MX2008007438A - Bicyclic heteroyclic compounds as antiinflammatory or antiallergic agents - Google Patents

Abstract

There are provided according to the invention compounds of formula (I) in free or salt form, wherein R1, R2, R4, R5, R6, D, X, W, m and n are as described in the specification, process for preparing them, and their use as pharmaceuticals.

Description

"COMPU THESE BICYCLIC HETEROCICLES AS AGENTS ANTIINFLAMATORIOS OR ANTIALÉRGICOS" FIELD OF THE INVENTION The present invention relates to organic compounds, their preparation and their use as pharmaceuticals.

BRIEF DESCRIPTION OF THE INVENTION In a first aspect, the present invention provides compounds of the formula (I): in free or salt form, wherein: D is independently selected from CR3 and N; R1 and R2 are, independently, H, halogen or C? -C8-alkyl, or R1 and R2, together with the carbon atom to which they are attached, form a C3-C1-carbocarboxyl group; R3 is selected from d-Cs-alkyl, halogen, cyano, hydroxy, amino, aminoalkyl, amine (di) alkyl, a C3-C1-carbocyclic group, C? -C8-haloalkyl, Ci-C-alkoxy-CT-Cs-alkyl and CrC8- hydroxyalkyl; each R4 is selected from halogen, C ^ Cs-alkyl, C? -C8-haloalkyl, a C3-C1-carbocyclic group, a C6-C1-aromatic carbocyclic group, nitro, clade, C? -C8- alkylsulfonyl, C ^ Cs-alkylsulfinyl, Ct-C-alkoxycarbonyl, d-C-alkoxy, Ci-Cs-haloalkoxy, carboxy, carboxy-Ci-C-alkyl, amino, C? -C8-alkylamino, di (C? C8-alkyl) amino, SO2NH2, (Ci-Cs-alkylaminoJsulfonyl, diid-Cs-alkyl) aminosulfonyl, aminocarbonyl, d -Cs-alkylaminocarbonyl, di (Ci-C8-alkyl) aminocarbonyl and a heterocyclic group consisting of 4 to 10 members; each R5 is independently selected from d-Cs-haloalkyl, -SO? -Ci-Cs-alkyl, -SO? -Ci-Cs-haloalkyl, or a heterocyclic group consisting of 4 to 14 members, when n is an integer from 2-3, or R5 is independently selected from when n is 1; R5a and R5 are independently separated from H, a heterocyclic group consisting of 4 to 14 members, a C6-C1-aromatic carbocyclic group, a C3-C1-carbocyclic group, and Ci-C-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C? 5-carbocyclic group, wherein at least one of p5a Q p5b is Ct-Cβ-alkyl substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C1 5-carbocyclic group, or R5a and R5 together with the nitrogen atom to which they are attached form a heterocyclic group composed of 4 to 14 members, R5c, R5d and R5e are independently selected from H, and C? -C8-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members, a C6-C group? 5-carbocyclic aromatic, or a C3-C1 5-carbocyclic group, or R5c together with R5d and R5e together with the nitrogen atoms to which they are attached and the carbonyl form a heterocyclic group composed of 5 to 14 members; R5f is H, Ci-Cβ-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a group C? -C8- carbocyclic composed of 3 to 15 atoms; R5g is selected from H, and d-Cs-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C group? 5-carbocyclic; R5f and R5g together with the group NSO2 to which they are bound form a heterocyclic group composed of 5 to 14 members; p5h and p5? are independently selected from H, and dCS-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C group? 5-carbocyclic, or R5h and R5 'together with the NCO group to which they are bound form a heterocycle composed of 5 to 14 members; R 5j and R 5k are independently separated from H, and d -Cs-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C 3 -C 5 carbocyclic group, or R 5j and R 5k together with the nitrogen atom to which they join form a heterocyclic group of 4 to 14 members; R5 ', R5m and R5q are independently selected from H, and Ci-Cβ-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C group? 5-carbocyclic, or R5 'together with R5m or R5q together with the nitrogen atoms of the aminosulfonamide to which they bind form a C5-C group? -Heterocyclic; is selected from a C4-C14-heterocyclic group, a C6-C1-aromatic carbocyclic group and a C3-C1-carbocyclic group; R6 is H or C? -C8-alkyl optionally substituted by a C3-C1 5-carbocyclic group, or a C3-C1-5 carbocyclic group W is a C6-C1-aromatic carbocyclic group or a C -C1 -heterocyclic group composed of 4 to 14 members, with the proviso that W not be benzothiazole; X is a bond, d-C8-alkyl optionally substituted by one or more groups selected from C? -C8-alkyl, halo-d -C8-alkyl, halo, oxo, hydroxyl, amino, aminoalkyl, and amino (dialkyl), (-T-ÍV), a heterocyclic group composed of 4 to 14 members, a C6- group C1-aromatic carbocyclic, -SO2-, -CONR7 (C1-C8-alkyl) -, or a C3-C1-carbocyclic group; Vi is C? -C7-alkyl optionally substituted by d-C8-alkyl, halo, oxo, hydroxyl, amino, amino-d-C8-alkyl, amino (di-C? -8-alkyl); V is C0-C7-alkyl optionally substituted by d -C8-alkyl, halo, oxo, hydroxyl, amino, amino-d-Cs-alkyl, amino (di-d-C8-alkyl); T is oxygen or N R7; R7 is H or d-C8-alkyl; where each C3-C1-carbocyclic group, C3-C15 aromatic carbocyclic group and each heterocyclic group consisting of 4 to 14 members, unless otherwise specified, is independently and optionally substituted by one or more groups selected from of halo, oxo, hydroxy, cyano, amino, nitro, carboxy, C? -C8-alkyl, halo-C? -C8-alkyl, Ci-Cs-alkoxy, C, -C8-alkylcarbonyl, d-C8-alkylsulfonyl, SO2NH2, (d-C8-alkylamino) -sulfonyl, dKd -Cs-alkylJaminosulfonyl, aminocarbonyl, C? -C8-alkylaminocarbonyl and di (d-C8-alkyl) aminocarbonyl, a C3-C? 5-carbocyclic group, an aromatic C6-C15-carbocyclic group, a heterocyclic group composed of 4 to 14 members, cyano- d-C8-alkyl, hydroxy-C8-alkyl, d-C8-haloalkyl, amino-Ci-C-alkyl, aminohydrox-d-C-alkyl and d-C8-alkoxy optionally substituted by aminocarbonyl; m is an integer from 0-3; n is an integer from 1 -3; and p is an integer from 0-4. According to formula (I), the compounds of formula (I) are conveniently in free or salt form, R4a is H or halogen. X is -CH2-. According to the formula (I), W is a C6-C group? 5 aromatic carbocyclic, for example, phenyl, where W is phenyl, is conveniently 2,4-substituted by R 5. According to formula (I), each R5 is independently and conveniently selected from d -C8-haloalkyl, preferably trifluoromethyl, and -SO 2 -d-C 8 -alkyl, preferably -SO 2 -CH 3. According to formula (I), R5 is conveniently I where R5) and R5k together with the nitrogen atom A to which they are attached form a heterocyclic group composed of 4 to 6 members, ie piperazine, azetidine, morpholine, piperidine and pyrrolidine. The heterocyclic group consisting of 4 to 6 members can be optionally substituted by d-C8-alkyl, preferably methyl, or R5j and R5k are independently selected from C? -C8-alkyl, preferably methyl or a C3-C1-carbocyclic group, such as cyclohexane, when n is 1. According to formula (I), when n is an integer from 2-3, each R5 is independently and conveniently where R5j and R5k together with the nitrogen atom to which they are bound form an integrated heterocyclic group by 4 to 6 members, ie piperazine, azetidine, morpholine, piperidine and pyrrolidine. The heterocyclic group consisting of 4 to 6 members can optionally be substituted by d-C8-alkyl, preferably methyl, or R5j and R5k are independently selected from d -C8-alkyl, preferably methyl or a C3-C1 5- group carbocyclic, such as cyclohexane. A more preferred embodiment of the present invention provides compounds of the formula (Ia) where R4a is H or fluorine; R9 is H or d-C8-haloalkyl; and R8 is selected from -SO2-C? -C8-alkyl, The terms used in the specification have the following meanings: "Replaced optionally", as used herein, denotes to the referred group that it can be substituted in one or more positions by any combination of the radicals listed below. "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine. "d -C8-alkyl" denotes d-C8-straight or branched chain alkyl, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, re-butyl , straight or branched chain pentyl, straight or branched chain hexyl, heptyl Straight chain or straight chain or straight chain or branched chain. "C3-C15-carbocyclic group", as used herein, denotes a carbocyclic group having from 3 to 15 carbon atoms in the ring that is saturated or partially saturated, such as a C3-C8-cycloalkyl. . Examples of C3-C1-carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group, such as bicyclooctyl, bicyclononyl, including indole and indenyl, and bicyclodecyl. "C3-C? 5-carbocyclic aromatic group", as used herein, denotes an aromatic group having from 6 to 15 carbon atoms in the ring. Examples of C3-C1-aromatic carbocyclic groups include, but are not limited to, phenyl, phenylene, benzene, naphthyl, naphthylene, naphthalenetrile or anthylene. "d-C8-alkoxy" denotes C? -C8-straight or branched chain alkoxy which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, fer-butoxy , straight or branched chain pentoxy, straight or branched chain hexyloxy, straight or branched chain heptyloxy or straight or branched chain octyloxy. Preferably, d-C8-alkoxy is C? -C4-alkoxy "d-C8-haloalkyl" and "C? -C8-haloalkoxy" denote d -C8-alkyl and C? -8-alkoxy as defined above, are substituted by one or more halogen atoms, preferably one, two or three halogen atoms, preferably fluorine, bromine or chlorine atoms. Preferably, d-C8-haloalkyl is C1-C4-alkyl substituted by one, two or three fluorine, bromine or chlorine atoms. "d -C8-alkylsulfonyl", as used herein, denotes d-C8-alkyl as defined above linked to -SO2-. "d-C8-alkylsulfinyl", as used herein, denotes d-C8-alkyl as defined above, linked to -SO-. "Amino-d -C8-alkyl" and "amino-C? -C8-alkoxy" denote amino linked through a nitrogen atom to a d-C8-alkyl, for example, NH2- (d-) C8) -, or to d-Cß-alkoxy, for example, NH2- (d-C8) -O-, respectively, as defined above. "Amino- (hydroxy) -d-C8-alkyl" denotes amine attached through a nitrogen atom to the C-C8-alkyl and hydroxy linked through an oxygen atom to the same d-C8-alkyl. "Carboxy-d-C8-alkyl" and "carboxy-C? -C8-alkoxy" denote carboxy attached via a carbon atom to C? -C8-alkyl or CrC8-alkoxy, respectively, as defined above. "d-C8-alkylcarbonyl", "d-C8-alkoxycarbonyl", and "d-C8-haloalkylcarbonyl" denote d-C8-alkyl, C? -8-alkoxy or d-C8-haloalkyl respectively, as defined previously linked through a carbon atom to a carbonyl group. "d -C8-alkoxycarbonyl denotes d-C8-alkoxy as defined above, wherein the oxygen and the alkoxy group are attached to the carbonyl atom." d-C8-alkylamino "and" d1 (d-C8 -alkyl) amino "denote C? -C8-alkyl as defined above linked through a carbon atom to an amino group The C? -C8-alkyl groups in di (d-C8-alkyl) amino can be same or different. "d-C8-alkylaminocarbonyl" and "di (d-C8-) alkyl) aminocarbonyl "denote d-C8-alkylamino and d, (dC8-alkyl) amino, respectively, as defined above attached through a nitrogen atom to the carbon atom of a carbonyl group." DHd-d-alkylJamino -d-Ca-alkyl "and" di (C? -C8-alkylo) amino-d -C8-alkoxy "denote di (C? -8-alkyl) amino as defined above are attached through a nitrogen atom to the carbon atom of a group -C 8 -alkyl or a C group -C 8 -alkoxy, respectively. "Heterocyclic group composed of 4 to 14 members" refers to a heterocyclic ring of 4 to 14 members containing at least one heterogeneous ring atom selected from the group consisting of nitrogen, oxygen and sulfur, which may be saturated, partially saturated or unsaturated (aromatic) Examples of heterocyclic groups composed of 4 to 14 members include, but are not limited to furan, azetidine, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, triazine, oxazine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1,4-oxathia, indazole, quinoline, indazole, indole or thiazole. The heterocyclic group consisting of 4 to 14 members may be unsubstituted or substituted. Preferred substituents include halo, cyano, oxo, hydroxy, carboxy, nitro, d -C8-alkyl, C? -8-alkylcarbonyl, cyano-Ci-Ca-alkyl, hydroxy-d-C8-alkyl, d-C8 -haloalkyl, amino-d-C8-alkyl, aminohydrox d-Cs-alkyl and C? -8-alkoxy substituted optionally by aminocarbonyl. Especially preferred substituents include halo, oxo, C? -C-alkyl, d-d-alkylcarbonyl, hydroxy-d-C-alkyl, d-C -haloalkyl, amino-C? ~ C -alkyl and amino (hydroxy) C? -C-alkyl. Throughout this specification and in the claims disclosed below, unless the context otherwise requires, the word "comprises", or variations such as "comprises" or "comprising", shall be understood to imply the inclusion of an integer set or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. When in formula (I), m or n are 2, the two substituents may be the same or different. When m or n is 3, two or all substituents may be the same or all three may be different. In a still further aspect, the present invention provides the use of a compound in the formula (I) in any of the aforementioned embodiments, in free or salt form, for the manufacture of a medicament for the treatment of an inflammatory condition or allergic, particularly of an inflammatory or obstructive disease of the respiratory tract.

Salts and Isomers Many of the compounds represented by the formula (I) are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. The pharmaceutically acceptable acid addition salts of the compound of the formula (I) they include those of inorganic acids, for example, hydrohalic acids, such as hydrochloric acid or hydrobromic acid; nitric acid; sulfuric acid; phosphoric acid; and organic acids, for example, aliphatic monocarboxylic acids, such as formic acid, acetic acid, diphenylacetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoroacetic acid, hippuric acid, propionic acid and butyric acid; aliphatic hydroxy acids such as lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid or malic acid; dicarboxylic acids, such as adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, sebacic acid or succinic acid; aromatic carboxylic acids, such as benzoic acid, p-chlorobenzoic acid or nicotinic acid; aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid; and sulfonic acids, such as ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, (+) - camphor-1-sulphonic acid, benzenesulfonic acid, naphthalene-2-sulphonic acid, Naphthalene-1, 5-disulfonic acid or p-toluenesulfonic acid. These salts can be prepared from compounds of the formula (I) through known salt formation methods. The compounds of formula (I) which contain acidic groups, for example, carboxyl, are also capable of forming salts with bases, in particular, pharmaceutically acceptable bases, such as those well known in the art; said suitable salts include metal salts, particularly alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium, calcium or zinc salts; or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases, such as benetamine, arginine, benzathine, diethanolamine, ethanolamine, 4 (2-hydroxy-ethyl) morpholine, 1- (2-hydroxyethyl) pyrrolidine,? / -methyl glutamine, piperazine, triethanolamine or tromethamine. These salts can be prepared by the compounds of the formula (I) by known salt formation methods. In those compounds wherein there is an asymmetric carbon atom or an axis of chirality, the compounds exist in individual optically active isomeric forms or as mixtures thereof, for example, as racemic or diastereomeric mixtures. The present invention encompasses both individual and optically active R and S isomers, as well as mixtures, for example, racemic or diastereomeric mixtures thereof. The specific preferred compounds of the formula (I) are described below in the Examples. The invention also provides a process for the preparation of compounds of the formula (I), in free or salt form, comprising the steps of: (i) (A) for the preparation of the compounds of the formula (I), wherein R6 is H, cleaving the ester group -COOR6 in a compound of the formula (I), wherein R6 is d-C8-alkyl optionally substituted by C3-C15-carboxylic, or a C3-C15-carboxylic group, and R1, R2, R4, R5, D, W, X, m and n are as defined above; or (B) for the preparation of compounds of the formula (I), wherein R6 is C? -C8-alkyl optionally substituted by a C3-C15-carbocyclic group which reacts a compound of the formula (II) where R6 is C? -C8-alkyl optionally substituted by a d-ds-carbocyclic group, or a C3-C15-carbocyclic group; and R1, R2, R4, A, D and m are as defined above with a compound of the formula (III) G -X-W- (R5) n (III) where G is a residual portion, for example, a halogen atom; and R5, W, X and n as defined above; and (ii) recovering the resulting compound of formula (I) in free or salt form. The variant (A) of the process can be carried out using known methods (or analogously as described hereinafter in the Examples) for the cleavage of carboxylic ester groups and can be carried out in situ after the preparation of a compound of the formula ( I), wherein R6 is d-C8-alkyl optionally substituted by a C3-C1-carbocyclic group. For example, the compound of the formula (I), wherein R6 is C? -C8-alkyl optionally substituted by a C3-C1-carbocyclic group, which is conveniently in solution in a polar organic solvent or a mixture thereof with water, can be reacted with an aqueous inorganic base, such as NaOH or LiOH to hydrolyze the ester group; where the base is NaOH, the reaction can be carried out at a temperature of 10-40 ° C, conveniently at room temperature, whereas when the base is LiOH the reaction can start at -5 ° C to 5 ° C and then continue at 1 0-40 ° C, conveniently at room temperature. The variant (B) of the process can be carried out using known procedures or analogously as described in the Examples below. For example, the compound of the formula (I I) can be reacted with an alkyl halide of the formula (I I I), where G is halogen; R5, W, X and n are as defined above, in the presence of an organic base, such as NaH; the reaction can be carried out in an organic solvent, for example, a polar aprotic solvent, such as? /,? / - dimethylformamide (DMF) and can be carried out at 1 0-40 ° C, conveniently at room temperature. The cleavage of the carboxylic acid esters can be carried out in situ when a compound of the formula (I I) is reacted with a compound of the formula (I I I) using DMSO and NaH. For example, when isolating a compound of the formula (I), the excess of inorganic base, NaH, in the presence of adventitious water can generate the water-based NaOH, which can hydrolyze the compound of the formula (I) to generate the derivative of carboxylic acid as described under variant (A) of the process. The compounds of the formula (I I) are known or can be obtained by known methods, for example, as described in the Patent of E. U.A. No. 3, 320,268, or analogously as described hereinafter in the Examples. The compounds of the formula (I I I) are known or can be obtained by known methods, or analogously, as described hereinafter in the Examples. The compounds of the formula (I) in free form can be converted into salt form and vice versa, in conventional manner. Compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. The compounds of the formula (I) can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as enantiomers, can be obtained in conventional manner, for example, through fractional crystallization, chiral HPLC resolution or asymmetric synthesis from corresponding and asymmetrically substituted, for example, optically active raw materials.

Pharmaceutical Use and Assays The compounds of the formula (I) and their pharmaceutically acceptable salts, hereinafter alternatively referred to as "agents of the invention", are useful as pharmaceuticals. In particular, the compounds have a good modeling activity of the CRTh2 receptor and can be tested in the following assays.

Filtration-binding assay protocol The binding of CRTh2 modulators is determined using membranes prepared from Chinese Hamster Ovary cells expressing human CRTh2 (CHO, K1-CRTh2). In order to produce the cell membranes, CHO.K1-CRTh2 cells grown in spinner bottles are harvested using a cell dissociation regulator (I nvitrogen). The cells are compressed by centrifugation (167 g, 5 minutes). The cell tablet is incubated in a hypotonic buffer (1.5 mM Tris-OH, 2 mM Mg CI2, 0.3 mM EDTA, 1 μM EGTA, 1 Complete ™ tablet) at 4 ° C for 30 minutes. At 4 ° C, the cells are homogenized using a Polytron® (I KA Ultra Turrax T25) for 5 bursts of 1 second. The homogenate is centrifuged (Beckman Optimum TM TL Ultracentrifuge, 48000 g, 30 minutes at 4 ° C). The supernatant is discarded and the membrane tablet is resuspended in homogenization buffer (75 mM Tris-OH, 12.5 mM MgCl2, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose, 1 tablet Complete ™ The membrane preparations are inoculated and stored at 80 ° C. Protein content is calculated using the Bradford Protein Assay Dye protein assay dye (Bio Rad) The binding of [3H] -PGD2 (1 57 C) In the absence (total binding) and in the presence (non-specific binding) of unlabeled PGD2 (1 μM), the subtraction of the cpm (counts per minute) from the union of [ 3H] -PGD2 in the presence of unlabeled PGD2 in excess from that observed in the absence of unlabelled PGD2 in excess is defined as the specific binding.The active CRTh2 modulators are able to compete with [3H] -PGD2 for binding to the receptor CRTh2 and are identified in a reduction in the binding number of cpm. it is carried out in 96-cell plates with Greiner U-shaped bottom, in a final volume of 1 00 μl per cell. The CHO membranes. K1-CRTh2 were diluted in assay buffer (1.0mM HEPES-KOH (pH 7.4), 1mM EDTA and 10mM MnCl2) and 10μg was added to each cell. It dilutes [3H] -PGD2 in regulator assay and added to each cell in a final concentration of 2.5 nM. In order to determine non-specific binding, the binding of [3 H] -PGD2 to the CRTh2 receptor is completed with the use of PGD2 at a final cell concentration of 1 μM. The experiment was performed in triplicate, adding the reagents to the cells in the following manner: - 25 μL of assay buffer for total binding or - 25 μL of PGD2 to determine non-specific binding - 25 μL of [3H] PGD2 - 50 μL of membranes - 25 μL of the test compound in DMSO / assay regulator. The plates are incubated at room temperature in a shaker for 1 hour, and then harvested (Tomtec Harvester 9600) on GF / C plates using a rinse buffer (10 mM H EPES-KOH, pH 7.4). The plate is dried for 2 hours, before the addition of Micro-Scint 20 ™ (50 μL), and sealed with TopSeal-S ™. Then, the plates are counted using a Packard Top Count counter instrument. The plates are then read on a Packard Topcount counter with the Scintillation 3H scintillation program (1 minute per cell). Ki values (dissociation constant for inhibition) were reported for the CRTh2 modulators. Ki values are determined using the Sigma Plot ™ software, using the Cheng-Prussoff equation: Ki = IC50 / 1 + [S] / Kd where S is the radioligand concentration and Kd is the dissociation constant Functional assay protocol CRTH2 cAMP This assay is performed on CHO cells. K1 -CRTh2. CAMP is generated in the cell by stimulating the cells with 5 μM of forskolin, an adenylate cyclase activator. PGD2 is added to activate the CRTh2 receptor, which results in the attenuation of the accumulation of cAM P induced by forskolin. The ability of potential antagonists of CRTh2 to inhibit PGD2-mediated attenuation of forskolin-induced cAMP accumulation in CHO cells is tested. K1 -CRTh2. For each concentration value in the dose-response curve, test compounds are prepared in stimulation buffer assay (HBSS, 5 mM HEPES, 1.0 μM I BMX + 0.1% human serum albumin) containing DMSO (3% vol / vol) and 5 μL / cell are added to a test plate (white plate of 384 cells). CHO cells. K1-CRTh2 cultured in tissue culture flasks are rinsed with PBS and harvested with dissociation buffer. The cells are rinsed with PBS and resuspended in stimulation buffer at a concentration of 0.4 x 1 06 / mL and added to the assay plate (10 μL / cell). The assay plate is incubated at room temperature in a shaker for 15 minutes. A mixture of agonist (1.0 nM of Prostaglandin D2) and 5 μM of forskolin in regulator stimulation assay and are added to the assay plate (5 μL / cell). In addition, a serial cAMP standard in assay stimulation regulator is diluted and added to separate the empty cells in the assay plate (20 μL / cell). The cAM P standard allows the quantification of cAMP generated in CHO cells. K1 -C RTh2. The assay plate is incubated at room temperature on a shaker for 60 minutes. Cell lysis regulator (Lysis regulator: Milli-Q H2O, 5 mM HEPES, 0.3% Tween-20, 0.1% human serum albumin) is added to a mixture of counts (with anti-aging acceptor count content). Alphascreen ™ cAMP, 0.06 units / μL, donor beads covered with streptavidin 0.06 units / μL, biotinylated cAMP 0.06 units / μL, 10 μM I BMX) prepared under dark conditions for 60 minutes before addition to the assay plate. The resulting lysis mixture is added to all the cells in the assay plate (40 μL / cell). The assay plate is sealed with Topseal-S ™ and incubated in the dark at room temperature on a shaker for 45 minutes. Then, the plate is counted using a Packard Fusion ™ instrument. The resulting per minute counts are converted to cAMP nM using the conventional prepared cAMP curve. The IC50 values (concentration of the CRTh2 antagonist required to inhibit 50% of the PGD2-mediated attenuation of the accumulation of forskolin-induced cAMP in CHO cells) are then determined.

CRTh2) using the Prism ™ software. The compounds of the Examples presented below generally have Ki values in the SPA binding assay below 1 μM. For example, the compounds of Examples 2, 4 and 5 have Ki values of 0.008, 0.052, and 0.036 μM respectively. The compounds of the Examples which are presented below generally have I C 50 values in the functional assay below 1 μM. For example, the compounds of Examples 2, 4 and 5 have I C50 values of 0.073, 0.033, and 0.099 μM respectively. The compounds of the formula (I), in free or salt form, are modulators of the chemoattractant receptor CRTh2 coupled to the G protein, expressed in Th2, eosinophil and basophil cells. PGD2 is the natural ligand for CRTh2. In this way, modulators that inhibit the binding of CRTh2 and PGD2 are useful in the treatment of allergic and anti-inflammatory conditions. The treatment according to the invention can be symptomatic or prophylactic. "Modulators" as used herein are intended to encompass antagonists, agonists, partial antagonists and / or partial agonists. Preferably, the modulars are antagonists. Accordingly, the agents of the invention are useful in the treatment of inflammatory or obstructive diseases of the respiratory tract, resulting, for example, in the reduction of tissue damage, inflammation of the respiratory tract, bronchial hyperreactivity, remodeling or evolution of the disease. Inflammatory or obstructive diseases of the respiratory tract to which the present invention is applicable include asthma of any type or genesis, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis-asthma, exercise-induced asthma, occupational asthma, and induced asthma after a bacterial infection . The treatment of asthma should also be understood as encompassing the treatment of subjects, for example, children under 4 or 5 years of age, who present symptoms of wheezing and who are diagnosed or who can be diagnosed as "whistling infants", a category of established patient of great medical concern and now usually identified as incipient or early phase asthmatics. (For convenience, this particular asthmatic condition is called "whistling infant syndrome"). The prophylactic efficacy in the treatment of asthma will be evidenced by the reduced frequency or by the severity of the symptomatic attack, for example, of the asthmatic or bronchoconstrictor attack, improved lung function or improved airway hyperreactivity. In addition, it can be evidenced through the reduced requirement of another symptomatic therapy, that is, a therapy for or that aims to restrict or address the symptomatic attack when it occurs, for example, anti-inflammatory (for example, corticosteroids) or bronchodilator. The prophylactic benefit in asthma, in particular, may be evident in patients prone to "dripping in the morning". The "morning drip" is a recognized asthmatic syndrome, common for a substantial percentage of asthmatics and characterized by asthma attacks, for example, between 4-6 a. m. , that is, at a normal time and substantially distant from any previously administered symptomatic asthma therapy. Other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary diseases. of the respiratory tract (COPD), including chronic bronchitis or dyspnea associated with it, emphysema, as well as exacerbation of airway hyperresponsiveness (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive airways consistent with another drug therapy, in particular, another inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of any type or genesis including, for example, acute, arachidic, catarrhal, croupy, chronic or phynoid bronchitis. In addition, inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory disease of the lungs, commonly occupational, often accompanied by airway obstruction, either chronic or watery, and occasioned by repeated inhalation of powders) of any type or genus, including, for example, alumnosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. With regard to its anti-inflammatory activity, in particular, in relation to the inhibition of eosinophilic activation, the agents of the invention are also useful in the treatment of eosinophil-related disorders, e.g. eosinophilia, in particular, disorders related to airway eosinophils, for example, involving morbid eosinophilic infiltration of pulmonary tissues including hypereosinophilia since it affects the respiratory tract and / or lungs, as well as, for example, disorders related to eosinophils of the respiratory tract resulting from or concomitant with the Lóffler syndrome; eosinophilic pneumonia; infestation of parasites, in particular metazoans, including tropical eosinophilia; bronchiopulmonary aspergillosis; polyarteritis nodosa including Churg-Strauss syndrome; eosinophilic granuloma; and disorders related to eosinophils that affect the respiratory tract caused by drug reaction. The agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitive angitis, urticaria, bullous pemphigoid, lupus erythematosus, pemfisus, epidermolysis bullosa adq uirida and other inflammatory or allergic conditions of the skin. The agents of the invention can also be used for the treatment of other diseases and conditions, in particular diseases or conditions that have an inflammatory component, for example, treatment of diseases and diseases of the eye, such as conjunctivitis, dry keratoconjunctivitis and conjunctivitis.

Spring diseases that affect the nose, including allergic rhinitis; and inflammatory diseases, in which autoimmune reactions are involved or have an autoimmune component or etiology, including autoimmune hematological disorders, for example hemolytic anemia, aplastic anemia, pure red blood cell anemia and idiopathic thrombocytopenia; systemic lupus erythematosus; polychondritis; scleroderma; Wegener's granulamatosis; dermatomyositis; chronic active hepatitis; My patient had severe, Steven-Johnson syndrome; idiopathic sprue; autoimmune inflammatory enteropathy, for example, ulcerative colitis and Crohn's disease; Endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis; chronic hypersensitive pneumonitis; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior); dry keratoconjunctivitis and spring keratoconjunctivitis; interstitial pulmonary fibrosis; psoriatic arthritis; and glo erulonef ritis, with and without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or minal-change nephropathy. Other diseases or conditions that can be treated with agents of the invention include septic shock; rheumatoid arthritis; osteoarthritis; proliferative diseases, such as cancer; mastocytosis, atherosclerosis; allograft rejection after transplantation; attacks; obesity; restenosis; diabetes, for example, type I diabetes mellitus (juvenile diabetes) and type I diabetes mellitus; diarrheal diseases; ischemic damage / revascularization; retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy; and conditions characterized by pressure Elevated infraocular or ocular aqueous humor secretion, such as glaucoma. Other diseases or conditions that can be treated with agents of the invention include neuropathic pain as described in WO 05/102338. The effectiveness of an agent of the invention for inhibiting inflammatory conditions, for example, in inflammatory diseases of the respiratory tract, can be demonstrated in an animal model, for example, a mouse or rat model, of inflammation diseases of the respiratory tract or other inflammatory conditions, for example, as described by Szarka et al. , J Immunol Methods, Vol. 202, pp. 49-57 (1997); Renzi et al. , Am Rev Respir Dis, Vol. 148, p. 932-939 (1 993); Tsuyuki et a !. , J Clin Invest, Vol. 96, p. 2924-2931 (1995); Cernadas et al. , Am J. Respir Cell Mol Biol, Vol. 20, p. 1-8 (1999); and Williams and Galli, J Exp Med, Vol. 1 92, p. 455-462 (2000). The agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances, such as anti-inflammatory, bronchodilator or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory diseases of the respiratory tract, such as those mentioned above, for example, as enhancers of the therapeutic activity of such drugs or as a means to reduce the required dosage or potential side effects of said drugs. An agent of the invention can be mixed with the other drug substance in a composition fixed pharmaceutical or may be administered separately, before, simultaneously with or after the other drug substance. Accordingly, the invention includes a combination of an agent of the invention as described hereinbefore with an anti-inflammatory, bronchodilator, antihistaminic antitussive drug substance, said agent of the invention and said drug substance being the same pharmaceutical composition or different. Such antiinflammatory drugs include steroids, in particular, glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesodine furoate or mometasone; or steroids described in WO 02/88167, WO 02/1 2266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51 , 60, 67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03/0481 81, WO 03/062259, WO 03/064445 and WO 03/07592; agonists of non-steroidal glucocorticoid receptors, such as described in WO 00/00531, WO 02/1 0143, WO 03/082280, WO 03/082787, WO 03/104195 and WO 04/005229; LTB4 antagonists, such as those described in the U.S. Pat. No. 5,451, 700; LTD4 antagonists, such as montelukast and zafiriukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKine), Roflumilast (Byk Gulden), V-1294A (Napp), BAY1 9-8004 (Bayer), SCH-351 591 (Schering-Plow), Arofylline (Almirall Prodesfarma) , PD 189659 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCI D ™ CC-1 0004 (Celgene), KW-4490 (Kyowa Hakko Kogyo), WO 03/104204 , WO 03/104205, WO 04/000814, WO 04/000839 and WO 04/005258 (Merck), as well as those described in WO 98/18796 and WO 03/39544; A2a agonists, such as those described in EP 1 052264, EP 1 241 1 76, EP 409594A2, WO 94/1 7090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99 / 24450, WO 99/24451, WO 99/38877, WO 99/41 267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/7701 8, WO 00/78774, WO 01/23999, WO 01/271 30, WO 01/271 31, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462 and WO 03 / 086408; A2b antagonists, such as those described in WO 02/42298; and beta (β) -2-adrenoceptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt form or solvate) of the formula (I) of WO 00/751 14, said document being incorporated herein by reference, preferably the compounds of the Examples thereof, especially a compound of the formula: OH and pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of the formula (I) of WO 04/16601. Other ß-2-adrenoreceptor agonists include compounds such as those described in WO 99/64035, WO 01/421 93, WO 01/83462, WO 02/066422, WO 02/070490, WO 02/076933, WO 2004/01 1416 and US 2002/0055651. Such bronchodilator drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CH F 4226 (Chiesi), but also those described in WO 01/041 18, WO 02/51 841, WO 02. / 53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 0424021, US 5171 744 and US 3714357. Such cotherapeutic unique antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, and fexofenadine hydrochloride. Combinations of agents of the invention and steroids, β-2 agonists, PDE4 inhibitors or LTD 4 antagonists can be used, for example, in the treatment of COPD or, particularly, asthma. The combinations of the agents of the invention and anticholinergic or antimuscarinic agents, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonist can also be used, for example, in the treatment of asthma or, particularly, COPD. Other useful combinations of agents of agents of the invention with anti-inflammatory drugs are those with antagonists of quirokin receptors, for example, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, CCR-1 0, CXCR 1, CXCR2, CXCR3, CXCR4 and CXCR5; particularly useful with CCR-3 antagonists, such as those described in WO 2002/026723, especially 4-. { 3 [(S) -4- (3,4-dichlorobenzyl) -morpholin-2-ylmethyl] -ureidomethyl} -benzamide and those described in WO 2003/077907, WO 2003/07939 and WO 2002/102775. Also particularly useful are CCR-5 antagonists, such as the Schering-Plow antagonists SC-351 125, SCH-55700 and SCH-D; Takeda antagonists, such as? / - [[4 - [[[6,7-dihydro-2- (4-methylphenyl) -5H-benzo-cyclohepten-8-yl] carbonyl] amino] phenyl] -methyl chloride ] tetrahydro -? /,? / - dimethyl-2H-pyran-4-aminium (TAK-770); and antagonists of CCR-5, described in US 6166037, WO 00/66558 and WO 00/66559. The agents of the invention can be administered through any appropriate route, for example, orally, for example, in the form of a tablet or capsule; parenterally, for example, intravenously; by inhalation, for example, in the treatment of inflammatory or obstructive diseases of the respiratory tract; intranasally, for example, in the treatment of allergic rhinitis; topically to the skin, for example, in the treatment of atopic dermatitis; or rectally, for example, in the treatment of inflammatory enteropathies. The present invention also provides a pharmaceutical composition comprising a compound of the formula (I) in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or vehicle therefor. The composition may contain a co-therapeutic agent, such as an anti-inflammatory bronchodilator or antihistamine drug as described above. Such compositions can be prepared using conventional diluents or excipients and techniques known in the galenic field. In this manner, oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g., patches. The compositions for inhalation may comprise aerosol formulations or other sprayable formulations or dry powder formulations. When the composition comprises an aerosol formulation, it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant, such as HFA 1 34a or HFA227 or a mixture thereof, and may contain one or more cosolvents known in the art. technique, such as ethanol (up to 20% by weight); and / or one or more surfactants, such as oleic acid or sorbitan trioleate; and / or one or more volumetric agents, such as lactose. When the composition comprises a dry powder formulation, it preferably contains, for example, the compound of the formula (I) having a particle diameter of up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the distribution of desired particle size and a compound that contributes to protection against deterioration of product performance due to moisture. When the The composition comprises a nebulized formulation, preferably containing, for example, the compound of formula (I) either dissolved or suspended, in a vehicle containing water, a cosolvent such as ethanol or propylene glycol, and a stabilizer, which can be a surfactant agent The invention includes: (a) an agent of the invention in inhalable form, for example, in an aerosol composition or other sprayable composition or in inhalable particles, for example, micronized form; (b) an inhalable medicament comprising an agent of the invention in inhalable form; (c) a pharmaceutical product comprising such an agent of the invention in inhalable form in association with an inhalation device; and (d) an inhalation device containing an agent of the invention in inhalable form. The doses of the agents of the invention employed in the practice of the present invention, of course, will vary depending on, for example, the particular condition to be treated, the desired effect and the mode of administration. In general, the daily doses suitable for oral administration are of the order of 0.01-1.00 mg / kg. The invention is illustrated through the following Examples.

EXAMPLES General Conditions LCMS are recorded in an Agilent 1 100 LC system with a Waters Xterra MS C 1 8 4.6 x 100 5 μM column, eluting with 5-95% of 10 mM aqueous ammonium bicarbonate in acetonitrile for 2.5 minutes, with ionization of electroatomization of negative ions or 5-95% of water + 0.1% of TFA in acetonitrile with ionization of electroatomization of positive ions. [M + H] + refers to monoisotopic molecular weights.

Abbreviations EtOH ethanol EtOAc ethyl acetate CH2CI2 dichloromethane HCl hydrochloric acid MgSO4 magnesium sulfate MeCN acetonitrile aq aqueous LiOH lithium hydroxide DMF N, N-dimethylformamide HPLC high performance liquid chromatography NaH sodium hydride Et2O diethyl ether PBr3 phosphorus tribromide NaOH sodium hydroxide THF tetrahydrofuran DMSO dimethyl sulfoxide Et3N triethylamine MeOH methanol H2SO4 sulfuric acid The following examples have been prepared using the procedure described in this R = F except in Example 1 where R a _ = H Example 1 Preparation of [1- (4-methylsulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-indol-3-yl] -acetic acid a) 4-Methanesulfonyl-2-trifluoromethyl-benzaldehyde: 4-Methanesulfonyl-2-trifluoromethyl-benzaldehyde (50.0 g, 0.26 mmol) is added to a suspension of sodium methanesulfonate (29.6 g, 0.29 mol) in DMSO (200 ml) at room temperature. The reaction mixture is heated to 90 °. C for 16 hours. The yellow slurry is poured into water with crushed ice (1 L), then filtered to deliver a white matte powder. b) (4-methanesulfonyl-2-trifluoromethyl-phenyl) -methanol: To a suspension of 4-methanesulfonyl-2-trifluoromethyl-benzaldehyde (49.2 g, 0.20 mmol) in dry EtOH (500 ml), cooled in a bath ice-cold, sodium borohydride (1 0.8 g, 0.22 mmol) is added, in portions for 30 minutes. The reaction mixture is allowed to slowly warm to room temperature and then continue stirring for 16 hours. The reaction mixture is poured into a beaker of chopped ice (700 ml) and adjusted to a pH of 1 with 2N of HCl (approximately 200 ml). The resulting pale yellow suspension is extracted with CH2Cl2 (3 * 1 50 mL), dried (MgSO4) and evaporated to dryness in vacuo, to yield a light yellow solid. c) 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-ene: To a suspension of (4-methanesulfonyl-2-trifluoromethyl-phenyl) -methanol (50.3 g, 0.20 mol) in dry Et2O (400 ml), cooled to 0 ° C, PBr3 (6.5 ml, 0.07 mmol) is added dropwise over 10 minutes. A yellow, sticky, thick suspension forms, which after stirring and warming to room temperature changes to a fine white suspension. The reaction mixture is again cooled to 0 ° C and water (200 ml) is added slowly. The suspension is neutralized at 10 ° C with 4N NaOH aq. (30 mi). The product is collected by filtration to deliver a white solid that is dried at 50 ° C under high vacuum. d) [1- (4-Methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-indol-3-yl] acetic acid methyl ester To a stirring solution of methyl (2-methyl) acid methyl-1 H-indol-3-yl) -acetic acid (2.0 g, 10.5 mmol) in dry DMF (25 mL) at 0 ° C, add NaH dropwise (0.46 g, 1 1 .5 mmol) as a 60% dispersion in mineral oil. The reaction mixture is stirred at 0 ° C for 1.5 hours, then Nal (1.72 g, 1 1 .5 mmol) and 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (3.65) are added. g, 1-1.5 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into water (100 ml) and EtOAc (50 ml) is added. An emulsion is formed that is filtered. Brine (20 ml) is added to the filtrate and the organic phase is separated and dried (MgSO 4). Evaporation in vacuo is delivered as a brown oil. Purification by flash chromatography on silica gel using 5: 1 iso-hexane: EtOAc, increasing the polarity to 3: 1 iso-hexane: EtOAc, gives the desired product; [M + H] + 440. e) [1 - (4-Methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1 H- acid indol-3-yl] -acetic acid To a stirring solution of [1- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-indol-3-yl] -acetic acid methyl ester (440) mg, 1.0 mmol) in 1: 1 THF: MeOH (20 mL) at room temperature, add 1 N aq NaOH. (5 mi). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is evaporated in vacuo, diluted with water (10 ml) and acidified to an acidic pH level with 6N aq HCl. The precipitated product is collected by filtration and recrystallized from 1: 3 isopropyl alcohol: water. The product is dried under high vacuum at 50 ° C; [M + HJ + 426.

Example 2 Preparation of [5-fluoro- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1Hyldol-3-yl] -acetic acid a) (5-fluoro-2-methyl) ethyl ester -1 H-indol-3-yl) -acetic: Using the procedure reported in US 4302589: To a suspension of commercially available 4-fluorophenylhydrazine hydrochloride (1 2.34 g, 78.5 mmol) and levulinic acid (7.70 ml, 75.0 mmol ), EtOH (95 mL), concentrated H2SO4 (7.5 mL) is added. The reaction mixture is refluxed under argon for 22 hours. The reaction mixture is poured into ice water (200 ml), then extracted with dichloromethane (100 ml). The organic phase is rinsed with brine (100 ml), dried (MgSO 4) and concentrated in vacuo. The resulting brown oil is purified by column chromatography on silica gel eluting with / so-hexane / EtOAc (6: 1) to deliver a brown solid.

Clear. Trituration with iso-hexane (4 * 2 mL) gives the main compound as a light yellow solid; [M + H] + 235. b) [5-Fluoro- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-indol-3-yl] -acetic acid ethyl ester: To a stirring solution of ethyl ester of (5-Fluoro-2-methyl-1 H-indol-3-yl) -acetic acid (1000 mg, 0.43 mmol) in dry DMSO (2 mL) at room temperature, sodium hydride (26 mg, 0.65 g) is added. mmol) as a 60% dispersion in mineral oil. After stirring at room temperature for 30 minutes, 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (21 6 mg, 0.68 mmol) (intermediate 1 c) and sodium iodide (1 02 mg, 0.68 mmol) are added. . The reaction mixture is stirred at room temperature for 60 hours. The reaction mixture is poured into water (20 ml) and extracted with EtOAc (20 ml). The organic phase is dried (MgSO4) and evaporated to dryness in vacuo. The crude product is purified by reverse phase chromatography on a C 18 isolute ™ cartridge, eluting at 0-1 00% MeCN in water, using a FlashMaster Personal ™ and GradMaster ™; [M + H] + 472. c) [5-Fluoro- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-indol-3-yl] -acetic acid: To a stirring solution of [5-fluoro] ethyl ester - (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1 H-indol-3-yl] -acetic acid (28 mg, 0.06 mmol) dissolved in THF (1 ml) at room temperature, 2N LiOH aq. (1 mi) The reaction mixture is stir at room temperature for 2 hours and partition between water / EtOAc (20 mL). The aqueous phase is separated and acidified with 1 N of aq HCl with a pH of 4. The product is extracted into EtOAc (20 mL), dried (MgSO4) and evaporated in vacuo; [M + H] + 444.

Example 3 Preparation of acid. { 5-fluoro-2-methyl-1 - [4- (morpholin-4-sulpholinyl) -benzyl] -1H-indol-3-yl} acetic a) 4- (4-bromomethyl-benzenesulfonyl) -morphine To a commercially available 4-bromomethyl benzenesulfonyl chloride stirring solution (1.0 g, 3.71 mmol) in dichloromethane (8 ml) at 0 ° C under an argon atmosphere, triethylamine (0.575 ml, 4.1 mmol) is added in one portion, followed by morpholine (0.359 ml, 4.1 mmol). The reaction mixture is stirred for 20 hours, warming slowly to room temperature. Then, the reaction mixture is diluted with 2N aq HCl. (40 mL) and extracted into dichloromethane (20 mL), dried (MgSO4) and evaporated to dry in vacuo to deliver the main compound. No mass ions are detected. b) Acid. { 5-fluoro-2-methyl-1 - [4- (morpholin-4-sulfonyl) -benzyl] -1 H -indole-3-yl} -acetic: To a stirring suspension of (5-fluoro-2-methyl-1H-indol-3-yl) -acetic acid ethyl ester (100 g, 0.43 mmol) in dry DMSO (1 mL), is added NaH (29 mg, 0.73 mmol). The reaction mixture is stirred at room temperature for 1 5 minutes, after which 4- (4-bromomethyl-benzenesulfonyl) -morpholine (1 36 mg, 0.43 mmol) is added. The reaction mixture is diluted with water (2 ml) and treated with 1 N aq HCl with an acidic pH. The crude reaction mixture is purified by reverse phase chromatography on a C 1 8 isolute ™ cartridge (70 g) eluting at 0-100% MeCN in water using a Flashmaster Personal ™ and GradMaster ™; [M + H] + 448.

Example 4 Preparation of acid. { 1 - [4- (Cyclohexyl-methyl-sulfamoyl) -benzyl] -5-fluoro-2-methyl-1 H-indol-3-yl} -acetic a) Bromomethyl-N-cyclohexyl-N-methyl-benzenesulfonamide: The main compound is prepared analogously to Example 3a by replacing morpholine with N-methylcyclohexamine to yield 4-bromomethyl-N-cyclohexyl-N-methyl-benzenesulfonamide; No mass ions are detected. b) Acid. { 1 - [4- (Cyclohexyl-methyl-sulfamoyl) -benzyl] -5-fluoro-2-methyl-1 H-indol-3-yl} -acetic To a stirring suspension of (5-fluoro-2-methyl-1H-indol-3-yl) -acetic acid ethyl ester (100 g, 0.43 mmol) in dry DMSO (1 mL), NaH is added. (29 mg, 0.73 mmol). The reaction mixture is stirred at room temperature for 15 minutes, after which 4-bromomethyl-N-cyclohexyl-N-methyl-benzenesulfonamide (499 mg, 0.43 mmol) is added. The reaction mixture is diluted with water (10 mL) and treated with 1 N aq HCl with an acidic pH. The product is extracted in 1: 1 EtOAc: Et2O (20 mL), rinsed with brine, dried (MgSO4) and evaporated in vacuo. The crude reaction mixture is purified by preparative MS-directed H PLC to deliver the main compound; [M + H] + 474.

Example 5 Preparation of acid. { 5-fluoro-2-methy1- [4- (pyrrolidine-1-sulfonyl) -benzyl] -1H-indol-3-yl} -acetic The main compound is prepared analogously to Example 4 by replacing N-methylcyclohexamine with pyrrolidone to deliver acid. { 5-fluoro-2-methyl-1 - [4- (pyrrolidine-1-sulfonyl) -benzyl] -1H-indol-3-yl} -acetic; [M + H] + 431.

Example 6 Preparation of acid. { 1 - [4- (Azetidine-1-sulfonyl) -benzyl] -5-fluoro-2-methyl-1 H-indol-3-M} -acetic The main compound is prepared analogously to Example 4 by replacing N-methylcyclohexyl amine with azetidine to deliver acid. { 1 - [4- (Azetidine-1-sulfonyl) -benzyl] -5-fluoro-2-methyl-1 H-indol-3-yl} -acetic. [M + H] + 41 7.

Claims (3)

1 . A compound of the formula (I) in free or salt form, wherein: D is independently selected from CR3 and N; R1 and R2 are, independently, H, halogen or d-C8-alkyl, or R1 and R2, together with the carbon atom to which they are attd, form a C3-C1-carbocyclic group; R3 is selected from d-C8-alkyl, halogen, cyano, hydroxyl, amino, aminoalkyl, amino (di) alkyl, a C3-C group? s-carbocyclic, C? -C8-haloalkyl, d-C8-alkoxy-C? -C8-alkylene and C I -CB-hydroxyalkyl; eR4 is selected from halogen, d-C8-alkyl, d-C8-haloalkyl, a C3-C1-carbocyclic group, a C6-C1-aromatic carbocyclic group, nitro, cyano, d-C8-alkylsulfon; lo, d-C8-alkylsulfonyl, C? -C8-alkoxycarbonyl, d-C8-alkoxy, C? -8-haloalkoxy, carboxy, carboxy-C? -C8-alkyl, amino, C? -C8-alkylanyl, di (d-C8-alkyl) amine, SO2NH2, (C? -C8-alkylamino) sulfonyl, di (d-C8-alkyl) aminosulfonyl, aminocarbonyl, Ci-Cs-alkylaminocarbonyl, di (C? - C8-alkyl) aminocarbonyl and a heterocyclic group consisting of 4 to 10 members; eR5 is independently selected from C? -C8-haloalkyl, -SO2-d-C8-alkyl, -SO2-d-C8-haloalkyl, or a heterocyclic group composed of 4 to 14 members, when n is an integer from 2-3, or R5 is independently selected from when n is 1; p5a and p5b are independently selected from H, a heterocyclic group consisting of 4 to 14 members, a C6-C1-aromatic carbocyclic group, a C3-C15-carbocyclic group, and d -C8-alkyl optionally substituted by a heterocyclic group integrated by 4 to 14 members or a C3-C group? 5-carbocyclic, wherein at least one of R5a or R5b is C? -C8-alkyl substituted by a heterocyclic group consisting of 4 to 14 members or a C3-Ci 5-carbocyclic group, or R5a and R5b together with the atom of nitrogen to which they are attd form a heterocyclic group consisting of 4 to 14 members, p5c p5 and p5e are independently selected from H, and d-C8-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members, C6-d5-aromatic carbocyclic group, or a C3-C1-carbocyclic group, or R5c together with R5d and R5e together with the nitrogen atoms to which they are attd and the carbonyl form a heterocyclic group composed of 5 to 14 members; R5f is H, d -C8-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C? -C8-carbocyclic group composed of 3 to 1 5 atoms; R5g is selected from H, and d -C8-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C1-carbocyclic group; R5f and R59 together with the group NSO2 to which they are attd form a heterocyclic group composed of 5 to 14 members; R5h and R5 'are independently selected from H, and d-C8-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C15-carbcyclic group, or R5 h and R5i together with the NCO group to which they join form a heterocycle composed of 5 to 14 members; R5 'and R5k are independently selected from H, and C? -C8-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C? 5-carbocyclic group, or R5j and R5k together with the nitrogen atom to which they are attd form a heterocyclic group of 4 to 14 members; R5 ', R5m and R5q are independently selected from H, and d-C8-alkyl optionally substituted by a heterocyclic group consisting of 4 to 14 members or a C3-C1-carbocyclic group, or R51 together with R5m or R5q together with the nitrogen atoms of the aminosulfonamide to which they are attd form a C5-d4-heterocyclic group; ^) is selected from a C -C14-heterocyclic group, an aromatic C6-Ci 5-carbocyclic group and a C3-C1-carbocyclic group; R6 is H or d-C8-alkyl optionally substituted by a C3-C15-carbocyclic group, or a C3-C1-carbocyclic group W is a C6-C group? 5-carbocyclic aromatic or a C4-C14-heterocyclic group composed of 4 to 14 members, with the proviso that W is not benzothiazole; X is a bond, C? -C8-alkyl optionally substituted by one or more groups selected from d-C8-alkyl, halo-C? -C8-alkyl, halo, oxo, hydroxyl, amino, aminoalkyl, and emino (dialkyl), (V ^ -T-ÍV), a heterocyclic group composed of 4 to 14 members, a C6-C1-aromatic carbocyclic group, -SO2-, -CONR7 (C, -C8-alkyl) -, or a C3-C15-carbocyclic group; Vi is C? -C7-alkyl optionally substituted by C? -C8- alkyl, halo, oxo, hydroxyl, amino, amino-C? -C8-alkyl, amino (d? -d-C8-alkyl); V is C 0 -C 7 -alkyl optionally substituted by d -C 8 -alkyl, halo, oxo, hydroxyl, amino, amino-d-C 8 -alkyl, amino (di-C C 8 -alkyl); T is oxygen or N R7; R7 is H or d-Cs-alkyl; where each group C3-C? 5-carbocyclic, C3-C? 5-carbocyclic aromatic group and each heterocyclic group consisting of 4 to 14 members, unless otherwise specified, is independently and optionally substituted by one or more groups selected from halo, oxo , hydroxy, cyano, amino, nitro, carboxy, C? -C8-alkyl, halo-C? -8-alkyl, C? -8-alkoxy, d-C8-alkylcarbonyl, C? -8-alkylsulfonyl, SO2NH2, (C?-C8-alkylamino) -sulfonyl, di (C?-C8-alkyl) aminosulfonyl, aminocarbonyl, C?-C8-alkylaminocarbonyl and di (d-C8-alkyl) aminocarbonyl, a C3-C1 group -carbocyclic, a C6-d s-carbocyclic aromatic group, a heterocyclic group composed of 4 to 14 members, cyano-C? -C8-alkyl, hydroxyl-C8-alkyl, d-C8-haloalkyl, amino -Ci-Cs-alkyl, amino (hydroxy) C? -C8-alkyl and d-C8-alkoxy optionally substituted by aminocarbonyl; m is an integer from 0-3; n is an integer from 1 -3; and p is an integer from 0-4.

2. A compound of the formula (I), wherein the compound of the formula in free or salt form, R4a is H or halogen; X is -CH2-; W is an aromatic C6-C16 carbocyclic group; each R5 is selected from d-C8-haloalkyl, and -SO2-d-C8-alkyl, or "Re is where R5j and R5k together with the nitrogen atom or to which they are attached form a heterocyclic group composed of to 6 members, where the heterocyclic group consisting of 4 to 6 members can optionally be substituted by Ci- C8-alkyl, or R5j and R5k are independently selected from Ci- C8-alkyl when n is 1, or when n is an integer from 2-3, each R5 is independent where R5j and R5k together with the nitrogen atom to which R "v., N. join form a heterocyclic group composed of 4 to 6 S, R5" ° or members, where the group heterocyclic composed of 4 a 6 members can be optionally substituted by d-C8-alkyl, or R5j and R5k are independently selected from d-C8-alkyl.

3. A compound of the formula (I) according to the claim 2, where the compound is of the formula (la) wherein R4a is H or fluorine, R9 is H or C? -C8-haloalkyl, and R8 is selected from -S02-d-C8-alkyl, A compound according to claim 1, substantially described with reference to any of Examples 5 A compound according to any of claims 1 to 4 for use as a pharmaceutical 6 Pharmaceutical compositions comprising a compound according to any of claims 1 to 4 7 Use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of a disease mediated by the CRTh2 receptor. 8. The use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of a neuropathic pain. 9. The use of a compound according to any of claims 1 to 4 in the manufacture of a medicament for the treatment of an inflammatory or allergic condition, particularly an inflammatory or obstructive airway disease. 10. A process for the preparation of compounds of the formula (I) according to claim 1, in free or salt form, comprising the steps for: (i) (A) for the preparation of compounds of the formula (I) , wherein R6 is H, cleaving the ester group -COOR6 in a compound of the formula (I), where R6 is d-C8-alkyl optionally substituted by C3-C1-5-carboxylic, or a C3-C1-carboxylic group, and R1, R2, R4, R5, D, W, X, m and n are as defined above; or (B) for the preparation of compounds of the formula (I), wherein R6 is d-C8-alkyl optionally substituted by a C3-C15-carbocyclic group which reacts a compound of the formula (I I) where R6 is -C8-alkyl-alkyl optionally substituted by a C3-C1-carclic group, or a C3-C1-carclic group; and R1, R2, R4, A, D and m are as defined above with a compound of the formula (III) G-X-W- (R5) n (III) where G is a leaving residue, for example, a halogen atom; and R5, W, X and n as defined above; and (ii) recovering the resulting compound of formula (I) in free or salt form. SUMMARY Compounds of the formula (I) in free or salt form are provided according to the invention, wherein R 1, R 2, R 4, R 5, R 6, D, X, W, m and n are as described in the specification, process to prepare them, and their use as pharmacists.