment of the host that is infected with Flaviviridae virus, comprises the formula (III), (IV) or (V) compound or pharmaceutically acceptable salt or prodrug of administering therapeutically effective amount , or their stereoisomers, tautomers or polymorphs, wherein:

R ¹ is H or phosphate (preferably H);

^R2 and ^R3 are independently H, phosphate, acyl or amino acid residue, wherein at least one of ^R2 and ^R3 is an amino acid residue;

W ⁴ is CX ³ ;

X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ ;

^R6 is alkyl; and

X is O, S, _SO2 or _CH2 .

In a third sub-embodiment, there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (III), (IV) or (V), or a stereoisomer, tautomer or polymorph thereof Form thing, also provides a kind of method that is used for the treatment of the host that is infected with Flaviviridae virus, comprises the formula (III), (IV) or (V) compound or pharmaceutically acceptable salt or prodrug of administering therapeutically effective amount , or their stereoisomers, tautomers or polymorphs, wherein:

R ¹ is H or phosphate (preferably H);

^R2 and ^R3 are independently H, phosphate, acyl or an amino acid residue, wherein at least one of ^R2 and ^R3 is an acyl group or an amino acid residue;

W ⁴ is CX ³ ;

X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ ;

^R6 is alkyl; and

X is O.

In a more preferred subembodiment, there is provided a compound of formula (IV(a)) or a pharmaceutically acceptable salt or prodrug, or a stereoisomer, tautomer or polymorph thereof, also A method for treating a host infected with a Flaviviridae virus is provided, comprising administering a therapeutically effective amount of a compound of formula (IV(a)):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

Base (Base) is defined here; optionally substituted by amine or cyclopropyl (eg, 2-amino, 2,6-diamino or cyclopropylguanosine);

R ⁷ is halogen (F, Cl, Br or I), but preferably F;

^R is H; phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate including Alkyl or arylalkylsulfonyl includes methylsulfonyl and benzyl, wherein the phenyl is optionally substituted with one or more of the same substituents as defined herein for aryl; lipids, including phospholipids; amino acids; A carbohydrate; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, provides wherein R ¹ or R ² are independently H or phosphate. In one embodiment, ^R is not phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); and

^R is phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate including alkyl Or arylalkylsulfonyl includes methylsulfonyl and benzyl, wherein the phenyl is optionally substituted with one or more of the same substituents as defined herein for aryl; lipids, including phospholipids; amino acids; carbohydrates ; peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, provides wherein R ¹ or R ² are independently H or phosphate. In one embodiment, ^R is not phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug);

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

Base, R, R ¹ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Y, Y ¹ , Y ² , Y ³ , W ^* , W ¹ , W ² , W ³ , W ⁴ , X , X ^* , X ¹ , X ² and X ³ are as defined above;

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

and

in;

R ⁸ and R ¹¹ are independently hydrogen, optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N( CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , cyano, NH- Acyl or N(acyl) ₂ ;

R ⁹ and R ¹⁰ are independently hydrogen, OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halo-lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, halo Alkynyl, 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), any Optionally substituted heteroaryl (preferably a 3-7 membered aromatic heterocyclic ring with one or more O, S and/or N), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , - CH ₂ C(O)O (lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S (lower alkyl), -CH ₂ C (O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O) )N(lower alkyl) ₂ , (CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S (lower alkyl), -(CH ₂ ) _m C( O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O )SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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(alk base), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S (lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl) , NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH(aralkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine );

m is each independently 0, 1 or 2; and

Alternatively, R ⁶ and R ¹⁰ , R ⁷ and R ⁹ , R ⁸ and R ⁷ or R ⁹ and R ¹¹ can combine to form a bridged compound, selected from: optionally substituted carbocycles (preferably 3-7 membered carbocycles) or an optionally substituted heterocycle (preferably a 3-7 membered heterocycle with one or more O, S and/or N); or

Alternatively, R ⁶ and R ⁷ or R ⁹ and R ¹⁰ can combine to form a spiro compound, selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably with one or 3-7 membered heterocyclic rings with multiple O, S and/or N).

In a specific preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a compound for use in 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 their stereoisomers, tautomers or polymorphs Types, of which:

· X is O, S, SO or _SO2 ; and/or

R ⁶ are independently optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁷ are independently -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 , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl , CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted having O, S and/or N independently or in combination as hetero Atomic 3-7 membered heterocycle; and/or

R ⁹ are independently 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, NO ₂ , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-chain Alkenyl, CONH-Alkynyl, CONH-Aralkyl, CONH-Cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl , CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted with O, S and/or N independently or in combination 3-7 membered heterocyclic rings as heteroatoms; and/or

R ¹⁰ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In a specific preferred alternative embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, is also provided 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 their stereoisomers, tautomers or polymorphs, wherein:

· X is O, S, SO or _SO2 ; and/or

^R6 and ^R7 combine to form a spirocyclic compound, selected from: optionally substituted 3-7 membered spiro carbocyclic rings or heterocyclic compounds with one or more N, O and/or S atoms, said heterocyclic compounds Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁹ are independently 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, NO ₂ , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-chain Alkenyl, CONH-Alkynyl, CONH-Aralkyl, CONH-Cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl , CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted with O, S and/or N independently or in combination 3-7 membered heterocyclic rings as heteroatoms; and/or

R ¹⁰ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In another specific preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein:

· X is O, S, SO or _SO2 ; and/or

R ⁶ are independently optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁷ are independently -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 , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl , CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted having O, S and/or N independently or in combination as hetero Atomic 3-7 membered heterocycle; and/or

R ⁹ and R ¹⁰ combine to form a spiro compound, selected from: optionally substituted 3-7 membered spiro carbocycles or heterocyclic compounds with one or more N, O and/or S atoms, said hetero rings Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁴ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In another specific preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein:

· X is O, S, SO or _SO2 ; and/or

^R6 and ^R7 combine to form a spirocyclic compound, selected from: optionally substituted 3-7 membered spiro carbocyclic rings or heterocyclic compounds with one or more N, O and/or S atoms, said heterocyclic compounds Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁹ and R ¹⁰ combine to form a spiro compound, selected from: optionally substituted 3-7 membered spiro carbocycles or heterocyclic compounds with one or more N, O and/or S atoms, said hetero rings Atoms alone or in combination with others as heteroatoms; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ² ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In a specific preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a compound for use in 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 their stereoisomers, tautomers or polymorphs Types, of which:

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

R ⁶ are independently optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , or (CH ₂ ) _m CONHR ⁴ ; and/or

^R7 are independently -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 , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl , CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted having O, S and/or N independently or in combination as hetero Atomic 3-7 membered heterocycle; and/or

R ⁹ are independently 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, NO ₂ , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-chain Alkenyl, CONH-Alkynyl, CONH-Aralkyl, CONH-Cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl , CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted with O, S and/or N independently or in combination 3-7 membered heterocyclic rings as heteroatoms; and/or

R ¹⁰ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In a specific preferred alternative embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, is also provided 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 their stereoisomers, tautomers or polymorphs, wherein:

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

^R6 and ^R7 combine to form a spirocyclic compound, selected from: optionally substituted 3-7 membered spiro carbocyclic rings or heterocyclic compounds with one or more N, O and/or S atoms, said heterocyclic compounds Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁹ are independently 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, NO ₂ , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-chain Alkenyl, CONH-Alkynyl, CONH-Aralkyl, CONH-Cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl , CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted with O, S and/or N independently or in combination 3-7 membered heterocyclic rings as heteroatoms; and/or

R ¹⁰ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In another specific preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein:

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

R ⁶ are independently optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁷ are independently -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 , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl , CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted having O, S and/or N independently or in combination as hetero Atomic 3-7 membered heterocycle; and/or

R ⁹ and R ¹⁰ combine to form a spiro compound, selected from: optionally substituted 3-7 membered spiro carbocycles or heterocyclic compounds with one or more N, O and/or S atoms, said hetero rings Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In another specific preferred embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein:

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

^R6 and ^R7 combine to form a spirocyclic compound, selected from: optionally substituted 3-7 membered spiro carbocyclic rings or heterocyclic compounds with one or more N, O and/or S atoms, said heterocyclic compounds Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁹ and R ¹⁰ combine to form a spiro compound, selected from: optionally substituted 3-7 membered spiro carbocycles or heterocyclic compounds with one or more N, O and/or S atoms, said hetero rings Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In a specific preferred embodiment, there is provided a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a compound for use in 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 their stereoisomers, tautomers or polymorphs Types, of which:

· X ^* is CH, CF, CY ³ or CR ⁴ ; and/or

R ⁶ are independently optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁷ are independently -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 , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl , CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted having O, S and/or N independently or in combination as hetero Atomic 3-7 membered heterocycle; and/or

R ⁹ are independently 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, NO ₂ , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-chain Alkenyl, CONH-Alkynyl, CONH-Aralkyl, CONH-Cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl , CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted with O, S and/or N independently or in combination 3-7 membered heterocyclic rings as heteroatoms; and/or

R ¹⁰ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

W is C-R" or N;

T and V are independently CH or N;

O is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

wherein R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In a specific preferred alternative embodiment, there is provided a compound of formula (VII) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or Polymorphs, wherein:

· X ^* is CH, CF, CY ³ or CR ⁴ ; and/or

^R6 and ^R7 combine to form a spirocyclic compound, selected from: optionally substituted 3-7 membered spiro carbocyclic rings or heterocyclic compounds with one or more N, O and/or S atoms, said heterocyclic compounds Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁹ are independently 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, NO ₂ , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-chain Alkenyl, CONH-Alkynyl, CONH-Aralkyl, CONH-Cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl , CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted with O, S and/or N independently or in combination 3-7 membered heterocyclic rings as heteroatoms; and/or

R ¹⁰ are each independently hydrogen, optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ² ) _m NO ² and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In another specific preferred embodiment, the compound or pharmaceutically acceptable salt or prodrug of formula (VII), or their stereoisomers, tautomers or polymorphs, also provides a 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 their stereoisomers, tautomers or polymorphs Types, of which:

· X ^* is CH, CF, CY ³ or CR ⁴ ; and/or

R ⁶ are independently optionally substituted lower alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , or (CH ₂ ) _m CONHR ⁴ ; and/or

R ⁷ are independently -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 , NH ₂ , N ₃ , NH-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 ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl , CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R ⁴ , (CH ₂ ) _m COOH, (CH ² ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ , optionally substituted 3-7 membered carbocycles, and optionally substituted having O, S and/or N independently or in combination as hetero Atomic 3-7 membered heterocycle; and/or

R ⁹ and R ¹⁰ combine to form a spiro compound, selected from: optionally substituted 3-7 membered spiro carbocycles or heterocyclic compounds with one or more N, O and/or S atoms, said hetero rings Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In another specific preferred embodiment, the compound or pharmaceutically acceptable salt or prodrug of formula (VII), or their stereoisomers, tautomers or polymorphs, also provides a 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 their stereoisomers, tautomers or polymorphs Types, of which:

· X ^* is CH, CF, CY ³ or CR ⁴ ; and/or

^R6 and ^R7 combine to form a spirocyclic compound, selected from: optionally substituted 3-7 membered spiro carbocyclic rings or heterocyclic compounds with one or more N, O and/or S atoms, said heterocyclic compounds Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁹ and R ¹⁰ combine to form a spiro compound, selected from: optionally substituted 3-7 membered spiro carbocycles or heterocyclic compounds with one or more N, O and/or S atoms, said hetero rings Atoms are selected alone or in combination with other heteroatoms; and/or

R ⁸ and R ¹¹ are independently H, CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOR ⁴ , (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CON(R ⁴ ) ₂ , (CH ₂ ) _m CONHR ⁴ and N-acyl; and/or

m is each independently 0 or 1; and/or

Base (Base) is selected from one of the following:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

W is C-R" or N;

T and V are independently CH or N;

O is CH, -CCl, -CBr, -CF, -CI, -CCN, -C-COOH, -C- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently 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, or a stereoisomer, tautomer or polymorph thereof, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is an alkyl group; (3) R ⁷ and R ⁹ are independently OR ² , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine , NO ₂ , amino, lower alkylamino or di(lower alkyl)amino; (4) R ⁸ and R ¹⁰ are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; (5 ) X is O, S, SO ₂ or CH ₂ ; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a second 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 a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkanes (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; (5) X is O, S, SO ₂ or CH ₂ ; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a third sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkanes Base amino, or two (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine , iodine, NO ₂ , amino, lower alkylamino or di(lower alkyl)amino; (4) R ⁸ and R ¹⁰ are H; (5) X is O, S, SO ₂ or CH 2 ; (6) W ⁴ is _CX3 ; and ₍ 7) ^X3 is _CH3 , _CF3 or _CH2CH3 .

In a fourth sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkanes Base amino, or two (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine , iodine, NO ₂ , amino, lower alkylamino or di(lower alkyl)amino; (4) R ⁸ and R ¹⁰ are independently H, alkyl (including lower alkyl), chlorine, bromine, or iodine; (5) X is O; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a fifth sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphic forms wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same substituents as defined herein for aryl ; Lipids, including phospholipids; Amino acids; Carbohydrates; Peptides; Cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate; ( 2) R ⁶ is an alkyl group; (3) R ⁷ and R ⁹ are independently OR ¹ ; (4) R ⁸ and R ¹⁰ are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; ( 5) X is O, S, SO ₂ or CH ₂ ; (6) W ⁴ is CX ₃ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a sixth sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or polymorphic forms wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or a stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same substituents as defined herein for aryl ; Lipids, including phospholipids; Amino acids; Carbohydrates; Peptides; Cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate; ( 2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine , bromine, iodine, NO ₂ , amino, lower alkylamino or di(lower alkyl)amino; (4) R ⁸ and R ¹⁰ are H; (5) X is O, S, SO ₂ or CH ₂ ; ( 6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a seventh sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is an alkyl group; (3) R ⁷ and R ⁹ are independently OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl , chlorine, bromine, iodine, NO ₂ , amino, lower alkylamino or di(lower alkyl)amino; (4) R ⁸ and R ¹⁰ are independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X is O; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In an eighth sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or two (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ are hydrogen; (6) X is O, S , SO ₂ or CH ₂ ; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a ninth sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or two (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ are independently H, alkyl (including lower alkanes base), chlorine, bromine or iodine; (5) X is O; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a tenth sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein: ( ¹ ) R independently is H or phosphate (including monophosphate, diphosphate, triphosphate, or stable phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); sulfonate includes alkyl or arylalkylsulfonyl includes methanesulfonyl and benzyl, wherein phenyl is optionally substituted with one or more of the same as in the definition of aryl herein Lipids, including phospholipids; amino acids; carbohydrates; peptides; cholesterol; or other pharmaceutically acceptable leaving groups that, when administered in vivo, provide compounds wherein ^R is independently H or phosphate ; (2) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxyl, O-alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or two (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl Base, O-alkenyl, chlorine, bromine, iodine, NO ₂ , amino, lower alkylamino, or di(lower alkyl)amino; (4) R ⁸ and R ¹⁰ are hydrogen; (5) X is O ; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In the eleventh sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or Polymorph, wherein; (1) R ¹ is independently H or phosphate; (2) R ⁶ is alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxyl, O -Alkyl, O-alkenyl, chlorine, bromine, fluorine, iodine, NO ₂ , amino, lower alkylamino or di(lower alkyl)amino; (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ are hydrogen; (5) X is O, S, SO ₂ or CH ₂ ; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH _{2 CH3} .

In a twelfth sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or Polymorphs, wherein: (1) R ¹ is independently H or phosphate; (2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ is hydrogen; (5) X is O, S, _SO2 or _CH2 ; ( ⁶ ) W4 is ^CX3 ; and (7) ^X3 is _CH3 , _CF3 or _{CH2CH3 .}

In a thirteenth sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or Polymorphs, wherein: (1) R ¹ is independently H or phosphate; (2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ is independently H, alkyl (including lower alkyl), chlorine, bromine or iodine; (5) X is O; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or _{CH2CH3 .}

In the fourteenth sub-embodiment, a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs is provided, and a 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 their stereoisomers, tautomers or polymorphs Crystal forms, wherein: (1) R ¹ is independently H or phosphate; (2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ² , alkyl (including lower alkyl) , alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO ₂ , amino, lower alkylamino, or di(lower alkyl)amino; (4) R ⁸ and R ¹⁰ is hydrogen; (5) X is O; (6) W ⁴ is CX ³ ; and (7) X ³ is CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a more preferred sub-embodiment, there is provided a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a 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 their stereoisomers, tautomers or polymorphs Crystal form, wherein:

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

(1) Base (Base) is 8-methylguanine; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methylcytosine; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methylthymidine; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methyluracil; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl: (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is phosphate; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is hydrogen; (3) R ⁶ is ethyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is hydrogen; (3) R ⁶ is propyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is hydrogen; (3) R ⁶ is butyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is O;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ is hydrogen and R ⁹ is hydroxyl; (5) R ⁸ and ^R are hydrogen; and (6) X is O;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is S;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6)X is SO ₂ ;

(1) Base (Base) is 8-methyladenine; (2) R ¹ is hydrogen; (3) R ⁶ is methyl; (4) R ⁷ and R ⁹ are hydroxyl; (5) R ⁸ and R ¹⁰ is hydrogen; and (6) X is CH ₂ ;

In a fifth major embodiment, there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (VIII), (IX) or (X), or a stereoisomer, tautomer or polymorph thereof Also provides 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 pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

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

Base ^* (Base ^* ) is a purine or pyrimidine base as defined herein;

R ¹² are independently substituted alkyl (including lower alkyl), CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkane group (including halogenated lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted alkenyl, haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH( lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH (lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N (lower alkyl base) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C( O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ ;

R ¹³ are independently substituted alkyl (including lower alkyl), CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkane group (including halogenated lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted 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 with one or more O, S and/or N 3-7 membered aromatic heterocycle), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C (O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O) NHR ⁴ , -(CH ₂ ) _m C(O)NH (lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N (lower alkyl) Alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C( O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , -O(R ⁴ ), -O(alkynyl), -O(aralkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S (lower alkyl), -S (alkenyl), -S (alkynyl), -S (arylalkyl), -S (cycloalkyl), -NHR ⁴ , -NR ⁴ R ⁵ , - NH (alkenyl), -NH (alkynyl), -NH (arylalkyl), -NH (cycloalkyl), SCN, OCN, NCO or fluorine;

Alternatively, R ¹² and R ¹³ can combine to form a spiro compound, selected from: optionally substituted carbocycle (preferably 3-7 membered carbocycle) or optionally substituted heterocycle (preferably with one or more O, S and /or 3-7 membered heterocycles of N); and

m is 0, 1 or 2 each independently.

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

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

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

and among them;

R ⁸ and R ¹¹ are independently hydrogen, optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N( CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halolower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, - CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , cyano, NH- Acyl or N(acyl) ₂ ;

R ⁹ and R ¹⁰ are independently hydrogen, OH, OR ² , optionally substituted alkyl (including lower alkyl), CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl (including halo-lower alkyl), CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, halo Alkynyl, 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), any Optionally substituted heteroaryl (preferably a 3-7 membered aromatic heterocyclic ring with one or more O, S and/or N), -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , - CH ₂ C(O)O (lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S (lower alkyl), -CH ₂ C (O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O) )N(lower alkyl) ₂ , (CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S (lower alkyl), -(CH ₂ ) _m C( O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O )SH, -C(O)SR ⁴ , -C(O)S(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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(alk base), -O(lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S (lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl) , NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (acyl), -N (lower alkyl) ₂ , -NH (alkenyl), -NH (alkynyl), -NH(aralkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine );

m is each independently 0, 1 or 2; and

Alternatively, R ⁸ and R ¹³ , R ⁹ and R ¹³ , R ⁹ and R ¹¹ or R ¹⁰ and R ¹² can combine to form a bridged compound, selected from: optionally substituted carbocycles (preferably 3-7 membered carbocycles) or an optionally substituted heterocycle (preferably a 3-7 membered heterocycle with one or more O, S and/or N); or

Alternatively, R ¹² and R ¹³ or R ⁹ and R ¹⁰ can combine to form a spiro compound, selected from optionally substituted carbocycles (preferably 3-7 membered carbocycles) or optionally substituted heterocycles (preferably with one or more O, S and/or N 3-7 membered heterocycle).

In a particular aspect of the present invention, there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (XIII) or (XIV), or their stereoisomers, tautomers or polymorphs, and also provides Provided is a method for treating a host infected with a Flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (XIII) or (XIV):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

_R3 is selected from H; mono-, di-, and triphosphates or stable phosphate prodrugs; acyl groups; sulfonate esters; optionally substituted alkylsulfonyl groups; optionally substituted arylsulfonyl groups; lipids; amino acids a carbohydrate; a peptide; cholesterol; and a pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein R is independently H, or _mono , di, and triphosphate;

X" is selected from one or more of O, S, SO, SO ₂ , N, NH, NR and CH ₂ , wherein any one of the aforementioned groups may be optionally substituted and may be in different positions to form 3 -7-membered ring;

R is H, alkyl or acyl;

B represents 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) ring); and

Base (Base) is selected from:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m COOH, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

_Q1 and _Q2 are independently N or CR;

R is H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; and

their tautomers.

In a second specific aspect of the present invention there is provided a compound or pharmaceutically acceptable salt or prodrug of formula (XV), (XVI) or (XVII), or their stereoisomers, tautomers or The polymorphic form also provides 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 pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

G and E are independently selected from CH ₃ , CH ₂ OH, CH ₂ F, CH ₂ N ₃ , CH ₂ CN, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ , ( CH ₂ ) _m CONR ₂ , (CH ₂ ) _m CONHR and N-acyl;

R is H, alkyl or acyl; and

m is 0 or 1;

R ³ and base (Base) are defined as formula (XIII).

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

In a third specific aspect of the present invention, there is provided a compound of formula (XVIII) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a A method for treating a host infected with a Flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (XVIII):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

M is selected from S, SO, and _SO2 and

R ₃ and base (Base) are defined as formula (XIII).

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

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein:

A is selected from optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR;

Y is selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F , CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR;

X is selected from -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, NO ₂ , NH ₂ , N ₃ , NH-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, CO ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ₂ , (CH ₂ ) _m CONHR, optionally substituted 3-7 membered carbocyclic rings, and optionally substituted 3-7 membered heterocyclic rings having O, S and/or N independently or in combination as heteroatoms ;

m is 0 or 1;

_R3 is selected from H; mono-, di-, and triphosphates or stable phosphate prodrugs; substituted or unsubstituted alkyl; acyl; sulfonate; optionally substituted alkylsulfonyl; optionally substituted Arylsulfonyl; Lipid; Amino acid; Carbohydrate; ^Peptide ; Cholesterol; triphosphate compounds; and

Base (Base) is an unnatural base selected from:

in:

R', R", R', and R"" are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ;

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- _CONH2 , or N;

Q ₁ and Q ₂ are independently N or CR""; and

Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH;

The provisos are that in bases (g) and (i), R', R"" are not H, OH, or _NH2 ; and Q, T, V, _Q2 , _Q5 and _Q6 are not N.

In another preferred embodiment, there is provided a compound of formula (IX) or a pharmaceutically acceptable salt or prodrug, or their stereoisomers, tautomers or polymorphs, and a compound for use in A method for treating a host infected with a Flaviviridae virus, comprising administering a therapeutically effective amount of a compound of formula (IX):

or pharmaceutically acceptable salts or prodrugs, or their stereoisomers, tautomers or polymorphs, wherein: R ¹ , R ² and R ³ are independently H; phosphate; straight chain, branched Chain or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxyalkyl; CO-substituted aryl; sulfonate; benzyl, where Phenyl is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; lipid; amino acid; carbohydrate; peptide; cholesterol; or a pharmaceutically acceptable ion degrouping which, when administered in vivo, provides a compound wherein R ¹ , R ² and/or R ³ are independently H or phosphate;

X is O, S, _SO2 or _CH2 ;

Base ^* (Base ^* ) is a purine or pyrimidine base;

R ¹² is C(Y ³ ) ³ ;

^Y3 is independently H, F, Cl, Br or I; and

R ¹³ is fluoro.

In a subembodiment X is O, and ^Y3 is H. In another subembodiment, when X is O and ^Y3 is H, ^R1 , ^R2 and ^R3 are also H.

II. Stereochemistry

It will be appreciated that the nucleosides of the present invention have multiple chiral centers and can exist and be isolated in optically active and racemic forms. Some compounds exhibit polymorphism. It is to be understood that the present invention includes any racemates, optical forms, diastereomers, polymorphs, or stereoisomers of the compounds of the present invention, or mixtures thereof, which have the properties described herein. use. It is well known in the art how to prepare optical forms (eg, resolution of racemates by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

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

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

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

i) Mechanical resolution of crystals - In this technique, macroscopic crystals are separated by manual separation of the individual enantiomers. This technique can be used if crystals of the separated enantiomers exist, i.e., the starting material is an aggregate, and the crystals are visually distinguishable;

ii) Simultaneous crystallization - in this technique the individual enantiomers are crystallized separately from the solution of the racemates, which is only possible if the latter are condensed bodies in the solid state;

iii) enzymatic resolution - in this synthetic technique the racemates are partially or completely separated by the difference in reaction rate of the enantiomers with the enzyme;

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

v) Chemical Asymmetric Synthesis - In this synthetic technique, the desired pair is synthesized from a chiral precursor under conditions that produce asymmetry (ie, chirality) in the product through the use of a chiral catalyst or chiral auxiliary. Enantiomer;

vi) Diastereomeric Resolution - In this technique, the individual enantiomers are converted into diastereomers by reaction of a racemic compound with an enantiomerically pure reagent (chiral auxiliary). The resulting diastereomers are then separated according to their more distinct structural differences by chromatography or crystallization, followed by removal of the chiral auxiliary to obtain the desired enantiomers;

vii) Primary and Secondary Asymmetric Transformation Methods - In this technique, the diastereomers in the racemate are brought into equilibrium to produce the predominant diastereomer in solution from the desired enantiomer, or, Predominant crystallization of the diastereomer in the desired enantiomer perturbs the equilibrium so that eventually all the starting material is converted from the desired enantiomer to the crystalline diastereomer, and then, the desired Enantiomers are liberated from diastereomers;

viii) Kinetic Resolution - This technique refers to the use of kinetic conditions in which enantiomers and chiral, non-racemic reagents or catalysts react with different reaction rates to obtain partial or complete fractions of racemates resolution (or further resolution of partially resolved compounds);

ix) Enantiospecific synthesis starting from non-racemic precursors - in this synthetic technique the desired enantiomer is obtained from an achiral starting material and, during the synthesis, its stereochemical integrity is Not or only minimally endangered.

x) Chiral Liquid Chromatography - In this technique the enantiomers of the racemates are separated in a liquid mobile phase on the basis of their different interactions with the stationary phase. The stationary phase can be made from a chiral material or the mobile phase can contain additional chiral materials to induce different interactions;

xi) Chiral Gas Chromatography - In this technique, the racemate is volatilized by the racemate and enantiomer having different interactions in the gaseous mobile phase with a non-racemic chiral absorbing phase containing immobilization and the enantiomers are separated;

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

xiii) Chiral membrane penetration resolution - In this technique, the racemate is contacted with a thin separating membrane. The separation membrane usually separates two miscible liquids, one containing the racemate, and this separation is carried out by selectively passing through the separation membrane using a driving force such as a concentration difference or a pressure difference. Since the membrane takes advantage of the property of allowing only one racemic enantiomer to pass through, the separation results in the nonracemic chiral form.

III. Definition

Unless otherwise specified, the term "alkyl" as used herein refers to a saturated straight-chain, branched-chain or cyclic primary, secondary or tertiary hydrocarbon group of usually 1-10 carbon atoms, specifically including methyl, CF ₃ , CCl ₃ , CFCl ₂ , CF ₂ Cl, ethyl, CH ₂ CF ₃ , CF ₂ CF ₃ , propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl base, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-di methyl butyl. The term includes substituted and unsubstituted alkyl groups, and specifically haloalkyl groups, and more particularly fluorinated alkyl groups. Non-limiting examples of moieties that can be used to replace alkyl are selected from halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, Cyanide, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected or protected if desired, are known to those skilled in the art, for example, in Greene , et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, which is incorporated herein by reference.

As used herein, unless otherwise specified, the term "lower alkyl" refers to a saturated straight-chain, branched-chain, or suitably cyclic (e.g., cyclopropyl) alkyl group, usually of 1 to 4 carbon atoms, including substituted and unreplaced cases.

The term "alkylamino" or "arylamino" refers to an amino group having one or two alkyl or aryl substituents, respectively. In this 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.

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

As used herein, unless otherwise indicated, the term "aryl" refers to phenyl, biphenyl or naphthyl, preferably phenyl. The term includes both substituted and unsubstituted instances. The aryl group may be substituted by any of the groups described, including but not limited to one or more groups selected from halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy , aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, which are either unprotected or protected as required, which are known to those skilled in the art known, 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 chlorine, bromine, iodine and fluorine.

The term "purine" or "pyrimidine" bases include, but are not limited to, adenine, ^N6 -alkylpurines, ^N6 -acylpurines (wherein the acyl group is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N ⁶ -benzylpurine, N ⁶ -halogenated purine, N ⁶ -vinylpurine, N ^{6 -acetylenic purine, N 6 -acylpurine} , N ⁶ -hydroxyalkylpurine, N ⁶ -Alkylaminopurine, N ⁶ -thioalkylpurine, N ² -alkylpurine, N ² -alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5- Methylcytosine, 6-azacytosine, including 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, including 5-fluorouracil, ^C5- Alkylpyrimidine, ^C5 -benzylpyrimidine, ^C5 -halogenated pyrimidine, C5 ^- vinylpyrimidine, ^C5 -ethynylpyrimidine, ^C5 -acylpyrimidine, C5-hydroxyalkylpurine ^{, C5-} ( Acyl)aminopyrimidine, C ⁵ -cyanopyrimidine, C ⁵ -iodopyrimidine, C ⁶ -iodopyrimidine, C ⁵ -Br-vinylpyrimidine, C ⁶ -Br-vinylpyrimidine, C ⁵ -nitropyrimidine , C ⁵ -amino-pyrimidine, N ² -alkylpurine, N ² -alkyl-6-thiopurine, 5-azacytidine, 5-azauracil, triazolopyridyl, imidazole Pyridyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. When necessary or desired, the functional oxygen and nitrogen on the base can be protected. Suitable protecting groups are well known to those skilled in the art, including trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl Silyl, tert-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', where R' is straight chain, branched chain, or cycloalkyl (including lower alkyl), amino acid, aryl includes phenyl, alkaryl, aralkyl includes benzyl, alkoxyalkyl includes methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl) , aryl includes phenyl optionally substituted by chlorine, bromine, fluorine, iodine, C ₁ to C ₄ alkyl or C ₁ to C ₄ alkoxy, sulfonate such as alkyl or aralkylsulfonyl includes methane Sulfonyl, mono, di or triphosphate, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, aralkyl including benzyl, alkoxyalkyl including methoxy ylmethyl, aryloxyalkyl such as phenoxymethyl. The aryl group in the ester preferably comprises a phenyl group. Specifically, the acyl group includes acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropylcarboxy, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl , phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl, 2-nitro-phenylacetyl Base, 4-chloro-phenylacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl radical, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl, tert-butyl Acetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl, 7H-dodeca-fluoroheptanoyl, 7-chloro Dodecafluoro-heptanoyl, 7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl, 7H-dodecafluoroheptanoyl, nonafluoro-3,6-dioxa-heptanoyl, Nonylfluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxy, 3,6-dichloro-2 -Methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, ω-aminooctanoyl, decanoyl, n-pentanoyl Decanoyl, stearoyl, 3-cyclopentyl-propionyl, 1-benzene-carboxy, O-acetylmandaloyl, pivaloylacetyl, 1-adamantane-carboxy, cyclohexane-carboxy, 2 , 6-pyridyldicarboxy, cyclopropane-carboxy, cyclobutane-carboxy, perfluorocyclohexylcarboxy, 4-methylbenzoyl, chloromethylisoxazolylcarbonyl, perfluorocyclohexylcarboxy, croton Acyl, 1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4-phenylbenzoyl. When the term acyl is used it refers specifically and independently to the following: acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl , Neo-heptanoyl, phenylacetyl, diphenylacetyl, α-difluoromethyl-phenylacetyl, bromoacetyl, 4-chloro-phenylacetyl, 2-chloro-2,2-diphenylacetyl radical, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiopheneacetyl, tert -Butylacetyl, Trichloroacetyl, Monochloro-acetyl, 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 -Carboxyl, 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, amino acids found in proteins, namely 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, said amino acid is in the L-configuration. Alternatively, the amino acid may be alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, Threonyl, Cysteinyl, Tyrosyl, Asparaginyl, Glutaminyl, Aspartylglutamyl, Lysyl, Arginyl, Histidyl, Beta-Alanyl, Beta -Valyl, β-leucyl, β-isoleucyl, β-prolyl, β-phenylalanyl, β-tryptophanyl, β-methionyl, β-glycyl, β-seryl, β-threonyl, β-cysteinyl, β-tyrosyl, β-asparaginyl, β-glutaminyl, β-aspartyl, β-glutamine Acyl, β-lysyl, β-arginyl or β-histidyl derivatives. Tables 1-24 list examples used in the present invention. When the term amino acid is used, it is considered to mean the following specifically and independently, respectively: D and L configurations alpha, beta, gamma or delta glycine, alanine, valine, leucine, isoleucine Acid, Methionine, Phenylalanine, Tryptophan, Proline, Serine, Threonine, Cysteine, Tyrosine, Asparagine, Glutamine, Aspartic Acid, Glutamine acid, ester of lysine, arginine and histidine.

The term "substantially free" or "substantially absent" as used herein refers to the nucleoside composition comprising at least 85% or 90%, preferably 95%, 98%, 99% or 100% by weight of all nucleosides. designated enantiomers of the nucleosides described above. In a preferred embodiment, in the methods and compounds of the invention, the compounds are substantially free of enantiomers.

Likewise, the term "isolated" means comprising at least 85%, 90%, 95%, 98%, 99% or 100% by weight of said nucleosides in a nucleoside composition, with the remainder comprising other chemical substances 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 can be altered by the compounds of the invention. The term host refers in particular to infected cells, cells and animals transfected with all or part of the flavivirus genome, in particular primates (including chimpanzees) and humans. In most applications of the invention in animals, the host is a human patient. However, in certain indications, veterinarians may also apply the invention (eg in chimpanzees).

The term "pharmaceutically acceptable salt or prodrug" is used throughout to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, ester salt or related groups) of a nucleoside compound, when all such forms are administered to After the patient, the nucleoside compound is provided. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among other acids well known in the pharmaceutical arts. Pharmaceutically acceptable prodrugs refer to compounds that are metabolized, eg, hydrolyzed or oxidized, in the host body to form the compounds of the invention. Typical examples of prodrugs include compounds having biologically labile protecting groups on the functional group portion 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 yield the active compound. The compounds of the present invention possess antiviral activity against viruses of the Flaviviridae family, or are metabolized to produce compounds having such activity.

IV. Prodrugs and Derivatives

The active compound may be administered in any salt or prodrug form to provide, directly or indirectly, the parent compound, or the compound itself, in the recipient to which it is administered. Non-limiting examples are pharmaceutically acceptable salts (or "physiologically acceptable salts"), and alkylated, acylated or otherwise modified at the 5' position or on a purine or pyrimidine base ( A "pharmaceutically acceptable prodrug" type of compound). Further, the modification can affect the biological activity of the compound, in some cases increasing the activity relative to the parent compound. Such compounds can readily be evaluated by preparing such 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 salt

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

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid affording a physiologically acceptable anion. Alkali metal (eg, sodium, potassium, or lithium) or alkaline earth metal (eg, calcium) salts of carboxylic acids are also available. In one embodiment, the salt is the hydrochloride salt of the compound. In another embodiment, said pharmaceutically acceptable salt is dihydrochloride.

B. Nucleotide Prodrug Components

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 triphosphates of such nucleosides reduces their polarity and entry into cells. Examples of substituents capable of replacing one or more hydrogens on the phosphate moiety are alkyl groups, aryl groups, steroids, carbohydrates including sugars, 1,2-diacylglycerols and alcohols. Many are described in R. Jones and N. Bischoferger, Antiviral Research, 1995, 27: 1-17. Any of these can be used in combination with the nucleosides disclosed herein to achieve the desired effect.

In an alternative embodiment, the nucleoside is provided as a phosphonate or SATE derivative.

The active nucleosides may also be provided in the form of 2', 3' and/or 5'-phosphoether ether lipids or 2', 3' and/or 5'-ether lipids. Non-limiting examples are described in references including (which are hereby incorporated by reference): Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi .1990. "Novel membrane-interactive etherlipod analogs that inhibit infectious HIV-1 production and induce defective virus formation" AIDSRes .Hum.Retro Viruses.6:491-501; Piantadosi, C., J.Marasco, C.J., S.L.Morris-Natschke, K.L.Meyer, F.Gumus, J.R.Surles, K.S.Ishaq, L.S.Kucera, N.Iyer, C.A.Wallen, S. Piantadosi, and E.J.Modest. 1991. "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity" J.Med.Chem .34: 1408.1414; Hosteller, K.Y., D.D. Richman, D.A. Carson, L.M. Stuhmiller, G.M.T. van Wijk, and H. van den Bosch. 1992. "Dimyristoylglycerol 3′-deoxythymidine diphosphate, 3′- Lipid prodrug of deoxythymine greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3′-deoxythymine diphosphate dimyristoylglycerol, a lipid produg of 3, -deoxythymine)", Antimicrob.Agents Chemother..36:2025.2029; Hosetler, K.Y., L.M.Stuhmiller, H.B.Lenting, H.van den Bosch, and D.D.Richman, 1990. "Azidothymine Synthesis and antiretroviral activity of phospholipid analogs ofazidothymine and other antiviral nucleosides" J. Biol. Chem. 265: 61127. Non-limiting examples of suitable lipophilic substituents or lipophilic agents disclosed in the U.S. patents that can be covalently bonded to nucleosides, preferably at the 2', 3' and/or 5'-OH positions of the nucleosides include: U.S. Patent Nos. 5,149,794 (September 22, 1992, Yatvin et al); No. 5,194,654 (March 16, 1993, Hostetler et al); 26 October 1993, Yatvin et al); 5,411,947 (Hostetler et al 2 May 1995); 5,463,092 (Hostetler et al 31 October 1995); 5,543,389 (6 August 1996 No. 5,543,390 (August 6, 1996, Yatvin et al.); No. 5,543,391 (August 6, 1996, Yatvin et al.); and No. 5,554,728 (September 10, 1996, Basava et al. ), the entire contents of which are hereby incorporated by reference. Applications that disclose lipophilic substituents or lipophilic preparations that can be linked to the nucleoside of the present invention include: WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910 , WO 94/26273, WO 96/15132, EP 0 350 287, EP 93917054.4 and WO 91/19721.

Also provided are aryl esters, especially phenyl esters. Non-limiting examples are disclosed in DeLambert et al., J. Med. Chem. 37:498 (1994). Carboxylate-containing phenyl esters with a phosphate attached to the ortho position are also provided. Khamnei and Torrence, J. Med. Chem.; 39:4109-4115 (1996). In particular, benzyl esters are provided which yield the parent compound, in some instances employing substituents in the ortho or para position to accelerate hydrolysis. Examples of prodrugs of this class are described in Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); Brook, et al., WO 91/19721; and Glazier et al., WO 91/19721.

Cyclic and acyclic phosphonates are also provided. Non-limiting examples are disclosed in Hunstone et al., J. Med. Chem. 27:440-444 (1984) and Starrett et al., J. Med. Chem. 37:1857-1864 (1994). In addition, cyclic 3',5'-phosphates are also provided. Non-limiting examples are disclosed in Meier et al., J. Med. Chem. 22:811-815 (1979). Also provided are cyclic 1',3'-propyl phosphonates and phosphates, such as one containing a fused aryl ring, i.e. a cyclosaligenyl ester (Meier et al., Bioorg. Med. Chem. Lett. 7:99- 104 (1997)). Preparation of cyclic 1',3'-propyl esters of unsubstituted monophosphates is also provided (Farquhar et al., J.Med.Chem. 26:1153 (1983); Farquhar et al., J.Med. Chem. 28:1358 (1985)). Additionally, cyclic 1',3'-propyl esters substituted at C-1' by pivaloyloxy methoxy are provided (Freed et al., Biochem.Pharmac. 38:3193 (1989 ); Biller et al., U.S. Pat. No. 5,157,027).

Cyclic phosphoramidates are known to be cleaved in vivo by oxidative mechanisms. Accordingly, 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; 3'-substituents include phenyl, methyl, trifluoromethyl, ethyl, propyl base, iso-propyl, and cyclohexyl. Various 1'-substituted analogs are also provided.

Phosphorus-containing cyclic ester compounds are also provided. Non-limiting examples are described below:

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

[2] Trivalent phosphate. Kryuchkov et al., Izv. Akad. Nauk SSSR, Ser. Khim. 6:1244 (1987). Some claimed compounds for the asymmetric synthesis of levodopa precursors. Sylvain et al., DE3512781A1;

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

[4] Phosphates. Neidlein et al., Hetreocycles 35: 1185 (1993).

Further, non-limiting examples of U.S. and international patent applications disclosing suitable cyclic phosphoramidate prodrugs include: U.S. Patent No. 6,312,662 to Erion et al. of Metabasis Therapeutics, Inc; WO 99/45016; WO00/52015; WO 01/47935; and WO 01/18013. In particular, prodrugs represented by the formula are provided:

in:

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

V and Z are linked together by an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, fused to the aromatic groups at the beta and gamma positions of the oxygen attached to the phosphorus atom based on

V and W are joined together by an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and is selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkane Substituents are thiocarbonyloxy and aryloxycarbonyloxy substituents attached to one of said carbon atoms at a distance of three atoms from the oxygen atom attached to the phosphorus atom;

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

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

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

p is the integer 2 or 3;

The restrictive conditions are:

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

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

· ^R2 is selected from ^R3 and -H;

· ^R is selected from alkyl, aryl, cycloaliphatic, and aralkyl;

· R ¹² is selected from -H and lower acyl;

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

V. Combination or Alternative Therapy

The active compounds of this invention may be administered in combination or in alternation with other anti-flavivirus or pestivirus agents, or in particular anti-HCV agents, for the treatment of any of the conditions described herein. In combination therapy, effective dosages of two or more agents are administered together, while in alternating or sequential therapy, effective dosages of each agent are administered sequentially or sequentially. Dosage depends on the rate of absorption, inactivation, and excretion of the drug, as well as other factors well known to those skilled in the art. It should be noted that dosage will also vary with the severity of the condition to be alleviated. It is also understood that for any particular patient, the particular dosing regimen and dosing schedule should be adjusted from time to 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, anti-HCV (or anti-pestivirus or anti-flavivirus) compounds with an _EC50 of 10-15 μM or preferably less than 1-5 μM are desired.

It is recognized that resistant variants of flaviviruses, pestiviruses or HCV emerge after prolonged treatment with antiviral agents. The most common type of resistance is due to mutations in the genes that encode the enzymes that allow the virus to replicate. The efficacy of the drug against viral infection can be prolonged, increased or restored by administering the compound in combination or alternately with a second or third antiviral compound capable of inducing and The main drug-induced mutations vary from mutation to mutation. Alternatively, the pharmacokinetics, biodistribution or other parameters of the drugs may be altered by such combined or alternate treatments. In general, combination therapy is often preferred over alternation therapy because combination therapy simultaneously exerts multiple stress effects on the virus.

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

Non-limiting examples include:

1) Protease inhibitors

Examples include substrate-based NS3 protease inhibitors (Attwood et al, Antiviral peptide derivatives (antiviral peptide derivatives), PCT WO 98/22496, 1998; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood et al. ., Preparation and use of amino acid derivatives as anti-viralagents (preparation and use as an amino acid derivative of an antiviral agent), German Patent Publication No. DE 19914474; Tunget al., Inhibitiors of serine proteases, particularly hepatitis C virus NS3 proteases (inhibitors of serine proteases, especially hepatitis C virus NS3 protease), PCT WO 98/17679), including alpha-ketoamides and hydrazinoureas, and terminating electrophiles such as boronic acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues (hepatitis C virus inhibitor peptide analogues), PCT WO 99/07734); NS3 protease inhibitors based on non-substrates such as 2,4,6-tri Hydroxy-3-nitro-benzamide derivatives (Sudo K. et al, Biochemical and Biophysical Research Communications, 1997, 238, 643-647; Sudo K. et al., Antiviral Chemistry and Chemotherapy, 1998, 9, 186), Including RD3-4082 and RD3-4078, the former is substituted by a 14-carbon chain on the amide, and the latter processes p-phenoxyphenyl. and Sch 68631, a phenanthrenequinone, an inhibitor of HCV protease (Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996).

Sch 351633, isolated from Penicillium griseofulvum, was identified as a protease inhibitor (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9:1949-1952). Eglin c, isolated from leeches, is a potential inhibitor of several serine proteases such as Streptomyces griseus (S. Griseus) proteases A and B, α-chymotrypsin, chymotrypsin, and subtilisin. Qasim M.A. et al., Biochemistry 36:1598-1607, 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 inhibiting HCV endopeptidase 2; Zhang et al. U.S. Patent No. 5,990,276 to Hepatitis C virus NS3 protease; U.S. Patent No. 5,538,865 to Reyes et al; WO 02/008251 to Corvas International, Inc; and WO 02/08187 and WO 02/008256 to Schering Corporation. HCV inhibitor peptides are disclosed in US Patent Nos. 6,534,523, 6,410,531 and 6,420,380 to Boehringer Ingelheim and WO 02/060926 to Bristol Myers Squibb. Diaryl peptides as HCVNS3 serine protease inhibitors are disclosed in WO 02/48172 by Schering Corporation. Imidazoleidinones as HCV NS3 serine protease inhibitors are disclosed in WO 02/08198 to Schering Corporation and WO 02/48157 to Bristol Myers Squibb. HCV protease inhibitors are also disclosed in WO 98/17679 to Vertex Pharmaceuticals and WO 02/48116 to Bristol Myers Squibb.

2) Thiazolidine derivatives, which showed relevant inhibitory effects in reversed-phase HPLC assays using NS3/4A fusion proteins and NS5A/5B substrates (Sudo K. et al., Antiviral Research, 1996, 32, 9 -18), especially compounds RD-1-6250 with fused cinnamoyl moieties substituted by long-chain alkyl groups, and RD4 6205 and RD46193;

3) Thiazolidines and N-benzanilides, which are identified in Kakiuchi N. et al. J. EBS Letters 421, 217-220; Takeshita N. et al., Analytical Biochemistry, 1997, 247, 242-246;

4) phenanthrenquinone (phenan-threnequinone), which was shown to have anti-protease activity in SDS-PAGE and autoradiographic assays, was isolated from the fermentation broth of Streptomyces sp. (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), Sch 68631 and Sch 351633, isolated from Penicillium griseofulvum, showed activity in scintillation approximation assay (SPA) (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952);

5) Helicase inhibitors (for example, Diana G.D. et al., Compounds, compositions and methods for treatment of hepatitis C, U.S. Patent No. 5,633,358; Diana G.D. et al., Piperidine derivatives, pharmaceutical compositions therefore and their use in the treatment of hepatitis C , PCT WO97/36554);)

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

7) Antisense phosphorothioate oligonucleotides (S-ODN) extend into the 5' non-coding region (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717), or include Nucleosides 326-348 at the 3' end of NCR and nucleosides 371-388 (Alt M. et al., Archives of Virology, 1997, 142, 589-599 located in the core coding region of HCV RNA; Galderisi U. et al., Journal of Cellular Physiology, 1999, 181, 251-257)) sequence complementarity;)

8) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent for the prevention and treatment of hepatitis C, (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, (prevention and treatment of viral diseases), Japanese Patent Publication No. JP-10101591);

9) Ribozymes such as anti-nuclease ribozymes (Maccjak D.J. et al., Hepatology 1999, 30, abstract 995) and those disclosed in U.S. Patent No. 6,043,077 by Barber et al. and U.S. Patent Nos. 5,869,253 and 5,610,054 by Draper et al. content; and

10) Nucleoside analogues have also been developed for the treatment of Flaviviridae virus infections.

11) Any compound described in International Application Nos. WO 01/90121 and WO 01/92282 of Idenix Pharmaceuticals;

12) Other patent applications disclosing the use of certain nucleoside analogs to treat hepatitis C virus include: PCT/CA00/01316 filed by BioChemPharma, Inc. (now Shire Biochem, Inc.) (WO 01/32153; 2000 filed November 3, 2001) and PCT/CA01/00197 (WO 01/60315; filed February 19, 2001); PCT/US02/01531 filed by Merck & Co., Inc. (WO 02/057425; filed 2002 filed January 18) and PCT/US02/03086 (WO02/057287; filed January 18, 2002), PCT/EP01/09633 filed by Roche (WO 02/18404; published August 21, 2001), and Pharmasset, Ltd's PCT Publication Nos. WO OIT9246 (filed April 13, 2001), WO02/32920 (filed October 18, 2001) and WO 02/48165.

13) PCT Publication No. WO 99/43691 by Emory University, entitled "2'-Fluoronucleosides" discloses the use of certain 2'-fluoronucleosides for the treatment of HCV.

14) Other miscellaneous compounds include: 1-amino-alkylcyclohexanes (Gold et al. U.S. Patent No. 6,034,134), alkyl lipids (Chojkier et al. U.S. Patent No. 5,922,757), vitamin E and other antioxidants (Chojkier et al. etc. U.S. Patent No. 5,922,757), squalene, amantadine, bile acid (Ozeki et al. U.S. Patent No. 5,846,964), N-(phosphonoacetyl)-L-aspartic acid, (Diana et al. No.), phthalamide (Diana et al. US Patent No. 5,633,388), polyadenylic acid derivatives (Wang et al. US Patent No. 5,496,546), 2', 3'-dideoxyinosine (Yarchoan et al. US Patent No. 5,026,687), benzimidazoles (Colacino et al. U.S. Patent No. 5,891,874), plant extracts (Tsai et al. U.S. Patent Nos. 5,837,257, Omer et al. piperidenes) (Diana et al. US Patent 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, Endo AMANTADINE® (amantadine) from Labs Solvay, HEPTAZYME® from RPI, IDN-6556 from Idun Pharma, XTL-002 from XTL, HCV/MF59 from Chiron, CIVACIR® (hepatitis C virus immunoglobulin) from NABI, ICN LEVOVIRIN® from RIBAPHARM, VIRAMIDINE® from ICN/RIBAPHARM, ZADAXIN® (thymosin alpha-1) from Sci Clone, thymosin and pegylated interferon from Sci Clone, CEPLENE® (histamine dihydrochloride) from Maxim, VX 950/LY 570310 from Vertex/Eli Lilly, ISIS 14803 from IsisPHARMACEUTICAL/ELAN, IDN-6556 from Idun Pharmaceuticals Inc., JTK 003 from AKROSPharma, BILN-2061 from Boehringer Ingelheim, CellCept (mycophenolate mofetil) from Roche ), Tularik’s T67, a β-tubulin inhibitor, Innogenetics’ therapeutic vaccine against E2, Fujisawa Healthcare, Inc’s FK788, IdB 1016 (Siliphos, oral silybin-phosphatdylcholine phytosome) ), ViroPharma/Wyeth’s RNA Replication Inhibitor (VP50406), Intercell’s Therapeutic Vaccine, Epimmune/Genencor’s Therapeutic Vaccine, Anadys’ IRES Inhibitor, Anadys’ ANA 245 and ANA 246, Avant’s Immunotherapy (Therapore), Corvas/ Protease Inhibitors from Schering, Helicase Inhibitors from Vertex, Fusion Inhibitors from Trimeris, T Cell Therapies from CellExSys, Polymerase Inhibitors from Biocryst, Targeted RNA Chemistry from PTC Therapeutics, Dication from Immtech, Int , Agouron's Protease Inhibitor, Chiron/Medivir's Protease Inhibitor, AVI BioPharma's Antisense Therapy, Hybridon's Antisense Therapy, Aethlon Medical's Blood Cleaner (hemopurifier), Merix's Therapeutic Vaccine, Bristol-Myers Squibb/Axys' Protease Inhibitors, Chron-VacC from Tripep, a therapeutic vaccine, UT 231B from United Therapeutics, protease, helicase and polymerase inhibitors from Genelabs Technologies, IRES inhibitors from Immusol, R803 from Rigel Pharmaceuticals, INFERGEN® from InterMune ( Interferon alpha con-1), Viragen's OMNIFERON® (natural interferon), Human Genome Sciences' ALBUFERON®, Ares-Serono's REBIF® (beta-1a interferon), BioMedicine's omega-interferon, Amarillo Biosciences' oral alpha - Interferon, InterMune's gamma-interferon, tau-interferon and gamma-1b interferon.

VI. Pharmaceutical Compositions

Pestiviruses, flaviviruses, HCV, or any other diseases having Hosts infected by the disorders described or other organisms that replicate by RNA-dependent RNA viral polymerases include humans, or for the purpose of treating any of the disorders described herein. The active substance may be administered in liquid or solid form by any suitable route, for example, orally, parenterally, intravenously, transdermally, subcutaneously or topically.

For pestivirus, flavivirus or HCV infection, the preferred dosage of the compound is about 1-50 mg/kg body weight per day, preferably 1-20 mg, more usually 0.1 to about 100 mg/kg body weight of the patient per day. Lower doses are preferred, eg 0.5-100 mg, 0.5-50 mg, 0.5-10 mg or 0.5-5 mg per kg body weight per day. Even lower doses are effective, so this range may include 0.1-0.5 mg per kg body weight per day. Effective dosage ranges for pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be released for pharmaceutically acceptable salt prodrugs. If the salt or prodrug is itself active, the effective dose can be estimated as 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 7-3000 mg, preferably 70-1400 mg of active compound per dosage unit. Oral doses of 50-1000 mg are usually convenient, including one or more doses of 50, 100, 200, 250, 300, 400, 500, 600, 700, 800, 900 or 1000 mg. Lower doses are preferred, eg 10-100 or 1-50 mg. Contemplated dosages may also be 0.1-50 mg or 0.1-20 mg or 0.1-10.0 mg. Furthermore, in the case of parenteral routes, such as by injection or inhalation, lower dosages may be used.

Ideally, the active ingredient is administered in such a way that the peak plasma concentration of the active compound is about 0.2-70 [mu]M, preferably about 1.0-10 [mu]M. This goal can be achieved eg by intravenous injection of a 0.1-5% active ingredient solution, optionally in saline, or by administration of a bolus of the active ingredient.

The concentration of the active compound in the pharmaceutical composition depends on the rate of absorption, inactivation, and excretion of the drug, as well as other factors well known to those skilled in the art. It should be noted that dosage will also vary with the severity of the condition to be alleviated. At the same time, it should also be understood that for any specific patient, the specific dosage regimen 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, and the aforementioned concentration ranges are only examples are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at one time, or divided into several small doses and administered at different time intervals.

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

Tablets, pills, capsules, lozenges, etc. 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; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint oil, methyl salicylate, or orange flavoring ( 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, dosage unit forms can contain various other materials which modify the physical form of the dosage form, for example, coatings of sugar, shellac, or other enteric coatings.

The compounds may also be administered as components of elixirs, suspensions, syrups, wafers, chewing gums and the like. A syrup may contain, in addition to the active ingredients, 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 substances which do not interfere with their desired action, or with substances which complement the desired action, such as antibiotics, antifungals, antifungal agents, Inflammatory 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 glycol, glycerol, propylene glycol or other synthetic solvents; antimicrobials such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and Reagents used to adjust osmotic pressure, such as sodium chloride or dextrose. The parent formulation can be enclosed in ampoules, disposable syringes or multiple dose vials of glass or plastic.

If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are formulated with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The above materials are commercially 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 US Patent No. 4,522,811, which is hereby incorporated by reference in its entirety. For example, by dissolving appropriate lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine, and cholesterol) in an inorganic solvent, which is then evaporated and forms a dry lipid film on the container surface To prepare liposome formulations. An aqueous solution of the active or its monophosphate, diphosphate and/or triphosphate derivatives is then added to the vessel. The container is then swirled by hand to dislodge the lipid material from the container surface and to disperse the lipid aggregates, thereby forming a liposomal suspension.

VII. Methods of Preparation of Active Compounds

The nucleosides of the invention can be synthesized by any method known in the art. In particular, the synthesis of the nucleosides of the invention can be accomplished by alkylation of an appropriately modified sugar, followed by glycosylation, or by glycosylation of the nucleoside followed by alkylation. The following non-limiting examples illustrate some general methods for obtaining the nucleosides of the invention.

A. Conventional synthesis method of 1′-C-branched nucleosides

1'-C-branched ribonucleosides of the following structure can be prepared by one of the following conventional methods:

Among them, Base, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Y, W ¹ , W ² , W ³ , X , X ¹ , X ² and X ³ are as defined herein.

1) Obtained by lactone modification

The key raw materials for this method are appropriately substituted lactones. The lactones are commercially available or may be prepared by any known method, including standard epimerization, substitution and cyclization techniques. According to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991, can be protected with an appropriate protecting group, preferably an acyl or silyl group. The lactone is optionally protected. The protected lactone is then reacted with a suitable coupling reagent, such as an organometallic carbon nucleophile (eg, Grignard reagent, organolithium, dialkylcopperlithium or R ⁶ -SiMe ₃ in TBAF), at an appropriate Coupling in an aprotic solvent at an appropriate temperature affords 1'-alkylated sugars.

The optionally activated sugar is then coupled to the base (BASE) according to methods well known to those skilled in the art, as taught in Townsend Chemistry of Nucleosides and Nucleotides Plenum Press, 1994. For example, the acylated sugar is coupled to the silylated base using a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyl triflate in a suitable solvent at a suitable temperature. basically.

Subsequently, suitable protecting groups, preferably acyl or silyl groups, can be used according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991 Nucleosides are deprotected as taught herein for the lactones.

In a specific embodiment, 1'-C-branched ribonucleosides are desirable. Scheme 1 shows the synthesis method of ribonucleosides. Alternatively, deoxyribonucleosides are also desirable. In order to obtain these nucleosides, the ribonucleosides formed can be optionally substituted according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991. protection, followed by reduction of the 2'-OH with an appropriate reducing agent. Optionally, the 2'-hydroxyl group is activated to facilitate its reduction; ie by Barton reduction.

Process 1

2. Other preparation methods of 1′-C-branched nucleosides

The key raw material for this method is appropriately substituted hexoses. The hexoses are commercially available or can be prepared by any known method, including standard epimerization (eg base treatment), substitution and coupling techniques. The hexoses can be selectively protected to give the appropriate hexafuranose. As taught in Townsend Chemistry of Nucleosides and Nucleotides , Plenum Press, 1994.

The 1'-hydroxyl group can optionally be activated as an appropriate leaving group, such as an acyl group or a halo by acylation or halogenation, respectively. The optionally activated sugar is then coupled to the base (BASE) by methods well known to those skilled in the art, as taught in Townsend Chemistry of Nucleosides and Nucleotides , Plenum Press, 1994 . For example, the acylated sugar is coupled to the silylated base using a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyl triflate in a suitable solvent at a suitable temperature. basically. Alternatively, halosugars are coupled to silylated bases in the presence of trimethylsilyl triflate.

If the 1'- _CH2 -OH is protected, it can be selectively deprotected according to methods well known in the art. The resulting primary hydroxyl groups are functionalized to obtain various C-branched nucleosides. For example. Using an appropriate reducing agent, the primary hydroxyl group is reduced to the methyl group. Alternatively, the hydroxyl group is activated prior to reduction to facilitate its reduction, ie by Barton reduction. In another embodiment, primary hydroxyl groups are first oxidized to aldehydes, which are then reacted with carbon nucleophiles such as Grignard reagents, organolithium, dialkylcopperlithium, or R6 ^- _SiMe3 in TBAF in appropriate Coupling in an aprotic solvent at an appropriate temperature.

In a specific embodiment, 1'-C-branched ribonucleosides are desirable. Scheme 2 shows the synthesis method of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. In order to obtain these nucleosides, the ribonucleosides formed can be optionally substituted according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991. protection, followed by reduction of the 2'-OH with an appropriate reducing agent. Optionally, the 2'-hydroxyl group is activated to facilitate its reduction; ie by Barton reduction.

Process 2

Furthermore, the corresponding L-enantiomers of the compounds of the present invention can be prepared according to the same general method (1 or 2) using the corresponding L-sugar or nucleoside L-enantiomers as starting materials.

B. Conventional synthesis method of 2′-C-branched nucleosides

2'-C-branched ribonucleosides of the following structure can be prepared by one of the following conventional methods:

Among them, Base, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Y, W ¹ , W ² , W ³ , X , X ¹ , X ² and X ³ are as defined herein.

1. Obtained by glycosylation of nucleobase with appropriately modified sugars

The key starting material for this method is an appropriately substituted sugar with 2'-OH and 2'-H, substituted with an appropriate leaving group (LG), such as acyl or halogen. Such sugars are commercially available or may be prepared by any known method, including standard epimerization, substitution, oxidation and reduction techniques. Then, the substituted sugar is oxidized with a suitable oxidizing agent in a compatible solvent at an appropriate temperature to obtain a 2'-modified sugar. Possible oxidizing agents are Jones' reagent (a mixture of chromic acid and sulfuric acid), Collins' reagent (dipyridine Cr(VI) oxide), Corey's reagent (pyridinium chlorochromate), pyridinium dichromate, Acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or polymer-supported potassium permanganate, Cl ₂ -pyridine, H ₂ O ₂ - Ammonium molybdate, NaBrO2 _- CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (Meerwin-Pondorf-Verley) (aluminum tert-butoxide and another ketone) and N-bromosuccinimide.

An organometallic carbon nucleophile (such as a Grignard reagent, organolithium, dialkylcopperlithium or R ⁶ -SiMe ₃ in TBAF) is then mixed with the ketone in a suitable aprotic solvent at an appropriate temperature Coupling yields 2'-alkylated sugars. Then, according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991, optionally with suitable protecting groups, preferably with acyl or silane group to protect the alkylated sugar.

The optional sugar is then coupled to the base (BASE) according to methods well known to those skilled in the art, as taught in Townsend Chemistry of Nucleosides and Nucleotides , Plenum Press, 1994. For example, the acylated sugar is coupled to the silylated base using a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyl triflate in a suitable solvent at a suitable temperature. basically. Alternatively, halosugars are coupled to silylated bases in the presence of trimethylsilyl triflate.

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

In a specific embodiment, 2'-C-branched ribonucleosides are desirable. Scheme 3 shows the synthesis method of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. In order to obtain these nucleosides, the ribonucleosides formed can be optionally substituted according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991. protection, followed by reduction of the 2'-OH with an appropriate reducing agent. Optionally, the 2'-hydroxyl group is activated to facilitate its reduction; ie by Barton reduction.

Process 3

2. Modification of Preformed Nucleosides

The key starting materials for this method are appropriately substituted nucleosides with 2'-OH and 2'-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 taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991, optionally with a suitable protecting group, preferably with an acyl or Silyl groups protect the nucleosides.

Subsequent oxidation of the suitably protected nucleoside with an appropriate oxidizing agent in a compatible solvent at an appropriate temperature yields the 2'-modified sugar. Possible oxidizing agents are Jones' reagent (a mixture of chromic acid and sulfuric acid), Colin's reagent (bipyridine Cr(VI) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid heavy Chromate (acid dichromate), potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or polymer-supported potassium permanganate, Cl ₂ -pyridine, H ₂ O ₂ -ammonium molybdate , NaBrO ₂ -CAN, HOAc solution of NaOCl, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (Meerwin-Pondorf-Verley) (aluminum tert-butoxide and another a ketone) and N-bromosuccinimide.

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

In a specific embodiment, 2'-C-branched ribonucleosides are desirable. Scheme 4 shows the synthesis method of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. In order to obtain these nucleosides, the ribonucleosides formed can be optionally substituted according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991. protection, followed by reduction of the 2'-OH with an appropriate reducing agent. Optionally, the 2'-hydroxyl group is activated to facilitate its reduction; ie by Barton reduction.

Process 4

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

C. Routine synthesis of 3′-C-branched nucleosides

3'-C-branched ribonucleosides of the following structure can be prepared by one of the following conventional methods:

Among them, Base, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Y, W ¹ , W ² , W ³ , X , X ¹ , X ² and X ³ are as defined herein.

1. Nucleobase Glycosylation with Appropriately Modified Sugars

The key starting material for this method is an appropriately substituted sugar with 3'-OH and 3'-H substituted with an appropriate leaving group (LG), such as acyl or halogen. Such sugars are commercially available or may be prepared by any known method, including standard epimerization, substitution, oxidation and reduction techniques. Then, the substituted sugar is oxidized with an appropriate oxidizing agent in a compatible solvent at an appropriate temperature to obtain a 3'-modified sugar. Possible oxidizing agents are Jones' reagent (a mixture of chromic acid and sulfuric acid), Collins' reagent (dipyridine Cr(VI) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, Acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or polymer-supported potassium permanganate, Cl ₂ -pyridine, H ₂ O ₂ - Ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent (aluminum tert-butoxide and another ketone) and N-bromosuccinimide.

An organometallic carbon nucleophile (such as a Grignard reagent, organolithium, dialkylcopperlithium or R ⁶ -SiMe ₃ in TBAF) is then mixed with the ketone in a suitable aprotic solvent at an appropriate temperature Coupling yields 3'-C-branched sugars. Then, according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991, optionally with suitable protecting groups, preferably with acyl or silane group to protect the alkylated sugar.

The optionally protected sugar is then coupled to the base (BASE) according to methods well known to those skilled in the art, as taught in Townsend Chemistry of Nucleosides and Nucleotides , Plenum Press, 1994 . For example, the acylated sugar is coupled to the silylated base using a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyl triflate in a suitable solvent at a suitable temperature. basically. Alternatively, halosugars are coupled to silylated bases in the presence of trimethylsilyl triflate.

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

In a specific embodiment, 3'-C-branched ribonucleosides are desirable. Scheme 5 shows the synthesis method of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. In order to obtain these nucleosides, the ribonucleosides formed can be optionally substituted according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991. protection, followed by reduction of the 2'-OH with an appropriate reducing agent. Optionally, the 2'-hydroxyl group is activated to facilitate its reduction; ie by Barton reduction.

Process 5

2. Modification of Preformed Nucleosides

The key starting materials for this method are appropriately substituted nucleosides 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 taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991, optionally with a suitable protecting group, preferably with an acyl or methyl group The silyl group protects the nucleoside.

Subsequent oxidation of the suitably protected nucleoside with an appropriate oxidizing agent in a compatible solvent at an appropriate temperature yields the 2'-modified sugar. Possible oxidizing agents are Jones' reagent (a mixture of chromic acid and sulfuric acid), Colin's reagent (bipyridine Cr(VI) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, acid heavy Chromate (acid dichromate), potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or polymer-supported potassium permanganate, Cl ₂ -pyridine, H ₂ O ₂ -ammonium molybdate , NaBrO2 _- CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Milvin-Pondorf-Walley reagent (aluminum tert-butoxide and another ketone), and N-bromo Substituted succinimide.

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

In a specific embodiment, 3'-C-branched ribonucleosides are desirable. Scheme 6 shows the synthesis method of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. In order to obtain these nucleosides, the ribonucleosides formed can be optionally substituted according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991. protection, followed by reduction of the 2'-OH with an appropriate reducing agent. Optionally, the 2'-hydroxyl group is activated to facilitate its reduction; ie by Barton reduction.

Process 6

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

D. Conventional synthesis method of 4′-C-branched nucleosides

4'-C-branched ribonucleosides of the following structure can be prepared by one of the following conventional methods:

Among them, Base, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Y, W ¹ , W ² , W ³ , X , X ¹ , X ² and X ³ are as defined herein.

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

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

In a preferred embodiment, the pentodialdo-furanoses are prepared from appropriately substituted hexoses. The hexoses are commercially available or can be prepared by any known method, including standard epimerization (eg base treatment), substitution and coupling techniques. The hexose may be in the furanose form or may be cyclized by any method known in the art, as taught in Townsend Chemistry of Nucleosides and Nucleotides , Plenum Press, 1994, preferably by selectively protecting the hexose sugar to obtain the appropriate hexafuranose.

Subsequently, the 4'-hydroxymethyl group of the hexafuranose is oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to obtain a 4'-aldehyde-modified sugar. Possible oxidizing agents are Swern's reagent, Jones' reagent (a mixture of chromic acid and sulfuric acid), Colin's reagent (dipyridine Cr(VI) oxide), Conrey's reagent (pyridinium chlorochromate), pyridinium dichromate, Acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or polymer-supported potassium permanganate, Cl ₂ -pyridine, H ₂ O ₂ - Ammonium molybdate, NaBrO2 _- CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Milvin-Pondorf-Walley reagent (aluminum tert-butoxide and another ketone) and N-Bromosuccinimide, although _H3PO4 , _DMSO and DCC are preferred in benzene/pyridine mixtures at room temperature.

Thereafter, suitable protecting groups, preferably acyl or silyl groups, may be used according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991 The pentodialdo-furanose is optionally protected with a pentodialdo-furanose group. Then in the presence of a base, such as sodium hydroxide, the protected glutaraldehyde (pentodialdo)-furanose can be combined with a suitable electrophilic alkyl, halo-alkyl (ie CF3), alkenyl or Alkynyl (ie allyl) coupling yields 4'-alkylated sugars. Alternatively, the protected pentodialdo-furanose can be coupled with the corresponding carbonyl, such as formaldehyde, in the presence of a base, such as sodium hydroxide, followed by coupling in a suitable polar solvent, such as dioxin Alkanes, which can be reduced by a suitable reducing agent at a suitable temperature to give 4'-alkylated sugars. In one embodiment, the reduction is performed using PhOC(S)Cl, DMAP, preferably in acetonitrile at room temperature, followed by reflux of ACCN and TMSS in toluene.

The optionally activated sugar is then coupled to the base (BASE) according to methods well known to those skilled in the art, as taught in Townsend Chemistry of Nucleosides and Nucleotides , Plenum Press, 1994 . For example, the acylated sugar is coupled to the silylated base using a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyl triflate in a suitable solvent at a suitable temperature. basically.

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

In a specific embodiment, 4'-C-branched ribonucleosides are desirable. Scheme 6 shows the synthesis method of ribonucleosides. Alternatively, deoxyribonucleosides are desirable. In order to obtain these nucleosides, the ribonucleosides formed can be optionally substituted according to methods well known to those skilled in the art, as taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991. protection, followed by reduction of the 2'-OH with an appropriate reducing agent. Optionally, the 2'-hydroxyl group is activated to facilitate its reduction; ie by Barton reduction.

In another embodiment of the invention, the L-enantiomer is desired. Accordingly, the corresponding L-enantiomers of the compounds of the present invention can be prepared according to the same conventional methods as described above, using the corresponding L-pentodialdo-furanose as a starting material.

E.2' and/or 3'-prodrug conventional synthesis method

The key starting material for this method is appropriately substituted 1', 2', 3' or 4'-branched β-D or β-L nucleosides. The branched chain 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 taught in Greene et al. Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991, optionally with a suitable protecting group, preferably with a silyl group The branched nucleosides are protected. The protected branched nucleoside can 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 give 1', 2', 2' and/or 3' prodrugs of 3' or 4'-branched β-D or β-L nucleosides. Alternatively, the protected branched chain nucleosides can then be combined with a suitable acyl group, such as a carboxylic acid, such as an alkanoic acid and and/or coupling of amino acid residues to obtain 2' and/or 3' prodrugs of 1', 2', 3' or 4'-branched β-D or β-L nucleosides. Possible coupling reagents are any reagents that facilitate coupling, including, but not limited to, Mitsunobu's reagents with triphenylphosphine or various carbodiimides (such as diisopropylazodicarboxylate and diethylazodicarboxylate) nitrogen dicarboxylates).

For example, simple amino-ethanols can be esterified using acid chlorides in a refluxing acetonitrile-benzene mixture (see Scheme 7 below: 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 hereby incorporated by reference. See Figures 2, 3 and 4.

Process 7

ACN: acetonitrile

The following examples illustrate the invention by way of illustration. It will be understood by those of ordinary skill in the art that these examples do not limit the invention and that changes may be made in details without departing from the spirit and scope of the invention. Example 1: Preparation of 1′-C-methyl riboadenine by 6-amino-9-(1-deoxy-β-D-psicofuranosyl) purine

Melting points were determined on a Mel-temp II apparatus and are uncorrected. NMR spectra were recorded on a Bruker 400 AMX spectrometer using ¹ H NMR at 400 MHz and ¹³ C NMR at 100 MHz with TMS as 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). Infrared (IR) spectra were measured on a Nicolet 510P Fourier transform infrared (FT-IR) spectrometer. Mass spectra were recorded on a Micromass Autospec high resolution mass spectrometer. Thin layer chromatography (TLC) analyzes were performed on Uniplates (silica gel) from Analtech Co. Flash column chromatography was performed using silica gel-60 (220-440 mesh) or vacuum flash chromatography using silica gel G (TLC grade, >440 mesh). Ultraviolet (UV) spectra were obtained by a Beckman DU 650 spectrophotometer. Elemental analyzes were performed at 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, MA) equipped with a Model 600 controller, a Model 996 photodiode array detector, and a Model 717 plus autosampler. Millennium 2010 software was used for system control, data acquisition and processing. A chiralyserpolarimetric detector, a Perkin-Elmer Model 241 MC polarimeter (Wilton, CT) was used to determine optical rotation.

Synthesis of 1′-C-methylribose-8-methyladenine

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

Process 8

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

wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

Wherein, R ¹ , R ² , R ³ , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are defined here.

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

Wherein, R ¹ , R ⁶ , R ⁷ , R ⁸ , X, R ⁹ , R ¹⁰ and base (Base) are as defined herein.

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

The target compound can be obtained according to the published method (REHarry-O'kuru, JMSmith, and MSWolfe, "Ashort, flexible route toward 2'-C-branched ribonucleosides", J.Org.Chem.1997, 62 , 1754-1759) preparation. (Process 9).

Process 9

(a) Dess-Martin periodinane; (b) MeMgBr/TiCl ₄ ; (c) BzCl, DMAP, Et ₃ N; (d) bis(trimethylsilyl)acetamide, N ⁶ -benzoyladenine , TMSOTf; (e)NH ₃ /MeOH

The 3'-prodrug of the 2'-branched chain nucleoside can be obtained according to the disclosed method (Syntetic Communications, 1978, 8(5), 327-333; J.Am.Chem.Soc., 1999,121(24) , 5661-5664) preparation. Alternatively, the 2'-branched nucleosides can be esterified without protection (Scheme 9b). Carbonyldiimidazole (377 mg, 2.33 mmol) was added to 15 ml of a solution of N-(tert-butoxycarbonyl)-L-valine (507 mg, 2.33 mmol) in anhydrous THF. The mixture was stirred at 20°C for 1 hour, at 50°C for 10 minutes, then added to 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-di methylformamide solution (10 mL), and stirred at 50°C. The reaction mixture was stirred at 50°C for 1 hour, followed by HPLC. HPLC analysis indicated that 52% of the product was the desired ester and 17% of the product was the starting material, in addition to by-products. When coupled with BOC-valine (BOC-Val), the 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl )-1H-pyrimidin-2-one's 3'-OH tends to react selectively.

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

wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

Wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

Wherein, R ¹ , R ² , R ³ , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , X and base (Base) are as defined herein.

Example 3: Preparation of 3'-C-methylribose-8-methyladenine

The target compound can be obtained according to published methods (RFNutt, MJDickinson, FWHolly, and E.Walton, "Branched-chain sugar nucleotides.III.3'C-methyladenine", J.Org.Chem.1968, 33 , 1789-1795 ) preparation (scheme 10).

Process 10

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

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

wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

Wherein, R ¹ , R ² , R ³ , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and base (Base) are as defined herein.

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

The target compound can be prepared according to the published method (Leonard, NJ; Carraway, KL "5-Amino-5-deoxyrbose derivatives.Synthese and use in the preparation of "reversed"nucleotides" J.Heterocycle.Chem. 1966,3,485 -489) preparation.

A solution of 50.0 g (0.34 mole) of dry D-ribose in 1.0 L of acetone, 100 mL of 2,2-dimethoxypropane, 200 mL of methanol containing 20 mL of methanol saturated with hydrogen chloride at 0° C. was stirred overnight at room temperature. The resulting solution was neutralized with pyridine and evaporated under reduced pressure. The resulting oil was partitioned between 400 mL water and 400 mL 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 column chromatography on silica gel [eluent: stepwise gradient of methanol in dichloromethane (1-2%)] to give pure 1 (52.1 g, 75% ). H ¹ -NMR(CDCl ₃ ): 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 CH ₃ ), 1.34 (s, 3H CH ₃ ); MS (matrix GT): FAB>0m/z 173(M-OCH3) ⁺ .

Example 5: Preparation of 1-O-methyl-2,3-0-isopropylidene-β-D-glutaraldehyde-ribofuranose-(2)

The target compound can be obtained according to published methods (Jones, G.H.; Moffatt, J.G.Oxidation of carbohydrates by the sulfoxide-carbodiimide and related methods.Oxidation with dicyclohexhylcarbodiimide-DMSO, diisopropylcarbodiimide-DMSO, acetic anhydride-DMSO, and od phosphorusDMSO pentoxide: 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 pyridine. Dicyclohexylcarbodiimide (DCC, 137.8 g, 0.67 mol) was added to a solution of 1 (68.2 g, 0.33 mole) in dry benzene (670 mL), DMSO (500 mL) and pyrimidine (13.4 mL). For the resulting solution, cool to 0 °C and add a solution of anhydrous crystalline orthophosphoric acid (16.4 g, 0.167 mmol) in anhydrous DMSO (30 mL). Under an argon atmosphere, the mixture was stirred at 0°C for 1.5 hours and at room temperature for 18 hours, diluted with ethyl acetate (1000 mL). A solution of oxalic acid dihydrate (63.1 g, 038 mol) in DMSO (30 mL) was added, the reaction mixture was stirred at room temperature for 1 hour, and then precipitated dicyclohexylurea (DCU) was removed by filtration. The filtrate was concentrated under reduced pressure to a volume of about 600 mL and neutralized with saturated aqueous sodium bicarbonate (400 mL). Brine (200 mL) was added, and the organic layer was extracted with ethyl acetate (4 x 1000 mL). The combined organic layers were concentrated to a volume of about 2000 mL, washed with saturated aqueous sodium bicarbonate (2 x 700 mL) and brine (2 x 700 mL) before being dried over sodium sulfate and evaporated under reduced pressure. A small portion of the crude residue was purified by silica gel column chromatography [eluent: chloroform/ether, 8:2] to give the structure of 2 as a pale yellow solid. ¹ H-NMR (CDCl ₃ ): δ9.61(s, 1H, H-5), 5.12(s, 1H, H-1), 5.08(d, 1H, H-2, J _2-3 = 5.9Hz ), 4.53 (d, 1H, H-3, J _3-2 = 6.0Hz), 4.51 (s, 1H, H-4), 3.48 (s, 1H, OCH ₃ ), 1.56 (s, 3H CH ₃ ) , 1.36 (s, 3H CH ₃ ); MS (matrix GT): FAB > 0 m/z 203 (M+H) ⁺ , 171 (M-OCH ₃ ) ⁺ .

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

The target compound can be obtained according to published methods (Leland, DL; Kotick, MP "Studies on 4-C-(hydroxymethyl)pentofuranoses.Synthesis of 9-[4-C-(hydroxymethyl)-aL-threo-pentofuranosyl]adenine" Carbohydr. Res . 1974, 38, C9-C11; Jones, GH; Taniguchi, M.; Tegg, D.; Moffatt, JG "4'-substituted nucleotides. 5. Hydroxylation of nucleotide 5'-aldehydes" J.Org.Chem . , 44, 1309-1317; Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. "Synthesis and cytotoxicity of 4′-C-and 5′-C- substituted Toyocamycins" Bioorg. Med. Chem . 2001, 9, 163-170).

Sodium hydroxide (2N, 300 mL) was added to the dioxane solution (830 mL) of the crude extraction material (2) obtained above and 37% formaldehyde (167 mL). The mixture was stirred at room temperature for 4 hours and neutralized by adding Dowex 50 WX2 (H ⁺ form). After the resin was filtered and washed with methanol, the combined filtrates were concentrated to dryness and co-evaporated several times with absolute ethanol. The sodium formate produced by precipitation in absolute ethanol was removed by filtration, the filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol dissolved in chloroform (0-4%)] to obtain pure 3 (42.2 g, 54% from 1), which was recrystallized from cyclohexylamine. Mp=94-95 (dec.) (lit.94-96.5; 97-98: Refs: 3, 4), ¹ H-NMR (DMSO-d ₆ ): δ4.65 (s, 1H, H-1) , 4.44-4.37(m, 3H, H-2, H-3 and OH-6), 4.27(t, 1H, OH-5, J=5.6Hz, J=6.0Hz), 3.42-3.34(m, 2H , H-5 and H-6) 3.29 (dd, 1H, H-5′, J _5′-OH = 5.4Hz, J5-5′ = 11.4Hz), 3.11 (dd, 1H, H-6′, J _6'-OH =5.7Hz, J6-6'=10.9Hz), 3.03(s, 3H, OCH ₃ ), 1.48(s, 3H CH3), 1.05(s, 3H CH ₃ ); MS(matrix GT): FAB>0 m/z 469(2M+H) ⁺ , 235(M+H) ⁺ , 203(M- _OCH3 ) ⁺ FAB<0 m/z 233(MH) ^- .

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

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

To a solution of 3 (41.0 g, 175 mmol) in pyridine (700 ml) was added a portion of di-p-methoxytrityl chloride (60.5 g, 178 mmol) at +4°C. The reaction mixture was stirred at room temperature for 3 hours. After methanol was added, 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, then evaporated to dryness. Purification by silica gel column chromatography [eluent: ethyl acetate/hexane 15/85] afforded pure 4 (63.0 g, 68%) as syrup. ¹ H-NMR (CDCl ₃ ): δ7.5-6.9 (m, 13H, MMTr), 4.89 (s, 1H, H-1), 4.72-4.62 (m, 3H, H-2, H-3 and OH -5), 3.82 (dd, 1H, H-5, J _5-OH = 5.5Hz, J5-5' = 10.5Hz), 3.79 (s, 6H, OCH3), 3.54 (dd, 1H, H-5' , J _5'-OH = 4.9Hz, J _5'-5 = 10.5Hz), 3.31 (s, 3H, OCH ₃ ), 3.24 (d, 1H, H-6, J _6'-6 = 9.2Hz), 3.13 (d, 1H, H-6′, J _6′-6 = 9.2Hz), 1.24 (s, 3H CH ₃ ), 1.15 (s, 3H CH ₃ ); MS (matrix GT): FAB>0 m/ z 303(DMTr) ⁺ .

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

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

To a solution of 4 (2.51 g, 4.68 mmol) in anhydrous pyridine (37 mL) was added benzoyl chloride (1.09 mL, 9.36 mmol) under argon atmosphere, and the reaction mixture was stirred at room temperature for 13 hours. It was then cooled to 0°C 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 (2 x 150 mL), water (1 x 150 mL), then dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 80% acetic acid (70.2 mL), and the mixture was stirred at room temperature for 3 hrs and concentrated to dryness. Purification by silica gel column chromatography [eluent: chloroform] gave pure 5 (1.40 g, 88%) as syrup. ¹ H-NMR (CDCl ₃ ): δ8.1-7.4 (m, 5H, C ₆ H ₅ CO), 5.08 (s, 1H, H-1), 4.77 (dd, 2H, H-2 and H-3 , J=6.1Hz, J=8.2Hz), 4.51(q, 2H, H-5 and H-5′, J=11.5Hz, J _5-5′ =23.8Hz), 3.91(t, 2H, H- 6 and H-6', J=12.3Hz), 4.38(s, 1H, OCH ₃ ), 2.2-1.8(brs, 1H, OH-6), 1.57(s, 3H CH ₃ ), 1.38(s, 3H CH ₃ ); MS(matrix GT): FAB>0 m/z 677(2M+H) ⁺ , 339(M+H) ⁺ , 307(M-OCH ₃ ) ⁺ , 105(C ₆ H ₅ CO) ⁺ FAB < 0 m/z 121 (C ₆ H ₅ CO ₂ ) ⁻ .

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

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

A solution of 5 (37.6 g, 0.111 mol), 4-dimethylaminopyridine (DMAP, 40.7 g, 0.333 mol) and phenoxythiocarbonyl chloride in anhydrous acetonitrile (1000 mL) was stirred at room temperature for 1 hour and concentrated to dryness. The residue was dissolved in dichloromethane (500 mL) and washed with 0.2M hydrochloric acid (2 x 500 mL) and water (500 mL) before being dried over sodium sulfate, evaporated under reduced pressure and co-evaporated several times with anhydrous toluene. The crude extract was dissolved in anhydrous toluene (880 mL) and tris(trimethylsilyl)silane (TMSS, 42.9 mL, 0.139 mol), followed by the addition of 1,1'-azobis(cyclohexylaminonitrile) ( ACCN, 6.8 g, 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 silica gel column chromatography [eluent: step gradient of diethyl ether in petroleum ether (5-20%)] to give pure 6 (26.4 g, 74%) as a yellow syrup. ¹ H-NMR (DMSO-d6): δ8.0-7.5 (m, 5H, C ₆ H ₅ CO), 4.85 (s, 1H, H-1), 4.63 (dd, 2H, H-2 and H- 3, J=6.1Hz, J=11.6Hz), 4.24(d, 1H, H-5, J _5-5' = 11.1Hz), 4.10(d, 1H, H-5', J _5'-5 = 11.1Hz), 3.17(s, 1H, OCH ₃ ), 1.38(s, 3H CH ₃ ), 1.30(s, 3H CH ₃ ), 1.25(s, 3H CH ₃ ); MS(matrix GT): FAB>0 m/z 291 (M-OCH ₃ ) ⁺ , 105 (C ₆ H ₅ CO ) ⁺ FAB<0 m/z 121 (C ₆ H ₅ CO ₂ ) ⁻ .

Example 10: Preparation of 5-O-benzoyl-4-C-methyl-1,2,3-O-acetyl-α,β-D-ribofuranose-(7)

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

α anomer: ¹ H-NMR (DMSO-d ₆ ): δ8.1-7.5 (m, 5H, C ₆ H ₅ CO), 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 ₃ CO ₂ ), 2.11 (s, 3H, CH ₃ CO ₂ ), 2.07 (s, 3H, CH ₃ CO ₂ ), 1.37 (s, 3H, CH ₃ ); MS (matrix GT): FAB ＞0 m/z 335(M-CH ₃ CO ₂ ^- ) ⁺ , 275(M-CH ₃ CO ₂ ^- +H) ⁺ , 105(C ₆ H ₅ CO) ⁺ , 43(CH ₃ CO) ⁺ FAB＜ 0 m/z 121(C ₆ H ₅ CO ₂ ) ⁻ , 59 (CH ₃ CO ₂ ) ⁻ .

β anomer: ¹ H-NMR (DMSO-d ₆ ): δ8.1-7.5 (m, 5H, C ₆ H ₅ CO), 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, CH ₃ CO ₂ ), 2.06(s, 3H, CH ₃ CO ₂ ), 2.02 (s, 3H, CH ₃ CO ₂ ), 1.30 (s, 3H, CH ₃ ); MS (matrix GT): FAB>0 m/z 335(M-CH ₃ CO ₂ ⁻ ) ⁺ , 275 (M-CH ₃ CO ₂ ^- +H) ⁺ , 105(C ₆ H ₅ CO) ⁺ , 43(CH ₃ CO) ⁺ FAB＜0 m/z 121(C ₆ H ₅ CO ₂ ) ^- , 59(CH ₃ CO ₂ ) ^- .

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

To a suspension of O-6-diphenylcarbamoyl-8-methyl- ^N2 -isobutyrylguanine in anhydrous toluene (20 mL) was added N,O-bis(trimethylsilyl)acetamide (1.92ML, 7.9mmol). The reaction mixture was heated at reflux for 1 hour. Compound 7 (1.55 g, 3.93 mmol) was dissolved in toluene (10 mL), followed by the addition of trimethylsilyl trifluoro-methanesulfonate (TMSTF) (915 mL, 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 (150 mL) and water (2 x 150 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel [eluent: step gradient of ether in petroleum ether (70-90%)] to afford 18.

Example 12: Preparation of 9-(4-C-methyl-β-D-ribofuranyl)-8-methylguanine-(19)

The target compound can be synthesized according to published methods from 18 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4'-C-methylnucleotides" Biosci. Biotechnol . Biochem. 1993, 57, 1433-1438) prepared.

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

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

A solution of 7 (1.10 g, 2.79 mmol) in anhydrous acetonitrile (50 mL) was treated with 8-methyladenine and tin tetrachloride (SnCl ₄ , 660 μL, 5.58 mmol) and stirred overnight at room temperature. The solution was concentrated under reduced pressure and diluted with chloroform (100 mL), followed by treatment with cold saturated aqueous sodium bicarbonate (100 mL). The mixture was filtered through celite, and the precipitate was washed with hot chloroform. The combined filtrates were washed with water (100ml) and brine (100ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel [eluent: step gradient of methanol (3-5%) in dichloromethane] to give 20.

Example 14: Preparation of 9-(4-C-methyl-β-D-ribofuranyl)-8-methyladenine-(21)

The target compound can be synthesized according to published methods from 20 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4'-C-methylnucleotides" Biosci. Biotechnol . Biochem. 1993, 57, 1433-1438) prepared.

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

In a similar procedure, but using the appropriate sugar and purine base, the following nucleosides of formula XXXXII can be prepared:

wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

A suspension of 6-methyluracil was treated at reflux with hexamethyldisilane (HMDS, 21 mL) and a catalytic amount of ammonium sulfate for 17 hours. After cooling to room temperature, the mixture was evaporated under reduced pressure to obtain a colorless oily residue, which was diluted with anhydrous 1,2-dichloroethane (7.5 mL). To the resulting solution was added a solution of 7 (0.99 g, 2.51 mmol) in anhydrous 1,2-dichloroethane (14 mL), followed by trimethylsilyl triflate (TMSTf, 0.97 mL, 5.02 mmol). Under an atmosphere of argon, the solution was stirred at room temperature for 2.5 hours, then diluted with chloroform (150 mL), washed with the same volume of saturated aqueous sodium bicarbonate and finally with water (2 x 100 mL). The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel [eluent: step gradient of methanol in chloroform (0-2%)] to obtain pure 8.

Example 16: Preparation of 1-(4-C-methyl-β-D-ribofuranyl)-6-methyluracil-(9)

The target compound can be synthesized according to published methods from 8 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4'-C-methylnucleotides" Biosci. Biotechnol . Biochem. 1993, 57, 1433-1438) prepared.

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

Example 17: Preparation of 1-(5-O-benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranyl)-4-thio-6-methyl -Uracil-(10)

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

Example 18: Preparation of 1-(4-C-methyl-β-D-ribofuranyl)-4-thio-6-methyluracil-(11)

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

Example 19: Preparation of 1-(4-C-methyl-β-D-ribofuranyl)-6-methylcytosine, hydrochloric acid form-(12)

Compound 11 was treated with methanolic ammonia solution (presaturated at -10°C) (12 mL) in a stainless steel pressure pot at 100°C for 3 hours, followed by cooling to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (40 mL) and water (40 mL). The aqueous layer was washed with dichloromethane (2 x 40 mL) 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 absolute ethanol (6.3 mL). To the solution was added 2N hydrochloric acid solution (1.5 mL), and the mixture was stirred before being concentrated under reduced pressure. Repeat the process twice to precipitate 12 from absolute ethanol.

Example 20: Preparation of 1-(5-O-benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranyl)-6-methylthymine-(13 )

A suspension of 6-methylthymidine was treated overnight at reflux with hexamethyldisilane (HMDg, 17 mL) and a catalytic amount of ammonium sulfate. After cooling to room temperature, the mixture was evaporated under reduced pressure to obtain a colorless oily residue, which was diluted with anhydrous 1,2-dichloroethane solution (6 mL). To the resulting solution was added a solution of 7 (1.0 g, 2.53 mmol) in anhydrous 1,2-dichloroethane (14 mL), followed by trimethylsilyl triflate (TMSTf, 0.98 mL, 5.06 mmol). Under an argon atmosphere, the solution was stirred at room temperature for 5 hours, then diluted with chloroform (150 mL), washed with the same volume of saturated sodium bicarbonate solution and finally with water (2 x 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-β-D-ribofuranyl)-6-methylthymine-(14)

The target compound can be synthesized according to published methods from 13 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H. "Synthesis of 4'-C-methylnucleotides" Biosci. Biotechnol . Biochem. 1993, 57, 1433-1438) prepared.

13 in methanolic ammonia solution (presaturated at -10°C) was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (60 mL) and water (60 mL). The aqueous layer was washed with dichloromethane (2 x 60 mL), concentrated under reduced pressure, and co-evaporated several times with absolute ethanol. Recrystallization from methanol afforded 14.

Example 22: Preparation of 1-(5,2,3-tri-O-acetyl-4-C-methyl-β-D-ribofuranyl)-6-methylthymine-(15)

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

Example 23: Preparation of 1-(5,2,3-tri-O-acetyl-4-C-methyl-β-D-ribofuryl)-4-thio-6-methylthymine-( 16)

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

Example 24: Preparation of 1-(4-C-methyl-β-D-ribofuranyl)-5-methyl-6-methylcytosine-(17), hydrochloric acid form

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

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

wherein, R ¹ , R ² , R ³ , X ¹ , X ² and Y are as defined herein.

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

Wherein, R ¹ , R ² , R ³ , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ² , R ⁶ , X and base (Base) are as defined herein.

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

Wherein, R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , X and base (Base) are as defined herein.

VIII. biological assay

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

Example 25: Anti-flavivirus or pestivirus activity

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

Determination of Nucleoside Phosphorylation to Active Triphosphate

To determine the metabolic mechanism of the compounds in cells, HepG2 cells obtained from the American Type Culture Collection (Rockville, MD) were grown in 225 ^cm tissue culture flasks supplemented with non-essential amino acids and 1% penicillin-streptavidin Medium was changed every 3 days and cells were passaged weekly in primed minimal essential medium. After contacting with 30 ml of trypsin-EDTA for 10 minutes and successively washing 3 times with the culture medium, after the adherent monolayer cells were detached, the pooled HepG2 cells were seeded in a ⁶ -well culture plate at a concentration of 2.5×106 cells per well, Exposure to 10 μM [ ³ H]-labeled active compound (500 dpm/pmol) for a certain period of time. These cells were maintained at 37°C in a 5% _CO2 environment. At selected time points, cells were washed 3 times with ice-cold phosphate buffered saline (PBS). Intracellular active compounds and their metabolites were extracted by incubating cell pellets with 60% methanol overnight at -20°C, followed by extraction with 20 μL of cold methanol for 1 hour in an ice bath. The extracts were then combined, dried under a gentle stream of filtered air, and stored at -20°C until HPLC analysis.

Bioavailability assay in macaques

One week before the start of the study, an indwelling (chronic) venous catheter and a subcutaneous venous access (VAP) were surgically inserted into the rhesus monkeys to facilitate blood collection and physical examination, including hematology and serum chemistry evaluation, and body weight was recorded. The active compound contained approximately 250 μCi of [ ³ H] in each administration to each monkey (total 6), ie administered at a dose of 10 mg/kg at a concentration of 5 m/ml. Administration was via intravenous bolus injection (3 monkeys, IV), or oral gavage (3 monkeys, PO). Each dosing syringe was weighed prior to each dosing to determine the amount of formulation administered. At indicated time intervals (approximately 18-0 hours pre-dose, 0-4, 4-8 and 8-12 hours post-dose), urine samples were collected by pan catch and processed. Likewise, at the indicated time intervals (before dosing, 0.25, 0.5, 1, 2, 3, 6, 8, 12, and 24 hours after dosing), through the indwelling intravenous catheter and VAP or in the indwelling intravenous catheter method Blood samples were collected from peripheral blood when not feasible. Blood and urine samples were analyzed to obtain peak concentration (C _max ), time to peak concentration (T _max )))), area under the curve (AUC), half-life of dose concentration (T _1/2 ), clearance rate (CL ), steady-state volume and distribution (V _ss ), and bioavailability (F).

Myelotoxicity Assay

Human bone marrow cells were collected from normal healthy volunteers, according to Sommadossi JP, Carlisle R. in "Toxicity of3'-azido-3'-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal humanhematopoietic progenitor cells in vitro" Antimicrobial Agents and Chemotherapy 1987; 31: 452-454; and Sommadossi JP, Schinazi RF, Chu CK, Xie MY in "Comparison of cytotoxicity of the(-)-and(+)-enantiomer of2′,3′-dideoxy- Mononuclear cells were isolated by Ficoll-Hypaque gradient centrifugation as described in 3'-thiacytidine in normal human bone marrow protenitor cells"Biochemical Pharmacology 1992;44:1921-1925. CFU-GM and BFU-E assays of cultures were performed using the double layer soft agar or methylcellulose method. Dilute the drug with tissue culture fluid and filter. After 14-18 days at 37°C in humidified air containing 5% _CO2 , 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

Using the above method, HepG2 cells were cultured in 12-well culture plates, and according to Pan-Zhou X-R, Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer VM in "Differential effects of antiretroviral nucleotide analogs onmitochondrial function in HepG2 cells" Antimicrob. Agents Chemother. 2000;44:496-503, HepG2 cells were exposed to various concentrations of the drug. Four days after drug exposure, lactate levels in the cultures were measured using the Boehringre lactate assay kit. Lactate levels were normalized to cell numbers determined by a hemocytometer.

Cytotoxicity assay

The cells were inoculated in the growth medium of a 96-well culture plate at an amount of 5×10 ³ -5×10 ⁴ /well, and incubated overnight at 37° C. in a humidified CO ₂ (5%) environment. New growth medium containing serial dilutions of drug was then added. After 4 days of incubation, cultures were fixed with 50% TCA and stained with thiorhodamine B. Optical density was measured at 550 nm. Cytotoxic concentrations are expressed as the concentration required to reduce cell number by 50% ( _CC50 ).

Cytoprotection Assay (CPA)

Basically according to Baginski, SG; Pevear, DC; SEIPEL, M.; Sun, SCC; Benetatos, CA; Chunduru, SK; ), the method described in 7981-7986, for this assay. 24 hours before use, MDBK cells (ATCC) were seeded in 96-well culture plates (4000 cells per well). After infection with BVDV (NADL strain, ATCC) at a multiplicity of infection (MOI) of 0.02 plaque-forming units per cell, serial dilutions of the test compound were added to infected and uninfected cells, and DMSO in culture medium The final concentration is 0.5%. Each dilution was performed in quadruplicate. Cell density and virus inoculation were adjusted to ensure that cells continued to grow throughout the assay and achieved greater than 90% virus-induced cell destruction in untreated controls four days after infection. Four days later, plates were fixed with 50% TCA and stained with rhodamine. At 550 nm, the optical density of each well was read using a plate reader. The 50% effective concentration ( _EC50 ) value is defined as the concentration of the compound that reduces the cytotoxic effect of the virus by 50%.

Plaque reduction assay

On two identical 24-well culture plates, the effective concentration of each compound was detected by the plaque number reduction assay. Cell monolayers were infected with 100 PFU of virus per well. Serial dilutions of test compounds in MEM supplemented with 2% inactivated serum and 0.75% methylcellulose were then added to the monolayer. The culture was further incubated at 37°C for 3 days, then fixed with 50% ethanol and 0.8% crystal violet, washed and air-dried. Plaques were then counted to determine the concentration required to achieve 90% virus inhibition.

Yield reduction assay

Concentrations of various compounds required for a 6-log reduction in viral load were tested by yield reduction assays on two identical 24-well plates. The assay is based on Baginski, S.G.; Pevear, D.C.; Seipel, M.; Sun, S.C.C.; Benetatos, C.A.; Chunduru, S.K.; 14), the method described in 7981-7986, was assayed with only minor modifications. Briefly, MDBK cells were seeded in 24-well culture plates (2 x 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 concentration of 0.5% DMSO in the growth medium. Each dilution was performed in triplicate. After three days, cell cultures (cell monolayers and supernatants) were lysed by three freeze-thaw cycles, and virus yield was quantified by plaque assay. Briefly, MDBK cells were seeded on 6-well culture plates (5 x 105 cells per well) 24 hours before use. Cells were inoculated with 0.2 ml of the test lysate for 1 hour, washed and layered with a 0.5% agarose solution in growth medium. Three days later, cell monolayers were 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 at which the viral load was reduced by 6-log was determined.

Example 26: In Vitro Antiviral Activity

In vitro antiviral activity was tested in the following cell lines: HIV-infected MT-4; Vero 76, SARS-infected African green monkey kidney cells; bovine viral diarrhea virus-infected BHK; poliovirus Sabin type 1-infected SB- 1; CVB-2, CVB-3, CVB-4, and CVA-9 infected by Coxsackieviruses B-2, B-3, B-4, and A-9; and REO-1 infected by double-stranded RNA viruses . Note: BVDV = bovine viral diarrhea virus; YFV = yellow fever virus; DENV = dengue virus; WNV = West Nile virus; CVB-2 = Coxsackie B-2 virus; SB-1 = Sabin poliovirus type 1 Viruses; and REO = double stranded RNA Reovirus.

β-D-2′-C-methyl-7-methyl-6-phenyl-3,3a,5,8a-tetrahydro-1,3,4,5,7a-penta-aza-s- CC ₅₀ and EC ₅₀ test results of indacen-8-one (compound F) CC ₅₀ CC ₅₀ CC _{50 EC50 EC50 EC50 EC50 EC50 EC50} compound MT-4 Vero76 BHK Sb-1 CVB-2 CVB-3 CVB-4 CVA-9 REO-1 f >100 >100 >100 43 37 49 39 60 2

β-D-2′-C-methyl-7-methyl-6-phenyl-3,3a,5,8a-tetrahydro-1,3,4,5,7a-penta-aza-s- CC ₅₀ test results of indacen-8-one (Compound F) CC ₅₀ compound BVDV YFV DENV2 WNV CVB-2 Sb-1 REO f >100 10 2.5 1.3 1 37 43 2

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

Claims (49)

1. Compounds of formula (I):

or a pharmaceutically acceptable salt thereof, in: R ¹ , R ² and R ³ are independently H, phosphate; linear, branched or cyclic alkyl; acyl; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy Alkyl, CO-substituted aryl, sulfonate; Benzyl, wherein phenyl is optionally substituted with one or more substituents; Alkylsulfonyl; Arylsulfonyl; Aralkylsulfonyl; Lipid amino acid; amino acid residue; carbohydrate ^; peptide; cholesterol ^; or other pharmaceutically acceptable leaving group, when administered in vivo ^, the leaving group can provide wherein compounds that are independently H or phosphate; wherein at least one of ^R2 and ^R3 is not hydrogen; and in: Y ¹ is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁴ ; X ¹ is linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO- Aryl, CO-O alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; and X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; and wherein each ^Y3 is independently H, F, Cl, Br or I; and R ⁴ and R ⁵ are each independently hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl. 2. Compounds of formula (II):

or a pharmaceutically acceptable salt thereof, in: R ¹ , R ² and R ³ are independently H, phosphate; linear, branched or cyclic alkyl; acyl; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy Alkyl, CO-substituted aryl, O sulfonate; Benzyl, where phenyl is optionally substituted with one or more substituents; Alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, lipid amino ^acid residues ^, carbohydrates; ^peptides ; or phosphate compounds; wherein at least one of ^R2 and ^R3 is not hydrogen; and in: Y ¹ is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁴ ; X ¹ is linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO- Aryl, CO-O alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; and X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; and wherein each ^Y3 is independently H, F, Cl, Br or I; and R ⁴ and R ⁵ are each independently hydrogen, acyl, alkyl, lower alkyl, alkenyl, alkynyl or cycloalkyl. 3. Compounds of formula (III), (IV) or (V): or their pharmaceutically acceptable salts, wherein: R ¹ , R ² and R ³ are independently H, phosphate; linear, branched or cyclic alkyl; acyl; CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxy Alkyl, CO-substituted aryl, sulfonate; Benzyl, wherein phenyl is optionally substituted with one or more substituents; Alkylsulfonyl; Arylsulfonyl; Aralkylsulfonyl; Lipid amino acid; amino acid residue; ^{carbohydrate ;} peptide; cholesterol ^; or other pharmaceutically acceptable leaving group, when administered in vivo, the leaving group can provide wherein compounds that are independently H or phosphate; wherein at least one of ^R2 and ^R3 is not hydrogen; and in: Base (Base) is selected from:

R and ^R are independently hydrogen, acyl, alkyl, ^lower alkyl, alkenyl, alkynyl or cycloalkyl; W ¹ , W ² , W ³ and W ⁴ are independently N, CH, CF, CI, CBr, CCl, CCN, CCH ₃ , CCF ₃ , CCH ₂ CH ₃ , CC(O)NH ₂ , CC(O )NHR ⁴ , CC(O)N(R ⁴ ) ₂ , CC(O)OH, CC(O)OR ⁴ or CX ³ ; W ^* is independently O, S, NH or NR ⁴ ; X is O, S, SO ₂ , CH ₂ , CH ₂ OH, CHF, CF ₂ , C(Y ³ ) ₂ , CHCN, C(CN) ₂ , CHR ⁴ or C(R ⁴ ) ₂ ; X ^* is CH, CF, CY ³ or CR ⁴ ; X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; X ³ are independently linear, branched or cyclic optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N ₃ , CN, -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C (O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , OH, OR ⁴ , -O(acyl), -O(lower acyl), -O(alkyl), -O (lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl), chlorine, bromine, Fluorine, iodine, NH ₂ , -NH(lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(acyl), -N(lower alkyl) ₂ , -NH(alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl) ₂ ; Y are independently selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR; R is H, alkyl or acyl; Y ¹ is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁴ ; Y ² are each independently O, S, NH or NR ⁴ ; and ^Y3 are independently H, F, Cl, Br or I; Wherein, if W ¹ , W ² and W ³ are N, for the base (Base) (B), W ⁴ cannot be CH; Wherein, if W ¹ is N, for bases (Base)(E), (F), (K), (L), (W) and (X), W ⁴ cannot be CH; R ⁶ are independently optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , any Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , - CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O )OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl) , -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ or cyano; R ⁷ are independently OH, OR ² , optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, any Optionally substituted heteroaryl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ₄ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)SH, - CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O) NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -( CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O) SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH (lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N (lower alkyl) ₂ , -C (O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)SH, -C(O)SR ⁴ , -C(O)S(lower alkyl ), -C(O)NH ₂ , -C(O)NHR ⁴ , -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(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S(lower alkyl), - S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(acyl), -N(lower alkyl) ₂ , -NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen; Alternatively, ^R and ^R can combine to form a spiro compound, selected from optionally substituted carbocycles or optionally substituted heterocycles; and m is 0, 1 or 2 each independently. 4. Compounds of formula (VI) or (VII):

or their pharmaceutically acceptable salts, in: ^R1 is H; phosphate; linear, 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 residue; carbohydrate a compound; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein ^R is H or phosphate; and, in: Base (Base) is selected from:

R and ^R are independently hydrogen, acyl, alkyl, ^lower alkyl, alkenyl, alkynyl or cycloalkyl; W ¹ , W ² , W ³ and W ⁴ are independently N, CH, CF, CI, CBr, CCl, CCN, CCH ₃ , CCF ₃ , CCH ₂ CH ₃ , CC(O)NH ₂ , CC(O )NHR ⁴ , CC(O)N(R ⁴ ) ₂ , CC(O)OH, CC(O)OR ⁴ or CX ³ ; W ^* are independently O, S, NH or NR ⁴ ; X is O, S, SO ₂ , CH ₂ , CH ₂ OH, CHF, CF ₂ , C(Y ³ ) ₂ , CHCN, C(CN) ₂ , CHR ⁴ or C(R ⁴ ) ₂ ; X ^* is CH, CF, CY ³ or CR ⁴ ; X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; X ³ are independently linear, branched or cyclic optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N ₃ , CN, -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C (O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , OH, OR ⁴ , -O(acyl), -O(lower acyl), -O(alkyl), -O (lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl), chlorine, bromine, Fluorine, iodine, NH ₂ , -NH(lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(acyl), -N(lower alkyl) ₂ , -NH(alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl) ₂ ; Y are independently selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, ( CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR; R is H, alkyl or acyl; Y ¹ is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁴ ; Y ² are each independently O, S, NH or NR ⁴ ; and ^Y3 are independently H, F, Cl, Br or I; Wherein, if W ¹ , W ² and W ³ are N, for the base (Base) (B), W ⁴ cannot be CH; Wherein if W ¹ is N, for bases (Base)(E), (F), (K), (L), (W) and (X), W ⁴ cannot be CH; R ⁶ are independently optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , any Optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , - CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH (lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) 2, -(CH ₂ ) _m C(O)N (lower alkyl) ₂ , -C(O )OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl) , -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ or cyano; R ⁷ are independently OH, OR ² , optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, any Optionally substituted heteroaryl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)SH, - CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O) NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -( CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O) SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH (lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N (lower alkyl) ₂ , -C (O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)SH, -C(O)SR ⁴ , -C(O)S(lower alkyl ), -C(O)NH ₂ , -C(O)NHR ⁴ , -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(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S(lower alkyl), - S (alkenyl), -S (alkynyl), -S (aralkyl), -S (cycloalkyl), NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(acyl), -N(lower alkyl) ₂ , -NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkyl), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen; Alternatively, ^R and ^R can combine to form a spiro compound, selected from: optionally substituted carbocycle or optionally substituted heterocycle; R ⁸ and R ¹¹ are independently hydrogen, optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O )OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl ), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C (O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ ,- (CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH (lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , cyano, NH-acyl or N(acyl) ₂ ; R ⁹ and R ¹⁰ are independently hydrogen, OH, OR ² , optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C( O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , (CH ₂ ) _m C(O) OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , C(O)OH, -C(O)OR ⁴ , -C(O)O (lower alkyl), -C(O)SH, -C(O)SR ⁴ , -C(O)S( lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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 (arylalkyl), -S (cycloalkyl), NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(acyl), -N(lower alkyl) ₂ , -NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkane radical), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen; m is each independently 0, 1 or 2; and Alternatively, R ⁶ and R ¹⁰ , R ⁷ and R ⁹ , R ⁸ and R ⁷ or R ⁹ and R ¹¹ can combine to form a bridged compound selected from: optionally substituted carbocycle or optionally substituted heterocycle, or , R ⁶ and R ⁷ or R ⁹ and R ¹⁰ can combine to form a spiro compound, selected from: optionally substituted carbocycle or optionally substituted heterocycle. 5. Compounds of formula (VIII), (IX) or (X):

or their pharmaceutically acceptable salts, wherein: R ¹ , R ² and R ³ are independently H, phosphate; linear, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxy Alkyl; CO-substituted aryl; Sulfonate; Benzyl, wherein phenyl is optionally substituted with one or more substituents; Alkylsulfonyl, arylsulfonyl; Aralkylsulfonyl; Lipid amino acid; amino acid residue; ^{carbohydrate ;} peptide; cholesterol ^; or other pharmaceutically acceptable leaving group, when administered in vivo, the leaving group can provide wherein compounds that are independently H or phosphate; wherein at least one of ^R2 and ^R3 is not hydrogen; and X is O, S, SO ₂ , CH ₂ , CH ₂ OH, CHF, CF ₂ , C(Y ³ ) ₂ , CHCN, C(CN) ₂ , CHR ⁴ or C(R ⁴ ) ₂ ; X ^* is CH, CF, CY ³ or CR ⁴ ; ^Y3 are independently H, F, Cl, Br or I; R and ^R are independently hydrogen, acyl, alkyl, ^lower alkyl, alkenyl, alkynyl or cycloalkyl; Base ^* (Base ^* ) is a purine or pyrimidine base; R ¹² are independently substituted alkyl, CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted alkenyl, Haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O) O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N( R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH( lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C( O)OR ⁴ , -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O) N (lower alkyl) ₂ ; R ¹³ are independently substituted alkyl, CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted alkenyl, Haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, _-CH2C (O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S (lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH (lower alkyl), -CH ₂ C (O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C( O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl ), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)SH, -C(O)SR ⁴ , -C(O)S (lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O) NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , -O(R ⁴ ), -O(alkynyl), -O(aryl Alkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S (alkynyl), -S(aralkyl), -S(cycloalkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(alkenyl), -NH(alkynyl), -NH(aryl alkyl), -NH(cycloalkyl), SCN, OCN, NCO or fluorine; Alternatively, ^R and ^R can combine to form a spiro compound selected from: optionally substituted carbocycle or optionally substituted heterocycle; and m is 0, 1 or 2 each independently. 6. Compounds of formula (XI) or (XII): or their pharmaceutically acceptable salts, wherein: ^R is H, phosphate; linear, 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 residue; carbohydrate A compound; a peptide; cholesterol; or other pharmaceutically acceptable leaving group which, when administered in vivo, provides a compound wherein ^R is H or phosphate; Base (Base) is selected from:

W ¹ , W ² , W ³ and W ⁴ are independently N, CH, CF, CI, CBr, CCl, CCN, CCH ₃ , CCF ₃ , CCH ₂ CH ₃ , CC(O)NH ₂ , CC(O )NHR ⁴ , CC(O)N(R ⁴ ) ₂ , CC(O)OH, CC(O)OR ⁴ or CX ³ ; W ^* are independently O, S, NH or NR ⁴ ; X is O, S, SO ₂ , CH ₂ , CH ₂ OH, CHF, CF ₂ , C(Y ³ ) ₂ , CHCN, C(CN) ₂ , CHR ⁴ or C(R ⁴ ) ₂ ; X ^* is CH, CF, CY ³ or CR ⁴ ; X ² is H, linear, branched or cyclic optionally substituted alkyl, CH ₃ , CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , CH ₂ OH, optionally substituted alkenyl, optionally substituted alkynyl, COOH, COOR ⁴ , COO-alkyl, COO-aryl, CO-Oalkoxyalkyl, CONH ₂ , CONHR ⁴ , CON(R ⁴ ) ₂ , chlorine, bromine, fluorine, iodine, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ; X ³ are independently linear, branched or cyclic optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, N ₃ , CN, -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C (O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , OH, OR ⁴ , -O(acyl), -O(lower acyl), -O(alkyl), -O (lower alkyl), -O(alkenyl), -O(alkynyl), -O(arylalkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S(alkynyl), -S(arylalkyl), -S(cycloalkyl), chlorine, bromine, Fluorine, iodine, NH ₂ , -NH(lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(acyl), -N(lower alkyl) ₂ , -NH(alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), -N (acyl) ₂ ; Y are independently selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, ( CH ₂ ) _m CONH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR; R is H, alkyl or acyl; Y ¹ is hydrogen, bromine, chlorine, fluorine, iodine, CN, OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁴ ; Y ² are each independently O, S, NH or NR ⁴ ; and ^Y3 are independently H, F, Cl, Br or I; Wherein, if W ¹ , W ² and W ³ are N, for the base (Base) (B), W ⁴ cannot be CH; Wherein, if W ¹ is N, for bases (Base)(E), (F), (K), (L), (W) and (X), W ⁴ cannot be CH; R and ^R are independently hydrogen, acyl, alkyl, ^lower alkyl, alkenyl, alkynyl or cycloalkyl; R ¹² are independently substituted alkyl, CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted alkenyl, Haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O) O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N( R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH( lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C( O)OR ⁴ , -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O) N (lower alkyl) ₂ ; R ¹³ are independently substituted alkyl, CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , substituted alkenyl, Haloalkenyl (but not Br-vinyl), substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, _-CH2C (O)OH, -CH ₂ C(O)OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S (lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH (lower alkyl), -CH ₂ C (O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C( O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl ), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)SH, -C(O)SR ⁴ , -C(O)S (lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O) NH(lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , -O(R ⁴ ), -O(alkynyl), -O(aryl Alkyl), -O(cycloalkyl), -S(acyl), -S(lower acyl), -S(R ⁴ ), -S(lower alkyl), -S(alkenyl), -S (alkynyl), -S(aralkyl), -S(cycloalkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(alkenyl), -NH(alkynyl), -NH(aryl alkyl), -NH(cycloalkyl), SCN, OCN, NCO or fluorine; and Alternatively, R ¹² and R ¹³ can combine to form a spiro compound, selected from: optionally substituted carbocycle or optionally substituted heterocycle; R ⁸ and R ¹¹ are independently hydrogen, optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, -CH ₂ C(O)OH, -CH ₂ C(O )OR ⁴ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl ), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , -(CH ₂ ) _m C(O)OH, -(CH ₂ ) _m C (O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ ,- (CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , -C(O)OH, -C(O)OR ⁴ , -C(O)O(lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -C(O)NH (lower alkyl), -C(O)N(R ⁴ ) ₂ , -C(O)N(lower alkyl) ₂ , cyano, NH-acyl or N(acyl) ₂ ; R ⁹ and R ¹⁰ are independently hydrogen, OH, OR ² , optionally substituted alkyl, CH ₃ , CH ₂ CN, CH ₂ N ₃ , CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, haloalkyl, CF ₃ , C(Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, CH ₂ CF ₃ , CF ₂ CF ₃ , C(Y ³ ) ₂ C(Y ³ ) ₃ , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle, optionally substituted heterocycle, optionally substituted heteroaryl, -CH ₂ C(O)OH, -CH ₂ C(O)OR ₄ , -CH ₂ C(O)O(lower alkyl), -CH ₂ C( O)SH, -CH ₂ C(O)SR ⁴ , -CH ₂ C(O)S(lower alkyl), -CH ₂ C(O)NH ₂ , -CH ₂ C(O)NHR ⁴ , -CH ₂ C(O)NH(lower alkyl), -CH ₂ C(O)N(R ⁴ ) ₂ , -CH ₂ C(O)N(lower alkyl) ₂ , (CH ₂ ) _m C(O) OH, -(CH ₂ ) _m C(O)OR ⁴ , -(CH ₂ ) _m C(O)O(lower alkyl), -(CH ₂ ) _m C(O)SH, -(CH ₂ ) _m C(O)SR ⁴ , -(CH ₂ ) _m C(O)S(lower alkyl), -(CH ₂ ) _m C(O)NH ₂ , -(CH ₂ ) _m C(O)NHR ⁴ , -(CH ₂ ) _m C(O)NH(lower alkyl), -(CH ₂ ) _m C(O)N(R ⁴ ) ₂ , -(CH ₂ ) _m C(O)N(lower alkyl) ₂ , C(O)OH, -C(O)OR ⁴ , -C(O)O (lower alkyl), -C(O)SH, -C(O)SR ⁴ , -C(O)S( lower alkyl), -C(O)NH ₂ , -C(O)NHR ⁴ , -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 (arylalkyl), -S (cycloalkyl), NO ₂ , NH ₂ , -NH (lower alkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH(acyl), -N(lower alkyl) ₂ , -NH(alkenyl), -NH(alkynyl), -NH(arylalkyl), -NH(cycloalkane radical), -N(acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen; m is each independently 0, 1 or 2; and Alternatively, R ⁸ and R ¹³ , R ⁹ and R ¹³ , R ⁹ and R ¹¹ or R ¹⁰ and R ¹² can combine to form a bridged compound, selected from: optionally substituted carbocycle or optionally substituted heterocycle; or Alternatively, R ¹² and R ¹³ or R ⁹ and R ¹⁰ can combine to form a spiro compound, selected from optionally substituted carbocycle or optionally substituted heterocycle. 7. Compounds of formula (XIII) or (XIV):

or their pharmaceutically acceptable salts, wherein: ^R3 is selected from H; mono-, di-, and triphosphates or stable phosphate prodrugs; acyl groups; sulfonate esters; optionally substituted alkylsulfonyl groups; optionally substituted arylsulfonyl groups; lipids; amino acids; Carbohydrates; Peptides; Cholesterol; and a pharmaceutically acceptable leaving group that, when administered in vivo, provides a compound wherein ^R3 is independently H, or mono, di, and triphosphate ; B represents a spiro compound, selected from optionally substituted carbocycles or optionally substituted heterocycles; Base (Base) is selected from:

and

in R', R", R' and R'' are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ; 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- _CONH2 , or N; _Q1 and _Q2 are independently N or CR; R is H, alkyl or acyl; and _Q3 , _Q4 , _Q5 and _Q6 are independently N or CH. 8. Compounds of formula (XIX), (XX), (XXI) (XXII) or (XXIII): or their pharmaceutically acceptable salts, wherein: A is selected from optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR; Y is selected from H, optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F , CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ , and (CH ₂ ) _m CONHR; R is H, alkyl or acyl; X is selected from -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, NO ₂ , NH ₂ , N ₃ , NH-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, CO ₂ -alkyl, CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl, CH ₂ OH, CH ₂ NH ₂ , CH ₂ NHCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ F, CH ₂ Cl, CH ₂ N ₃ , CH ₂ CN, CH ₂ CF ₃ , CF ₃ , CF ₂ CF ₃ , CH ₂ CO ₂ R, (CH ₂ ) _m COOH, (CH ₂ ) _m COOR, (CH ₂ ) _m CO-NH ₂ , (CH ₂ ) _m CONR ₂ , (CH ₂ ) _m CONHR, optionally substituted 3-7 membered carbocyclic rings, and optionally substituted 3-7 membered carbocycles having O, S and/or N independently or in combination as heteroatoms Heterocycle; m is 0 or 1; _R3 is selected from H; mono-, di-, and triphosphates or stable phosphate prodrugs; substituted or unsubstituted alkyl; acyl; sulfonate; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipids; amino acids; carbohydrates; _peptides ; cholesterol; Mono, di, and triphosphate compounds; and Base (Base) is an unnatural base selected from:

in: R', R", R' and R'' are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ring Alkyl, Br-vinyl, -O-alkyl, O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, O-cycloalkyl, NH ₂ , NH-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 , CO ₂ -Alkyl, CONH-Alkyl, CON-Dialkyl, OH, CF ₃ , CH ₂ OH , (CH ₂ ) _m OH, (CH ₂ ) _m NH ₂ , (CH ₂ ) _m COOH, (CH ₂ ) _m CN, (CH ₂ ) _m NO ₂ and (CH ₂ ) _m CONH ₂ ; 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- _CONH2 , or N; Q ₁ and Q ₂ are independently N or CR'; and Q ₃ , Q ₄ , Q ₅ and Q ₆ are independently N or CH; The provisos are: in bases (g) and (i), R', R _' '' are not H, OH, or NH2; and Q, T, V, _Q2 , _Q5 and _Q6 are not N. 9. Compounds of formula (IX):

or a pharmaceutically acceptable salt thereof, wherein: R ¹ , R ² and R ³ are independently H, phosphate; linear, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl; CO-aryloxy ylalkyl; CO-substituted aryl; sulfonate; benzyl, wherein the phenyl is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; lipid amino acid; amino acid residue; ^{carbohydrate ;} peptide; cholesterol ^; or other pharmaceutically acceptable leaving group, when administered in vivo, the leaving group can provide wherein compounds that are independently H or phosphate; X is O, S, _SO2 or _CH2 ; Base ^* (Base ^* ) is a purine or pyrimidine base; R ¹² is C(Y ³ ) ₃ ; ^Y3 is independently H, F, Cl, Br or I; and R ¹³ is fluoro. 10. The compound of claim 9, wherein X is O and ^Y3 is H. 11. The compound of claim 10, wherein ^R1 , ^R2 and ^R3 are H. 12. A method of treating a host infected with a Flaviviridae virus, comprising administering an effective amount of a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof. 13. The method of claim 12, wherein said virus is hepatitis C virus. 14. The method of claim 12, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination or alternately with another antiviral agent. 15. The method of claim 14, wherein said another antiviral agent is selected from the group consisting of: interferon, ribavirin, interleukin, NS3 protease inhibitor, cysteine protease inhibitor, phenanthrenequinone, thiazolidine Derivatives, thiazolidine, N-benzanilide, phenanthrenequinone, helicase inhibitors, polymerase inhibitors, nucleotide analogs, gliotoxin, cerulenin, antisense phosphorothioate oligomer Deoxynucleotides, inhibitors of IRES-dependent translation and ribozymes. 16. The method of claim 15, wherein said another antiviral agent is interferon. 17. The method of claim 16, wherein the other antiviral agent is selected from the group consisting of: pegylated alpha-2a interferon, alphacon-1 interferon, native interferon, albuferon, beta-1a interferon, omega-interferon interferon, alpha-interferon, gamma-interferon, tau-interferon, delta-interferon and gamma-1b interferon. 18. The method of claim 12, wherein said compound, or a pharmaceutically acceptable salt thereof, is in dosage unit form. 19. The method of claim 18, wherein said dosage unit contains 50-1000 mg or 0.1-50 mg of said compound. 20. The method of claim 18, wherein the dosage unit is a tablet or capsule. 21. The method of claim 12, wherein the host is a human. 22. The method of claim 12, wherein said compound, or a pharmaceutically acceptable salt thereof, is in substantially pure form. 23. The method of claim 12, wherein said compound, or a pharmaceutically acceptable salt thereof, is at least 90% by weight of the beta-D-isomer. 24. The method of claim 12, wherein said compound, or a pharmaceutically acceptable salt thereof, is at least 95% by weight of the beta-D-isomer. 25. The method of claim 12, wherein said compound is in the form of a pharmaceutically acceptable salt selected from the group consisting of: besylate, mesylate, acetate, citrate, malonate, tartrate, succinate Salt, Benzoate, Sodium Vitamin C, α-Ketoglutarate, α-Glycerophosphate, Formate, Fumarate, Propionate, Glycolate, Lactate, Pyruvate, Oxalate , maleate, salicylate, sulfate, nitrate, bicarbonate, carbonate, hydrobromide, hydrochloride, dihydrochloride and orthophosphate. 26. The method of claim 25, wherein said pharmaceutically acceptable salt is the hydrochloride. 27. A pharmaceutical composition, comprising the compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein, the content of the compound is an effective amount that can treat infection of the Flaviviridae virus, and the compound is included in the pharmaceutically acceptable in the carrier. 28. The pharmaceutical composition of claim 27, wherein the carrier is suitable for oral administration. 29. The pharmaceutical composition of claim 27, comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition is capable of treating a host infected with West Nile virus, yellow fever virus, dengue virus or BVDV. 30. The composition of claim 27, wherein the Flaviviridae virus is hepatitis C virus. 31. The pharmaceutical composition of claim 29, wherein said compound, or a pharmaceutically acceptable salt thereof, is in dosage unit form. 32. The composition of claim 31, wherein said dosage unit contains 0.1-50 mg or 50-1000 mg of said compound or a pharmaceutically acceptable salt thereof. 33. The composition of claim 31, wherein said dosage unit is a tablet or capsule. 34. The pharmaceutical composition of claim 27, further comprising a second antiviral agent. 35. The pharmaceutical composition of claim 34, wherein said another antiviral agent is selected from the group consisting of interferon, ribavirin, interleukin, NS3 protease inhibitor, cysteine protease inhibitor, phenanthrenequinone, Thiazolidine derivatives, thiazolidine, N-benzoanilide, phenanthrenequinone, helicase inhibitors, polymerase inhibitors, nucleotide analogs, gliotoxin, cerulenin, antisense phosphorothioate Oligodeoxynucleotides, inhibitors of IRES-dependent translation and ribozymes. 36. The pharmaceutical composition of claim 35, wherein the other antiviral agent is interferon. 37. The pharmaceutical composition of claim 36, wherein the other antiviral agent is selected from the group consisting of: pegylated alpha-2a interferon, alphacon-1 interferon, native interferon, albuferon, beta-1a interferon, omega - Interferon, alpha-interferon, gamma-interferon, tau-interferon, delta-interferon and gamma-1b interferon. 38. The pharmaceutical composition of claim 27, wherein said compound, or a pharmaceutically acceptable salt thereof, is in substantially pure form. 39. The pharmaceutical composition of claim 27, wherein at least 90% by weight of said compound or a pharmaceutically acceptable salt thereof is the beta-D-isomer. 40. The pharmaceutical composition of claim 27, wherein at least 95% by weight of said compound or a pharmaceutically acceptable salt thereof is the beta-D-isomer. 41. The pharmaceutical composition of claim 27, further comprising a pharmaceutically acceptable carrier suitable for oral, parenteral, inhalation or intravenous administration. 42. The pharmaceutical composition of claim 27, wherein said pharmaceutically acceptable salt is selected from the group consisting of: besylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, Benzoate, Sodium Vitamin C, Alpha-Ketoglutarate, Alpha-Glyceryl Phosphate, Formate, Fumarate, Propionate, Glycolate, Lactate, Pyruvate, Oxalate, Malate salts, salicylates, sulfates, nitrates, bicarbonates, carbonates, hydrobromides, hydrochlorides, dihydrochlorides and orthophosphates. 43. The pharmaceutical composition of claim 42, wherein said pharmaceutically acceptable salt is the hydrochloride. 44. A compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for use in the treatment of a host infected with a Flaviviridae virus. 45. The compound of claim 44, wherein said virus is hepatitis C virus. 46. The compound of claim 44, wherein said host is a human. 47. Use of a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a host infected with a Flaviviridae virus. 48. The use of claim 44, wherein the virus is hepatitis C virus. 49. The use of claim 44, wherein said host is a human.

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