MXPA06009117A - Indazole derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of Formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein m, k, B, R1, R2 and R3 are those defined herein, and compositions comprising the same. Also provided are methods for preparing compounds of formula (I) and using the same in treating p38 mediated disorders in a patient.

Description

INDAZO DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM DESCRIPTION OF THE INVENTION The present invention relates to indazole derivatives, a process for their preparation, pharmaceutical preparations comprising them, and methods for their use. Mitogen-activated protein kinase (MAP) is a family of proline-directed serine / threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals - which include nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. A group of MAP kinases is p38 kinase group that includes several isoforms (e.g., p38a, p39β, p38α and p38d). The p38 kinases are responsible for the phosphorylation and activation of transcription factors, as well as other kinases, and are activated by physical and chemical stress, pro-inflammatory cytokines and bacterial lipolisaccharides. Most importantly, p38 phosphorylation products have been shown to mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2. Each of these cytokines has been implicated in numerous disease states and conditions. For example, TNF-a is a cytokine produced mainly REF. : 174726 by activated monocytes and macrophages. Their excessive or unregulated production has been implicated as the play of a causative role in the pathogenesis of rheumatoid arthritis. More recently, the inhibition of TNF production has been shown to have wide application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma. TNF "has also been implicated in viral infections, such as HIV, influenza virus, and herpes viruses including herpes simplex virus type-1 (HSV-1), simplex-type-2 virus (HSV-2) ), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Earr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others. Similarly, IL-1 is produced by monocytes and activated macrophages, and plays a role in many pathophysiological responses including rheumatoid arthritis, fever, and reduced bone resorption. Additionally, the involvement of p38 has been implicated in sudden attack, Alzheimer's disease, osteoarthritis, lung injury, septic shock, angiogenesis, dermatitis, psoriasis and atopic dermatitis. J. "Exp. Opin. Ther. Patents, 2000, 10 (1) .Inhibition of these cytokines by inhibition of p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states. I or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein: R1 is aryl, heteroaryl, aralkyl or cycloalkyl; R2 is aryl, heteroaryl, cycloalkyl or heterocyclyl; m is from 0 to 4; R3 is hydrogen, Ci-Cg alkyl, haloCi-Cß alkyl, cyano, nitro, amino, hydroxyl, alkoxy, heteroalkyl, heterocyclyl, hydroxycycloalkyl or ~ C (= 0) -Ra, wherein R is hydrogen, Ci-alkyl Ce, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclyl; is 0 or 1; and B is O, S (0) j, CH (0R), NR or C (= 0), where j is 0, 1 or 2; Rb is hydrogen or Ci-Ce alkyl, Rc is hydrogen, C?-C6 alkyl, -C (= 0) -Ra or -S02Re, where Rd is C?-C6 alkyl, aryl or aralkyl; and Re is C? -C alkyl.

Another aspect of the present invention provides a pharmaceutical formulation comprising one or more compounds of formula I and a pharmaceutically acceptable carrier, diluent, and / or excipient thereof. The compounds of the invention are inhibitors of protein kinases, and exhibit effective activity against p38 in vivo. These are selective against p38 kinase with respect to cyclin-dependent kinases and tyrosine kinases. Accordingly, the compounds of the present invention can be used for the treatment of diseases mediated by proinflammatory cytokines such as TNF and IL-1. A) Yes, another aspect of the present invention provides a method for treating diseases or conditions mediated by p38 wherein a therapeutically effective amount of one or more compounds of the formula I is administered to a patient. All publications cited in this description are incorporated herein by reference in their entirety. Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below. It should be appreciated that, as used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the text is clearly stated otherwise.

"Alkyl" means a linear saturated monovalent hydrocarbon portion of one to six carbon atoms or a branched saturated monovalent hydrocarbon portion of three to six carbon atoms, for example methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. "Alkylene" means a linear saturated divalent hydrocarbon portion of one to six carbon atoms or a branched saturated divalent hydrocarbon portion of three to six carbon atoms, for example methylene, ethylene, 2,2-dimethylethylene, propylene, -methylpropylene, butylene / pentylene and the like. "Alkoxy" means a portion of formula -OR, wherein R is an alkyl portion as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy and the like. "Alkoxyalkyl" means a portion of formula Ra'-0-Rb'-, wherein Ra 'is C 1 -C 5 alkyl and is alkylene as defined herein. Examples of alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl, and 1- (2-methoxyethyl) -3- methoxypropyl. "Alkylsulfonylalkyl" means a portion of formula Ra'-S02-Rb'-, where Ra 'is C1-C5 alkyl and Rb' is alkylene as defined herein. Exemplary alkylsulfonylalkyl groups include, by way of example, 3-methanesulfonylpropyl, 2-methanesulfonylethyl, 2-methanesulfonylpropyl, and the like. "Amino" means a portion -NR'R, where R 'and R each independently is hydrogen or C1-C5 alkyl. "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon portion which is optionally substituted by one or more, preferably one, two or three, substituents, each of which is preferably selected from the group consisting of C 1 -C 5 alkyl, hydroxy, alkoxy, C?-C6 haloalkyl, haloalkoxy, halo, nitro, cyano, amino, mono- and di-alkylamino Ci-Ce, methylenedioxy, ethylenedioxy, acyl, heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, and optionally substituted heteroalkyl. A particularly preferred aryl substituent is halide. More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like, each of which may be substituted or unsubstituted. "Aralkyl" refers to a portion of the formula Ara-Rz-, where Ara is optionally substituted by aryl and Rz is alkylene as defined herein. "Substituted aralkyl" or "optionally substituted aralkyl" refers to aralkyl wherein the aryl radical is substituted or optionally substituted respectively. "Cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon portion of three to seven ring carbons eg, cyclopropyl, cyclobutyl, cyclohexyl, 4-methyl-cyclohexyl, and the like. The cycloalkyl may be optionally substituted by one or more substituents, preferably one, two or three substituents. Preferably, the cycloalkyl substituent is selected from the group consisting of L-C6 alkyl, hydroxy, alkoxy, halo-C1-C5 alkyl, haloalkoxy, halo, amino, mono- and di-C1-6 alkylamino, heteroalkyl, acyl , "aryl" and "heteroaryl" "Cycloalkylalkyl" refers to a portion of formula Rc ~ Rd-, where Rc is cycloalkyl and Rd is alkylene as defined herein. "Halo", "halogen" and "halide" are used in a interchangeable herein and refer to fluorine, chlorine, bromine, or iodine Preferably the halides are fluorine and chlorine with fluorine which is a particularly preferred halide. "Haloalkyl" means C? -C6 alkyl substituted by one or more halo atoms the same or different, for example, -CH2C1, -CF3, -CR2CF3, -CH2CCl3, and the like. "Heteroalkyl" means an alkyl portion as defined herein wherein one or more, preferably one, two or three hydrogen atoms have been replaced by a substituent selected independently of the group constituted of -0Ra, -NRbRc (where n is 0 or 1 is 2b and Rc are both independently C1-C6 alkyl, cycloalkyl or cycloalkylalkyl, and 0 if not) and -S (0) nRd (where n is an integer of 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, where Ra is hydrogen, acyl, alkoxycarbonyl, alkyl Ca-Ce, cycloalkyl or cycloalkylalkyl; R and Rc are independently from each other hydrogen, acyl, alkoxycarbonyl, C?-C6 alkyl, cycloalkyl, Ci-Ce alkylsulfonyl, aminosulfonyl, mono- or di-alkylaminosulfonyl C1-C6, amino-Ci-Ce alkyl, mono- or di- C 1 -C 6 alkylamino C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkoxy alkyl, C 1 -C 6 hydroxy alkylsulfonyl or C 1 -C 6 alkoxy alkylsulfonyl; and when n is 0, Rd is hydrogen, C?-C6 alkyl, cycloalkyl, cycloalkylalkyl, or aryl, and when n is 1 or 2, Rd is Ci-Cß alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl. Representative examples include but are not limited to 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1. methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methyl-sulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like. Accordingly, hydroxy-Ci-Cß alkyl and alkoxy-Ci-Ce alkyl are derived from heteroalkyl. "Heteroaryl" means a monovalent monocyclic or bicyclic moiety of 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, 0, or S (preferably N u 0) , the remaining ring atoms are C, with the understanding that the point of attachment of the heteroaryl radical will be in an aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one, two or three substituents each of which is independently selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, hydroxy, alkoxy, halo, nitro and cyano. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, imidazo [1,2- a] -pyridinyl, imidazo [2, 1-b] thiazolyl, and their derivatives.

"Heteroarylalkyl" refers to a portion of the formula Arz-Ry-, where Arz is heteroaryl and R? is alkylene as defined herein. "Heterocyclyl" means a non-aromatic saturated or unsaturated cyclic portion of 3 to 8 ring atoms wherein one or two ring atoms are heteroatoms selected from N, O, or S (0) n (where n is an integer of 0 a 2), preferably N or O, the remaining ring atoms are C, where one or two C atoms can be optionally substituted by a carbonyl group. The heterocyclyl ring can be independently substituted by one or more, preferably one, two or three substituents, each of which is selected, independently from C -Cß alkyl, haloCi-C 1 alkyl, hydroxy C 1 -C 6 alkyl, halo, nitro, cyano, cyano-Ci-Ce alkyl, hydroxy, alkoxy, amino, mono- and di-alkylamino-C ?, aralkyl, - (X) nC (0) Re (where X is O or NRf, n is 0 or 1, Re is hydrogen, Ci-Ce alkyl, haloCi-Ce alkyl, hydroxy (when n is 0), alkoxy, amino, mono- and di-alkylamino Ci-Cs, or optionally substituted phenyl, and Rf is H or C? -C6 alkyl), -alkylene-C (0) Rg (where Rg is C? -CS / -ORh or X-? Alkyl) and Rh is hydrogen, C? -C6 alkyl or haloC1-C6alkyl , and R1 and RJ are independently hydrogen or Ci-Ce alkyl), and -S (0) nRk (where n is an integer from 0 to 2) such that when n is 0, Rk is hydrogen, C! -C6 alkyl , cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, Rk is C ± -Cβ alkyl, cycloalkyl, cycloalkylalkyl, amino, acyla mino, mono-alkylamino Ci-Ce, or di-alkylamino C? -C6. A particularly preferred group of heterocyclyl substituents includes Ci-Ce alkyl, haloC C-C6 alkyl, hydroxyCi-Ce alkyl, halo, hydroxy, alkoxy, amino, mono- and di-alkylamino Ci-Ce, aralkyl, and - S (0) nR. In particular the term heterocyclyl includes, but is not limited to, tetrahydrofuranyl, pyridinyl, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino- 1-oxide, thiomorpholino-1,1-dioxide, 4- (1, l-dioxo-tetrahydro-2H-thio-pyranyl), pyrrolinyl, imidazolinyl, N-methanesulfonyl-piperidin-4-yl, and their derivatives, each of which may be optionally substituted. "Hydroxyalkyl" refers to a heteroalkyl derivative and refers in particular to an alkyl portion as defined herein which is substituted by one or more, preferably one, two or three hydroxy groups, with the proviso that the same carbon atom does not have more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-ethylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl. , 2-hydroxy-l-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl. "Hydroxycycloalguyl" refers to a derivative of the cycloalkyl radical as defined herein and specifically refers to a cycloalkyl portion as defined herein where one or more, preferably, one, two or three hydrogen atoms in the cycloalkyl radical they have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyanohexyl, and the like. "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, ie, an atom or a group capable of moving through a nucleophile and includes halo (such as chlorine, bromine and iodine), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (eg example, acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (for example, 2,4-dinitrophenoxy), methoxy, N, 0-dimethylhydroxylamino, and the like. "Optionally substituted phenyl" means a phenyl ring that is optionally substituted with one or more substituents, preferably one or two substituents selected from the group consisting of C?-C6 alkyl, hydroxy, alkoxy, halo-C 1 -C alkyl, haloalkoxy , halo, nitro, cyano, amino, methylenedioxy, ethylenedioxy and acyl.

"Pharmaceutically acceptable excipient" means an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and in no way biologically or otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. . A "pharmaceutically acceptable excipient" as used in the specification and claims includes one or more of such excipient. "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. These salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acid benzoic, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethane sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, acid 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, butylacetic acid tertiary, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, - for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with such an organic base-as ethanolamine, diethanolamine, triethanolamine triethanolamine tromethamine, N-methylglucamine and the like. The terms "pro-drug" and "prodrug" are used interchangeably "agui" and refer to any compound that releases an active mother drug according to formula I in vivo when this prodrug is administered to a mammalian subject. The rhodrugs of a compound of formula I are prepared by modifying one or more functional groups present in the compound of formula I so that the modification or modifications can be divided in vivo to release the parent compound. Prodrugs include compounds of formula I wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula I is linked to any group that can be divided in vivo to regenerate the free hydroxy, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, di-alkylaminoacetates Ci-Cß, for ions, phosphates, sulfates and benzoate derivatives) and carbamates (e.g. N, N-dimethylaminocarbonyl) of hydroxy functional groups , ester groups (for example ethyl esters, morpholine ethanol esters) of carboxyl functional groups, N-acyl derivatives (for example N-acetyl) bases N-Mannich, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehydic functional groups in compounds of formula I, and the like, see Bundegaard, "Design of Prodrugs" pl-92, Elesevier, New York-Oxford (1985). "Protective group" - refers to a group of atoms that, when attached to a reactive group of a molecule, masks it, reduces or inhibits its reactivity. Examples of protecting groups can be found in Green and Wuts, Protective Groups in Organic Chemistry (Wiley, 2nd ed.1991) and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, vol. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenyl ethyloxycarbonyl (FMOC) , nitro-veratriloxycarbonyl (NVOC) and the like. Representative hydroxy protecting groups include those in which the hydroxy group is acylated or alkylated, such as benzyl and trityl ethers as well as C 1 -C 6 alkyl ethers, tetrahydropyranyl ethers, C 1 -C 6 tri-alkylsilyl ethers and ethers of alilo. "Treating" or "treating" a disease includes: (1) preventing the disease, i.e., preventing the clinical symptoms of the disease from developing in a mammal that may be susceptible or predisposed to such a disease and that still does not shows or experiences the symptoms of it; (2) inhibit the disease, that is, stop or reduce the development of a disease or its clinical symptoms; or (3) relieving the disease, that is, causing the regression of the disease or its clinical symptoms. "A therapeutically effective amount" means the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve such treatment for the disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, as well as age, weight, etc. of the mammal that is intended to treat. As used herein, the terms "defined above" and "defined herein" are used interchangeably in the present and, when referring to a variable, are incorporated by reference to broad definitions of the variable as well as preferred definitions, more preferred and very preferred, if any. "Modulator" means a molecule that interacts with a target. The interactions include but are not limited to: agonist, antagonist and the like, as defined herein. "Optional" or "optionally" means that the event or circumstance described below may but need not occur, and that the description includes cases where the event or circumstance occurs and assumptions in which it does not occur. "Pathological state" means any disease, condition, symptom or indication. "inert organic solvent" or "inert solvent" means that the solvent is inert under the conditions of the reaction described in connection therewith, including for example benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents. "Solvates" means solvent addition forms which contain stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to retain a fixed molar ratio of solvent molecules within their crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is an alcohol, then the solvate formed is an alcoholate. Hydrates are formed by combining one or more molecules of water with one of the substances in which the water retains its molecular status of H20, such combination is capable of forming one or more hydrates. "Subject" means mammals and not mammals.

Mammals means any member of the group of mammals, including humans, but not limited to it; non-human primates, for example chimpanzees and other species of apes and monkeys; animals of cattle interest, for example cows, horses, sheep, goats and pigs; domestic animals, for example rabbits, dogs and cats; laboratory animals, including rodents, for example rats, mice and guinea pigs and the like. Examples of non-mammals include but are not limited to: birds and the like. The term "subject" does not denote a particular age or sex.

The terms. "have the meaning defined above" or "have the meaning defined herein" when referring to a variable incorporates by reference the broad definition of the variable and also the preferred, most preferred and especially preferred definitions thereof, if any. . The terms "treatment", "contact" and "reaction" referred to a chemical reaction mean the addition or mixing of two or more reagents under suitable conditions to obtain their indicated and / or desired product. It should be noted that the reaction produced by the indicated and / or desired product may not result directly from the combination of two reactants initially added, that is, it may be necessary to obtain one or more intermediates in the reaction mixture, which subsequently lead to the formation of the indicated and / or desired product. In general, the nomenclature used in this application is based on the AUTONOM ™ v.4.0 program, a computerized system of the Beilstein Institute for the generation of the systematic nomenclature of the IUPAC. The chemical structures presented here are generated using the ISIS® program, version 2.2. Any open valence that appears in a ca, oxygen or nitrogen atom of the represented structures indicates the presence of a hydrogen.

In embodiments of the invention wherein each of R1, R2, R3, Ra, Rb, Rc or Rd is C? -C6 alkyl or contains an alkyl portion, such alkyl is preferably lower alkyl, ie C? -C6 alkyl, and more preferably C? -C alkyl. In many modes, k is 0. In certain modes, k is 1 and B is NRb. In certain embodiments, R2 is optionally substituted phenyl, optionally substituted thienyl, or optionally substituted pyridyl. In certain embodiments, R2 is optionally substituted phenyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted indolyl, optionally substituted benzothienyl, or optionally substituted benzofuranyl. Preferably, R 2 is 2-chlorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-benzyloxyphenyl, 3-benzyloxyphenyl, 4-dimethylaminophenyl, 4-aminophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3-trifluoromethylphenyl, pyrid- 3-yl, 4- (pyrid-2-yl) phenyl, 3-isopropoxyphenyl, 3,5-dimethylphenyl, 1,3-benzodioxol-5-yl, 3-morpholinophenyl, 4-morpholinophenyl, 3- (4-methyl) piperazin-1-yl) -phenyl, 4- (4-methyl-piperazin-1-yl) -phenyl, N-methyl-N- (2-methoxyethyl) -phenyl or 2,4-difluorophenyl, 4-isopropyloxyphenyl, - (2-pyridin-2-yl-ethoxy) -phenyl, thien-2-yl, benzothiophen-3-yl, benzothiophen-2-yl, furan-2-yl, benzofuran-4-yl, indol-3-yl , 3-chloro-4-propoxyphenyl, biphenyl, pyridin-3-yl-phenyl, and 3,4,5-trimethoxyphenyl. In embodiments wherein R 2 is heterocyclyl, R 2 may be piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1,1-dioxythiomorpholinyl, or 1,1-dioxytetrahydrothiofuranyl. In certain embodiments, R 1 is optionally substituted phenyl, such as 2-halophenyl or 2,4-dihalophenyl. More specifically, R1 may be 2,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, phenyl, 2-chlorophenyl, 3,4-difluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4- methylphenyl, 4-methoxyphenyl, 3,4-dichlorophenyl, 1,3-benzodioxol-5-yl, methyl, isopropyl, cyclohexyl, and 2,4-difluorobenzyl. More preferred are 2-halophenyl and 2, 4-dihalophenyl, and most preferred is 2-fluorophenyl. The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are eguivalent to unsolvated forms and are intended to be within the scope of the invention. In addition to the compounds described above, the compounds of the present invention include all tautomeric forms. In addition, the present invention also includes all pharmaceutically acceptable salts of these compounds together with prodrug forms of the compounds and all stereoisomers either in pure guiral form or a racemic mixture or other form of mixture. The compounds of formula I are capable of further forming pharmaceutically acceptable acid addition salts. All of these forms are within the scope of the present invention. The pharmaceutically acceptable acid addition salts of the compounds of formula I include salts derived from inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphoric and the like, as well as salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also contemplated are salts of amino acids, such as arginate and the like and gluconate, galacturonate (see for example Berge et al., J. of Pharmaceutical Science 66: 1-19, (1977).] The acid addition salts of the compounds can be obtained by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner.The free base form can be regenerated by contacting the salt form with a base and isolating the free base from the base. a conventional way.Free-base forms differ from their respective salt forms in some way in certain physical properties, such as solubility in polar solvents, but otherwise, the salts are equivalent to their corresponding free bases for the purposes of The present invention In certain embodiments wherein k is 0, the compounds of the invention may be represented by formula II (II) wherein A, R1, R2, m and R3 are as described above. In certain embodiments of formula II, R1 and R2 may both be optionally substituted by phenyl, such that the compounds of the invention have the formula III where p and q each independently has a value of 0 to 4; each R 4 is independently halo, C 1 -C 6 alkyl, alkoxy, haloalkyl, or cyano; each R 5 is independently halo, C 1 -C 6 alkyl, haloCi-Ce alkyl, cyano, heteroalkyl, heterocyclyl, hydroxycycloalkyl or -C (= 0) -Re, where Re is C al-C6 aligyl, heteroalkyl, aryl, aralkyl , heteroaryl or heterocyclyl; And m and R3 are as defined herein. In certain embodiments of formula III wherein R3 is hydrogen, the compounds of the invention may be represented by formula IV wherein p, q, R4 and R5 are as defined herein. Representative compounds according to the invention are shown below in Table 1. TABLE 1 obtained by a great variety of methods, which are represented in the illustrative synthesis reaction schemes and are described below. The starting materials and reagents used for the preparation of these compounds are generally available from those commercially available, such as Aldrich Chemical Co. or can be obtained by methods known to those skilled in the art and are described in the following references such as: Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons, New York, 1991, volumes 1-15; Rodd 's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, volumes 1-5 and Supplementáis; and Organic Reactions, Wiley & Sons, New York, 1991, volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications in these synthetic reaction schemes can be made and will be suggested by one skilled in the art having referred to for the description contained in this Application application.

The starting and intermediate materials of the synthesis reaction schemes can be isolated and purified, if desired, by applying conventional techniques, which include but are not limited to filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional methods, which include physical constants and spectral data. Unless indicated otherwise, the reactions described herein are preferably carried out in an atmosphere of inert gas, at atmospheric pressure and in a range of reaction temperatures from about -78 ° C to 150 ° C, more preferably about 0 ° C and about 125 ° C and -more preferably and conventionally at about room temperature (ta), for example about 20 ° C. One of the specific methods for the preparation of compounds of the invention is shown in Reaction Scheme I below, wherein PG is a protecting group.

Reaction Scheme 1 In Reaction Scheme I, fluoronitrotoluene is reacted with phenol b in the presence of a mild base such as potassium carbonate, to give a phenoxy nitrotoluene c. The nitrotoluene c is then reduced using catalyzed hydrogenation or other reduction technique, to provide phenoxy aminotoluene d. The phenoxy aminotoluene d is subjected to a cyclization reaction by treatment with isoamyl nitrate to form phenoxy indazole e. Phenoxy indazole is subjected to iodine under basic conditions to provide a phenoxy iodoindazine, which is then protected via Boc, Fmoc or other suitable protection scheme, to produce a protected phenoxy iodoindazole g. The protected phenoxy iodoindazole g is treated with a phenylboronic acid h in the presence of a suitable catalyst to form a phenoxy phenylindazole j, which is deprotected to provide an indazole derivative according to the invention. One skilled in the art will understand that certain modifications to the above reaction schemes are contemplated and within the scope of the present invention. For example, - certain stages will involve the use of protection groups for functional groups that are not compatible with particular reaction conditions. Various hydroxyaryl and hydroxyheteroaryl compounds in place of phenol b, and various aryl and heteroarylboronic acids can be used in place of phenylboronic acid h. In the following section of the examples more specific details of the production of the compounds of the invention are given. The present invention includes pharmaceutical compositions containing at least one compound of the present invention or a single isomer or a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable excipient. and optionally other therapeutic and / or prophylactic ingredients. In general, the compounds of the present invention will be administered in a therapeutically effective amount or any of the modes of administration acceptable for agents intended for similar purposes. Suitable dosing ranges are, for example, 1-500 mg per day, preferably 1-100 mg per day and with special preference 1-30 mg per day, depending on many factors, for example the severity of the disease to be treated, age- and relative health of the subject, power of the compound used, route and form of administration, indication to which the administration is directed and preferences and experience of the physician attending the patient. One skilled in the art to treat these diseases will be able to evaluate the therapeutically effective amount of the compounds of the present invention for a given disease. In general, the compounds of the present invention will be administered in the form of pharmaceutical formulations containing them and are suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral administration (including intramuscular administration, intraarterial, intrathecal, subcutaneous and intravenous) or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral using a convenient regimen of daily doses that can be adjusted to the severity of the condition. A compound or compounds of the present invention, together with one or more conventional adjuvants, excipients or diluents, can be incorporated into the form of the pharmaceutical compositions and unit doses The pharmaceutical compositions and dosage unit forms can contain conventional ingredients in conventional proportions , with or without additional compounds or active ingredients, and the unit dosage forms can contain any suitable effective amount of the active ingredient, according to the desired daily dosage range to be applied.The pharmaceutical compositions can be administered in the form of solids , for example filled tablets or capsules, semisolids, powders, sustained-release or liquid formulations, such as solutions, suspensions, emulsions, elixirs or filled capsules for oral use, or in the form of suppositories for rectal or vaginal use, or in the form of sterile injectable solutions for us or parenteral. Formulations containing one (1) milligram of active ingredient or, more broadly, about 0.01 to one hundred (100) milligrams per tablet, are therefore representative and suitable unit dosage forms. The compounds of the present invention can be formulated in a wide variety of dosage forms for oral administration. The pharmaceutical compositions and dosage forms may contain a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active ingredient. The pharmaceutically acceptable excipients may be solid or liquid. Solid preparations include powders, tablets, pills, capsules, seals (hollow wafers), suppositories and dispersible granules. A solid excipient may further contain one or more substances that further act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material. In powders, the excipient is in general a finely divided solid, mixed with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with the excipient which has a sufficient binding capacity in suitable proportions and is compacted to achieve the desired shape and size. The powders and tablets preferably contain one (1) to seventy (70) percent active ingredient. Suitable excipients include but are not limited to: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter and the like. The term "preparation" designates the formulation of the active compound together with the encapsulating material as an excipient, giving rise to a capsule in which the active principle, with or without excipient, is wrapped by the excipient, which is associated with it. Likewise, seals (hollow wafers) and pills are included. Tablets, powders, capsules, pills, seals (hollow wafers) and pills can have solid forms suitable for oral administration. Other forms suitable for oral administration include preparations in liquid form, among which are emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions or solid form preparations which are intended to be converted into liquid form preparations immediately before use. . The emulsions can be prepared in solutions, for example in aqueous propylene glycol solutions or they can contain emulsifying agents, for example lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with a viscous material, for example natural or synthetic gums, resins, ethylcellulose, sodium carboxymethylcellulose and other known suspending agents. Solid form preparations include solutions, suspensions and emulsions and, in addition to the active component, may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like. The compounds of the present invention can be formulated for parenteral administration (for example by injection, for example bolus injection or continuous infusion) and can be presented in unit dosage forms in ampoules, pre-packaged syringes, small-volume infusion containers or containers. multidose, which also contain a preservative. The compositions may also take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous excipients, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (e.g. ethyl oleate) and may contain formulatory agents, e.g. preservatives, humectants, emulsifiers or suspension, stabilizers and / or dispersants. Alternatively, the active ingredient can be presented in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution for reconstitution before use in a suitable vehicle, for example sterile, pyrogen-free water. The compounds of the present invention can also be formulated for topical administration on the epidermis in the form of ointments, creams or lotions or in the form of transdermal plaster (patch). The ointments and creams can be formulated, for example, with an aqueous or oily base, by adding suitable thickeners and / or gelling agents. The lotions can be formulated on an aqueous or oily basis and will generally carry one or more emulsifying agents, stabilizers, dispersants, suspending agents, thickeners or colorants. Formulations suitable for topical administration in the mouth include lozenge-shaped lozenges containing an active ingredient in a flavored base, typically sucrose and acacia or tragacanth.; the tablets containing the active ingredient in an inert base, for example gelatin and glycerin or sucrose and acacia; and oral lotions containing the active ingredient in a suitable excipient. The compounds of the present invention can be formulated for administration in the form of suppositories. First a low melting point wax is melted, for example a mixture of fatty acid glycerides or cocoa butter and then the active ingredient is dispersed therein homogeneously, for example by stirring. The molten homogeneous mixture is then poured into molds of the appropriate volume, allowed to cool and solidify. The compounds of the present invention can be formulated for vaginal administration. Pessaries, buffers, creams, gels, pastes, foams or sprays which, in addition to the active ingredient, contain suitable carriers are known as suitable in the art. The compounds of the present invention can be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulations can be delivered in the form of single or multi-dose. In the latter case of a dropper or pipette, the use may be made by the same patient who is administered an adequate predetermined volume of the solution or suspension. In the case of the sprayer, the use can be made for example by means of a spray pump that atomizes a fixed, calibrated quantity. The compounds of the present invention can be formulated for aerosol administration, especially for the respiratory tract, including intranasal administration. In general, the compound should have a small particle size, for example in the order of five (5) microns or less. Such a particle size can be obtained by means already known in the art, for example by micronization. The active ingredient is supplied in a pressurized container containing a suitable propellant, for example a chlorofluorinated hydrocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. Conveniently, the aerosol may also contain a surfactant, for example lecithin. The dose of drug can be controlled by a calibrated valve.

Alternatively, the active ingredients may be supplied in the form of a dry powder, for example a powdery mixture containing the compound in a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropylmethylcellulose and polyvinylpyrrolidone.

(PVP). The powdery excipient will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form, for example in capsules or cartridges for example of gelatin or in blister packs, from which the powder can be administered by means of an inhaler. If desired, the formulations can be manufactured with an enteric coating, adapted to the continued or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous in the case that a continued release is necessary and when compliance with a treatment regimen by the patient is crucial. The compounds of transdermal delivery systems are frequently incorporated into a solid, adhesive support on the skin. The compound of interest can be further combined with a penetration enhancer, for example Azone (1-dodecylazacycloheptan-2-one). Delivery systems with continuous release are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a soluble lipid membrane, for example silicone rubber or a biodegradable polymer, for example polylactic acid. The pharmaceutical preparations are preferably present in unit dosage forms. In such forms the preparation is subdivided into unit doses containing appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package contains discrete quantities of the preparation, for example packaged tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, seal (hollow wafer) or even a tablet, or it can be an appropriate number of any of them in packaged form. Other pharmaceutically suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. In the following examples, representative pharmaceutical formulations containing a compound of the present invention are described. The compounds of the invention are useful for, but are not limited to the treatment of any disorder or pathological state of a human or other mammal, exacerbated or caused by an excess or decontrol of the production of TNF or p38-kinase in such a mammal rdingly, the present invention provides a method for treating a p38-mediated disease comprising administering an effective amount of a compound of the invention or a pharmaceutically ptable salt, solvate or prodrug thereof to a subject or patient in need thereof. . The compounds of the invention are useful for, but are not limited to, the treatment of inflammation in a subject and the use in antipyretic condition for the treatment of fever. The compounds of the invention could be useful for treating arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. Such compounds could be useful for the treatment of pulmonary disorders or lung inflammation, including the syndrome of adult respiratory failure, pulmonary sarcoidosis, asthma, silicosis and chronic inflammatory lung diseases. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, sepsis gra-negative, malaria, meningitis, secondary caguexia of an infection or malignant pathology, secondary cachexia of acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), pneumonia and virus herpes The compounds are also useful for the treatment of bone resion diseases, for example osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune diseases, including the rejection reaction of the graft itself and rejection of foreign grafts. , cardiovascular diseases, including atherosclerosis, thrombosis, congestive heart failure and cardiac reperfusion injury, renal reperfusion injury, hepatic disorders, nephritis and myalgias due to infection. The compounds are also useful for treating Alzheimer's disease, influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), skin-related diseases, for example psoriasis, eczema, burns, dermatitis, keloid formation and of the tissue of the incised wounds. In addition, the compounds of the invention are useful for the treatment of gastrointestinal pathological conditions, for example inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds are also useful for the treatment of ophthalmic diseases, for example retinitis, retinopathies, uveitis, ocular photophobia and severe ocular tissue injury. The compounds can also be used to treat angiogenesis, including neoplasia; metastasis; pathological conditions of ophthalmology, for example corneal graft rejection, ocular neovascularization, neovascularization of the retina, including neovascularization subsequent to injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma, ulcerative diseases, for example gastric ulcer, non-malignant disease states, for example hemangiomas, including infantile hemangiomas, nasopharyngeal angiofibroma and avascular bone necrosis, diabetic nephropathy and cardiomyopathy and disorders of the female reproductive system, for example endometriosis. The compounds can also be used to prevent the production of cyclooxygenase-2 and have analgesic properties. Accordingly, the compounds of formula I are useful for the treatment of pain.

Other uses of the compounds of formula I include the treatment of HCV, severe asthma, psoriasis, chronic obstructive pulmonary disease (COPD) and other diseases. they can be treated with an anti-TNF compound. Apart from being useful for human treatment, these compounds are also useful for the "veterinary treatment of companion animals, exotic animals and animals of livestock interest, including mammals, rodents and the like. horses, dogs and cats The compounds of the present invention can also be used in combination therapies, totally or partially, in place of other conventional anti-inflammatories, for example together with steroids, cyclooxygenase-2 inhibitors, NSAIDS, DMARDs, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB antagonists and LTA4-hydrolase inhibitors As used in this description, the term "TNF-mediated disorder" denotes any or all of the disorders and pathological conditions in which the disorder is involved. TNF (tumor necrosis factor), either by controlling the TNF itself, or by provoking it instead of TNF, another monocycline is released, for example but not limited to IL-1, IL-6 or IL-8. Thus, any pathological condition in which IL-1, for example, is the predominant component and whose production or action is exacerbated or secreted in response to TNF could be considered as a disorder mediated by TNF. As used in this description, the term "p38-mediated disorder" indicates any or all of the pathological states in which p38 intervenes, either by controlling the p38 itself, or by releasing another factor other than p38, for example but not limited to: .IL-1, IL-6 or IL-8. A pathological state in which IL-1 is, for example, a preponderant component and whose production or action is exacerbated or secreted in response to p38 could therefore be considered as a disorder mediated by p38. Since TNF-β has a tight structural homology with TNF-a (also known as cachectin) and since each of them induces similar biological responses and binds to the same cellular receptor, the synthesis of both TNF-a and of TNF-β is inhibited by the compounds of the present invention and therefore in this description a collective reference to both in the form of "TNF" is made, unless explicitly stated otherwise.

Examples The following preparations and examples are provided to enable those skilled in the art to clearly understand and practice the present invention. They should not be taken as limiting the scope of the invention, but as merely illustrative and representative examples thereof. Unless stated otherwise, all temperatures including melting points (ie, p.f.) are expressed in degrees centigrade (° C) Example 1: Synthesis of 3- (2-chloro-phenyl) -6- (2-fluoro-phenoxy) -IH-indazole following the procedure of Esguema 1 -previous. Step 1. Preparation of 4- (2-fluoro-phenoxy) -2-trotoluene.

To 4-fluoro-2-nitrotoluene (25 g, 0.016 mol), 2-fluorophenol (15.8 ml, 0.017 mol) in NMP (350 ml) was added potassium carbonate (22.27 g, 0.016 mol) and the mixture was stirred at 160 ° C for 48 h. After cooling to RT, water (350 ml) was added and the solution was extracted into ethyl acetate (2 × 150 ml). The combined organic extracts were dried over Na2SO4, filtered, concentrated and the residue purified by flash chromatography eluting with Hex: EtOAc 95: 5 to give 15.17 g of 4- (2-fluoro-phenoxy) -2- nitrotoluene: MS: 248 (M + H).

Step 2. Preparation of 5- (2-fluoro-phenoxy) -2-methylphenyl amine. 4- (2-fluoro-phenoxy) -2-nitrotoluene (15.17 g, 0.061 mol) and Pd / C (1.67 g) in ethanol (150 ml) were stirred under a hydrogen atmosphere for 48 h, then the mixture was filtered off. The residue was concentrated through celite and the filtrate was concentrated under vacuum and purified by flash chromatography eluting with Hex: EtOAc 9: 1 to give 10.9 g of 5- (2-fluoro-phenoxy) -2-methyl-phenylamine: MS: 218 (M + H) Stage 3 Preparation of 6- (2-fluoro-phenoxy) -iH-indazole.

To a suspension of 5- (2-fluoro-phenoxy) -2-methyl-phenylamine (2.4 g, 11.04 mmol), acetic anhydride (3.36 g, 33.12 mmol) and anhydrous potassium acetate (1.10 g, 11.16 mmol) in benzene ( 36 ml) at 80 ° C, isoamyl nitrite ~ (2.22 ml, 16.56 mmol) was added dropwise over 30 minutes and the reaction mixture was stirred at this temperature overnight. After cooling to RT, the formed precipitate was filtered and the filtrate was concentrated under vacuum and the residue was treated with 5N HCl (4.5 ml) then conc. HCl (2.5 ml); the mixture was heated at 55 ° C for 2.5 h, then- at 60 ° C for 15 min. The reaction mixture was cooled to RT, extracted into benzene (15 ml), the aqueous phase made basic with NH40H, extracted into EtOAc (2x25 ml), the combined organic phases were dried over Na2SO, filtered, concentrated and The residue was purified by flash chromatography eluting with Hex: EtOAc 7: 3 to give 1.8 g of 6- (2-fluoro-phenoxy) -lH-indazole: MS: 229 (M + H).

Step 4. Preparation of 6- (2-fluoro-phenoxy) -3-iodo-lH-indazole.

Iodine (1.53 g, 6.02 mmol) and grains of potassium hydroxide (805 mg, 14.3 mmol) were successively added to a solution of DMF of 6- (2-fluoro-phenoxy) -lH-indazole (1.35 g, 5.92 mmol) at TA under agitation. After 1.5 h the reaction was poured into sodium bisulfite solution and extracted into EtOAc (2 x 20 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated and the residue was purified by flash chromatography eluting with Hex: EtOAc 9: 1 to give 1.9 g of 6- (2-fluoro-phenoxy) -3-iodo-1H- indazole: MS: 355 (M + H).

Step 5. Preparation of 6- (2-fluoro-phenoxy) -3-iodo-indazole-1-carboxylic acid tert-butyl ester.

Reflux was carried out for 2 and a half hours at 6- (2-fluoro-phenoxy) -3-iodo-lH-indazole (1.9 g, 5.36 mmol), di-tert-butyl-dicarbonate (1.4 g, 6.43 mmol) and 4-dimethylaminopyridine (33 mg, 0.26 mmol) in THF (10 mL). The reaction mixture was cooled to RT, concentrated in vacuo and the residue was purified by flash chromatography Hex: EtOAc 9: 1 to give 2.4 g of 6- (2-fluoro-phenoxy) -3- tert-butyl ester. Iodo-indazole-1-carboxylic acid: MS: 455 (M + H).

Step 6. Preparation of 3- (2-Chloro-phenyl) -6- (2-fluoro-phenoxy) -indazole-1-carboxylic acid tert-butyl ester.

To a solution of (Ph3P) 4Pd (36 mg, 0.03 mmol) in dioxane (4 ml) was added under argon 6- (2-fluoro-phenoxy) -3-iodo-indazole-1-carboxylic acid tert-butyl ester. (140 mg, 0.3 mmol) and the solution was stirred for 10 mm, then 2-chlorophenyl boronic acid (96.4 mg, 0.6 mmol) in ethanol (1.2 ml) was added. After 10 min, potassium carbonate (132 mg, 0.9 mmol) in water (0.4 ml) was added and the mixture was stirred at 85 ° C under argon for 18 h. The mixture was cooled to RT, filtered through Celite, partitioned between water and EtOAc, the separated organic phase was dried over Na2SO, filtered, concentrated and the residue was purified by flash chromatography eluting with Hex: EtOAc 9: 1. to give 90 mg of 3- (2-chloro-phenyl) -6- (2-fluoro-phenoxy) -indazole-1-carboxylic acid tert-butyl ester: MS: 345 (M + H).

Step 7. Preparation of 3- (2-chloro-phenyl) -6- (2-fluoro-phenoxy) -IB.- indazole A solution of 3- (2-chloro-phenyl) -6- tert -butyl ester (2-fluoro-phenoxy) -indazole-1-carboxylic acid (90 mg, 0.2 mmol) and sodium methoxide (22 mg, 0.41 mmol) in methanol (2 mL) was stirred at RT for 1 h, and then concentrated under vacuum . The residue was diluted with EtOAc, washed with water, dried over Na 2 SO 4, filtered, concentrated and the residue purified by flash chromatography eluting with Hex: EtOAc 4: 1 to give 42 mg of 3- (2-chloro-phenyl) ) -6- (2-fluoro-phenoxy) -lH-indazole: MS (M + H) + = 339. Example 2: "In vitro" assay of p38- (MAP) kinase. The inhibitory activity of the p38- (MAP) kinase "in vitro" of the compounds of this invention is determined by measuring the transfer of? -33P-ATP? -phosphate by the action of p-38 kinase to the basic protein of myelin (MBP), using a minor modification of the method described by Ahn et al., J. Biol. Chem. 266: 4220-4227, (1991). The phosphorylated form of the recombinant p38-MAP-kinase is co-expressed with SEK-1 and MEKK in E. Coli (see, Khokhlatchev et al., J. Biol. Chem. 272: 11057-11062, 1997) and then purify by affinity chromatography using a nickel column. The phosphorylated p38 MAP-kinase is diluted with kinase buffer (20 M 3- (N-morpholino) propanesulfonic acid, pH 7.2, 25 mM β-glycerol phosphate, ethylene glycol bis (beta-aminoethyl ether) -N, N, N ', N' -tetraacetic 5 mM, 1 mM sodium orthovanadate, 1 mM dithiothreitol, 40 mM magnesium chloride). The compound to be tested is dissolved in DMSO and only DMSO (control) is added and the samples are incubated at 30 ° C for 10 min. The reaction of the kinase is initiated by the addition of a mixed substrate containing MBP e? -ATP-P33. After an additional 20 min incubation at 30 ° C, the reaction is terminated by adding 0.75% phosphoric acid. The phosphorylated MBP is then separated from the residual? -ATP-P33 using a phosphocellulose membrane (Millipore, Bedford, MA) and quantified using a scintillation counter (Packard, Meriden, CT) Applying the above procedure, it is found that the compounds of the invention are p38-MAP-kinase inhibitors. For example, 4- [6- (2-fluoro-phenoxy) -1H-indazol-3-yl] -phenol exhibits a p38 IC50 (μM) of 0.028.

Example 3: Formulations Pharmaceutical preparations for administration by various routes are formulated as indicated in the following tables. The term "active ingredient" or "active compound" used in the tables means one or more compounds of the formula I.

Composition for oral administration Ingredient% p./p. Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5% The Xy ingredients are mixed and packaged in capsules containing 100 mg each; The content of one capsule is approximately equivalent to the total daily dose.

Composition for oral administration Ingredient% p./p. Active component 20.0% Magnesium stearate 0.5% Croscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidone) 1.0% The ingredients are combined and granulated using a solvent, for example methanol. The formulation is then dried and pressed into tablets (containing about 20 mg of the active principle) with a machine suitable for the manufacture of tablets.

Composition oral administration Ingredient Active compound quantity 1.0 g fumaric acid 0.5 g sadistic chloride 2.0 g. methyl-paraben 0.15 g propyl-paraben 0.05 g granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml coloring 0.5 mg distilled water, q.s. up to 100 ml The ingredients are mixed to form a suspension intended for oral administration. Formulation-parenteral Ingredient% p./p. active component 0.25 g sodium chloride, q.s. until isotonic water for injection 100 ml The active ingredient is dissolved in a portion of the water for injection. Then a sufficient amount of sodium chloride is added with stirring to make the solution isotonic. The solution is completed to the desired weight with the remaining water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Suppository formulation Ingredients% p / p active component 1.0% polyethylene glycol 1000 74.5% polyethylene glycol 4000 24.5% All the ingredients are melted at the same time, mixed on a steam bath and poured into molds, whose total weight capacity is 2.5 g.

Topical formulation Ingredients active compound grams 0.2-2 Span 60 2 Tween 60 2 mineral oil 5 petrolatum - 10 methyl paraben 0.15 propyl paraben 0.05 BHA (hydroxy-anisole butylated) 0.01 water up to 100 All the ingredients, except water, are combined and heated with stirring at 60 ° C. A sufficient amount of water with vigorous stirring is added at 60 ° C to emulsify the ingredients and then a sufficient amount of water is added to complete the 100 g.

Nasal Spray Formulations Various aqueous suspensions containing 0.025 to 0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients, for example, microcrystalline cellulose, sodium carbiximethylcellulose, dextrose, and the like. Hydrochloric acid is added to adjust the pH. Nasal spray formulations can be administered by a calibrated pump that delivers 50 to 100 microliters of formulation at each performance. A typical dosing schedule would be 2 to 4 nebulizations every 4-12 hours. The present invention has been described with reference to the specific embodiments thereof, but it is assumed by those skilled in the art that various changes can be made and materials can be substituted by other equivalents without departing from the true spirit and scope of the invention. In addition, many modifications can be introduced to adapt them to a situation, material, composition of matter, process, stage or stages of process, for the spirit and objective scope of the present invention. All modifications are considered to be within the scope of the appended claims. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

2. Having described the invention as above, the content of the following claims is claimed as property: 1. Compound of formula I or pharmaceutically acceptable salts, solvates or prodrugs thereof, characterized in that: R1 is aryl, heteroaryl, aralkyl or cycloalkyl; Rz is aryl, heteroaryl, cycloalkyl heterocyclyl; m is from 0 to 4; R3 is hydrogen, Ci-Ce alkoyl, Ci-Ce haloalumyl, cyano, nitro, amino, hydroxyl, alkoxy, heteroalkyl, heterocyclyl, hydroxycycloalkyl or -C (= 0) -Ra, wherein Ra is hydrogen, cycloalkyl Cß, heteroalguyl, aryl, aralkyl, heteroaryl or heterocyclyl; k is 0 or 1; and B is 0, S (0) j, CH (0Rb), NRC or C (= 0), where j is 0, 1 or 2; Rb is hydrogen or Ci-Cß alkyl, Rc is hydrogen, alkyl L-C6, -C (= 0) -Rd or -S02Re, where Rd is C?-C6 alkyl, aryl or aralkyl; and Re is C? -C6 alkyl. 2. Compound in accordance with the claim 1, characterized in that k is 0.
3. 3. Compound in accordance with the claim 2, characterized in that R1 is optionally substituted phenyl.
4. 4. Compound in accordance with the claim 3, characterized in that Ra is 2-halophenyl or 2,4-dihalophenyl.
5. 5. Compound according to claim 3, characterized in that R2 is optionally substituted phenyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted indolyl, benzothienyl? optionally substituted, or optionally substituted benzofuranyl.
6. 6. Compound according to claim 1, characterized in that it has the formula II wherein A, R1, R2, m and R3 are as defined in claim 1. 7. Compound according to claim 6, characterized in that it has the formula III wherein - p and q each independently has a value from 0 to 4; each R 4 is independently halo, C? -C6 alkyl, alkoxy, C? _6 haloalkyl, or cyano; each R 5 is independently halo, C 1 -C 5 alkyl, haloCi-Ce alkyl, cyano, heteroalguyl, heterocyclyl, hydroxycycloalkyl or -C (= 0) -RT, where Re is Ci-Ce alkenyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclyl; and m and R3 are as defined in claim
7. 7. Compound according to claim 7, characterized in that it has the formula IV (IV) wherein p, g, R4 and R5 are as defined in claim
8. 8.
9. 9. Compound according to claim 1, characterized in that it is selected from: 6- (2-fluoro-phenoxy) -3-phenyl -lH-indazole; 3- (2-chloro-phenyl) -6- (2-fluoro-phenoxy) -lH-indazole; 6- (2-fluoro-phenoxy) -3- (3-methoxy-phenyl) -lH-indazole; 3- (5-bromo-2-methoxy-phenyl) -6- (2-fluoro-phenoxy) -1H-indazole; 6- (2-fluoro-phenoxy) -3-thiophen-3-yl-lH-indazole; 6- (2-fluoro-phenoxy) -3-o-tolyl-lH-indazole; 6- (2-fluoro-phenoxy) -3- (4-methoxy-2-methyl-phenyl) -1H-indazole; 3-benzo [b] thiophen-3-yl-6- (2-fluoro-phenoxy) -1H-indazole; 6- (2-fluoro-phenoxy) -3- (2-methoxy-phenyl) -lH-indazole; 3- (2,5-dimethoxy-phenyl) -6- (2-fluoro-phenoxy) -1H-indazole; 3- (2-chloro-phenyl) -5- (2-fluoro-phenoxy) -iH-indazole; 2-Oxide of 3- (2-chloro-phenyl) -5- (2-fluoro-phenoxy) -lH-indazole; 6- (2-fluoro-phenoxy) -3-furan-3-yl-lH-indazole; 6- (2-fluoro-phenoxy) -3-furan-3-yl-lH-indazol-6- (2-fluoro-phenoxy) -3-furan-3-yl-lH-indazole; 3- (3-benzyloxy-phenyl) -6- (2-fluoro-phenoxy) -IH-indazole; 3- (3-chloro-4-propoxy-phenyl) -6- (2-fluoro-phenoxy) -1H-indazole; 6- (2-fluoro-phenoxy) -3- (3-isopropoxy-phenyl) -1H-indazole; 3- (3, 5-dimethyl-phenyl) -6- (2-fluoro-phenoxy) -1H-indazole; . { 4- [6- (2-fluoro-phenoxy) -lH-indazol-3-yl] -phenyl} dimethyl amine; 6- (2-fluoro-phenoxy) -3- (4-isopropoxy-phenyl) -1H-indazole; . 3-benzo [b] thiophen-2-yl-6- (2-fluoro-phenoxy) -1H-indazole; 6- (2-fluoro-phenoxy) -3- (2-trifluoromethyl-phenyl) -1H-indazole; 6- (2-fluoro-phenoxy) -3-m-tolyl-lH-indazole; 6- (2-fluoro-phenoxy) -3-p-tolyl-lH-indazole; 3- (4-chloro-phenyl) -6- (2-fluoro-phenoxy) -lH-indazole; 3-diphenyl-4-yl-6- (2-fluoro-phenoxy) -lH-indazole; 6- (2-fluoro-phenoxy) -3- (lH-indol-3-yl) -lH-indazole; 3- (3-chloro-phenyl) -6- (2-fluoro-phenoxy) -lH-indazole; 3- (3, 4-dimethoxy-phenyl) -6- (2-fluoro-phenoxy) -1H-indazole; 3- (4-bromo-phenyl) -6- (2-fluoro-phenoxy) -1H-indazole; 6- (2-fluoro-phenoxy) -3- (3, 4, 5-trimethoxy-phenyl) -1H-indazole; 6- (2-fluoro-phenoxy) -3- (4-pyridin-3-yl-phenyl) -1H-indazole; [5- (2-fluoro-phenoxy) -lH-indazol-3-yl] -phenyl-amine; and 4- [6- (2-fluoro-phenoxy) -lH-indazol-3-yl] -phenol.
10. 10. Composition, characterized by comprising a pharmaceutically acceptable excipient; and a compound according to claim 1.
11. 11. Method for treating disorders mediated by p38, characterized in that it comprises administering to a patient a therapeutically effective amount of a compound according to claim 1.
12. 12. Method according to claim 11 , characterized by p38 mediated disorder is arthritis, Crohn's disease, irritable bowel syndrome, adult respiratory distress syndrome, or chronic obstructive pulmonary disease, or Alzheimer's disease.
13. 13. Compound of formula I according to claim 1, characterized by being for use as an active therapeutic substance, in particular as an active anti-inflammatory substance.
14. 14. Pharmaceutical composition, in particular for so in the treatment of inflammation, characterized by comprising a compound according to claim 1 and a therapeutically inert carrier.
15. 15. Use of a compound according to claim 1 for the manufacture of a medicament comprising a compound according to claim 1 for the treatment of inflammation.