MXPA97009660A - Antivira compounds - Google Patents

Abstract

The present invention relates to a compound of the formula I: characterized in that: R is independently hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, methyl, methylsulfinyl, methylsulfonyl or dimethylamino, R3 is thiazol-2-yl, phenyl or - SO 2 -R 4 wherein R 4 is C 1 -C 4 alkyl, C 1 -C 4 alkylamino or phenyl, or a pharmaceutically acceptable salt thereof

Description

COMPOUNDS ANTJVTRP? T? F.

DESCRIPTION OF THE INVENTION The incidence of viral upper respiratory disease, the common cold, is immense. It has been estimated that almost one billion cases appear annually in the United States alone. Rinovirus, a member of the picornaviridae family, is the leading cause of the common cold in humans. Because more than 110 rhinovirus strains have been identified, the development of a practical rhinovirus vaccine is not feasible, and chemotherapy seems to be the most desirable approach. Another member of the picornavirus family are enteroviruses, which include eighty human pathogens. Many of these enteroviruses produce symptoms similar to the cold. Others may cause more serious diseases such as polio, conjunctivitis, aseptic meningitis and myocarditis. The disease related to rhinovirus infection is evidenced by nasal discharge and obstruction. In addition, it has been implicated in otitis media, predisposes to the development of bronchitis, exacerbates sinusitis and has been implicated in the precipitation of asthmatic attacks. Although it is considered by many as simply an inconvenience, its frequent presentation in individuals who would otherwise REF: 26350 are healthy and the resulting economic importance in terms of absenteeism in jobs and visits to doctors make it an object of extensive research. The ability of clinical compounds to suppress virus growth in vitro can be easily demonstrated using virus plaque suppression tests or a cytopathic effect test (CPE). ____ Siminoff Applied Microbiology, 9 (1), 66 (1961). Although they have been identified for chemical compounds that inhibit picornaviruses such as rhinoviruses, many are unacceptable due to 1) limited activity spectrum, 2) undesirable side effects, or 3) inability to prevent infection or disease in animals or humans. See Textboo of Human Virolosy. edited by Robert B. Belshe, chapter 16, "Rhinoviruses," Roland A. Levando ski, 39-405 (1985). Therefore, despite the recognized therapeutic potential associated with a rhinovirus inhibitor and the research efforts expended so far, a viable therapeutic agent has not yet emerged. For example, antiviral benzimidazole compounds have been described in U.S. Patent Nos. 4,008,243, 4,018,790, 4,118,573, 4,118,742 and 4,174,454. Accordingly, it is a primary objective of this invention to provide novel benzimidazole compounds which inhibit the growth of picornaviruses, such as rhinoviruses (bovines and humans), enteroviruses such as polioviruses, coxsackievirus of groups A and B, or ecoviruses, cardioviruses such as encephalomyocarditis virus (EMC) and adevirus such as virus of diseases of the feet and mouth. The present invention provides compounds of formula I where: a is 1, 2, 3, 4 or 5; each R is independently hydrogen, hydroxy, thiol, halo, cyano, haloalkyl cyanoalkyl of CLC ^ nitro, amino, alkylamino of C ^ ^, dialkylamino of alkenyl of C2-C6, carbamoyl, carbamoyloxy, carbamoylamino, N-alkylcarbamoyl of CÍ- C4, -OCF3, -OCCI3, N, N-dialkylcarbamoyl of Cx-C4, CLC alkoxy, C ^ C ^ alkoxycarbonyl alkoxycarbonyloxy, CX-C4 alkoxycarbonylamino, formyl, C2-C4 alkanoyl, formyloxy, C2-C4 alkanoyloxy, formylamino, C2-C4 alkanoylamino, C1-C1 alkylthio, Cx-C4 alkylsulfinyl or CLC, alkylsulfonyl; R ° is hydrogen, halo, Cj- ^ alkyl or c-C alkoxy • R 2 is hydrogen, amino, -NHC (O) (alkyl of -NHS02 (Cx-Cg alkyl); R3 is Cx- alkyl C6, denyl, substituted phenyl, furyl, thienyl, thiazol-2-yl, 2-acetamido-4-methyl-thiazol-5-yl, 1,4-thiadiazol-2-yl, 2-methyl-l, 3 , 4-thiadiazol-5-yl, 2-methylamino-l, 3,4-thiadiazol-5-yl, -NR5R6, -S02-R4 or a group of the formula: R4 is dimethylamino, C1-C6 alkyl, haloalkyl of Cx-Cg, cycloalkyl of C3-C? , phenyl, substituted phenyl or trifluoromethyl; and R5 and R6, taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino or morpholino; with the proviso that when a is 1; then R can not be hydrogen, chloroalkyl, bromine, iodine, nitro or trifluoromethyl; 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, R2 and R3 are as defined in the above. The present invention relates to benzimidazole compounds of formula I, as described above, which are useful as antiviral agents. Such compounds are also useful for preparing additional antiviral compounds such as various vinylacetylenebenzimidazole compounds. All temperatures indicated here are in degrees Celsius (° C). All measurement units used herein are units by weight, except for liquids, which are units of volume.

As used herein, the term "alkyl" represents a straight or branched alkyl chain having from 1 to 6 carbon atoms Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , t-butyl, pentyl, neo-pentyl, hexyl and the like The term "Ci-Cg alkyl" includes within its definition the term "CÍ-J alkyl." The term "C2-C6 alkenyl" represents a linear or branched alkenyl chain of 2 to 6 carbon atoms Typical C2-C6 alkenyl groups include ethenyl, prop-1-enyl, isopropenyl, but-2-enyl, isobut-1-enyl, sec-but-2- enyl, pent-4-enyl, pent-1-enyl, hex-3-enyl and the like The term "halo" represents chloro, fluoro, bromo or iodo The term "haloalkyl of CÍ-CÍ" represents a linear alkyl chain or branched having one to four carbon atoms with 1, 2 or 3 halogen atoms attached thereto Typical haloalkyl groups include chloro ethyl, 2-bromoethyl, 1-chlorosopropyl, 3-fluoropropyl, 3-bromobutyl, 3-chloroisobutyl, iodo-t-butyl, trichloromethyl, trifluoromethyl, 2,2-chloro-iodoethyl, 2,3-dibromopropyl and the like.

The term "C1-C4 cyanoalkyl" represents a straight or branched alkyl chain having from one to four carbon atoms with a cyano portion attached thereto.

Typical cyanoalkyl groups of C_-Ct include cyanomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoisopropyl, 3-cyanopropyl, 3-cyanobutyl, cyano-t-butyl and the like. The term "Cx-C4 alkylthio" represents a linear 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. The term "C ^ C alkoxy" represents a straight or branched alkyl chain of one to four carbon atoms attached to an oxygen atom.The typical C ^ -C ^ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like The term "C 1 C alkoxycarbonyl" represents a straight or branched alkoxy chain having from one to four carbon atoms attached to the carbonyl moiety. Typical ^ - ^ alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and the like. The term "C-L-C alkoxycarbonyloxy," represents a straight or branched alkoxy chain having from one to four carbon atoms attached to a carbonyloxy moiety.

Typical alkoxycarbonyloxy groups of ^^ include methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, and the like. The term "Cx-C4 alkoxycarbonylamino" represents a straight or branched alkoxy chain having from one to four carbon atoms attached to a carbonylamino moiety. Typical C ^^ alkoxycarbonylamino groups include methoxycarbonylamino, ethoxycarbonylamino, propoxycarboni lamino, isopropoxycarboni lamino, butoxycarbonylamino and the like. The term "C 1 C alkylamino" represents a straight or branched alkyl chain having from one to four carbon atoms attached to an amino group Typical C1-C 1 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like The term "C 1 -C 4 dialkylamino" represents two linear or branched alkyl chains of one to four carbon atoms linked to a common amino group Typical dialkylamino groups include dimethylamino, ethylmethylamino, methylpropylamino , ethyl isopropylamino, ethylisopropylamino, butylmethylamino, butylmethylamino, sec-butylethylamino and the like The term "N-alkylcarbamoyl of LQ," represents a linear or branched alkyl chain having from one to four carbon atoms attached to the nitrogen atom or a carbamoyl moiety Typical N-alkylcarbamoyl groups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butyl lcarbamoyl and N-t-butylcarbamoyl and the like. The term "C2-C4 alkanoyl" represents a straight or branched alkyl chain having from one to three carbon atoms attached to a carbonyl moiety. Typical C2-C4 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl and the like. The term "C2-C4 alkanoyloxy" represents a linear or branched alkyl chain of one to three carbon atoms attached to a carbonyloxy moiety. Typical C2-C4 alkanoyloxy groups include ethanoyloxy, propanoyloxy, isopropanoyloxy, butanoyloxy, and the like. The term "C2-C4 alkanoylamino" represents a linear or branched alkyl chain of one to three carbon atoms attached to a carbonylamino group. Typical C2-C4 alkanoylamino groups include ethanoylamino, propanoylamino, isopropanoylamino, butanoylamino, and the like. The term "C 1 C alkylsulfinyl" represents a straight or branched alkyl chain having one to four carbon atoms attached to a sulfinyl moiety Typical C 1 C alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl and the like The term "C 1 alkylsulfonyl" represents a straight or branched alkyl chain of 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 term "substituted phenyl" represents a phenyl ring substituted with ul-3 substituents halo, cyano, C 1 alkyl, C 1 -C 4 alkoxy, or trifluoromethyl The term "substituted C 3 -C 7 cycloalkyl" represents a ring cycloalkyl substituted with 1-3 substituents halo, cyano, C 1 -C 4 alkyl, C 1 alkoxy or C 1 -C 4 haloalkyl. As mentioned above, the invention These include pharmaceutically acceptable salts of the compounds defined by formula I. Although generally neutral, a compound of the invention may possess a sufficiently acidic, sufficiently basic condition or both functional groups, and consequently may react with any of various inorganic bases and inorganic or 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 with an inorganic base. Such salts are known as acid addition salts and base addition salts. Acids commonly used 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 acid, methanesulfonic acid, oxalic acid, acid p-bromomethylsulfonic, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, furamate, maleate, butin-l, 4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propansulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid and those formed with organic acids such as maleic acid and methanesulfonic acid. The base addition salts include those derived from inorganic bases such as ammonium or alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates and the like. Such bases useful for preparing the salts of this invention include, therefore, sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, carbonate calcium and the like. Particularly preferred are the salt forms of potassium and sodium. It should be recognized that a particular counter ion that is part of any salt of this invention is not critical in so far as the salt, in its entirety, is pharmacologically acceptable and to the extent that the counterion does not contribute undesired qualities to the salt in its entirety. Preferred compounds of this invention are those compounds which: a is 1, 2 or 3; each R is independently hydrogen, halo, C 1 -C ^ alkyloxy, C 1 -C ^ alkylthio, C-L-C ^ alkylsulfinyl, C 1 -C 4 alkylsulfonyl, trifluoromethyl, dialkylamino, ^^ O -OCF 3; R ° is hydrogen, halo or alkyl of R 2 is amino; R3 is thiazol-2-yl, phenyl, substituted phenyl or -S02-R4; R 4 is alkyl or phenyl; or a pharmaceutically acceptable salt thereof. Of these preferred compounds, those compounds of formula I are preferred in which: a is 1 or 2; each R is independently hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl, methylsulfonyl or dimethylamino; R ° is hydrogen; R3 is thiazol-2-yl, phenyl or -S02-R4; or a pharmaceutically acceptable salt thereof.

Of these compounds, those compounds of the formula are further preferred: wherein: R is independently hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl, methylsulfonyl or dimethylamino. R3 is -S02-CH (CH3) 2 O -S02-N (CHJ2, or a pharmaceutically acceptable salt thereof) Of these compounds, the most preferred compounds are: or a pharmaceutically acceptable salt thereof. Another group of preferred compounds are those compounds of the formula: wherein: a is 1, 2 or 3; each R is independently hydrogen, halo, methyl, ethyl, methoxy or ethoxy; R3 is phenyl alkyl, substituted phenyl, thiazol-2-yl or -S02R4; R4 is Ci-Cg alkyl, phenyl, dimethylamino or C3-C7 cycloalkyl; or a pharmaceutically acceptable salt thereof. Another group of preferred compounds are those compounds of the formula: wherein: a is 1, 2 or 3; each R is independently hydrogen, halo, methyl, ethyl, methoxy, ethoxy; R3 is C1-C6 alkyl, phenyl, substituted phenyl, thiazol-2-yl? or -S02-R4; R4 is C3-Cg alkyl, phenyl, dimethylamino or C3-C cycloalkyl?; or a pharmaceutically acceptable salt thereof. The compounds of formula I can be prepared according to procedures detailed in the art. For example, ketone compounds can be prepared substantially as described in Paget et al. , U.S. Patent Serial No. 4,118,742, incorporated herein by reference. In general, Paget et al .. describe the preparation of such ketone compounds by ring closure of a 3,4-diaminobenzophenone followed by reaction with sulfonyl halide to provide the desired compounds. In addition, the compounds of formula I can be prepared according to the following Reaction Scheme II.

Reaction Scheme II oxidi base agent zante Reduction Sulfonylation (optional) Cyclization wherein: X is cyano or -COOR ', wherein R' is alkyl XI is halo; R "is hydrogen, phenyl alkyl or substituted phenyl, and, R, R °, R2 and R3 are as defined above, Reaction Scheme II above is carried out when reactions 1-4 are carried out. Once a reaction is complete, the intermediate compound can be isolated, if desired by methods known in the art, For example, the compound can be crystallized and then collected by filtration, or the reaction solvent can be removed by extraction, evaporation. or decanting The intermediary compound can be further purified, if desired, by common techniques such as crystallization or chromatography on solid supports such as silica gel or alumina, before carrying out the next step of the reaction scheme. .1 is carried out by first exposing an appropriately substituted halonitroaniline and an appropriately substituted phenylacetonitrile or benzoate to a base in an organic solvent for 1 a 24 hours at a temperature 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-butoxide, lithium diisopropylamide (LDA). A preferred base is potassium t-butoxide. Examples of suitable solvents for use in this reaction include dimethylformamide, dimethylacetamide, and the like. The choice of solvent is not critical to the extent that the solvent used is inert in the reaction carried out and the reagents are sufficiently solubilized to carry out the desired reaction. The ketone precursor is generally prepared from about 1 to 15 hours when the reaction is initiated at 0 ° C and allowed to advance to room temperature. The ketone precursor is preferably oxidized in the same reaction mixture without isolation or prior purification. In particular, the ketone precursor is reacted with an oxidizing agent for 30 minutes to 15 hours at a temperature from about 0 ° C to about 30 ° C to provide the corresponding ketone compound. Typical oxidizing agents include hydrogen peroxide, oxygen and air. 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 from about 30 to 5 hours when the reaction is carried out between 0 ° C and room temperature. The reaction is preferably monitored by CCD, for example, to ensure that the reaction has ended. In reaction II.2, the nitro substituent on the ketone is reduced according to procedures in the art to provide the corresponding diaminobenzophenone compound. For example, the nitro substituent can be reduced by catalytic hydrogenation, for example, by combining the ketone isolated from reaction II.l with hydrogen gas in ethanol or tetrahydrofuran and a catalyst. A preferred catalyst is palladium carbon or Raney nickel. The choice of solvent is not critical in the medical one in which the solvent used is inert in the reaction that is carried out and the nitro reagent is sufficiently solubilized to carry out the desired reaction. Hydrogen gas is typically used at a pressure of up to about 4.2 kg / cm2 (60 psi), preferably at a pressure of about 2.1 kg / cm2 (30 psi). The reaction is generally complete substantially after 1 to 24 hours when carried out at a temperature in the range from about 0 ° C to about 40 ° C. Preferably, the reaction is carried out at a temperature in the range from about 20 ° C to about 30 ° C for about 2 to 5 hours. In reaction II.3, the diaminobenzophenone compound isolated from reaction II.2 wherein R "is hydrogen can be sulfonylated with an appropriately substituted sulfonyl halide of the formula R4-S02-halide in substantial accordance with the procedure detailed above for provide the corresponding sulfamidobenzophenone compounds.

In reaction II.4, the compound isolated from reaction II.3 is cyclized by means of a nitrile intermediate by first exposing the sulfamidobenzophenone compound to a base in an alcohol solvent such as isopropanol followed by reaction with cyanogen bromide. Typically, the sulfonamido benzophenone and the base are reacted at a temperature from about 0 ° C to about 30 ° C. A preferred base is sodium hydroxide, preferably added in the form of an aqueous solution (approximately 1-4M). When the sulfonamido benzophenone is completely dissolved, the resulting solution is combined with cyanogen bromide. Cyanogen bromide is typically added in the form of a solution (3-7M), for example, in acetonitrile). The reaction is generally completed after 1 to 18 hours, when the reaction mixture is stirred at room temperature. However, in certain cases the nitrile intermediate will precipitate from the reaction mixture in the next 10 to 20 minutes from the start of the reaction. In order to produce the desired ketone, this precipitate is isolated and then refluxed in an alcohol solvent such as isopropanol for 1 to 4 hours to provide the desired ketone compound of formula I. The compounds of the formula: wherein: X 'and R ° are as defined in the foregoing; and R "is Ci-Cg alkyl, phenyl or substituted phenyl used in reaction II.1 above, to prepare the compounds of formula I wherein R3 is Ci-Cg alkyl, phenyl or substituted phenyl, are prepared by displacing the chloro or fluoro substituent in a compound of the formula wherein Y is chloro or fluoro, with the proviso that Y can not be chloro when X 'is fluoro, with a primary amine of the formula NH2R3 in which R3 is Ci-Cg alkyl, phenyl or substituted phenyl, in an organic solvent. The reaction is optionally carried out in the presence of an acid scavenger such as potassium carbonate or a large excess of the primary amine. Typical solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, and the like. Generally the reaction is completed in 1 to 20 hours when carried out at a temperature from about 20 ° C to about 80 ° C. The alkylated halonitroaniline is then reacted as described in Reaction Scheme II above. Compounds of formula I can be prepared wherein R2 is -NHC (0) (alkyl of or -NHS02 (C? -C6 alkyl) By acylation or sulfonylation of a compound of formula I, wherein R2 is amino, in accordance with procedures known in the art. For example, the amine compound can be acylated with a suitable acyl halide, isocyanate or chloroformate, preferably in the presence of an acid scavenger such as a tertiary amine, preferably triethylamine. Preferred acylating agent is acetic anhydride The reaction is typically carried out at a temperature from about -20 ° C to about 25 ° C. Typical solvents for this reaction include ethers and chlorinated hydrocarbons, preferably diethyl ether, chloroform or chloride Methylene The amine can be sulfonylated by reaction with a suitably substituted sulfonilant agent in an aprotic solvent Typical sulfonilants include halide suitably substituted sulfonyl or sulfonic acid anhydrides. A preferred sulfonylating agent is the sulfonyl chloride of the formula (Cx-C6 alkyl) -S02C1. The reaction is typically carried out at a temperature from about -30 ° C to about 50 ° C in an aprotic solvent such as tetrahydrofuran. The amine reactant is generally used in equimolar proportions relative to the acylating or sulfonylating reagent, and preferably in the presence of equimolar amounts of an acid scavenger such as a tertiary amine. A preferred acid scavenger for this reaction is N-methylmorpholine (NMM). The compounds used as starting materials in the synthesis of the compounds of this invention are known in the art., and, insofar as they are not commercially available, they can be easily synthesized by conventional methods commonly used in the art. It will be understood by those familiar with the art that in carrying out the processes described in the above it may be desirable to introduce chemical protecting groups into the reagents in order to prevent secondary reactions from taking place. Any amine, alcohol, alkylamine or carboxy group which can be present in the reagents can be protected using conventional protecting groups for amino or for carboxy which do not adversely alter the rest of the molecule's ability to react in the desired manner . The various protecting groups can then be removed simultaneously or successively using methods known in 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 reagents are generally combined in a mutual solvent such as diethyl ether or benzene, for acid addition salts, or water or alcohols for base addition salts. The salts are usually separated by precipitation from the solution in about the next hour to about 10 days and can be isolated by filtration or by other conventional methods. The following example preparations further illustrate specific aspects of the present invention. However, it should be understood that these examples are included for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way and should not be considered in this manner.

In the following example preparations, the terms melting point, nuclear magnetic resonance spectrum, electronic impact mass spectrum, mass spectrum by field desorption, mass spectrum by fast atomic bombardment, infrared spectrum, ultraviolet spectrum, elemental analysis , high performance liquid chromatography and thin layer chromatography are abbreviated "pf", "NMR", "EMIE", "EM (DC)", "EM (BAR)", "IR", "UV", Analysis ", "CLAP" and "CCD", respectively, EM (DC) data are presented as the mass number unless otherwise indicated, in addition, the absorption maximum listed in the IR spectrum is only of interest and not All the maxima are observed In conjunction with the NMR spectrum, the following abbreviations are used: "s" is singlet, "d" is doublet, "dd" is doublet of doublets, "t" is triplet, "c" is quartet, "m" is multiplet, "dm" is a doublet of multiplets and "s broad", "broad d", "broad t" and "broad m" are a singlet, doublet, triplet and multiplet, respectively. "J" indicates the coupling constant in Hertz (Hz). Unless indicated otherwise, the NMR data refers to the free base in the target compound. The NMR spectra are obtained on a Bruker Corp. 270 MHz instrument or on a General Electric QE-300, 300 MHz instrument. Chemical shifts are expressed in delta od values (parts per million, low field from tetramethylsilane). The EM (DC) spectra are taken on a Varion-MAT 731 spectrometer using carbon dendrite emitters. The EMIE spectra are obtained in a CEC 21-110 instrument from Colsolidated Electrodynamics Corpoation. The IR spectra are obtained on a Perkin-Elmer 281 instrument. The UV spectra are obtained on a Cary 118 instrument. The CCDs are carried out on E. Merck silica gel plates. The melting points are uncorrected.

Example 1 A. 3-amino-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-fluorophenylanitrile in 200 ml of dimethylformamide are added 22.44 g (200 mmol) of potassium butoxide, under nitrogen. The resulting reaction mixture is warmed to room temperature and reacted overnight. When the reaction has been substantially complete, as indicated by CCD (eluent of 40% ethyl ate in hexane), the reaction mixture is cooled to 0 ° C followed by the addition of 30 ml of hydrogen peroxide. When the reaction has been substantially complete, as indicated by CCD (eluent of 40% ethyl ate in hexane), the reaction mixture is poured into 1 liter of hydrochloric acid (aqueous) which results in the formation of a precipitate yellow / orange. This precipitate is isolated by filtration. Yield: 23.3 g (89%).

B. 3,4-diamino-4 '-fluorobenzofennna To a solution of 21 g of the subtitled compound of example IA in 250 ml of tetrahydrofuran and 250 ml of ethanol is added 3.0 g of Raney nickel catalyst. The resulting reaction mixture is stirred overnight under 2.1 kg / cm2 (30 psi) of hydrogen (gas) and then filtered. The resulting filtrate is concentrated in vacuo to give a yellow solid which is used without further purification. c 4-amino-3-isQprQpilgnlfQnilamidQ-4, '-fluorobenzophenone To a solution of 18.14 g (79 mmol) of the compound of Example IB in 160 ml of anhydrous methylene chloride and 32 ml of anhydrous pyridine are added 13.25 ml (118 mmoles) of isopropylsulfonyl chloride. The resulting reaction mixture is reacted at room temperature for about 5 hours, under nitrogen. When the reaction is substantially complete, as indicated by CCD (eluent of ethyl ate), the reaction mixture is poured into 400 ml of 1H hydrochloric acid (aqueous). The resulting mixture is diluted with 300 ml of ethyl ate and the resulting layers are separated, the organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark red gum. This gum is purified using preparative CLAP (gradient eluent of 30-60% ethyl ate in hexane). The fractions containing the desired compound are combined and dried in vacuo to provide 17.11 g of a yellow gum which is used, without further purification. Performance: 65% To a solution of 17.11 g (51 mmol) of the subtitle compound of Example IC and 25 ml of 2U sodium hydroxide (aqueous) in 100 ml of isopropanol, 10 ml of 5M cyanogen bromide are added. The resulting reaction mixture is reacted at room temperature for about 30 minutes which results in the formation of a precipitate. This precipitate is isolated by filtration to provide 11.68 g of a solid. This solid is resuspended in 250 ml of isopropanol and the resulting mixture is refluxed until all of the material is dissolved and then cooled to provide 0.0 g of the subtitle compound (crystals). Performance: 55%. Analysis for C17H16FN303S: Calculated: C, 56.50; H, 4.46; N, 11.63; Found: C, 56.71; H, 4.48; N, 11.82 MS (DC): 361. X H NMR (300 MHz, d 6 -DMSO): 6 1.32 (d, J = 7 Hz, 6H); 3.96 (septet, J = 7.0 Hz, 1H); 7.34-7.44 (m, 5H); 7.63 (dd, J = 1.6, 8.3 Hz, 1 HOUR); 7.79-7.83 (m, 2H); 7.95 (d, J = 1.5 Hz, 1H).

Example 2 A. 4-amino-3-isopropylsulfonamido-4 '-di (methyl) aminobenzophenone A solution of 2 g of the subtitle compound of Example IC, 2 g of potassium carbonate and 100 ml of anhydrous dimethylamine is reacted for about 16 hours at 120 ° C. The reaction mixture is subsequently dried in vacuo to provide a residue. This residue is suspended in a mixture of ethyl acetate and 1N hydrochloric acid (aqueous). The desired subtitle compound is isolated from the organic layer and used without further purification.

To a cold (0 ° C) solution containing 35.64 g (98.6 mmol) of the compound of Example 3A, 400 ml of isopropanol and 50 ml of sodium hydroxide (aqueous) is added 19.8 ml of a solution of 5M cyanogen bromide ( 98.6 mmoles). The resulting reaction mixture is heated to room temperature which results in the formation of a tan precipitate. This precipitate is isolated by filtration, washed with diethyl ether and then dried in vacuo. Yield: 28.8 g (76%) MS (DC): 386. X H NMR (300 MHz, d 6 -DMSO): d 1.25 (d, 6H); 3.05 (s, 6H); 3.90 (m, 1H); 6.80 (d, 2H); 7.25-7.85 (m, 7H).

Example 3 The title compound is prepared substantially in accordance with the procedure detailed in Examples 1A-1D.

MS (DC): 361.2. X H NMR (300 MHz; d 6 -DMSO): d 1.25 (d, 6H); 3.95 (m, 1H); 7.25-7.70 (m, 6H); 7.95 (s, 1H); IR (CHC13):? 3397, 3016, 1640, 1604, 1588, 1541, 1443, 1387, 1361, 1284, 1271, 1155, 1044, 840 cm "A The following compounds are prepared substantially in accordance with the procedure detailed in Example 1A-D, unless otherwise indicated.

Example 4 MS (DC): 357. X H NMR (300 MHz, d 6 -DMSO): δ 1.36 (d, J = 6.7 Hz, 6H); 2.38 (s, 3H); 3.60 (septet, J = 6.7 Hz, 1H); 6.50 (broad s, 2H); 7. 25 (d, J = 4.7 Hz, 1H); 7.45 (m, 1H); 7.57 (m, 2H); 7.78 (m, 12H). IR (CHC13)? 3398, 2985, 1645, 1608, 1361 and 1279 cprA Example 5 Analysis for C17HlsF2N3? 3? 3S: Calculated: C, 53.82; H, 3.99; N, 11.08; Found: C, 53.63; H, 3.90; N, 11.03. MS (DC): 379.3. 'E NMR (300 MHz; d6-DMSO): d 1.30 (d, 6H); 3.95, (m, 1H); 7.31-7.65 (m, 7H); 7.95 (s, 1H). IR (CHCl3): 3507, 3397, 2982, 1640, 1594, 1541, 1442, 1361, 1324, 1266, 1155, 1124, 1045, 989 cm'1. Example 6 MS (DC): 427. X H NMR (300 MHz, d g -DMSO): d 1.25 (d, 6 H); 3.95 (m, 1H); 7.28 (d, 1H); 7.44 (s, 2H); 7.50-7.65 (m, 4H); 7.82 (d, 1H); 7.95 (s, 1H); IR (CHC13):? 3507, 3397, 2982, 1640, 1604, 1541, 1443, 1387, 1361, 1262, 1174, 1156, 1044, 920 cirfA Example 7 MS (DC): 362.1. X H NMR (300 MHz, d 6 -DMSO): d 2.95 (s, 6H); 7.31-7.75 (m, 8H); 7.95 (s, 1H). IR (CHC13):? 3504, 3461, 3397, 2977, 1637, 1603, 1586, 1538, 1445, 1390, 1285, 1170, 1053, 970, 840 cm'1, Example 8 Analysis for C17H15F2N303S: Calculated: C, 53.82; H, 3.99; N, 11.08; Found: C, 53.63; H, 4.05; N, 11.33. MS (DC): 379.1. X H NMR (300 MHz, d 6 -DMSO): d 1.30 (d, J = 2.4 Hz, 6H); 3.95 (septet, J = 2.4 Hz, 1H); 7.35 (d, J = 2.5 Hz, 1H); 7.46 (s, 2H); 7.56-7.80 (m, 3H); 7.75-7.85 (m, 1H); 7.94 (s, 1H): IR (CHC13):? 3480, 1649.4, 1599.2, 1545.2, 1512.4, 1360, 1312.7, 1290, 1180.6, 1120.8, 1046.5, 584.6 cm'A UV / VIS? ^ = 321.5 nm (E = 15637); 248.0 nm (E = 13856); 211.5 nm (E = 27821).

Example 9 Analysis for C18H18FN304S: Calculated: C, 55.23; H, 4.63; N, 10.73; Found: C, 55.12; H, 4.65; N, 10.53. MS (DC): 391.2. X H NMR (300 MHz; dg-DMSO): d 1.29 (d, J = 2.2 Hz, 6H); 3.93 (septet, J = 2.2 Hz, 1H); .7.95 (s, 3H); 7.28 7. 38 (m, 2H); 7.52-7.64 (m, 3H), 7.90 (s, 1H). IR (CHC13):? 3397.1, 1639.7, 1608.8, 1579.9, 1542.3, 1518.2, 1442, 1279 cpT \ UV / VIS? -_ x = 318 nm (E = 22070); 247 nm (E = 12107); 211 nm (E = 31784).

Example 10 The title compound is prepared substantially in accordance with Example 29A-E. Analysis for C21H17N302: Calculated: C, 73.45; H, 4.99; N, 12.24: Found: C, 73.31; H, 5.08; N, 12.11. MS (DC): 343. X H NMR (300 MHz, CDC13): d 3.90 (s, 3H); 5.19 (s, 2H); 7.07-7.83 (m, 12H). IR (CHC13):? 3506.1, 3406.7, 3012.2, 1631, 1610.7, 1526.9, 1515. 2, 1454.5, 1274.4, 1254.8, 1219.2, 836.3 cm "1. UV / VIS? ^ = 330 nm (E = 17200); 213 cm (E = 35900).

Example 11 Analysis for C17H16FN303S: Calculated: C, 56.50; H, 4.46; N, 11.63; S, 8. 82 Found: C, 56.61; H, 4.49; N, 11.52; S, 8.70 MS (DC): 361. LH NMR (300 MHz, d6-DMSO): d 1.30 (d, 6H), 3.95 (m, 1H); 7.20-7.70 (m, 8H); 7.98 (s, 1H).

Example 12 MS (DC): 361. H NMR (300 MHz, CDC13): d 1.44 (d, J = 6.9 Hz, 6H); 3.68 (septet, J = 6.9, 1H); 6.26 (s, 2H); 7.29 (m, 2H); 7.48 (m, 2H); 7.61 (m, 1H); 7.85 (dd, J = 1.0, 6.8, 2H).

Example 13 MS (DC): 357. X H NMR (300 MHz; de-DMS0): d 1.32 (d, J = 6.6 Hz, 6H); 2.34 (s, 3H); 3.92 (septet, J = 6.6 Hz, 1H); 7.02 (d, J = 8.5 Hz, 1H); 7.12 (m, 2H); 7.44 (d, J = 8.5Hz, 1 HOUR); 7.56 (m, 2H); 7.73 (m, 3H).

Example 14 Analysis for C18H19N3? 3S: Calculated: C, 55.51; H, 4.92; N, 10.79; S, 16. 46; Found: C, 55.60; H, 4.63; N, 10.58; S, 16.22. MS (CD): 389.

Example 15 MS (DC): 405. X H NMR (300 MHz, d g -DMSO): d 1.30 (d, 6 H); 2.82 (s, 3H); 3.96 (, 1H); 7.30-7.70 (m, 8H); 7.98 (s, 1H) Example 16 MS (DC): 421. * H NMR (300 MHz, d6-DMSO): d 1.30 (d, 6H); 3.35 (s, 3H); 3.95 (m, 1H); 7.30-8.20 (, 9H).

Example 17 MS (DC): 377. X H NMR (300 MHz, d g -DMSO): d 1.75 (d, 6 H); 3.90 (m, 1H); 7.40-7.90 (m, 9H).

Example IB Analysis for C17H16FN303S: Calculated: C, 56.50; H, 4.46; N, 11.63; S, 8. 87; Found: C, 56.70; H, 4.72; N, 11.78; S, 8. 81. MS (DC): 361 * H NMR (300 MHz, dg-DMSO): d 1.30 (d, 6H), 3.95 (m, 1H); 7.10-7.80 (m, 9H).

Example 19 Analysis for C19H21N303S: Calculated: C, 61.44; H, 5.70; N, 11.31; S, 8. 63; Found: C, 61.06; H, 5.92; N, 11.14; S, 8.54. MS (DC): 371. * H NMR (300 MHz, d6-DMS0): d 1.30 (d, 6H); 2.29 (s, 3H); 2.31 (S, 1H); 3.92 (m, 1H); 7.20-7.65 (m, 7H); 7.90 (s, 1H).

Example 20 MS (DC): 379. X H NMR (300 MHz, CDC13): d 1.41 (d, 6H); 3.70 (m, 1H); 6.60 (s, 2H), 7.10-7.30 (m, 3H); 7.35 (d, 1H); 7.72 (d, 1H); 8.18 (s, 1H).

Example 21 Analysis for C17H15N303SF2: Calculated: C, 53.82; H, 3.98; N, 11.08; Found: C, 52.71; H, 3.89; N, 10.94. MS (DC): 379 (M *). : H NMR (300 MHz, d6-DMS0): d 1.31 (d, 6H); 3.94 (septet, 1H); 7.33 (d, 2H); 7.39 (m, 2H); 7.54 (s, 2H); 7.61 (d, 1H); 7.70 (m, 1H) and 7.99 (s, 1H). IR (CHC13):? 3376, 1666, 1640, 1604, 1481, 1283 and 1272 C? TA UV / VIS (95% EtOH):? MX = 324 nm (E = 20915); 242 nm (E = 13981).

Example 22 Analysis for C17H16C1N303S: Calculated: C, 54.04; H, 4.27; N, 11.12; Found: C, 54.26; H, 4.48; N, 11.25. MS (DC): 377.4. * H NMR (300 MHz; dg-DMSO): ß 1.25 (d, 6H); 3.95 (m, 1H); 7.28 (d, 1H); 7.44 (s, 2H); 7.55-7.78 (m, 5H); 7.95 (S, 1H). IR (KBr):? 3438, 2987, 1674, 1643, 1606, 1552, 1473, 1355 1291, 1245, 1210, 1154, 1126, 1045, 729 and 624 cm "A Example 23 Analysis for C16H14N403SF2: Calculated: C, 50.52; H, 3.71; N, 14.73; Found: C, 549.18; H, 3.84; N, 13.84. MS (DC): 380 (*). H NMR (300 MHz; dg-DMSO): d 1.20 (s, 3H); 1.22 (s, 3H); 7.17 (m, 2H); 7.40 (d, 1H); 7.72 (dd, 1H) and 8.16 (s, 1H). IR (CHC13):? 3457, 1661, 1484 and 1376 cpf \ UV / VIS (95% EtOH): ^ = 327.5 nm (E = 15694.9); 246.5 nm (E = 9643.2); 216.0 nm (E = 20014.8).Example 24 Analysis for C20H12Cl2FN3O3S: Calculated: C, 51.74; H, 2.60; N, 9.05; Found: C, 51.70; H, 2.68; N, 8.85. MS (DC): 464. 13 C NMR (75 MHz, d6-DMSO): d 113.13, 115.23, 118.35, 124.71, 125.44, 127.50, 127.94, 129.81, 130.16, 131.73, 132.50, 133.83, 134.75, 136.27, 139.87, 146.68, 154. 11, 159.70, 162.96 and 192.69 PPM Example 25 MS (DC): 420. 13 C NMR (75 MHz, d6-DMSO): d 114.39, 114.68, 116.55, 117.94, 119. 90, 121.60, 126.47, 129.40, 129.77, 131.30, 131. 60, 132.77, 138.34, 140.10, 141.35, 148.59, 155. 28, 161.22, 164.47, 171.20 and 194.20 ppm.

IR (KBr): 3454, 3773, 3009, 2236, 1664, 1280 and 590 cpT \ Example 26 Analysis calculated for C17H16FN303S: Calculated: C, 56.50; H, 4.46; N, 11.63; Found: C, 56.25; H, 4.40; N, 11.39. MS (DC): 361. 13 C NMR (75 MHz, dg-DMSO): d 13.42, 17.80, 56.05, 114.85, 116.61, 117.11, 120.09, 126.77, 129.18, 129.64, 131.91, 141.83, 148.76, 156.29, 161.52, 164.78 and 194.62 ppm.

Example 27 Analysis for C17H15N303SF2: Calculated: C, 53.82, H, 3.98; N, 11.08; Found: C, 53.70; H, 4.28; N, 10.94. MS (DC): 379 (M *). X H NMR (300 MHz, d 6 -DMSO): d 1.31 (d, 6H); 3.94 (septet, 1H); 7.30 (m, 2H); 7.41-7.70 (m, 5H) and 7.97 (s, 1 HOUR) . IR (CHC13):? 3430, 1654, 1640, 1605, 1284 and 1270 cm'A UV / VIS (95% EtOH):? ". X = 322.00 nm (E = 19922); 243.00 nm (E-14651).

Example 28 Analysis for C17H15N303SF2: Calculated: C, 53.82; H, 3.98; N, 11.08; Found: C, 54.00; H, 4.02; N, 11.18. MS (DC): 379 (M +). * H NMR (300 MHz; d6-DMSO): d 1.30 (d, 6H); 3.95 (septet, 1 HOUR); 7.33 (m, 3H); 7.59 (m, 3H); 7.68 (m, 1H) and 7.99 (S, 1H). IR (CHC13):? 3396, 1661, 1640, 1624, 1603, 1540, 1272 and 1008 cm1. UV / VIS (95% EtOH):? MX = 323 nm (E = 22678); 241 nm (E = 13593).

Example 29 TO.

To a cold (0 ° C) mixture of 43.35 ml (400 mmol) of 2,4-difluoronitrobenzene and 55 g (approximately 400 mmol) of potassium carbonate in 400 ml of tetrahydrofuran are added approximately 34.4 ml of isopropylamine (400 mmol) . The resulting reaction mixture is warmed to room temperature and reacted for about 60 hours and then filtered. The potassium carbonate is washed with ethyl acetate and the organic fractions are then concentrated under reduced pressure resulting in recrystallization of the desired compound which is subsequently isolated by filtration and washed with a small volume of hexane. Yield: 66.37 g, yellow crystals (84%).

B. 3-isopropylamino-4-nitro-2 '.3' -difluorobenzophenone To a cold (0 ° C) mixture of 7.65 g (50 mmol) of 2,3-difluorophenylacetonitrile and 9.9 g (50 mmol) of the sub-title compound of Example 29A in 80 ml of dimethylformamide is added 11.22 g (100 mmol) of potassium t-butoxide. The reaction mixture is warmed to room temperature and reacted for about 1 hour. When the reaction is substantially complete, determined by CCD, the mixture is cooled to 0 ° C, followed by the addition of 15 ml of a 30% solution of hydrogen peroxide. The mixture is warmed to room temperature, stirred overnight in one liter of IN hydrochloric acid which results in the formation of 16 g of an orange solid which is used without further purification.

C. 3-isopropylamino-4-amino-2 '. '-difluorobenzophenone The compound of Example 29B is hydrogenated in 250 ml of tetrahydrofuran using 2.1 g of Raney nickel catalyst under 4.2 kg / cm2 (60 psi) of hydrogen (gas) for 6 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to provide 14 g of a solid which is used without further purification.

To a cold (0 ° C) mixture of 14 g of the compound of Example 29C in 125 ml of isopropyl alcohol is added one equivalent of cyanogen bromide (9.6 ml of a 5M solution in acetonitrile). The resulting mixture is warmed to room temperature and stirred for about 2 days and then concentrated under reduced pressure to provide a residue. This residue is redissolved in ethyl acetate and then subjected to sonication which results in the formation of 13.0 g of crystals. Analysis for C17H16N3OBrF2: Calculated: C, 51.53; H, 4.07; N, 10.61; Br, 20.17; Found: C, 51.64; H, 4.17; N, 10.51; Br, 20.41. MS (DC): 315 (M *). "H NMR (300 MHz; d6-DMSO): d 1.56 (d, 6H); 4.85 (septet, 1H); 7.41 (m, 2H); 7.33 (d, 1H); 7.67 (d, 1H); 7.74 (d, 1H); m, 1H), 8.01 (s, 1H) and 8.87 (s, 2H). IR (CHC13):? 3088, 2984, 1663, 1626, 1481, 1304 and 1276 cm.l. UV / VIS (95% EtOH) :? ^ = 318 nm (E = 11480); 223 nm (E = 24524).

The desired compound is obtained by adding IN sodium hydroxide to the compound of Example 29D in ethyl acetate. The resulting layers are separated and the organic phase is separated under reduced pressure. Yield: 9.34 g (62%). Analysis for C17H1SN30F2: Calculated: C, 64.76; H, 4.80; N, 13.33; Found: C, 64.97; H, 4.78; N, 13.40. MS (DC): 315 (M *). X H NMR (300 MHz, d 6 -DMS0): d 1.38 (d, 6H); 3.67 (septet, 1H); 7.01 (s, 2H); 7.18 (d, 1H); 7.35 (m, 3H); 7.66 (s, 1H); and 7.77 (s, 1H). IR (CHC13):? 3380, 2910, 1652, 1608, 1522, 1307, 1276 and 1264 cm "1. UV / VIS (95% EtOH):? Mx = 341 nm (E = 21011); 220.5 NM (E = 26966).

Example 30 Analysis for C17H14N303SF3: Calculated: C, 51.38; H, 3.55; N, 10.57; Found: C, 49.10; H, 3.37; N, 10.08. MS (DC): 397 (M *). : H NMR (300 MHz; dg-DMSO): d 1.31 (d, 6H); 3.96 (septet, 1H), 7.33 (d, 1H); 7.49 (m, 2H); 7.56 (s, 2H); 7.63 (d, 1H) and 7.99 (s, 1H). IR (KBr):? 3430, 1649, 1603, 1312, 1290 and 1044 cm "A Example 31 MS (DC): 415.1 (M *). J H NMR (300 MHz; d 6 -DMSO): d 1.31 (d, J = 6.0 Hz, 6H); 3.38 (broad s, 2H); 4.00 (septet, J = 6.0 Hz, 1H); 7.32 (d, J = 9.0 Hz, 1H); 7.61 (d, J = 9.0 Hz, 1H); 7.67 (d, J = 9.0 Hz, 1H) and 8.13 (, 1H). IR (CHC13):? 3430, 1649, 1603, 1312, 1290 and 1044 cm "A Example 32 Analysis for C17H14N303SF3: Calculated: C, 51.38; H, 3.55; N, 10.57; Found: C, 51.49; H, 3.82; N, 10.63. MS (DC): 397.1 (M *). H NMR (300 MHz; dg-DMSO): d 1.30 (d, 6H); 3.95 (m, 1H); 7.34 (d, 1H); 7.49 (s, 2H); 7.67 (m, 3H) and 7.95 (s, 1H). IR (CHC13):? 3430, 1649, 1603, 1312, 1290 and 1044 cm "A UV / VIS (95% EtOH):? = 325.0 nm (E = 17252); 248.0 (E = 16010).

Example 33 The title compound is prepared substantially as described in Example 29A-E Analysis for C18HlßN3OF: Calculated: C, 69.44; H, 5.83; N, 13.50; Found: C, 69.68; H, 6.06; N, 13.39. MS (DC): 311 (M *).

Example 34 Analysis for C18HlßN304SF: Calculated: C, 55.23; H, 4.64; N, 10.74; Found: C, 55.36; H, 4.96; N, 10.54. MS (DC): 391 (M +). X H NMR (300 MHz, d 6 -DMSO): d 1.28 (d, 6H); 3.86 (s, 3H); 3.91 (septet, 1H); 6.94 (m, 2H); 7.30 (d, 1H); 7.43 (s, 2H); 7.50 (m, 1H); 7.58 (d, 1H) and 7.93 (s, 1H). IR (CHC13):? 3420, 1640, 1616, 1281, 1271 and 1157 cm "A UV / VIS (95% EtOH): ^ = 321 nm (E = 22629); 239 nm (E = 13360).

Example 35 MS (DC): 404 (M *). JH NMR (300 MHz; dg-DMSO): d 3.25 (m, 4H); 3.60 (m, 4H); 7.50 (m, 8H) and 7.92 (s, 1H).

Example 36 The title compound is prepared substantially as described in Example 29A-E. Analysis for C 17 H 14 N 3 OF: Calculated: C, 68.67; H, 5.42; N, 14.13; Found: C, 68.87; H, 5.67; N, 13.90. MS (DC): 297 (M *).

Example 37 Analysis for ClßH19N304S: Calculated: C, 57.90; H, 5.13; N, 11.25; Found: C, 58.28; H, 5.28; N, 10.68. MS (DC): 373 (M +). XH NMR (250 MHz, d6-DMSO): d 1.28 (d, 6H); 3.68 (s, 3H); 3.88 (septet, 1H); 7.08 (t, 1H); 7.17 (d, 1H); 7.28 (m, 2H); 7.42 (s, 2H); 7.53 (m, 2H) and 7.91 (s, 1H). IR (CHC13):? 3400, 1639, 1601, 1541, 1443, 1299, 1283, 1269 and 1250 cm "A UV / VIS (95% EtOH): ,,, ^ = 320 nm <E = 20778); 238 nm (E = 14166) .

Example 38 The title compound is prepared substantially as described in Example 29A-E.

Analysis for C21H15N302F2: Calculated: C, 66.48; H, 3.98; N, 11.08; Found: C, 66.26; H, 4.04; N, 11.02. MS (DC): 379 (M *). X H NMR (250 MHz, d g -DMSO): d 3.86 (s, 3 H); 6.88 (s, 2H); 7.11-7.46 (broad m, 9H) and 7.63 (m, 1H). IR (CHC13):? 3400, 3030, 1610, 1525, 1515, 1278, 1271 and 1254 cm "UV / VIS (95% EtOH): ^ = 336 nm (E = 19022); 222 nm (E = 30571).

Example 39 Analysis for C17H14N203SF2: Calculated: C, 56.04; H, 3.87; N, 7.69; Found: C, 56.26; H, 3.95; N, 7.91. MS (DC): 364 (M *). H NMR (300 MHz, dg-DMSO): d 1.30 (d, 6H); 4.10 (septet, 1H); 7.45 (m, 2H); 7.76 (m, 1H); 7.88 (d, 1H); 8.02 (d, 2H); 8.25 (s, 1H) and 8.92 (s, 1H). IR (CHC13):? 3030, 1668, 1482, 1381, 1369, 1271, 1154 and 1134 cm "UV / VIS (95% EtOH):? = 278 nm (E = 18062).

Example 40 Analysis for C15H10N3? 3SCl2F: Calculated: C, 44.79; H, 2.51; N, 10.45; Found: C, 43.97; H, 2.48; N, 10.10. MS (DC): 402 (M *). H NMR (300 MHZ; dg-DMSO): d 7.38 (d, 1H); 7.48-7.72 (m, 7H), 7.97 (s, 1H) and 8.17 (s, 1H). IR (KBr):? 3480, 2941, 1671, 1554, 1290 and 1038 cm "A UV / VIS (95% EtOH):? ^ = 319.5 nm (E = 14927), 245.5 nm (E-13189), 207 nm (E = 21594).

The compounds of Examples 41-43 are prepared substantially as described in Example 29A-E.

Example 41 Analysis for C19H? 7N3OF2: Calculated: C, 66.85; H, 5.02; N, 12.31; Found: C, 66.75; H, 5.07; N, 12.12.

Example 42 Analysis for C 17 H 14 N 3 OF: Calculated: C, 69.14; H, 4.78; N, 14.23; Found: C, 68.88; H, 4.73; N, 13.95. MS (DC): 295 (M +).

Example 43 Analysis for C19H18N3OF: Calculated: C, 70.57; H, 5.61; N, 12.99; Found: C, 70.20; H, 5.67; N, 12.47. MS (DC): 323 (M4). Example 44 Analysis for C19H17N3OF2: Calculated: C, 66.85; H, 5.02; N, 12.31; Found: C, 66.97; H, 5.31; N, 12.12. MS (DC): 341 (M +).

Example 45 Analysis for C24H16N3? 3SF: Calculated: C, 64.71; H, 3.62; N, 9.43; Found: C, 64.62; H, 3.84; N, 8.21. MS (DC): 445. a H NMR (75 MHz, d6-DMSO): d 111.18, 112.98, 115.80, 124.31, 125.47, 125.52, 127.59, 129.34, 130.78, 131.23, 133.59, 136.96, 147.23, 151.72, 154.72, 163.38. . and 193.36 ppm.

Example 46 Analysis for C22H2gN303SF: Calculated: C, 61.23; H, 6.07; N, 9.74; Found: C, 61.00; H, 6.16; N, 9.78 MS (DC): 431. X H NMR (75 MHz, d g -DMSO): d 13.80, 21.92, 22.36, 26.86, 28.13, 30.98, 53.06, 113.45, 115.21, 115.70, 118.73, 125.35, 127.76, 128.72, 154.27, 130.52, 131. 00, 140.45, 147.45, 154.91, 160.15, 163.40 and 193.20 ppm.

Example 47 Analysis for C18H12N303S2F: Calculated: C, 53.86, H, 3.01; N, 10.47; Found: C, 54.04; H, 3.11; N, 10.40. MS (DC): 401 X H NMR (75 MHz, d 6 -DMSO): 113.66, 115.49, 118.57, 125.16, 128. 25, 129.64, 130.32, 134.78, 135.05, 137.37, 140. 06, 147.63, 154.28, 159.92, 163.17 and 192.91 ppm.

Example 48 Analysis for C18H17N403SF: Calculated: C, 55.66; H, 4.41; N, 14.42, S, 8. 25; F, 4.89; Found: C, 55.89; H, 4.32; N, 14.34; S, 7.96; F, 5.10. MS (DC): 388 (M ').

X H NMR (300 MHz, d g -DMSO): d 7.95 (s, 1 H); 7.50 (m, 8H); 3.40 (m, 4H) and 1.80 (m, 4H). IR (KBr):? 1635.45, 1601.81, 1586.11, 1536.21, 1444.75, 1393.76, 1299.51; 1284.49, 1271.26 and 1168.78 cm "A UV / VIS (95% EtOH):? ^ = 322.0 nm (E = 18243.2); 247.0 nm (E = 16351.80).

As indicated above, the compounds of the present invention are useful as antiviral agents. They have demonstrated inhibitory activity against various enteroviruses and rhinoviruses. One embodiment of the present invention is a method of treating or preventing infection by picornaviridae 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 inhibition of picornaviridae contemplated by the present method includes therapeutic or prophylactic treatment, as appropriate. The specific dose of the compound administered according to this invention to obtain the therapeutic or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the condition or disease that is being treated and the individual that is being treated. A typical daily dose will contain a dosage level from about 0.01 mg / kg to about 50 mg / kg of body weight of an active compound of this invention. Preferred daily doses will generally 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 various routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. The compounds of the present invention are preferably formulated before their 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 0.1% to 99.9% by weight of the formulation. By the term "pharmaceutically acceptable" is meant that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and is not harmful 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 mixed with a carrier, or diluted with a carrier, or encircled or included 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 can be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Therefore, the compositions may be in the form of tablets, pills, powders, dragees, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, up to 10% by weight of the active compound, soft and hard gelatine capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like. The following formulation examples are illustrative only and are not considered 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, dry 200 Magnesium stearate 10 Total 460 mg Formulation 2 A tablet is prepared using the following ingredients: Quantity (ms (capsule) Active ingredient 250 Microcrystalline cellulose 400 Silicon dioxide, smoked 10 Stearic acid 5 Total 665 mg The components are mixed and compressed into tablets, each weighing 665 mg.

Formulation 3 An aerosol solution is prepared containing the following components: AND_____? Active ingredient 0.25 Methanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00 Total 100.00 The active compound is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a refilling device.

Subsequently, the required amount is fed to a stainless steel container and diluted with the rest of the propellant. Valve units are placed in the container.

Formulation 4 They are made as follows tablets, each containing 60 mg of the active ingredient: Quantity (mg / tablet) Active ingredient 60 Starch 45 Microcrystalline cellulose 35 polyvinyl pyrrolidone (as a 10% solution in water) 4 Carboxymethyl sodium starch 4.5 Magnesium stearate 0.5 Talcum 1 Total 150 The active ingredient, starch and cellulose are passed through a No. 45 mesh American sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resulting powder and the mixture is then passed through a No. 14 mesh American sieve. The granules produced in this way are dried at 50 ° C and passed through a sieve. North American mesh number 18. Subsequently, sodium carboxymethyl starch, magnesium stearate and talc are added to the granules, which have previously passed through a 60 mesh American sieve, and after mixing, they are compressed in a tabletting machine to produce tablets, each weighs 150 mg.

Formulation 5 Capsules are prepared as follows, each containing 80 mg of the active ingredient: 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 mixed and passed through a No. 45 mesh American sieve and filled into hard gelatin capsules in amounts of 200 mg.

Formulation 6 They are made as follows suppositories, each contains 225 mg of the active ingredient: Active ingredient: 225 mg Saturated fatty acid glycerides 2,000 mg Total 2,225 mg The active ingredient is passed through a No. 60 mesh American sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of 2 g nominal capacity and allowed to cool.

Formulation 7 Suspensions are prepared as follows, each containing 50 mg of active ingredient per 5 ml of dose: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Taste c.v. Color c.v. Total purified water of 5 ml The ingredients are passed through a No. 45 mesh American sieve and mixed with sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of water and added, with stirring. Subsequently, enough water is added to produce the required volume.

Formulation 8 An intravenous formulation can be prepared as follows: Active ingredient 100 mg Isotonic saline 1000 ml The solution of the above ingredients is generally 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 viruses.

Testing method African green monkey kidney cells (BSC-1) or HeLa cells (5-3) are grown in 25 ce Falcon flasks at 37 ° C in medium 19 with 5% fetal bovine serum (FBS) and native, penicillin. (150 units / 1 ml) and streptomycin (150 μg / ml). When the confluent monolayers are formed, the supernatant growth medium is removed and 0.3 ml of an appropriate dilution of the virus (echo, Mengo, Coxsackie, polio or rhinovirus) is added to each flask. After absorption for 1 hour at room temperature, the layers of virus-infected cells are superimposed with a medium comprising a 1 percent part of Ionagar No. 2 and a part of double strength 199 medium FBS, penicillin and streptomycin. which contains the drug at concentrations of 100, 50, 25, 12, 6, 3 and 0 μg / ml. Flasks containing no medication served as control for the test. The concentrated solutions of vinylacetylenebenzimidazole compounds are diluted with dimethylsulfoxide to a concentration of 104 μg / ml. Subsequently the flasks are incubated for 72 hours at 37 ° C for polio, coxsackie, echo and mengo viruses, and for 120 hours at 32 ° C for rhinovirus. Virus plaques are observed in those areas where the virus has infected and reproduced in the cells. A solution of 10 percent formalin and 2 percent sodium acetate is added to each flask to inactivate the virus and fix the sheet of cells to the surface of the flask. Virus plates, regardless of size, were counted after staining with surrounding cell areas, with crystal violet. The plate count is compared to the control account for each drug concentration. The activity of the test compound is expressed as a percentage of 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 IC50 symbol. The test results of various compounds of formula I are summarized in Tables 1 and 2, below, by example number and indicate the test virus and percent inhibition of plaque reduction which is present as IC50 ( μg / ml). Such IC50 values represent the amount of test compounds necessary to inhibit 50% of plaque formation.

Table 1 __? _ S L- ± μg / ml) Example No. PV-1 RhV-14 CS-21C 3 2.14 5 3.9 6 0.329 11 1.7 0.44 20 0.19 1.32 PV (poliovirus); RhV (rhinovirus); CS (Coxsackie virus) numbers after virus designation represent particular strains. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (9)

1 . A compound, characterized in that it is of the formula I where: a is 1, 2, 3, 4 or 5; each R is independently hydrogen, hydroxy, thiol, halo, cyano, C 4 -C 4 cyanoalkyl, C 1 -C 4 haloalkyl, nitro, amino, C 1 -C 4 dialkylamino of C 1 -C 4, azido, carboxy, Ci alkyl -Cg, C2-C6 alkenyl, carbamoyl, carbamoyloxy, carbamoylamino, N-alkylcarbamoyl of C! -C4, -OCF3, -0CC13, N, N-dialkylcarbamoyl of C ^ -C ^, Ci-C4 alkoxy, alkoxycarbonyl C ^ C ^ Ct-C4 alkoxycarbonyloxy, C, -C4 alkoxycarbonylamino, formyl, C2-C4 alkanoyl, formyloxy, C2-C4 alkanoyloxy, formylamino, C2-C4 alkanoylamino, C ^ C ^ alkyl ^ alkylsulfinyl -C4 or alkylsulfonyl of Cj-C4; R ° is hydrogen, halo, C ^ ^ alkyl or alkoxy R2 is hydrogen, amino, -NHC (O) (C1-C6 alkyl) or -NHS02 (Cj-Cg alkyl); R3 is C1-C6 hydroxyalkyl alkyl, C3-C7 cycloalkyl, substituted C3-C7 cycloalkyl, phenyl, substituted phenyl, naphthyl, furyl, thienyl, thiazolidinyl, thiazol-2-yl, 2-acetamido-4-methyl- thiazol-5-yl, 1, 3, 4-thiadiazol-2-yl, 2-methyl-l, 3,4-thiadiazol-5-yl, 2-methylamino-1, 3,4-thiadiazol-5-yl, -NR5R6, -S02-R4 or a group of the formula: R4 is dimethylamino, CL-C6 alkyl, haloalkyl of Cj-Cg, C3-C7 cycloalkyl, phenyl, substituted phenyl, naphthyl, thienyl, trifluoromethyl or -NR5R6; and R5 and R6, taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino or morpholino; with the proviso that when a is 1; then R can not be hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, chlorine, bromine, iodine, nitro or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that it is of formula I where: a is 1, 2, 3, 4 or 5; each R is independently hydrogen, hydroxy, thiol, halo, cyano, C?-C 4 cyanoalkyl, C?-C halo haloalkyl, nitro, amino, C?-C 4 alkylamino, C C dial dial dialkylamino, azido, carboxy, alkyl of Cx-Cg, C2-C6 alkenyl, carbamoyl, carbamoyloxy, carbamoylamino, N-alkylcarbamoyl of C? -C4, -0CF3, -0CC13, N, N-dialkylcarbamoyl of C? -C4, C? -C4 alkoxy, C?-C 4 alkoxycarbonyl, C?-C alco alkoxycarbonyloxy, Ca-C 4 alkoxycarbonylamino, formyl, C 2 -C 4 alkanoyl, formyloxy, C 2 -C 4 alkanoyloxy, formylamino, C 2 -C 4 alkanoylamino, Cilt-C 4 alkylthio , C 1 -C 4 alkylsulfinyl or C 1 -C 4 alkylsulfonyl; R ° is hydrogen, halo, C 1 -C 4 alkyl or alkoxy R2 is hydrogen, amino, -NHC (O) (C? -C6 alkyl) or -NHS02 (C? -C6 alkyl); R3 is C6-C6 alkyl, phenyl, substituted phenyl, furyl, thienyl, thiazol-2-yl, 2-acetamido-4-methyl-thiazol-5-yl, 1,4-thiadiazol-2-yl, 2-methyl-l, 3,4-thiadiazol-5-yl, 2-methylamino-l, 3,4-thiadiazol-5-yl, -NR5R6, -S02-R4 or a group of the formula: R * is dimethylamino, C? -C6 alkyl, C? -C? Haloalkyl, C3-C7 cycloalkyl, phenyl, substituted phenyl, or trifluoromethyl; and R5 and R *, taken together with the nitrogen atom to which they are attached form pyrrolidino, piperidino or morpholino, - with the proviso that when a is 1; then R can not be hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, chlorine, bromine, iodine, nitro or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, characterized in that it is of formula I1": wherein: a is 1, 2 or 3; each R is independently hydrogen, halo, methyl, ethyl, methoxy or ethoxy; R3 is C6-C6 alkyl, phenyl, substituted phenyl, thiazole-2-yl or -S02R4; R 4 is C 1 -C 6 alkyl, phenyl, dimethylamino or C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2, characterized in that it is of formula I "": wherein: a is 1, 2 or 3; each R is independently hydrogen, halo, methyl, ethyl, methoxy, ethoxy; R3 is C? -C6 alkyl, phenyl, substituted phenyl, thiazol-2-yl or -S02-R4; R 4 is C 1 -C 6 alkyl, phenyl, dimethylamino or C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 2, characterized in that it is of the formula: wherein: R is independently hydrogen, fluoro, methyl, ethyl, methoxy, ethoxy, methylthio, methylsulfinyl, methylsulfonyl or dimethylamino. R3 is -S02-CH (CH3) 2 or -S02-N (CH3) 2; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 2, characterized in that it is: fifteen 25 or a pharmaceutically acceptable salt thereof,

7. A pharmaceutical formulation, characterized in that it comprises a compound of formula I or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 5, associated with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.

8. A compound of formula I, or a pharmaceutically acceptable salt thereof, characterized in that it is in accordance with any of claims 1 to 5, for use as a pharmaceutical substance.

9. A process for preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 5, the process is characterized in that it comprises: a) exposing a compound of the formula: to a base in an alcohol solvent; and subsequently b) reacting the resulting anion with cyanogen bromide to provide the corresponding nitrile which is cyclized to provide a compound of formula I; c) optionally converting the compound of formula I to a pharmaceutically acceptable salt thereof. The present application provides a series of benzimidazole compounds which inhibit the growth of picornaviruses, such as rhinovirus, enterovirus, cardiovirus, poliovirus, coxsackievirus of groups A and B, ecovirus and Mengo virus. Such compounds are also useful as intermediates for preparing additional antiviral compounds of benzimidazole.