ANTI-VIRAL COMPOUNDS

Abstract: The present application provides a series of benzimidazole compounds which inhibit the growth of picornaviruses, such as rhinoviruses, enteroviruses, polioviruses, coxsackieviruses of the A and B groups, echo virus and Mengo virus and flaviviruses such as hepatitis C and bovine diarrheal virus.

Description: A TI-VIRAL COMPOUNDS The present invention is in the field of human medicine, particularly in the treatment of viral infections. More particularly, the present invention relates to the treatment of rhinoviral, enteroviral and flaviviral inventions . The incidence of viral upper respiratory disease, the common cold, is immense. It has been estimated that nearly a billion cases annually appear m the United States alone. Rhinovirus, a member of the picornaviridae family, is the major cause of the common cold in humans. Because more than 110 strains of rhinoviruses have been identified, the development of a practical rhinovirus vaccine is not feasible, and chemotherapy appears to be the more desirable approach. Another member of the picornavirus family is the enterovirus, which includes approximately eighty human pathogens. Many of these enteroviruses cause cold-like symptoms; others can cause more serious diseases such as polio, conjunctivitis, aseptic meningitis and myocarditis. Illness related to rhinovirus infection is evidenced by nasal discharge and obstruction. Furthermore, it has been implicated in otitis media, predisposes the development of bronchitis, exacerbates sinusitis, and has been implicated in the precipitation of asthmatic altoclis. Although t is considered by many to be a mere nuisance, its frequent occurrence m otherwise healthy individuals and the resulting economic importance in terms of employee absenteeism and physician visits have made it the subject of extensive investigation. The ability of chemical compounds to suppress the growth of viruses m vitro may be readily demonstrated using a virus plaque suppression test or a cytopathic effect test (CPE) . Cf Simmoff. Applied Microbiology, 9(1), 66 (1961) . Although a number of chemical compounds that inhibit picomaviruses such as rhinoviruses have been identified, many are unacceptable due to 1) limited spectrum of activity, 2) undesirable side effects or 3) inability to prevent infection or illness in animals or humans. See Textbook of Human Virology, edited by Robert B. Belshe, chapter 16, "Rhinoviruses, " Roland A. Levandowski, 391-405 (1985) . Thus, despite the recognized therapeutic potential associated with a rhinovirus inhibitor and the research efforts expended thus far, a viable therapeutic agent has not yet emerged. For example, antiviral benzimidazole compounds have been disclosed in U.S. Pat. Ser. Nos . 4,008,243, 4,018,790, 4,118,573, 4,118,742, 4,174,454 and 4,492,708. In general, the compounds disclosed in the above patents do not have a desirable pharmacological profile for use in treating rhinoviral infections. Specifically, these compounds do not possess satisfactory oral bioavailability or a high enough inhibitory activity to compensate for their relatively low oral bioavailability to permit their widespread use. In addition, it is widely accepted in the art that compounds used to treat rhinoviral infections should be very safe from a toxicological standpoint. Accordingly, it is a primary object of this invention to provide novel benzimidazole compounds which inhibit the growth of picomaviruses, such as rhinoviruses, enteroviruses such as polioviruses, coxsackieviruses of the A and B groups, or echo virus and which have a desirable pharmacological profile. The benzimidazole compounds may also be used to inhibit flaviviruses such as hepatitis C and bovine diarrheal virus (BVDV) . The present invention provides compounds of formula I wherein : each R is independently hydrogen, halo, cyano, ammo, halo(C 1 -C 4 ) alkyl, di (C 1 -C 4 )alkylammo, azido, Ci-Cβ alkyl, carbamoyl, carbamoyloxy, carbamoylammo, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfmyl, C 1 -C 4 alkylsulfonyl, pyrrolid o, pipeπdino or morpholino; R° is hydrogen, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R 1 is halo, cyano, hydroxy, methyl, ethyl, me hoxy, ethoxy, methylthio, methylsulf yl or methylsulfonyl; R 2 is hydrogen, ammo or -NHC (0) (Ci-Cβ alkyl) ; R 3 is dimethylam o, C 1 -C 10 alkyl, halo (C 1 -C 6 ) alkyl , C 3 -C 7 cycloalkyl, substituted C 3 -C 7 cycloalkyl, phenyl, substituted phenyl, naphthyl, thienyi, thiazolidmyl, furyl, pyrrolidmo, piperidino, morpholino or a group of the formul : R 4 and R 5 are independently hydrogen or C 1 -C 4 alky_L ; with the proviso that when R is in the 2- or 6-posιtιon, then R cannot be halo, cyano, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfmyl or methylsulfonyl; or a pharmaceutically acceptable salt thereof. The present invention also provides pharmaceutical formulations comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient therefor. The present invention also provides a method for inhibiting a picornavirus comprising administering to a host in need thereof, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein a, R, R°, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above. The present invention relates to benzimidazole compounds of formula I, as described above, that are useful as antiviral agents. All temperatures stated herein are in degrees Celsius (°C) . All units of measurement employed herein are in weight units except for liquids which are in volume units. As used herein, the term "Cι-Cχo alkyl" represents a straight or branched alkyl chain having from one to ten carbon atoms. Typical Ci-Cio alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl, neo-pentyl, hexyl, 2-methylhexyl, heptyl and the like. The term "Ci-C o alkyl" includes within its definition the terms "Cχ-C 6 alkyl" and "C 1 -C 4 alkyl." "Halo" represents chloro, fluoro, bro o or lodo. "Halo (C 1 -C 4 ) alkyl" represents a straight or branched alkyl chain having from one to four carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo (C 1 -C 4 )alkyl groups include chloromethyl, 2-bromoethyl, 1- chloroisopropyl, 3-fluoropropyl, 3-bromobutyl, 3- chloroisobutyl, lodo-t-butyl, trichloromethyl, trifluoromethyl, 2, 2-chloro-ιodoethyl , 2, 3-dιbromopropyl and the like. "C 1 -C 4 alkylthio" represents a straight or branched alkyl chain having from one to four carbon atoms attached to a sulfur atom. Typical C 1 -C 4 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like. "C 1 -C 4 alkoxy" represents a straight or branched alkyl chain having from one to four carbon atoms attached to an oxygen atom. Typical C 1 -C 4 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. "Di (C 1 -C 4 ) alkylammo" represents two straight or branched alkyl chains having from one to four carbon atoms attached to a common ammo group. Typical dι(Cι- C 4 ) alkylammo groups include dimethylammo, ethylmethylammo, methylpropylammo, ethylisopropylamino, butylmethylammo, sec-butylethylam o and the like. "C 1 -C 4 alkylsulfmyl " represents a straight or branched alkyl chain having from one to four carbon atoms attached to a sulfmyl moiety. Typical C 1 -C4 alkylsulfmyl groups include methylsulfmyl, ethylsulfmyl, propyl-sulfmyl, isopropyl-sulfmyl, butylsulfmyl and the like. "C 1 -C 4 alkylsulfonyl" represents a straight or branched alkyl chain having from one to four carbon atoms attached to a sulfonyl moiety. Typical C 1 -C 4 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like. "Substituted phenyl" represents a phenyl ring substituted with 1-3 substituents selected from the following: halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, ammo or halo(Cι-C 4 )alkyl. "Substituted C 3 -C 7 cycloalkyl" represents a cycloalkyl ring substituted with 1-3 substituents selected from the following: halo, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, ammo or halo(Cι-C 4 )alkyl . The claimed compounds can occur in either the cis or trans isomer. For the purposes of the present application, cis refers to those compounds where the carboxamide moiety is cis to the benzimidazole ring and trans refers to those compounds where the carboxamide moiety is trans to the benzimidazole ring. Both isomers are included the scope of the claimed compounds. As mentioned above, the invention includes the pharmaceutically acceptable salts of the compounds defined by formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, ethanesulfonic acid, oxalic acid, p-bromophenylsul onic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succmate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dιoate, hexyne-1, 6-dιoate, benzoate, chlorobenzoate, methylbenzoate, d itrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ -hydroxybutyrate, glycollate, tartrate, methanesulfonate, ethanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2- sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and sulfuric acid, and those formed with organic acids such as maleic acid and methanesulfonic acid. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred. It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. Preferred compounds of this invention are those compounds of the formula: where: each R is independently hydrogen, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or di (C 1 -C 4 ) alkylammo; R° is hydrogen; R 2 is ammo; R 3 is dimethylammo, C 1 -C 6 alkyl, halo(Cχ-C 6 ) alkyl, C 3 - C 7 cycloalkyl, substituted C 3 -C 7 cycloalkyl, thienyi, thiazolidmyl, pyrrolidmo, piperid o or morpholino; R 4 is hydrogen, methyl or ethyl; R 5 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof. Of these preferred compounds, more preferred are those compounds of formula I where: each R s independently hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, dimethylammo; R° is hydrogen; R 3 is dimethylamino, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl or pyrrolidmo; or a pharmaceutically acceptable salt thereof. Of these compounds, the most preferred compounds are: or a pharmaceutically acceptable salt thereof. The compounds of the formula I may be prepared according to procedures detailed in the art. For example, the compounds of formula I may be prepared by reacting a suitably substituted acetamide with a base to provide the corresponding anion which is then reacted with a suitably substituted ketone of formula IA to provide a carbmol intermediate. The reactions are typically carried out an organic solvent for one to twelve hours at a temperature of from about -90°C to room temperature using an excess of the base and acetamide reactant relative to the ketone reactant . The acetamide is preferably protected with a suitable protecting group prior to use m the reaction. Typical bases include sodium hydride, lithium dusopropylamide (LDA) and n-butyllithium. A preferred base is n-butyllithium Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction A solvent that is suitable for use in this reaction is tetrahydrofuran although the acetamide reactant can also be used as a solvent. The carbmol intermediate is generally prepared from about one to eighteen hours when the reaction is initiated at -78°C and allowed to slowly warm to room temperature. The reaction may be monitored by HPLC and quenched by the addition of an acid when it is substantially complete. Typical acids include hydrochloric acid, hydrobromic acid, formic ac d and the like. A preferred acid is concentrated hydrochloric ac d. The resultant carbmol intermediate is preferably dehydrated without prior isolation or purification. In particular, the carbmol intermediate is reacted with an acid for thirty minutes to twelve hours at a temperature of from about room temperature to the reflux temperature of the mixture to provide the desired compound of formula I. Typical acids include hydrochloric acid, hydrobromic acid, formic acid, acetic acid and combinations of acids. A preferred acid combination is formic acid containing 1-6% concentrated hydrochloric acid. The desired compound is generally prepared m from about thirty minutes to seven hours when the reaction is carried out at just below the reflux temperature of the mixture. The reaction is preferably monitored by HPLC, for example, to ensure that the reaction goes to completion. The compounds of formula I are preferably isolated and the resulting cis/trans isomers separated using procedures known in the art. For example, the cis and trans forms of the isolated compounds may be separated using column chromatography, for example reverse phase HPLC. The compounds may be eluted from the column using an appropriate ratio of acetonitrile and water or methanol and water. The cis form of the compound may be converted to a cis/trans mixture by exposure to hυ irradiation and recycled through the above-mentioned purification process. The ketone intermediates of formula IA used in the above reaction may be prepared as detailed in the art. For example, the compounds of formula I may be prepared according to the following Reaction Scheme I. Reaction Scheme I 3. Sulfonylation where : X is cyano or -COOR', where R' is C 1 -C 4 alkyl; X' is halo; and a, R, R°, R 1 , R 2 and R 3 are defined above. Reaction Scheme I, above, is accomplished by carrying out reactions 1-4. Once a reaction s complete, the intermediate compound may be isolated, if desired, by procedures known the art. For example, the compound may be crystallized and then collected by filtration, or the reaction solvent may be removed by extraction, evaporation or decantation. The intermediate compound may be further purified, if desired, by common techniques such as crystallization or chro atography over solid supports such as silica gel or alumina, before carrying out the next step of the reaction scheme. Reaction 1.1 is accomplished by first exposing an appropriately substituted halo-mtroanilme and an appropriately substituted phenylacetonitrile or benzoate to a base in an organic solvent for one to twenty four hours at a temperature of from about -10°C to about 40°C to provide a ketone precursor. The reaction is typically carried out using equimolar proportions of the reactants in the presence of two equivalents of the base. Typical bases include sodium hydride, potassium t-butox de, lithium dusopropylamide (LDA) . A preferred base is potassium t- butoxide. Examples of solvents suitable for use m this reaction include dimethylformamide, dimethylacetamide and the like. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the reactants are sufficiently solubilized to effect the desired reaction. The ketone precursor is generally prepared in from about one to fifteen hours when the reaction is initiated at 0°C and allowed to progress at room temperature. The ketone precursor is preferably oxidized m the same reaction mixture without prior isolation or purification. In particular, the ketone precursor is reacted with an oxidizing agent for thirty minutes to fifteen hours at a temperature of from about 0°C to about 30°C to provide the corresponding ketone compound. Typical oxidizing agents include hydrogen peroxide, oxygen and air. The oxygen and air are typically bubbled through the reaction mixture. A preferred oxidizing agent is hydrogen peroxide, preferably in a 30% solution. The ketone is generally prepared m from about thirty to five hours when the reaction is carried out between 0°C and room temperature. The reaction is preferably monitored by TLC, for example, to ensure that the reaction goes to completion. In reaction 1.2, the nitro substituent on the ketone is reduced according to procedures known in the art to provide the corresponding diammobenzophenone compound. For example, the nitro substituent may be reduced by catalytic hydrogenation, for example by combining the ketone isolated from reaction 1.1 with hydrogen gas in ethanol or tetrahydrofuran and a catalyst . A preferred catalyst is palladium-on-carbon or Raney nickel. Solvent choice is not critical so long as the solvent employed is inert to the ongoing reaction and the nitro reactant is sufficiently solubilized to effect the desired reaction. The hydrogen gas is typically used at a pressure of up to 60 psi, preferably at or about 30 psi. The reaction is generally substantially complete after about 1 to 24 hours when conducted at a temperature in the range of from about 0°C to about 40°C. The reaction is preferably conducted at a temperature m the range of from about 20°C to about 30°C for about 2 to 5 hours . In reaction 1.3, the diammobenzophenone compound isolated from reaction 1.2 may be sulfonylated with an appropriately substituted sulfonyl halide of the formula R 4 - S0 2 ~halιde substantially accordance with the procedure detailed above to provide the corresponding sulfonamido benzophenone compounds. In reaction 1.4, the compound isolated from reaction 1.3 is cyclized via a nitrile intermediate by first exposing the sulfonamido benzophenone compound to a base an alcoholic solvent such as isopropanol followed by reaction with cyanogen bromide. Typically, the sulfonamido benzophenone and base are reacted at a temperature of from about 0°C to about 30°C. A preferred base is sodium hydroxide, preferably added m the form of an aqueous solution (about 1-4M) . When the sulfonamido benzophenone is completely dissolved, the resultant solution is combined with cyanogen bromide. The cyanogen bromide is typically added in the form of a solution (3-7M for example in acetonitrile) . The reaction is generally complete after one to eighteen hours when the reaction mixture is stirred at room temperature. However, in certain instances nitrile intermediate will precipitate out of the reaction mixture. In order to form the desired ketone, this precipitate is isolated and then refluxed in an alcoholic solvent such as isopropanol for one to four hours to provide the desired ketone compound of formula I . Alternatively, the compound isolated from reaction 1.3 is cyclized via a nitrile intermediate by exposing the sulfonamido benzophenone compound to a base in a chlorinated solvent such as methylene chloride followed by reaction with cyanogen bromide. Typically, the sulfonamido benzophenone and base are reacted at a temperature of from about 0°C to about the reflux temperature of the mixture. A preferred base is lithium ethoxide. The sulfonamido benzophenone and the base typically form a slurry which is then combined with cyanogen bromide. The cyanogen bromide is typically added in the form of a solution (3-7M for example in methylene chloride) . The reaction is generally complete after one to eighteen hours when the reaction mixture is stirred at a temperature range of 0°C to the reflux temperature. The compounds of formula I where R 2 is -NHC (0) (Cι~C 6 alkyl) may be prepared by acylatmg a compound of formula I, where R 2 is ammo, according to procedures known m the art . For example, the amme compound may be acylated with a suitable acyl halide, isocyanate or chloroformate, preferably m the presence of an acid scavenger such as a tertiary amme, preferably triethylam e. A preferred acylatmg agent is acetic anhydride. The reaction is typically carried out at a temperature of from about -20°C to about 25°C. Typical solvents for this reaction include ethers and chlorinated hydrocarbons, preferably diethylether, chloroform or methylene chloride. The amme reactant is generally employed equimolar proportions relative to the acylatmg reactant, and preferably in the presence of equimolar quantities of an acid scavenger such as a tertiary amme. A preferred acid scavenger for this reaction is N-methylmorpholme (NMM) The compounds employed as initial starting materials m the synthesis of the compounds of this invention are known in the art, and, to the extent not commercially available are readily synthesized by standard procedures commonly employed in the art . It will be understood by those in the art that in performing the processes described above it may be desirable to introduce chemical protecting groups into the reactants in order to prevent secondary reactions from taking place. Any amme, alcohol, alkylamme or carboxy groups which may be present on the reactants may be protected using any standard ammo-, alcohol- or carboxy- protecting group which does not adversely affect the remainder of the molecule's ability to react in the manner desired. The various protective groups may then be removed simultaneously or successively using methods known m the art . The pharmaceutically acceptable salts of the invention are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid or base. The reactants are generally combined in a mutual solvent such as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene, and the like for acid addition salts, or water, an alcohol or a chlorinated solvent such as methylene chloride for base addition salts. The salts normally precipitate out of solution within about one hour to about ten days and can be isolated by filtration or other conventional methods. The following Preparations and Examples further illustrate specific aspects of the present invention. It is to be understood, however, that these examples are included for illustrative purposes only and are not intended to limit the scope of the invention m any respect and should not be so construed. In the following Preparations and Examples, the terms melting point, nuclear magnetic resonance spectra, electron impact mass spectra, field desorption mass spectra, fast atom bombardment mass spectra, infrared spectra, ultraviolet spectra, elemental analysis, high performance liquid chroma ography, and thin layer chromatography are abbreviated "m.p. ", "NMR", "EIMS", "MS(FD) ", "MS (FAB) ", "IR", "UV", "Analysis", "HPLC", and "TLC", respectively. The MS(FD) data is presented as the mass number unless otherwise indicated. In addition, the absorption maxima listed for the IR spectra are only those of interest and not all of the maxima observed. In conjunction with the NMR spectra, the following abbreviations are used: "s" is singlet, "d" is doublet, "dd" is doublet of doublets, "t" is triplet, "q" is quartet, "m" is multiplet, "dm" is a doublet of multiplets and "br.s", "br.d", "br.t", and "br.m" are broad singlet, doublet, triplet, and multiplet respectively. "J" indicates the coupling constant in Hertz (Hz) . Unless otherwise noted, NMR data refers to the free base of the subject compound. The NMR spectra were obtained on a Brϋker Corp. 270 MHz instrument or on a General Electric QE-300 300 MHz instrument. The chemical shifts are expressed in delta, δ values (parts per million downfield from tetramethyl- silane) . The MS(FD) spectra were taken on a Varion-MAT 731 Spectrometer using carbon dendrite emitters. EIMS spectra were obtained on a CEC 21-110 instrument from Consolidated Electrodynamics Corporation. IR spectra were obtained on a Perkin-Elmer 281 instrument. UV spectra were obtained on a Cary 118 instrument. TLC was carried out on E. Merck silica gel plates. Melting points are uncorrected. Example 1 A. 3-A ino-4-nitro-4'-fluorobenzophenone To a cold (0°C) solution of 17.25 g (100 mmol) of 5- chloro-2-nitroaniline and 12 ml (100 mmol) of 4- fluorophenylacetonitrile in 200 ml of dimethylformamide, was added 22.44 g (200 mmol) of potassium t-butoxide, under nitrogen. The reaction mixture was warmed to room temperature and reacted overnight. When the reaction was substantially complete, as indicated by TLC (eluent of 40% ethyl acetate in hexane) , the reaction mixture was cooled to 0°C followed by the addition of 30 ml of hydrogen peroxide. When the reaction was substantially complete, as indicated by TLC (eluent of 40% ethyl acetate in hexane) , the reaction mixture was poured into 1 liter of IN hydrochloric acid (aqueous) which resulted in the formation of a yellow/orange precipitate. This precipitate was isolated by filtration. Yield: 23.3 g (89%) . B. 3.4-Diamino-4'-fluorobenzophenone To a solution of 21 g of Example IA in 250 ml of tetrahydrofuran and 250 ml of ethanol, was added 3.0 g of Raney Nickel catalyst . The reaction mixture was stirred overnight under 30 of hydrogen (gas) and then filtered. The resultant filtrate was concentrated in vacuo to provide a yellow solid which was used without further purification. C . 4-Amino-3-isopropylsulfonamido-4'-fluorobenzophenone To a solution of 18.14 g (79 mmol) of Example IB in 160 ml of anhydrous methylene chloride and 32 ml of anhydrous pyridine, was added 13.25 ml (118 mmol) of isopropylsulfonylchloride. The reaction mixture was reacted at room temperature for 5 hours, under nitrogen. When the reaction was substantially complete, as indicated by TLC (eluent of ethyl acetate) , the reaction mixture was poured into 400 ml of IN hydrochloric acid (aqueous) . The resulting mixture was diluted with 300 ml of ethyl acetate and the resulting layers were separated, the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to provide a dark red gum. This gum was purified using Preparatory HPLC (gradient eluent of 30-60% ethyl acetate in hexane) . The fractions containing the compound were combined and dried in vacuo to provide 17.11 g of a yellow gum that was used without further purification. Yield: 65% To a solution of 17.11 g (51 mmol) of Example 1C and 25 ml of 2N sodium hydroxide (aqueous) in 100 ml of isopropanol, was added 10 ml of a 5M cyanogen bromide. The reaction mixture was reacted at room temperature for 30 minutes resulting in the formation of a precipitate. This precipitate was isolated by filtration to provide 11.68 g of a solid. This solid was resuspended in 250 ml of isopropanol and the mixture was refluxed until all of the material had dissolved and then cooled to provide 10.0 g of the desired compound. Yield: 55%. Analysis for C 17 H 16 FN 3 O 3 S: Calcd: C, 56.50; H, 4.46; N, 11.63; Found: C, 56.71; H, 4.48; N, 11.82. MS(FD) : 361. X H NMR (300 MHz; dβ-DMSO) : δ 1.32 (d, J=7 Hz, 6H) ; 3.96 (septet, J=7.0Hz, 1H) ; 7.34-7.44 (m, 5H) ; 7.63 (dd, J=l,6 8.3 Hz, 1H) ; 7.79-7.83 (m, 2H) ; 7.95 (d, J=1.5Hz, 1H) . To a cold (-78°C) solution of bis (tπmethylsilyl) - acetamide (8 equivalents) in tetrahydrofuran, was slowly added a solution of 2.5M n-butyllithium (8 equivalents) in hexane. To the resultant mixture was added Example IE (1 equivalent) . The reaction mixture was stirred for 8 hours at -78°C and then allowed to warm to room temperature. When the reaction was substantially complete, as indicated by HPLC, the reaction was quenched by the addition of concentrated hydrochloric acid (approximately 1 equivalent) and then concentrated in vacuo to provide an oil which was then redissolved m formic acid containing 1% concentrated hydrochloric acid. The resultant mixture was allowed to react for 4 hours at 95°C. When the reaction was substantially complete, as indicated by HPLC, the mixture was concentrated m vacuo to provide an oil. This oil was separated using reverse phase HPLC (eluent of acetonitrile in water) to provide the cis and trans isomers . CIS not characterized trans Analysis for C19H19N4O3SF : Calcd: C, 56.71; H, 4.76; N, 13.92; S, 7.97; F, 4.72; Found: C, 56.96; H, 4.76; N, 13.90; S, 7.96; F, 4.90. MS(FD) : 402 (M + ) . λ H NMR (300 MHz; d 6 -DMSO) : δ 1.20 (d, 6H) ; 3.80 (m, 1H) ; 6.35 (s, 1H) ; and 7.10 ( , 11H) . IR (CHCI3) : υ 3465, 3140, 1680, 1658, 1600, 1554, 1395, 1353, 1265, 1216, 1157, 1139, 1047, 689, 593 and 425 cm "1 . UV/VIS (95% EtOH) : λ max = 312.50 nm (E=15680.556) ; 245.00 n (E=26956.305) . The following compounds were prepared substantially in accordance with the procedure detailed in Example 1A-E. Example 2 CIS Analysis for C 19 H 19 N 4 O 3 SF: Calcd: C, 56.71; H, 4.76; N, 13.92; Found: C, 56.50; H, 4.78; N, 13.84. MS(FD) : 402 (M + ) . X H NMR (300 MHz; d 6 -DMSO) : δ 1.27 (d, 6H) ; 3.85 (septet, 1H) ; 6.41 (s, 1H) ; 6.91 (d, 1H) ; 7.04 ( , 5H) ; 7.20 (m, 2H) and 7.39 (m, 3H) . IR (KBr) : υ 3464, 3453, 1663, 1554, 1444, 1361, 1273 and 1046 cm -1 . UV/VIS (95% EtOH) : λ ma χ = 258 nm (E=25450) ; 214 nm (E=39883) . trans Analysis for C 1 9H 19 N 4 O 3 SF: Calcd: C, 56.71; H, 4.76; N, 13.92; S, 7.97; F, 4.72; Found: C, 56.96; H, 5.00; N, 13.68; S, 7.81; F, 5.02 MS(FD) : 402 (M + ) . ! H NMR (300 MHz; d 6 -DMSO) : δ 1.20 (d, 6H) ; 3.82 (m, 1H) ; 6.40 (s, 1H) and 7.20 (m, 11H) . IR (KBr) : υ 3464, 3479, 3174, 1651, 1604, 1580, 1553, 1442, 1401, 1353, 1323, 1272, 1222, 1154, 1128, 1045, 795, 694, 633 and 592 cm "1 . UV/VIS (95% EtOH) : λ max = 313.50 nm (E=17116.398) ; 214.50 nm (E=32578.988) . CIS Analysis for C 18 H 18 N 5 O 3 SF: Calcd: C, 53.59; H, 4.50; N, 17.36; Found: C, 53.22; H, 4.39; N, 16.86. MS(FD) : 403 (M + ) . X H NMR (300 MHz; d δ -DMSO) : δ 2.78 (s, 6H) ; 6.44 (s, 1H); 6.93 (m, 2H) ; 6.96 (s, 1H) ; 7.04 (m, 2H) ; 7.11 (m, 1H) ; 7.18 (m, 2H) ; 7.27 (s, 2H) and 7.39 (m, 2H) . IR (KBr) : υ 3436, 3100, 1665, 1384, 1174 and 1042 cm "1 . UV/VIS (95% EtOH) : λ ma χ = 258 nm (E=26203) ; 216 nm (E=41563) . trans Analysis for C 18 H 18 N5O 3 SF: Calcd: C, 53.59; H, 4.50; N, 17.36; Found: C, 53.82; H, 4.39; N, 17.13. MS(FD) : 403 (M + ) . !H NMR (300 MHz; d6~DMSO) : δ 1.25 (d, 6H) ; 6.40 (s, 1H) and 7.20 (m, 11H) . CIS Analysis for C20H21N4O3SF : Calcd: C, 57.68; H, 5.08; N, 13.45; S, 7.70; F, 4.56; Found: C, 57.52; H, 4.95; N, 13.17; S, 7.45; F, 4.57. MS(FD) : 415.9 (M + ) . 1-H NMR (300 MHz; d 6 -DMSO) : δ 1.25 (d, 6H) ;2.55 (d, 3H) : 3.85 (m, IH) ; 6.39 (s, IH) ; 7.20 (m, 9H) and 7.95 (q, IH) . IR (CHCI 3 ) : υ 3453, 3398, 3004, 1639, 1611, 1583, 1549, 1525, 1485, 1467, 1441, 1413, 1387, 1360., 1267, 1176, 1156, 1136, 1044 and 824 crrrX UV/VIS (95% EtOH) : λ ma χ = 258.5 nm (E=25875) ; 214.0 nm (E=38753) . trans Analysis for C 2 0H 21 N 4 O 3 SF: Calcd: C, 57.68; H, 5.08; N, 13.45; S, 7.70; F, 4.56; Found: C, 57.97; H, 4.97; N, 13.18; S, 7.45; F, 4.59. MS(FD) : 415.9 (M + ) . 1 H NMR (300 MHz; d 6 -DMSO) : δ 1.25 (d, 6H);2.55 (d, 3H) : 3.85 (m, IH) ; 6.42 (s, IH) ; 7.20 (m, 9H) and 7.95 (9, IH) . UV/VIS (95% EtOH) : λ ma = 311.5 nm (E=19175) ; 214.0 nm (E=34437) . Example 5 2 cis Analysis for C19H20N5O3SF: Calcd: C, 54.67; H, 4.83; N, 16.78; Found: C, 54.80; H, 4.74; N, 16.55. MS(FD) : 417 (M + ) . X H NMR (300 MHz; d 6 -DMSO) : δ 2.48 (d, 3H) ; 2.81 (s, 6H) ; 6.34 (s, IH) ; 6.82 (d, IH) ; 7.0 (m, 4H) ; 7.15 (m, 2H) ; 7.33 (m, 2H) and 7.89 ( , IH) . IR(KBr) : υ 3457, 3306, 3101, 1659, 1381, 1174 and 580 cm" 1 . UV/VIS (95% EtOH) : λm ax = 258 nm (E=25801) ; 216 nm (E=38667) . trans Analysis for C 19 H20N 5 O 3 SF: Calcd: C, 54.67; H, 4.83; N, 16.78; Found: C, 54.89; H, 4.71; N, 17.01. MS(FD) : 417 (M + ) . X H NMR (300 MHz; d δ -DMSO) : δ 2.51 (d, 3H) ; 2.75 (s, 6H) ; 6.39 (s, IH) ; 6.89 ( , 2H) ; 7.01 (m, 3H) ; 7.11 (m, 2H) 7.24 (s, IH) ; 7.34 (m, IH) and 7.95 (m, IH) . IR(KBr) : υ 3462, 3362, 3087, 1662, 1380, 1165 and 969 cm" 1 . UV/VIS (95% EtOH) : λ max = 313 nm (E=19257) ; 245 nm (E=17029) ; 221 nm (E=30798) . CIS Analysis for C 19 H 19 N 4 O 3 SCI : Calcd: C, 54.48; H, 4.67; N, 13.38; Found: C, 54.50; H, 4.61; N, 13.17. MS(FD) : 418 (M + ) . X H NMR (300 MHz; d6-DMSO) : δ 1.25 (d, 6H) ; 3.84 (septet, IH) ; 6.41 (s, IH) ; 6.92 (d, IH) ; 7.03 (m, 3H) ; 7.21 (m, 4H) and 7.22 (m, 3H) . IR (KBr) : υ 3453, 3160, 1655, 1636, 1619, 1552, 1351 and 689 cm- 1 . UV/VIS (95% EtOH) : λ max = 260 nm (E=26091) ; 215.5 (E=46127) . trans Analysis for C 19 H 19 N 4 O 3 SCI : Calcd: C, 54.48; H, 4.57; N, 13.38; Found: C, 54.23; H, 4.39; N, 13.19. MS(FD) : 418 (M + ) . 2 H NMR (300 MHz; de-DMSO) : δ 1.24 (d, 6H) ; 3.97 (septet, IH) ; 6.43 (s, IH) ; 6.94 (s, IH) ; 7.01 (d, IH) ; 7.11 (s, 2H) ; 7.17 (m, 2H) ; 7.37 (m, 3H) and 7.48 (s, IH) . IR (KBr) : υ 3608, 3461, 3148, 1648, 1603, 1553, 1395, 1353, 1144, 1042 and 680 cm "1 . UV/VIS (95% EtOH) : λ max = 315 nm (E=17310) ; 216 (E=37056) . CIS Analysis for C21H23N4O 3 SF : Calcd: C, 58.59; H, 5.38; N, 13.01; S, 7.45; F, 4.42; Found: C, 58.67; H, 5.45; N, 12.88; S, 7.42; F, 4.62. MS(FD) : 430.0 (M + ) . 1 H NMR (300 MHz; dg-DMSO) : δ 0.90 (t, 3H) ; 1.25 (d, 6H) : 3.02 (m, 2H) ; 3.85 (m, IH) ; 6.40 (s, IH) ; 7.20 (m, 9H) and 7.95 (t, IH) . UV/VIS (95% EtOH) : λ max = 258.0 nm (E=24526) . trans Analysis for C21H23N4O3SF : Calcd: C, 58.59; H, 5.38; N, 13.01; Found: C, 58.44; H, 5.50; N, 12.80. MS(FD) : 430.0 (M + ) . 1 H NMR (300 MHz; d6~DMSO) : δ 0.97 (t, 3H) ; 1.25 (d, 6H) : 3.03 (m, 2H) ; 3.85 (m, IH) ; 6.42 (s, IH) ; 7.20 (m, 9H) and 8.00 (t, IH) . UV/VIS (95% EtOH) : λ max = 309 nm (E=18345) . cis Analysis for C 21 H 23 N 4 O 4 SF: Calcd: C, 56.49; H, 5.19; N, 12.55; Found: C, 56.32; H, 5.06; N, 12.43. : H NMR (300 MHz, DMSO-d δ ) : δ 7.86 ( , IH) ; 7.35 (s, IH) ; 7.20-7.05 (m, 4H); 7.02 (s, 2H) ; 6.99 (d, IH) ; 6.87 (d, 2H) ; 6.29 (S, IH) ; 3.83 (s, 3H) ; 2.51 (d, 3H) ; 1.25 (d, 6H) . IR (CHCI 3 ) : 3413, 3025, 1638, 1516 and 1273 cm "1 . MS(FD) : 446 (M + ) . UV/Vis (95% EtOH) : λ max = 286 nm (E=20748) ; 261 nm (E=23024) . trans Analysis for C 21 H 23 N 4 O 4 SF: Calcd: C, 56.49; H, 5.19; N, 12.55; Found: C, 56.74; H, 5.08; N, 12.48. X E NMR (300 MHz, DMSO-d δ ) : δ 7.94 (m, IH) ; 7.41 (m, IH) ; 7.19 (d, IH) ; 7.10 (m, 3H) ; 6.99 (m, 2H) ; 6.89 (d, IH) ; 6.30 (s, IH) ; 3.87 (s, 3H) ; 2.58 (d, 3H) ; 1.24 (d, 6H) . IR (CHCI 3 ) : 3415, 3006, 1638, 1517 and 1271 cm "1 . MS(FD) : 446 (M + ) . UV/Vis (95% EtOH) : λ max = 304 nm (E=19544) . ) 2 CIS Analysis for C20H 2 0N 4 O3SF2 : Calcd: C, 55.29; H, 4.64; N, 12.90 Found: C, 55.27; H, 4.51; N, 12.77 !H NMR (300 MHz, DMSO-d δ ) : δ 7.94 (d, J=5Hz, IH) ; 7.38 (s, IH) ; 7.23 (td, J=8,2Hz, IH) ; 7.20 (d, J=8Hz, IH) ; 7.03 (S, 2H) ; 6.94 (dd, J=8,lHz, IH) ; 6.85 (dd, J=8,lHz, IH) ; 6.42 (s, IH) ; 3.83 (septet, J=7Hz, IH) ; 2.57 (d, J=5Hz, 3H) ; 1.21 (d, J=7Hz, 6H) . IR (CHCI 3 ) : 3495, 3451, 3381, 2995, 1640, 1620, 1604, 1592, 1548, 1441, 1435, 1358, 1176, 1155, 1121 and 990 cm" 1 . MS(FD) : 434 (M + ) . UV/Vis (95% EtOH) : λ max = 258.0 nm (E=25762) . trans Analysis for C 20 H 20 N 4 O 3 SF 2 : Calcd: C, 55.29; H, 4.64; N, 12.90; Found: C, 55.52; H, 4.61; N, 12.91. W NMR (300 MHz, DMSO-d 6 ) : δ 8.09 (d, J=5Hz, IH) ; 7.40 (d, J=lHz, IH) ; 7.21 (d, J=lHz, IH) ; 7.19 (d, J=lHz, IH) ; 7.16 (s, 2H) ; 7.01 (dd, J=8,lHz, IH) ; 6.82 (dd, J=8,lHz, IH) ; 6.43 (s, IH) ; 3.86 (septet, J=7Hz, IH) ; 2.59 (d, J=5Hz, 3H) ; 1.22 (d, J=7Hz, 6H) . IR (CHCI 3 ) : 3460, 3400, 3000, 1638, 1621, 1591, 1580, 1547, 1442, 1433, 1267, 1175 and 1121 cm "1 . MS(FD) : 434 (M + ) . UV/Vis (95% EtOH) : λ raax = 313.0 n (E=18537) ; 245.0 nm (E=17095) , 214.0 nm (E=32953) . Example 10 ) 2 cis Analysis for C21H23N4O3SF : Calcd: C, 58.59; H, 5.38; N, 13.01; S, 7.45; F, 4.42; Found: C, 58.55; H, 5.37; N, 12.92; S, 7.33; F, 4.70. X H NMR (300 MHz, DMSO-d 6 ) : δ 7.20 (m, 9H) ; 6.52 (s, IH) ; 3.80 (m, IH) ; 2.85 (s, 3H) ; 2.75 (s, 3H) ; 1.22 (d, 6H) MS(FD) : 430 (M + ) . UV/Vis (95% EtOH) : λ max = 257.0 nm (E=22850) . trans ; Analysis for C21H23N4O3SF : Calcd: C, 58.59; H, Found: C, 58.33; H, X H NMR (300 MHz, DMSO-dβ) 3.87 (m, IH) ; 2.88 ( MS(FD) : 430 (M + ) . UV/Vis (95% EtOH) : λ max = 302.0 nm (E=06629 Example 11 CIS Analysis for C 2 1H22N 5 O 3 SF: Calcd: C, 56.87; H, 5.00; N, 15.79; S, 7.24; F, 4.28; Found: C, 57.12; H, 5.08; N, 15.54; S, 7.13; F, 4.58, X H NMR (300 MHz, DMSO-d 6 ) : δ 7.95 (9, IH) ; 7.20 (m, 9H) ; 6.39 (s, IH) ; 3.30 (m, 4H) ; 2.55 (d, 3H) ; 1.75 (m, 4H) MS (FD) : 443 (M + ) UV/Vis (95% EtOH) λ m,ax 257.25 nm (E=24158; 216.25 nm (E=36468) . trans Analysis for C 2 1H22N 5 O 3 SF: Calcd: C, 56.87; H, 5.00 N, 15.79; S, 7.23; F, 4.28 Found: C, 57.06; H, 4.94 N, 15.82; S, 7.04; F, 4.57 l -H NMR (300 MHz, DMSO-d6) δ 7.98 (9, IH) ; 7.20 (m, 9H) ; 6.42 (s, IH) ; 3.22 (m, 4H) ; 2.75 (d, 3H) 1.75 ( , 4H) IR (KBr) : 3407, 3099, 1673, 1639, 1603, 1580 1553, 1474, 1441, 1378, 1323, 1266, 1219, 1169, 1042 1019, 621, and 571 cm -1 . MS (FD) 443 (M + ) . UV/Vis !95% EtOH) : λm X = 312.0 nm (E=18743; 245.0 nm (E=17025! • 219.0 nm (E=29873) . Example 12 CIS Analysis for C22H15CI2FN4O3SF : Calcd: C, 52.29; H, 2.99; N, 11.09; Found: C, 53.25; H, 3.25; N, 12.29. X H NMR (300 MHz, DMSO-d 6 ) : δ 8.30 (d, J=2.4Hz, IH) ; 7.85 (dd, J=ll.0,2.4Hz, IH) ; 7.72 (d, J=8.6Hz, IH) ; 7.34- 6.85 (m, 11H) ; 6.41 (s, IH) . 13 C NMR (75 MHz, DMSO-d 6 ) : δ 166.49, 163.28 160.05, 152.23, 146.85, 143.95, 141.76, 136.02 135.11, 133.57, 132.36, 131.41, 130.46, 129.92, 129.88 125.90, 123.36, 123.27, 115.11, 114.84, 113.78, 112.78. IR (CHCI 3 ) : 3490, 3404, 3010, 1663, 1644, 1611, 1582, 1456, 1441, 1383, 1179, 1053 cm "1 . MS(FD) : 504 (M + ) . UV/Vis (95% EtOH) : λ max = 257.0 nm (E=20637; trans Analysis for C22H15N4O3SCI2F : Calcd: C, 52.29; H, 2.99; N, 11.09; Found: C, 52.22; H, 3.06; N, 10.89. X H NMR (300 MHz, DMSO-d6) : δ 8.21 (d, J=2.5Hz, IH) ; 7.89 (dd, J=8.5,2.5Hz, IH) 7.74 (d, J=8.5Hz, IH) ; 7.38-7.14 (m, 8H) ; 7.02 (s, IH) 6.87 (d, J=7.6Hz, 2H) and 6.35 (s, IH) . 13 C NMR (75 MHz, DMSO-dδ) : δ 166.59 163.17, 159.94, 153.04, 147.60, 143.06, 141.62 136.42, 135.20, 134.08, 133.00, 132.75, 131.46, 130.24 129.99, 129.48, 125.14, 124.24, 121.58, 115.85, 114.28 111.31. IR (KBr) : 3441, 3088, 1676, 1602, 1583, 1557, 1396 1382, 1277, 1177, 1054, 585, 568, 531 cm "1 . MS(FD) : 504 (M + ) . UV/Vis (95% EtOH) : λ max = 309.0 nm (E=17313) ; 307.0 nm (E=17289) . Example 13 CIS Analysis for C 20 H 15 N 4 O 3 S 2 F: Calcd: C, 54.29; H, 3.42; N, 12.66; Found: C, 52.34; H, 3.17; N, 11.77. X H NMR (300 MHz, DMSO-d 6 ) : δ 8.13 (d, J=4.7Hz, 1HI 7.97 (d, J=3.5Hz, IH) ; 7.52 (s, IH) ; 7.44-6.92 (m, llH 6.45 (s, IH) . 13 C NMR (75 MHz, DMSO-dδ) : δ 166.83 160.12, 152.32. 146.62, 144.10, 142.74, 136.59 134.79, 134.65, 130.41, 129.98, 128.28, 126.36, 123.78 123.36, 115.06, 114.90, 114.79, 114.06, 113.59. IR (CHCI3) : 1659, 1641, 1609, 1582, 1386, 1371 and 1176 cm" 1 . MS(FD) : 442 (M + ) . UV/Vis (95% EtOH) : λ max = 255.0 nm (E=31371) . trans Analysis for C20H15N4O3S2F: Calcd: C, 54.29; H, 3.42; N, 12.66; Found: C, 54.30; H, 3.29; N, 12.29. λ n NMR (300 MHz, DMSO-dδ) : δ 8.13 (d, J=4.7Hz, IH) (d, J=3.7Hz, IH) ; 7.44-6.94 (m, 12H) ; 6.45 (s, 13 C NMR (75 MHz, DMSO-dβ) : δ 166.60, 163.25, 160.03, 148.00, 143.82, 142.04, 141.93, 137.23, 135.12, 133.24, 129.59, 128.45, 125.43, 124.79, 121.39, 115.64, 114.20, 111.74. IR (KBr) : 3454, 3102, 1669, 1604, 1581, 1557, 1389, 1374, 1271, 1175, 674, 582 cm "1 . MS(FD: 442 (M + ) . UV/Vis (95% EtOH) : λ max = 312.0 nm (E=17060) ; 245.0 nm (E=21643) ; 215.0 nm (E=29162) . Example 14 CIS Analysis for C26H19N4O3SF : Calcd: C, 64.19; H, 3.94; N, 11.52; Found: C, 63.53; H, 3.84; N, 11.00. 1 H NMR (300 MHz, DMSO-dβ) : δ 8.45 (d, J=9.4Hz, IH) ; 8.37 (t, J=7.7Hz, IH) ; 8.13 (dd, J= 9.5,3.4Hz, IH) ; 7.69- 7.61 (m, 4H) ; 7.41-6.87 (m, llH) ; 6.43 (s, IH) . 13 C NMR (75 MHz, DMSO-dβ) : δ 166.49, 163.22, 159.99, 152.16, 146.76, 143.97, 141.82, 136.11, 133.31, 131.03, 130.37, 129.83, 129.15, 128.86, 127.06, 126.69, 125.36, 124.04, 123.40, 123.38, 123.29, 122.41, 114.98, 114.66, 113.78, 112.76. IR (KBr) : 3465, 1656, 1636, 1611, 1583, 1554, 1441, 1388, 1170, 765, 592 cπrX MS(FD) : 486 (M + ) . UV/Vis (95% EtOH) : = 291.3 nm (E=17022) ; 258.3 nm (E=23737) . trans Analysis for C26H19N4O3SF : Calcd: C, 64.19; H, 3.94; N, 11.52; Found: C, 64.32; H, 3.87; N, 11.27. 1-H NMR (300 MHz, DMSO-dε) : δ 8.41-8.37 (m, 2H) ; 8.19-8.12 (m, 2H) ; 7.70-7.64 (m, 4H) ; 7.45-7.37 ( , 5H) ; 7.23 (m, IH) ; 7.11 (s, IH) ; 7.07 (s, IH) ; 6.89-6.84 (m, 2H) ; 6.36 (s, IH) . 13 C NMR (75 MHz, DMSO-d 6 ) : δ 167.82, 164.58, 161.36, 154.41, 148.98, 144.50, 143.14, 138.01, 134.05, 132.55, 132.42, 131.37, 130.98, 130.88, 130.52, 128.88, 128.30, 126.47, 125.69, 125.11, 123.80, 122.52, 117.11, 117.05, 115.46, 112.52. IR (KBr) : 3422, 3306, 3067, 1672, 1641, 1623, 1611, 1595, 1554, 1472, 1371, 1275, 1266, 1224, 1168, 1039, 771, 766, 680, 639, 595, 568 cm "1 . MS(FD) : 486 (M + ) . UV/Vis (95% EtOH) : λ max = 309.0 nm (E=22660) . Example 15 CIS Analysis for C23H16N5O3SF : Calcd: C, 59.86; H, 3.50; N, 15.18; Found: C, 59.30; H, 3.62; N, 14.56. X H NMR (300 MHz, DMSO-dε) : δ 8.63 (s, 1 H) ; 8.27 (dt, J=8.0, 1.4Hz, IH) ; 7.85 (t, J=8.0Hz, IH) ; 7.69 (s, IH) 7.47-7.41 (m, 2H) ; 7.32 (s, IH) ; 7.22-7.04 (m, 6H) ; 6.98 (s, IH) ; 6.85 (dd, J=8.1,1.3Hz, IH) and 6.46 (s, IH) . IR (CHCI3) : 3448, 3383, 3316, 3203, 3106, 3083, 2235, 1659, 1634, 1610, 1581, 1554, 1441, 1383, 1170, 1089 and 586 cm "1 . MS(FD) : 461.1 (M + ) . UV/Vis (95% EtOH) λ ma χ = 255.3 nm (E=27006) . trans Analysis for C 23 H1 6 N 5 O 3 SF: Calcd: C, 59.86; H, 3.50; N, 15.18; Found: C, 58.76; H, 3.64; N, 15.48. X H NMR (300 MHz, DMSO-d δ ) : δ 8.55 (s, IH) ; 8.28 (d, J=8.0Hz, IH) ; 8.11 (d, J=8.0Hz, IH) ; 7.86 (t, J=8.0Hz, IH) ; 7.83 ( , IH) ; 7.48-6.94 (m, 10H) ; 6.49 (s, IH) . IR (KBr) : 3445, 3334, 3072, 3060, 3039, 2238, 1669, 1641, 1624, 1610, 1593, 1577, 1556, 1475, 1377, 1273, 820, 690 cm "1 . MS(FD) : 461 (M + ) . UV/Vis (95% EtOH) : λ max = 304.0 (16049) . Example 16 cis Analysis for C19H19N4O3SF : Calcd: C, 56.71; H, 4.76; N, 13.92; Found: C, 56.96; H, 4.78; N, 14.21. X H NMR (300 MHz, DMSO-d 6 ) : δ 7.41-6.90 (m, 11H) ; 6.40 (s, IH) ; 3.61 (t, J=7.7Hz, 2H) ; 1.55 (qt, J=7.7,7.4Hz, 2H) 0.87 (t, J-7.4HZ, 3H) . 13 C NMR (75 MHz, DMSO-dδ) : δ 167.05, 163.63, 160.40, 152.99, 147.39, 144.48, 142.48, 130.24, 125.92, 124.10, 123.40, 115.48, 115.36, 115.05, 114.41, 113.47, 54.28, 16.32, 12.02. IR (KBr) : 3468, 3452, 3134, 3075, 2979, 2967, 1665, 1601, 1583, 1554, 1483, 1443, 1398, 1365, 1345, 1272, 1262, 1164, 1160, 1048, 557 and 537 cm "1 . MS(FD) : 402.1 (M + ) . UV/Vis (95% EtOH) : λ max = 258.0 nm (E=23378) ; 213.0 nm (E=38249) . trans Analysis for C19H19N4O3SF : Calcd: C, 56.71; H, 4.76; N, 13.92; Found: C, 56.74; H, 4.78; N, 14.06. *H NMR (300 MHz, DMSO-d 6 ) : δ 7.48-6.92 (m 11H) ; 6.43 (s, IH) ; 3.61 (t, J=7.7Hz, 2H) ; 1.56 (qt, J= 7.7 , 7.4Hz , 2H) and 0.88 (t, J=7.4Hz, 3H) . 13 C NMR (75 MHz, DMSO-dβ) : δ 166.70, 163.19, 159.98, 153.21, 148.09, 143.21, 142.02, 131.12, 129.46, 125.41, 124.40, 121.40, 116.04, 115.48, 114.13, 110.97, 58.60, 16.35, 11.99. IR (KBr) : 3500, 3440, 2979, 2936, 1690, 1662, 1616, 1604, 1554, 1443, 1395, 1357, 1318, 1263 and 1166 cm "1 . MS(FD) : 402.1 (M + ) . UV/Vis (95% EtOH) : λ max = 312.8 nm (E=17309) ; 214.0 nm (E=32445) . cis Analysis for C20H20N4O3SF2 : Calcd: C, 55.29; H, 4.64; N, 12.90; Found: C, 55.37; H, 4.72; N, 12.81. 1 H NMR (300 MHz, DMSO-d 6 ) : δ 7.92 (d, J=5Hz, IH) ; 7.50-7.24 (m, 4H) ; 7.20 (dd, J=8,lHz, 2H) ; 7.02 (s, 2H) ; 6.84 (d, J=8Hz, IH) ; 6.38 (s, IH) ; 3.86 (septet, J=7Hz, IH) ; 2.57 (d, J=5Hz, 3H) and 1.22 (d, J=7Hz, 6H) . IR (CHC1 3 ) : 2999, 1639, 1608, 1547, 1515, 1359 and 1277 cm" 1 . MS(FD) : 434.2 (M + ) . UV/Vis ( 95% EtOH ) : λ max = 257 . 0 nm ( E=23774 ) ; 213 . 0 nm ( E=37807 ) . trans Analysis for C20H 2 0N4O3SF 2 : Calcd: C, 55.29; H, 4.64; N, 12.89; Found: C, 55.35; H, 4.66; N, 12.94. i H NMR (300 MHz, DMSO-d 6 ) : δ 8.03 (d, J=5Hz, IH) ; 7.41-7.38 (m, 2H) ; 7.25-7.15 (m, 4H) ; 6.98 (dd, J=8,lHz, IH) ; 6.81 (m, IH) ; 6.41 (s, IH) ; 3.86 (septet, J=7Hz, IH) ; 2.57 (d, J=5Hz, 3H) ; 1.25 (d, J=7Hz, 6H) . IR (KBr) : 3429, 1661, 1642, 1598, 1545, 1514, 1424, 1386, 1271, 1232, 1152 and 1038 cirr 1 . MS(FD) : 434 (M + ) . UV/Vis (95% EtOH) : λ max = 312.0 nm (E=19163) ; 242.0 nm (E=16969) ; 215.0 nm (E=31257) . Example 18 cis Analysis for C 24 H2 9 N 4 O 3 SF: Calcd: C, 61.00; H, 6.18; N, 11.85; Found: C, 60.99; H, 6.46; N, 11.98. λ E NMR (300 MHz, DMSO-dδ) : δ 7.41-6.90 (m, 11H) ; 6.41 (s, IH) ; 3.62 (t, J=7.4Hz, 2H) ; 1.52 ( , 2H) ; 1.26-1.13 (m, 10H) ; 0.82 (t, J=6.9Hz, 3H) . 13 C NMR (75 MHz, DMSO-d 6 ) : δ 167.00, 163.66, 160.43, 153.05, 147.44, 144.55, 142.51, 130.34, 130.25, 125.95, 124.03, 123.42, 115.35, 115.07, 114.41, 113.41, 52.62, 30.95, 28.13, 28.04, 26.84, 22.30, 21.92, 13.80. IR (CHC1 3 ) : 3399, 2929, 1663, 1640, 1610, 1583, 1548, 1441, 1387, 1266 and 1165 cm "1 . MS(FD) : 472 (M + ) . UV/Vis (95% EtOH) : λ max = 257.5 nm (E=22994) ; 231.0 nm (E=38882) . trans Analysis for C24H29N4O3SF: Calcd: C, 61.00; H, 6.18; N, 11.85; Found: C, 60.77; H, 6.04; N, 11.66. X H NMR (300 MHz, DMSO-dδ) : δ 7.40-6.92 (m, 11H) ; 6.43 (s, IH) ; 3.62 (t, J=7.4Hz, 2H) ; 1.52 (m, 2H) ; 1.26-1.12 (m, 10H) ; 0.82 (t, J=6.8Hz, 3H) . 13 C NMR (75 MHz, DMSO-d 6 ) : δ 166.68, 163.20, 159.98, 153.26, 148.11, 143.24, 142.06, 133.15, 131.12, 129.51, 129.39, 125.35, 124.38, 121.43, 115.99, 115.50, 114.15, 110.96, 52.77, 30.96, 28.08, 28.04, 26.78, 22.29, 21.91, 13.80. IR (CHCI3) : 3400, 2929, 1661, 1639, 1608, 1602, 1581, 1546, 1443, 1387, 1266 and 1165 cm "1 . MS(FD) : 472 (M + ) . UV/Vis (95% EtOH) : λ max = 313.5 nm (E=16928) ; 213.8 nm (E=31390) . Example 19 cis Analysis for C 17 H 13 N 4 O 3 SCI 2 F: Calcd: C, 46.06; H, 2.96; N, 12.64; Found: C, 47.02; H, 3.03; N, 13.00. X H NMR (300 MHz, DMSO-d 6 ) : δ 7.95 (s, IH) ; 6.94-7.41 (m, 10H) ; 6.44 (s, IH) and 6.43 (s, IH) . 13 C NMR (75 MHz, DMSO-d 6 ) : δ 167.01, 163.63, 160.39, 152.86, 147.34, 144.21, 142.46, 130.58, 130.20, 126.79, 124.15, 123.48, 115.31, 114.58, 114.34, 112.06, 79.13. IR (KBr) : 3461, 1667, 1609, 1582, 1557, 1441, 1395 and 1173 cm "1 . MS(FD) : 443 (M + ) . UV/Vis (95% EtOH) : λ max = 258.0 nm (E=20646) . trans Analysis for C 17 H 13 N 4 O 3 SCI 2 F: Calcd: C, 46.06; H, 2.96; N, 12.64; Found: C, 47.23; H, 3.12; N, 13.13. 1 H NMR (300 MHz, DMSO-d δ ) : δ 8.08 (s, IH) ; 7.42-6.99 (m, 11H) and 6.44 (s, IH) . 13 C NMR (75 MHz, DMSO-de) : δ 166.68, 163.16, 159.94, 153.04, 147.72, 143.09, 141.79, 133.46, 130.84, 129.48, 125.33, 121.82, 116.01, 115.66, 114.18, 111.99, 79.43. IR (KBr) : 3490, 3160, 1652, 1600, 1582, 1558, 1478, 1441, 1394 and 1267 cm "1 . MS(FD) : 443 (M + ) . UV/Vis (95% EtOH) : λ max = 309.3 nm (E=16978) . Example 20 CIS not characterized trans Analysis for C 21 H 22 N 5 O 4 ΞF: Calcd: C, 54.89; H, 4.83 N, 15.24; S, 6.98; F, 4.13; Found: C, 55.04; H, 4.83 N, 15.45; S, 7.03; F, 3.98. 1 H NMR (300 MHz, DMSO-d δ ) δ 7.96 (q , IH) ; 7.20 (m, 9H) ; 6.43 (s, IH) 3.52 (m, 4H) ; 3.15 m, 4H) and 2.50 (d, 3H) . MS(FD) : 459 (M + ) Example 21 C S Analysis for C2 0 H2 1 N4O4SF: Calcd: C, 55.55; H, 4.89; N, 12.95; Found: C, 55.67; H, 4.97; N, 13.09. λ NMR (300 MHz, DMSO-d 6 ) : δ 7.39 (s, IH) ; 7.26 (s, IH) 7.15 (m, 3H) ; 7.00 ( , 3H) ; 6.89 (m, 2H] 6.32 (s, IH) 3.83 (s, 3H) and 1.23 (d, 6H) . IR (KBr) : 3093, 1660, 1641, 1610, 1514, 1438, 1358 and 1274 cm "1 . MS(FD) : 432 (M + ) . UV/Vis (95% EtOH) : λ max = 291.5 nm (E=18471) ; 261 nm (E=19398) ; 212 nm (E=37042) . trans Analysis for C 20 H 21 N 4 O 4 SF: Calcd: C, 55.55; H, 4.89; N, 12.95; Found: C, 55.75; H, 4.96; N, 12.97. X H NMR (300 MHz, DMSO-d 6 ) : δ 7.39 (s, 2H) ; 7.19 (d, IH) ; 7.10 (m, 3H) ; 6.99 (m, IH) ; 6.92 (m, 3H) ; 6.31 (s, IH) ; 3.87 (s, 3H) and 1.22 (d, 6H) . IR (KBr) : 3400, 3001, 1659, 1638, 1516, 1442 and 1385 cm" 1 . MS(FD) : 432 (M 4 ) . UV/Vis (95% EtOH) : λ max = 309 n (E=17842) ; 212 nm (E=31338) . Example 22 CIS Analysis for C1 H18N4O3SF 2 : Calcd: C, 54.28; H, 4.32; N, 13.33, Found: C, 54.54; H, 4.54; N, 13.12 X NMR (300 MHz, DMSO-d 6 ) : δ 7.40 (m, 2H) ; 7.28 (m, IH) ; 7.21 (d, IH) ; 6.90-7.10 (m, 6H) ; 6.29 (S, IH) ; 3.86 (septet, IH) ; and 1.23 (d, 6H) . IR (KBr) : 3456, 3072, 1673, 1661, 1618, 1591, 1359 and 863 cm "1 . MS(FD) : 420 (M + ) . UV/Vis (95% EtOH) : max = 258 nm (E=26044 214 nm (E=40148) . trans Analysis for C19H18N4O3SF2 : Calcd: C, 54.28; H, 4.32 N, 13.33 Found: C, 54.45; H, 4.42 N, 13.54 1-H NMR (300 MHz, DMSO-d6) : δ 7.58 (s, IH) ; 7.39 (s, IH) ; 7.18 (d, J=8Hz, 2H) ; 7.17 (s, 2H) ; 7.01 (d, J=8Hz, IH) 6.98 (s, IH) ; 6.82 (d, J=8Hz, 2H) ; 6.48 (s, IH) ; 3.86 (septet, J=7Hz, IH) and 1.21 (d, J=7Hz, 6H) . IR (KBr) : 3466, 3413, 3173, 1653, 1628, 1591, 1549, 1394, 1356, 1265 1265, 1257, 1155, 1115, 981 and 694 cm "1 . MS(FD) : 420.1 (M + ) . Example 23 cis Analysis for C 19 H1 7 N 4 O 3 SF 3 : Calcd: C, 52.05; H, 3.91; N, 12.78; Found: C, 50.76; H, 4.11; N, 12.16. X H NMR (300 MHz, DMSO-dε) : δ 7.40 (d, J=l.lHz, IH) ; 7.33 (s, IH) ; 7.22-6.99 (m, 6H) ; 6.91 (dd, J=8.1,1.4Hz, IH) ; 6.45 (s, IH) ; 3.84 (septet, J=6.8Hz, IH) and 1.25 (d, J=6.8Hz, 6H) . IR (CHCI 3 ) : 3400, 1665, 1639, 1607, 1579, 1564, 1440, 1385, 1360, 1155, 1048 cm "1 . MS(FD) : 438.0 (M + ) . UV/Vis (95% EtOH) : λ max = 257.0 nm (E=22034) ; 214.0 nm (E=36315) . trans Analysis for C19H17N4O3SF3 : Calcd: C, 52.05; H, 3.91; N, 12.78; Found: C, 52.17; H, 3.78; N, 12.55. l E NMR (300 MHz, DMSO-d 6 ) : δ 7.52 (s, IH) ; 7.41 (d, J=1.5Hz, IH) ; 7.20 (d, J=8.4Hz, IH) ; 7.14-6.98 (m, 6H) ; 6.48 (s, IH) ; 3.87 (septet, J=6.8Hz, IH) and 1.25 (d, J=6.8Hz, 6H) . IR (KBr) : 3464, 3398, 3174, 1654, 1615, 1610, 1550, 152! 1398, 1357, 1156, 1045, 1034, 815, 695, 614, 533 cm "1 . MS(FD) : 438.0 (M+) . UV/Vis (95% EtOH) : λ max = 316.0 nm (E=16981) ; 244.0 nm (E=16471) ; 214.0 nm (E=31812) . NH-CH cis Analysis for C 20 H 19 N 4 O 3 SF 3 : Calcd: C, 53.09; H, 4.23; N, 12.38; Found: C, 52.37; H, 4.33; N, 12.06. X H NMR (300 MHz, DMSO-d δ ) : δ 7.91 (d, J=4.7Hz, IH) ; 7.37 (d, J=l.lHz, IH) ; 7.20 (d, J=8.3Hz, 2H) ; 7.15 (d, J=6.8Hz, IH) ; 7.03 (s, IH) ; 6.87 (dd, J=8.1,1.2Hz, 1H1 6.41 (s, IH) ; 3.85 (septet, J=6.8Hz, IH) ; 2.52(s, 3H) and 1.25 (d, J=6.8Hz, 6H) . IR (KBr) : 3436, 3251, 3083, 1653, 1615, 1605, 1557, 1530, 1440, 1386, 1354, 1272, 1041, 693, 624 and 586 cm "1 . MS(FD) : 452.1 (M + ) . UV/Vis (95% EtOH) : λ max = 258.0 nm (E=25278) ; 214.0 nm (E=39044) . trans Analysis for C2 0 H 19 N 4 O 3 SF 3 : Calcd: C, 53.09; H, 4.23 N, 12.38; Found: C, 52.97; H, 4.28 N, 12.26. : H NMR (300 MHz, DMSO-de) : δ 8.08 (d, J=4.7Hz, IH) 7.43 (d, J=1.6Hz, IH) ; 7.20 (d, J=8.3Hz, IH) ; 7.11 :s, 2H: 7.07 (dd, J=7.0, 1.5Hz, IH) ; 6.98 (dd, J=8.6,1.9Hz, IH) ; 6.46 (s, IH) ; 3.87 (septet, J=6.8Hz, IH) ; 2.57 (d, J=4.6Hz, 3H) and 1.25 (d, J=6.8Hz, 6H) . IR (KBr) : 3455, 2992, 1661, 1615, 1604, 1554, 1523, 1442, 1355, 1038 and 754 cm "1 . MS(FD) : 452.0 (M + ) . UV/Vis (95% EtOH) : λ max = 316.0 nm (E=19481) ; 245.0 nm (E=17652) ; 215.0 nm (E=32385) . Example 25 CIS Analysis for C19H18 4O3SF2 : Calcd: C, 54.28; H, 4.32; N, 13.33; Found: C, 54.51; H, 4.40; N, 13.28. τ NMR (300 MHz, DMSO-d δ ) : δ 7.39-7.29 (m, 5H) ? 7.20 (d, J=8.0Hz, IH) ; 7.08-6.98 (m, 3H) ; 6.90 (d, J=8.0Hz, 1HI 6.38 (s, IH) ; 3.83 (septet, J=6.8Hz, IH) and 1.24 (d, J=6.8Hz, 6H) . IR (KBr) : 3449, 3130, 1655, 1637, 1622, 1610, 1602, 1552, 1516, 1481, 1443, 1392, 1355, 1276, 1264, 1175, 1155, 1048, 826, 731, 691, 607, 525 cm "1 . MS(FD) : 420.1 (M + ) . UV/Vis (95% EtOH) : λ max = 257.0 nm (E=20610) ; 213.0 nm (E=33139) . trans Analysis for C 1 H 1 8 4 O 3 SF 2 : Calcd: C, 54.28; H, 4.31; N, 13.33; Found: C, 54.38; H, 4.27; N, 13.33. *H NMR (300 MHz, DMSO-d 6 ) δ 7.45 (s, IH) ; 7.41-7.37 (m, 5H) ; 7.20 (d, J=8.2Hz, 2H) ; 7.09 (s, IH) ; 6.97 (d, J=4.0Hz, IH) ; 6.94 (s, IH) ; 3.85 (septet, J=6.8Hz, IH) and 1.23 (d, J=6.8Hz, 6H) . IR (KBr) : 3447, 3398, 3171, 1648, 1627, 1607, 1547, 1518, 1399, 1356, 1271, 1264, 1156, 1116, 607 cm "1 . MS(FD) : 420 (M + ) . UV/Vis (95% EtOH) : λ max = 313.0 nm (E=17947) ; 215.0 nm (E=30778) . Example 26 cis Analysis for C21H23N4O3SF : Calcd: C, 58.59; H, 5.38; N, 13.01; S, 7.45; F, 4.41; Found: C, 58.85; H, 5.40; N, 13.04; S, 7.68; F, 4.70. λ E NMR (300 MHz, DMSO-d 6 ) δ 7.78 (9, IH) ; 7.18 (m, 9H) ; 3.80 (m, IH) ; 2.38 (d, 3H) ; 1.85 (s, 3H) and 1.20 (d, 6H) . MS (FD) : 430 (M + ) . UV/Vis (95% EtOH) : λ max = 262.0 nm (E=16605) . Analysis for C21H23N4O3SF : Calcd: C, 58.59; H, 5.38; N, 11.01; S, 7.45; F, 4.41; Found: C, 58.86; H, 5.28; N, 12.78; S, 7.31; F, 4.71. X H NMR (300 MHz, DMSO-dδ) δ 7.78 (9, IH) ; 7.0 ( , 9H) ; 3.82 (m, IH) ; 2.40 (d, 3H) ; 1.85 (s, 3H) and 1.25 (d, 6H) . MS (FD) : 430 (M + ) . UV/Vis (95% EtOH) : λ max = 260.0 nm (E ^ 17940) ; 211.2 nm (E-37534) . Exam 1e 27 CIS Analysis for C 20 H 20 N 5 O 4 SF: Calcd: C, 53.92; H, 4.52; N, 15.72; S, 7.19; F, 4.26; Found: C, 53.87; H, 4.51; N, 15.51; S, 7.28; F, 4.21. X H NMR (300 MHz, DMSO-d 6 ) : δ 7.20 (m, llH) ; 6.43 (s, IH) ; 3.55 ( , 4H) and 3.15 (m, 4H) . MS(FD) : 445 (M + ) . UV/Vis (95% EtOH) : λ max = 313.0 nm (E=16841) ; 219.0 nm (E=28615) . The present compounds appear to inhibit replication of plus-strand viral RNA by interfering with the structure and/or function of the viral replication complex (a membrane-bound complex of viral and cellular proteins) . Mutant rhinovirus and enterovirus have been isolated which demonstrate very low levels of drug tolerance. These mutants contain a single amino acid substitution in the protein that is expressed by the viral gene known as "3A". Therefore, the compounds of the present invention inhibit the rhinovirus and enterovirus by inhibiting a 3A function. The 3A gene encodes a hydrophobic protein which serves as the scaffolding protein that attaches the proteins of the replication complex to intracellular membranes. The replicative strategy of flaviviruses such as hepatitis C virus (HCV) and bovine diarrheal virus (BVDV) is similar to that of the rhinovirus and enterovirus, discussed above. In particular, both families of virus contain single-stranded, messenger-sense RNA that replicates in a cytoplasmic complex via a minus-strand RNA intermediate. In addition, both families of virus translate their genome into a polyprotein that is subsequently cleaved. Furthermore, the replication complexes of both viruses are tightly associated with intracellular membranes. Finally, both families of virus have analogous genomic structures including the presence of a 5 ' and 3' non-translated region which are required by the viruses for replication. There are two HCV proteins that have been implicated with this intracellular association: NS2 and NS4. It is postulated that either NS2 or NS4 is analogous to the picornavirus 3A protein. Accordingly, another embodiment of the present invention is a method of treating or preventing a flavivirus infection comprising administering to a host in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. It is preferred to inhibit hepatitis C. As noted above, the compounds of the present invention are useful as antiviral agents . They have shown inhibitory activity against various enterovirus and rhinovirus. An embodiment of the present invention is a method of treating or preventing picornaviridae infection comprising administering to a host in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The term "effective amount" as used herein, means an amount of a compound of formula I which is capable of inhibiting viral replication. The picornaviridae inhibition contemplated by the present method includes either therapeutic or prophylactic treatment, as appropriate. The specific dose of compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the condition being treated and the individual being treated. A typical daily dose will contain a dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention. Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and mtranasal . The compounds of the present invention are preferably formulated prior to administration. Therefore, another embodiment of the present invention is a pharmaceutical formulation comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient therefor. The active ingredient in such formulations comprises from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium) ; ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile mjectable solutions, sterile packaged powders and the like. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way. The term "active ingredient" means a compound according to formula I or a pharmaceutically acceptable salt thereof. Formulation 1 Hard gelatin capsules are prepared using the following ingredients : Quantity (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesium stearate 10 Total 460 mg Formulation 2 A tablet is prepared using the ingredients below: Quantity (mq/capsule) Active ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg. Formulation 3 An aerosol solution is prepared containing the following components: The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to 30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant . The valve units are then fitted to the container. Formulation 4 Tablets, each containing 60 mg of active ingredient, are made as follows: Active ingredient Starch Microcrystalline cellulose Polyvmylpyrrolidone (as 10% solution m water) Sodium carboxymethyl starch Magnesium stearate Talc Total The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvmylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Formulation 5 Capsules, each containing 80 mg of active ingredient, are made as follows : Quantity (mg/capsule) Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities . Formulation 6 Suppositories, each containing 225 mg of active ingredient, are made as follows: Active ingredient 225 mg Saturated fatty acid glyceπdes 2,000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool . Formulation 7 Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to total 5 ml The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume. Formulation 8 An intravenous formulation may be prepared as follows : Active ingredient 100 mg Isotonic saline 1,000 ml The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute. The following experiment was carried out to demonstrate the ability of the compounds of formula I to inhibit certain virus. Test Method for Anti-picornaviral Assay African green monkey kidney cells (BSC-1) or Hela cells (5-3) were grown in 25 cc Falcon flasks at 37°C in medium 199 with 5 percent inactivated fetal bovine serum (FBS) ; penicillin (150 units 1 ml) and streptomycin (150 micrograms per milliliter (μg/ml)) . When confluent monolayers were formed, the supernatant growth medium was removed and 0.3 ml of an appropriate dilution of virus (echo, Mengo, Coxsackie, polio or rhinovirus) were added to each flask. After absorption for one hour at room temperature, the virus infected cell sheet was overlaid with a medium comprising one part of 1 percent Ionagar No. 2 and one part double strength Medium 199 with FBS, penicillin and streptomycin which contains drug at concentrations of 100, 50, 25, 12, 6, 3 and 0 μ g/ml . The flask containing no drug served as the control for the test. The stock solutions of vinyl acetylene benzimidazole compounds were diluted with dimethylsulfoxide to a concentration of 10 4 μ g/ml . The flasks were then incubated for 72 hours at 37°C for polio, Coxsackie, echo and Mengo virus and 120 hours at 32°C for rhinovirus . Virus plaques were seen in those areas were the virus infected and reproduced in the cells. A solution of 10 percent formalin and 2 percent sodium acetate was added to each flask to inactivate the virus and fix the cell sheet to the surface of the flask. The virus plaques, irrespective of size, were counted after staining the surrounding cell areas with crystal violet . The plaque count was compared to the control count at each drug concentration. The activity of the test compound was expressed as percentage plaque reduction, or percent inhibition. Alternatively, the drug concentration which inhibits plaque formation by 50 percent can be used as a measure of activity. The 50 percent inhibition is indicated by the symbol IC50. In vitro CPE/XTT anti-BVDV Assay MDBK cells were dispersed in the 96-wells microtiter plate at 10,000 cells per well with Minimum Essential Medium containing Earl's balanced salt solution (EBSS) , 2% horse serum, penicillin (100 units/ml) and streptomycin (100 μg/ l) . Plates were grown at 37°C CO incubator overnight. The MDBK cells were then infected with ~ 0.02 moi (multiplicity of infection) of bovine viral diarrhea virus (BVDV, ATCC VR-534) . After allowing the virus to adsorb to the cells for 1-2 hours, medium containing serial dilutions of drug or medium alone was added to the wells. After further incubating for 3-4 days (when extensive cpe was apparent in medium alone wells) , the antiviral effect of testing drugs were assessed by performing a XTT assay as described below. XTT [2, 3-bis (methoxy-4-nitro-5-sulfophenyl) -2H- tetraazolium-5-carboxanilide, inner salt, sodium salt] at Img/ml for warm medium without FBS were freshly prepared and used immediately. For each 5 ml of the XTT solution, 25 μl of 5mM of PMS (phenazine methosulfate) in phosphate buffer saline was added. Then 50 μl of the freshly prepared XTT/PMS mixture was added to each of the microtiter wells. Incubate at 37°C (CO for 3-4 hours or until color change is prominent. Read absorptance at 450 nm/ref . 650 nm in a spectrophotometer. The concentration of drug required to cause 50% cytotoxic effect as compared to the no drug no virus control (TC^) and which to inhibit the development of virus cytopathic effect (cpe) by 50% (IC^) was then determined from the liner portion of each dose response curve.

Claims: Claims 1. A compound of the formula I wherein: a is 0, 1, 2 or 3; each R is independently hydrogen, halo, cyano, amino, halo(C1-C 4 )alkyl, di (C1-C 4 )alkylamino, azido, Ci-Cβ alkyl, carbamoyl, carbamoyloxy, carbamoylamino, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, pyrrolidino, piperidino or morpholino; R° is hydrogen, halo, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R 1 is halo, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl or methylsulfonyl; R 2 is hydrogen, amino or -NHC(O) (Cχ-C 6 alkyl) ; R 3 is dimethylamino, C1-C 1 0 alkyl, halo(C 1 -C 6 ) alkyl, C 3 -C 7 cycloalkyl, substituted C 3 -C 7 cycloalkyl, phenyl, substituted phenyl, naphthyl, thienyi, thiazolidinyl, furyl, pyrrolidino, piperidino, morpholino or a group of the formula: S ^ X R 4 and R 5 are independently hydrogen or C 1 -C 4 alkyl; with the proviso that when R is in the 2- or 6-position, then R cannot be halo, cyano, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl or methylsulfonyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 where: where: a is 0, 1 or 2; each R is independently hydrogen, halo, C -C alkyl, C 1 -C 4 alkoxy or di (C 1 -C 4 )alkylamino; R° is hydrogen; R 2 is ammo; R 3 is dimethylammo, Cχ-C 6 alkyl, halo (Ci-Cβ) alkyl, C 3 - C 7 cycloalkyl, substituted C 3 -C 7 cycloalkyl, thienyi, thiazolidmyl, pyrrolidmo, piperidino or morpholino; R 4 is hydrogen, methyl or ethyl; R 5 is hydrogen, methyl or ethyl; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2 where: each R is independently hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, dimethylammo; R° is hydrogen; R 3 is dimethylammo, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl or pyrrolidino; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3 which is: 10 NH 2 or a pharmaceutically acceptable salt thereof . 5. A pharmaceutical formulation comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, associated with one or more pharmaceutically acceptable carriers, diluents or excipients . 6. A compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, for use as a pharmaceutical. 7. A compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, for use as an antiviral.

Inventors: JUNGHEIM LOUIS N, MILLER SHAWN C, SPITZER WAYNE A, TEBBE MARK J, VICTOR FRANTZ, JUNGHEIM, LOUIS, N., MILLER, SHAWN, C., SPITZER, WAYNE, A., TEBBE, MARK, J., VICTOR, FRANTZ
Applicants: LILLY CO ELI, ELI LILLY AND COMPANY
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, C07D235, C07D409