RU2437892C2 - Modified 2- and 3-nucleosides and use thereof to produce medicinal agent, having hepatitis c inhibiting activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

or pharmaceutically acceptable salts thereof, having hepatitis C inhibiting activity, pharmaceutical composition based on said compounds and use thereof to produce a medicinal agent. In compounds of formula (IX) R¹ and R² independently denote H, phosphate or acyl; X denotes O; the base* is a purine base; R¹² denotes C(Y³)₃; Y³ denotes H and R¹³ denotes fluorine.

EFFECT: improved properties of the compound.

30 cl, 4 dwg, 26 ex

Description

Cross reference to related applications

This application claims priority for provisional application for US patent No. 60/392350, filed June 28, 2002, provisional application for US patent No. 60/466194, filed April 28, 2003, and provisional application for US patent No. 60/470949, filed May 14 2003, the contents of each of which are incorporated herein by reference.

Field of Invention

This invention relates to the field of pharmaceutical chemistry, in particular to a 2'-and / or 3'-prodrug of 6-modified 1 ', 2', 3 'or 4'-branched pyrimidine nucleoside or 8-modified 1', 2 ', 3 'or 4'-branched purine nucleoside, intended for the treatment of infections of Flaviviridae, such as viral infection of hepatitis C.

BACKGROUND OF THE INVENTION

Flaviviridae viruses

The Flaviviridae family of viruses contains at least three distinct genera: pestiviruses that cause disease in cattle and pigs; flaviviruses, which are the main cause of diseases such as dengue and yellow fever, and hepativiruses, the only member of which is HCV (hepatitis C virus). The genus of flaviviruses includes more than 68 members, divided into groups based on serological kinship (Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical symptoms vary and include fever, encephalitis, and hemorrhagic fever (Fields Virology, Editors: Fields, BN, Knipe, DM, and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA, 1996, Chapter 31, 931-959) . Flaviviruses of global importance that are associated with human disease include dengue hemorrhagic viruses (DHF), yellow fever virus, shock syndrome and Japanese encephalitis virus (Halstead, SB, Rev. Infect. Dis., 1984, 6, 251-264 ; Halstead, SB, Science, 239: 476-481, 1988; Monath, TP, New Eng. J. Med., 1988, 319, 641-643).

The pestivirus genus includes bovine viral diarrhea virus (BVDV), classic swine fever virus (CSFV, also called swine cholera virus), and sheep border disease virus (BDV) (Moennig, V. et al. Adv. Vir. Res. 1992, 41.53-98). Pestivirus infections of domesticated animals (cattle, pigs and sheep) are causing significant economic losses worldwide. BVDV causes mucosal disease in cattle and has significant economic value in 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 as extensively characterized as animal pestiviruses. However, serological studies indicate a significant human exposure to pestiviruses.

Pestiviruses and hepaciviruses are closely related virus groups in the Flaviviridae family. Other closely related viruses in this family include GB virus A, agents like GB virus A, GB virus B and GB virus C (also called hepatitis G virus, HGV). The hepatitis virus group (hepatitis C virus; HCV) consists of a number of closely related, but genotypically different viruses that infect humans. There are approximately 6 HCV genotypes and more than 50 subtypes. Due to the similarities between pestiviruses and hepatitis viruses, combined with the weak ability of hepatitis viruses to grow efficiently in cell culture, bovine viral diarrhea virus (BVDV) is often used as a substitute for studying the HCV virus.

The genetic organization of pestiviruses and hepativiruses is very similar. These RNA positive RNA viruses have the only large open reading frame (ORF) encoding all viral proteins necessary for viral replication. These proteins are expressed as a polyprotein, which is co- and post-translationally processed by both cellular and virus-encoded proteinases, with the formation of mature viral proteins. The viral proteins responsible for the replication of the viral RNA genome are located approximately at the carboxy-terminal position. Two-thirds of ORFs are called non-structural (NS) proteins. The genetic organization and polyprotein processing of the non-structural protein part of ORF for pestiviruses and hepativiruses are very similar. For both pestiviruses and hepatitis viruses, mature non-structural (NS) proteins in sequential order from the amino-terminal group of the non-structural protein coding region to the carboxy-terminal ORF group consist of p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B.

The NS proteins of pestiviruses and hepativiruses together have sequence domains that are characteristic of specific protein functions. For example, the NS3 proteins of viruses in both groups have amino acid sequence motifs characteristic of serine proteinases and helicase (Gorbalenya et al. (1988) Nature 333: 32; Bazan and Fletterick (1989) Virology 171: 637-639; Gorbalenya et al. (1989 ) Nuckeic Acid Res. 17.3889-3897). Similarly, the NS5B proteins of pestiviruses and hepativiruses have motifs characteristic of RNA-driven RNA polymerases (Koonin, E.V. and Dolja, V.V. (1993) Crit. Rev. Biochim. Molec. Biol. 28: 375-430).

The actual roles and functions of the NS proteins of pestiviruses and hepativiruses in the life cycle of viruses are directly similar. In both cases, NS3 serine protease is responsible for the entire proteolytic processing of polyprotein precursors to the right of its position in the ORF (Wiskerchen and Collett (1991) Virology 184: 341-350; Bartenschlager et al. (1993) J. Virol. 67: 3835-3844; Eckart et al. (1993) Biochem. Biophys. Res. Comm. 192: 399-406; Grakoui et al. (1993) J. Virol. 67: 2832-2843; Grakoui et al. (1993) Proc. Natl. Acad Sci. USA 90: 10583-10587; Hijikata et al. (1993) J. Virol. 67: 4665-4675; Tome et al. (1993) J. Virol. 67: 4017-4026). The NS4F protein in both cases acts as a cofactor with 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 protein of both viruses also acts as a 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, NS5B proteins of pestiviruses and hepativiruses have the predicted activities of RNA-driven RNA polymerases (Behrens et al. (1996) EMBO J. 15: 12-22; Lchmannet 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. (1988) J. Virol. 72.9365-9369).

Hepatitis C virus

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J. Hepatol. 32: 98-112, 2000). HCV causes a slowly developing viral infection and is the main cause of cirrhosis and hepatocytic carcinoma (Di Besceglie, AM and Bacon, BR, Scientific American, Oct .: 80-85, (1999); Boyer, N. et al. J. Hepatol. 32 : 98-112, 2000). It is estimated that 170 million people are infected with HCV worldwide (Boyer, N. et al. J. Hepatol. 32: 98-112, 2000). Cirrhosis caused by chronic hepatitis C infection causes 8,000-12,000 deaths per year in the United States, and HCV infection is a major indicator for liver transplantation.

HCV is known to cause at least 80% of post-transfusion hepatitis and a significant portion of random acute hepatitis. Preliminary evidence also suggests the involvement of HCV in many cases of “idiopathic” chronic hepatitis, “cryptogenic” cirrhosis, and probably hepatocellular carcinoma unrelated to other hepatitis viruses, such as hepatitis B virus (HBV). It turned out that a small part of healthy people are chronic carriers of HCV, and this part varies depending on geographic location and other epidemiological factors. Their number may substantially exceed the number of patients with HBV, although the information is still preliminary; how many of these individuals have subclinical chronic liver disease is unclear (The Merck Manual. ch. 69, p. 901, 16 ^th ed., (1992)).

HCV is an enveloped virus containing a gene of positive sense single-stranded RNA with approximately 9.4 kb. The viral genome consists of a 5'-untranslated region (UTR), a long open reading frame encoding a polyprotein precursor with approximately 3011 amino acids, and a short 3'-UTR. 5'-UTR is the most conserved part of the HCV genome and is important for the initiation and regulation of polyprotein translation. The translation of the HCV genome is initiated by a cap-independent mechanism known as the internal ribosome entry. This mechanism involves the binding of ribosomes to an RNA sequence known as the internal ribosome entry site (IRES). Recently it was found that the structure of the pseudo-RNA is an essential structural element of IRES HCV. Viral structural proteins include nucleocapsid cow protein (C) and two envelope glycoproteins, E1 and E2. HCV also encodes two proteinases, a zinc-dependent metalloproteinase encoded in the NS2-NS3 region, and a serine protease encoded in the NS3 region. These proteinases are required to cleave specific regions of the precursor polyprotein to form mature peptides. The carboxyl half of non-structural protein 5, NS5B, contains an RNA-dependent RNA polymerase. The function of the remaining non-structural proteins, NS4A and NS4B, and the function of NS5A (amino-terminal half of non-structural protein 5) remain unknown.

A significant part of modern antiviral research focuses on the development of improved treatments for chronic HCV infections in humans (Di Besceglie, 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 almost a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit the replication of a number of viruses, including HCV, and when used as the only treatment for hepatitis C infections, IFNs can in some cases suppress serum HCV-RNA to levels that are not measurable. In addition, IFN can normalize serum aminotransferase levels. Unfortunately, the effect of IFN is temporary, and a prolonged reaction occurs only in 8% -9% of patients chronically infected with HCV (Gary L. Davis. Gastroenterology 118: S104-S114, 2000). In most patients, however, treatment with interferon is difficult to tolerate; it causes severe, flu-like symptoms, weight loss, and a decline in energy and vitality.

Several patents describe the treatment of Flaviviridae, including HCV, using consensus interferon-based therapies. For example, US Pat. No. 5,980,884, Blatt et al., Describes methods for re-treating patients affected by HCV using interferon consistency. US Pat. No. 5,942,223 to Bazer et al. Describes anti-HCV therapy using sheep or bovine interferon-tau. In US patent No. 5928636, Alber et al., Describes the combination therapy of interleukin-12 and interferon alfa for the treatment of infectious diseases, including those caused by HCV. US Pat. No. 5,849,696 to Chretien et al. Describes the use of thymosin, alone or in combination with interferon, for treating HCV infection. US Pat. No. 5,830,455 to Valtuena et al. Describes combination therapy for treating HCV infection using interferon and a free radical scavenger. US Pat. No. 5,738,845 to Imakawa describes the use of proteins, human interferon tau, for treating HCV infection. Other methods of treating interferon-based HCV infection are described in US Pat. No. 5676942, Testa et al., US Pat. No. 5,372,808, Blatt et al., And US Pat. No. 5,849,696. A number of patents also describe pegylated forms of interferon, for example, US Pat. 5747646, 5792834 and 5834594, Hoffmann-La Roche Inc .; PCT Publication No. WO 99/32139 and WO 99/32140, Enzon; WO 95/13090 and US Pat. Nos. 5738846 and 5711944, Shering, and US Patent No. 5908621, Glue et al.

Interferon alfa-2a and interferon alfa-2b are currently approved as monotherapy for the treatment of HCV infection. Roferon® (Roche) is a recombinant form of interferon alpha-2a. Pegasys® (Roche) is a pegylated (i.e. modified with polyethylene glycol) form of interferon alpha-2a. Intron® A (Schering Corporation) is a recombinant form of interferon alpha-2b and PEG-Intron® (Schering Corporation) is a pegylated form of interferon alpha-2b.

Other forms of interferon alfa, as well as interferon beta, gamma, tau and omega are currently in clinical development for the treatment of HCV infection. For example, infergen (interferon alfacon-1), developed by InterMune, omniferon (natural interferon), developed by Viragen, albuferon, developed by Human Genome Sciences, rebif (interferon beta-1a), developed by Ares-Serono, omega interferon, are being developed BioMedicine, oral interferon alpha, developed by Amarillo Biosciences, and interferon gamma, interferon tau and interferon gamma-1b, developed by InterMune.

Ribavirin

Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is a synthetic, non-inducing interferon, an antiviral nucleoside analogue wide spectrum of action, sold under the trade name Virazole (The Merck Index, 11 ^th edition , Editor: Budavari, S., Merck & Co., Inc., Rahway, NJ, p. 1304, 1989). Ribavirin is described and claimed in United States Patent No. 3,798,209 and RE 29835. Ribavirin is structurally similar to guanosine and has in vitro activity against several 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 HCV-RNA levels (Gary L. Davis. Gastroenterology 118: S104-S114, 2000). Thus, single ribavirin is not effective in lowering viral RNA levels. In addition, ribavirin has significant toxicity and is known to cause anemia.

Ribavirin is not approved for monotherapy against HCV. It is approved in combination with interferon alfa-2a or interferon alfa-2b for the treatment of HCV infection.

The combination of interferon and ribavirin

Combination therapy with alpha interferon and ribavirin is the current standard for the treatment of chronic hepatitis C. The combination of interferon and ribavirin for treating HCV infection has been described as effective in treating patients not treated with interferon (Battaglia, AM et al., Ann. Pharmacother. 34: 487-494, 2000), as well as for treating patients when available histological disease (Berenguer, M. et al. Antivir. Ther. 3 (Suppl. 3): 125-136, 1998). Studies have shown that more patients with hepatitis C are susceptible to combination therapy with pegylated interferon-alpha / ribavirin than to combination therapy with un-pegylated interferon alfa. However, as with monotherapy, significant side effects develop during combination therapy, including hemolysis, flu-like symptoms, anemia, and fatigue (Gary L. Davis. Gastroenterology 118: S104-S114, 2000).

For combination therapy with PEG-Intron® (peginterferon alfa-2b) and Ribetol® (Ribavirin, USP), capsules are available from Schering Corporation. Ribetol® (Schering Corporation) was also approved in combination with Intron® A (interferon alfa-2b, recombinant, Schering Corporation). Pegasys® (pegylated interferon alfa-2a) from Roche and Kopegus® (ribavirin) are also approved for the treatment of HCV infection.

PCT Publication Nos. WO 99/59621, WO 00/37110, WO 01/81359, WO 02/32414 and WO 03/024461, Shering Corporation, describe the use of combination therapy with pegylated interferon alfa and ribavirin for treating HCV infection. PCT Publication Nos. WO 99/15194, WO 99/64016 and WO 00/24355, Hoffmann-La Roche Inc., also describe the use of pegylated interferon alfa and ribavirin in combination therapy for treating HCV infection.

Additional Treatments for Flaviviridae Infections

New antiviral agents are currently being developed for Flaviviridae infections, especially hepatitis C. Specific inhibitors of HCV-derived enzymes, such as protease, helicase and polymerase inhibitors, are being developed. Drugs are also being developed that inhibit other stages of HCV replication, for example, 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 the entry of HCV into cells (by blocking its receptor), and nonspecific cytoprotective agents that block cell damage caused by a viral infection. In addition, molecular approaches are also being developed for the treatment of hepatitis C, for example, ribozymes, which are enzymes that destroy specific viral RNA molecules, and antisense oligonucleotides, which are small complementary DNA segments that bind to viral RNA and inhibit viral replication, are being investigated. Several treatments for HCV infection are indicated in a review by Bymock et al. Antiviral Chemistry & Chemotherapy, 11: 2; 79-95 (2000) and De Francesco et al. in Antiviral Research, 58: 1-16 (2003).

Examples of classes of drugs that are being developed for the treatment of Flaviviridae infections include:

(1) Protease Inhibitors

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 Pub. DE 19914474; Tung et al. Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease, PCT WO 98/17679), including alpha-ketoamides and hydrazine ureas, and inhibitors, which have an electrophile in the end position, such as boronic acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor peptide tests, PCT WO 99/07734).

Non-substrate-based NS3 protease inhibitors, such as 2,4,6-trihydroxy-3-nitrobenzamide 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 being substituted on the amide with a chain of 14 carbon atoms and the latter having a para-phenoxyphenyl group.

Sch 68631, phenanthrenquinone, is an HCV protease inhibitor (Chu M. et al., Tetrahedron Letters 37: 7229-7232, 1996). In another example, Sch 351633, isolated from Penicillium griseofulvum fungi, was identified as a protease inhibitor by the same authors (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9: 1949-1952). Nanomolar activity against the HCV NS3 protease enzyme was achieved by the development of selective inhibitors based on macromolecular eglin c. Eglin c isolated from leeches is a potent inhibitor of several serine proteases, such as S. griseus proteases A and B, α-chymotrypsin, chymase and subtilisin. Qasim M.A. et al., Biochemistry 36: 1598-1607, 1997.

Several US patents describe protease inhibitors for treating HCV infection. US Pat. No. 6,004,933 to Spruce et al. Describes a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2. US Pat. No. 5,990,276, Zhang et al., Describes synthetic NS3 protease inhibitors of hepatitis C. The inhibitor is the sequence of an NS3 protease substrate or an NS4A cofactor substrate. The use of restriction enzymes for the treatment of HCV infection is described in US Pat. No. 5,538,865 to Reyes at al. Peptides as inhibitors of HCV NS3 serine protease are described in WO 02/008251, Corvas International, Inc., and WO 02/08187 and WO 02/008256, Schering Corporation. Tripeptide HCV inhibitors are described in US patent No. 6534523, 6410531 and 6420380, Boehringer Ingelheim, and WO 02/060926, Bristol Myers Squibb. Diaryl peptides as inhibitors of HCV NS3 serine protease are described in WO 02/48172, Schering Corporation. Imidazolinedinones as HCV NS3 serine protease inhibitors are described in WO 02/08198, Schering Corporation, and WO 02/48157, Bristol Myers Squibb. WO 98/17679, Vertex Pharmaceuticals, and WO 02/48116, Bristol Myers Squibb, also disclose HCV protease inhibitors.

(2) Thiazolidine derivatives that exhibit acceptable inhibition in reverse phase HPLC analysis with NS3 / 4A fusion protein and NS5A / 5B substrate (Sudo K. et al., Antiviral Research, 1996, 32, 9-18), especially compound RD -1-6250 having a condensed cinnamoyl moiety substituted with a long alkyl chain, RD4 6205 and RD4 6193.

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

(4) Phenantrenquinone possessing anti-protease activity in SDS-PAGE and autoradiographic analysis isolated from fermentation culture broth Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and Sch 351633 isolated from Penucillium griseofulvum fungi that demonstrate activity in scintillation approximation analysis (Chu M. et al., Bioorganic and Medicinal Chemistry Letters, 9, 1949-1952).

(5) Helicase inhibitors (e.g., Diana GD et al, Compounds, compositions and methods for treatment of hepatitis C, US Pat. No. 5,633,358; Diana GD et al., Piperidine derivatives, pharmaceutical compositions and and their use in the treatment of hepatitis C, PCT WO 97/36554).

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

(7) Antisense phosphorothioate oligodeoxynucleotides (S-ODNs) complementary to sequence regions in the 5'-non-coding region (NRC) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717), or nucleotides 326-348, containing the 3'-end of NCR, and nucleotides 371-388 located in the core coding region of HCV RNA (Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal of Cellular Physiology, 1999, 181, 251-257).

(8) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Publication, JP -10101591).

(9) Ribozymes, such as nuclease-resistant ribozymes (Maccjak, DJ et al., Hepatology, 1999, 30, abstract 995), and ribozymes described in US Pat. No. 6,043,077, Barber et al., And US Pat. No. 5,869,253 and 5610054, Draper et al.

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

Idenix Pharmaceutical describes the use of branched nucleosides in the treatment of flaviviruses (including HCV) and pestiviruses in International Patent Publication Nos. WO 01/90121 and WO 01/92282. Specifically, a method for treating hepatitis C infection (and flaviviruses and pestiviruses) in humans and other host animals is described in Idenix publications, which include administering an effective amount of biologically active 1 ', 2', 3 'or 4'-branched β-D - or β-L-nucleosides or their pharmaceutically acceptable salts or derivatives, administered either singly or in combination with another antiviral agent, optionally in a pharmaceutically acceptable carrier.

Other patent applications describing the use of certain nucleoside analogues for the treatment of hepatitis C virus infection include PCT / CA00 / 01316 (WO 01/32153, filed November 3, 2000) and PCT / CA01 / 00197 (WO 01/60315, filed 19 February 2001), filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT / US02 / 01531 (WO 02/057424, filed January 18, 2002) and PCT / US02 / 03086 (WO 02/057287; filed January 18, 2002), filed by Merck & Co., Inc., PCT / EP01 / 09633 (WO 02/18404; published August 21, 2001) filed by Roche and PCT Publication No. WO 01/79246 (filed April 13, 2001), WO 02/32920 (filed October 18, 2001) and WO 02/48165, Pharmasset, Ltd.

PCT Publication No. WO 99/43691, Emory University, entitled "2'-fluoronucleosides," describes the use of certain 2'-fluoronucleosides for treating HCV infection.

Eldrup et al. (Oral Session V. Hepatitis C Virus, Flaviviridae;. 16 ^th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga)) describe bond structures 2'-modified nucleosides with an activity for inhibiting HCV.

Bhat et al. (Orall Session V. Hepatitis C Virus, Flaviviridae, (Oral Session V, Hepatitis C Virus, Flaviviridae; 16 ^th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga.) P.A75) described the synthesis and pharmacokinetic properties of analogues nucleosides as possible inhibitors of HCV RNA replicas The authors indicated that 2'-modified nucleosides show strong inhibitory activity in cell-based replicon assays.

Olsen et al. (Orall Session V. Hepatitis C Virus, Flaviviridae;. 16 ^th International Conference on Antiviral Research (April 27, 2003, Savannah, Ga) p.A76) have also described the effect of 2'-modified nucleosides on HCV RNA replication.

(11) Other diverse compounds, including 1-aminoalkylcyclohexanes (US Pat. No. 6,034,134, Gold et al.), Alkyl lipids (US Pat. No. 5,922,757, Chojkier et al.), Vitamin E and other antioxidants (US Pat. No. 5,992,757, Chojkier et al. .), squalene, amantadine, bile acids (US patent No. 5846964, Ozeki et al.), N- (phosphonoacetyl) -L-aspartic acid (US patent No. 5830905, Diana et al.), benzenedicarboxamides (US patent No. 5633388, Diana et al.), Derivatives of polyadenyl acid (US patent No. 5496546, Wang et al.), 2 ', 3'-dideoxyinosine (US patent No. 5026687, Yarchoan et al.), Benzimidazoles (US patent No. 5891874, Colacino et al .) extracts plants (US patent No. 5837257, Tsai et al, US patent No. 5725869, Omer et al, and US patent No. 6056961) and piperidines (US patent No. 5830905, Diana et al.).

(12) Other compounds currently undergoing preclinical or clinical development for treatment for hepatitis C virus virus include: Schering-Plow interleukin-10, Interneuron IP-501, Vertex Merimebodib (VX-497), amantadine® (Symmetrel) from Endo Labs Solvay, heptazim® from RPI, IDN-6556 from Idun Pharma., XTL-002 from XTL., HCV / MF59 from Chiron, civacir® (hepatitis C immune globulin) from NABI, levovirin® from ICN / Ribapharm, Viramidine® from ICN / Ribapharm, Zadaxin® (thymosin alpha-1) from Sci Clone, thymosin plus pegylated interferon from Sci Clone, Ceplen® (hist dihydrochloride foreign) company Maxim, VX 950 / LY 570310 company Vertex / Eli Lilly, ISIS 14803 company Isis Pharmaceutical / Elan, IDN-6556 company Idun Pharmaceuticals, Inc., JTK 003 company AKROS Pharma, BILN-2061 company Boehringer Ingelheim, CellCept (mycophenolate mofetil) from Roche, T67, Tularik β-tubulin inhibitor, therapeutic vaccine directed to E2 from Innogenetics, FK788 from Fujisawa Healthcare, Inc., IdB 1016 (silifos, oral silybin-phosphatidylcholine phytosome), RNA replication inhibitors (VP50406) from ViroPharma / Wyeth, Intercell therapeutic vaccine, Epimmune / Genencor therapeutic vaccine, Anadys IRES inhibitor, ANA 245 and Anadys ANA 246, immunotherapy (therapist) firm s Avant, Corvas / Schering protease inhibitor, Vertex helicase inhibitor, Trimeris fusion inhibitor, CellExSys T cell therapy, Biocryst polymerase inhibitor, chemical compounds targeting RNA from PTC Therapeutics, dication of Immtech, Int. , Agouron protease inhibitor, Chiron / Medivir protease inhibitor, AVI BioPharma antisense therapy, Hybridon antisense therapy, Aethlon Medical hemopurifiable, Merix therapeutic vaccine, Bristol-Myers Squibb / Axys protease inhibitor, ChronVacC, Tripe therapeutic vaccine , UT 231B from United Therap eutics, protease, helicase and polymerase inhibitors from Genelabs Technologies, IRES inhibitors from Immusol, R803 from Rigel Pharmaceuticals, infergen® (interferon alfacon-1) from InterMune, omniferon (natural interferon) from Viragen, albuferon® from Human Genome Sciences, rebif® (interferon beta-1a) from Ares-Serono, omega interferon from BioMedicine, oral interferon alpha from Amarillo Biosciences, interferon gamma, interferon tau and interferon gamma-1b from InterMune.

Nucleoside prodrugs have previously been described for the treatment of other forms of hepatitis. In WO 00/09531 (filed August 10, 1999) and WO 01/96353 (filed June 15, 2001), Idenix Pharmaceuticals, discloses 2'-deoxy-β-L-nucleosides and their 3'-prodrugs for treating HCV infection. US Pat. No. 4,957,924 to Beauchamp describes various therapeutic acyclovir esters.

In light of the fact that HCV infection has reached epidemic levels worldwide and is causing tragic consequences for an infected patient, there remains an urgent need to provide new effective pharmaceutical agents for the treatment of hepatitis C, which would have low toxicity to the host.

In addition, with the growing threat of other flaviviridae infections, there remains an urgent need to provide new effective pharmaceutical agents that would have low toxicity to the host.

Thus, it is an object of the present invention to provide a compound, method and composition for treating a hepatitis C virus infected host.

Another objective of the present invention is to provide a method and composition suitable for treating patients infected with pestiviruses, flaviviruses or hepatitis viruses.

SUMMARY 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 preparations containing these compounds can be used for prevention and treatment of Flaviviridae infections and other related conditions, such as antibody-positive conditions against Flaviviridae and Flaviviridae-positive conditions, chronic liver inflammation caused by HCV, cirrhosis, acute hepatitis, transient hepatitis, chronic persistent hepatitis, and overwork. These compounds or preparations can also be used prophylactically to prevent or slow the development of a clinical disorder in patients who have antibodies against Flaviviridae, or who have a positive reaction to Flaviviridae antigen, or who have been exposed to Flaviviridae.

A method is also described for treating a Flaviviridae virus infection in a host, including a human, which comprises administering an effective amount of a 2'- or 3'-prodrug of a biologically active 1 ', 2', 3 'or 4'-branched β-D- or a β-L-nucleoside or a pharmaceutically acceptable salt thereof, administered either singly or in combination or sequentially with another anti-Flaviviridae agent, optionally in a pharmaceutically acceptable carrier. The term 2′-prodrug, as used herein, refers to a 1 ′, 2 ′, 3 ′, or 4′-branched β-D or β-L nucleoside that has a biologically cleavable moiety at the 2'-position, including but not limited to acyl and, 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 that has a biologically cleavable portion at the 3 ′ position, including but not limited to acyl and, 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, α-ketoglutarate and α-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, salicylate sulfonate, nitrate, bicarbonate, hydrobromate, hydrobromide, hydroiodide, carbonate and salts of phosphoric acid. A particularly preferred embodiment is a mono- or dihydrochloride salt.

In one embodiment, the 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleoside includes biologically cleavable residues at the 2 ′ and / or 5 ′ positions. Preferred residues are esters of natural or synthetic D- or L-amino acids, including D- or L-valyl, more preferred are esters of L-amino acids, such as L-valyl, and alkyl esters, including acetyl. Thus, the present invention, in particular, includes a 2'-ester of D- or -L-amino acids and 2 ', 5'-ester of D- or -L-diamino acids, preferably an ester of L-amino acids, 1', 2 ', 3' or 4'-branched β-D- or β-L-nucleosides with any desired purine or pyrimidine base, where the parent drug optionally has an EC _{50 of} less than 15 micromoles and, even more preferably, less than 10 micromoles; 2 '- (alkyl or aryl) ether or 2', 5'-di (alkyl or aryl) ether 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleosides with any desired purine or a pyrimidine base, where the parent drug optionally has an EC _{50 of} less than 10 or 15 micromoles, and 2 ', 5'-diesters 1', 2 ', 3' or 4'-branched β-D- or β-L- prodrugs nucleosides, where (i) the 2'-ester is an ester of a natural or synthetic D- or L-amino acid, more preferably an L-amino acid ester, the 5'-ester is an alkyl or aryl ester; (ii) both esters are, independently, natural or synthetic D- or L-amino acid esters, more preferably both are L-amino acid esters; (iii) both esters are independently alkyl or aryl ethers and (iv) 2'-ether is independently alkyl or aryl ether and 5'-ether is a natural or synthetic D- or L-amino acid ester, more preferably an L-amino acid ester, where the parent drug optionally has an EC _{50 of} less than 10 or 15 micromoles.

Examples of prodrugs falling within the scope of the invention are β-D-2 ', 6-dimethylcytidine 2'-D- or L-valine ester; Β-D-2 ', 6-dimethylthymidine 2'-L-valine ester; Β-D-2 '2'-L-valine ester, 8-dimethyladenosine, β-D-2', 2'-L-valine ester, 8-dimethylguanosine; Β-D-2 ', 6-dimethyl-5-fluorocytidine 2'-L-valine ester; Β-D-2 '2-L-valine ester, 6-dimethyluridine; Β-D-2 ', 6-dimethylcytidine 2'-acetyl ester; Β-D-2 ', 6-dimethylthymidine 2'-acetyl ester; Β-D-2 '2'-acetyl ether, 8-dimethyladenosine, β-D-2', 2'-acetyl ether, 8-dimethylguanosine; Β-D-2 ', 6-dimethyl-5-fluorocytidine 2'-acetyl ester; and β-D-2 ', 6-dimethyl esters (cytidine, 5-fluorouracil, uridine or thymidine) or β-D-2', 8-dimethyl esters (guanosine, adenosine or inosine) where (i) the 2'-ester is an amino acid ester or (ii) the 2'-ester is an alkyl or aryl ester.

Further examples of prodrugs falling within the scope of the invention are β-D-2 ′, 6′-dimethylcytidine 2 ′, 5′-L-diviline ester (dival-2 ′, 6-diMe-L-dC); Β-D-2 ', 6-dimethylthymidine 2', 5'-L-diviline ester; Β-D-2 ', 8-dimethyladenosine 2', 5'-L-diviline ester; Β-D-2 ', 8-dimethylguanosine 2', 5'-L-diviline ester; Β-D-2 ', 6-dimethyl-5-fluorocytidine 2', 5'-L-diviline ester; Β-D-2 ', 6-dimethyluridine 2', 5'-L-diviline ester; 2 ', 5'-diacetyl ether D-2', 6-dimethylcytidine; Β-D-2 ', 6-dimethylthymidine 2', 5'-diacetyl ether; 2'-5'-diacetyl ether β-D-2 ', 8-dimethyladenosine; Β-D-2 ', 8-dimethylguanosine 2', 5'-diacetyl ether; Β-D-2 ', 5'-diacetyl ether, 6-dimethyl-5-fluorocytidine and β-D-2', 5'-diesters, 6-dimethyl (6-dimethyl (cytidine, 5-fluorocytidine, uridine or thymidine) or 2-, 5'-diesters β-D-2 ', 8-dimethyl (guanosine, adenosine or inosine), where (i) 2'-ether is an amino acid ester and 5'-ether is an alkyl or aryl ether ; (ii) both esters are esters of amino acids, (iii) both esters are independently alkyl or aryl esters, or (iv) 2'-ester is an alkyl or aryl ester and 5'-ester is an amino acid ester.

In another embodiment, the 3 ′ prodrug of the 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleoside includes biologically cleavable residues at the 3 ′ and / or 5 ′ positions. Preferred residues are esters of natural or synthetic D- or L-amino acids, such as valyl, more preferred are esters of L-amino acids, such as L-valyl, and alkyl esters, including acetyl. Thus, the present invention, in particular, includes a 3'-L-amino acid ester and a 3 ', 5'-L-diamino acid ester 1', 2 ', 3' or 4'-branched β-D- or β-L- nucleosides with any desired purine or pyrimidine base, where the parent drug optionally has an EC _{50 of} less than 15 micromoles and, even more preferably, less than 10 micromoles; 3 '- (alkyl or aryl) ether or 3', 5'-L-di (alkyl or aryl) ether 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleosides with any the desired purine or pyrimidine base, where the parent drug optionally has an EC _{50 of} less than 10 or 15 micromoles, and prodrugs of 3 ', 5'-diesters 1', 2 ', 3' or 4'-branched β-D- or β- L-nucleosides, where (i) the 3'-ester is an ester of a natural or synthetic D- or L-amino acid and the 5'-ester is an alkyl or aryl ester; (ii) both esters are, independently, natural or synthetic

D- or L-amino acids; (iii) both esters are independently alkyl or aryl ethers and (iv) 3'-ether is independently alkyl or aryl ether and 5'-ether is a natural or synthetic D- or L-amino acid ester, where the parent drug optionally has an EC ₅₀ less than 10 or 15 micromoles.

Examples of prodrugs within the scope of the invention are β-D-2 ', 6-dimethylcytidine 3'-L-valine ester; Β-D-2 '3-L-valine ester, 6-dimethylthymidine; Β-D-2 '3'-L-valine ester, 8-dimethyladenosine, β-D-2' 3'-L-valine ester, 8-dimethylguanosine; Β-D-2 '3-L-valine ester, 6-dimethyl-5-fluorocytidine; Β-D-2 '3'-L-valine ester, 6-dimethyluridine; Β-D-2 '3'-acetyl ester, 6-dimethylcytidine; Β-D-2 ', 6-dimethylthymidine 3'-acetyl ester; Β-D-2 '3'-acetyl ether, 8-dimethyladenosine, β-D-2' 3'-acetyl ether, 8-dimethylguanosine; Β-D-2 ', 6-dimethyl-5-fluorocytidine 3'-acetyl ester; and 3'-esters of β-D-2 ', 6-dimethyl (cytidine, 5-fluorurcitidine, uridine or thymidine) or 3'-esters of β-D-2', 8-dimethyl (guanosine, adenosine or inosine) wherein (i) the 3'-ester is an amino acid ester or (ii) the 3'-ester is an alkyl or aryl ester.

Further examples of prodrugs falling within the scope of the invention are β-D-2 ′, 6′-dimethylcytidine 3 ′, 5′-L-diviline ester (dival-2 ′, 6-diMe-L-dC); Β-D-2 ', 6-dimethylthymidine 3', 5'-L-diviline ester; 3 ', 5'-L-diviline ester β-D-2', 8-dimethyladenosine; Β-D-2 ', 8-dimethylguanosine 3', 5'-L-diviline ester; Β-D-2 ', 6-dimethyl-5-fluorocytidine 3', 5'-L-diviline ester; Β-D-2 ', 6-dimethyluridine 3', 5'-L-diviline ester; 3 ', 5'-diacetyl ether D-2', 6-dimethylcytidine; Β-D-2 ', 6-dimethylthymidine 3', 5'-diacetyl ether; 3 ', 5'-diacetyl ether β-D-2', 8-dimethyladenosine; Β-D-2 '3, 5'-diacetyl ether, 8-dimethylguanosine; 3 ', 5'-diacetyl ether β-D-2', 6-dimethyl-5-fluorocytidine and 3 ', 5'-diesters of β-D-2', 6-dimethyl (cytidine, 5-fluorocytidine, uridine or thymidine) or 3-, 5'-diesters β-D-2 ', 8-dimethyl (guanosine, adenosine or inosine), where (i) the 3'-ester is an amino acid ester and the 5'-ester is an alkyl or aryl ester ; (ii) both esters are esters of amino acids, (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 prodrug of a 1 ', 2', 3 'or 4'-branched β-D or β-L nucleoside includes biologically cleavable residues at the 2'-, 3'- and / or 5'-positions . Preferred residues are esters of natural or synthetic D- or L-amino acids, including D- or L-valyl, more preferred are esters of L-amino acids, such as L-valyl, and alkyl esters, including acetyl. Thus, this invention, in particular, includes an ether of 2 ′, 3′-L- or D-amino acids and an ether of 2 ′, 3 ′, 5′-L- or D-triamino acids 1 ′, 2 ′, 3 ′ or 4 '-branched β-D- or β-L-nucleosides, preferably L-amino acids, with any desired purine or pyrimidine base, where the parent drug optionally has an EC _{50 of} less than 15 micromoles and, even more preferably, less than 10 micromoles ; 2 ', 3'-di (alkyl or aryl) ether or 2', 3 ', 5'-L-tri (alkyl or aryl) ether 1', 2 ', 3' or 4'-branched β-D- or β-L-nucleosides with any desired purine or pyrimidine base, where the parent drug optionally has an EC _{50 of} less than 10 or 15 micromoles, and 2 ', 3'-diesters 1', 2 ', 3' or 4'-branched prodrugs β-D- or β-L-nucleosides, where (i) the 2'-ester is an amino acid ester and the 3'-ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) both esters are independently alkyl or aryl ethers; and (iv) 2'-ether is independently alkyl or aryl ether and 3'-ether is an amino acid ester, where the parent drug optionally has an EC _{50 of} less than 10 or 15 micromoles. In addition, the invention includes 2 ′, 3 ′, 5′-esters of 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L-nucleosides, where (i) all three esters are amino acid esters; (ii) all three esters are independently alkyl or aryl esters; (iii) the 2'-ester is an amino acid ester, the 3'-ester is an amino acid ester and the 5'-ester is an alkyl or aryl ester; (iv) the 2'-ester is an amino acid ester, the 3'-ester is an alkyl or aryl ester and the 5'-ester is an alkyl or aryl ester; (v) the 2'-ester is an alkyl or aryl ester, the 3'-ester is an alkyl or aryl ester and the 5'-ester is an amino acid ester; (vi) the 2'-ester is an alkyl or aryl ester, the 3'-ester is an amino acid ester and the 5'-ester is an amino acid ester; (vii) 2'-ether is an alkyl or aryl ether, 3'-ether is an amino acid and 5'-ether is an alkyl or aryl and (viii) 2'-ether is an amino acid, 3'-ether is alkyl or aryl ether and 5'-ether is an amino acid ester, where the parent drug optionally has an EC _{50 of} less than 10 or 15 micromoles.

Examples of prodrugs falling within the scope of the invention include 2 ', 3'-L-diviline ester β-D-2', 6-dimethylcytidine (dival-2 ', 6-diMe-L-dC); Β-D-2 ', 6-dimethylthymidine 2', 3'-L-diviline ester; Β-D-2 ', 3'-L-diviline ester β-D-2', 8-dimethyladenosine, 2 ', 3'-β-D-diviline ester β-D-2', 8-dimethylguanosine; Β-D-2 ', 6-dimethyl-5-fluorocytidine 2', 3'-L-diviline ester; Β-D-2 ', 6-dimethyluridine 2', 3'-L-diviline ester; Β-D-2 ', 6-dimethylcytidine 2', 3'-diacetyl ether; Β-D-2 ', 6-dimethylthymidine 2', 3'-diacetyl ether; Β-D-2 ', 8-dimethyladenosine 2', 3'-diacetyl ether; Β-D-2 ', 8-dimethylguanosine 2', 3'-diacetyl ether; Β-D-2 ', 6-dimethyl-5-fluorocytidine 2', 3'-diacetyl ether; and 2 ′, 3′-diesters β-D-2 ′, 6-dimethyl (cytidine, 5-fluorocytidine, uridine or thymidine) or 2 ′, 3′-diesters β-D-2 ', 8-dimethyl ( guanosine, adenosine or inosine), wherein (i) the 2'-ester is an amino acid ester and the 3'-ester is an alkyl or aryl ester; (ii) both esters are amino acid esters; (iii) 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 scope of the invention include 2 ', 3', 5'-L-trivalin β-D-2 ', 6-dimethylcytidine ester (trival-2', 6-diMe-L-dC); 2 ', 3', 5'-L-trivalin ester of β-D-2 ', 6-dimethylthymidine; 2 ', 3', 5'-L-trivalin ester of β-D-2 ', 8-dimethyladenosine; 2 ', 3', 5'-L-trivalin ester of β-D-2 ', 8-dimethylguanosine; 2 ', 3', 5'-L-trivalin ester of β-D-2 ', 6-dimethyl-5-fluorocytidine; 2 ', 3', 5'-L-trivalin ester of β-D-2 ', 6-dimethyluridine; 2 ', 3', 5'-triacetyl ether of D-2 ', 6-dimethylcytidine; 2 ', 3', 5'-triacetyl ether β-D-2 ', 6-dimethylthymidine; 2 ', 3', 5'-triacetyl ether β-D-2 ', 8-dimethyladenosine; 2 ', 3', 5'-triacetyl ether β-D-2 ', 8-dimethylguanosine; 2 ', 3', 5'-triacetyl ether β-D-2 ', 6-dimethyl-5-fluorocytidine and 2', 3 ', 5'-triesters β-D-2', 6-dimethyl (cytidine, 5-fluorocytidine, uridine or thymidine) and 2 ', 3', 5'-triesters β-D-2 ', 8-dimethyl (guanosine, adenosine or inosine), where (i) all three esters are amino acid esters; (ii) all three esters are independently alkyl or aryl ethers, (iii) 2'-ether is an amino acid ester, 3'-ether is an amino acid ester and 5'-ether is an alkyl or aryl ether; (iv) the 2'-ester is an amino acid ester, the 3'-ester is an alkyl or aryl ester and the 5'-ester is an alkyl or aryl ester; (v) the 2'-ester is an alkyl or aryl ester, the 3'-ester is an alkyl or aryl ester and the 5'-ester is an amino acid ester; (vi) the 2'-ester is an alkyl or aryl ester, the 3'-ester is an amino acid ester and the 5'-ester is an amino acid ester; (vii) 2'-ether is an alkyl or aryl ether, 3'-ether is an amino acid and 5'-ether is an alkyl or aryl and (viii) 2'-ether is an amino acid, 3'-ether is alkyl or aryl ether and 5'-ether is an amino acid ester.

In a first basic embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (I) to treat:

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

R ¹ , R ² and R ³ are independently H, phosphate (including mono-, di- or triphosphate and stabilized 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 ester, including alkyl or aralkylsulfonyl, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted with one or more substituents, as described in the definition given here for aryl; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; a lipid comprising a phospholipid; amino acid and amino acid residue; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable, removable group that is capable of providing a compound in which R ¹ , R ² and / or R ³ are independently H, phosphate (including mono-, di- or triphosphate), for example, when administered in vivo; where in one embodiment, R ² and / or R ^{3 is} not a phosphate (including mono-, di- or triphosphate or a stabilized phosphate prodrug);

where at least one of R ² and R ^{3 is} not hydrogen, and where

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

X ¹ represents an optionally substituted straight, branched or branched chain 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, COO-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 represents hydrogen, optionally substituted straight, branched or cyclic 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, COO-alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON (R ⁴ ) ₂ , chloro, bromo, fluoro, iodo, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ and

where each Y ³ represents independently H, F, Cl, Br or I;

each R ⁴ and R ⁵ is independently hydrogen, acyl (including lower acyl), alkyl (including, but not limited to, methyl, ethyl, propyl and cyclopropyl), lower alkyl, alkenyl, alkynyl or cycloalkyl.

In embodiments described herein, R ¹ , R ^2, and / or R ³ may be a pharmaceutically acceptable, removable group that is capable of providing a compound in which R ¹ , R ² and / or R ³ are independently H or phosphate (including mono -, di- or triphosphate), for example, when administered in vivo.

In a second main embodiment, there is provided a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (II) for treatment:

or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, 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 main embodiment, there is provided a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective for treating an amount of a compound of formula (III), (IV) or (V):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

the base is selected from the group consisting of

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

each W ¹ , W ² , W ³ and W ⁴ is 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 ;

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

X represents 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 * represents CH, CF, CY ³ or CR ⁴ ;

X ² represents H, optionally substituted straight, branched or cyclic 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, COO-alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON (R ⁴ ) ₂ , chloro, bromo, fluoro, iodo, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ;

each X ³ is optionally substituted straight chain, branched or cyclic 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, halogenated alkyl (including halogenated lower alkyl), CF ₃ , C (Y ³ ) ₃ , 2-Br-ethyl, CH ₂ F, CH ₂ Cl, GH 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 (aralkyl), -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) ₂ , -NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), - N (acyl) ₂ ;

each Y is independently selected from the group consisting of 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;

where R represents H, alkyl or acyl;

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

each Y ² is independently O, S, NH or NR ⁴ ; each Y ³ is independently H, F, Cl, Br or I;

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

where for the base (E), (F), (K), (L), (W) and (X) W ⁴ cannot be CH if W ¹ represents N;

each R ⁶ is 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, halogenated alkyl (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 , 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;

each R ⁷ is 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, halogenated alkyl (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 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably 3-7 membered carbocyclic ring), optionally substituted heterocycle (preferably 3- 7 membered heterocyclic something ring having one or more O, S and / or N), optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having 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 (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 (aralkyl), -NH (cycloalkyl), -N ( acyl) ₂ , azido, cyano, SCN, OCN, NCO or

halogen (fluorine, chlorine, bromine, iodine);

alternatively, R ⁶ and R ⁷ may together form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or several O, S and / or N); and

each m is independently 0, 1, or 2.

In a fourth embodiment, there is provided a compound of formula (VI) or (VII), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula ( VI) or (VII):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

base, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Y, Y ¹ , Y ² , Y ³ , W ¹ , W ² , W ³ , W ⁴ , W * , X, X *, X ¹ , X ² and X ³ have the meanings indicated above;

where in one embodiment, R ⁸ in formula (VI) is —OH or —NH ₂ only when X is a carbon atom; and where

each R ⁸ and R ¹¹ is 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, halogenated alkyl (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 , 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 ;

each R ⁹ and R ¹⁰ independently represents 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, halogenated alkyl (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 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring), optionally substituted heterocycle (preferably 3-7 membered g terotsiklicheskoe ring having one or more O, S and / or N), optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having 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 (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 (aralkyl), -NH (cycloalkyl), -N (acyl) ₂ , azido, cyano, SCN, OCN, NCO or

halogen (fluorine, chlorine, bromine, iodine);

each m is 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 may together form a bridging compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic rings) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and / or N); or

alternatively, R ⁶ and R ⁷ or R ⁹ and R ¹⁰ may together form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably 3-7- member heterocyclic ring having one or more O, S and / or N).

In a fifth main embodiment, there is provided a compound of formula (VIII), (IX) or (X), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective for treating an amount of a compound of formula (VIII), (IX) or (X):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

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

base * is a purine or pyrimidine base, as described above;

each R ¹² is 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, halogenated alkyl (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) 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 ;

each R ¹³ is 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, halogenated alkyl (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 a 3-7 membered carbocyclic ring), optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or several O, S and / or N) an optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having 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) 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 (aralkyl), -S (cycloalkyl), -NHR ⁴ , -NR ⁴ R ⁵ , -NH (alkenyl), -NH (alkynyl), -NH (aralkyl), -NH (cycloalkyl), SCN, OCN, NCO or fluoro;

alternatively, R ¹² and R ¹³ together form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or several O, S and / or N), and

each m is independently 0, 1, or 2.

In a sixth main embodiment, there is provided a compound of formula (XI) or (XII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of the formula (XI) or (XII):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

in the alternative case, the base * is replaced by a base in formulas (XI) and (XII) and

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 have the meanings indicated above;

and where, in one embodiment, R ⁸ in the formula (XI) is —OH or —NH ₂ only when X is a carbon atom, and where

each R ⁸ and R ¹¹ is 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, halogenated alkyl (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 , 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 ;

each R ⁹ and R ¹⁰ is 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, halogenated alkyl (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 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring), optionally substituted heterocycle (preferably 3-7 membered g terotsiklicheskoe ring having one or more O, S and / or N), optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having 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 (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 (aralkyl), -NH (cycloalkyl ), -N (acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

each m is 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 may together form a bridging compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic rings) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and / or N); or

alternatively, R ¹² and R ¹³ or R ⁹ and R ¹⁰ may together form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably 3-7- member heterocyclic ring having one or more O, S and / or N).

In a specific aspect of the invention, there is provided a compound of formula (XI) or (XII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula ( XI) or (XII):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

R _{3 is} selected from the group consisting of H, mono-, di- or triphosphate or a stabilized phosphate prodrug; acyl; sulfonate ether; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acids; carbohydrate; a peptide, cholesterol and a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of forming a compound in which R ₃ is independently H or mono-, di- or triphosphate;

X ”is selected from the group consisting of one or more of O, S, SO, SO ₂ , N, NH, NR and CH ₂ groups, where any of the above groups may be optionally substituted and may be located in different positions so that a 3-7 membered ring formed;

R represents H, alkyl or acyl and

B represents a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and / or N );

the base is selected from the group consisting of groups:

Where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 represents CR — or N;

T and V independently represent CH or N;

Q represents CH, —CCl, —CBr, —CF, —Cl, —CCN, —C — COOH, —C — CONH ₂ or N;

Q ₁ and Q ₂ independently represent N or CR;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

their tautomeric forms.

In a second specific aspect of the invention, there is provided a compound of formula (XV), (XVI or (XVII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective treatment amounts of a compound of formula (XV), (XVI) or (XVII):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

G and E are independently selected from the group consisting of 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 represents H, alkyl or acyl and

R ′, R ′ ′, R ′ ′ ′ ′, R ′ ′ ′ ′ and R ³ and the base have the meanings indicated in formula (XIII).

Alternatively, in the compound of formula (XVII), at most one of G and E may further be hydrogen.

In a third specific aspect of the invention, there is provided a compound of formula (XVIII), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (XVIII) to treat:

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

M is selected from the group consisting of S, SO, and SO ₂ , and

R ′, R ″, R ″ ″, R ″ ″ and R ₃ and the base have the meanings indicated for formula (XIII).

In a fourth specific aspect of the invention, there is provided a compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective treatment amount of a compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

A is selected from the group consisting of 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 the group consisting of 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;

X is selected from the group consisting of -OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aryl, -O-aralkyl, -O-cycloalkyl- , O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, 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, an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination;

m is 0 or 1;

R represents H, alkyl or acyl;

R ₃ selected from the group consisting of H; mono-, di- or triphosphate or a stabilized phosphate prodrug; substituted or unsubstituted alkyl; acyl; sulfonate ether; optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acids; carbohydrate; a peptide, cholesterol and a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of forming a compound in which R ₃ is independently H or mono-, di- or triphosphate; and

the base is a non-natural base selected from the group:

Where

each R ', R ", R'" and R "" is independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkenyl, 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 represents C-R "or N;

T and V independently represent CH or N;

Q represents CH, —CCl, —CBr, —CF, —Cl, —CCN, —C — COOH, —C — CONH ₂ or N;

Q ₁ and Q ₂ independently represent N or CR "" and

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

with the proviso that in the bases (g) and (i) R ', R ”” is not H, OH or NH ₂ and Q, T, V, Q ₂ , Q ₅ and Q _{6 are} not N.

In one embodiment, the amino acid residue is a residue of the formula C (O) C (R ¹¹ ) (R ¹² ) (NR ¹³ R ¹⁴ ), where

R ¹¹ represents an amino acid side chain and where, as in proline, R ¹¹ may optionally be attached to R ¹³ to form a cyclic structure or, alternatively, R ¹¹ is an alkyl, aryl, heteroaryl or heterocyclic radical;

R ¹² represents hydrogen, alkyl (including lower alkyl) or aryl and

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

In another preferred embodiment, at least one of R ² and R ³ is an amino acid residue, preferably L-valinyl.

The β-D and β-L nucleosides of the present invention can inhibit Flaviviridae polymerase activity. Nucleosides can be screened for their ability to inhibit Flaviviridae polymerase activity in vitro in accordance with the screening methods described here in more detail. The activity spectrum can be easily determined by evaluating the compound in the assays described herein, or other validation assay.

In one embodiment, the effectiveness of the compound against Flaviviridae is measured by the concentration of the compound necessary to reduce the number of plaques of the virus in vitro by the methods described here in more detail, by 50% (i.e. EC _{50 of the} compound). In preferred embodiments, the parent compound of the prodrug compound has an EC _{50 of} less than 25, 15, 10, 5, or 1 micromole. In preferred embodiments, the compound has an EC ₅₀ lower than 15 or 10 micromoles as measured by the polymerase assay described in Ferrari et al., Jnl. Of Vir., 73: 1649-1654.1999; Ishii et al., Hepatology, 29: 1227-1235, 1999; Lohmann et al., Jnl. of Bio. Chem., 274: 10807-10815, 1999; or Yamashita et al., Jnl. of Bio. Chem., 273: 15479-15486, 1998.

In another embodiment, combination and / or alternative therapy is provided. In combination therapy, an effective dose of two or more agents is administered together, while in alternative therapy, an effective dose of each agent is administered sequentially. Doses will depend on the absorption, inactivation, excretion rates of the drug, as well as other factors known to the person skilled in the art. It should be noted that dose rates will also vary depending on the severity of the condition that needs to be alleviated. In addition, it should be clear that for any particular subject, the regimens and schedules for taking a particular drug should be adjusted over time in accordance with the needs of the patient and the professional assessment of the person administering or observing the administration of the compositions.

The invention relates to a combination of at least two prodrugs described herein. The invention further provides at least one of the described 2'- and 3'-prodrugs in combination or in alternation with a second nucleoside that is active against Flaviviridae and includes, but is not limited to the parent drug, any of the prodrugs indicated herein those. β-D-2 ', 6-dimethylcytidine, β-D-2', 6-dimethylthymidine, β-D-2 ', 8-dimethyladenosine, β-D-2', 8-dimethylguanosine, β-D-2 ' 6-dimethyl-5-fluorocytidine and / or β-D-2 ', 6-dimethyluridine. Alternatively, 2'- or 3'-prodrugs can be administered in combination or in alternation with another anti-Flaviviridae agent having an EC _{50 of} less than 10 or 15 micromoles, or prodrugs thereof, or pharmaceutically acceptable salts.

Non-limiting examples of antiviral agents that can be used in combination with the compounds described herein include 1) interferon and / or ribavirin; 2) substrate-based NS3 protease inhibitors; 3) non-substrate based inhibitors; 4) thiazolidine derivatives; 5) thiazolidines and benzanilides; 6) phenanthrenquinone; 7) NS3 inhibitors; 8) HCV helicase inhibitors, (9) polymerase inhibitors, including inhibitors of RNA-dependent RNA polymerase; (10) antisense oligodeoxynucleotides; (11) inhibitors of IRES-dependent translation; (12) nuclease-resistant ribozymes; and (13) other compounds that are active against Flaviviridae. The invention further includes administering a prodrug in combination or in alternation with an immune modulator or other pharmaceutically active viral replication modifier including biological material such as a protein, peptide, oligonucleotide or gamma globulin, including, but not limited to, interferon, interleukin or oligonucleotides that are antisense for genes expressing or regulating the replication of Flaviviridae.

The invention further includes administering a prodrug in combination or in alternation with an immune modulator or other pharmaceutically active viral replication modifier including biological material such as a protein, peptide, oligonucleotide or gamma globulin, including, but not limited to, interferon, interleukin or oligonucleotides that are antisense for genes expressing or regulating the replication of Flaviviridae.

In particular, the present invention relates to the following:

(a) a compound of formula (XIII) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

(b) pharmaceutical compositions comprising a compound of formula (XIII) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, together with a pharmaceutically acceptable carrier or diluent;

(c) pharmaceutical compositions comprising a compound of formula (XIII) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent;

(d) pharmaceutical compositions for treating a Flaviviridae infection in a host, containing a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, together with a pharmaceutically acceptable carrier or diluent;

(e) pharmaceutical compositions for treating a Flaviviridae infection in a host, containing a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent;

(f) methods for treating a Flaviviridae infection in a host comprising administering a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent;

(g) methods for treating a Flaviviridae infection in a host, comprising administering a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent;

(h) using a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent, for treating a Flaviviridae infection in a host;

(i) the use of a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent, for treating a Flaviviridae infection in a host;

(j) using a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent, in the manufacture of a medicament for the treatment of a Flaviviridae infection in a host, and

(k) using a compound of formula (I) to (XXIII), or a pharmaceutically acceptable salt thereof, or a prodrug thereof with one or more other effective antiviral agents, optionally with a pharmaceutically acceptable carrier or diluent, in the manufacture of a medicament for the treatment of a Flaviviridae infection in a host.

In an alternative embodiment, the parent nucleoside compound of any of the 2'- or 3'-prodrugs (i.e., nucleosides without 2'- or 3'-cleavable moieties) is provided for the treatment of Flaviviridae infection, especially hepatitis C.

Brief Description of the Drawings

Figure 1 is a structure of various non-limiting examples of nucleosides of the present invention, as well as other known nucleosides, in particular IFAU and ribavirin.

Figure 2 is a non-limiting example of the steps of esterifying a 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside to produce a 2'-prodrug. The same general procedure could be used to prepare a 3'-prodrug with selective protection of 2'- and 5'-hydroxyl groups or protection of 2'-, 3'- and 5'-hydroxyl groups and selective deprotection of 3'-hydroxyl.

FIG. 3 is a non-limiting example of the steps of esterifying a 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleoside to produce a 3′-prodrug.

Figure 4 is a non-limiting example of the steps of esterifying a 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleoside to produce a 2 ′, 3′ prodrug.

DETAILED DESCRIPTION OF THE INVENTION

The invention described herein is a compound, method and composition for treating Flaviviridae infection in humans and other host animals. The method comprises administering an effective amount of a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside anti-Flaviviridae, as described herein, or a pharmaceutically an acceptable salt, or prodrug, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral (i.e., anti-HCV) activity, or are metabolized to a compound that exhibits such activity. HCV is a member of the Flaviviridae family. HCV is placed in a new monotypic genus, hepativirus. Thus, in one embodiment, Flaviviridae is HCV. In an alternative embodiment, Flaviviridae is a flavivirus or pestivirus.

The 2'- and / or 3'-prodrugs of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside are acyl derivatives of a secondary or tertiary alpha alcohol to a secondary or tertiary carbon atom. Due to the steric hindrance of these prodrugs compared to the 5'-prodrugs, acyl derivatives of the primary alcohol, these prodrugs differently modulate the biological properties of the molecule in vivo. It has been found that 2'- and / or 3'-prodrugs of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside can provide a drug with an increased half-life in the body and an improved pharmacokinetic profile .

A 2'- or 3'-prodrug in a preferred embodiment has a cleavable acyl group and, most specifically, an amino acid residue derived from any natural and synthetic α-, β-, γ- or δ-amino acid, including, but not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid has an L configuration. Alternatively, the amino acid derivative may be alanyl, valinyl, leucinyl, isoleucinyl, proinyl, phenylalanyl, tryptophanyl, methioninyl, glycinyl, serynyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl anilinyl, lisinyl, lisinyl, lisinyl, lisinyl , β-valinyl, β-leucinyl, β-isoleucinyl, β-proline, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serynyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-arginine or β-histidinyl. In one particular embodiment, the residue is valine ester. A particularly preferred compound is the 2 ′, 6-dimethylribocytidine 3′-valine ester.

The oral bioavailability of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside as a neutral base and as a salt with HCl is low for rodents and primates, but not humans. It has been found that there is significant competition for the 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleoside with other nucleosides or nucleoside analogs for absorption or transfer from the gastrointestinal tract and competition for other nucleosides or nucleoside analogs for absorption with 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside. To increase oral bioavailability and reduce the drug-drug interaction potential, 2'- and 3'-prodrugs of 1 ', 2', 3 'or 4'-branched β-D or β-L nucleoside with higher bioavailability were obtained than the original molecule, and a reduced effect on the bioavailability of other nucleosides or nucleoside analogues used in combination.

The 2'-, 3'- and / or 5'-mono-, -di- or trivalin ester of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside has a higher oral bioavailability than the original 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside, and reduced interaction with other nucleosides or nucleoside analogs when used in combination, compared to 1', 2 ', 3' or 4'-branched β-D- or β-L-nucleoside.

The 2'-, 3'- and / or 5'-mono-, -di- or trivalin ester of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside can be converted to the original 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleoside by deesterification in the mucous membrane of the gastrointestinal tract, blood or liver. The 2'-, 3'- and / or 5'-mono-, -di- or trivalin ester of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside can be actively transferred from the cavity of the gastrointestinal tract after oral delivery to the bloodstream by the function of an amino acid carrier in the mucous membrane of the gastrointestinal tract. This explains the increase in oral bioavailability compared to the original 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside, which is mainly carried by the nucleoside transporter function. There is also reduced competition for the absorption of 2'-, 3'- and / or 5'-mono-, di- or trivalin esters of 1 ', 2', 3 'or 4'-branched β-D- or β-L -nucleoside with other nucleosides or nucleoside analogues that are carried by the function of the nucleoside transporter, and not by the function of the amino acid carrier. When partial deesterification of the 1 ', 2', 3 'or 4'-branched β-D or β-L-nucleoside is partially deesterified prior to competing absorption, the mono- and diviline ester continues to be adsorbed using the amino acid transport function . Thus, the desired result of better absorption or bioavailability and reduced competition with other nucleosides or nucleoside analogs for absorption into the bloodstream can be maintained.

In conclusion, the present invention includes the following features:

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

(b) a 2'- and / or 3'-prodrug of a 1'-, 2'-, 3'- or 4'-branched β-D- or β-L-nucleoside described herein and its pharmaceutically acceptable salts and compositions for use in the treatment and / or prevention of Flaviviridae infection, especially in patients diagnosed as having Flaviviridae infection or at risk of becoming infected with hepatitis C;

(c) a 2'- and / or 3'-prodrug of a 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside described herein and its pharmaceutically acceptable salts and compositions described herein essentially in the absence of opposing enantiomers of the described nucleoside or essentially isolated from a mixture with other chemical enantiomers;

(d) a method for producing a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside, described in more detail below;

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

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

(g) pharmaceutical preparations containing a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside or a pharmaceutically acceptable salt thereof together with another parent 1 A ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside, optionally in a pharmaceutically acceptable carrier or diluent;

(h) a method for treating and / or preventing a disease of a host infected with Flaviviridae, which comprises administering an effective amount of a 2 ′ and / or 3 ′ prodrug of 1 ′, 2 ′, 3 ′ or 4′-branched β-D- or β-L-nucleoside, a pharmaceutically acceptable salt or composition thereof;

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

(j) a method for the treatment and / or prophylaxis of a disease of a host infected with Flaviviridae, which comprises administering an effective amount of a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or a β-L-nucleoside, a pharmaceutically acceptable salt or composition thereof, with a different starting 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleoside;

(k) a method for treating and / or preventing a disease of a host infected with Flaviviridae, which comprises administering an effective amount of a 2'- and / or 3'-prodrug of β-D-2'-methylcytidine, or a pharmaceutically acceptable salt or composition thereof;

(l) a method for treating and / or preventing a disease of a host infected with Flaviviridae, which comprises administering an effective amount of a 2'-valyl or acetyl ester of β-D-2'-methylcytidine, or a pharmaceutically acceptable salt thereof, or a composition thereof;

(m) the use of a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside and a pharmaceutically acceptable salt or composition thereof for treatment and / or prevention host Flaviviridae infections;

(n) the use of a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside, its pharmaceutically acceptable salt or composition in combination and / or alternation with one or more effective anti-HCV agents for the treatment and / or prophylaxis of a Flaviviridae infection in a host;

(o) the use of a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside, or a pharmaceutically acceptable salt thereof, or a composition with a different starting 1 A '-, 2'-, 3'- or 4'-branched β-D- or β-L-nucleoside for the treatment and / or prophylaxis of a Flaviviridae infection in a host;

(p) the use of a 2'- and / or 3'-prodrug of β-D-2'-methylcytidine, or a pharmaceutically acceptable salt thereof, or its composition for the treatment and / or prevention of a Flaviviridae infection in a host;

(q) the use of β-D-2′-methylcytidine 3'-valyl or acetyl ester, or a pharmaceutically acceptable salt thereof, or composition for treating and / or preventing Flaviviridae infection in a host;

(r) the use of a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside or its pharmaceutically acceptable salts and compositions in the manufacture of a medicament for the treatment of and / or prevention of infection with Flaviviridae;

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

(t) the use of a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside, or a pharmaceutically acceptable salt thereof, or a composition with a different starting 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside in the manufacture of a medicament for the treatment and / or prophylaxis of a Flaviviridae infection in a host;

(u) the use of a 2'- and / or 3'-prodrug of β-D-2'-methylcytidine, or a pharmaceutically acceptable salt thereof, or composition in the manufacture of a medicament for the treatment and / or prevention of a Flaviviridae infection in a host and

(v) the use of β-D-2′-methylcytidine 3'-valyl or acetyl ester, or a pharmaceutically acceptable salt thereof, or composition thereof in the manufacture of a medicament for the treatment and / or prevention of a Flaviviridae infection in a host.

Flaviviridae included in the scope of the present invention are generally discussed in Fields Virology, Editors: Fields, BN, Knipe, DM, and Howley, PM, Lippincott-Raven Publishers, Philadelphia, PA, Chapter, 31, 1996. In a specific embodiment, Flaviviridae is HCV. In an alternative embodiment, Flaviviridae is a flavivirus or pestivirus. Specific flaviruses include, but are not limited to: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bussuquara, Cacipacore, Carey Island, Dakar bat, Dengue 1 virus, Dengue 2 virus, Dengue 3 virus, Dengue 4 virus, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, Hypr, Ilheus, Israeli turkey meningoencephalitis virus, Japanese-type encephalitis virus, Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjurin kiurjanga, Liu virus Lowing, Meaban, Modoc, Montana myotis leukoencephalitis virus, encephalitis of Murray valley, Naranjal, Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, Rio Bravo, Rocio, Royal Farm, virus tick-borne tick-borne encephalitis, Saboya, St. Louis encephalitis virus, Sal Vieja, San Perlita, Saumares Reef, Sepik, Sokuluk, Spondweni, Statford, Tembusu, Tyuleniy, Uganda S, Usutu, Wesselsborn, West Nile, yellow virus, Yaounde and Zika.

Pestiviruses included in the scope of this invention are discussed generally in Fields Virology, Editors: Fields, B.N., Knipe, D.M., and Howley, P.M. Lippincott-Raven Publishers, Philadelphia, PA, Chapter, 31, 1996. Specific pestiviruses include, without limitation: bovine viral diarrhea virus (“BVDV“), classic swine fever virus (“CSFV”, also called swine cholera virus) and sheep border disease virus (“BDV”).

I. Active compounds

In a first basic embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (I) to treat:

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

R ¹ , R ² and R ³ independently represents H, phosphate (including mono-, di- or triphosphate and stabilized 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 ester, including alkyl or aralkylsulfonyl, including methanesulfonyl and benzyl, where the phenyl group is optionally substituted with one or more substituents, as described in the definition given here for aryl; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; a lipid comprising a phospholipid; amino acid and amino acid residue; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable, removable group that is capable of providing a compound in which R ¹ , R ² and / or R ³ are independently H, phosphate (including mono-, di- or triphosphate), for example, when administered in vivo; where in one embodiment, R ² and / or R ^{3 is} not a phosphate (including mono-, di- or triphosphate or a stabilized phosphate prodrug);

where at least one of R ² and R ^{3 is} not hydrogen;

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

X ¹ represents an optionally substituted straight, branched or branched chain 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, COO-alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON (R ⁴ ) ₂ , chloro, bromo, fluoro, iodo, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ ;

X ² represents hydrogen, optionally substituted straight, branched or cyclic 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, COO-alkoxyalkyl, CONH ₂ , CONHR ⁴ , CON (R ⁴ ) ₂ , chloro, bromo, fluoro, iodo, CN, N ₃ , OH, OR ⁴ , NH ₂ , NHR ⁴ , NR ⁴ R ⁵ , SH or SR ⁵ and

where each Y ³ represents independently H, F, Cl, Br or I;

each R ⁴ and R ⁵ is 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 embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable thereof an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form, where

R ¹ represents H or phosphate (preferably H);

R ² and R ³ independently represent H, phosphate, acyl or amino acid residue, where at least one of R ² and R ³ represents an acyl or amino acid residue;

X ¹ represents CH ₃ , CF ₃ or CH ₂ CH ₃ ;

X ² represents H or NH ₂ and

Y represents hydrogen, bromine, chlorine, fluorine, iodine, NH ₂ or OH.

In a second main embodiment, there is provided a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (II) for treatment:

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ , Y ³ , X ¹ and X ² have the meanings indicated above.

In a preferred embodiment, there is provided a compound of formula (II), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (II), or its pharmaceutically acceptable salt, or prodrugs, or stereoisomeric, tautomeric or polymorphic forms, where:

R ¹ represents H or phosphate (preferably H);

R ² and R ³ independently represent H, phosphate, acyl or amino acid residue, where at least one of R ² and R ³ represents an acyl or amino acid residue;

X ¹ represents CH ₃ , CF ₃ or CH ₂ CH ₃ ;

X ² represents H, F, Cl, Br, I or CH ₃ and

Y represents hydrogen, bromine, chlorine, fluorine, iodine, NH ₂ or OH.

In a third main embodiment, there is provided a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective for treating an amount of a compound of formula (III), (IV) or (V):

or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y, Y ¹ and X ² are as defined above;

the base is selected from the group consisting of:

each W ¹ , W ² , W ³ and W ⁴ independently represents 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 ;

each W * independently represents O, S, NH or NR ⁴ ;

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

where for the base (E), (F), (K), (L), (W) and (X) W ⁴ cannot be CH if W ¹ represents N;

X represents 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 * represents CH, CF, CY ³ or CR ⁴ ;

each X ³ independently represents an optionally substituted straight chain, branched or cyclic 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, halogenated alkyl (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 , 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 (bottom higher acyl), -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), 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 ;

each Y ² independently represents O, S, NH or NR ⁴ ;

each Y ³ independently represents H, F, Cl, Br or I;

each R ⁶ independently represents 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, halogenated alkyl (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 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted or unsubstituted 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;

each R ⁷ independently represents 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, halogenated alkyl (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 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring), optionally substituted heterocycle (preferably 3-7 membered heterocycle cal ring having one or more O, S and / or N), optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having 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 alk l), -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 (aralkyl), -NH (cycloalkyl), - N (acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

alternatively, R ⁶ and R ⁷ may together form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or several atoms O, S and / or N), and

each m is independently 0, 1, or 2.

In a first embodiment, there is provided a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective treatment the amount of a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where

R ¹ represents H or phosphate (preferably H);

R ² and R ³ are independently H, phosphate, acyl or an amino acid residue, where at least one of R ² and R ³ is an acyl or amino acid residue;

W ⁴ represents CX ³ ;

X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ ;

R ⁶ represents alkyl and

X represents O, S, SO ₂ or CH ₂ .

In a second embodiment, there is provided a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form or method of treating a host infected with Flaviviridae, comprising administering an amount of the compound effective for treatment of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where:

R ¹ represents H or phosphate (preferably H);

R ² and R ³ are independently H, phosphate, acyl or an amino acid residue, wherein at least one of R ² and R ³ is an amino acid residue;

W ⁴ represents CX ³ ;

X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ ;

R ⁶ represents alkyl and

X represents O, S, SO ₂ or CH ₂ .

In a third embodiment, there is provided a compound of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form or method of treating a host infected with Flaviviridae, comprising administering an effective amount of the compound for treatment of formula (III), (IV) or (V), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where:

R ¹ represents H or phosphate (preferably H);

R ² and R ³ are independently H, phosphate, acyl or an amino acid residue, where at least one of R ² and R ³ is an acyl or amino acid residue;

W ⁴ represents CX ³ ;

X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ ;

R ⁶ represents alkyl and

X represents O.

In an even more preferred embodiment, a compound of formula (IV (a)) is provided, or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form or method of treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (IV) to treat (but)):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

the base has the meanings indicated here and is optionally substituted with an amine or cyclopropyl (for example, 2-amino, 2,6-diamino or cyclopropylguanosine);

R ⁷ represents halogen (F, Cl, Br or I), although preferably represents F;

R ¹ represents H; phosphate (including monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ or R ² independently represents H or phosphate. In one embodiment, R ^{2 is} not a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), and

R ² represents phosphate (including monophosphate, diphosphate, triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ or R ² independently represents H or phosphate. In one embodiment, R ^{2 is} not a phosphate (including monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug).

In a fourth main embodiment, there is provided a compound of formula (VI) or (VII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form or method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) to treat ) or (VII):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

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 have the meanings indicated above;

where in one embodiment, R ⁸ in formula (VI) is —OH or —NH ₂ only when X is a carbon atom; and

where each of R ⁸ and R ¹¹ independently represents 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, halogenated alkyl (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 , 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 al yl), - (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 ;

each R ⁹ and R ¹⁰ independently represents 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, halogenated alkyl (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 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring), optionally substituted heterocycle (preferably 3-7 membered g terotsiklicheskoe ring) having one or more O, S, and / or N), optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having 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 (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 (aralkyl), -NH (cycloalkyl ), -N (acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

each m is 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 may together form a bridging compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic rings) or an optionally substituted heterocycle (preferably a 3-7 membered carbocyclic ring having one or more O, S and / or N atoms) or

alternatively, R ⁶ and R ⁷ or R ⁹ and R ¹⁰ may together form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably 3-7- member carbocyclic ring having one or more atoms O, S and / or N).

In a particularly preferred embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X represents O, S, SO or SO ₂ ;

- each R ⁶ independently represents 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 ;

- each R ⁷ independently represents —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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

- each R ⁹ is 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-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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

each R ¹⁰ represents 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 , (CH ₂ ) _m CONHR ⁴ , and / or

- each of R ⁸ and R ¹¹ independently represents 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

each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In a particularly preferred alternative embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) for treatment or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where

- X represents O, S, SO or SO ₂ ; and / or

- R ⁶ and R ⁷ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each R ⁹ is 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-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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

each R ¹⁰ represents 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 , (CH ₂ ) _m CONHR ⁴ , and / or

- each of R ⁸ and R ¹¹ independently represents 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

each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 , (CH ₂ ) _m CONH ₂ ;

W represents CR — or N;

T and V independently represent CH or N;

Q represents CH, —CCl, —CBr, —CF, —Cl, —CCN, —C — COOH, —C — CONH ₂ or N;

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt or prodrug thereof, and a method of treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt thereof, or prodrugs, or stereoisomeric, tautomeric or polymorphic forms in which

- X represents O, S, SO or SO ₂ , and / or

- each R ⁶ independently represents 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

- each R ⁷ independently represents —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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

- R ⁹ and R ¹⁰ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each of R ⁸ and R ¹¹ independently represents 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

each m is 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ″ R ″ ″ and R ″ ″ independently selected from the group consisting of 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 , (CH ₂ ) _m CONH ₂ ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) to treat or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X represents O, S, SO or SO ₂ ; and / or

- R ⁶ and R ⁷ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said independently hetero atoms being taken individually or in combination with each other; and / or

- R ⁹ and R ¹⁰ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each of R ⁸ and R ¹¹ is 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

each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, optionally 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In a particularly preferred embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X represents 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

- each R ⁶ independently represents 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

- each R ⁷ independently represents —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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring independently having O, S and / or N as a heteroatom taken separately or in combination, and / or

- each R ⁹ is 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-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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

each R ¹⁰ represents 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

- each of R ⁸ and R ¹¹ independently represents 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

each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In a particularly preferred alternative embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) for treatment or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X represents 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 and R ⁷ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each R ⁹ is 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-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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

each R ¹⁰ represents 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 , (CH ₂ ) _m CONHR ⁴ , and / or

- each of R ⁸ and R ¹¹ independently represents 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

each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) to treat or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X represents 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

- each R ⁶ independently represents 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

- each R ⁷ independently represents —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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

- R ⁹ and R ¹⁰ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each of R ⁸ and R ¹¹ is 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

- each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In another particularly preferred alternative embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) to treat ), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X represents 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 and R ⁷ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said heteroatoms being independently taken individually or in combination with each other; and / or

- R ⁹ and R ¹⁰ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each of R ⁸ and R ¹¹ is 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

- each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In a particularly preferred embodiment, there is provided a compound of formula (VII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an amount of a compound of formula (VII) that is effective for treatment, or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X * represents CH, CF, CY ³ or CR ⁴ , and / or

- each R ⁶ independently represents 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

- each R ⁷ independently represents —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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

- each R ⁹ is 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-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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

each R ¹⁰ represents 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 , (CH ₂ ) _m CONHR ⁴ , and / or

- each of R ⁸ and R ¹¹ independently represents 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

- each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

where R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In a particularly preferred alternative embodiment, there is provided a compound of formula (VII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VII) to treat or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X * represents CH, CF, CY ³ or CR ⁴ ; and / or

- R ⁶ and R ⁷ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said heteroatoms being independently taken individually or in combination with each other; and / or

- each R ⁹ is 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-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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

each R ¹⁰ represents 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 , (CH ₂ ) _m CONHR ⁴ , and / or

- each of R ⁸ and R ¹¹ independently represents 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

- each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, there is provided a compound of formula (VII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VII) for treatment or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X * represents CH, CF, CY ³ or CR ⁴ , and / or

- each R ⁶ independently represents 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

- each R ⁷ independently represents —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 , an optionally substituted 3-7 membered carbocyclic and optionally substituted 3-7 membered heterocyclic ring having independently O, S and / or N as a heteroatom, taken alone or in combination, and / or

- R ⁹ and R ¹⁰ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each of R ⁸ and R ¹¹ is 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

- each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R, R, R, , -O-alkyl, -O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, -O-acyl, NH-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 represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In another particularly preferred embodiment, there is provided a compound of formula (VII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VII) for treatment or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

- X * represents CH, CF, CY ³ or CR ⁴ ; and / or

- R ⁶ and R ⁷ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- R ⁹ and R ¹⁰ together form a spiro compound selected from the group consisting of an optionally substituted 3-7 membered spirocarbocyclic or heterocyclic compound having one or more N, O and / or S atoms, said hetero atoms being taken individually or in combinations with each other; and / or

- each of R ⁸ and R ¹¹ is 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

- each m is independently 0 or 1, and / or

- the base is selected from one of the following bases:

and where

each of R, R, R, , -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 , (CH ₂ ) _m CONH ₂ ;

W represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and its tautomeric forms.

In a first embodiment, a compound of formula (VI), or a pharmaceutically acceptable salt, or prodrug, or stereoisomeric, tautomeric or polymorphic form thereof, and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable thereof, is provided an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents H or phosphate (including monophosphate, diphosphate, triphosphate or stabilization phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents, as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ independently is H or phosphate, (2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ² , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (4) R ⁸ and R ¹⁰ independently represent H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) X represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a second embodiment, a compound of formula (VI), or a pharmaceutically acceptable salt, or prodrug, or stereoisomeric, tautomeric or polymorphic form thereof, and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable compound thereof, is provided an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently is H or phosphate (including monophosphate, diphosphate, triphosphate or stabilizer phosphated prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of producing a compound in which R ¹ is independently H or phosphate, (2) R ⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O- alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, 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 independently represent H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) X represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a third embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently is H or phosphate (including monophosphate, diphosphate, triphosphate or stabilizer phosphated prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ independently is H or phosphate, (2) R ⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O- alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (4) R ⁸ and R ¹⁰ are H; (5) X represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a fourth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents H or phosphate (including monophosphate, diphosphate, triphosphate or stable isolated phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ independently is H or phosphate, (2) R ⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy, O- alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² , alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (4) R ⁸ and R ¹⁰ independently represent H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) X represents O; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a fifth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of the compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently is H or phosphate (including monophosphate, diphosphate, triphosphate or stabilizer oved phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ is H or phosphate, (2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ¹ ; (4) R ⁸ and R ¹⁰ independently represent H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) X represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a sixth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents H or phosphate (including monophosphate, diphosphate, triphosphate or stabilization phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ independently is 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 represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a seventh embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently is H or phosphate (including monophosphate, diphosphate, triphosphate or stabilizer phosphated prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ independently represents 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, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (4) R ⁸ and R ¹⁰ are H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) X represents O; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In an eighth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently is H or phosphate (including monophosphate, diphosphate, triphosphate or stabilizer phosphated prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ independently represents H or phosphate; (2) R ⁶ represents alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, 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 represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a ninth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents H or phosphate (including monophosphate, diphosphate, triphosphate or stabilizer phosphated prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ is H or phosphate; (2) R ⁶ represents alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, 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 independently H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) X represents O; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a tenth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable amount thereof an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently is H or phosphate (including monophosphate, diphosphate, triphosphate or stabilizer phosphated prodrug); acyl (including lower acyl); alkyl (including lower alkyl); a sulfonate ester including alkyl or arylalkylsulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as described in the definition of aryl herein; lipid, including phospholipid; an amino acid; carbohydrate; peptide; cholesterol or another pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ independently represents H or phosphate; (2) R ⁶ represents alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (3) R ⁷ and R ⁹ are independently OR ² , alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino; (4) R ⁸ and R ¹⁰ are hydrogen; (5) X represents O; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In an eleventh embodiment, a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form thereof, and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable compound thereof, is provided an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents H or phosphate; (2) R ⁶ represents alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, 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 represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a twelfth embodiment, a compound of formula (VI), or a pharmaceutically acceptable salt, or prodrug, or stereoisomeric, tautomeric or polymorphic form thereof, and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically acceptable compound thereof an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents H or phosphate; (2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ are hydrogen; (5) X represents O, S, SO ₂ or CH ₂ ; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a thirteenth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents H or phosphate; (2) R ⁶ is alkyl; (3) R ⁷ and R ⁹ are independently OR ² ; (4) R ⁸ and R ¹⁰ independently represent H, alkyl (including lower alkyl), chloro, bromo or iodo; (5) X represents O; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In a fourteenth embodiment, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI) or a pharmaceutically an acceptable salt or prodrug, or a stereoisomeric, tautomeric or polymorphic form in which (1) R ¹ independently represents 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, chloro, bromo, iodo, NO ₂ , amino, lower alkylamino or di (lower alkyl) amino (4) R ⁸ and R ¹⁰ are hydrogen; (5) X represents O; (6) W ⁴ represents CX ³ and (7) X ³ represents CH ₃ , CF ₃ or CH ₂ CH ₃ .

In even more preferred embodiments, there is provided a compound of formula (VI), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form and method of treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (VI), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form in which

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

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

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

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

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

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

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

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

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

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

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

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

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

In a fifth main embodiment, there is provided a compound of formula (VIII), (IX) or (X), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective for treating an amount of a compound of formula (VIII), (IX) or (X):

or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where:

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

base * is the purine or pyrimidine base as defined herein;

each R ¹² independently represents 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, halogenated alkyl (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 ( ) 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 ;

each R ¹³ independently represents 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, halogenated alkyl (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 carbocyclic ring), optionally substituted heterocycle (preferably 3-7 membered heterocyclic ring, having one or more O, S and / Whether N), optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having 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) SH, -C (O) SR ⁴ , -C (O) S ( lower alkyl), -C (O) NH ₂ , -C (O) NHR ⁴ , -C (O) NH (lower alkyl l), —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 (aralkyl), -S ( cycloalkyl), —NHR ⁴ , —NR ⁴ R ⁵ , —NH (alkenyl), —NH (alkynyl), —NH (aralkyl), —NH (cycloalkyl), SCN, OCN, NCO or fluoro;

alternatively, R ¹² and R ¹³ may in place form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or several atoms O, S and / or N), and

each m is independently 0, 1, or 2.

In a sixth main embodiment, there is provided a compound of formula (XI) or (XII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of the formula (XI) or (XII):

or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where:

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 have the meanings indicated above;

where in one embodiment, R ⁸ in the formula (XI) is —OH or —NH ₂ only when X is a carbon atom; and where

each R ⁸ and R ¹¹ independently represents 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, halogenated alkyl (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 , 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 ;

each R ⁹ and R ¹⁰ independently represents 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, halogenated alkyl (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 , optionally substituted alkenyl, haloalkenyl, Br-vinyl, optionally substituted alkynyl, haloalkynyl, optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring), optional substituted heterocycle (preferably 3-7 member a heterocyclic ring having one or more O, S and / or N atoms), an optionally substituted heteroaryl (preferably a 3-7 membered heteroaromatic ring having one or more O, S and / or N atoms), -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 al kil) 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 (aralkyl), -NH (cycloalkyl), -N (acyl) ₂ , azido, cyano, SCN, OCN, NCO or halogen (fluorine, chlorine, bromine, iodine);

each m is independently 0, 1 or 2 and

alternatively, R ⁸ and R ¹³ , and R ⁹ and R ¹³ , R ⁹ and R ¹¹ or R ¹⁰ and R ¹² may together form a bridging compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered a carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and / or N); or

alternatively, R ¹² and R ¹³ or R ⁹ and R ¹⁰ may together form a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably 3-7- member heterocyclic ring having one or more O, S and / or N).

In a specific aspect of the invention, there is provided a compound of formula (XIII) or (XIV), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula ( XIII) or (XIV):

or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where:

R ₃ selected from the group consisting of H; mono-, di- or triphosphate or a stabilized phosphate prodrug; acyl; sulfonate ester, optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acids; carbohydrate; peptide; cholesterol and a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ₃ independently represents H or mono-, di- or triphosphate;

X ”is selected from the group consisting of one or more of O, S, SO, SO ₂ , N, NH, NR and CH ₂ groups, where any of the above groups may be optionally substituted and may be in different positions, so that a 3-7 membered ring formed;

R represents H, alkyl or acyl;

B represents a spiro compound selected from the group consisting of an optionally substituted carbocycle (preferably a 3-7 membered carbocyclic ring) or an optionally substituted heterocycle (preferably a 3-7 membered heterocyclic ring having one or more O, S and / or N ) and

the base is selected from the group consisting of bases:

Where

each of R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR;

R represents H, alkyl or acyl;

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, and

its tautomeric forms.

In a second specific aspect of the invention, there is provided a compound of formula (XV), (XVI) or (XVII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective for treating an amount of a compound of formula (XV), (XVI) or (XVII):

or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, where:

G and E are independently selected from the group consisting of H, 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 or N-acyl;

R represents H, alkyl or acyl;

m is 0 or 1 and

R ³ and the base have the meanings indicated for formula (XIII).

Alternatively, for a compound of formula (XVII), at most one of G and E may also be hydrogen.

In a third specific aspect of the invention, there is provided a compound of formula (XVIII), or a pharmaceutically acceptable salt thereof, or a prodrug, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (XVIII) to treat:

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

M is selected from the group consisting of S, SO, and SO ₂ , and

R ₃ and the base have the meanings indicated for formula (XIII).

In a fourth specific aspect of the invention, there is provided a compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method for treating a host infected with Flaviviridae, comprising administering an effective treatment amount of a compound of formula (XIX), (XX), (XXI), (XXII) or (XXIII):

or its pharmaceutically acceptable salt or prodrug, or stereoisomeric, tautomeric or polymorphic forms, where

And selected from the group consisting of 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;

Y is selected from the group consisting of 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 represents H, alkyl or acyl;

X is selected from the group consisting of —OH, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, —O-alkyl, —O-alkenyl, —O-alkynyl, —O-aryl, —O-aralkyl, —O-cycloalkyl, -O-acyl, F, Cl, Br, I, CN, NC, SCN, OCN, NCO, 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 and (CH ₂ ) _m CONHR, an optionally substituted 3-7 membered carbocycle and an optionally substituted 3-7 membered heterocyclic ring having O, S and / or N as a heteroatom present as a single atom or in combination;

m is 0 or 1;

R ₃ selected from the group consisting of H; mono-, di- or triphosphate or a stabilized phosphate prodrug; substituted or unsubstituted alkyl; acyl; sulfonate ester, optionally substituted alkylsulfonyl; optionally substituted arylsulfonyl; lipid; amino acids; carbohydrate; peptide; cholesterol and a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ₁ independently represents H or mono-, di- or triphosphate, and

the base is a non-natural base selected from the group:

Where:

each R ′, R ′ ′, R ″ ″ and R ″ ″ ′ is independently selected from the group consisting of 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 represents CR — or N;

T and V independently represent CH or N;

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

Q ₁ and Q ₂ independently represent N or CR ′ ′ ′ ′ and

Q ₃ , Q ₄ , Q ₅ and Q ₆ independently represent N or CH, with the proviso that in bases (g) and (i) R ′, R ′ ′ ′ ′ are not H, OH or NH ₂ and Q, T, V, Q ₂ , Q ₅ and Q ₆ cannot be N.

In another preferred embodiment, there is provided a compound of formula (IX), or a pharmaceutically acceptable salt or prodrug thereof, or a stereoisomeric, tautomeric or polymorphic form, as well as a method of treating a host infected with Flaviviridae, comprising administering an effective amount of a compound of formula (IX) to be treated:

or its stereoisomeric, tautomeric or polymorphic form, or its pharmaceutically acceptable salt, where:

R ¹ , R ² and R ³ independently represent H; phosphate; straight chain, branched or cyclic alkyl; acyl; CO-alkyl; CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl; sulfonate ether; benzyl in which the phenyl group is optionally substituted with one or more substituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; lipid; an amino acid; carbohydrate; peptide; cholesterol or a pharmaceutically acceptable leaving group which, when administered in vivo, is capable of providing a compound in which R ¹ , R ² and / or R ³ independently represent H or phosphate,

X represents O, S, SO ₂ or CH ₂ ;

base * is a purine or pyrimidine base;

R ¹² represents C (Y ³ ) ₃ ;

Y ³ independently represents H, F, Cl, Br or I and

R ¹³ represents fluorine.

In one embodiment, X is O and Y ³ is H. In another embodiment, when X is O and Y ³ is H, R ¹ , R ² and R ^{3 are} also H.

II. Stereochemistry

Obviously, the nucleosides of the present invention have several chiral centers and can exist in the form of isolated optically active and racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present invention contains any racemic, optically active, diastereomeric, polymorphic or stereoisomeric form or mixtures of such forms of a compound of the invention that possess the applicable properties described herein. It is well known in the art how to obtain optically active forms (for example, by resolution of the racemic form by recrystallization methods, synthesis from optically active starting materials, chiral synthesis or chromatographic resolution using a chiral stationary phase).

In particular, since the 1'- and 4'-carbon atoms of a nucleoside are chiral, their non-hydrogen substituents (base and CHOR groups, respectively) can be either in the cis (on one side) or in the trans position (on opposite sides) relative to the system sugar rings. Therefore, the four optical isomers are represented by the following configurations (with the orientation of the sugar residue in the horizontal plane, so that the oxygen atom is located behind): cis (with both groups “up”, which corresponds to the configuration of β-D nucleosides existing in nature), cis (with by both groups “below”, which is a β-L configuration that does not exist in nature), trans (C2'-substitute is “above” and C4'-substitute is below) and trans (C2'-substitute is “below” and C4 'is the substituent at the top). “D-nucleosides” are cis nucleosides with a naturally existing configuration and “L-nucleosides” are cis nucleosides with a non-naturally occurring configuration.

Similarly, most amino acids are chiral (named as L and D, where the L-enantiomer has a naturally occurring configuration) and can exist as separate enantiomers.

Examples of methods for producing optically active materials are known in the art and include at least the following methods.

i) physical separation of crystals — a method by which macroscopic crystals of individual enantiomers are separated by a manual method. This method can be used if crystals of individual enantiomers exist, i.e. the material is a conglomerate and the crystals are visually distinguishable;

ii) simultaneous crystallization - a method by which individual enantiomers crystallize separately from a racemate solution, the method is possible only if the latter is a conglomerate in the solid state;

iii) enzymatic separation — a method by which partial or complete separation of the racemate is achieved due to different reaction rates of the enantiomers with the enzyme;

iv) enzymatic asymmetric synthesis - a synthesis method by which, at least in one step of the synthesis, an enzymatic reaction is used to obtain an enantiomerically pure or enantiomerically enriched synthetic precursor of the desired enantiomer;

v) chemical asymmetric synthesis - a synthetic method by which the desired enantiomer is synthesized from an achiral precursor under conditions in which asymmetry (i.e., chirality) appears in the product, which can be achieved using chiral catalysts or chiral excipients;

vi) separation of diastereomers — a method in which a racemic compound is reacted with an enantiomerically pure reagent (chiral excipient) that converts individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their new, more distinguishable structural differences and the chiral auxiliary is later removed to obtain the desired enantiomer;

vii) asymmetric transformations of the first and second order - the method by which the diastereomers from the racemate are brought to equilibrium with the predominance of the desired enantiomer in the diastereomer solution or in which the predominant crystallization of the diastereomer of the desired enantiomer violates the equilibrium state, so that upon subsequent equilibria essentially all the material is converted into the crystalline diastereomer of the desired enantiomer. The desired enantiomer is then isolated from the diastereomer;

viii) kinetic separation - this method relates to the achievement of partial or complete separation of the racemate (or further separation of the partially separated compound) due to the unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;

ix) enantiospecific synthesis from non-racemic precursors - a synthetic method by which the desired enantiomer is obtained from non-chiral starting materials and in which the stereochemical safety does not deteriorate or deteriorates only minimally throughout the synthesis;

x) chiral liquid chromatography — a method by which the enantiomers of the racemate are separated in the liquid mobile phase due to their different interactions with the stationary phase. The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral material to cause different interactions;

xi) chiral gas chromatography - the method by which the racemate is vaporized and the enantiomers are separated due to their different interactions in the gas mobile phase with a column containing a stationary non-racemic chiral absorbent phase;

xii) extraction with chiral solvents — a method by which enantiomers are separated by the predominant dissolution of one enantiomer in a given chiral solvent;

xiii) transfer through chiral membranes - the method by which the racemate is in contact with a thin membrane barrier. The barrier typically separates two miscible liquids, one containing a racemate, and a driving force, such as a difference in concentration or pressure, causes a preferred transfer through the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through it.

III. Definitions

The term “alkyl,” as used herein, unless otherwise indicated, refers to a saturated, unbranched, branched or cyclic primary, secondary or tertiary hydrocarbon, typically of C ₁ -C ₁₀ composition, and specifically includes 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, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl , 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, and specifically includes halogenated alkyl groups, and even more specifically fluorinated alkyl groups. Non-limiting examples of residues with which the alkyl group may be substituted are selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected or protected, if necessary, as is known to a person skilled in the art, for example, as indicated in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, included in this way by reference.

The term "lower alkyl", as used herein, unless otherwise indicated, refers to a C ₁ -C ₄ saturated unsubstituted, branched or, if necessary, cyclic (eg cyclopropyl) alkyl group, including both substituted and unsubstituted residues.

The term “alkylamino” or “arylamino” refers to an amino group that has one or two alkyl or aryl substituents, respectively. Unless specifically stated herein, when alkyl is a suitable residue, lower alkyl is preferred. Similarly, when alkyl or lower alkyl is a suitable residue, unsubstituted alkyl or lower alkyl is preferred.

The term “protected,” as used herein, unless otherwise indicated, refers to a group that is attached to an oxygen, nitrogen, or phosphorus atom to prevent further interaction or for other purposes. A person skilled in the art of organic synthesis knows a large number of protecting groups for oxygen and nitrogen atoms.

The term “aryl” as used herein, unless otherwise specified, refers to phenyl, biphenyl or naphthyl, preferably phenyl. The term includes both substituted and unsubstituted residues. The aryl group may be substituted by any desired residue, including, but not limited to, one or more residues selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy , nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected or protected, if necessary, as is known to a person skilled in the art, for example, as indicated in Greene, et al., Protective Groups in Organic Synthesis , John Wiley and Sons, Seco nd Edition, 1991, incorporated herein by reference.

The term “alkaryl” or “alkylaryl” refers to an alkyl group with an aryl substituent. The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent.

The term “halogen” as used herein includes chloro, bromo, iodo and fluoro.

The term “purine” or “pyrimidine” base includes, but is not limited to, adenine, N ⁶ -alkylpurines, N ^6- acylpurines (where acyl is C (O) (alkyl, aryl, alkylaryl or arylalkyl), N ⁶ -benzylpurine, N ⁶ -halogenopurine, N ⁶ -vinylpurine, N ⁶ -acetylenylpurine, N ⁶ -acylpurine, N ⁶ -hydroxyalkylpurine, N ⁶ -alkylaminopurine, N ⁶ -thioalkylpurine, N ² -alkylpurines, N ² -alkyl-6- thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and / or 4-mercaptopopyrimidine, uracil, 5-halogenouracil, including 5-fluorouracil, -Alkilpirimidiny C ^5, C ⁵ -benzilpirimidiny, -galogenpirimidiny C ^5, C ⁵ -vinilpirimidin, -atsetilenilpirimidin C ^5, C ⁵ -atsilpirimidin, -gidroksialkilpirin C ^5, C ⁵ -amidopirimidin, -tsianopirimidin C ^5, C ⁵ -yodpirimidin, -yodpirimidin C ^6, C ⁵ -Br-vinyl pyrimidine, C ⁶ -Br-vinyl pyrimidine, C ⁵ -nitropirimidin, C ⁵ -aminopirimidin, N -alkilpuriny ^2, N ² -alkyl-6-thiopurines, 5-azacytidine, 5-azauratsilil , triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurin, and 6-chloropurine. When necessary or desired, functional oxygen or nitrogen groups on the base can be protected. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, trityl, alkyl groups and acyl groups such as acetyl and propionyl, methanesulfonyl and p-toluenesulfonyl.

The term “acyl” or “O-linked ester” refers to a group of formula C (O) R ′, wherein R ′ is straight, branched or cyclic alkyl (including lower alkyl), an amino acid, aryl, including phenyl, alkaryl, aralkyl including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl, or substituted alkyl (including lower alkyl), aryl, including phenyl, optionally substituted with chlorine, bromine, fluorine, iodine, C ₁ - With _4- alkyl or C ₁ -C ₄ -alkoxy, sulfonate esters such as alkyl or aralkylsul fonyl, including methanesulfonyl, mono-di- or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl. Aryl groups in esters optimally contain a phenyl group. Particularly, the acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropylcarboxy, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neoheptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, α-methoxymethyl-α-methyloxymethyl-acetyl-phenyl-acetyl-acetyl-methyl-phenyl-acetyl-acetyl, bromoacetyl, 2-nitrobenzeneacetyl, 4-chlorobenzeneacetyl, 2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiophenacetyl, chlorosulfonylacetyl, 3-chlorosulfonylmethyl phenoxyacetyl, t ret-butylacetyl, trichloroacetyl, monochloroacetyl, dichloroacetyl, 7H-dodekaftorgeptanoil, perftorgeptanoil, 7H-dodekaftorgeptanoil, hlordodekaftorgeptanoil-7, 7-hlordodekaftorgeptanoil, dodekaftorgeptanoil-7H, 7H-dodekaftorgeptanoil, nonafluoro-3,6-dioksageptanoil, nonafluoro-3,6 dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl-3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxybenzoyl, 4- (1,1,2,2-tetrafluoroethoxy) benzoyl, 2-bromopropionyl, omega aminocapril, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentylpropionyl, 1-benzenecarboxyl, O-acetylma ndelyl, pivaloylacetyl, 1-adamantanecarboxyl, cyclohexanecarboxyl, 2,6-pyridinedicarboxyl, cyclopropanecarboxyl, cyclobutanecarboxyl, perfluorocyclohexylcarboxyl, 4-methylbenzoyl, chloromethylisoxazolylcarbonyl, perfluorocyclohexylcarbonyl-1-methyl-1-methyl-1-methyl 1-pyrrolidinecarbonyl, 4-phenylbenzoyl. When the term acyl is used, it means that it is a specific and independent description of acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neoheptanoyl, phenylacetyl, diphenylacetyl, α-trifluoromethylphenylacetyl, 4-bromo -chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiophenacetyl, tert-butylacetyl, trichloroacetyl, monochloracetyl, dichloroacetyl, methoxy benzoyl, 2-bromopropionyl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentylpropionyl, 1-benzenecarboxyl, pivaloylacetyl, 1-adamantanecarboxyl, cyclohexanecarboxyl, 2,6-pyridinedicarboxyl, methyl-4-cyclobutylcarbonyl, 1-methyl 1H-indazole-3-carbonyl, 2-propenyl, isovaleroyl, 4-phenylbenzoyl.

The term “amino acid” includes natural and synthetic α-, β-, γ- or δ-amino acids and includes, but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In a preferred embodiment, the amino acid has an L configuration. Alternatively, the amino acid residue may be alanyl, valinyl, leucinyl, isoleucinyl, proinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serynyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lyninyl, lyninyl, linyl, , β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serynyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-arginine or β-histidinyl. Tables 1-24 provide examples of amino acid species of the present invention. When the term amino acid is used, it is considered that it is a specific and independent description of each of the esters of α-, β-, γ- or δ-glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine with D and L configurations.

As used herein, the term “substantially free” or “substantially absent” refers to a nucleoside composition that contains at least 85 or 90 wt.%, Preferably 95%, 98%, 99% or 100 wt.% specific enantiomer of the specified nucleoside. In a preferred embodiment, in the methods and compounds of this invention, the compounds are essentially enantiomers that do not contain opposite enantiomers.

Similarly, the term "isolated" refers to a nucleoside composition that contains at least 85%, 90%, 95%, 98%, 99% or 100 wt.% Nucleoside, the rest are other chemical species or enantiomers.

The term "host", as used here, refers to a unicellular or multicellular organism in which the virus can replicate, including cell lines and animals, preferably humans. Alternatively, the host may carry part of the Flaviviridae viral genome, the replication or function of which may be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with the entire genome or part of the Flaviviridae genome, and animals, in particular primates (including chimpanzees) and humans. In most animal uses of the present invention, the host is a human patient. With some indications, however, the use of the present invention in veterinary medicine is certainly expected (for example, in the treatment of chimpanzees).

The term “pharmaceutically acceptable salt or prodrug” is used throughout the description to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, ester salt or related group) of a nucleoside compound that, when administered to a patient, provides for the formation of a nucleoside compound. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include salts formed from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, as well as numerous other acids well known in the pharmaceutical field. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example, hydrolyzed or oxidized in the host to form a compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on the functional residue of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The compounds of the present invention possess antiviral activity against Flaviviridae or are metabolized to a compound that has such activity.

IV. Prodrugs and derivatives

The active compound may be administered in the form of any salt or prodrug that, when administered to a recipient, is capable of directly or indirectly forming the parent compound or which itself has activity. Non-limiting examples are pharmaceutically acceptable salts (alternatively referred to as “physiologically acceptable salts”) and a compound that has been alkylated, acylated or otherwise modified at the 5'-position of a purine or pyrimidine base (type of “pharmaceutically acceptable prodrug”). In addition, modifications may affect the biological activity of the compound, in some cases increasing activity relative to the parent compound. This can be easily assessed by obtaining a salt or prodrug and testing its antiviral activity by the methods described herein or by other methods known in the art.

A. Pharmaceutically acceptable salts

In cases where the compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are acid addition salts with organic acids formed by the addition of acids that form a physiologically acceptable anion, e.g. tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, α-glycerophosphate formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate and salicylate. Suitable inorganic salts may also be prepared, including sulfate, nitrate, bicarbonate, carbonate salts, hydrobromate and phosphoric acid salts. In a preferred embodiment, the salt is a mono- or dihydrochloride salt.

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

B. Nucleotide prodrug preparations

Nucleosides described herein can be introduced as a nucleotide prodrug to enhance activity, bioavailability, stability, or other changes in the properties of a nucleoside. A number of ligands of nucleotide prodrugs are known. In general, alkylation, acylation or other lipophilic modification of a mono-, di- or triphosphate nucleoside reduces polarity and allows it to pass into cells. Examples of substituent groups that can replace one or more hydrogen atoms on a phosphate residue are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many of these are described in R. Jones and N. Bischoferger, Antiviral Research, 1995, 27: 1-17. Any of them can be used in combination with the described nucleosides to achieve the desired effect.

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

The active nucleoside can also be presented as a 2'-, 3'- and / or 5'-phosphoether with a lipid or a 2'-, 3'- and / or 5'-ether with a lipid. Non-limiting examples are described, which include the following references: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HTV-1 production and induce defective virus formation." AIDS Res. 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. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymine diphosphate dimyristoylglycerol, a lipid prodrug 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. "Synthesis and antiretroviral activity of phospholipid analogs of azidothymine and other antiviral nucleosides." J. Biol. Chem. 265: 61127.

Non-limiting examples of US patents that describe suitable lipophilic substituents that can be covalently incorporated into a nucleoside, preferably at the 2'-, 3'- and / or 5'-OH position of a nucleoside or lipophilic preparations, include US Pat. Nos. 5,149,794 (September 22, 1992, Yatvin et al.); 5,194,654 (March 16, 1993, Hostetler et al.); 5223263 (June 29, 1993, Hostetler et al.); 5,256,641 (October 26, 1993, Yatvin et al.); 5,411,947 (May 2, 1995, Hostetler et al.); 5,463,092 (October 31, 1995, Hostetler et al.); 5,543,389 (August 6, 1996, Yatvin et al.); 5,543,390 (August 6, Yatvin et al.); 5543391 (August 6, 1996, Yatvin et al.) And 5554728 (September 10, 1996; Basava et al.), All of which are incorporated herein by reference. Foreign patent applications that describe lipophilic substituents that can be attached to nucleosides of the present invention or lipophilic preparations include WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910 , WO 94/26273, WO 96/15132, EP 0350287, EP 93917054.4 and WO 91/19721.

Aryl esters, especially phenyl esters, are also proposed. Non-limiting examples are described in DeLambert et al., J. Med. Chem. 37: 498 (1994). Phenyl esters containing a carboxylic acid ester in the ortho position to phosphate are also proposed. Khamnei and Torrence, J. Med. Chem .; 39: 4109-4115 (1996). In particular, benzyl esters have been proposed which generate the parent compound, in some cases using substituents in the ortho or para position to accelerate hydrolysis. Examples of this class of prodrugs are described by 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 non-cyclic phosphonate esters are also proposed. Non-limiting examples are described in Hunston 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′-phosphate esters are provided. Non-limiting examples are described in Meier et al. J. Med. Chem. 22: 811-815 (1979). Cyclic 1 ', 3'-propanylphosphonate and phosphate esters, such as those containing a fused aryl ring, i.e. cyclosaligenyl ether (Meier et al., Bioorg. Med. Chem. Lett. 7: 99-104 (1997)). Unsubstituted cyclic 1 ', 3'-propanyl monophosphate esters are also proposed (Farquhar et al., J. Med. Chem. 26: 1153 (1983); Farquhar et al., J. Med. Chem. 28: 1358 (1985) ) In addition, cyclic 1 ′, 3′-propanyl esters are proposed which are substituted by the pivaloyloxymethyloxy group at C-1 ′ (Freed et al., Biochem. Pharmac. 38: 3193 (1989); Biller et al., US Patent No. 5157027).

It is known that phosphoramidates are cleaved in vivo by an oxidative mechanism. Thus, in one embodiment of the present invention, various substituted 1 ′, 3′-propanyl cyclic phosphoramidates are provided. Non-limiting examples are proposed in Zon, Progress in Med. Chem. 19, 1205 (1982). In addition, a number of 2'- and 3'-substituted proesters have been proposed. 2'-Substituents include methyl, dimethyl, bromo, trifluoromethyl, chloro, hydroxy and methoxy; 3'-substituents include phenyl, methyl, trifluoromethyl, ethyl, propyl, isopropyl and cyclohexyl. Various 1'-substituted analogs are also proposed.

Cyclic esters of phosphorus compounds are also proposed. Non-limiting examples are described in the following publications:

- [1] di- and triesters of phosphoric acids, as described in Nifantyev et al., Phosphorus, Sulfur Silicon and Related Elements, 113: 1 (1996); Wijnberg et al., EP-180276 A1;

- [2] esters of phosphorus (III) acids. Kryuchkov et al., Izv. Akad. Nauk SSSR, Ser. Khim. 6: 1244 (1987). Some compounds are claimed to be useful for asymmetric synthesis of L-Dopa precursors. Sylvain et al., DE 3512781 A1;

- [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] phosphonates. Neidlein et al., Heterocycles 35: 1185 (1993).

In addition, non-limiting examples of applications for US patents and international patents that describe suitable cyclic phosphoramidate prodrugs include US patent No. 6312662; WO 99/45016; WO 00/52015; WO 01/47935 and WO 01/18013, Erion et al. from Metabasis Therapeutics, Inc. Specifically, prodrugs of the following formula are provided.

Where

- V and Z are joined together through an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted by hydroxy, acyloxy, alkoxycarbonyloxy or aryloxycarbonyloxy attached to a carbon atom, which is the third atom of both O groups, attached to a phosphorus atom; or

- V and Z are joined together through an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, which is fused with an aryl group in beta and gamma position to O attached to the phosphorus atom;

- V and W are joined together via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy and aryloxycarbonyloxy attached to one of these carbon atoms which is the third atom from both O groups attached to the phosphorus atom;

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

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

- Z is selected from the group consisting of —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 ³ , —NHCO ₂ R ³ , —CH ₂ NHaryl, - (CH ₂ ) _p —OR ¹² and - (CH ₂ ) _p —SR ¹² ;

- p is an integer of 2 or 3;

- provided that:

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

- (b) when Z is —R ² then at least one of V, W and W ′ is not —H, alkyl, aralkyl or an alicyclic radical;

- R ² selected from the group consisting of R ³ and -H;

- R ³ selected from the group consisting of alkyl, aryl, alicyclic radical and aralkyl;

- R ^{12 is} selected from the group consisting of —H and lower acyl;

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

V. Combination or alternative therapy

The active compounds of the present invention can be administered in combination or alternation with another anti-flavivirus or pestivirus agent or, in particular, with an anti-HCV agent for the treatment of any of the conditions described herein. In combination therapy, effective doses of two or more agents are administered together, while in alternation or therapy with sequential steps, an effective dose of each agent is administered in stages or sequentially. The doses administered will depend on the absorption, inactivation and excretion rates of the drug, as well as other factors known to one skilled in the art. It should be noted that the dose values will also vary depending on the severity of the condition, which should be alleviated. In addition, it should be clear that for any particular subject, certain modes and schedules of drug administration should be adjusted over time in accordance with the needs of the patient and the professional assessment of the person administering or controlling the administration of the compositions. In preferred embodiments, an anti-HCV (or anti-pestivirus or anti-flavivirus) compound that exhibits an EC _{50 of} 10-15 μM or, preferably, less than 1-5 μM, is desirable.

It has been found that drug-resistant variants of flaviruses, pestiviruses, or HCV can appear after prolonged treatment with an antiviral agent. Drug resistance most commonly occurs due to a mutation in a gene that encodes an enzyme used in viral replication. The efficacy of a drug against viral infection can be prolonged, increased, or restored by administering a compound in combination or alternating with a second and, possibly, third antiviral compound that induces a mutation other than the mutation that is caused by the main drug. In an alternative case of pharmacokinetics, biodistribution or other parameter of a drug may be altered by such combination or alternative therapy. In general, combination therapy is usually preferred over alternative therapy because it induces multiple simultaneous stresses on the virus.

Any of the viral disease treatments described in the “Background of the Invention” section of this invention may be used in combination or alternation with the compounds described herein. Non-limiting examples include:

1) protease inhibitors

Examples thereof include 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 DE 19914474; Tung et al. Inhibitor of serine proteases, particularly hepatits C virus NS3 protease, PCT WO 98/17679), including alpha ketoamides and hydrazinoureas, and inhibitors that have an electrophile in the end position, such as boronic acid or phosphonate (Llinas-Brunet et al, Hepatitis C inhibitor peptide analog, PCT WO 99/07734); non-substrate-based NS3 protease inhibitors such as 2,4,6-trihydroxy-3-nitrobenzamide 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 having a 14-carbon atom substituted on the amide and the latter having a para-phenoxyphenyl group; and Sch 68631, phenanthrenquinone, an HCV protease inhibitor (Chi M. et al., Tetrahedron Letters 37: 7229-7232, 1996).

Sch 351633 isolated from Penicillium griseofulvum fungi 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 potent inhibitor of several serine proteases, such as proteases A and B of S. griseus, α-chymotrypsin, chymase and subtilisin. Qasim M.A. et al., Biochemistry 36: 1598-1607, 1997.

US patents describing protease inhibitors for treating HCV include, for example, US Pat. No. 6,004,933, Spruce et al., Which describes a class of cysteine protease inhibitors for inhibiting HCV endopeptidase 2; US patent No. 5990276, Zhang et al., which describes synthetic hepatitis C virus NS3 protease inhibitors; US patent No. 5538865, Reyes et al .; WO 02/008251, Corvas International, Inc., and WO 02/08187 and WO 02/008256, Schering Corporation. Tripeptides as HCV inhibitors are described in US Pat. Nos. 6,534,523, 6,410,531 and 6,420,380, by Boehringer Ingelheim, and WO 02/060926, Bristol Myers Squibb. Diaryl peptides as inhibitors of HCV NS3 serine protease are described in WO 02/48172, Schering Corporation. Imidazolinedinones as HCV NS3 serine protease inhibitors are described in WO 02/08198, Schering Corporation, and WO 02/48157, Bristol Myers Squibb. WO 98/17679, Vertex Pharmaceuticals, and WO 02/48116, Bristol Myers Squibb, also disclose HCV protease inhibitors;

2) Thiazolidine derivatives that show acceptable inhibition in the reverse phase HPLC analysis of the NS3 / 4A fusion protein and NS5A / 5B substrate (Sudo K. et al., Antiviral Research, 1996, 32, 9-18), especially compound RD-1 -6250 having a condensed cinnamoyl residue substituted with a long alkyl chain, RD4 6205 and RD4 6193;

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

4) Phenanthrenquinone having anti-protease activity in the SDS-PAGE assay and autoradiography and isolated from fermentation culture broth Streptomyces sp., Sch 68631 (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229, 7232), and Sch 351633 isolated from Penicillium griseofulvum fungi, which demonstrates activity in a scintillation proximal test (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949-1952);

5) Helicase inhibitors (Diana GD et al., Compounds, compositiobs and methods for treatment of hepatitis C, US Pat. No. 5,633,358; Diana GD et al., Piperidine derivatives, pharmaceutical composition and their use in the treatment hepatitis C, PCT WO 97/36554);

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

7) Antisense phosphorothioate oligodeoxynucleotides (S-ODNs) complementary to sequence segments in the 5'-non-coding region (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22, 707-717), or nucleotides 326-348, containing the 3'-terminal portion of the NCR and nucleotides 371-388 located in the coding region of the HCV RNA region (Alt M. et al., Archives of Virology, 1997, 142, 589-599; Galderisi U. et al., Journal of Cellular Physiology, 1999, 181, 251-257);

8) Inhibitors of IRES-dependent translation (Ikeda N. et al., Agent for the prevention and treatment of hepatitis C, Japanese Patent Publication JP-08268890; Kai Y. et al. Prevention and treatment of viral diseases, Japanese Patent Publication JP- 10101591);

9) Ribozymes, such as nuclease-resistant ribozymes (Maccjak, DJ et al., Hepatology 1999, 30, abstract 995), and ribozymes described in US Pat. No. 6,043,077, Barber et al., And US Pat. Nos. 5,869,253 and 5,600,054, Draper et. al .; and

10) Nucleoside analogues have also been developed for the treatment of Flaviviridae infection;

11) Any of the compounds described by Idenix Pharmaceuticals in International Patent Publications No. WO 01/90121 and WO 01/92282;

12) Compounds in other patent applications describing the use of certain nucleoside analogues for the treatment of hepatitis C virus infection, and such patent applications include: PCT / CA00 / 01316 (WO 01/32153; registered November 3, 2000), PCT / CA01 / 00197 (WO 01/60315; registered February 19, 2001), registered by BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT / US02 / 01531 (WO 02/057425; registered January 18, 2002) and PCT / US02 / 03086 (WO 02/057287 registered January 18, 2002) registered by Merck & Co., Inc., PCT / EP01 / 09633 (WO 02/18404; published August 21, 2001), registered by Roche, and PCT Publication No. WO 01/72246 (registered April 13, 2001), WO 02/32920 (registered October 18, 2001) and WO 02/48165, Pharmasset, Ltd., publication PCT No. WO 99/43691, Emory University, entitled "2'-Fluoronucleosides", which describes the use of certain 2'-fluoronucleosides for the treatment of HCV.

14) Other diverse compounds, including 1-aminoalkylcyclohexanes (US Pat. No. 6,034,134, Gold et al.), Alkyl lipids (US Pat. No. 5,922,757, Chojkier et al.), Vitamin E and other antioxidants (US Pat. No. 5,922,757, Chojkier et al.), squalene, amantadine, bile acids (US patent No. 5846964, Ozeki et al.), N- (phosphonoacetyl) -L-aspartic acid (US patent No. 5830905, Diana et al.), benzene dicarboxamides (US patent No. 5633388 , Diana et al.), Derivatives of polyadenyl acid (US patent No. 5496546, Wang et al.), 2 ', 3'-dideoxyinosine (US patent No. 5026687, Yarchoan et al.), Benzimidazoles (US patent No. 5891874, Colacino et al.), extract s plants (US patent 5,837,257 №, Tsai et al., US Patent 5,725,859 №, Omer et al., and U.S. Patent № 6,056,961) and piperidines (U.S. Patent 5,830,905, Diana et al.).

15) Other compounds currently undergoing preclinical or clinical development for the treatment of diseases caused by hepatitis C virus include: interleukin-10, developed by Schering-Plow, IP-501, developed by Interneuron, merimebodib (VX-497), developed by Vertex, amantadine® (Symmetrel), developed by Endo Labs Solvay, heptazim®, developed by RPI, IDN-6556, developed by Indun Pharma., XTL-002, developed by XTL., HCV / MF59, developed by Chiron, civacir® (hepatitis immune globulin C) developed by NABI, levovirin®, developed by ICN / Ribapharm, viramidine®, p developed by ICN / Ribapharm, zadaxin® (thymosin alpha-1), developed by Sci Clone, thymosin plus pegylated interferon, developed by Sci Clone, cloven® (histamine dihydrochloride), developed by Maxim, VX 950 / LY 570310, developed by Vertex 14803, developed by Isis Pharmaceutical / Elan, IDN-6556, developed by Idun Pharmaceuticals, Inc., JTK 003, developed by AKROS Pharma, BILN-2061, developed by Boehringer Ingelheim, CellCept (developed by mycophenolate mofetil), developed by Roche, T67, β-tubule inhibitor developed by Tularik, a therapeutic vaccine directed to E2, developed by Innogenetics, FK788, developed Fujisawa Healthcare, Inc., IdB 1016 (silifos, oral silybinphosphatidylcholinphytosomes), RNA replication inhibitors (VP50406), developed by ViroPharma / Wyeth, therapeutic vaccine developed by Intercell, therapeutic vaccine developed by Epimmune / IRENESA AN, AnenysA AN, AnenysA AN and ANAD 246 developed by Anadys, immunotherapy (therapist) developed by Avant, protease inhibitor developed by Corvas / SChering, helicase inhibitor developed by Vertex, fusion inhibitor developed by Trimeris, T-cell therapy developed by CellExSys, polymerase inhibitor developed by Biocryst, RNA-targeted chemical compounds developed by PTC Therapeutics, dication using Immtech, Int., protease inhibitor developed by Agouron, protease inhibitor developed by Chiron / Medivir, antisense therapy developed by AVI BioPharma, antisense therapy, developed Hybridon, a blood purifier developed by Aethlon Medical, a therapeutic vaccine developed by Merix, a protease inhibitor developed by Bristol-Myers Squibb / Axys, ChronVacC, a therapeutic vaccine developed by Tripep, UT 231B, developed by United Therapeutics, ingi Generabs Technologies protease, helicase and polymerase inhibitors, IRES inhibitors, developed by Immusol, R803, developed by Rigel Pharmaceuticals, Infergen® (interferon alfacon-1), developed by InterMune, omniferon (natural interferon), developed by Viragen, Albuferon® Sciences, rebif® (interferon beta-1a), developed by Ares-Serono, omega interferon, developed by BioMedicine, oral interferon alpha, developed by Amarillo Biosciences, interferon gamma, interferon tau and interferon gamma-1b, developed by InterMune.

VI. Pharmaceutical Compositions

Hosts, including people infected with pestivirus, flavivirus, HCV, or in any other condition described here, or infected with another organism that replicates via RNA-dependent viral polymerase RNA, or suffering from any other disease described, can be treated by administering to the patient an effective the amount of the active compound, or its pharmaceutically acceptable prodrug, or salt in the presence of a pharmaceutically acceptable carrier or diluent. The active materials may be administered by any suitable route, for example, by the oral, parenteral, intravenous, intradermal, subcutaneous or local route, in liquid or solid form.

A preferred dose of the compound for pestivirus, flavivirus or HCV will be in the range of from about 1 to 50 mg / kg, preferably 1-20 mg / kg of body weight per day, more typically from 0.1 to about 100 mg per kilogram of recipient body weight in a day. Lower doses may be preferred, for example, doses of 0.5-100 mg, 0.5-50 mg, 0.5-10 mg or 0.5-5 mg per kilogram of body weight per day. Even lower doses may be applicable, and thus ranges may include 0.1-0.5 mg per kilogram of body weight per day. The range of effective doses of pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the starting nucleoside to be delivered. If the salt and prodrug itself is active, the effective dose can be estimated, as indicated above, using a mass of salt or prodrug or by other methods known to a person skilled in the art.

The compound is suitably administered in unit dosage form, including, but not limited to, a dosage form containing 7-3000 mg, preferably 70-1400 mg of active ingredient per unit dosage form. Usually suitable is an oral dose of 50-1000 mg contained in one or more dosage forms with 50, 100, 200, 250, 300, 400, 500, 600, 700, 800, 900 or 1000 mg. Lower doses may be preferred, for example, from 10-100 to 1-50 mg. Estimated doses are also 0.1-50 mg, or 0.1-20 mg, or 0.1-10.0 mg. In addition, lower doses may be used if administered by the non-oral route, such as, for example, by injection or inhalation.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound from about 0.2 to 70 μM, preferably from about 1.0 to 10 μM. This can be achieved, for example, by intravenous injection of a 0.1-5% solution of the active ingredient, optionally in physiological saline, or by administering the active ingredient as a bolus.

The concentration of the active compound in the composition of the drug will depend on the absorption, inactivation and rate of excretion of the drug, as well as other factors known to the person skilled in the art. It should be noted that dose rates will also vary with the severity of the condition that needs to be alleviated. In addition, it should be clear that for any particular subject, the regimens and schedules for the administration of a particular drug should be adjusted over time in accordance with the needs of the patient and the professional assessment of the person administering or observing the administration of the compositions, and that the concentration ranges indicated here are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered once or may be divided into a series of smaller doses that must be administered at varying time intervals.

A preferred method of administering the active compound is the oral method. Oral compositions typically contain an inert diluent or an edible carrier. They can be incorporated into gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be mixed with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents and / or auxiliary materials may be included as part of the composition.

Tablets, pills, capsules, lozenges and the like may contain any of the following ingredients or compounds of a similar nature: a binder, such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterols; glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin, or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it contains, in addition to the material of the type indicated above, a liquid carrier such as a fatty oil. In addition, the unit dosage forms may contain various other materials that modify the physical form of the unit dose, for example, coatings of sugar, shellac or other enteric agents.

The compound may be administered as a component of an elixir, suspension, syrup, cachet, chewing gum or the like. The syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and some preservatives, colorants and flavoring agents.

The compound, or its pharmaceutically acceptable prodrug, or salts can also be mixed with other active materials that do not weaken the desired effect, or with materials that increase the desired effect, such as antibiotics, antifungal agents, anti-inflammatory agents or other antiviral agents, including including other nucleoside compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical use may include the following components: a sterile diluent, such as water for injection, saline, fatty oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and tonicity agents such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, multi-dose syringes or vials available, made of glass or plastic.

When administered intravenously, the preferred carrier is saline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are formulated with carriers that can protect the compound against rapid removal from the body, for example in the form of a controlled release preparation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate polymer, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods of obtaining such preparations should be known to a person skilled in the art. Materials can also be obtained commercially from Alza Corporation.

Liposome suspensions (including liposomes "targeted" to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. They can be obtained by methods known to a person skilled in the art, for example, as described in US Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome preparations can be prepared by dissolving suitable lipid (s) (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine and cholesterol) in an inorganic solvent, which is then evaporated to form a thin film of dried lipid on the surface after evaporation. An aqueous solution of the active compound or its monophosphate, diphosphate and / or triphosphate derivative is then introduced into the container. The contents of the container are then vortexed manually to release the lipid material from the walls of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

VII. The method of obtaining active compounds

The nucleosides of the present invention can be synthesized by any method known in the art. In particular, the synthesis of the present nucleosides can be achieved either by alkylation of a suitably modified sugar followed by glycosylation or glycosylation followed by alkylation of the nucleoside. The following non-limiting embodiments illustrate some general nucleoside production methodology of the present invention.

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

1'-C-branched ribonucleosides of the following structure:

where the 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 have the meanings indicated here, can be obtained by one of the following general methods.

1) Lactone modification

A key starting material for this process is suitably substituted lactone. The lactone can be purchased or can be obtained by any known method, including methods of epimerization, substitution and cyclization. The lactone may optionally be protected with a suitable protecting group, preferably an acyl or silyl group, by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The protected lactone may then be coupled with a suitable coupling agent such as an organometallic nucleophile for a carbon atom such as Grignard reagent, organolithium compound, lithium dialkyl copper or R ⁶ -SiMe ₃ in TBAF using a suitable non-polar solvent at a suitable temperature to give 1'-alkylated sugar.

The optionally activated sugar can then be combined with the base by methods well known to those skilled in the art, as indicated by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be combined with a silylated base under the influence of a Lewis acid such as tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate, in a suitable solvent at a suitable temperature.

Then the nucleoside can be released from the protective group by methods well known to the person skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is a 1'-C-branched ribonucleoside. The synthesis of ribonucleoside is shown in Scheme 1. Alternatively, the desired compound is deoxyribonucleoside. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-OH can be reduced with a suitable reducing agent. 2'-Hydroxyl may optionally be activated to facilitate reduction, i.e. by recovery according to the Barton method.

Scheme 1

2. An alternative way to obtain 1'-C-branched nucleosides

A key material for this process is suitably substituted hexose. Hexose can be purchased or can be obtained by any known method, including methods of standard epimerization (for example, by treatment with alkali), substitution and combination. Hexose can be selectively protected to provide suitable hexafuranose, as indicated by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994.

1'-Hydroxyl may optionally be activated by a suitable leaving group, such as an acyl group or halogen, by acylation or halogenation, respectively. Optionally, the activated sugar can then be coupled with the base by methods well known to one skilled in the art, as indicated by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be combined with a silylated base under the influence of a Lewis acid such as tetrachloride tin, titanium tetrachloride or trimethylsilyl triflate, in a suitable solvent at a suitable temperature. Alternatively, the halogen sugar can be combined with a silylated base in the presence of trimethylsilyl triflate.

The group 1'-CH ₂ -OH, if protected, can be selectively deprotected by methods well known in the art. The resulting primary hydroxyl can be functionalized to produce various C-branched nucleosides. For example, primary hydroxyl can be reduced to form methyl using a suitable reducing agent. Alternatively, hydroxyl may be activated prior to reduction to facilitate the reaction, i.e. through recovery according to the Barton method. In an alternative embodiment, the primary hydroxyl can be oxidized to an aldehyde, then combined with a nucleophile for a carbon atom, such as Grignard reagent, organolithium compound, lithium dialkyl copper or R ⁶ -SiMe ₃ in TBAF, using a suitable non-polar solvent at a suitable temperature.

In a specific embodiment, the desired compound is a 1-C'-branched ribonucleoside. The synthesis of ribonucleoside is shown in Scheme 2. Alternatively, the desired compound is deoxyribonucleoside. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-OH can be reduced with a suitable reducing agent. 2'-Hydroxyl may optionally be activated to facilitate reduction, i.e. by recovery according to the Barton method.

Scheme 2

In addition, the L-enantiomers corresponding to the compounds of the invention can be obtained by the same general methods (1 or 2) based on the corresponding L-sugar or L-enantiomer of the nucleoside as starting material.

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

2'-C-branched ribonucleosides of the following structure:

where the base, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , Y, W ¹ , W ² , W ³ , X, X ¹ , X ² and X ³ have the meanings indicated here, and can be obtained by one of the following general methods.

1. Glycosylation of a nucleoside base with a suitably modified sugar.

A key starting material for this process is a suitably substituted sugar with 2'-OH, 2'-H and with a suitable leaving group (LG), for example, an acyl group or halogen. Sugar can be purchased or can be obtained by any known method, including standard methods of epimerization, substitution, oxidation and recovery. The substituted sugar can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to give 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 reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymeric carrier, Cl ₂ -pyridine, Н ₂ О ₂ -ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meervein's reagent Pondorf Verley (aluminum tert-butoxide with another ketone ) And N-bromosuccinimide.

Then, by combining an organometallic nucleophile for a carbon atom, such as Grignard reagent, organolithium compound, lithium dialkyl copper or R ⁶ -SiMe ₃ in TBAF, with a ketone using a suitable non-polar solvent at a suitable temperature, a 2'-alkylated sugar is obtained. Alkylated sugar may optionally be protected with a suitable protecting group, preferably an acyl or silyl group, by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

Optionally, the activated sugar can then be coupled with the base by methods well known to one skilled in the art, as indicated by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be combined with a silylated base under the influence of a Lewis acid such as tetrachloride tin, titanium tetrachloride or trimethylsilyl triflate, in a suitable solvent at a suitable temperature. Alternatively, the halogen sugar can be combined with a silylated base in the presence of trimethylsilyl triflate.

Then the nucleoside can be released from the protective group by methods well known to the person skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is a 2-C'-branched ribonucleoside. The synthesis of ribonucleoside is shown in Scheme 3. Alternatively, the desired compound is deoxyribonucleoside. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-OH can be reduced with a suitable reducing agent. 2'-Hydroxyl may optionally be activated to facilitate reduction, i.e. by recovery according to the Barton method.

Scheme 3

2. Modification of the preformed nucleoside.

A key starting material for this method is a suitably substituted nucleoside with 2'-OH, 2'-H. The nucleoside can be purchased or can be obtained by any known method, including standard methods of combination. The nucleoside may optionally be protected with suitable protecting groups, preferably acyl or silyl groups, by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

A suitable protected nucleoside can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to give 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 reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymeric carrier, Cl ₂ -pyridine, Н ₂ О ₂ -ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meervein's reagent Pondorf Verley (aluminum tert-butoxide with another ketone ) And N-bromosuccinimide.

The nucleoside can then be freed from the protecting group by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is a 2-C'-branched ribonucleoside. The synthesis of ribonucleoside is shown in Scheme 4. Alternatively, the desired compound is deoxynucleoside. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-OH can be reduced with a suitable reducing agent. 2'-Hydroxyl may optionally be activated to facilitate reduction, i.e. by recovery according to the Barton method.

Scheme 4

In another embodiment, the desired compounds are L-enantiomers. Therefore, the L-enantiomers corresponding to the compounds of the invention can be obtained by the same aforementioned general methods from the corresponding L-sugar or L-enantiomer of the nucleoside as starting material.

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

3'-C-branched ribonucleosides of the following structure:

where the base, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Y, W ¹ , W ² , W ³ , X, X ¹ , X ² and X ³ have the meanings indicated here, and can be obtained by one of the following general methods.

1. Glycosylation of a nucleoside base with a suitably modified sugar.

A key starting material for this process is suitably substituted sugar with 3'-OH, 3'-H and a suitable leaving group (LG), for example, an acyl group or halogen. Sugar can be purchased or can be obtained by any known method, including standard methods of epimerization, substitution, oxidation and recovery. The substituted sugar can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to give a 3'-modified sugar. Possible oxidizing agents are Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine Cr (VI) oxide), Corey reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymeric carrier, Cl ₂ -pyridine, Н ₂ О ₂ -ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meervein's reagent Pondorf Verley (aluminum tert-butoxide with another ketone ) And N-bromosuccinimide.

Then, by combining an organometallic nucleophile for a carbon atom such as Grignard reagent, an organolithium compound, lithium dialkyl copper or R ⁶ -SiMe ₃ in TBAF, with a ketone using a suitable non-polar solvent at a suitable temperature, a 3'-C-branched sugar is obtained. The 3'-C-branched sugar may optionally be protected with a suitable protecting group, preferably an acyl or silyl group, by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The optionally protected sugar can then be combined with the base by methods well known to those skilled in the art, as indicated by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be combined with a silylated base under the influence of a Lewis acid such as tetrachloride tin, titanium tetrachloride or trimethylsilyl triflate, in a suitable solvent at a suitable temperature. Alternatively, the halogen sugar can be combined with a silylated base in the presence of trimethylsilyl triflate.

Then the nucleoside can be released from the protective group by methods well known to the person skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is a 3'-C-branched ribonucleoside. The synthesis of ribonucleoside is shown in Scheme 5. Alternatively, the desired compound is deoxyribonucleoside. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-OH can be reduced with a suitable reducing agent. 2'-Hydroxyl may optionally be activated to facilitate reduction, i.e. by recovery according to the Barton method.

Scheme 5

2. Modification of the preformed nucleoside

A key starting material for this method is a suitably substituted nucleoside with 3'-OH, 3'-H. The nucleoside can be purchased or can be obtained by any known method, including combination techniques. The nucleoside may optionally be protected with suitable protecting groups, preferably acyl or silyl groups, by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

A suitably protected nucleoside can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to give 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 reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide, phase transfer catalysts such as chromic acid or permanganate supported on a polymeric carrier, Cl ₂ -pyridine, Н ₂ О ₂ -ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meervein's reagent Pondorf Verley (aluminum tert-butoxide with another ketone ) And N-bromosuccinimide.

The nucleoside can then be freed from the protecting group by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is a 3'-C-branched ribonucleoside. The synthesis of ribonucleoside is shown in Scheme 6. Alternatively, the desired compound is deoxyribonucleoside. To obtain these nucleosides, the formed ribonucleoside can optionally be protected by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-OH can be reduced with a suitable reducing agent. 2'-Hydroxyl may optionally be activated to facilitate reduction, i.e. by recovery according to the Barton method.

Scheme 6

In another embodiment, the desired compounds are L-enantiomers. Therefore, the L-enantiomers corresponding to the compounds of the invention can be obtained by the same aforementioned general methods from the corresponding L-sugar or L-enantiomer of the nucleoside as starting material.

D. General synthesis of 4'-C-branched nucleosides

4'-C-branched ribonucleosides of the following structure:

where the 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 have the meanings indicated here, and can be obtained by one of the following general methods.

1. Modification of pentodialdofuranose

A key starting material for this process is suitably substituted pentodialdofuranose. Pentodialdofuranose can be purchased or can be obtained by any known method, including standard methods of epimerization, substitution and cyclization.

In a preferred embodiment, pentodialdofuranose is prepared from suitably substituted hexose. Hexose can be purchased or can be obtained by any known method, including standard methods of epimerization (for example, by alkaline treatment), substitution and combination. Hexose can be either in the form of furanose or cyclized by any method known in the art, such as the methodology described by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994, preferably by selectively protecting the hexose to produce suitable hexafuranose.

4'-Hydroxymethylene hexafuranose can then be oxidized with a suitable oxidizing agent in a compatible solvent at a suitable temperature to give a 4'-aldomodified sugar. Possible oxidizing agents are Swern reagents, Jones reagent (a mixture of chromic acid and sulfuric acid), Collins reagent (dipyridine Cr (VI) oxide), Corey reagent (pyridinium chlorochromate), pyridinium dichromate, acid dichromate, potassium permanganate, MnO ₂ , ruthenium tetroxide phase transfer catalysts such as chromic acid or permanganate supported on a polymeric support, Cl ₂ -pyridine, Н ₂ О ₂ -ammonium molybdate, NaBrO ₂ -CAN, NaOCl in HOAc, copper chromite, copper oxide, Raney nickel, palladium acetate, Meerwein-Pondorf-Verley reagent (aluminum tert-butoxide with another ketone) and N-bromosuccinimide, although it is preferable to use H ₃ PO ₄ , DMSO and DCC in a benzene / pyridine mixture at room temperature.

Then, pentodialdofuranose may optionally be protected with a suitable protecting group, preferably an acyl or silyl group, by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. In the presence of a base such as sodium hydroxide, protected pentodialdofuranose can then be combined with suitable electrophilic alkyl, haloalkyl (eg CF ₃ ), alkenyl or alkynyl (eg allyl ) to give 4'-alkylated sugar. Alternatively, the protected pentodialdofuranose can be combined with a corresponding carbonyl-containing compound, for example formaldehyde, in the presence of a base such as sodium hydroxide, in a suitable polar solvent such as dioxane, at a suitable temperature, the coupling product can then be reduced with a suitable reducing agent to give 4 '-alkylated sugar. In one embodiment, the reduction is carried out using PhOC (S) Cl, DMAP, preferably in acetonitrile, at room temperature, followed by treatment with ACCN and TMSS under reflux in toluene.

Optionally, activated sugar can then be combined with a base by methods well known in the art, as indicated by Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994. For example, an acylated sugar can be combined with a silylated base under the influence of a Lewis acid such as tin tetrachloride, tetrachloride titanium or trimethylsilyl triflate, in a suitable solvent at a suitable temperature.

The nucleoside can then be freed from the protecting group by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a specific embodiment, the desired compound is a 4'-C-branched ribonucleoside. Alternatively, the desired compound is a deoxyribonucleoside. To obtain these deoxyribonucleosides, the formed ribonucleoside may optionally be protected by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, and then 2'-OH can be reduced with a suitable reducing agent. 2'-Hydroxyl may optionally be activated to facilitate the reaction, i.e. through recovery by the Barton reaction.

In another embodiment, the desired compounds are L-enantiomers. Therefore, the L-enantiomers corresponding to the compounds of the invention can be obtained by the same above-mentioned general methods based on the corresponding L-pentodialdofuranose as starting material.

E. General synthesis of 2'- and / or 3'-prodrugs

A key starting material for this method is suitably substituted 1 ′, 2 ′, 3 ′ or 4′-branched β-D or β-L nucleosides. Branched nucleoside can be purchased or can be obtained by any known method, including the methods described here. The branched nucleoside may optionally be protected by a suitable protecting group, preferably a silyl group, by methods well known to those skilled in the art, as indicated by Greene et al. Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. The protected branched nucleoside can then be combined with a suitable acyl donor, such as acyl chloride or acid anhydride, in a suitable protic or aprotic solvent at a suitable temperature to give 2'- and / or 3'-prodrugs of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside. Alternatively, the protected branched nucleoside can then be combined with a suitable acyl-introducing compound, such as carboxylic acid, to administer an acyl such as acyl alkanoic acid and / or amino acids, optionally in the presence of a suitable coupling agent, in a suitable aprotic solvent at a suitable temperature to obtain a 2'- and / or 3'-prodrug of 1 ', 2', 3 'or 4'-branched β-D- or β-L-nucleoside. Possible coupling reagents are any reagents that promote coupling and include, but are not limited to, Mitsunobu reagents (e.g., diisopropylazadicarboxylate and diethyl azodicarboxylate) with triphenylphosphine or various carbodiimides.

For example, amino alcohols can simply be esterified using acid chlorides in a refluxing mixture of acetonitrile-benzene (see Scheme 7 below: Synthetic Communications, 1978, 8 (5), 327-333, thus incorporated by reference). Alternatively, the esterification can be 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.

Scheme 7

ACN: acetonitrile

The present invention is described by way of illustration in the following examples. One of ordinary skill in the art should understand that these examples are in no way limiting and that details of the details can be made without departing from the spirit and scope of the present invention.

EXAMPLE 1: Obtaining 1'-C-methylriboadenine with 6-amino-9- (1-deoxy-β-D-psicofuranosyl) purine

Melting points were determined on a Mel-temp II instrument and were not corrected. NMR spectra were recorded on a Bruker 400 AMX spectrometer at 400 MHz for ¹ H NMR and 100 MHz for ¹³ C NMR using TMS as an internal standard. Chemical shifts (δ) are indicated in parts per million (ppm) and the signals are indicated in the form s (singlet), d (doublet), t (triplet), sq (quartet), m (multiplet) or wide. s (extended singlet). IR spectra were measured on a Nicolet 510P IR spectrometer with FT (Fourier transducer). Mass spectra were recorded on a Micromass Autospec high resolution mass spectrometer. TLC was performed on Uniplates (silica gel) purchased from Analtech Co. Column chromatography was performed using either silica gel-60 (220-440 mesh) for flash chromatography or silica gel G (grade TLC,> 440 mesh) for vacuum flash column chromatography. UV spectra were obtained on a Beckman DU 650 spectrophotometer. Elemental analysis was performed by Atlantic Microlab, Inc., Norcross, GA, or Galbraith Laboratories, Inc., Knoxville TN. HPLC was performed on a Waters HPLC system (Millipore Corporation, Milford, MA) equipped with a Model 600 regulator, Model 996 photodiode array detector, and Model 717 plus autosampler. Millennium 2010 software was used to control the system, obtain and process data. To determine the optical rotation, a chiral laser polarimetric detector, a Perkin-Elmer polarimeter, model 241МC (Wilton, CT) were used.

Synthesis of 1'-C-methylribo-8-methyladenine

The title compound may also be prepared according to a published method (J. Farkas, and F. Sorm, "Nucleic acid components and their analogs. XCIV. Synthesis of 6-amino-9- (l-deoxy-β-D- psicofuranosyl) purine "Collect. Czech. Chem. Commun. 1967, 32, 2663-2667; J. Farkas, Collect. Czech. Chem. Commun. 1966, 31.1535) (Scheme 8).

Scheme 8

In the same manner, but using the appropriate sugar and purine bases, the following nucleosides of formula XXIV are prepared.

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

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

where 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 bases, the following nucleosides of formula XXVI are obtained

where R ¹ , R ² , R ³ , R ⁶ , X and the base have the meanings indicated here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of formula XXVII are obtained

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of formula XXVIII are obtained

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of formula XXIX are obtained

where R ¹ , R ⁶ , R ⁷ , R ⁸ , X, R ⁹ , R ¹⁰ and the base have the meanings indicated here.

EXAMPLE 2: Obtaining 2'-C-methylribo-8-methyladenine

The title compound was prepared according to a published method (RE Harry-O'kuru, JM Smith, and MS Wolfe, “A short, flexible route toward 2'-C-branched ribonucleosides”, J. Org. Chem. 1997, 62 , 1754-1759) (Scheme 9).

Scheme 9

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

A 3'-prodrug of a 2'-branched nucleoside is prepared according to a published method (Synthetic Communications, 1978, 8 (5), 327-333; J. Am. Chem. Soc., 1999, 121 (24), 5661-5664) . Alternatively, the 2'-branched nucleoside may be esterified without protection (Scheme 9b). Carbonyldiimidazole (377 mg, 2.33 mmol) is added to a solution of N- (tert-butoxycarbonyl) -L-valine (507 mg, 2.33 mmol) in 15 ml of anhydrous tetrahydrofuran. The mixture was stirred at 20 ° C. for one hour and at 50 ° C. for 10 minutes, and then 4-amino-1- (3,4-dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) - was added to the solution 1H-pyrimidin-2-one (500 mg, 1.95 mmol), 4- (dimethylamino) pyridine (25 mg, 0.195 mmol), triethylamine (5 ml) in anhydrous N, N-dimethylformamide (10 ml), which also stirred at 50 ° C. The reaction mixture was stirred at 50 ° C for one hour and then analyzed by HPLC. HPLC analysis showed the formation of 52% of the desired ester, 17% of the starting material in addition to undesirable by-products. 3'-OH 4-amino-1- (3,4-dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) -1H-pyrimidin-2-one tends to selectively interact with BOC-Val.

Similarly, but using the appropriate sugar and purine bases, the following nucleosides of formula XXX are prepared

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

Alternatively, using the appropriate sugar and pyrimidine bases, the following nucleosides of formula XXXI are prepared

where 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 bases, the following nucleosides of formula XXXII are prepared

where R ¹ , R ² , R ³ , R ⁶ , X and the base have the meanings indicated here.

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

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

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

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

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

where R ¹ , R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , X and the base have the meanings indicated here.

EXAMPLE 3: Obtaining 3'-C-methylribo-8-methyladenine

The title compound can be prepared according to a published method (RF Nutt, MJ Dickinson, FW Holly and E. Walton, “Branched-chain sugar nucleosides. III. 3'-C-methyladenin”, J. Org. Chem. 1968 , 33, 1789-1795) (Scheme 10).

Pattern 10

(a) RuO ₂ / NaIO ₄ ; (b) MeMgI / TiCl ₄ ; (c) HCl / MeOH / H ₂ O; (d) BzCl / pyridine; (e) AcBr, HBr / AcOH; (f) mercury (II) -6-benzamidopurin; (g) NH ₃ / MeOH.

Similarly, but using the appropriate sugar and purine bases, the following nucleosides of formula XXXVI are obtained

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

Alternatively, using the appropriate sugar and pyrimidine bases, the following nucleosides of formula XXXVII are prepared

where 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 bases, the following nucleosides of formula XXXVIII are obtained

where R ¹ , R ² , R ³ , R ⁶ , X and the base have the meanings indicated here.

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

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

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

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

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

where R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X and the base have the meanings indicated here.

EXAMPLE 4: Obtaining 1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose - (1)

The title compound can be prepared according to a published method (Leonard, NJ Carraway, KL “5-Amino-5-deoxyribose derivatives. Synthesis and use in the preparation of“ reversed ”nucleosides” J. Heterocycl. Chem. 1966, 3 , 485-489).

A solution of 50.0 g (0.34 mol) 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, is stirred for nights at room temperature. The resulting solution was neutralized with pyridine and evaporated under reduced pressure. The resulting oil is partitioned between 400 ml of water and 400 ml of methylene chloride. The aqueous layer was extracted twice with methylene chloride (400 ml). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (1-2%) in methylene chloride], to thereby give pure I (52.1 g, 75%) as a yellow syrup. ¹ H-NMR (CDCl ₃ ): δ 5.00 (s, 1H, H-1), 4.86 (d, 1H, H-2, J _2-3 = 5.9 Hz), 4.61 ( d, 1H, H-3, J _3-2 = 5.9 Hz), 4.46 (t, 1H, H-4, J _4-5 = 2.7 Hz), 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 (GT matrix): FAB> 0 m / z 173 (M-OCH ₃ ) ⁺ .

EXAMPLE 5: Obtaining 1-O-methyl-2,3-O-isopropylidene-β-D-pentodialdioriborofuranose - (2)

The title compound was prepared according to the published method (Jones, GH; Moffatt, JG Oxidation of carbohydrates by the sulfoxide-carbodiimide and related methods. Oxidation with dicyclohexylcarbodiimide-DMSO, diisopropylcarbodiimide-DMSO, acetic anhydride-DMSO, and phosphorus-DMSO, and phosphorus-DMSO, and phosphorus : in Methods in Carbohydrate Chemistry; Whisler, RL and Moffatt, JL Eds; Academic Press: New York, 1972; 315-322).

Compound 1 was evaporated twice with anhydrous pyridine. To a solution of 1 (68.2 g, 0.33 mol) in anhydrous benzene (670 ml), DMSO (500 ml) and pyridine (13.4 ml) was added dicyclohexylcarbodiimide (DCC, 137.8 g, 0.67 mol) . To the resulting solution, cooled to 0 ° C, add a solution of anhydrous crystalline phosphoric acid (16.4 g, 0.167 mmol) in anhydrous DMSO (30 ml). The mixture is stirred for 1.5 hours at 0 ° C and 18 hours at room temperature in an argon atmosphere, diluted with ethyl acetate (1000 ml). A solution of oxalic acid dihydrate (63.1 g, 0.38 mol) in DMSO (30 ml) was added and the reaction mixture was stirred at room temperature for 1 hour and then filtered to remove precipitated dicyclohexylurea (DCU). The filtrate was concentrated to a volume of approximately 600 ml under reduced pressure and neutralized with a saturated aqueous solution of sodium bicarbonate (400 ml). Saturated 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 approximately 2000 ml, washed with saturated aqueous sodium hydrogen carbonate solution (2 x 700 ml) and saturated brine (2 x 700 ml) before drying over sodium sulfate and evaporated under reduced pressure. A small portion of the crude residue was purified by silica gel chromatography [eluent: chloroform / ethyl ether, 8: 2] to confirm the structure of compound 2, which was obtained as a yellow solid. ¹ H-NMR (CDCl ₃ ): δ 9.61 (s, 1H, H-5), 5.12 (s, 1H, H-1), 5.08 (d, 1H, H-2, J _{2 -3} = 5.9 Hz), 4.53 (d, 1H, H-3, J _3-2 = 6.0 Hz), 4.51 (s, 1H, H-4), 3.48 (s , 1H, OCH ₃ ), 1.56 (s, 3H CH ₃ ), 1.36 (s, 3H CH ₃ ); MC (GT matrix): FAB> 0 m / z 203 (M + H) ⁺ , 171 (M-10 OCH ₃ ) ⁺ .

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

The title compound can be prepared according to the published method (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 nucleosides, 5. Hydroxylation of nucleoside 5'-aldehydes " J Org. Chem. 1979, 44, 1309-1317; Gunic, E .; Girardet, J.-L .; Pietrzkowski, Z .; Esler, C .; Wang, G. "Synthesis and cytotoxicity of 4'-C- and 5'-C-substituted Tovocamvcins (Bioorg , Med. Chem. 2001, 9, 163-170).

To a solution of the crude material (2) obtained above and 37% aqueous formaldehyde (167 ml) in dioxane (830 ml) was added aqueous sodium hydroxide (2 N, 300 ml). The mixture was stirred at room temperature for 4 hours and neutralized by the addition of dovex 50 WX 2 (H ⁺ form). The resin was filtered off, washed with methanol and the combined filtrates were concentrated to dryness and evaporated several times with absolute ethanol. Sodium formate, which precipitates from absolute ethanol, is removed by filtration, the filtrate is concentrated to dryness and the residue is purified by silica gel column chromatography [developing solution: stepwise gradient of methanol (0-4%) in chloroform] to obtain compound 3 (42.2 g, 54 % of 1), which is recrystallized from cyclohexane. T. pl. = 94-95 (decomp.) (Lit. data: 94-96.5; 97-98: references: 3, 4), ¹ H-NMR (DMSO-d ₆ ): δ 4.65 (s, 1H, H-1), 4.44-4.37 (m, 3H, H-2, H-3 and OH-6), 4.27 (t, 1H, OH-5, J = 5.6 Hz, J = 6.0 Hz), 3.42-3.34 (m, 2H, H-5 and H-6), 3.29 (dd, 1H, H-5 ', J _5'-OH = 5.4 Hz, J _{5-5 '} = 11.4 Hz), 3.11 (dd, 1H, H-6', J _6'-OH = 5.7 Hz, J _{6-6 '} = 10.9 Hz), 3.03 (s, 3H, OCH ₃ ), 1.48 (s, 3H CH ₃ ), 1.05 (s, 3H CH ₃ ); MC (GT matrix): FAB> 0 m / z 469 (2M + H) ⁺ , 235 (M + H) ⁺ , 203 (M-OCH ₃ ) + FAB <0 m / z 233 (MH) ^- .

EXAMPLE 7: Preparation of 6-O-Monomethoxytrityl-4-C-hydroxymethyl-1-O-methyl-2,3-diisopropylidene-β-D-ribofuranose - (4)

The title compound can be prepared according to a published method (Gunic, E .; Girardet, J.-L .; Pietrzkowski, Z .; Esler, C .; Wang, G. “Synthesis and citotoxicity of 4'-C- and 5'-C-substituded Toyocamycins "Bioorg. Med. Chem. 2001, 9, 163-170).

To a solution of 3 (41.0 g, 175 mmol) in pyridine (700 ml) was added portionwise dimethoxytrityl chloride (60.5 g, 178 mmol) at + 4 ° C. The reaction mixture was stirred for 3 hours at room temperature. After adding methanol, the reaction mixture was concentrated (200 ml) and then dissolved in ethyl acetate (2 L). The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, water and dried over sodium sulfate and then evaporated to dryness. Purification by silica gel column chromatography [developing solution: ethyl acetate / hexane, 15/85] afforded pure compound 4 (63.0 g, 68%) as a syrup. ¹ H-NMR (CDCl ₃ ): δ 7.5-6.9 (m, 13H, MMTr), 4.89 (s, 1H, H-1), 4.72-4.62 (m, 3H, H-2, H-3 and OH-5), 3.82 (dd, 1H, H-5, J _5-OH = 5.5 Hz, J _{5-5 '} = 10.5 Hz), 3.79 (s, 6H, OCH ₃ ), 3.54 (dd, 1H, H-5 ', J _5'-OH = 4.9 Hz, J _5'-5 = 10.5 Hz), 3.31 (s , 3H, OCH ₃ ), 3.24 (d, 1H, H-6, J _{6-6 '} = 9.2 Hz), 3.13 (d, 1H, H-6', J _6'-6 = 9.2 Hz), 1.24 (s, 3H CH ₃ ), 1.15 (s, 3H CH ₃ ); MS (GT matrix): 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-ribofuranose - (5)

The title compound can be prepared according to a published method (Gunic, E .; Girardet, J.-L .; Pietrzkowski, Z .; Esler, C .; Wang, G. “Synthesis and citotoxicity of 4'-C- and 5'-C-substituded Toyocamycins "Bioorg. Med. Chem. 2001, 9, 163-170).

To a solution of 4 (2.51 g, 4.68 mmol) in anhydrous pyridine (37 ml), benzoyl chloride (1.09 ml, 9.36 mmol) was added in an argon atmosphere, and the reaction mixture was stirred for 13 hours at room temperature. Then the reaction mixture was cooled to 0 ° C and the reaction was stopped with ice-cold water (100 ml). The aqueous layer was extracted with methylene chloride (3 x 200 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate (2 x 150 ml), water (1 x 150 ml) and 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 hours and concentrated to dryness. Purification by silica gel column chromatography [developing solution: chloroform] affords pure compound 5 (1.40 g, 88%) as a syrup. ¹ H-NMR (CDCl ₃ ): δ 8.1-7.4 (m, 5H, C ₆ H ₅ CO), 5.08 (s, 1H, H-1), 4.77 (dd, 2H, H-2 and H-3, J = 6.1 Hz, J = 8.2 Hz), 4.51 (q, 2H, H-5 and H-5 ', J = 11.5 Hz, J _{5- 5 '} = 23.8 Hz), 3.91 (t, 2H, H-6 and H-6', J = 12.3 Hz), 4.38 (s, 1H, OCH ₃ ), 2.2- 1.8 (br s, 1H, OH-6), 1.57 (s, 3H CH ₃ ), 1.38 (s, 3H CH ₃ ); MS (GT matrix): 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 title compound can be prepared according to a published method (Gunic, E .; Girardet, J.-L .; Pietrzkowski, Z .; Esler, C .; Wang, G. “Synthesis and citotoxicity of 4'-C- and 5'-C-substituted Toyocamycins "Bioorg. Med. Chem. 2001, 9, 163-170).

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 methylene chloride (500 ml) and washed successively with 0.2 M hydrochloric acid (2 x 500 ml) and water (500 ml) before drying over sodium sulfate, evaporated under reduced pressure and evaporated several times with anhydrous toluene. The crude material was dissolved in anhydrous toluene (880 ml) and tris (trimethylsilyl) silane (TMSS, 42.9 ml, 0.139 mol) and 1,1'-azobis (cyclohexanecarbonitrile) (ACCN, 6.8 g, 27.8 mmol) were added. ) The reaction mixture was stirred at reflux for 45 minutes, cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of diethyl ether (5-20%) in petroleum ether], to thereby give pure compound 6 (26.4 g, 74%) as a pale yellow syrup. ¹ H-NMR (DMSO-d ₆ ): δ 8.0-7.5 (m, 5H, C ₆ H ₅ CO), 4.85 (s, 1H, H-1), 4.63 (dd, 2H, H-2 and H-3, J = 6.1 Hz, J = 11.6 Hz), 4.24 (d, 1H, H-5, J _{5-5 '} = 11.1 Hz), 4 10 (d, 1H, H-5 ', J _5'-5 = 11.1 Hz), 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 (GT matrix): 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 an 80% aqueous solution of acetic acid (250 ml). The solution is heated at 100 ° C for 3 hours. The volume is then reduced by half and evaporated together with absolute ethanol and pyridine. The oily residue was dissolved in pyridine (280 ml) and then cooled to 0 ° C. Acetic anhydride (80 ml) and 4-dimethylaminopyridine (500 mg) are added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 L) and washed successively with saturated aqueous sodium hydrogen carbonate, 1 M hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of diethyl ether (30-40%) in petroleum ether] to obtain pure compound 7 (16.2 g, 60%) as a light yellow syrup. A small portion of the material is re-purified by silica gel chromatography [same eluent system] to separate the α and β anomers.

α-Anomer: ¹ H-NMR (DMSO-d ₆ ): δ 8.1-7.5 (m, 5H, C ₆ H ₅ CO), 6.34 (pt, 1H, H-1, J = 2 , 4 Hz, J = 2.1 Hz), 5.49 (m, 2H, H-2 and H-3), 4.33 (q, 2H, H-5 and H-5 ', J = 11, 6 Hz, J = 18.7 Hz), 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 (GT matrix): 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 ): δ 8.1-7.5 (m, 5H, C ₆ H ₅ CO), 5.99 (s, 1H, H-1), 5, 46 (d, 1H, H-2, J _2-3 = 5.3 Hz), 5.30 (d, 1H, H-2, J _2-3 = 5.3 Hz), 4.39 (d, 1H, H-5, J _{5-5 '} = 11.7 Hz), 4.19 (d, 1H, H-5', J _5'-5 = 11.7 Hz), 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 (GT matrix): 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-ribofuranosyl) -8-methylguanine - (eighteen)

To a suspension of O-6-diphenylcarbamoyl-8-methyl-N ² -isobutyryl guanine in anhydrous toluene (20 ml) was added N, O-bis (trimethylsilyl) acetamide (1.92 ml, 7.9 mmol). The reaction mixture was allowed to warm under reflux for 1 hour. Compound 7 (1.55 g, 3.93 mmol) was dissolved in toluene (10 ml) and trimethylsilyl trifluoromethanesulfonate (TMSTf) (915 ml, 4.72 mmol) was added. The mixture was heated under reflux for 30 minutes. The solution was then cooled to room temperature and neutralized with a 5% aqueous solution of sodium bicarbonate. The reaction mixture was diluted with ethyl acetate (200 ml). The organic phase is washed with 5% aqueous sodium hydrogen carbonate solution (150 ml) and water (2 x 150 ml). The organic layer was dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of diethyl ether (70-90%) in petroleum ether], to thereby give compound 18.

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

The title compound can be prepared according to the published method from compound 18 (Waga, T .; Nishizaki, T .; Miyakawa, I .; Orhui, H .; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

A solution of 18 in a solution of ammonia in methanol (preferably saturated at -10 ° C) (20 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (60 ml) and water (60 ml). The aqueous layer was washed with methylene chloride (2 x 60 ml), concentrated under reduced pressure. The residue was purified by RP18 column chromatography [water / acetonitrile eluent, 95/5], to thereby give compound 19.

EXAMPLE 13: 9- (2,3-Di-O-acetyl-5-O-benzoyl-4-C-methyl-β-D-ribofuranosyl) -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 (IV) chloride (SnCl ₄ , 660 μl, 5.58 mmol) and stirred at room temperature overnight . The solution was concentrated under reduced pressure, diluted with chloroform (100 ml) and treated with cold saturated aqueous NaHCO ₃ solution (100 ml). The mixture was filtered on celite and the precipitate was washed with hot chloroform. The filtrates were combined, washed with water (100 ml) and brine (100 ml), dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (3-5%) in dichloromethane], to thereby give compound 20.

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

The title compound can be prepared according to a published method from compound 20 (Waga, T .; Nishizaki, T .; Miyakawa, I .; Orhui, H .; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

A solution of compound 20 in a solution of ammonia in methanol (preferably saturated at -10 ° C) (50 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (100 ml) and water (100 ml). The aqueous layer was washed with methylene chloride (2 x 100 ml) and concentrated under reduced pressure. The residue was purified by silica gel chromatography [eluent: stepwise gradient of methanol (10-30%) in ethyl acetate], to thereby give compound 21.

Similarly, but using suitable sugar and purine bases, the following nucleosides of formula XXXXII are prepared.

where 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-ribofuranosyl) -6-methyluracil - (8)

A suspension of 6-methyluracil was treated with hexamethyldisilazane (HMDS, 21 ml) and a catalytic amount of ammonium sulfate for 17 hours under reflux. After cooling to room temperature, the mixture was evaporated under reduced pressure, and the residue obtained as a colorless oil was diluted with anhydrous 1,2-dichloroethane (7.5 ml). Compound 7 (0.99 g, 2.51 mmol) in anhydrous 1,2-dichloroethane (14 ml) was added to the resulting solution, followed by the addition of trimethylsilyl trifluoromethanesulfonate (TMSTf, 0.97 ml, 5.02 mmol). The solution was stirred for 2.5 hours at room temperature under argon, then diluted with chloroform (150 ml), washed with the same volume of a saturated aqueous solution of sodium bicarbonate, and finally with water (2 x 100 ml). The organic phase is dried over sodium sulfate, then evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography [developing solution: stepwise gradient of methanol (0-2%) in chloroform], to thereby give pure compound 8.

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

The title compound can be prepared according to a published method from compound 8 (Waga, T .; Nishizaki, T .; Miyakawa, I .; Orhui, H .; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

A solution of 8 in a solution of ammonia in methanol (pre-saturated at -10 ° C) (27 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was partitioned between methylene chloride (40 ml) and water (40 ml). The aqueous layer was washed with methylene chloride (2 x 40 ml), concentrated under reduced pressure and evaporated several times with absolute ethanol. Recrystallization from absolute ethanol / methanol gives compound 9.

EXAMPLE 17: Preparation of 1- (5-O-benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl) -4-thio-6-methyluracil - (10)

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

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

A solution of compound 10 in a solution of ammonia in methanol (pre-saturated at -10 ° C) (27 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was partitioned between methylene chloride (40 ml) and water (40 ml). The aqueous layer was washed with methylene chloride (2 x 40 ml), concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [developing solution: stepwise gradient of methanol (5-7%) in methylene chloride] to obtain compound 11, which was lyophilized.

EXAMPLE 19: Obtaining the hydrochloride form of 1- (4-C-methyl-β-D-ribofuranosyl) -6-methylcytosine - (12)

Compound 11 is treated with a solution of ammonia in methanol (pre-saturated at -10 ° C) (12 ml) at 100 ° C in a stainless steel bomb for 3 hours, then cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was partitioned between methylene chloride (40 ml) and water (40 ml). The aqueous layer was washed with methylene chloride (2 x 40 ml), concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [developing solution: methylene chloride / methanol / ammonium hydroxide, 65/30/5]. The collected fractions were evaporated under reduced pressure and in absolute ethanol (6.3 ml). To the solution add 2 N. hydrochloric acid solution (1.5 ml) and the mixture was stirred before concentration under reduced pressure. The procedure is repeated twice and compound 12 is precipitated from absolute ethanol.

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

A suspension of 6-methylthymine is treated with hexamethyldisilazane (HMDS, 17 ml) and a catalytic amount of ammonium sulfate overnight under reflux. After cooling to room temperature, the mixture was evaporated under reduced pressure, and the residue obtained as a colorless oil was diluted with anhydrous 1,2-dichloroethane (6 ml). Compound 7 (1.0 g, 2.53 mmol) in anhydrous 1,2-dichloroethane (14 ml) was added to the resulting solution, followed by the addition of trimethylsilyl trifluoromethanesulfonate (TMSTf, 0.98 ml, 5.06 mmol). The solution was stirred for 5 hours at room temperature under argon, then diluted with chloroform (150 ml), washed with the same volume of a saturated aqueous solution of sodium bicarbonate, and finally with water (2 x 100 ml). The organic phase is dried over sodium sulfate, then evaporated under reduced pressure. The resulting crude material was purified by silica gel column chromatography [developing solution: 2% methanol in chloroform] to obtain pure compound 13.

EXAMPLE 21: Obtaining 1- (4-C-methyl-β-D-ribofuranosyl) -6-methylthymine - (14)

The title compound can be prepared according to a published method from compound 13 (Waga, T .; Nishizaki, T .; Miyakawa, I .; Orhui, H .; Meguro, H. “Synthesis of 4'-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993, 57, 1433-1438).

A solution of 13 in a solution of ammonia in methanol (pre-saturated at -10 ° C) (60 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (60 ml) and water (60 ml). The aqueous layer was washed with methylene chloride (2 x 60 ml), concentrated under reduced pressure and evaporated several times with absolute ethanol. Recrystallization from methanol gives compound 14.

EXAMPLE 22: Preparation of 1- (5,2,3-tri-O-acetyl-4-C-methyl-β-D-ribofuranosyl) -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 [developing solution: stepwise gradient of methanol (0-5%) in methylene chloride], to thereby give compound 15.

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

Lawesson's reagent (119 mg, 0.29 mmol) was added under argon to a solution of 15 in anhydrous 1,2-dichloroethane (11 ml), and the reaction mixture was stirred overnight under reflux. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [developing solution: stepwise gradient of methanol (1-2%) in chloroform], to thereby give pure compound 16.

EXAMPLE 24: Obtaining the hydrochloride form of 1- (4-C-methyl-β-D-ribofuranosyl) -5-methyl-6-methylcytosine - (17)

Compound 16 is treated with a solution of ammonia in methanol (pre-saturated at -10 ° C) (10 ml) at 100 ° C in a stainless steel bomb for 3 hours, then cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was partitioned between methylene chloride (30 ml) and water (30 ml). The aqueous layer was washed with methylene chloride (2 x 30 ml), concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [developing solution: 20% methanol in methylene chloride], to thereby give compound 17. This compound was dissolved in EtOH 100% (1.5 ml), treated with 2 N. hydrochloric acid solution (0.3 ml) and the mixture was stirred before concentration under reduced pressure. The procedure is repeated twice and compound 17 is precipitated from absolute ethanol.

Alternatively, using the appropriate sugar and pyrimidine bases, the following nucleosides of formula XXXXIII are obtained

where 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 bases, the following nucleosides of formula XXXXIV are prepared

where R ¹ , R ² , R ³ , R ⁶ , X and the base have the meanings indicated here.

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

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of formula XXXXVI are obtained

where R ¹ , R ² , R ⁶ , X and the base have the meanings indicated here.

Alternatively, using the appropriate sugar and pyrimidine or purine bases, the following nucleosides of formula XXXXVII are obtained

where R ¹ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , X and the base have the meanings indicated here.

Viii. Biological tests

Several assays are suitable for determining the activity of test compounds against viruses. Some of these biological analyzes are described below.

EXAMPLE 25: Activity against flaviviruses or pestiviruses

Compounds that can be active against flaviviruses or pestiviruses by inhibiting the polymerase of flavivirus or pestivirus, by inhibiting other enzymes necessary in the replication cycle, or in other ways.

Analysis of nucleoside phosphorylation to obtain active triphosphate

To determine the cellular metabolism of the compounds, HepG2 cells obtained from the American Type Culture Collection (Rockville, MD) were grown in 225 cm ³ tissue culture flasks in a minimal, essential medium supplemented with essential amino acids, 1% penicillin-streptomycin. The medium is updated every three days and the cells are subcultured for one week. After separation of the adhered monolayer by 10 minutes exposure to 30 ml of trypsin-EDTA mixture and three successive washes with medium, HepG2 confluent cells were seeded at a density of 2.5 x 10 ⁶ cells per well in a 6-well plate and exposed to 10 μM [ ³ H] - labeled active compound (500 decays per min / pmol) for certain periods of time. Cells are maintained at 37 ° C in an atmosphere with 5% CO ₂ . At selected time points, the cells are washed three times with chilled ice, phosphate buffered saline (PBS). The intracellular active compound and its corresponding metabolites are extracted by incubating the cell pellet overnight at −20 ° C. with 60% methanol, followed by extraction with an additional 20 μl of cold methanol for one hour in an ice bath. The extracts are then combined, dried by passing a weak stream of air passing through the filter, and stored at −20 ° C. until HPLC analysis.

Dog accessibility bioavailability assay

Within 1 week before the start of the study, a dog-like monkey is surgically implanted with a permanent venous catheter and a subcutaneous venous input device (VAP) to facilitate blood collection and objective examination, including assessment of hematology and serum biochemistry, and body weight is recorded. Each monkey (a total of six) receives approximately 250 μCi of ³ H activity with each dose of the active compound at a dose level of 10 mg / kg at a dose concentration of 5 mg / ml, either by means of an intravenous bolus (3 monkeys, intravenous administration) or by oral feeding through a gastric tube (3 monkeys, oral administration). Each dosing syringe is weighed before dosing in order to determine the amount of drug administered by gravimetric methods. Urine samples are collected through a fixed device for the urinal (vessel) at certain time intervals (approximately 18-0 hours before dosing, 0-4, 4-8 and 8-12 hours after dosing) and processed. Blood samples are collected (before dosing, 0.25, 0.5, 1, 2, 3, 6, 8, 12, and 24 hours after dosing) also through a permanent venous catheter and VAP or from a peripheral vessel if the procedure for a permanent venous catheter is impossible. Blood and urine samples are analyzed to determine the maximum concentration (C _max ), the time when the maximum concentration (T _max ), the area under the curve (AUS), the half-life of the dosed compound (T _1/2 ), clearance CL), volume in stationary state and distribution (V _ss ) and bioavailability (F).

Bone marrow toxicity analysis

Human bone marrow cells are harvested from volunteers with normal health and the mononuclear population is separated by Ficoll-Hypaque gradient centrifugation as previously described by Sommadossi JP, Carlisle R. "Toxicity of 3'-azido-3'-deoxythymidine and 9- (1,3-dihydroxy -2-propoxymethyl) guanine for normal human hematopoietic progenitor cells in vitro "Antimicrobial Agents and Chemotherapy 1987; 31: 452-454; and Sommadossi JP, Schinazi RF, Chu CK, Xie MY. "Comparison of cytotoxicity of the (-) - and (+) - enantiomer of 2 ', 3'-dideoxy-3'-thiacytidine in normal human bone marrow progenitor cells" Biochemical Pharmacology 1992; 44: 1921-1925. Culture analyzes for CFU-GM and BFU-E are carried out using a bilayer soft agar or methyl cellulose method. Medicines are diluted in tissue culture medium and filtered. After 14-18 days at 37 ° C in an atmosphere of humidified air with 5% CO _{2, the} number of colonies with more than 50 cells is counted using an inverted microscope. The results are presented as percent inhibition of colony formation in the presence of the drug compared to solvent control cultures.

Mitochondrial Toxicity Analysis

HepG2 cells are cultured in 12-well plates as described above and exposed to various drug concentrations as indicated by Pan-Zhou XR, Cui L, Zhou XJ, Sommadossi JP, Darley-Usmer VM “Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cell ”Antimicrob. Agents Chemother. 2000; 44: 496-503. Lactic acid levels in the culture medium 4 days after drug exposure were measured using a Boehringer lactic acid analysis kit. Lactic acid levels are normalized by the number of cells measured by counting with a hemocytometer.

Cytotoxicity assay

Cells are seeded at a rate between 5 x 10 ³ and 5 x 10 ⁴ / well in 96-well plates in culture medium and cultured overnight at 37 ° C. in a humidified atmosphere with CO ₂ (5%). Then add a new nutrient medium containing drugs after dilution. After incubation for 4 days, the cultures are fixed in 50% TCA and stained with sulforodamine B. The optical density is determined at 550 nm. The concentration of cytotoxicity was expressed as the concentration required to reduce the number of cells by 50% (CC ₅₀ ).

Cell Protection Assay (CPA)

The analysis is carried out essentially as described by Baginski, SG; Pevear, DC; Seipel, M .; Sun, SCC; Benetatos, CA; Chunduru, SK; Rice, CM and MS Collett “Mechanism of action of a pestivirus antiviral compound” PNAS USA 2000, 97 (14), 7981-7986. MDBK (ATCC) cells were seeded on 96-well culture plates (4000 cells per well) 24 hours before use. After BVDV infection (NADL strain, ATCC) with a multiplicity of infection (MOI) of 0.02 plaque forming units (PFU) per test cell, both tested and uninfected cells are added test compounds after serial dilutions in nutrient medium with a final concentration of DMSO 0.5 % Each dilution is tested in four replicates. Cell densities and virus infection are adjusted to ensure continuous cell growth throughout the experiment and achieve more than 90% virus-induced cell destruction in untreated controls four days after infection. After four days, the plates were fixed with 50% TCA and stained with sulforodamine B. The optical density of the wells was determined in a microplate reader at 550 nm. Values of 50% effective concentration (EC ₅₀ ) are defined as the concentration of a compound that causes a 50% reduction in the cytopathic effect of the virus.

Plaque Reduction Analysis

For each compound, the effective concentration is determined in duplicate in 24-well plates by plaque reduction assays. Monolayers of cells infect 100 PFU / well of the virus. Then, test compounds with serial dilutions in MEM supplemented with 2% inactivated serum and 0.75% methylcellulose are added to monolayers. The cultures are further incubated at 37 ° C for 3 days, then fixed with 50% ethanol and 0.8% crystalline violet, washed and dried in air. Then plaques were counted to determine the concentration for 90% inhibition of the virus.

Virus yield (yield) reduction analysis

For each compound, the concentration to obtain a 6-log reduction in viral loading was determined in duplicate in 24-well plates by yield reduction assays. The analysis is carried out as described by Baginski, S. G .; Pevear, D.C .; Seipel, M .; Sun, S.C.C .; Benetatos, C.A .; Chunduru, S.K .; Rice, C.M. and M.S. Collett “Mechanism of action of a pestivirus antiviral compound” PNAS USA 2000, 97 (14), 7981-7986, with minor modifications. Briefly, MDBK cells are seeded in 24-well plates (2 x 105 cells per well) 24 hours prior to infection with BVDV (NADL strain) at a multiplicity of infection (MOI) of 0.1 PFU per cell. Test compounds with serial dilutions are added to the cells in a nutrient medium with a final concentration of DMSO of 0.5%. Each dilution is tested in triplicate. After three for cell culture (monolayers of cells and supernatants), they are lysed with three freeze / thaw cycles and the virus yield is quantified by plaque assay. Briefly, MDBK cells are seeded on 6-well plates (5 x 105 cells per well) 24 hours before use. Cells are inoculated with 0.2 ml of test lysates for 1 hour, washed and coated with 0.5% agarose in culture medium. After 3 days, monolayers of cells are fixed with 3.5% formaldehyde and stained with 1% crystalline violet (w / v in 50% ethanol) to visualize plaques. Plaques were counted to determine the concentration to obtain a 6-log reduction in viral load.

EXAMPLE 26: In Vitro Antiviral Activity

In vitro antiviral activity was tested in the following cell lines: MT-4 for HIV; Vero 76, African Green Monkey Kidney Cells for SARS; KSS for bovine viral diarrhea virus; Sb-1 for type 1 Sabin poliovirus; CVB-2, CVB-3, CVB-4 and CVA-9 for Coxsackie V-2, B-3, B-4 and A-9 viruses and REO-1 for (double-stranded) RNA viruses. Notes: BVDV = bovine viral diarrhea virus; YFV = yellow fever virus, DENV = dengue fever virus; WNV = West Nile virus, CVB-2 = Coxsackie B-2 virus; Sb-1 = poliomyelitis virus type 1 Sabin and REO = double-stranded RNA virus.

The results of the determination of CC ₅₀ and EC ₅₀ for β-D-2'-C-methyl-7-methyl-6-phenyl-3,3a, 5,8a-tetrahydro-1,3,4,5,7a-pentaase-sym -indacen-8-one (compounds F)

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

The results of the determination of SS ₅₀ for β-D-2'-C-methyl-7-methyl-6-phenyl-3,3a, 5,8a-tetrahydro-1,3,4,5,7a-pentaaz-sym-indacene -8-she (compound F)

CC ₅₀ Compound Bvdv Yfv Denv2 Wnv CVB-2 Sb-1 REO F > 100 10 2.5 1.3 one 37 43 2

The present invention has been described with reference to its preferred embodiments. Variants and modifications of the invention will be apparent from the above detailed description of the invention.

Claims (30)

1. The compound of formula (IX):

or a pharmaceutically acceptable salt thereof,
where R ¹ and R ² independently represent H; phosphate or C (O) R ', where R' is straight chain, branched or cyclic alkyl (including lower alkyl), an amino acid, aryl including phenyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl such as phenoxymethyl, or substituted alkyl (including lower alkyl), aryl, including phenyl, optionally substituted with chlorine, bromine, fluorine, iodine, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy, sulfonate esters, such as alkyl or aralkyl sulfonyl, including methanesulfonyl, mono-di or triphosphate e Fir, trityl or monomethoxytrityl, substituted benzyl, alkaryl, aralkyl, including benzyl, alkoxyalkyl, including methoxymethyl, aryloxyalkyl, such as phenoxymethyl;
X represents O;
base * is a purine base;
R ¹² represents C (Y ³ ) ₃ ;
Y ³ independently represents H and
R ¹³ represents fluorine. 2. The compound according to claim 1, where R ¹ and R ² represent N. 3. A pharmaceutical composition having an inhibitory activity against hepatitis C containing an effective amount of a compound or its pharmaceutically acceptable salt according to any one of claims 1 and 2 in a pharmaceutically acceptable carrier. 4. The pharmaceutical composition according to claim 3, where the carrier is suitable for oral delivery. 5. The pharmaceutical composition according to claim 4, where the compound or its pharmaceutically acceptable salt is presented in unit dosage form. 6. The composition according to claim 5, where the standard dosage form contains 0.1-50 mg or 50-1000 mg of the compound or its pharmaceutically acceptable salt. 7. The composition of claim 5, wherein said unit dosage form is a tablet or capsule. 8. The pharmaceutical composition according to claim 3, additionally containing a second antiviral agent. 9. The pharmaceutical composition of claim 8, where the second antiviral agent is selected from the group consisting of interferon, ribavirin, interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, phenanthrenone, a thiazolidine derivative, thiazolidine, benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analog, , cerulenin, antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation and ribozyme. 10. The pharmaceutical composition according to claim 9, where the second antiviral agent is interferon. 11. The pharmaceutical composition of claim 10, where the second antiviral agent is selected from the group consisting of pegylated interferon 2a, interferon alfacon-1, natural interferon, albuferon, interferon beta-1a, omega-interferon, interferon alpha, interferon gamma, interferon tau, interferon delta and interferon gamma-1b. 12. The pharmaceutical composition according to claim 3, where the compound or its pharmaceutically acceptable salt is in substantially pure form. 13. The pharmaceutical composition according to claim 3, where the compound or its pharmaceutically acceptable salt contains at least 90 wt.% Β-D isomer. 14. The pharmaceutical composition according to claim 3, where the compound or its pharmaceutically acceptable salt contains at least 95 wt.% Β-D isomer. 15. The pharmaceutical composition according to claim 3, additionally containing a pharmaceutically acceptable carrier suitable for oral, parenteral, inhalation or intravenous delivery. 16. The pharmaceutical composition according to claim 3, where the pharmaceutically acceptable salt is selected from the group comprising tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, α-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, silicylate, sulfate, nitrate, bicarbonate, carbonate, hydrobromate, hydrochloride, dihydrochloride and phosphoric acid salt. 17. The pharmaceutical composition according to clause 16, where the pharmaceutically acceptable salt is a hydrochloride salt. 18. The use of the compound or its pharmaceutically acceptable salt according to any one of claims 1 and 2 in the preparation of a medicament having inhibitory activity against hepatitis C virus. 19. The application of claim 18, wherein the drug further comprises a second antiviral agent. 20. The use according to claim 19, where the second antiviral agent is selected from the group comprising interferon, ribavirin, interleukin, NS3 protease inhibitor, cysteine protease inhibitor, phenanthrenone, thiazolidine derivative, thiazolidine, benzanilide, helicase inhibitor, polymerase inhibitor, nucleotide analog, gliotoxin, cerulenin, antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation and ribozyme. 21. The application of claim 20, where the second antiviral agent is interferon. 22. The application of claim 21, where the second antiviral agent is selected from the group consisting of pegylated interferon 2a, interferon alfacon-1, natural interferon, albuferon, interferon beta-1a, omega-interferon, interferon alpha, interferon gamma, interferon tau, interferon delta and interferon gamma-1b. 23. The use of claim 18, wherein the compound or a pharmaceutically acceptable salt thereof is presented in unit dosage form. 24. The use of claim 23, wherein the unit dosage form contains 0.1-50 mg or 50-1000 mg of the compound or a pharmaceutically acceptable salt thereof. 25. The use of claim 23, wherein said unit dosage form is a tablet or capsule. 26. The application of claim 18, wherein the compound or a pharmaceutically acceptable salt thereof is in substantially pure form. 27. The application of claim 18, wherein the compound or a pharmaceutically acceptable salt thereof contains at least 90 wt.% Of the β-D isomer. 28. The use of claim 18, wherein the compound or a pharmaceutically acceptable salt thereof contains at least 95% by weight of the β-D isomer. 29. The application of claim 18, wherein the pharmaceutically acceptable salt is selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, α-glycerophosphate, formate, fumarate, propionate, glycolate , lactate, pyruvate, oxalate, maleate, silicicylate, sulfate, nitrate, bicarbonate, carbonate, hydrobromate, hydrochloride, dihydrochloride and phosphoric acid salt. 30. The application of clause 29, where the pharmaceutically acceptable salt is the hydrochloride salt.

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