MX2008013668A

MX2008013668A - Anti-viral agents that activate rnase l.

Info

Publication number: MX2008013668A
Application number: MX2008013668A
Authority: MX
Inventors: Robert Silverman; Paul Torrence; Babal Kant Jha; Paula Francom
Original assignee: Cleveland Clinic Foundation
Priority date: 2006-04-25
Filing date: 2007-04-25
Publication date: 2009-01-27
Also published as: AU2007243403A1; CN101460471A; CA2650028A1; EP2016062A2; WO2007127212A3; RU2008146422A; JP2009536622A; IL194890A0; KR20090007609A; WO2007127212A2

Abstract

RNase L Activators and methods of using the same are disclosed herein.

Description

ANTIVIRAL AGENTS THAT ACTIVATE ARNASA L FINANCING OF GOVERNMENT The invention was funded, in whole or in part, by a grant NIH (NCI) 1R01 CA044059-21 from the National Institutes of Health. The government (of the United States) has certain rights in the invention. RELATED REQUESTS This application claims the benefit of United States Provisional Application No. 60 / 795,069, filed on April 25, 2006, the contents of which are incorporated herein by reference. BACKGROUND OF THE INVENTION Preclinical studies on RNase L, an antiviral enzyme in the interferon system (IFN), have suggested that it is an important target for cancer therapeutics and antiviral agents (Adah SA, Bayly SF, Cramer H, Silverman RH, Torrence PF (Curr Med Chem. August 2001; 8 (10): 1189-212) For example, the hereditary prostate cancer susceptibility locus 1 (HPC1) was recently mapped to the RNase L gene ( Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P, Bujnovszky P, Makalwska I, Baffoe-Bonni A, Faith D, Smith J, Stepah D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Atikainen M, Schleutker J, Klinger K, Conners T, Xiang Y, Wang Z, Demarzo A, Papdopoulos N, Kallioniemi 0-P, Burk R, Meyers D, Gronberg H, eltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J. Nature Genetics, January 22, 2002). In addition, the gene that confers resistance to flavivirus, including West Nile virus, was mapped to a gene in the RNase L (OASlb) pathway (Perelygin AA, Scherbik SV, Zhulin IB, Stockman B, Li Y, Brinton MA Proc Nati Acad Sci USA, July 9, 2002; 99 (14): 9322-7). In nature, RNase L is activated during the antiviral response of interferon by oligoadenylates with uncommonly small 2 ', 5'-internucleotide bonds (known as "2-5A") (Kerr IM, Brown RE Proc Nati Acad Sci USA. January 1978; 75 (1): 256-60; Zhou A, Hassel BA, Silverman RH, Cell., 1993 Mar. 12; 72 (5); 753-65). In addition, it has been previously shown that RNase L participates in the cellular antiproliferative activity of IFN (Hassel BA, Zhou A, Sotomayor C, Maran A, Silverman RH, EMBO J. August 1993, 12 (8): 3297-304). 2-5A induces through RNase L the degradation of ribosomal RNA (rRNA) and messenger RNA (mRNA), thereby reducing the levels of protein synthesis, properties that if applied to Smooth aortic muscle cells, could prevent restenosis after angioplasty. However, 2-5 A has undesirable properties for a therapeutic agent due to the fact that: 1) it is unstable in serum and in cells due to the action of phosphodiesterases and phosphatases; and 2) it is an intracellular mediator that does not cross plasmatic membranes. Therefore, there is a need for new RNAse L activators for clinical use. SUMMARY OF THE INVENTION The invention is based on the discovery of several compounds that activate RNase L (see Example 3) (hereinafter, the "described RNase L activators"). These RNase L activators have antiviral activity (see Example 6), including against parainfluenza virus 3 (HPIV3), picornavirus and encephalomyocarditis virus (EMCV). The described RNase L activators also inhibit the proliferation of smooth muscle cells in vi tro (see Example 7) and, therefore, have utility in the treatment of restenosis. It has been unexpectedly discovered that the RNase activators described are not cytotoxic (Example 5). Based on these findings, novel RNAse L activators, pharmaceutical compositions comprising these, are described herein.

RNAse L activators and methods of treatment with these RNase L activators. The described RNase activators, pharmaceutical compositions comprising them and methods of treatment using them are described with particularity in the claims. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1A-1F are graphs showing the dose response and kinetics of RNAse L activation versus concentration in ~ (Figures 1A-1C) or versus time in minutes (Figures 1D- 1E) with 2-5A or small molecular activators. The assays were by the RNase L FRET method and were performed at 22 ° C. (A, D) ppp (A2 'p5?) 2; (B, E) Compound 1; and (C, F) Compound 2. Figure 2 shows the structures of small molecular activators of RNAse L (Compounds 1-12) and their EC50 concentrations necessary for 50% degradation in the FRET RNA probe. NA means no activity. Figure 3 shows (A, B) alternative ribonuclease assays and (C) RNase L dimerization assays for 2-5A, compound 1 (C-1) and compound 2 (C-2). (A) Trimeric 2-5A 25 n (lanes 1, 2), C-l 25 ~ M (lanes 3, 4), C-2 25 -M (lanes 5, 6) with or without RNase L 25nM in presence of the RNA substrate, GGACUTJUUTJUUCCCUuJUUUUCC [32P] pCp, at 22 ° C for 30 min. (B) 2-5A trimeric 25n (lanes 2, 3), Cl 25 ~ M (lanes 4, 5), C-2 25 ~ M (lanes 6, 7) were incubated with or without 25 nM RNAse L and RNA, C7U2Ci2- [32P] pCp, at 22 ° C for 30 min. The excised RNAs were separated in sequencing gels of 20% acrylamide / 7 M urea / TBE. (C) Covalent crosslinking of RNase L by dimethyl suberimidate (D S). DMS was incubated with RNase L and trimer 2-5A (lanes 2 to 5), C-1 (lanes 6 to 9) or C-2 (lanes 10 to 13). After polyacrylamide gel electrophoresis with SDS, the proteins were transferred to nitrocellulose and probed with monoclonal antibody against RNase L. Figures 4A and 4B are graphs showing the displacement of biotin binding to 2-5A with RNase L for compounds 1 and 2, as determined by surface plasmon resonance. The biotinylated 2-5A was immobilized on a streptavidin biosensor chip (Biacore). RNase L (10 nM) in the presence of varying concentrations of compound 1 (A) or compound 2 (B) was allowed to flow on the chip at a rate of 20 μm / min for five minutes. The sensograms were recorded and analyzed using the Bia-evalon ™ software. In each case, the Rmax versus the increasing concentration of the compound in -M.

Figures 5A-5C are graphs showing the cytotoxicity of Compounds 1 and 2 for DU125 cells in an MTS conversion assay. Cytotoxicity was measured by absorbance at 490 nanometers versus concentration on ~ M on Day 1 (Figure 5A), Day 2 (Figure 5B) and Day 3 (Figure 5C). The results for Compound 1 are represented by blue; and the results for Compound 2 are represented by red. Figures 6A-6B are graphs showing the cytotoxicity of Compounds 1 and 2 for Hela M cells in an MTS conversion assay. Cytotoxicity was measured by absorbance at 490 nanometers versus concentration on ~ M on Day 1. The results for Compound 1 are represented by blue; and the results for Compound 2 are represented by red. Figure 6A shows the results for Hela M cells expressing RNase L; Figure 6B shows the results for Hela M cells expressing a RNase L mutant without nuclease activity. Figure 7 shows images under an inverted fluorescence microscope showing that Compound 2 suppresses HPIV3 / GFP replication. HeLa M cells deficient in RNAse L were used as control cells with vector empty, expressing wild-type RNase L or expressing an imitant RNase Lase without nuclease activity (R667A). Images were captured using an inverted fluorescence microscope. Figure 8 is a bar graph showing the antiviral effect of compound 2 at concentrations in ~ M against encephalomyocarditis virus (EMCV), as measured by the number of plates x 10"7. Figure 9 includes a graph bar showing the growth of MEF RL + + cells cultured with 0, 25 and 50 μ? of Compound 2. The bar graph shows the percentage of viral plaques obtained compared to the control (compound 2 0 μ ?, 100% = 2.5 x 104 PFU / ml) The increase in the concentration of compound 2 decreased the occurrence of virus production, as determined by the plaque assay, directly under each concentration of compound 2 is the corresponding agar plate stained with red Once again, the plates indicate decreased virus production with increasing compound 2 concentration, as determined by the plaque assay.Figure 10 is a bar graph showing the percentage of viral plaques obtained. or for MEF cells RL + +, BSC 40 and MEF RL "_ cultured in the absence or presence of compound 2. Compound 2 inhibited the virus titer for MEF cells RL + / + and BSC 40. Cells lacking the RNase L gene were resistant to compound 2. (Untreated controls (compound 2 0 μ? PFU / ml 100% counts: MEF RL + / +: 2.5 x 104; BSC 40: 2.5 x 104; and MEF RL_ / ": 3, 5 X 104) Figure 11 is an image of treated MEF RL + / + cells (compound 2 50 μ?) and untreated (compound addition 2.0 μ?) on agar plates stained with neutral red The presence of compound 2 resulted in a decreased virus plate count Figure 12: Table containing the exact virus plate counts as determined by the plate assay for both MEF RL + / + cells and MEF RL "/ _. Virus production in MEF RL + / + cells decreased in the presence of compound 2. Compound 2 did not decrease virus production in MEF cells RL_ / ". Virus dilution indicates that a 10-fold dilution of virus resulted in a 10-fold decrease in virus plaque count DETAILED DESCRIPTION OF THE INVENTION A "subject" is preferably a human being but can also be a veterinary animal, a farm animal or a laboratory animal in need of treatment for a viral infection, cancer or restenosis. Viral infections that can be treated with the described ASa L activators include viruses with single-stranded RNA by their genome. Examples include orthomyxoviruses (e.g., influenza virus), paramyxoviruses (e.g., respiratory syncytial virus and human parainfluenza virus 3), rhabdoviruses (e.g., rabies virus), togaviruses (e.g., rubella virus and rabies virus). western equine encephalitis), picornaviruses (eg, poliovirus and coxsackievirus), flaviviruses (eg, West Nile virus, Dengue virus and hepatitis C virus), bunyaviruses (eg, Lacrosse virus, Rift Valley fever and hantavirus), retroviruses (eg, XMRV gammaretrovirus and HIV-1 and 2 lentiviruses), filoviruses (eg, Ebola virus, hemorrhagic fever virus) or hepatitis B virus ( a DNA virus with an intermediate genomic RNA).

The described RNase L activators can also be used to treat infections of certain DNA viruses including human papillomaviruses, herpes simplex viruses 1 and 2, cytomegalovirus and human herpesvirus 8. In addition, the described RNAse L activators can also be used to treat infections of certain DNA virus including virus of smallpox (smallpox virus), monkeypox virus, molluscum contagiosum virus, Epstein-Barr virus, adenovirus, varicella zoster virus, human herpesvirus 6, human herpesvirus 7, parvovirus B19, adeno-associated virus, BK virus and JC virus too. Transfection of PC3 or DU145 cells with 2-5A causes apoptosis (Xiang Y, Wang Z, Murakami J, Plummer S, Klein EA, Carpten JD, Trent JM, Isaacs WB, Casey G, Silverman RH Cancer Res. 15 Oct 2003; 63 (20): 6795-801). Both DU145 and PC3, cell lines obtained from prostate cancer cases with brain and bone metastases respectively, are wild-type for RNase L. In addition, transfection of 2-5A causes caspase-dependent apoptosis in ovarian carcinoma cells human via a mitochondrial pathway (Rusch L, Zhou A, Silverman RH. J "Interferon Cytokine Res. December 2000; 20 (12): 1091-100.) In addition, 2-5A bound to an antisense against telomerase RNA caused apoptosis and antitumor activities against DU145 tumors in nude mice (Kondo Y, Koga S, Komata T, Kondo S. Oncogene, April 27, 2000; 19 (18): 2205-11) Based on the foregoing, the described RNase L activators can be used to treat cancers, examples of cancers that can be treated with RA asa L activators disclosed include, but are not limited to, human sarcomas and carcinomas, eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphaniosarcoma, lymphangioendotheliosarcoma, synovitis, mesothelioma, Ewing tumor, leiomyosarcoma , rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma , medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, ilm tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma , epithelial carcinoma, gli Ooma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma and retinoblastoma. The RNase L activators described are commonly used to treat prostate cancer, ovarian cancer, brain cancer or bone cancer.

Restenosis is a condition that can develop in blood vessels that have undergone coronary procedures or peripheral procedures with PTCA balloon catheters (for example, percutaneous transluminal angioplasty). Restenosis is the development of scar tissue from approximately three to six months after the procedure and results in a narrowing of the blood vessels. Restenosis is caused by excessive proliferation of smooth muscle. Because the described RNase L activators inhibit smooth muscle proliferation, it is thought that these compounds can be used to inhibit, treat and / or prevent restenosis. The term "alkyl", as used herein, refers to saturated straight or branched chain hydrocarbons. "Haloalkyl" is an alkyl substituted with one or more halogens. The term "halogen" refers to F, Cl, Br or I. Preferably, the halogen in a haloalkyl or haloalkoxy is F. The term "aromatic group" used alone or as part of a larger moiety as in "aralkyl", includes carbocyclic aromatic rings and heteroaryl rings. The term "aromatic group" can be used interchangeably with the terms "aryl", "aryl ring", "aromatic ring", "aryl group" and "aromatic group". "Aralkyl" is an alkyl group substituted with an aromatic group. "Fenalkyl" is an alkyl group substituted with a phenyl group. A "monocyclic aromatic group" is an aromatic group with only one ring. The carbocyclic aromatic ring groups have only carbon atoms in the ring and include monocyclic aromatic rings such as phenyl. The term "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group" and "heteroaromatic group", used alone or as part of a larger moiety such as in "heteroaralkyl" or "heteroarylalkoxy" refers to an aromatic group with one or more heteroatoms such as nitrogen, sulfur or oxygen as a ring atom. Monocyclic heteroaryl groups have five or six members and one or more heteroatoms in the ring, such as nitrogen, oxygen and sulfur. Examples of monocyclic heteroaryl groups include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl , 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, - pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl and 3-thienyl. A "substitutable carbon atom of the ring" in an aromatic group is a ring carbon atom attached to a hydrogen atom. The hydrogen can optionally be replaced by a suitable substituent group. Therefore, the term "ring substitutable carbon atom" does not include ring carbon atoms that are shared when two rings are condensed. In addition, "substitutable ring carbon atom" does not include ring carbon atoms when the structure represents that they are already attached to a residue other than hydrogen. Examples of suitable substituents on the substitutable carbon atom of the ring of an aryl group (eg, phenyl) include halogen, R °, -OR °, 0 (haloalkyl), -SR °, trialkylsilyl, boronate, alkylboronate, dialkylboronate, -N02, -CN, -N (R ') 2, NR'C02Ro, -NR'C (0) R ° (-NR' NR 'C (0) R °, -N (R') C (0) N (R 1) 2, NR'NR'C (0) N (R ') 2, -NR 1 NR' C02R °, -C (0) C (O) R °, -C (O) CH2C (0 ) R °, -C02R °, -C (0) R °, -C (0) N (R °) 2, -0C (0) R °, -0C (0) N (R °) 2, -S (0) 2R °, -S02N (R ') 2, -S (0) R °, -NR'S02N (R') 2, -NR'S02R °, -C (= S) N (R ') 2 , -NR 1 -C (= NH) -N (R 1) 2 and -C (= NH) -N (R ') 2 or two carbon atoms adjacent to the ring may be substituted with 1,2-methylene-dioxy or 1,2-ethylene-dioxy. Each R ° is independently hydrogen or an alkyl group. Each R 'is hydrogen or an alkyl group. When it is specified that an aralkyl group has a certain number of carbon atoms, it is understood that this is the number of carbon atoms in the alkyl portion of the aralkyl that is specified. For example, a C1-C2 aralkyl group has one or two carbon atoms in the alkyl portion.

The pharmaceutically acceptable salts include acid salts of a described RNase L activator that contains an amine or other basic group and can be obtained by reacting the compound with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like. Other examples of these salts include sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [for example (+) -tartrates, (-) -tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. Salts of a described RNase L activator containing a carboxylic acid group or other group can be prepared functional acid by reaction with a suitable base. Said pharmaceutically acceptable salt can be prepared with a base that produces a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts prepared from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine,?,? ' -dibenzylethylenediamine, 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine, tri- (2-hydroxyethyl) amine, procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietyl amine, β, β'-bisdehydroabietliamine, glucamine, N- methylglucamine, collidine, quinine, quinoline and basic amino acids such as lysine and arginine. "Treatment" or "to treat" refers to both therapeutic and prophylactic treatment. An "effective amount" is the amount of a described RNase L activator in which a beneficial clinical (prophylactic or therapeutic) response is achieved when the compound is administered to a subject in need of treatment. For the treatment of a viral infection, a "clinical response "beneficial" includes a reduction in the severity of symptoms associated with the disease (eg, fever), a reduction in the longevity of the disease and / or a delay in the onset of symptoms associated with the disease compared with the absence For the treatment of cancer, a beneficial clinical response includes a reduction in tumor mass, a reduction in the rate of tumor growth, a reduction in metastases, a reduction in the severity of symptoms associated with cancer and / or an increase in the longevity of the subject compared to the absence of treatment.For restenosis, a "beneficial clinical response" includes a slowing or reduction of narrowing of a blood vessel that has undergone angioplasty. A described RNase L activator administered to a subject will depend on the type and severity of the disease or condition and the characteristics of the the subject's characteristics, such as health in general, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease or condition. The specialist will be able to determine appropriate dosages depending on these and other factors. Typically, the effective amounts of the activator of RNase L described vary between about 0.1 mg / kg of body weight per day and about 1000 mg / kg of body weight per day and, preferably, between 1 mg / kg of body weight per day and 100 mg / kg of weight body per day. The RNase L activators described and pharmaceutically acceptable salts, solvates and hydrates thereof can be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include solid fillers or inert diluents and sterile aqueous or organic solutions. The RNase activator described will be present in said pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for the formulation and administration of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 19"edition, ack Publishing Co., Easton, PA (1995). For oral administration, the activator of described RNase or salts thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.

The tablets, pills, capsules and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a colorant and a flavoring such as cherry or orange flavor. For parenteral administration, the RNase L activators described or salts thereof can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. By example, solutions may be used in sesame or peanut oil, aqueous propylene glycol and the like, as well as aqueous solutions of pharmaceutically acceptable salts of the water soluble compounds. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the development of microorganisms. In addition to the formulations described above, the described RNase L activators can also be formulated as a long-acting formulation, such as a prolonged-release preparation. Such long-acting formulations can be administered by implantation or, for example, subcutaneously or by intramuscular injection. Preferably, the described RNase L activators or pharmaceutical formulations containing these compounds are in a unit dosage form for administration to a mammal. The unit dosage form can be any unit dosage form known in the art including, for example, a capsule, an IV bag, a tablet or a vial. The amount of the RNase activator described in a unit dose of The composition is an effective amount and can be varied according to the particular treatment involved. It can be appreciated that it may be necessary to make routine variations in dosing depending on the age and condition of the patient. The dosage will also depend on the route of administration, which may be by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal. Synthetic Strategy: The compounds of the generalized formula III will be synthesized following the procedure described by Faull and Hull [Faull and Hull. "Some reactions of Ethyl 2-Anilino-4-oxo-4, 5-dihydrothiophen-3-carboxylate." Perkin Transactions 1, 1981, 1078-1082]. Z2 in Formula I is S (isothiocyanate) or O (isocyanate). Condensation with substituted benzaldehydes will generate compounds of the structure represented in Formula IV. The modification of Ring A is carried out by selection of substituted aldehydes. The modification of Ring B is described in Schemes 3 and 4.

Scheme 1: rv The synthesis of Compound 1 follows this scheme directly. The isothiocyanatobenzene (V) will be coupled with ethyl 4-chloro-3-oxobutanoate (VI) under Faull and Hull conditions. The condensation of the intermediate of 2,3-dihydrothiophene (VII) with 3-hydroxybenzaldehyde will produce compound 1. Scheme 2: Modification of the substituents on Ring B will be done prior to the Faull-Hull synthesis described in Scheme 1. A representative synthetic strategy for to produce Compound XII is shown in Scheme 3. The readily available (E) -methyl (VIII) 3- (3-nitrophenyl) acrylate can be catalytically reduced to give the corresponding amine (IX). The formation of isothiocyanate (X) by coupling the amine and carbon disulfide in the presence of DCC produces the starting reagent similar to I in Scheme 1. The production of Compound XII follows the synthetic scheme of Faull-Hull. Scheme 3: The phosphonate compound XVIII will be prepared as shown in Scheme 4. Commercially available 3-aminophenol (XIII) will be protected by conventional methodology with dibenzyl pyrocarbonate in dioxane / H20 (1: 1) with NaOH or Et3N (to produce XIV). Deprotonation of the protected aminophenol with sodium hydride and coupling with the p-toluenesulfonyloxymethane phosphonate previously described in DMF (to produce compound XV) are followed by removal of the benzyloxycarbonyl protecting group by transfer hydrogenation (to produce compound XVI). The conversion of the free amine to the isothiocyanate and the condensation with ethyl 4-chloro-3-oxobutanoate to form the thiophene ring are directly analogous to the synthesis of compound XII. After coupling of the thiophene ring with 3-hydroxybenzaldehyde, selective deprotection of the dimethyl phosphonate ester (XVII) with aqueous pyridine is carried out to produce compound XVIII.

Scheme 4: Compound XVIII The invention is illustrated by the following examples, which are not intended to be limiting in any way. EXAMPLIFICATION Example 1 - Assay to identify agents that activate RNase L The assay is based on fluorescence resonance energy transfer (FRET). The method includes recombinant human RNase L produced in insect cells from a baculovirus vector and purified by FPLC (Thakur CS, Xu Z, Wang Z, Novince Z, Silverman RH A convenient and sensitive fluorescence resonance energy transfer assay for RNase L and 2 ', 5' oligoadenylates, Methods Mol Med 2005; 116: 103-13). The cleavable RNA substrate is a synthetic oligoribonucleotide of 36 nucleotides with a fluorophore (6-carboxyfluorescein, FAM) at the 5'-terminal end and a fluorescence buffer (black hole quencher-1, BHQ1), at the 3'-end. The RNA sequence is from the intergenic region of the genomic RNA of the paramyxovirus respiratory syncytial virus (RSV). The RSV sequence was selected because it contains several cleavage sites for RNase L (UU or UA) in an optimal context for cleavage. To demonstrate the effectiveness of the assay, RNA cleavage reactions were performed in 96-well black microtiter plates containing RNAse L, cleavable FRET RNA substrate and 2-5A. An EC50 (activator concentration to give 50% of maximal activation) of 0.3 nM with authentic 2-5A trimer [p3A (2 'p5?) 2] is routinely obtained as the activator of RNase L (Figure 1A ). The dephosphorylated trimer, A (2'p5'A) 2, was unable to activate RNase L, in accordance with the above findings (Figure 1A and D). Dong B, Xu L, Zhou A, Hassel BA, Lee X, Torrence PF, Silverman RH.

Intrinsic molecular activities of the interferon-induced 2-5A-dependent RNAase. J Biol Chem 1994; 269 (19): 14153-8. The inactive dephosphorylated 2-5A molecule is referred to as the "2-5A core". The signal to interference ratio was approximately 10: 1 and the test was very robust. There was no increase in the signal over time in reactions that contained RNA but lacked RNAse L or 2-5A. Example 2 - Identification of RNAse L inhibitors A high throughput scan was performed as described in Example 1 in the ChemBridge DIVERset of 34,000 small molecules (ChemBridge Co., San Diego). Compounds that provided signals at least 4 times above the background were selected as potential positives for the new assay. Seven "successes" were obtained (Figure 2, compounds 1 to 7).

The successes had molecular weights ranging from 298 to 470 Da and were able to activate RNase L in a micromolar range (EC50 between 22 and 99 ~ M) (Figures 1 and 2). The kinetics of RNA cleavage in the FRET assay shows almost maximal activation by pppA (2'p5'A) 2 in 15 minutes, while compounds 1 and 2 required 60 to 90 minutes to achieve the maximum level of RNA degradation (Figures 1D-F).

Other structure compounds related to these activators were identified in the ChemBridge repository using a searchable database (http://www.hit21ead.com). Two compounds of structure related to compound 1 were active (compounds 8-11) or inactive (compound 12) (Figure 2). Example 3 - Compounds 1 and 2 activate RNase L in ribonuclease assays with labeled substrates To verify that these compounds are indeed capable of activating RNase L, alternative conventional ribonuclease assays were performed with two different 32P labeled RNA substrates (Figures 3A and B). In these tests, 25 μ? of compound 1 (Figure 3A, lanes 3 and 4) and 25 μ? of compound 2 (Figure 3A, lanes 5 and 6) in the presence and absence of purified human RNase L with the synthetic RNA substrate GGACUUUUUUUCCCUUUUUUUCC- [32P] pCp (SEQ ID NO: 1). RNase L activated by 2-5 A or compounds 1 or 2 cleaved the substrate at the 3 'end of the UU dinucleotide sequence, in accordance with the findings of the FRET assay. Activation of RNase L by the major compounds 1 and 2 was further confirmed using a specific substrate sequence C7U2Ci2 (Figure 3B) (SEQ ID NO.

No.: 2). Compound 1 (25 μ?) (Lanes 4 and 5) and compound 2 (25 μ?) (Lanes 6 and 7) were separately incubated in the presence and absence of RNase L with the radiolabeled RNA substrate. RNase L activated by 2-5A, compound 1 or compound 2 cleaved the substrate at the 3 'end of the UU dinucleotide sequence. In the absence of activator, no product bands were detected. The dimerization of RNase L is a prerequisite for the activation of the nuclease. -To control the dimerization of RNase L, protein cross-linking assays were performed (Figure 3C). The oligomeric state of RNase L was determined in western blots probed with a monoclonal antibody against RNase L. Monomeric RNase L converted to dimer in the presence of 2-5A, compound 1 or compound 2 (Figure 3C). These data show that micromolar levels of compounds 1 and 2 activate RNase L and cause the enzyme to dimerize. Example 4 - Compounds 1 and 2 interact with the 2-5A analog binding domain of RNAse L A competitive binding assay of 2-5A using surface plasmon resonance in a Biacore model 3000 ™ was used to determine whether the activators interact with the 2-5A binding domain of RA asa L. The 2-5A analog used in these assays [? 5 '(A2'p) 3A bound through its 2', 3 'ribose -terminal with biotin] is obtained courtesy of Dr. H. Sawai (Gunma University, Japan) for these attempts. Streptavidin chips (Biacore Inc.) were previously coated with 2 -5A-biotin. Mixtures of RNase L (10 nM) and variable concentrations of compound 1 or compound 2 or RNase L itself were passed over the chips. The sensograms were recorded and the maximum resonance units (Rmax) at equilibrium were plotted against the compound concentrations using the Bia-evaluation ™ computer program (Figure 4). There was a dose-dependent decrease in the resonance response with compound 1 or 2. The data indicate that these compounds compete with 2-5A for RNase L binding. Analysis of the data indicated that the binding constants (Kd) ) for compounds 1 and 2 were 18 μ? and 12 μ?, respectively. Example 5 - Compounds 1 and 2 are not cytotoxic based on a tetrazolium conversion assay The cytotoxicity of compounds 1 and 2 was evaluated by MTS (tetrazolium) conversion assays (Promega). Treatments with compound 1 to 50 ~ for 3 days reduced cell viability to 76.3% and 98.2% of control levels (untreated) for DU145 and HeLa cells, respectively. Treatments with compound 2 (also at 50 ~ for 3 d) reduced cell viability, as a percentage of that of untreated cells, up to 95.2% and 86.5% for DU145 and HeLa cells, respectively. The results for DU145 cells are shown in Figure 5; and the results for Hela M cells are shown in Figure 6. As can be seen from the results, these compounds lack significant cytotoxicity. Example 6 - Compound 2 shows antiviral activity against parainfluenza 3 virus, picornavirus and encephalomyocarditis virus. To determine antiviral activity, cells were infected with a recombinant human parainfluenza 3 virus (HPIV3) into which green protein cDNA had been inserted. fluorescent (GFP) between the P and M genes (provided by collaboration with A. Banerjee) (Figure 7). The cell lines used are HeLa M cells that are deficient in RNAse L or HeLa M cells that stably express wild-type RNAse L or a mutant RNase L without nuclease activity (R667A) (from a CMV promoter in vector pcDNAneo ). The cells were infected at an MOI of 0.1 with HPIV3 / GFP in medium without serum (DMEM) for 1 hour. The media was removed, the cells were washed in PBS and complete media with 10% FBS was added in the absence or presence of 50 ~ M compound. At 24 h post-infection, the cells were examined under an inverted fluorescence microscope. It is evident that characteristic (green) syncytia were observed with HPIV3 / GFP infection of both HeLa M cells deficient in RNase L with vector alone or expressing mutant RNase L (R667A) treated as untreated. In contrast, compound 2 abruptly inhibited virus growth and suppressed syncytia formation in cells expressing wild-type RNase L. Fluorescence measurements indicated that compound 2 reduced viral growth by 8-fold in cells expressing wild-type RNase L, while there was only a 1.2-fold reduction in viral growth in the other two cell lines. In similar experiments, compound 1 also had antiviral activity. The antiviral activity of compound 2 was also obtained against the encephalomyocarditis virus (see Figure 8) and picornavirus (data not shown). Therefore, these compounds, which have a reduced toxicity, could have an antiviral activity general and are antiviral drugs candidates. Example 7 - The described activators of RNAse L inhibit the proliferation of smooth muscle cells The proliferation of clonal cell line A10 (obtained from the thoracic aorta of DB1X embryonic rats and possessing many of the characteristic properties of smooth muscle cells) was determined using CellTiter 96 * AQueous colorimetric cell proliferation assay, as described (Promega). This method uses the tetrazolium compound [3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxytoxhoxy) -2- (4-sulfophenyl) -2H-tetrazolium, MTS] and phenazine methosulfate (PMS) ), an electron coupling reagent. Cells were seeded (3 x 10 4 cells / well) in 96-well culture plates and treated with different concentrations of the compounds for 24 hours. CellTiter 96 * AQueous reagents (30% v / v dilution in PBS), 50 F1 were added to each well. The plates were incubated at 37 ° C for 2 h and the absorbance at 490 nm was measured with a 96-well plate reader (Molecular Devices, Spectra Max 340 model). The results demonstrate that the proliferation of smooth cells was inhibited thereby indicating that these compounds can function as a new class of therapeutic agents for prevention of restenosis. Compound 1 was tested. Example 8 - Compound 2 shows antiviral activity against Vaccinia virus (Strain: Western Reserve (WR)), a DNA virus of the poxvirus family Experimental Protocol: Virus strain: Western Reserve (WR) Cells: Immortalized mouse embryonic fibroblasts (EF) were cultured in RPMI supplemented with 10% FBS and w / v. Hamster brood kidney (BHK21) and African green monkey kidney (BSC40) cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, p / s and 1-glu. Title: BHK21 (hamster breeding kidney cells) for plate tests. MOI: Vaccinia virus (Western Reserve) 5 UFP using medium without serum for infection (virus stock: 1 x 109 PFU / ml) Compounds: Compound 2 at 0, 25 and 50 μ? in triplicate. Infection: Samples were collected from each sample 24 hours post-infection. Method: MEF (RNase L) RL + +, MEF (RNase L) RL_ "and BSC 40 cells were seeded in plates with 6 wells. they infected cells with an 80-85% confluence with Vaccinia virus (WR) at 5 PFU / ml using medium without serum. After 45 minutes, the cells were washed with PBS and the cells were re-cultured with freshly prepared medium with compound 2. After 24 hours post-infection the media was removed, the cells were scraped in PBS and frozen and thawed. times before determining the virus titers in BHK21 cells, the indicator cell line. Plate assay: BHK21 cells were seeded in 12-well plates, a complete monolayer of the cells was infected with different dilutions of virus using serum-free media. After 45 minutes post-infection, the media was removed and the cells were washed twice with PBS and replaced with agar medium [mixture of 2% agarose + (ME 2x + 20% FBS)], after two days the second layer of agar medium with 0.05% neutral red was added to count the plates. The results are shown in Figures 9, 10, 11 and 12 and are described in the Brief description section of the figures. Although this invention has been particularly shown and described with ret to preferred embodiments of the It will be understood by those skilled in the art that various changes may be made in the form and details thereof without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMS 1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the follg structural formula or a pharmaceutically acceptable salt thereof, wherein: Ring A and Ring B are optionally and independently substituted on any one or more ring substitutable carbon atoms; Y is CH, N or N + -0", Z1 and Z2 are independently O or S, Z3 is CR1 or N, R1 is -H, -C (0) H, -C (0) R20, -C (0) OR30 or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR30, -OC (0) H and -OC (0) R20 or R1 group represented by the follg structural formula R2 is -H or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, -OC (0) H or -OC (0) R20; each R20 is independently C1-C3 alkyl or C1-C3 haloalkyl; and R 30 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or a group represented by a structural formula selected from: 3. The pharmaceutical composition of claim 2 wherein the compound is represented by the follg structural formula: or a pharmaceutically acceptable salt thereof. 4. The pharmaceutical composition of claim 1 wherein: Ring A is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, - C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (O) R21 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, C (0) OR21, -OC (0) H or -OC (0) R21 or Ring A is optionally substituted with a group represented by the follg structural formula: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21, (CH2) 3R4 °, -CH2OCH2R40, -OCH2R40 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, -C (0) 0R21, -OC (O) H or -0C (0) R21; each R21 is independently H, C1-C3 alkyl or C1-C3 haloalkyl R40 is -COOH, -PO3H2, -SO3H, -P02H or -S02H. 5. The pharmaceutical composition of claim 4 wherein: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -OR2 , -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21, - (CH2) 3R40, -CH2OCH2R40 or a C1-alkyl group C3 substituted with hydroxyl, -0R21, keto, -C (0) OR21, -OC (0) H or -OC (0) R21; each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl. 6. The pharmaceutical composition of claim 4 or 5 wherein each R20 is independently C1-C3 alkyl, each R21 is independently C1-C3 alkyl, each R30 is independently C1-C3 alkyl and R2 is -H. 7. The pharmaceutical composition of claim 2 wherein the compound is represented by the follg structural formula: a pharmaceutically acceptable salt thereof The pharmaceutical composition of claim 7 wherein: Ring A is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, - C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, C (0) 0R21, -OC (0) H or -OC (0) R21 or with a group represented by the follg structural formula: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21, (CH2) 3R4 °, -CH2OCH2R40 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, -C ( 0) OR21, -OC (0) H or -OC (0) R21; each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl; and R40 is -COOH, -PO3H2, -SO3H, -P02H or -S02H. 9. The pharmaceutical composition of claim 8 wherein each R21 is independently C1-C3 alkyl, and R2 is -H. 10. The pharmaceutical composition of claim 2 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 11. The pharmaceutical composition of claim 10 wherein: Ring A is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21 (-OC (0) H, -OC (0) R21 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, C (0) OR21, -OC (0) H or -OC (0) R21 or with a group represented by the following structural formula: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) 0R21, -OC (0) H, -OC (0) R21, (CH2) 3R40, -CH2OCH2R40 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, -C (0) OR21, -OC (0) H or -OC (0) R21; each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl; and R40 is -COOH, -PO3H2, -SO3H, -P02H or -S02H. 12. The pharmaceutical composition of claim 11 wherein each R21 is independently C1-C3 alkyl and R2 is - H. 13. The pharmaceutical composition of claim 1 wherein the compound is represented by a structural formula selected from: or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition comprising a vehicle or pharmaceutically acceptable diluent and a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: Z3 and Z4 are independently 0 or S; Ring C and Ring D are optionally and independently substituted on any one or more substitutable ring carbon atoms; R3 is -H or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, -OC (O) H and -OC (O) R20; and each R20 is independently C1-C3 alkyl or haloalkyl. 15. The pharmaceutical composition of claim 14 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 16. The pharmaceutical composition of claim 15 wherein Ring C is optionally substituted on any one or more substitutable carbon atoms of the ring with C 1 -C 3 alkyl, halogen, = 0, hydroxyl or C 1 -C 3 alkoxy. 17. The pharmaceutical composition of claim 16 wherein Ring D is optionally substituted on one or more carbon atoms substitutable with halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, nitro, cyano, hydroxy, -0R21, -C (0 ) H, C (0) R21, -C (0) 0R21, -0C (0) H, -0C (0) R21 or a C1-C3 alkyl group substituted with halogen, hydroxyl, -OR21, keto, -C ( 0) OR21, -0C (0) H or -0C (0) R21 and each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl. 18. The pharmaceutical composition of claim 17 wherein R3 is -H. 19. The pharmaceutical composition of claim 18 wherein Ring C is unsubstituted. 20. The pharmaceutical composition of claim 14 wherein the compound is represented by a structural formula selected from: or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: Z5 and Z6 are independently O or S; Ring E and Ring F are optionally and independently substituted on any one or more ring substitutable carbon atoms; R6 is -H or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, - OC (0) H and -OC (0) R20; R7 and R8 are independently -H, a C1-C5 alkyl group or a C1-C5 haloalkyl group; Y each R20 is independently C1-C3 alkyl or haloalkyl. 22. The pharmaceutical composition of claim 21 wherein Z5 is S and Z6 is 0. 23. The pharmaceutical composition of claim 22 wherein Ring E and Ring F are optionally and independently substituted on one or more carbon atoms substitutable with halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, nitro, cyano, hydroxy, - 0R21, -C (0) H, -C (0) R21, -C (0) 0R21, -0C (0) H, -0C (0) R21 or a C1-C3 alkyl group substituted with halogen, hydroxyl, - 0R21, keto, -C (0) 0R21, -0C (0) H or -0C (0) R21; and each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl. 24. The pharmaceutical composition of claim 23 wherein R6 is -H. 25. The pharmaceutical composition of claim 24 wherein R7 and R8 are independently -H or a methyl. 26. The pharmaceutical composition of claim 21 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: X1 and X2 are independently CH2 > NH or O; X3 is -OC (O) -, -OC (S) -, -SC (O) -, -SC (S) -, -C (O) -, C (S) -, -CH2-, -CH ( CH3) -, -NHC (O) -, -C (0) NH-, -NHC (S) - or -C (S) NH-; Z8 and Z9 are independently S or O; Ring G is optionally substituted on any one or more ring substitutable carbon atoms; R9 is a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, - OC (0) H and -OC (0) R20; R10 and R11 are independently -H or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR2 °, -OC (0) H and -OC (0) R20; R12 is -H; a C1-C5 alkyl group optionally substituted with one or more groups represented by R21; a monocyclic aromatic group optionally substituted on any one or more substitutable carbon atoms of the ring with a group represented by R22; or a monocyclic C1-C3 aralkyl group optionally substituted on any one or more substitutable carbon atoms of the ring with R23; each R20 is independently C1-C3 alkyl or C1-C3 haloalkyl; each R21 is independently halogen, hydroxyl, OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, -OC (0) H or -OC (O) R20; each R22 and R23 is independently C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -OR24, -C (0) H, C (0) R24, -C (0) OR24, -OC (0) H, -OC (0) R24 or C1-C3 alkyl substituted with hydroxyl, -OR24, keto, -C (0) OR24, -OC ( 0) H or -OC (0) R24 and R24 is C1-C3 alkyl or C1-C3 haloalkyl. 28. The pharmaceutical composition of claim 27 wherein R1 is -H; a C1-C5 alkyl group optionally substituted with a group represented by R21; a phenyl group optionally substituted with a group represented by R22; or a C1-C3 phenalkyl group optionally substituted on any one or more substitutable carbon atoms of the ring with R23. 29. The pharmaceutical composition of claim 28 wherein the compound is represented by the following structural formula or a pharmaceutically acceptable salt thereof. 30. The pharmaceutical composition of claim 29 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein X3 is -O-C (O) - or -C (O) -. 31. The pharmaceutical composition of claim 30 wherein wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 32. The pharmaceutical composition of claim 31 wherein Ring G is optionally substituted on any one or more ring carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -OR25, - C (0) H, -C (0) R25, -C (0) OR25, -OC (0) H, -OC (0) R25 or C1-C3 alkyl substituted with hydroxyl, -OR25, keto, C (0) ) OR25, -OC (0) H or -OC (0) R25 and each R25 is independently C1-C3 alkyl or C1-C3 haloalkyl. 33. The pharmaceutical composition of claim 32 wherein R9 is a C1-C5 alkyl group optionally substituted with halogen, hydroxyl, C1-C3 alkoxy or C1-C3 haloalkoxy. 34. The pharmaceutical composition of claim 33 in the one that R is -H; an alkyl group optionally substituted with a group represented by R21; or a benzyl group optionally substituted on any one or more substitutable carbon atoms of the ring with R23; R21 is halogen, hydroxyl, C1-C3 alkoxy or Cl-C3 haloalkoxy; each R23 is independently C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -OR24, -C (0) H, -C (0) R24, C (0) OR24, -OC (0) H, -OC (0) R24 or C1-C3 alkyl substituted with hydroxyl, -OR24, keto, -C (0) OR24, -OC (0) H or -OC (0) R24. 35. The pharmaceutical composition of claim 34 wherein R10 is methyl, halomethyl or hydroxymethyl. 36. The pharmaceutical composition of claim 35 wherein R9 is C1-C5 alkyl; R10 is -C (C1) 3; and R12 is C1-C5 alkyl or benzyl. 37. The pharmaceutical composition of claim 27 wherein the compound is represented by a structural formula selected from: a pharmaceutically acceptable salt thereof method for treating a subject with an infection comprising administering an effective amount of the Pharmaceutical composition of any one of claims 1-37 to the subject. 39. The method of claim 38, wherein the viral infection is caused by a virus with a single-stranded RNA genome. 40. The method of claim 38 wherein the virus is orthomyxovirus (e.g., influenza virus), paramyxovirus (e.g., respiratory syncytial virus and human parainfluenza virus 3), rhabdovirus (e.g., rabies virus), togavirus (e.g. example, rubella virus and western equine encephalitis virus), picornavirus (eg, poliovirus and coxsackievirus), flavivirus (eg, West Nile virus, Dengue virus and hepatitis C virus), bunyavirus ( for example, LaCrosse virus, Rift Valley fever virus and hantavirus), retroviruses (eg, XMRV gammaretrovirus and HIV-1 and 2 lentiviruses), filoviruses (eg, Ebola virus, fever virus) hemorrhagic) or hepatitis B virus (a DNA virus with an intermediate genomic RNA). The method of claim 38, wherein viral infection is caused by a virus with a genora DNA 42. The method of claim 41, wherein the virus is human papillomavirus, herpes simplex virus 1 and 2, cytomegalovirus or human herpesvirus 8. 43. The method of claim 41, wherein the virus is smallpox (variola virus), monkeypox virus, molluscum contagiosum virus, Epstein-Barr virus, adenovirus, varicella zoster virus, human herpesvirus 6, human herpesvirus 7, parvovirus B19, adeno-associated virus, BK virus and JC virus, human papillomavirus, herpes simplex virus 1 and 2, cytomegalovirus or human herpesvirus 8. 44. A method for treating a subject with cancer comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 1-37. 45. The method of claim 44 wherein the cancer is prostate cancer, ovarian cancer, brain cancer or bone cancer. 46. A method for treating restenosis in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 1-37. 47. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: Ring A and Ring B are optionally and independently substituted on any one or more ring substitutable carbon atoms; Y is CH, N or N + -0"; Z1 and Z2 are independently O or S; Z3 is CR1 or N; R1 is -H, -C (0) H, -C (0) R20, -C (O) OR30 or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) 0R3 °, -0C (0) H and -0C (0) R20 or R1 is a group represented by the following structural formula: R2 is -H or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) 0R20, -0C (0) H or -0C (0) R20; each R20 is independently C1-C3 alkyl or C1-C3 haloalkyl; and R 30 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or a group represented by a structural formula selected from: 63 49. The compound of claim 48 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 50. The compound of claim 47 wherein: Ring A is substituted on any one or more ring-substitutable carbon atoms with halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, C (0) OR21, -OC (0) H or -OC (0) R21 or Ring A is optionally substituted with a group represented by the following structural formula: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, Cl-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -0R21, -C (0) H, -C (0 ) R21, -C (0) 0R21, -OC (0) H, -OC (0) R21, - (CH2) 3R40, -CH2OCH2R40, -OCH2R40 or a C1-C3 alkyl group substituted with hydroxyl, OR21, keto, -C (0) OR21, -OC (0) H or -OC (0) R21; each R21 is independently H, C1-C3 alkyl or C1-C3 haloalkyl; and R40 is -COOH, -P03H2, -S03H, -P02H or -S02H. 51. The compound of claim 50 wherein: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21, (CH2) 3R40, -CH2OCH2R40 or a C1-C3 alkyl group substituted with hydroxyl , -OR21, keto, -C (0) OR21, -OC (0) H or -OC (0) R21; each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl. 52. The compound of claim 50 or 51 wherein each R20 is independently C1-C3 alkyl, each R21 is independently C1-C3 alkyl, each R30 is independently C1-C3 alkyl and R2 is -H. 53. The compound of claim 48 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 54. The compound of claim 53 wherein: Ring A is substituted on any one or more ring-substitutable carbon atoms with halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, C (0) OR21, -OC (0) H or -OC (0) R21 or with a group represented by the following structural formula: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21, (CH2) 3R40, -CH2OCH2R40 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, -C (0) OR21, -OC (0) H or -OC (0) R21; each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl; and R40 is -COOH, -P03H2, -S03H, -P02H or -S02H. 55. The compound of claim 54 wherein each R21 is independently C1-C3 alkyl, and R2 is -H. 56. The compound of claim 48 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 57. The compound of claim 56 wherein: Ring A is substituted on any one or more ring-substitutable carbon atoms with halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0 ) H, -C (0) R21, -C (0) OR21, -OC (0) H, -0C (0) R21 or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, C (0) 0R21, -0C (0) H or -0C (0) R21 or with a group represented by the following structural formula: Ring B is substituted on any one or more ring-substitutable carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, OR21, -C (0) H, -C (0) R21, -C (0) OR21, -OC (0) H, -OC (0) R21, (CH2) 3R40, -CH2OCH2R4Q or a C1-C3 alkyl group substituted with hydroxyl, -OR21, keto, -C ( 0) OR21, -OC (0) H or -OC (0) R21; each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl; and R40 is -COOH, -P03H2, -S03H, -P02H or -S02H. 58. The compound of claim 57 wherein each R21 is independently C1-C3 alkyl and R2 is -H. 59. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: Z3 and Z4 are independently 0 or S; Ring C and Ring D are optionally and independently substituted on any one or more substitutable ring carbon atoms, - R 3 is -H or a C 1 -C 5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, -OC (0) H and -0C (0) R20; and each R20 is independently C1-C3 alkyl or haloalkyl, with the proviso that the compound is not represented by a structural formula selected from: a pharmaceutically acceptable salt thereof 60. The compound of claim 59 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 61. The compound of claim 60 wherein Ring C is optionally substituted on any one or more substitutable carbon atoms of the ring with C 1 -C 3 alkyl, halogen, = 0, hydroxyl or C 1 -C 3 alkoxy. 62. The compound of claim 61 wherein Ring D is optionally substituted on one or more carbon atoms substitutable with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -0R21, -C (0) H, -C (0) R21, C (0) OR21, -0C (0) H, -0C (0) R21 or a C1-C3 alkyl group substituted with halogen, hydroxyl, -0R21, keto, -C (0) ) OR21, -OC (0) H or -0C (0) R21 and each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl. 63. The compound of claim 62 wherein R3 is -H. 64. The compound of claim 63 wherein Ring C is unsubstituted. 65. A compound represented by the following formula structural: or a pharmaceutically acceptable salt thereof, wherein: Z5 and Z6 are independently O or S; Ring E and Ring F are optionally and independently substituted on any one or more ring substitutable carbon atoms; R6 is -H or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, -OC (0) H and -OC (0) R20; R7 and R8 are independently -H, a C1-C5 alkyl group or a C1-C5 haloalkyl group; and each R20 is independently C1-C3 alkyl or haloalkyl, with the proviso that the compound is represented by a structural formula other than: a pharmaceutically acceptable salt thereof 66. The compound of claim 65 wherein Z5 is S and Z6 is O. 67. The compound of claim 66 wherein Ring E and Ring F are optionally and independently substituted on one or more carbon atoms substitutable with halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, nitro, cyano, hydroxy, -OR 21 , -C (0) H, -C (0) R21, -C (0) 0R21, -0C (0) H, -OC (0) R21 or a C1-C3 alkyl group substituted with halogen, hydroxyl, -OR21 , keto, -C (0) OR21, -OC (0) H or -OC (0) R21; and each R21 is independently C1-C3 alkyl or C1-C3 haloalkyl. 68. The compound of claim 67 wherein R6 is -H. 69. The compound of claim 68 wherein R7 and R are independently -H or a methyl. 70. A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein: X1 and X2 are independently CH2, NH or O; X3 is -O-C (O) -, -O-C (S) -, -S-C (O) -, -S-C (S) -, -C (O) -, C (S) -, -CH2-, -CH (CH3) -, -NHC (O) -, -C (0) NH-, -NHC (S) - or -C (S) NH-; Z8 and Z9 are independently S or O; Ring G is optionally substituted on any one or more ring substitutable carbon atoms; R9 is a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, - OC (O) H and - OC (O) R20; R10 and R11 are independently -H or a C1-C5 alkyl group optionally substituted with one or more groups selected from halogen, hydroxyl, -0R20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, -OC (0) H and -OC (0) R20; R12 is -H; a C1-C5 alkyl group optionally substituted with one or more groups represented by R21; a monocyclic aromatic group optionally substituted on any one or more substitutable carbon atoms of the ring with a group represented by R22; or a monocyclic C1-C3 aralkyl group optionally substituted on any one or more substitutable carbon atoms of the ring with R23; each R20 is independently C1-C3 alkyl or C1-C3 haloalkyl; each R21 is independently halogen, hydroxyl, OR20, nitro, cyano, -C (0) H, -C (0) R20, -C (0) OR20, -OC (0) H or -OC (O) R20; each R22 and R23 is independently C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -OR24, -C (0) H, -C (0) R24, -C (0) OR24, -OC (0 ) H, -OC (0) R24 or C1-C3 alkyl substituted with hydroxyl, -OR24, keto, -C (0) 0R24, -OC (0) H or -OC (0) R24 and R24 is C1-C3 alkyl or C1-C3 haloalkyl, with the condition that the compound is not represented by a structural formula selected from: a pharmaceutically acceptable salt thereof 71. The compound of claim 70 wherein R is -H; a C1-C5 alkyl group optionally substituted with a group represented by R21; a phenyl group optionally substituted with a group represented by R22; or a C1-C3 phenalkyl group optionally substituted on any one or more substitutable carbon atoms of the ring with R23. 72. The compound of claim 71 wherein the compound is represented by the following structural formula. a pharmaceutically acceptable salt thereof 73. The compound of claim 72 wherein the compound is represented by the following structural formula: a pharmaceutically acceptable salt thereof, wherein O-C (O) - or -C (O) -. 74. The compound of claim 73 wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof. 75. The compound of claim 74 wherein Ring G is optionally substituted on any one or more ring carbon atoms with halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -OR25, -C (0) H, C (0) R25, -C (0) OR25, -OC (0) H, -OC (0) R25 or C1-C3 alkyl substituted with hydroxyl, -OR25, keto, -C (0) OR25, -OC (0) H or -OC (0) R25 and each R25 is independently C1-C3 alkyl or C1-C3 haloalkyl. 76. The compound of claim 75 wherein R9 is a C1-C5 alkyl group optionally substituted by halogen, hydroxyl, C1-C3 alkoxy or C1-C3 haloalkoxy. 77. The compound of claim 76 wherein R12 is -H; an alkyl group optionally substituted with a group represented by R21; or a benzyl group optionally substituted on any one or more substitutable carbon atoms of the ring with R23; R21 halogen, hydroxyl, C1-C3 alkoxy or C1-C3 haloalkoxy; each R23 is independently C1-C3 alkyl, C1-C3 haloalkyl, nitro, cyano, hydroxy, -OR24, -C (0) H, -C (0) R24, C (0) 0R24, -0C (0) H, -OC (0) R24 or C1-C3 alkyl substituted with hydroxyl, -OR24, keto, -C (0) 0R24, -OC (0) H or -OC (0) R24. 78. The compound of claim 77 wherein R10 is methyl, halomethyl or hydroxymethyl. 79. The compound of claim 78 wherein R9 is C1-C5 alkyl; R10 is -C (C1) 3; and R12 is C1-C5 alkyl or benzyl.