MXPA06009400A - Therapeutic agents - Google Patents

Abstract

The present invention relates to compounds of formula (I) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Description

DERIVATIVES OF 1, 5-DIFENILPIRAZOL REPLACED IN POSITION 3 USEFUL AS CB1 MODULATORS FIELD OF THE INVENTION The present invention relates to certain compounds of the formula I, to processes for preparing said compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION It is known that some EC modulators (known as antagonists or inverse agonists) are useful in the treatment of obesity, psychiatric and neurological disorders.

(WO01 / 70700 EP 658,546 and EP 656,354). However, there is a need for EC modulators with improved physicochemical properties and / or DMPK properties and / or improved pharmacodynamic properties. Pyrazoles that have anti-inflammatory activity are described in WO documents 95/15316, WO96 / 38418, WO97 / 1 1704, WO99 / 64415, EP 418 845 and WO2004050632. WO2004050632 discloses [2- [4- [3- [(ethylmethylamino) carbonyl] -1- (4-methoxyphenyl) -1H-pyrazol-5-yl] -phenoxy] -ethyl] carbamate, 1-dimethylethyl, 5- [4- (2-Aminoethoxy) phenyl] -N-ethyl-1- (4-methoxyphenyl) -N-methyl-1 H-pyrazole-3-carboxamide, 1 - [[5- [4- (2- aminoethoxy) phenyl] -1- (4-methoxyphenyl) -1 H -pyrazol-3-yl] carbonyl] piperidin and [2- [4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1 H-pyrazol-5-yl] -phenoxy] ethyl] -carbamic acid 1,1-dimethylethyl carbamate. All compounds exemplified in WO2004050632 and salts thereof are excluded from the scope of the claims of the compound of the present invention. It is disclosed that the 1,5-diarylpyrazole-3-carboxamide derivatives have CB modulating activity! in US 5,624,941, WO01 / 29007, WO2004 / 052864, WO03 / 020217, US 2004/01 19972, Journal of Medical Chemistry, 46 (4), 642-645 2003, Bioorganic & Medicinal Chemistry Letters, 14 (10), 2393-2396 2004, Biochemical Pharmacology, 60 (9), 1315-1323 2000, Journal of Medicinal Chemistry, 42 (4), 769-779 1999 and U.A. 2003199536.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to a compound of the formula (I) and pharmaceutically acceptable salts thereof, wherein R1 represents a) a C?, 3 alkoxy group substituted with one or more of the following i) fluoro ii) a group NRcRd in which Rc and R independently represent H, a C 1-6 alkyl group or a C 1-6 alkoxycarbonyl group with the proviso that one of R c and R d is different from H or iii) a 1,3-dioxolan-2-yl group b) R 1 represents an alkoxy group of C4-6 optionally substituted with one or more of the following i) fluoro ii) a group NRcRd in which Rc and Rd independently represent H, a C1-6 alkyl group or a C1-6 alkoxycarbonyl group with the proviso that one of Rc and Rd is different from H or iii) a 1,3-dioxolan-2-yl group c) a group of the formula in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1 , 2 or 3 groups represented by Z, d) a group R5S (O) 2O or R5S (O) 2NH in which R5 represents a C1-6 alkyl group optionally substituted with one or more fluoro , or R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z e) a group of the formula (R6) 3 Si in which R6 represents a C1-6 alkyl group 6 which may be the same or different of) a group of the formula RbO (CO) O in which Rb represents a C 1-6 alkyl group optionally substituted with one or more fluoro; Ra represents halogen, an alkyl group of C? -3 or an alkoxy group of C? _3; m is O, 1, 2 or 3; R 2 represents an alkyl group of C 1-3, a alkoxy group of 0 3, hydroxy, nitro, cyano or halogen n is 0, 1, 2 or 3; R3 represents a) a group X-Y-NR7R8 in which X is CO or SO2, Y is absent or represents NH optionally substituted with a C1-3 alkyl group; and R7 and R8 independently represent: an alkyl group of C6-6 optionally substituted with 1, 2, or 3 groups represented by W; a C3-15 cycloalkyl group optionally substituted with 1, 2, or 3 groups represented by W; a cycloalkyl (C3.15) -alkylene group of C? -3 optionally substituted with 1, 2, or 3 groups represented by W; a group - (CH2) r (phenyl) s in which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and phenyl groups, independently, they are optionally substituted with one, two or three groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen in which the heterocyclic group is optionally substituted with one or more C1-3 alkyl, hydroxy or benzyl groups; a group - (CH2) tHet in which t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted with one or more C1-3 alkyl groups and Het represents an aromatic heterocycle optionally substituted with one , two or three groups which are selected from C1-5 alkyl group, a C5 alkyl alkoxy group or halogen group in which the alkyl and alkoxy group are optionally substituted, independently, with one or more fluoro; or R7 represents H and R8 is as defined above; or R7 and R8 together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or additional nitrogen; wherein the heterocyclic group is optionally substituted with one or more C? -3 alkyl, hydroxy, fluoro or benzyl groups; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl, each optionally substituted with 1, 2 or 3 Z groups; R4 represents H, halogen, hydroxy, cyano, an alkyl group of C6-6, a C1-6 alkoxy group or a (C1-6) alkoxy-C1-6alkylene group which contains a maximum of 6 carbon atoms , of which, each of said groups is optionally substituted with one or more of fluoro or cyano; Z represents an alkyl group of C? -3, a C1 -3 alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, monoalkylamino or dialkylamino Ct-3, alkylsulfonyl of C? _3, C 1 alkoxycarbonyl, carboxy, cyano, carbamoyl, monoalkyl Ci. 3) -carbamoyl or dialkyl (C?, 3) carbamoyl and acetyl; and W represents hydroxy, fluoro, an alkyl group of C? -3, an alkoxy group of C? -3, amino, monoalkylamine of C1-3 or dialkylamino of C1-3, a group alkoxycarbonyl of C1-6 or a heterocyclic amine which is selected from morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl in which the heterocyclic amine is optionally substituted with an alkyl group of C1.3 or hydroxyl; but excluding [2- [4- [3 - [(ethylmethylamino) carbonyl] -1- (4-methoxyphenyl) -1 H -pyrazol-5-yl] phenoxy] ethyl] carbamate 1,1-dimethylethyl and [2- [4- [1 - (methoxy-en-l) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl] -phenoxy] -ethyl] -carbamic acid-1,1-dimethylethyl ester. In one embodiment, the invention relates to a compound of the formula (I) and pharmaceutically acceptable salts thereof, wherein R1 represents a) a C? -3 alkoxy group substituted with one or more fluoro or C4.6 alkoxy group optionally substituted by one or more fluoro, b) a group of the formula phenyl (CH2) pO- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, c) a group R5S (O) 2O or R5S (O) 2NH in which R5 represents a C1-6 alkyl group optionally substituted with one or more fluoro, or R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z, d) a group of the formula (R6) 3Si in which R6 represents an alkyl group of C? -6 which may be the same or different or e) a group of the formula RbO (CO) O in which Rb represents an alkyl group of C? -6 optionally substituted with one or more fluoro; Ra represents halogen, an alkyl group of C1-3 or an alkoxy group of C1..3, m is 0, 1, 2 or 3; R 2 represents an alkyl group of C 1, a C 1 alkoxy group, hydroxy, nitro, cyano or halogen n is 0, 1, 2 or 3; R3 represents a) a group X-Y-NR7R8 in which X is CO or SO2, Y is absent or represents NH optionally substituted with a C1-3 alkyl group; and R7 and R8 independently represent: a C1-6 alkyl group optionally substituted with 1, 2 or 3 groups represented by W; a C3-1 cycloalkyl group optionally substituted with 1, 2 or 3 groups represented by W; a (C3-15) cycloalkyl-C-optionally substituted alkylene group, optionally substituted with 1, 2, or 3 groups represented by W; a group - (CH2) r (phenyl) s in which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 or otherwise s is 1 or 2 and the phenyl groups are optionally substituted, independently, with one, two or three groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen in which the heterocyclic group is optionally substituted with one or more alkyl groups of C-? _ 3, hydroxy or benzyl; a group - (CH2) tHet in which t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted with one or more C? -3 alkyl groups and Het represents an aromatic heterocycle optionally substituted with one, two or three groups which are selected from C?-5 alkyl group, a C? _ 5 alkoxy group or halogen; or R7 represents H and R8 is as defined above; or R7 and R8 together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or additional nitrogen; wherein the heterocyclic group is optionally substituted with one or more C1.3 alkyl, hydroxy, fluoro or benzyl groups; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl, each optionally substituted with 1, 2 or 3 Z groups; R4 represents H, halogen, hydroxy, cyano, an alkyl group of C6-6, a lower alkoxy group or an alkoxy group (C6-6) -alkylene of C6-6 which contains a maximum of 6 carbon atoms, of which each of the groups is optionally substituted with one or more of fluoro or cyano; Z represents an alkyl group of C3_3, a C3_3 alkoxy group, hydroxy, halogen, trifluromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, C1-3 monoalkylamino or C1-3 dialkylamino, alkylsulfonyl of C1-3, C? -3 alkoxycarbonyl, carboxy, cyano, carbamoyl, C1-3-monoalkylcarbamoyl or dialkylcarbamoyl of C? -3 and acetyl; and W represents hydroxy, fluoro, an alkyl group of C? -3, an alkoxy group of d-3, amino, C1-3 monoalkylamino or dialkylamino of C? _3, a C1-6 alkoxycarbonyl group or a heterocyclic amine which is selected from morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl in which the heterocyclic amine is optionally substituted with a C1-3 alkyl or hydroxyl group. In another embodiment, the invention relates to a compound of the formula (I) and pharmaceutically acceptable salts thereof, wherein R1 represents a) a C3-3 alkoxy group substituted with one or more fluoro or C4-6 alkoxy group optionally substituted with one or more fluoro, b) a group of the phenyl formula (CH2) pO- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, c) a group R5S (O) 2O or R5S (O) 2NH in the which R5 represents an alkyl group of C6-6 optionally substituted with one or more fluoro, or R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z or d) a group of the formula (R6) 3 Si in which R6 represents an alkyl group of d-6 which may be the same or different; R a represents halogen, an alkyl group of C? _3 or an alkoxy group of C? -3; m is 0, 1, 2 or 3; R2 represents a C1-3 alkyl group, a C1-3 alkoxy group, hydroxy, nitro, cyano or halogen; n is 0, 1, 2 or 3; R3 represents a) a group X-Y-NR7R8 in which X is CO or SO2, Y is absent or represents NH optionally substituted with a C1-3 alkyl group; and R7 and R8 independently represent: an C? _ alquilo alkyl group optionally substituted with 1, 2, or 3 groups represented by W; a C3-? 5 cycloalkyl group optionally substituted with 1, 2 or 3 groups represented by W; an optionally substituted C3_3 cycloalkyl (C3.5) -alkylene group, optionally substituted with 1, 2, or 3 groups represented by W; a group - (CH2) r (phen1l) s in which r is 0, 1, 2, 3 or 4, s is 1 when r is 0, otherwise s is 1 or 2 and the phenyl groups are optionally substituted, independently with one, two or three groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen in which the heterocyclic group is optionally substituted with one or more C? -3 alkyl groups, hydroxy or benzyl; a group - (CH2) tHet in which t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted with one or more C1-3 alkyl groups and Het represents an aromatic heterocycle optionally substituted with one , two or three groups which are selected from C 1 -C 5 alkyl group) a C 1 alkoxy group or halogen; or R7 represents H and R8 is as defined above; or R7 and R8 together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or additional nitrogen; wherein the heterocyclic group is optionally substituted with one or more C? -3 alkyl, hydroxy, fluoro or benzyl groups; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl, of which each is optionally substituted with 1, 2 or 3 Z groups; R4 represents H, an alkyl group of C6-6, a C1-6 alkoxy group or an alkoxy group (C6-6) alkylene of Cs containing a maximum of 6 carbon atoms, of which, each one of the groups is optionally substituted with one or more of fluoro or cyano; Z represents an alkyl group of C3-3, a C1-3 alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, C1-3 monoalkylamino or C1-3-dialkylamino, alkylsulfonyl of C? -] C3_3 alkoxycarbonyl, carboxy, cyano, carbamoyl, C1-3 monoalkylcarbamoyl, or C1-3 dialkylcarbamoyl and acetyl; and W represents hydroxy, fluoro, a C1-3 alkyl group, a C1.3 alkoxy group, amino, C1-3 monoalkylamino or C3-3 dialkylamino, or a heterocyclic amine selected from morpholinyl, pyrrolidinyl , piperidinyl or piperazinyl in which the heterocyclic amine is optionally substituted with a C1-3 alkyl or hydroxyl group. In particular groups of compounds of the formula (I) described in the three previous modalities, R3 represents a group as described in paragraph a) above. In additional particular groups of compounds of these three previous embodiments in which R3 represents a group as described in paragraph a) above, the compounds in which R3 represents N, N-dialkylcarbamoyl of C1-6 or R3 represents a group XY -NR7R8 in which X is CO, Y is absent and R7 and R8 together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following : oxygen, sulfur or additional nitrogen; wherein the heterocyclic group is optionally substituted with one or more C1-3 alkyl, hydroxy, fluoro or benzyl groups; They are excluded. Even in particular groups of compounds of formula I described in the first three embodiments above, R3 represents piperidin-1-carbamoyl. It will be understood that in cases where a substituent Z is present in more than one group, these substituents are selected independently and may be the same or different. The same applies to W. Similarly when m is 2 or 3 then the groups Ra are selected independently so that they can be the same or different and likewise when n is 2 or 3 then the groups R2 are they select independently so that they can be equal or different. The term cycloalkyl of C3-? 5 includes monocyclic, bicyclic, tricyclic and spiro systems, for example, cyclopentyl, cyclohexyl and adamantyl. The term "heteroaryl" means an aromatic 5-, 6- or 7-membered monocyclic ring or a 9- or 10-membered bicyclic ring, with up to five ring heteroatoms selected from oxygen, nitrogen, and sulfur. Suitable aromatic heteroaryl groups include, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenil. , benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl. Preferably furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1, 3,5-triazenyl and more preferably pyrrolyl, thienyl, imidazolyl, oxazolyl or pyridyl. Suitable 5- to 8-membered heterocyclic groups saturated or partially unsaturated containing one or more heteroatoms selected from nitrogen, oxygen or sulfur include, for example, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-1,3-thiazoly, 1,3-thiazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazolin, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, more preferred tetahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-3-yl, morpholino, piperidino, piperidin-4-yl or piperazin-1 - ilo. Suitable groups in which R 1 represents a group R 5 S (O) O in which R 5 represents an alkyl group of d-6 optionally substituted with one or more fluoro include methanesulfonyloxy, ethanesulfonyloxy, n-propylsulfonyloxy, n-butylsulphonyloxy, 3- methyl b uta n-1-sulfonyloxy, 3,3-dimethylbutan-1-sulfonyloxy, fluoromethylsulfonyloxy, difluoromethylsulfonyloxy, trifluoromethylsulfonyloxy, mono, di or tri (fluoroethyl) sulfonyloxy, 3,3,3-trifluoropropy 1-1-sulphonyloxy, or 4,4,4-trifluorobutyl-1-sulfonyloxy. Suitable groups in which R1 represents a C? -3 alkoxy group substituted with one or more fluoro or C _6 alkoxy group optionally substituted with one or more fluoro include butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluromethoxy, trifluoromethoxy, trifluoroethoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy and 6,6,6-trifluorohexyloxy. Suitable groups in which R1 represents a group R5S (O) 2O in which R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z include phenylsulfonyloxy, thienylsulfonyloxy or pyridylsulfonyloxy optionally replaced with 1, 2 or 3 groups represented by Z. In a particular group of compounds of the formula I, R1 represents a) a Ci-β alkoxy group substituted with one or more of the following i) fluoro, i) a NRcRd group in wherein Rc and Rd independently represent H, a C1-6 alkyl group or an alkoxycarbonyl group of d-6 with the proviso that one of Rc and Rd is different from H or iii) a 1! 3-dioxolan- 2-ilo! b) R1 represents a C6 alkoxy group optionally substituted with one or more of the following i) fluoro, ii) a group NRcRd in which Rc and Rd independently represent H, a C1-6 alkyl group or alkoxycarbonyl group of d-6 with the proviso that one of Rc and Rd is different from H or iii) a 1,3-dioxolan-2-yl group, c) a R5S (O) 2O group in which R5 represents an alkyl group of d.6 optionally substituted with one or more fluoro, or R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z, d) a group of the formula RbO (CO) O wherein Rb represents an alkyl group of d6 optionally substituted with one or more fluoro; Ra represents halogen; m is 0, 1, 2 or 3; R2 represents halogen; n is 0, 1, 2 or 3; R3 represents a group CONR7R8 in which R7 represents H and R8 represents a cycloalkyl group of C3-? 5 optionally substituted with a group represented by W or R8 represents a group - (CH2) t Het in which t is 0 and Het represents pyridyl optionally substituted with one, two or three groups which are selected from optionally substituted C1-5 alkyl group, independently, with one or more fluoro; or R3 represents a group CONHNR7R8 in which NR7R8 represents piperidino or morpholino; and R 4 represents H, halogen or an alkyl group of d 6 which is optionally substituted with one or more fluoro; Z represents halogen; and W represents an alkoxycarbonyl group of Cl-6- A particular group of compounds of the formula I is represented by the formula IA IA in which R1 is a) a C4-β alkoxy group optionally substituted with one or more fluoro, b) a group of the formula phenyl (CH2) pO- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or three groups represented by Z, c) a group R5S (O) 2O or R5S (O) 2NH in which R5 represents a C6 alkyl group optionally substituted with one or more fluoro, or R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z in which Z is as previously defined, d) a group of the formula (R6) 3 Si in which R6 represents a C1-6 alkyl group which may be the same or different or, e) a group of the formula RO (CO) O in which R represents an alkyl group of C? -6 optionally substituted by one or more fluoro; Ra represents halogen and m is 0, 1 or 2; R2a represents chlorine; R2b represents chlorine; R2c represents H or fluoro; R3 represents a group CONHNR7R8 in which NR7R8 represents piperidino or morpholino or R3 represents a group CONHR8 in which R8 represents a C5-7 cycloalkyl group optionally substituted with a C1-6 alkoxycarbonyl group or R8 represents an optionally substituted pyridyl; and R 4 represents H, an alkyl group of d-3 or halogen. A particular group of compounds of the formula I is represented by the formula IA in which R1 is a) a C6 alkoxy group optionally substituted with one or more fluoro, b) a group of the formula phenyl (CH2) pO- wherein p is 1, 2 or 3 and the phenyl ring is optionally substituted with one, two or three groups represented by Z, c) a group R5S (O) 2O or R5S (O) 2NH in which R5 represents a group d-6 alkyl optionally substituted with one or more fluoro, or R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z, d) a group of the formula (R6) 3 If in which R6 represents an alkyl group of d-6 which may be the same or different or e) a group of the formula RbO (CO) O in which Rb represents an alkyl group of d-β optionally substituted with one or more fluoro; Ra represents halogen and m is 0, 1 or 2; R2a represents chlorine; R2b represents chlorine; R2c represents H; R3 represents a group CONHNR7R8 in which NR7R8 represents piperidino or morpholino or R3 represents a group CONHR8 in which R8 represents a C5-7 cycloalkyl group optionally substituted with a C1-6 alkoxycarbonyl group; and R 4 represents a C 1-3 alkyl group or halogen. a further particular group of compounds of the formula I is represented by the formula I B IB in which R1 is a) a C4-6 alkoxy group optionally substituted with one or more fluoro, b) a group of the formula phenyl (CH2) pO- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, c) a group R5S (O) 2O or R5S (O) 2NH in which R5 represents a C1-6 alkyl group optionally substituted with one or more fluoro, or R5 represents phenyl or a heteroaryl group each of which is optionally substituted with 1, 2 or 3 groups represented by Z or d) a group of the formula (R6) 3 Si in which R6 represents a C1-6 alkyl group which it can be the same or different; Ra1 represents halogen or H; Ra2 represents halogen or H; R2a represents chlorine; R2b represents chlorine; R2c represents halogen or H; R3 represents a group CONHN R7R8 in which NR7R8 represents piperidino; and R4 represents a C1-3 alkyl group. In a particular group of compounds of formula I, formula IA or formula IB, R1 represents a C4-6 alkoxy group optionally substituted with one or more fluoro. In a further particular group of compounds of the formula I, formula IA or formula IB, R1 represents a group R5S (O) 2O or R5S (O) 2NH in which R5 represents an alkyl group of C? -6 optionally substituted with one or more fluoro, or R 5 represents a heteroaryl group optionally substituted with 1, 2 or 3 groups represented by Z. In a still further group R 1 represents a group R 5 S (O) 2 O in which R 5 represents a C 1-6 alkyl group optionally substituted with one or more fluoro. In a particular even additional group of compounds of the formula I, formula IA or formula IB, R 1 represents a group of the formula (R 6) 3 in which R 6 represents an alkyl group of d-6 which may be the same or different. A particular group of compounds of the formula I is represented by the formula IC IC in which R1 is a) a C6 alkoxy group optionally substituted with one or more fluoro, b) a R5S (O) 2O group in which R5 represents a C1-6 alkyl group optionally substituted with one or more fluoro; R2a represents chlorine; R2 represents chlorine; R3 represents a group CONHNR7R8 in which NR7R8 represents piperidino or morpholino; and R 4 represents an alkyl group of C 1-3 or halogen. In a particular group of compounds of the formula IC, R1 is a group R5S (O) 2O in which R5 represents a C1-6 alkyl group substituted with one or more fluoro. More particularly, R1 is a group R5S (O) O in which R5 represents a C3-6 alkyl group substituted with one or more fluoro. Additional values of R1, R2, R3, R4 and Ra in the compounds of formula I, formula IA, formula I B, or formula IC are indicated below. It will be understood that said values may be used in cases where it is appropriate with any of the definitions, claims or modalities defined later in the present invention or previously therein. R1 represents 4,4, 4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsulfonyloxy, 4,4,4-trifluorobutyl-1-sulphonyloxy, 3,3, 3-trifluoropropyl-1-sulphonyloxy, propoxycarbonyloxy, 2- (1, 3 -dioxolan-2-yl) ethoxy, N-ethyl-2-aminoethoxy, N-tert-butoxycarbonyl-N-ethyl-2-aminoethoxy, 3-methylbutan-1-sulfonyloxy, 3,3-dimethylbutan-1-sulfonyloxy, -chloro-2-thienylsulfonyloxy, 2-thienylsulfonyloxy or 3-pyridylsulfonyloxy. R1 represents a C4_6 alkoxy group substituted with one or more fluoro. R represents 4,4,4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsul- onyloxy, 4,4,4-trifluorbutoyl-1-sulphonoyloxy, 3,3,3-trifluoropropy- 1 -sulfonyloxy, propoxycarbonyloxy, 2- (1 , 3-dioxolan-2-yl) ethoxy, N-ethyl-2-aminoethoxy, or N-tert-butoxycarbonyl-N-ethyl-2-aminoethoxy.

R1 represents 4,4,4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsulfonyloxy, 4,4,4-trifluorobutyl-1-sulphonyloxy, 3,3,3-trifluoropropyl-1-sulphonyloxy or propoxycarbonyloxy. R1 represents 4,4,4-trifluorobutoxy, n-butylsulfonyloxy or n-propylsulfonyloxy. R2 represents chloro or fluoro and n is 2 or 3. R3 represents N- (piperidin-1-yl) carbamoyl, 5- (trifluoromethyl) -pyridin-2-yl] -amino} -carbonyl, morpholin-4-ylcarbamoyl or N- (1-methoxycarbonyl-1-cyclopentyl-carbamoyl) R4 represents C1-4 alkyl or halogen, R4 represents methyl or bromine, m is 0 or when m is 1 or 2, Ra represents a fluoro.In a further particular group of compounds of formula I, formula IA, formula IB or formula IC or any embodiments thereof, R3 represents N- (piperidin-1 -yl) -carbamoyl. "Pharmaceutically acceptable salt", in cases where such salts are possible, it includes both pharmaceutically acceptable basic and acid addition salts A suitable pharmaceutically acceptable salt of a compound of the formula I is, for example, an acid addition salt of a compound of the formula I which is sufficiently basic, for example an acid addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid, or, for example, a salt of a compound of the formula I which is sufficiently acidic, for example an alkaline or alkaline earth metal salt such as sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) -amine. Throughout the description and appended claims, a given chemical formula or name should encompass all stereoisomers and optical isomers and racemates thereof as well as mixtures in different proportions of the separated enantiomers, in which said isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as, for example, hydrates. The isomers can be separated using conventional techniques, for example chromatography or fractional crystallization. Enantiomers can be isolated by racemate separation, for example by fractional crystallization, resolution or HPLC. The diastereomers can be isolated by separation of mixtures of isomers, for example, by fractional crystallization, HPLC or flash chromatography. Alternatively, the stereoisomers can be made by chiral synthesis from chiral starting materials under conditions that do not cause racemisation or epimerization, or by conversion into derivatives, with a chiral reagent. All stereoisomers are included within the scope of the invention. All tautomers, in cases where possible, are included within the scope of the invention. The present invention also encompasses compounds that contain one or more isotopes, for example 14C, 1 1 C or 19F and their use as labeled compounds in isotopic form for pharmacological and metabolic studies. The present invention also encompasses prodrugs of a compound of formula I which are compounds that are converted to a compound of formula I in vivo. The following definitions should be applied throughout the description and the appended claims. Unless indicated or otherwise stated, the term "alkyl" denotes an alkyl group either straight or branched. Examples of such alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl. Unless indicated or otherwise stated, the term "alkoxy" denotes an O-alkyl group, in which alkyl is as defined above. Unless otherwise stated or stated, the term "halogen" should mean fluoro, chloro, bromo or iodo. The specific compounds of the invention are one or more of the following: Ester 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazole-3- iI] butan-1-sulfonic acid phenyl; 1 - (2,4-Dichlorophenyl) -4-methyl-5- [4- (4,4,4-trifluorobutoxy) phenyl] -1H-pyrazole-3-carboxylic acid piperidin-1-alamide; Ester 4- [2- (2,4-dichloro-phenyl) -4-methyl-5- (piperidin-1-l-carbamoyl) 2H-pyrazol-3-yl] -phenyl acid of propan-1 - sulfonic; Ester 4- [2- (2,4-dichlorophenol) -4-methyl-5- (morpholin-4-yl-carbamoyl) -2H-pyrazol-3-yl] phenyl of propane-1-sulfonic acid; Ester 4-3- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-yl] -phenyl acid of 3,3,3-trifluoropropan- 1-sulfonic; 4-4- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-yl] -phenyl ester of 4,4,4-trifluorobutan- 1-sulfonic; Ester [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-yl] -2,6-difluoro-phenyl of propan-1 acid sulfonic; 4- (2- (2,4-Dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester of propan-1-sulfonic acid; Ester 4- [4-bromo-2- (2,4-dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl] -propan-1-sylonic acid; 1 -. { [(1 - (2,4-dichlorophenyl) -4-methyl-5-. {4 - [(propylsulfonyl) oxy] phenyl] -1. 1 H -pyrazol-3-yl) carbonyl] amino} methyl cyclopentanecarboxylate; Propyl ester of the 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester of carbonic acid; 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} phenyl thiophene-2-sulfonate; 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} phenyl-pyridine-3-sulfonate; [2- (4-. {1 - (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-yl-amino) carbonyl] -1 H -pyrazol-5-yl}. Phenoxy ) ethyl butyl tert-butyl carbamate; 1- (2,4-dichloropheni) -5-. { 4- [2- (ethylamino) ethoxy] phenyl} -4-methyl-N-piperidin-1-yl-1 H-pyrazole-3-carboxamid; 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carboyl] -1H-pyrazole-5-yl} phenyl 3-methylbutan-1-sulfonate; 3,3-dimethylbutan-1-sulfonate of 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(p -peridin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} phenyl; 3- [1 - (2,4-dichloro-phenyl) -4-methyl-3- (. {[[5- (trifluoromethyl) pyridin-2-yl] amino] 3,3,3-trifluoropropan-1-sulfonate .}. carbonyl) -1H-pyrazol-5-yl] phenyl; 1 - (2,4-dicorophenii) -5-. { 4- [2- (1, 3-dioxolan-2-yl) ethoxy] phenol} -4-methyl-N-piperidin-1-yl-1 H-pyrazole-3-carboxamide; 4- (2- (2,4-Dichloro-3-fluorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl] -propane-1-sulfonic acid ester; and 5-Chloro-thiophene-2-sulfonic acid ester 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl} ester; as well as pharmaceutically acceptable salts thereof.

Preparation methods The compounds of the formula I in which Ra, R2, R3, R4, m and n are as previously defined and R1 represents a group R5S (O) N H can be prepared by reacting a compound of the formula I I I I wherein Ra, R2, R3, R4, m and n are as previously defined, with an agent for sulfonation of the formula R5SO2L in which R5 is as previously defined and L represents a leaving group, for example chlorine, in a solvent inert, for example dichloromethane, in the presence of a base, for example triethylamine, at a temperature in the range of -25 ° C to 150 ° C. The compounds of the formula I in which R 1 represents a) a d-3 alkoxy group substituted with one or more fluoro or C 4-6 alkoxy group optionally substituted with one or more fluoro or b) a group of the formula phenyl (CH 2) ) pO- in which p is 1, 2 or 3, and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, or c) a group R5S (O) 2O, can be prepared by reacting a compound of the formula lll lll wherein R a, R 2, R 3, R 4, m and n are as previously defined with any of a) an alkylating agent of the formula R 9 X in which R 9 represents an alkyl group of d-3 substituted with one or more fluoro or alkyl group of C4-6 optionally substituted with one or more fluoro and X represents a leaving group, for example chlorine, bromine or iodine, in an inert solvent, for example acetone, in the presence of a base, for example potassium carbonate, at a temperature in the range of -25 ° C to 150 ° C; or b) an alkylating agent of the formula R9X in which R9 represents a group of the formula phenyl (CH2) p- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, and X represents a leaving group, for example chlorine, bromine or iodine, in an inert solvent, for example acetone, in the presence of a base, for example potassium carbonate, at a temperature in the range of -25 ° C up to 150 ° C; or c) an agent for sulfonation of the formula R5SO2L in which R5 is as previously defined and L represents a leaving group, for example chlorine, in an inert solvent, for example dichloromethane, in the presence of a base, for example triethylamine, a temperature in the range of -25 ° C to 150 ° C; respectively. The compounds of the formula I in which Ra, R1, R2, R4, m and n are as previously defined and R3 represents a group XY-NR7R8 in which X is CO, Y is absent or represents NH optionally substituted with an alkyl group of C? _3 and R7 and R8 are as previously defined can also be prepared by reacting a compound of formula IV wherein Ra, R1, R2, R4, m and n are as previously defined and R10 represents an alkyl group of C? -6 with a compound of the formula V R7R8YNH2 V in which Y, R7 and R8 are as previously defined or a salt thereof in an inert solvent, for example toluene, in the presence of a Lewis acid, for example trimethylaluminium, at a temperature in the range of -25 ° C to 150 ° C. The compounds of the formula I in which R3 represents a group XY-NR7R8 in which X is SO, Y is absent or represents NH optionally substituted with an alkyl group of d-3 and R7 and R8 are as previously defined also prepare by reacting a compound of formula VI SAW wherein Ra, R1, R2, R4, m and n are as previously defined and A represents a leaving group, for example halogen, for example chlorine, with a compound of the formula V in which Y, R7 and R8 are as previously defined or a salt thereof in an inert solvent, for example THF or dichloromethane in the presence of a base, for example potassium carbonate, triethylamine or pyridine, at a temperature in the range of -25 ° C to 150 ° C. The compounds of formula I, IV and VI can be prepared using methods analogous to the following method.

It is believed that some intermediary compounds are novel and form part of the present invention. Those skilled in the art will appreciate that during the reaction sequence some functional groups may require protection followed by deprotection at an appropriate stage, see "Protective Groups in Organic Synthesis", 3rd edition (1999) by Greene and Wuts.

PHARMACEUTICAL PREPARATIONS The compounds of the invention are usually administered by the routes of oral, parenteral, intravenous, intramuscular, subcutaneous or other injectable, buccal, rectal, vaginal, transdermal and / or nasal routes and / or by inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending on the disorder and the patient to be treated and the route of administration, the compositions may be administered in varying doses. Appropriate daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001 -10 mg / kg of body weight, preferably 0.01 -1 mg / kg of body weight. Oral formulations, in particular tablets or capsules, are preferred, which can be formulated using methods known to those skilled in the art to provide doses of the active compound in the range of 0.5 mg to 500 mg, for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg. In accordance with a further aspect of the invention, there is also provided a pharmaceutical formulation that includes any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable diluents and / or adjuvants.

Pharmacological Properties The compounds of the formula (I) are useful for the treatment of obesity or the condition of overweight, (for example, promotion of weight loss and maintenance of weight loss), prevention of weight gain (for example induced by medication or following the cessation of smoking), to modulate appetite and / or satiety, eating disorders (eg overeating, anorexia, bulimia and eating due to compulsion), cravings (for drugs, tobacco, alcohol , any macro-nutrients of aperitif type or non-essential food items), for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorders, anxiety, anxiety-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (eg, Gilles de la Tourette syndrome), attention disorders such as ADD / ADHD, stress, and neurological disorders such as dementia and cognitive and / or memory dysfunction (eg, amnesia, Alzheimer's disease, Pick's dementia, aging dementia, vascular dementia, light cognitive impairments, cognitive decline related to age, and mild dementia of aging), neurological and / or neurodegenerative disorders (e.g. multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease and Alzheimer's disease), disorders related to demyelination, neuro-inflammatory disorders (e.g. Guillain Barre syndrome). The compounds are also potentially useful for the prevention or treatment of addiction disorders and behaviors and additives (eg, alcohol and / or drug abuse, pathological gambling habit, kleptomania), drug withdrawal disorders (eg, abstinence from alcohol with or without disturbances of perception, delirium for abstaining from alcohol, abstaining from amphetamines, abstaining from cocaine, refraining from nicotine, abstaining from opioid, abstaining from sedative, hypnotic or anxiolytic agents with or without disturbances in perception, delirium by abstention of sedative, hypnotic or anxiolytic agents; and symptoms of abstention due to other substances), mood disorder, anxiety and / or sleep induced by alcohol and / or drug with onset during abstention, and relapse of alcohol and / or drugs. The compounds are also potentially useful for the prevention or treatment of neurological dysfunctions such as dystonia, dyskinesia, akathisia, tremors and spasticity, treatment of spinal cord damage, neuropathy, migraine, wakefulness disorders, sleep disorders (e.g. disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma. The compounds are also potentially useful for the treatment of immune, cardiovascular disorders (eg atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, heart disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy , myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (for example, conditions that show reduced metabolic activity or a decrease in resting energy expenditure as a percentage of fat-total free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, g lucosa in difficult fasting, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL-cholesterol levels and / or high LDL-cholesterol, low adiponectin levels), reproductive and endocrine disorders (eg treatment of hypogonadism in male individuals, treatment of infertility or as abnormalities / menstrual emeniopathy, contraceptive, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects deficient in GH, hirsutism in female individuals, short stature normal variant) and diseases related to the respiratory systems (for example asthma and chronic obstructive pulmonary disease) and gastrointestinal (for example dysfunction of Gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea a, gall bladder disease, cholelithiasis, gastroesophageal reflux related to obesity, ulcers). The compounds are also potentially useful as agents in the treatment of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast tissue, ovary, endometrium, cervical neck, gallbladder, bile duct), cranial pharynx, Prader syndrome. Willi, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorder and inflammatory disorders (eg arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds are also potentially useful as agents in the treatment of acalacia (esophageal). In another aspect, the present invention provides a compound of formula I as previously defined for use as a medicament. In a further aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment of obesity or the condition of overweight, (eg, promotion of weight loss and maintenance of loss of weight), prevention of weight gain (for example induced by medication or after the cessation of smoking), to modulate appetite and / or satiety, eating disorders (for example, overeating, anorexia, bulimia and eating by compulsion), cravings (for drugs, tobacco, alcohol, any macro-nutrients of aperitif type or non-essential food items), for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorders, anxiety, anxiety-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (for example, Gilles de la Tourette syndrome), attention disorders such as ADD / ADHD, stress, and neurological disorders such as dementia and cognitive and / or memory dysfunction (eg, amnesia, Alzheimer's disease, Pick's dementia, aging dementia, vascular dementia, light cognitive impairments, cognitive decline related to age, and mild dementia of aging), neurological and / or neurodegenerative disorders (e.g. multiple sclerosis, Raynaud's syndrome, in Parkinson's disease, Huntington's disease and Alzheimer's disease), disorders related to demyelination, neuroinflammatory disorders (for example, Guillain-Barré syndrome). The compounds are also potentially useful for the prevention or treatment of addiction disorders and behaviors and additives (eg, alcohol and / or drug abuse, pathological gambling habit, kleptomania), drug withdrawal disorders (eg, abstinence from alcohol with or without disturbances of perception; delirium for abstaining from alcohol; abstention of amphetamines; abstention from cocaine; nicotine abstention; abstention of opioid; abstention of sedative, hypnotic or anxiolytic agents with or without disturbances in perception; delirium by abstaining from sedative, hypnotic or anxiolytic agents; and symptoms of abstention due to other substances), mood disorder, anxiety and / or sleep induced by alcohol and / or drug with onset during abstention, and relapse of alcohol and / or drugs. The compounds are also potentially useful for the prevention or treatment of neurological dysfunctions such as dystonia, dyskinesia, akathisia, tremors and spasticity, treatment of spinal cord damage, neuropathy, migraine, wakefulness disorders, sleep disorders (e.g. disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma. The compounds are also potentially useful for the treatment of immune, cardiovascular disorders (eg atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, heart disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy , myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (for example, conditions that show reduced metabolic activity or a decrease in resting energy expenditure as a percentage of fat-total free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, g lucosa in difficult fasting, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL-cholesterol levels and / or high LDL-cholesterol, low adiponectin levels), reproductive and endocrine disorders (for example treatment of hypogonadism in male individuals, treatment of infertility or as abnormalities / menstrual emeniopathy, contraceptive, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), subjects deficient in GH, hirsutism in female individuals, short stature, normal variant) and diseases related to respiratory systems (for example, asthma and chronic obstructive pulmonary disease) and gastrointestinal (for example, dysfunction of Gastrointestinal motility or intestinal propulsion, diarrhea, emesis, na usea, gallbladder disease, cholelithiasis, gastroesophageal reflux related to obesity, ulcers). The compounds are also potentially useful as agents in the treatment of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast tissue, ovary, endometrium, cervical neck, gallbladder, bile duct), cranial pharynx, Prader syndrome. Willi, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorder and inflammatory disorders (eg arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. In a still further aspect, the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the formula to a patient in need thereof for the prophylaxis or treatment of obesity or overweight condition, (e.g. , promotion of weight loss and maintenance of weight loss), prevention of weight gain (for example induced by medication or after the cessation of smoking), to modulate appetite and / or satiety, eating disorders (for example overeating, anorexia, bulimia and eating for compulsion), cravings (for drugs, tobacco, alcohol, any macro-nutrients of snack type or food items not essentials), for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorders, anxiety, anxiety-depressive disorders, depression, mania, obsessive-compulsive disorders, disorders for the control of Impulse (for example, Gilles de la Tourette syndrome), attention disorders such as ADD / ADHD, stress, and neurological disorders such as dementia and cognitive and / or memory dysfunction (eg, amnesia, Alzheimer's disease, Pick's dementia) , dementia due to aging, vascular dementia, light cognitive impairments, cognitive decline related to age, and mild dementia of aging), neurological and / or neurodegenerative (for example, multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease and Alzheimer's disease), disorders related to de-myelination, neuro-inflammatory disorders (for example, Guillain-Barré syndrome) . The compounds are also potentially useful for the prevention or treatment of addiction disorders and behaviors and additives (eg, alcohol and / or drug abuse, pathological gambling habit, kleptomania), drug withdrawal disorders (eg, abstinence from alcohol with or without disturbances of perception; delirium for abstaining from alcohol; abstention of amphetamines; abstention from cocaine; nicotine abstention; abstention of opioid; abstention of sedative, hypnotic or anxiolytic agents with or without disturbances in perception; delirium by abstaining from sedative, hypnotic or anxiolytic agents; and symptoms of abstention due to other substances), mood disorder, anxiety and / or sleep induced by alcohol and / or drug with onset during abstention, and relapse of alcohol and / or drugs. The compounds are also potentially useful for the prevention or treatment of neurological dysfunctions such as dystonia, dyskinesia, akathisia, tremors and spasticity, treatment of spinal cord damage, neuropathy, migraine, wakefulness disorders, sleep disorders (e.g. disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma. The compounds are also potentially useful for the treatment of immune, cardiovascular disorders (eg atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, heart disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy , myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (for example, conditions that they show reduced metabolic activity or a decrease in resting energy expenditure as a percentage of fat-total free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyper-lipidemia, hyper-triglyceridemia, hyper-uricacidemia, tolerance to glucose difficult tada, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwickian syndrome), type 1 diabetes, type II diabetes, low HDL-cholesterol levels and / or high LDL-cholesterol, low adiponectin levels), reproductive and endocrine disorders (eg treatment of hypogonadism in male individuals, treatment of infertility or as abnormalities / menstrual emeniopathy, contraceptive, polycystic ovarian disease, sexual dysfunction and reproductive in women and men (erectile dysfunction), subjects deficient in GH, hirsutism in female individuals, short stature normal variant) and diseases related to the respiratory systems (for example asthma and chronic obstructive pulmonary disease) and gastrointestinal (for example dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, gastroesophageal reflux related to obesity, ulcers). The compounds are also potentially useful as agents in the treatment of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast tissue, ovary, endometrium, cervical neck, gallbladder, bile duct), cranial pharynx, Prader syndrome. Willi, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorder and inflammatory disorders (eg arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds of the present invention are particularly suitable for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention or reversion of weight gain (e.g., rebounds). , induced by medication or after the cessation of smoking), for modulation of appetite and / or satiety, eating disorders (for example, overeating, anorexia, bulimia and compulsive eating), cravings (towards drugs or drugs, tobacco, alcohol, any macro-nutrient snack type or non-essential food items). The compounds of the formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders such as ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders (e.g. multiple sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease. The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (eg diarrhea). The compounds are also potentially useful as agents in the treatment of indications of extended abuse, addiction and / or relapse, for example to treat dependence on drugs (nicotine, ethanol, cocaine, opiates, etc.) and / or to treat withdrawal symptoms. of drugs (nicotine, ethanol, cocaine, opiates, etc.). The compounds can also eliminate the increase in weight that normally accompanies cessation of smoking. In another aspect, the present invention provides a compound of formula I as previously defined for use as a medicament. In a further aspect, the present invention provides the use of a compound of the formula I in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxiety-depressive disorders , depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders such as ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (eg, multiple sclerosis), disease of Parkinson's disease, Huntington's disease and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (for example diarrhea), and indications of widespread abuse, addiction and / or relapse, for example to treat drug dependence (nicotine, ethane ol, cocaine, opiates, etc.) and / or treat abstinence symptoms of adjectival substances (nicotine, ethanol, cocaine, opiates, etc.). In a still further aspect, the present invention provides a method for treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders. , anorexia, bulimia, attention disorders such as ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. multiple sclerosis), Parkinson's disease, Huntington's chorea and Alzheimer's disease, immune, cardiovascular disorders , reproductive and endocrine, septic shock, diseases related to the respiratory and gastrointestinal systems (eg diarrhea), and indications of widespread abuse, addiction and / or relapse, for example to treat dependence on adjectives (nicotine, ethanol, cocaine, opioids, etc.), and / or to treat symptoms of ab The presence of addictive substances (nicotine, ethanol, cocaine, opiates, etc.) which comprises administering a pharmacologically effective amount of a compound of the formula I to a patient in need of the same. The compounds of the present invention are particularly suitable for the treatment of obesity, for example by reducing appetite and body weight, maintaining weight reduction and preventing rebounding. The compounds of the present invention can also be used to prevent or reverse the weight gain induced by medicament., for example weight gain caused by treatment or anti-psychotic (neuroleptic) treatments. The compounds of the present invention can also be used to prevent or reverse the weight gain associated with cessation of smoking.

Combination Therapy The compounds of the invention can be combined with another therapeutic agent that is useful in the treatment of obesity such as anti-obesity drugs, which affect energy expenditure, glycolysis, gluconeogenesis, glycogenolysis, lipolysis, lipogenesis, fat absorption. , storage of fats, excretion of fats, the mechanisms of hunger and / or satiety and / or cravings, appetite / motivation, food intake, or gastrointestinal motility. The compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidemias, dyslipidemias, diabetes, sleep-light, asthma, cardiac disorders, atherosclerosis, macrovascular and microvascular diseases, steatosis of the liver, cancer, joint disorders, and gallbladder disorders. For example, a compound of the present invention may be used in combination with another therapeutic agent that lowers blood pressure or reduces the LDL ratio: HDL or an agent that causes a decrease in circulating levels of LDL- cholesterol. In patients with diabetes mellitus, the compounds of the invention can also be combined with therapeutic agents used to treat complications related to microangiopathies. The compounds of the invention can also be used together with other therapies for the treatment of obesity and its associated complications of the metabolic syndrome and type II diabetes, these include drugs like biguanide, insulin (synthetic insulin analogs) and oral anti-hyperglycemic agents (these they are divided into prandial glucose regulators and alpha-glucosidase inhibitors). In another aspect of the invention, the compound of formula I, or a pharmaceutically acceptable salt thereof, can be administered in association with a PPAR modulator. PPAR modulating agents include but are not limited to a PPAR alpha and / or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of said salts or prodrugs thereof. Suitable PPAR alpha and / or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of said salts or prodrugs thereof are well known in the art. In addition, the combination of the invention can be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol reducing agent. Cholesterol reducing agents referenced in this application include but are not limited to inhibitors of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase). Appropriately, the HMG-CoA reductase inhibitor is a statin. In the present application, the term "cholesterol-lowering agent" also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive. The present invention also includes a compound of the present invention in combination with an inhibitor of the ileo bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a resin for binding to bile acid. The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel. According to a further aspect of the present invention there is provided a combination treatment comprising administering an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier. , with the simultaneous, sequential or separate administration of one or more of the following agents that are selected from 2: A CETP inhibitor (cholesteryl ester transfer protein); a cholesterol absorption antagonist; an inhibitor of MTP (microsomal transfer protein); a nicotinic acid derivative, including slow release and combination products; a phytosterol compound; probucol; an anticoagulant; an omega 3 fatty acid; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an anti-hypertensive compound for example an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha-adrenergic blocker, a beta-adrenergic blocker, an alpha / beta-adrenergic blocker mixed, an adrenergic stimulant, a calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic or a vasodilator; a modeler of the melanin concentrating hormone (MCH); an NPY receiver modulator; an orexin receptor modulator; a phosphoinositide-dependent protein kinase modulator (PDK); or nuclear receptor modulators (eg, LXR, FXR, RXR, GR, ERRa, β, PPARα, β, and RORalpha), a monoamine-transmitting modulating agent, eg, a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressant agent (TCA), a specific noradrenergic and serotonergic antidrepressant (NaSSA); antisychotic agent for example olanzapine and clozapine, a serotonin receptor modulator, a leptin modulator / leptin receptor, a ghrelin modulator / ghrelin receptor; a DPP-IV inhibitor; or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment. In accordance with a further aspect of the present invention, there is provided a combination treatment comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier. , with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low calorie diets (LCD). Therefore, in a further feature of the invention, a method is provided for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment comprising administering to said animal an amount effective of a compound of the formula I, or a pharmaceutically acceptable salt thereof in simultaneous administration, in sequence or separately with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof.

Therefore, in a further feature of the invention, a method is provided for treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment comprising administering to said animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof in simultaneous administration, in sequence or separately with an effective amount of a compound from one of the other classes of compounds described in this combination section or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof. In accordance with a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a compound derived from one of the other classes of compounds described in this combination section or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier. In accordance with a further aspect of the present invention, there is provided a kit comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a compound derived from one of the other classes of compounds described in this combination section or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof. In accordance with a further aspect of the present invention, a kit is provided comprising: a) a compound of the formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms. In accordance with a further aspect of the present invention, a kit is provided comprising: a) a compound of the formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first dosage form unitary b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate, or prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms. In accordance with another characteristic of the invention, there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof, in the manufacture of a medicament for use in the treatment of obesity and its associated complications in a warm-blooded animal, such as man. In accordance with another characteristic of the invention, there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidemic conditions in a warm-blooded animal, such as man. In accordance with a further aspect of the present invention, there is provided a combination treatment comprising administering an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier. , with the simultaneous administration, in sequence or separately of an effective amount of one of the other compounds described in this combination section, or a salt, solvate, solvate of said salt or a pharmaceutically acceptable prodrug thereof, optionally together with a diluent or pharmaceutically acceptable carrier to a warm-blooded animal, such as man in need of such therapeutic treatment. Also, a compound of the invention can also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity, (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, heart disease, non-alcoholic steato-hepatitis, osteo-arthritis and some cancers) and psychiatric and neurological conditions. It will be understood that there are accepted definitions from the medical point of view of obesity and overweight. A patient can be identified, for example, by measuring the body mass index (BMI), which is calculated by dividing the weight in kilograms between the height in square meters, and comparing the result with the definitions.

Pharmacological activity. The compounds of the present invention are active against the receptor product of the CB1 gene. The affinity of the compounds of the invention for central cannabinoid receptors can be demonstrated in methods described in Devane et al, Molecular Pharmacology, 1988, 34, 605 or those described in WO01 / 70700 or EP 656354. Alternatively, the test can be performed as follows. 10 μg of prepared membranes from stably transfected cells with the CB1 gene are suspended in 200 μl of 100 mM NaCl, 5 mM MgCl 2, 1 mM EDTA, 50 mM HEPES (pH 7.4), 1 mM DTT, 0.1% BSA and 100 μM of GPD. To this is added a concentration of agonist (CP55940) of CE80. The required concentration of the test compound of 0.1 μCi [35 C] -GTP? S. The reaction is allowed to advance at 30 ° C for 45 minutes. The samples are then transferred onto GF / B filters using a cell harvester and washed with buffer for washing (50 mM Tris (pH 7.4), 5 mM MgCl 2, 50 mM NaCl). The filters are then covered with scintillation fluid and counted against the amount of [35 S] -GTP? S retained by the filter. The activity is measured in the absence of all ligands (minimal activity) or in the presence of a CE8o concentration of compound CP55940 (maximum activity). These activities are set as activity of 0% and 100% respectively. At various concentrations of the new ligand, the activity is calculated as a percentage of the maximum activity and plotted. The data are adjusted using the equation y = A (BA) / 1 + ((C / x) UD)) and the Cl50 value is determined as the concentration required to provide the maximum inhibition half of GTP? S binding under the conditions used. The compounds of the present invention are active in the BC1 receptor (Clso < 1 micromolar). The most preferred compounds have IC50 < 200 nanomolar. For example, the IC50 of Example 10 is 6.0 nM and of Example 1 1 is 6.4 nM. It is believed that the compounds of the invention are selective CB 1 antagonists or inverse agonists. Potency, selectivity profile and propensity to side effect may limit the clinical utility of current known compounds that have CB1 antagonist / inverse agonist properties. In this regard, the pre-clinical evaluation of compounds of the present invention in models of gastrointestinal and / or cardiovascular function indicate that they offer significant advantages in comparison with the representative CB 1 inverse antagonist / antagonist agents. The compounds of the invention may provide additional benefits in terms of potency, selectivity profile, bioavailability, plasma half-life, hemato-encephalic permeability, plasma protein binding (eg, higher free drug fraction) or solubility in comparison with representative reference CB1 inverse antagonist / antagonist agents. The utility of the compounds of the present invention in the treatment of obesity and related conditions was demonstrated by a reduction in body weight in obese mice induced by cafeteria diet. C57B 1 / 6J female mice are supplied, ad libitum, access to a dense-calorie "cafeteria" diet (soft chocolate / cocoa-type snacks, fatty cheese and nougat) and normal laboratory food for 8-10 weeks. The compounds to be evaluated are then administered systemically (iv, ip, se or po) once per route for a minimum of 5 days, and the body weights of the mice are monitored on a daily basis. The simultaneous assessment of adiposity is carried out by means of DEXA imaging in the baseline and at the conclusion of the study. Blood sampling is also done to evaluate changes in plasma markers related to obesity.

EXAMPLES Abbreviations AcOH acetic acid DCEM dichloromethane DMF dimethyl formamide DEA diethylamine DI EA N, N-di-isopropylethylamine DMAP 4-dimethylamino pyridine EtOAc ethyl acetate Et 3 N triethylamine Ej or EJ example LiHMDS lithium hexamethyldisilazide MeOH methanol MeCN acetonitrile t.a. or T: At room temperature TEA triethylamine THF tetrahydrofuran t triplet s singlet d doublet q quaint qutette m multiplet br width bs singlet width dm doublet multiplets bt triplet width dd doublet doublets General experimental procedures Mass spectra are recorded on either a single quadrupole Micromass ZQ mass spectrometer or a single quadrupole Micromass ZQ mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS). The 1 H NMR measurements are made on either a Varian Mercury 300 or a Varian Inova 500 spectrometer, which operate at frequencies of 300 and 500 MHz respectively. Chemical shifts are given in ppm with CDCI3 as the standard reference standard. CDCI3 is used as a solvent for NMR unless otherwise indicated. The purification is carried out in a semi-preparative HPLC (High Performance Liquid Chromatography) with a mass activated fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with a C8 column of 19 x 100 mm. The mobile phase used is, if nothing else is indicated, acetonitrile and buffer solution (0.1 M ammonium acetate: acetonitrile 95: 5). For isolating the isomers, a Kromasil CN E9344 column (250 x 20 mm internal diameter) is used. Heptane: ethyl acetate: DEA 95: 5: 0.1 is used as the mobile phase (1 ml / minute). The reaction collection is guided using a UV detector (330 nm).

Typical HPLC parameters for purity analysis: Column: Zorbax Eclipse XDB-C8 150 x 4.6 mm Analysis time: 15 min. Flow: 1.5 ml / minute Mobile phase: A: water 5% MeOH B: MeOH Temperature: 40 ° C Detector: UV at 240 nm EXAMPLES OF THE INVENTION EXAMPLE 1 Step A 1 - (4-benzyloxyphenyl) propan-1 -one 4-hydroxypropiophenone (15.0 g, 0.10 mole) is dissolved in acetone (200 ml) together with potassium carbonate (13.8 g, 0.10 mole). Benzyl bromide (17.1 g, 0.10 mole) is added and the reaction mixture is refluxed overnight. After cooling to room temperature the mixture is filtered and concentrated on the rotary evaporator to obtain 24.0 g (100%) of the title compound as a white solid.

Step B 1- (4-benzyloxyphenyl) -2-bromopropan-1 -one. Suspend 1- (4-benzyloxyfeni) propan-1-one (4.80 g, 20.0 mmol) in acetic acid (25 ml) and cool to 0 ° C. Bromine (3.20 g, 20.0 mmol) is added dropwise and the reaction mixture is stirred for two hours at room temperature, at which point the reaction mixture is a yellow, clear solution. After cooling, water (100 ml) is added and the product is extracted with ether (2 x 100 ml). The combined organic extracts are washed with water, sodium bicarbonate and brine. The organic phase is dried (Na2SO4), filtered and evaporated leaving the title compound as a pale yellow solid (6.17 g, 97%).

Step C 2-F2- (4-Benzyloxy-phenyl) -2-oxo-etip-3-oxo-butyric acid ethyl ester A solution of sodium ethoxide is generated from metallic sodium (0.53 g, 23.0 mmol) ) in 30 ml of absolute ethanol. To this solution is added ethyl acetoacetate (3.00 g, 23.0 mmol) at 0 ° C. After 30 minutes this solution is added to a solution of 1- (4-benzyloxyphenyl) -2-bromo-propan-1 -one (6.17 g, 19.0 mmol) in ethanohtoluene (30: 15 ml) and the reaction mixture Shake during the night. Acid treatment with 1 M HCl, extraction with ethyl acetate (3 x), washing with brine, drying (Na 2 SO 4), filtration and evaporation leaves a crude product which is purified by flash chromatography (hexane: EtOAc 95: 5 - 70:30) which makes it possible to obtain 5.18 g of the title compound as a pale yellow oil.

Step D 5- (4-Benzyloxyphenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid A solution of sodium ethoxide is generated from metallic sodium (0.19 g, 8.26 mmoles) in 20 ml of absolute ethanol. To this solution is added 2- [2- (4-benzyloxyphenyl) -2-oxo-ethyl] -3-oxo-butyric acid ethyl ester (2.13 g, 6.00 mmol) and the reaction mixture is stirred at room temperature for 30 minutes. A previously prepared solution of sodium chloride is added in 5 portions., 4-dichlorophenyldiazonium (prepared from 2,4-dichloroaniline (1.19 g, 7.30 mmol) in 3 ml of 24% HCl and sodium nitrite (0.52 g, 7.50 mmol) in 3 ml of water at 0 ° C) keeping the temperature below 5 ° C. After stirring at room temperature for 2.5 hours, water is added, and the product is extracted with EtOAc (3 x). The combined organic extracts are dried (Na2SO), filtered and evaporated. The residue is dissolved in ethanol (40 ml) and sodium hydroxide (0.80 g, 20.0 mmol) in 10 ml of water is added. After 2 hours of boiling under reflux, the reaction mixture is cooled, acidified with HCl and the product extracted with EtOAc (3 x). After washing, drying (Na2SO4), filtering and concentrating, the residue is purified by flash chromatography (hexane.EtOAc 70: 30-50: 50) which allows to obtain 1.84 g (68% >);) of the title compound as a pale yellow solid.

Step 5- Piperidin-1-yl-amide of 5- (4-benzyloxyphenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid 5- (4-benzyloxyphenyl) is suspended ) -1- (2,4-Dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid (1.84 g, 4.07 mmol) in dichloromethane and a few drops of DMF are added followed by the addition of oxalyl (1.03 g, 8.14 mmol). The reaction mixture is refluxed for two hours. After cooling to room temperature, the solvent is removed and the crude acyl chloride is redissolved in dichloromethane and cooled to 0 ° C. Triethylamine (1.5 ml, 8.20 mmol) is added followed by 1-aminopiperidine (0.5 ml, 4.50 mmol). The cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. Water is added and the product is extracted with dichloromethane (3 x). The combined extracts are dried (Na2SO), filtered and evaporated. Flash chromatography (hexane: EtOAc 80: 20-70: 30) allows to obtain 1.13 g (52%) of the title compound as a solid.

Step F 1- (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-yl-amide Acid piperidin-1-yl-amide is dissolved 5- (4-benzyloxyphenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 1.87 mmol) in 25 ml of absolute ethanol together with 100 mg of palladium on carbon (10% of Pd). The reaction is hydrogenated with a balloon overnight. Filtration, concentration and flash chromatography (hexane: EtOAc 50: 50-EtOAc) allows 0.83 g (100%) of the title compound to be obtained as a solid.

Step G Ester 4-r2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-carbamoyl) 2H-pyrazol-3-n-phenyl of propan-1-sulfonic acid Piperidine is dissolved 1 - (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid 1-l-amide (222 mg, 0.50 mmol) in dichloromethane (10 ml) and triethylamine (0.07 ml, 0.50 mmol) is added. Propanesulfonyl chloride (71 mg, 0.50 mmol) is added at 0 ° C, the cooling bath is removed and the reaction is stirred at room temperature for 2 hours. Water is added and the product is extracted with dichloromethane, dried (Na2SO), filtered and concentrated. Flash chromatography (hexane: EtOAc 70: 30-50: 50) allows a product to be obtained which is recrystallized from hexane: EtOAc to obtain 135 mg (49%) of the title compound as a white solid. P.f.190 ° C. 1 H NMR (CDCl 3): d 7.66 (1 H, broad s), 7.44-7.17 (7H, m), 3.25 (2H, t), 2.90 (4H, m), 2.39 (3H, s), 2.09-1 .97 (2H, m), 1.78 (4H, m), 1.45 (2H, m), 1.17 (3H, t). MS m / z 573 (M + Na) EXAMPLE 2 1- (2,4-Dichlorophenyl) -4-methyl-5-r4- (4,4,4-trifluorobutoxy) -phenn-1 H-pyrazole-3-piperidin-1-yl-amide carboxylic 1 - (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-yl-amide is dissolved from Example 1, Step F (250 mg, 0.56 mmole) in acetone (10 ml) and potassium carbonate (77 mg, 0.56 mmol) was added followed by 1-iodo-4,4,4-tpfluorobutane (140 mg, 0.56 mmol). The reaction mixture is allowed to boil under reflux overnight, concentrated and purified by flash chromatography (hexane: EtOAc 70:30 - 60:40) allowing 130 mg (42%) of a colored solid to be obtained White which is triturated with hexane: EtOAc 95: 5 and filtered. 1 H NMR (CDCl 3): d 7.63 (1 H, broad s), 7.43 (1 H, m), 7.30 (2H, m), 7.10-7.00 (2H, m), 6.85-6.78 (2H, m), 4.05 (2H, t), 2.90 (4H, m), 2.40-2.19 (5H, sym), 2.15-1.97 (2H, m), 1.78 (4H, m), 1.45 (2H, m). MS m / z 577 (M + Na). HPLC: 98.4% EXAMPLE 3 Ester 4-r2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazole-3-in-phenyl butan-1-sulfonic acid 1 - (2,4-Dichlorophenyl) -5- (4-hydroxy-phenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-yl-amide is dissolved, which is prepared as described in Example 1, Step F (350 mg, 0.78 mmol) in dichloromethane (10 ml) and triethylamine (0.1 ml, 0. 78 mmoles). Butanesulfonyl chloride (0.12 g, 0.78 mmol) is added at 0 ° C, the cooling bath is removed and the reaction is stirred at room temperature overnight. Water is added, the product is extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Instant vaporization chromatography (hexane: EtOAc 70: 30-50: 50) allows a product to be obtained which is recrystallized from hexane: EtOAc to obtain 200 mg (45%) of the title compound as a solid. 1 H NMR (CDCl 3): d 7.48-7.19 (8H, m), 3.29 (2H, m), 2.96 (4H, m), 2.41 (3H, s), 2.09-1.97 (2H, m), 1 .81 (4H, m), 1 .64-1 .50 (4 H, m), 1 .02 (3H, t).

EXAMPLE 4 Propan-1-sulfonic acid 4-r2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazole-3-in-phenyl ester Step A 5- (4-Benzyloxyphenyl) -1- (2,4-dichlorophenyl) -4-methyl-1 H-pyrazo-3-carboxylic acid morpholin-4-ylamide To a solution of 5- (4-benzyloxyphenyl) acid ) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid, which is prepared as described in Example 1, Step D (1.118 g, 2.6 mmol) in 25 ml. of CH2Cl2 are added 2 drops of DMF followed by oxalyl chloride (0.44 ml, 5.2 mmol). The mixture is allowed to boil at reflux for 2 hours, cooled to room temperature and evaporated to dryness. The residue is dissolved in 25 ml of CH 2 Cl and cooled to 0 ° C. Triethylamine (0.73 ml, 5.2 mmol) is added followed by 1-aminopiperidine (0.28 ml, 2.9 mmol) and the mixture is stirred at room temperature for 3 hours. Water (100 ml) is added and the mixture is extracted with CH2Cl2 (3 x 50 ml), dried (Na2SO), filtered and concentrated. Flash chromatography (silica, hexane: EtOAc 1: 2, EtOAc) allows 21.5 mg (15%) of the title compound to be obtained as a white solid.

Step B 1- (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 5-morpholin-4-ylamide is dissolved (4-benzyloxyphenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid (215 mg, 0.40 mmol) in 20 ml of CH2Cl2 and cooled to 0 ° C. Boron tribromide (78 μl, 0.80 mmol) is added by dropping and the reaction mixture is stirred at room temperature for 2.5 hours. Water (50 ml) is added and the solution is extracted with EtOAc (3 x 50 ml). The combined organic phases are dried (Na 2 SO 4), filtered and concentrated. Flash chromatography (silica, hexane: EtOAc 1: 2, EtOAc) allows 180 mg (99%) of the title compound to be obtained as a white solid.

Step C Ester 4-f2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazole-3-p-phenyl of propan-1-sulfonic acid It is cooled to 0 ° C a solution of morpholin-4-ylamide of 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid (180 mg, 0.40 mmol) in 10 ml of CH2Cl2. Triethylamine (56 μL, 0.40 mmol) is added followed by 1-propan-sulfonyl chloride (45 μL, 0.40 mmol) and the reaction mixture is stirred at room temperature for 5 hours. Water is added and the mixture is extracted with CH2Cl (3 x 20 ml), dried (Na2SO), filtered and concentrated. Flash chromatography (silica, hexane.EtOAc 1: 2) affords 82 mg (46%) of the title compound as a white solid. 1 H NMR (CDCU): d 7.7 (1 H, s), 7.5-7.4 (1 H, m), 7.4-7.1 (6H, m), 3.9-3.8 (4H, m), 3.3-3.2 (2H, m), 3.0-2.9 (4H, m), 2.4 (3H, s), 2.1-1.9 (2H, m), 1.2 (3H, t). MS m / z 576 (M + Na). HPLC: 98.0%.

EXAMPLE 5 Ester 4-r2- (2,4-dichlorophenyl) -4-methyl-5- (p -peridin-1-ylcarbamoyl) -2H-pyrazole-3-ill-phenyl 3,3,3-trifluoropropanol- 1 - sulfonic Step A 1- (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-yl-amide Acid-piperidin-1-yl-amide is dissolved 5- (4-Benzyloxy-phenyl) -1 - (2,4-dichlorophen-I) -4-methyl-1H-pyrazole-3-carboxylic acid, which is prepared as described in Example 1, Step E (330 mg, 0.62 mmol) in 20 ml of CH2Cl2 and cooled to 0 ° C. Boron bromide (120 μL, 1.24 mmol) is added dropwise and the reaction mixture is stirred at room temperature for 1 hour. Water (50 ml) is added and the solution is extracted with EtOAc (3 x 20 ml). The combined organic phases are dried (Na 2 SO 4), filtered and concentrated. Flash chromatography (silica, hexane: EtOAc 1: 3, EtOAc) allows 130 mg (47%) of the title compound to be obtained as a white solid.

Step B Ester 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-n-phenyl-3,3-dichloric acid 3-trifluoropropan-1-sulfonic acid A solution of 1 - (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1 H- piperidin-1-yl-amide is cooled to 0 ° C. pyrazole -3-carboxylic acid, (130 mg, 0.30 mmol) in 10 ml of CH2Cl2. Triethylamine (42 μl, 0.30 mmol) is added followed by 3,3,3-trifluoropropan-1-sulfonium chloride (59 mg, 0.30 mmol), which is purchased from Manchester Organics (but can also be prepared in a manner analogous to the method described in W0 200010968 for 4,4,4-trifluorobutan-1-sulfonyl chloride), and the reaction mixture is stirred at room temperature for 2 hours, water is added and the mixture is extracted with CH 2 Cl (3 x 20 ml), dried (Na2SO), filtered and concentrated. Flash chromatography (silica, hexane: EtOAc 7: 3, 6: 4) allows to obtain 150 mg (82%) of the title compound as a white solid. P.f. 160 ° C. 1 H NMR (CDCl 3): d 7.7 (1 H, broad s), 7.5-7.2 (7H, m), 3.6-3.5 (2H, m), 3.0-2.7 (6H, m), 2.4 (3H, s) , 1 .9-1 .7 (4H, m), 1 .6-1.4 (2H, m). MS m / z 628 (M + Na). HPLC: 92.5%.

EXAMPLE 6 Ester 4-r2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazole-3-p-phenyl 4,4,4-trifluorobutan-1 - sulphonic. 1- (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid, piperidin-1-yl-amide, is dissolved in dichloromethane (20 ml). is prepared as described in Example 5, Step A (0.49 g, 1.20 mmol), cooled to 0 ° C and triethylamine (0.67 mL, 4.8 mmol) is added followed by 4,4,4-trifluorobutan chloride. -l-sulfonyl, which is prepared as described in WO200010968, (0.38 g, 1.80 mmol). The reaction mixture is stirred at room temperature overnight. Water is added, the product is extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Flash chromatography (hexane: EtOAc 1: 1 -EtOAc) followed by recrystallization (hexane: EtOAc) afforded 0.32 g (43%) of the title compound as a colorless solid. 1 H NMR (CDCl 3): d 7.80 (1 H, broad s), 7.50-7.19 (7H, m), 3.40 (2H, m), 3.05-2.90 (4H, m), 2.50-2.20 (7H, sym) , 1.92-1.70 (4H, m), 1.57-1.40 (2H, m). MS m / z 641 (M + Na) HPLC: 96.5% EXAMPLE 7 Ester r2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-carbamoyl) -2H-pyrazole-3-ip -2, ß-difluorophenyl of propan-1-sulfonic acid Step A 1 - (4-benzylloxy-3, 5-difluorof in yl) -propan-1 -one Dissolve 1 - (3,5-difluoro-4-hydroxyphenyl) -propan-1 -one (5.00 g , 26.9 mmole) in acetone (100 ml) together with potassium carbonate (3.90 g, 28.2 mmol). Benzyl bromide (4.82 g, 28.2 mmol) is added and the reaction mixture is allowed to reflux overnight. After cooling to room temperature the mixture is filtered and concentrated on a rotary evaporator to obtain 7.43 g (100%) of the title compound as a white solid.

Step B 1 - (4-benzyloxy-3,5-dif-luo-phenyl) -2-b-romopropan-1 -one Suspend 1 - (4-benzyloxy-3,5-difluorophenyl) -propan-1-one (7.43 g, 26.9 mmoles) in acetic acid (35 ml). Bromine (4.28 g, 26.8 mmol) is added dropwise and the reaction mixture is stirred for two hours at room temperature, at which point the reaction mixture is a yellow, clear solution. After cooling, ice water (100 ml) is added and the product is extracted with ether (2 x 100 ml). The combined organic extracts are washed with water, sodium bicarbonate solution and brine. The organic phase is dried (Na2SO), filtered and evaporated leaving 9.30 g (98%) of the title compound as a pale yellow oil.

Step C 2-Acetyl-4- (4-benzyloxy-3,5-d-phorophenyl) -3-methyl-4-oxobutyric acid ethyl ester A solution of sodium ethoxide is generated from metallic sodium (0.74 g) , 32.0 mmoles) in 40 ml of absolute ethanol. To this solution is added ethyl acetoacetate (4.16 g, 32.0 mmol) at 0 ° C. After 30 minutes this solution is added to a solution of 1- (4-benzyloxy-3,5-difluorophenyl) -2-bromopropan-1 -one (9.30 g, 26.2 mmol) in ethanol: toluene (40:20 ml) and the reaction mixture is stirred overnight. Acid treatment with 1 M HCl, extraction with ethyl acetate (3 x), washing with brine, drying (Na 2 SO), filtration and evaporation leaves a crude product which is purified by flash chromatography (hexane: EtOAc 95: 5- 70:30) which allows obtaining 6.95 g (66%) of the title compound as an oil.

Step D 5- (4-Benzyloxy-3,5-difluorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid A solution of sodium ethoxide is generated from metallic sodium (0.53 g, 22.0 mmol) in 60 ml of absolute ethanol.

To this solution is added 2-acetyl-4- (4-benzyloxy-3,5-difluorophenyl) -3-methyl-4-oxobutyric acid ethyl ester (6.95 g, 17.2 mmol) and the reaction mixture is stirred at room temperature. environment for 30 minutes. A previously prepared solution of 2,4-dichlorophenyldiazonium chloride (prepared from 2,4-dichloroaniline (3.39 g, 21.0 mmoles) in 9 ml of 24% HCl and sodium nitrite 1 is added in 5 portions. (48 g, 21 .0 mmoles) in 3 ml of water at 0 ° C) keeping the temperature below 5 ° C. After stirring at 0 ° C for 2 hours, the reaction mixture is allowed to come to room temperature and is stirred overnight. Water is added, the product is extracted with EtOAc (3 x). The combined organic extracts are dried (Na2SO), filtered and evaporated leaving 9.20 g of the crude ethyl ester as an oil. The residue (9.20 g) is dissolved in ethanol (120 ml) and sodium hydroxide (2.30 g, 57.5 mmol) in 15 ml of water is added. After 2 hours of boiling under reflux, the reaction mixture is cooled, acidified with HCl and the product extracted with EtOAc (3 x). After washing, drying (Na SO4), filtering and concentrating, the residue is purified by flash chromatography (hexane: EtOAc: AcOH 80: 20: 2-hexane: EtOAc: AcOH 50: 50: 2) which allows to obtain 5.46 g (65%, two steps) of the title compound as a solid.

Step E Piperidin-1-yl-amide of 5- (4-benzyloxy-3,5-difluorof in il) -1 - (2, 4-d-chloro-phenyl-4-methyl-1 H -pyrazole-3-carboxylic acid) lico 5- (4-Benzyloxy-3,5-difluorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid (5.46 g, 1.2 mmole) in dichloromethane is suspended. (60 ml) and add a few drops of DMF followed by the addition of oxalyl chloride (4.70 ml, 55.8 mmol) The reaction mixture is allowed to boil at reflux for 1.5 hours, after cooling to room temperature, it is removed the solvent and the crude acyl chloride are redissolved in dichloromethane, cooled to 0 ° C, Et3N (3.10 ml, 22.2 mmol) followed by 1-aminopiperidine (1.2 ml, 1.2 mmol) is added. The cooling bath and the reaction mixture are stirred at room temperature overnight, water is added and the product is extracted with dichloromethane (3 x), the combined extracts are dried (Na2SO), filtered and evaporated. vaporization Instantaneous ion (hexane: EtOAc 80: 20-70: 30) allows to obtain 1.86 g (30%) of the title compound as a yellow solid.

Step F 5- (4-Hydroxy-3,5-d? -fluorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid, 5- Piperidin-1-yl-amide it dissolves 5- (4-benzyloxy-3,5-difluorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid piperidin-1-yl-amide (1.86 g, 3.25 mmol) in 50 ml of dichloromethane and cooled to -78 ° C. BBr3 (0.60 ml, 6.50 mmol) is slowly added and the reaction mixture is stirred at 0 ° C for 30 minutes. Water is added and the product is extracted with CH 2 Cl 2 (x 3). The combined organic extracts are dried (Na 2 SO 4), filtered and concentrated. Flash chromatography (50:50 hexane: EtOAc) allows 0.64 g (41%) of the title compound to be obtained as a pale yellow solid.

Step G Ester [2- (2,4-dichlorophenyl) -4-methyl-5- (p -peridin-1-ylcarbamoyl) -2H-pyrazol-3-yn-2,6-difluorophenyl of propan-1 acid Sulfonic 5- (4-hydroxy-3,5-difluorophenyl) -1 - (2,4-dichlorophenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid piperidin-1-yl-amide is dissolved (0.64) g, 1.32 mmol) in dichloromethane (20 ml), cooled to 0 ° C and triethylamine (0.18 ml, 1.32 mmol) was added followed by propanesulfonyl chloride (0.19 g, 1.31 mmol). The reaction mixture is stirred at room temperature overnight. Water is added, the product is extracted with dichloromethane, dried (Na2SO), filtered and concentrated. Flash chromatography (hexane: EtOAc 70: 30-50: 50) allows 410 mg (53%) of the title compound to be obtained as a pale yellow solid. 1 H NMR (CDCl 3): d 7.66 (1 H, broad s), 7.60-7.24 (4H, m), 6.97-6.78 (1 H, m), 3.50-3.37 (2H, m), 3.02-2.80 (4H , m), 2.40 (3H, s), 2.20-2.00 (2H, m), 1.92-2.72 (4H, m), 1 .60-1.40 (2H, m), 1 .08 (3H, t) . MS m / z 609 (M + Na). HPLC: 97.5%.

EXAMPLE 8 Propan-1-sulfonic acid 4-r2- (2,4-dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazole-3-yl-phenyl Step A 4- (4-Benzyloxyphenyl) -2,4-dioxobutyric acid ethyl ester To a solution of LiHMDS (88 mL, 1 M in THF) in ether (50 mL) under nitrogen at -78 ° C is added for 1 hour. time a suspension of 1- (4-benzyloxyphenyl) -ethanone (20 g, 88.4 mmol) dissolved in ether (150 ml) and THF (50 ml). The resulting mixture is stirred at -78 ° C for 1 hour and then oxalic acid diethyl ester (14.2 g, 97.2 mmol) is added. The resulting mixture is slowly warmed to room temperature and then left overnight. The reaction mixture is diluted with pentane (90 ml) and the crude product precipitated as its lithium salt. The collected solid (27.2 g) is dried under vacuum and used directly in the next step.

Step B 5- (4-Benzyloxyphenyl) -1 - (2,4-dichlorophenyl) -1 -1 H -pyrazole-3-carboxylic acid ethyl ester 4- (4-benzyloxyphenyl) -2-ethyl ester is suspended, 4-dioxobutyric (27.2 g, as the Li salt from the previous step) in ethanol (350 ml) and 2,4-dichlorophenylhydrazine is added (17.8 g, 83.3 mmol). The reaction mixture is stirred overnight at room temperature. The solvent is then removed under reduced pressure and the residue is dissolved in acetic acid and the resulting mixture is refluxed for 24 hours. The reaction mixture is diluted with ethyl acetate (1 l) and then washed with saturated NaHCO 3 (6 x 250 ml) and brine (100 ml). The organic layer is dried (MgSO), filtered and concentrated under reduced pressure to obtain an oil. The oil is purified by flash chromatography (SiO, 20%> EtOAc in heptane). The product fraction is concentrated under reduced pressure and the remaining material is further purified by recrystallization (ethyl acetate / heptane) to obtain a white solid (19.6, 57% in the 2 steps). 1 H NMR (CDCl 3): d 1 .42 (t, 3 H), 4.45 (q, 2 H), 5.03 (s, 2 H), 6.88 (d, 2 H), 7.01 (s, 1 H), 7.1 1 (d , 2H), 7.3-7.45 (m, 8H). MS: 467 (M + 1).

Step C 1- (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -1H-pyrazole-3-carboxylic acid ethyl ester To a solution of 5- (4-benzyloxyphenyl) -1- ethyl ester (2,4-dichlorophenyl) -1H-pyrazole-3-carboxylic acid (735 mg, 1.57 mmol) and (CH3) 2S (0.58 ml, 7.86 mmol) in dichloromethane (30 ml) under nitrogen is added BF3-etherate of diethyl (1.0 g, 7.86 mmol) by dripping. The resulting mixture is stirred overnight at room temperature. Then (CH3) 2S (0.58 ml, 7.86 mmol) and BF3-diethyl etherate (1.0 ml, 7.86 mmol) are added and the resulting mixture is stirred for another 3 days.

The reaction mixture is diluted with dichloromethane to 80 ml and washed with water (3 x 30 ml) and brine (40 ml). The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to obtain a white solid (573 mg, 96%). The raw material is used directly. 1 H NMR (CDCl 3): d 1 .41 (t, 3H), 4.44 (q, 2H), 6.74 (d, 2H), 7.00 (s, 1 H), 7.06 (d, 2H), 7.3-7.45 ( m, 3H). MS: 375 (M-1).

Step D 1 - (2,4-Dichlorophenol) -5- [4- (propane-1-sulphonyloxy) -phenyl] | -1H-pyrazole-3-carboxylic acid ethyl ester 1 - (ethyl ester is suspended. 2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -1H-pyrazole-3-carboxylic acid (510 mg, 1.35 mmol) in dichloromethane (20 ml) under nitrogen and triethylamine (0.75 ml, 5.4 mmol) is added. The resulting mixture is cooled to 0 ° C and 1-propanesulfonyl chloride (0.30 ml, 2.7 mmol) is added dropwise The mixture is stirred at 0 ° C for 1 hour, the reaction mixture is then diluted to 40 ml with dichloromethane and then washed with saturated NaHCO3 (3 x 20 ml) and brine (20 ml) The organic layer is dried (MgSO), filtered and concentrated under reduced pressure to obtain an oil (0.64 g, 98%). The crude material is used as is without further purification 1 H NMR (CDCl 3): d 1.12 (t, 3 H), 1.43 (t, 3 H), 2.01 (m, 2 H), 3.23 (m, 2 H), 4.46 (q , 2H), 7.07 (s, 1 H), 7.19-7.46 (m, 7H), MS: 483 (M + 1).

Step E Ester 4- [2- (2,4-Dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazole-3-p-phenyl of propan-1-sulfonic acid Dissolve 1-aminopiperidine hydrochloride (36 mg, 0.26 mmol) in toluene (1.0 ml) under nitrogen atmosphere. Trimethylaluminum (2 M in toluene, 0.17 ml) is added by dripping at room temperature. The resulting mixture is then stirred at room temperature for 40 minutes. This mixture is then added to a stirred suspension of 1- (2,4-dichloro-phenyl) -5- [4- (propan-1-sulfonyloxy) phenyl] -1H-pyrazole-3-ethyl ester. carboxylic acid (42 mg, 0.087 mmol) in DCM (1.0 ml) and the resulting mixture is heated at 60 ° C overnight. The reaction is quenched by the addition of water and then separated between water (20 ml) and DCM (20 ml). The organic layer is washed with water (3 x 10 mL) and then concentrated under reduced pressure. The residue is purified by reverse phase HPLC, C8 column, 5-100% acetonitrile in water (buffer: 0.1M ammonium acetate). The product fraction is diluted with ethyl acetate and washed with water several times. The organic layer is concentrated under reduced pressure and the residue is dried by freezing to obtain a white solid (26 mg, 55%). 1 H NMR (CDCl 3): 1.1 (t, 3 H), 1.43 (m, 2 H), 1.76 (m, 4 H), 2.00 (m, 2 H), 2.85 (m, 4 H), 3.22. (m, 2H), 7.1 1 (m, 1 H), 7.20 (m, 4H), 7.37 (m, 2H), 7.49 (m, 1 H). MS: 537 (M + 1).

EXAMPLE 9 Propan-1-sulfonic acid 4-r4-bromo-2- (2,4-dichlorophenopy-5- (piperidin-1-ylcarbamoyl) -2H-pyrazole-3-ill-phenyl) Step A 4-Bromo-1- (2,4-dichlorophenyl) -5- [4- (propane-1-sulfonyloxy) phenin-1 H-pyrazole-3-carboxylic acid ethyl ester Acid ethyl ester is dissolved 1- (2,4-Dichlorophenyl) -5- [4- (propan-1-sulfonyloxy) -phenyl] -1H-pyrazole-3-carboxylic acid, which is prepared as described in Example 8, Step D (597 mg, 1.23 mmol) in dichloromethane (15 ml) and bromine (0.06 ml, 1.23 mmol) in dichloromethane (1 ml) is added and the resulting mixture is stirred at room temperature overnight. Additional bromine is added (0.06 ml, 1.23 mmol) and the mixture is stirred for another 20 hours. The reaction mixture is diluted to 80 ml with dichloromethane and then washed with saturated NaHCO3 (40 ml), 20% Na S2O5 (40 ml), saturated NaHCO3 (2 x 40 ml) and brine (40 ml). The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to obtain an orange oil (0.598, 73%). The raw material is used without further purification. 1 H NMR (CDCl 3): d 1 .12 (t, 3 H), 1.44 (t, 3 H), 2.01 (m, 2 H), 3.24 (m, 2 H), 4.48 (q, 2 H), 7.2-7.46 (m, 7H). MS: 561 Step • B Ester 4- [4-bromo-2- (2,4-diphenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl-1-phenyl acid of propan-1 acid -sulfonic This compound is prepared in a manner similar to that described in Example 8, Step E, by reacting 4-bromo-1 - (2, 4-d, chlorofenic acid ethyl ester, il) -5- [4- (propan-1-sulphonoyloxy) -phenyl] -1H pyrazole-3-carboxylic acid with 1-aminopiperidine hydrochloride to obtain 26 mg of the title compound as a white solid. Performance: 25%. 1 H NMR (CDCl 3): 1.12 (t, 3H), 1.43 (m, 2H), 1.74 (m, 4H), 2.01 (m, 2H), 2.90 (m, 4H), 3.24 (m, 2H), 7.21-7.45 (m, 7H). MS: 615.

EXAMPLE 10 1-fr (1 - (2,4-dichlorophenin-4-methyl-5-f4r (propylsulfon> noxi-phenyl-1H-pyrazole-3-ip-carbonin-amino > methyl-cyclopentanecarboxylate) Step A Methyl 1-aminocyclopentanecarboxylate hydrochloride Thionyl chloride (1.5 ml) is dissolved in methanol (15 ml) and poured into 1-aminocyclopentanecarboxylic acid (100 mg, 0.774 mmol). The mixture is refluxed for 1 hour. The solvent is evaporated to obtain the product (107 mg, 77%). 1 H NMR (399.964 MHz) d 9.00-8.60 (br, 3H), 3.79 (s, 3H), 2.23 (s, 4H), 2.14-2.00 (m, 2H), 1.90-1.76 (m, 2H) .

Step B 1 - ( { Í5-r4- (benzyloxy) phenyl-1 - (2,4-dichlorophenyl) -4-m eti 1-1 Hp i razo l-3-i l-ca rbon il -amino) - Ccy penta n Methyl carboxylate A solution of 5- [4-benzyloxy) phenyl] -1 - (2, 4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid, which is prepared as described in example 1, Step D (59 mg, 0.130 mmol) in DCM (2 ml) with a chloride solution of oxalyl (2 ml) in DCM (20 ml). A drop of DMF is added and the reaction is continued at room temperature in the dark for 1 hour. The solvent is evaporated, DCM (2 ml) is added and the acyl chloride mixture is added to a mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride (23 mg, 0.130 mmol) in DCM (2 ml) and K2CO3 (aqueous, 10% by weight, 2 ml). The reaction is continued at room temperature for 3 hours. The phases are separated and the organic phase is washed with water and dried with MgSO 4 to obtain the product (71 mg, 94%). 1 H NMR (399.964 MHz) d 7.43-7.23 (m, 9H), 7.06-7.00 (m, 2H), 6.93-6.87 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.40 -2.30 (m, 2H), 2.34 (s, 3H), 2.14-2.04 (m, 2H), 1 .87-1 .77 (m, 4H). MS m / z 578, 580, 582 (M + H) +.

Step C 1 - ( { M - (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1 H -pyrazol-3-yl "lcarbonyl.} -amino) -cyclopentanecarboxylic acid methyl ester Boron trifluoride etherate (1 56 μL, 1.23 mmol) is added to a mixture of 1 - ( { [5- [4- (benzyloxy) phenyl] -1 - (2,4-dicyorophenyl) -4 methyl-methyl-1 H-pyrazol-3-yl] -carbonyl.}. -amino) cyclopentane-carboxylate (51 mg, 0.088 mmol) and dimethyl sulfide (90 μl, 1.23 mmol) in DCM (2 ml. The reaction is continued at room temperature in the dark for 46 hours, water and DCM are added, the phases are separated and the organic phase is washed with water and dried with MgSO (39 mg, 90%). (399.964 MHz) d 7.60-6.60 (m, 8H), 3.72 (s, 3H), 2.43-2.23 (m, 2H), 2.26 (s, 3H), 2.15-2.00 (m, 2H), 1.85-1. 75 (m, 4H) MS m / z 488, 490, 492 (M + H) +.

Step D 1 -. { [(1 - (2,4-dichlorophenyl) -4-methyl-5-. {4-r (propyl-sulfonyl) -oxi-phenyl> -1 H -pyrazol-3-yl) -carbonyl-amino} methyl-cyclopentanecarboxylate TEA (100 μl) and then 1-propanesulfonyl chloride (30 μl, 0.268 mmol) are added to a mixture of 1- ( { [1 - (2,4-dichlorophenyl) -5- (4 methyl-hydroxyphenyl) -4-methyl-1 H -pyrazol-3-yl] -carbonyl.}., .amino-methylcyclopentanecarboxylate (39 mg, 0.080 mmol) in dry DCM (1.5 mL) at -78 ° C. . The reaction is continued at -78 ° C under N2 (g) for 1.5 hours. Water and DCM are added and the temperature is raised to room temperature. The phases are separated and the organic phase is washed with water and dried with MgSO. The product is purified by preparative HPLC (column C8, kromasil, ammonium acetate (aqueous, 0.1 M): acetonitrile, the product starts to exit at approximately 88% acetonitrile) to obtain the product as an almost white powder ( 17 mg, 35%). 1 H NMR (399.964 MHz) d 7.45-7.39 (br, 1 H), 7.32-7.28 (m, 2H), 7.27-7.19 (m, 3H), 7.18-7.12 (m, 2H), 3.76 (s, 3H ), 3.26-3.20 (m, 2H), 2.40-2.30 (m, 2H), 2.35 (s, 3H), 2.15-2.05 (m, 2H), 2.05-1.95 (m, 2H), 1.88 -1 .78 (m, 4H), 1 .12 (t, 3H). HRMS calculated for [C27H2gCI2N3O6S + H] +: 594.123. Found: 594.121.

EXAMPLE 11 Propyl ester of 4-r2- (2,4-dichloro-phenyl-4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-y-phenyl carbonic acid ester) 1 - (2,4-Dichloro-phenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-yl-amide is dissolved which is prepared as described in Example 1, Step F (0.44 g, 1.00 mmol) in dichloromethane (10 ml) and triethylamine (0.28 ml, 2.24 mmol) is added. Propyl chloroformate (0.14 ml, 1.24 mmol) is added at 0 ° C, and the reaction is stirred for 40 minutes, concentrated and the product is purified by flash chromatography (hexane: EtOAc 70: 30-50: 50) to obtain 345 mg (65%) of the title compound. Further purification by preparative HPLC yields 239 mg of the title compound. 1 H NMR (CDCU): d 7.71-7.18 (8H, m), 4.24 (2H, t), 2.93 (4H, m), 2.40 (3H, s), 1.78 (6H, m), 1.46. (2H, m), 1 .03 (3H, t). MS m / z 553 (M + Na) HPLC: 94.15% EXAMPLE 12 Tiofen-2-sulfonate of 4-f1 - (2,4-dichlorophenyl) -4-methyl-3- r (piperidin-1-ylamino) carbonn-1 H-pyrazol-5-yl > -phenyl Thiophene-2-sulfonyl chloride (433 mg, 2.37 mmol) in DCM (2.5 ml) is added to a mixture of 1- (2,4-dichloropheni) -5- (4-hydroxyphenyl) -4-methyl-N- piperidin-1-yl-1 H-pyrazole-3-carboxamide which is prepared as described in Example 1, Step F (200 mg, 0.45 mmol) and TEA (0.5 mL, 3.59 mmol) in DCM (2.5 mL) at -78 ° C, under N2 (g). The reaction is continued at -78 ° C for 2 hours and then at room temperature for 19 hours. Water is added and the phases are separated. The organic phase is washed with water and dried with MgSO 4. The product is further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aqueous, 0.1M): acetonitrile, the product starts to exit at 100% acetonitrile) to obtain an almost white powder (158 mg, 60 mg). %). 1 H NMR (399.964 MHz) d 7.71 -7.67 (m, 1 H), 7.67-7.57 (br, 1 H), 7.50-7.46 (m, 1 H), 7.35 (s, 1 H), 7.25 (s, 2H), 7.07-7.00 (m, 3H), 6.98-6.92 (m, 2H), 2.86-2.76 (m, 4H), 2.29 (s, 3H), 1 .73- 1.65 (m, 4H), 1. 42-1.33 (m, 2H). HRMS calculated for [C26H24Cl2N4O4S2 + H] +: 591.069. Found: 591 .067.

EXAMPLE 13 Pyridin-3-yl-sulfonate hydrochloride of 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3-r (p -peridin-1-ylamino) carbonip-1 H -pyrazol-5-yl) -phenyl Step A: Pyridin-3-yl sulfonate of 4 ~ M - (2,4-dichloropheni-4-methyl-3 - [(piperidin-1 -lamino) carbon.p-1 H-pyrazol-5-yl} -phenyl A suspension of pyridine-3-sulfonyl chloride (144 mg, 0.67 mmol) in DCM (10 ml) is added to a mixture of 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-N-piperidin-1-yl-1 H-pyrazole-3-carboxamide, which is prepared as described in example 1, Step F (200 mg, 0.45 mmol) and TEA (0.5 ml, 3.59 mmol) ) in DCM (2.5 ml) at -78 ° C, under N2 (g) The reaction is continued at -78 ° C for 1.5 hours and then at room temperature for 30 minutes.Water is added and the organic phases are separated. The organic phase is washed with water and dried over MgSO 4. The product is further purified by flash chromatography (SiO2, toluene: ethyl acetate, the product exits to 42% ethyl acetate) to obtain a colored powder. almost white (216 mg, 82%). 1 H NMR (399.964 MHz) d 8.95-8.85 (m, 2H), 8.10-8.04 (m, 1 H), 7.64 (s, 1 H), 7.50-7.45 (m, 1 H), 7.44-7.40 (m, 1 H), 7.34- 7.24 (m, 2H), 7.09-7.04 (m, 2H), 7.00-6.95 (m, 2H), 2.88-2.78 (m, 4H), 2.33 (s, 3H), 1.78-1.68 (m, 4H), 1.46-1.36 (m, 2H). HRMS calculated for [C27H25Cl2N5O4S + H] +: 586.108. Found: 586.1 1 1.

Step B Pyridin-3-sulfonate hydrochloride of 4 ~ M - (2,4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl '| -1H-pyrazol-5-yl > phenyl Pyridine-3-sulfonate of 4- is dissolved. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} phenyl (150 mg, 0.26 mmol) in 0.1 M HCl in acetic acid (10 ml) and dried by freezing to obtain the salt as a white powder (1.59 mg, 99.8%).

EXAMPLE 14 r2- (4- (1 - (2,4-Dichlorophenyl) -4-methyl-3-r (piperidin-1-ylamino) carbonip-1 H -pyrazol-5-yl) -phenoxy) -etilpethyl- tert-butyl carbamate Step A: Ethyl (tert-butyl 2-hydroxyethylcarbamate) D-tert-butyl dicarbonate (3.19 g, 14.6 mmol) in THF (10 ml) is added to 2- (ethylamino) -ethanol (1.00 g, 11). 2 mmoles) and reacted at room temperature for 3 hours.The solvent is evaporated under reduced pressure to obtain the crude product (2.28 g). 1 H NMR (499.961 MHz) d 3.71 -3.65 (br, 2H), 3.55-3.35 (br, 1 H), 3.35-3.30 (br, 2H), 3.30-3.20 (br, 2H), 1.43 (s, 9H ), 1.07 (t, 3H).

Step B r2- (4- { 1 - (2,4-Dichlorophenin-4-methyl-3-y (piperidin-1-ylamino) -carbonan-1 H -pyrazol-5-yl-phenoxy) - Terbutyl Ethyl-1-ethylcarbamate. 1- (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-N-piperidin-1-l-1 H-pyrazole-3-carboxamide, which is prepared, is mixed. as described in Example 1, Step F (151.6 mg, 0.34 mmol) and tert-butyl ethyl- (2-hydroxyethyl) -carbamate (408.6 mg, 1.73 mmol) in toluene (1 mL) and they react repeatedly in an individual node microwave oven at 180 ° C. The total reaction time is 2 hours.Canatomethylenetri-N-butylphosphorane is added before each heating (total amount 925 mg, 3.83 mmol). The solvent is evaporated and the product is purified by preparative HPLC (Kromasil C8 column, ammonium acetate (aqueous, 0.1M): acetonitrile, the product exits at 100% acetonitrile) and flash chromatography (SiO2, toluene: ethyl acetate). ethyl, the product exits at 30% ethyl acetate) to obtain an almost white powder (125 mg, 60%). 1 H NMR (399.964 MHz) d 7.62 (s, 1 H), 7.37 (s, 1 H), 7.23 (s, 2H), 7.01 -6.95 (m, 2H), 6.81 -6.75 (m, 2H), 4.05 -3.95 (br, 2H), 3.55-3.45 (br, 2H), 3.35-3.25 (br, 2H), 2.86-2.78 (br, 4H), 2.32 (s, 3H), 1 .75-1 .65 ( m, 4H), 1.41 (s, 9H), 1.45-1.35 (m, 2H), 1.08 (t, 3H). MS m / z 616, 618, 620 (M + H) +.

EXAMPLE 15 1- (2,4-Dichlorophenyl) -5- dihydrochloride. { 4-r2- (ethylamino) ethoxy-1-phenyl-4-methyl-N-piperidin-1-yl-1 H-pyrazole-3-carboxamide Thionyl chloride (1 mL, 13.71 mmol) in methanol (10 mL) is added to a suspension of [2- (4-. {1 - (2,4-dichlorophenyl) -4-methyl-3 - [(piperidine -1-amino) -carbonyl] -1H-pyrazol-5-yl.}. -phenoxy) -ethyl] -ethyl tert-butyl ester from example 14Step B (137 mg, 0.22 mmol) in methanol (2 ml). After 2.5 hours the solvent is evaporated and the product is dried by freezing. The compound is purified by preparative HPLC (Kromasil C8 column, ammonium acetate (aqueous, 0.1M): acetonitrile, the product exits at 72% acetonitrile), dried by freezing and finally dissolved in 0.1M HCl in acetic acid (15 ml) and dried by freezing again to obtain an almost white powder (53 mg, 40%). 1 H NMR (399.964 MHz) d 7.54-7.47 (m, 2H), 7.44-7.39 (m, 1 H), 7.19-7.14 (m, 2H), 7.01 -6.96 (m, 2H), 4.24 (t, 2H), 3.41 (t, 2H), 3.18-3.06 (m, 6H), 2.27 ( s, 3H), 1.87-1.78 (m, 4H), 1.57-1.48 (m, 2H), 1.32 (t, 3H). HRMS calculated for [C26H3? CI2N5? 2 + H] +: 516.193. Found: 516,195.

EXAMPLE 16 3-methylbutan-1-sulfonate of 4-. { 1- (2,4-dichlorophenyl) -4-methyl-3- r (piperidin-1-ylamino) -carbonyl-1 H-pyrazol-5-yl > -phenyl 3-Methylbutan-1-sulfonyl chloride (84 mg, 0. 49 mmol) in DCM (2 ml) was added to a mixture of 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-N-piperidin-1-yl-1 H-pyrazole-3-. carboxamide, which is prepared as described in Example 1, Step F (100 mg, 0.23 mmol) and TEA (0.5 mL, 3.59 mmol) in DCM (2 mL) at -78 ° C, under N2 (g) . The reaction is continued at -78 ° C for 1 hour. Water is added and the phases are separated. The organic phase is washed with water and dried with MgSO 4. The product is further purified by preparative HPLC (Kromasil C8 column, ammonium acetate (aqueous, 0.1M): acetonitrile, the product exits at 100% acetonitrile) to obtain an almost white powder (94 mg, 72%) . 1 H NMR (399.964 MHz) d 7.85-7.45 (br, 1 H), 7.38 (s, 1 H), 7.29-7.25 (m, 2H), 7.23-7.18 (m, 2H), 7.16-7.1 1 (m , 2H), 3.25-3.18 (m, 2H), 2.88-2.80 (m, 4H), 2.33 (s, 3H), 1 .86-1.77 (m, 2H), 1.76-1.65 (m, 5H), 1.45-1.34 (m, 2H), 0.92 (d, 6H). HRMS calculated for [C27H32Cl2N4O4S + H] +: 579,160. Found: 579,159.

EXAMPLE 17 3, 3-dimethylbutan-1-sulfonate of 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3- r (piperidin-1-ylamino) -carbonip-1 H-pyrazol-5-yl} -phenyl 3,3-Dimethylbutan-1-sulfonyl chloride (59 mg, 0.32 mmol) in DCM (2 ml) is added to a mixture of 1- (2,4-dichlorophenyl) -5- (4-hydroxypheni) -4- methyl-N-piperidin-1-yl-1 Hp-aceol-3-carboxamide, which is prepared as described in Example 1, Step F (103 mg, 0.23 mmol) and TEA (0.5 mL, 3.59 mmol) in DCM ( 2 ml) at -78 ° C, under N2 (g). The reaction is continued at -78 ° C for 1 hour. Water is added and the phases are separated. The organic phase is washed with water and dried with MgSO 4. The product is further purified by preparative HPLC (Cromasil column C8, ammonium acetate (aqueous, 0.1M): acetonitrile, the product exits at 100%> acetonitrile) to obtain an almost white powder (94 mg, 68%). %). 1 H NMR (399.964 MHz) d 8.20-7.40 (br, 1 H), 7.36 (s, 1 H), 7.28-7.22 (m, 2H), 7.21 -7.16 (m, 2H), 7.15-7.09 (m, 2H), 3.20-3.13 (m, 2H), 2.87-2.80 (m, 4H), 2.31 (s, 3H), 1.83-1.76 (m, 2H), 1 .73-1.65 (m , 4H), 1 .43-1 .32 (m, 2H), 0.89 (s, 9H). HRMS calculated for [C28H3 CI2N4O4S + H] +: 593.176. Found: 593,176.

EXAMPLE 18 3, 3, 3-trif Ioropropan-1-sulfonate 4-M- (2,4-d-chlorofenyl) -4- methyl-3- ( { R5- (trifluoromethyl) -pyridin- 2-in-amino > carbonyl) -1 H-pyrazole-5-illphenyl Step A 5-f4- (benzyloxy) phenyl1-1- (2,4-dichlorophenyl) -4-methyl- N- [5- (trifluoromethylpyridin-2-yn-1 H -pyrazole-3-carboxamide) Oxalyl chloride is added (1 ml) in DCM (4 ml) was added to a suspension of 5- [4- (benzyloxy) phenyl] -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazole-3-carboxylic acid, which is prepared as described in example 1, Step D (202 mg, 0.45 mmol) in DCM (4 ml), 1 drop of DMF is added and the reaction is continued at room temperature for 1 hour. of oxalyl chloride under reduced pressure and the acyl chloride is suspended in DCM (4 ml) and added to 5- (trifluoromethyl) -pyridin-2-amine (87.6 mg, 0.54 mmole) in DCM / K2CO3 (10% strength). , aqueous) (1/1, 8 ml) The reaction is continued at room temperature for 24 hours, then 50 mg of DMAP is added and the reaction is continued at room temperature for 1 hour.The phases are separated and the organic phase is separated. Wash with water and dry with MgSO.The product is further purified by chromatography. Instantaneous vaporization (SiO2, toluene) (108 mg, 41%). 1 H NMR (399.964 MHz) d 9.66 (s, 1 H), 8.58-8.48 (m, 2H), 7.95-7.90 (m, 1 H), 7.44 - / .14 (m, 8H), 7.10-7.04 ( m, 2H), 6.94-6.90 (m, 2H), 5.02 (s, 2H), 2.42 (s, 3H). MS m / z 597.599, 601 (M + H) +.

Step B 1 - (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-N- [5- (trifluoromethyl) -pyridin-2-yl-1 H -pyrazole-3-carboxamide is suspended. - [4- (benzyloxy) -phenyl] -1 - (2,4-dichlorophenyl) -4-methyl-N- [5- (trifluoromethyl) -pyridin-2-yl] -1 H -pyrazole-3-carboxamide ( 108 mg, 0.18 mmol) in 4.1 M HBr in acetic acid (10 ml) and reacted at room temperature for 6 hours. Ethanol (95%, 75 ml) is added and the solvent is evaporated under reduced pressure. Methanol is added and the product is neutralized with NaHCO3 (1 M, aqueous). The solvent is evaporated and the mixture is dissolved in DCM and water. The phases are separated and the organic phase is washed with water and dried with MgSO 4 (87 mg, 95%). 1 H NMR (399.964 MHz) d 9.64 (s, 1 H), 8.58-8.48 (m, 2H), 7.97-7.91 (m, 1 H), 7.45-7.41 (m, 1 H), 7.32-7.23 (m, 2H), 7.03-6.98 (m, 2H), 6.80-6.75 (m, 2H), 5.50-5.30 (br, 1 H), 2.40 (s, 3H). MS m / z 507, 509, 51 1 (M + H) +.

Step C: 3,3-trifluoropropan-1-sulfonate of 4-M - (2,4-dichlorophenyl) -4-methyl-3- ( { [5- (trifluoromethyl) pyridin-2-aminoaminocarbonyl) - 1 H-pyrazole-5-ill-phenyl 3,3,3-trifluoropropane-1-sulfonyl chloride (105 mg, 0.53 mmol) is added to a mixture of 1- (2,4-dichlorophenyl) -5- (4 -hydroxyphenyl) -4-methyl-N- [5- (trifluoromethyl) -pyridin-2-yl] -1H-pyrazole-3-carboxamide (87 mg, 0.17 mmol) and TEA (0.5 mL, 3.59 mmol) in DCM (3 ml) at -78 ° C, under N2 (g). The reaction is continued at -78 ° C for 2 hours and then at room temperature overnight. Water is added and the organic phases are separated. The organic phase is washed with water and dried with MgSO 4. The product is further purified by preparative HPLC (Kromasil C8 column, ammonium acetate (aqueous, 0.1M): acetonitrile, the product exits at 100% acetonitrile) to obtain an almost white colored powder (86 mg, 75%). 1 H NMR (399.964 MHz) d 9.70 (s, 1 H), 8.57-8.48 (m, 2H), 7.99-7.92 (m, 1 H), 7.43 (s, 1 H), 7.32 (s, 2H), 7.28-7.19 (m, 4H), 3.53-3.44 (m, 2H), 2.85-2.71 ( m, 2H), 2.42 (s, 3H). HRMS calculated for [C26H18Cl2F6N4O4S + H] +: 667.041. Found: 667,031.

EXAMPLE 19 1- (2,4-dichlorophenyl) -5-. { 4-r2- (1, 3-dioxolan-2-yl) -ethoxy-1-phenyl > -4- methyl-N-piperidin-1-yl-1 H-pyrazole-3-carboxamide Reflux 2- (2-bromoethyl) -1,3-dioxolane (60 mg, 0.33 mmol), 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-N-piperidine is refluxed. -1-yl-1 H-pyrazole-3-carboxamide which is prepared as described in Example 1, Step F (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) in acetonitrile (25 mg). ml) for 15 hours. The solvent is evaporated, water and DCM are added, the phases are separated and the organic phase is washed with water and dried (MgSO4). The product is further purified by preparative HPLC (Kromasil C8 column, ammonium acetate (aqueous, 0.1M): acetonitrile, the product exits 100%) of acetonitrile) to obtain an almost white powder (60 mg, 49% ). 1 H NMR (399.964 MHz) d 7.80-7.50 (br, 1 H), 7.36 (s, 1 H), 7.21 (s, 2H), 7.00-6.94 (m, 2H), 6.80-6.74 (m, 2H) , 5.02 (t, 1 H), 4.04 (t, 2H), 3.96-3.78 (m, 4H), 2.86-2.78 (m, 4H), 2.30 (s, 3H), 2.09 (q, 2H), 1. 74-1 .65 (m, 4H), 1 .42-1 .32 (m, 2H). HRMS calculated for [C27H3oCI2N4O4 + H] +: 545.172. Found: 545,172.

EXAMPLE 20 Ester 4-r2- (2,4-dichloro-3-fluorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoy-2H-pyrazole-3-in-phenylpropan-1-sulphonic) Step A 1 - (2,4-Dichloro-3-fluorophenyl) -5- (4-methoxyphenyl) -4-methyl-1H-pyrazole-3-carboxylic acid A solution of sodium ethoxide is generated from metallic sodium (0.18 g, 7.89 mmoles) in 20 ml of absolute ethanol. To this solution is added 2-acetyl-4- (4-methoxy-phenyl) -3-methyl-4-oxo-butyric acid ethyl ester (1.73 g, 5.92 mmol) and the reaction mixture is stirred at room temperature. environment for 30 minutes. A previously prepared solution of 2,4-dichloro-3-fluorodiazonium chloride (prepared from 2,4-dichloro-3-fluoroaniline (1.30 g, 7.22 mmol) in 3 ml of HCl is added in 5 portions. 24% and sodium nitrite (0.51 g, 7.39 mmol) in 3.5 ml of water at 0 ° C) maintaining the temperature below 5 ° C. After stirring at room temperature for 2.5 hours water is added, the product is extracted with EtOAc (3 x). The combined organic extracts are dried (Na 2 SO 4), filtered and evaporated. The residue is dissolved in ethanol (40 ml) and sodium hydroxide (1.00 g, 25.0 mmol) in 5 ml of water is added. After boiling for 2 hours under reflux, the reaction mixture is cooled, acidified with HCl and the product is extracted with EtOAc (3 x). After washing, drying (Na2SO), filtering and concentrating, the residue is purified by flash chromatography (hexane: EtOAc 70: 30-50: 50) which allows to obtain 1.37 g (31%) of the title compound as a solid of light brown color.

Step B: Piperidin-1-yl-amide of 1 - (2,4-dichloro-3-f luoro-f in yl) -5- (4-methoxy-phenyl) -4-methyl-1 H-pyrazole-3 -carboxylic acid 1 - (2,4-Dichloro-3-fluoro-phenyl) -5- (4-methoxy-phenyl) -4-methyl-1H-pyrazole-3-carboxylic acid (1 .37 g, 3.43 mmol) in dichloromethane (20 ml) and a few drops of DMF are added followed by the addition of oxalyl chloride (0.87 g, 6.86 mmol). The reaction mixture is refluxed for two hours. After cooling to room temperature the solvent is removed and the crude acyl chloride is redissolved in dichloromethane (20 ml), cooled to 0 ° C, Et N (0.96 ml, 6.94 mmol) is added followed by 1 -aminopiperidine. (0.37 ml, 3.62 mmol). The cooling bath is removed and the reaction mixture is stirred at room temperature overnight. Water is added and the product is extracted with dichloromethane (3 x), the combined extracts are dried (Na 2 SO 4), filtered and evaporated. Flash chromatography (50:50 hexane: EtOAc) allows 0.79 g (48%) of the title compound to be obtained as a light brown solid.

Step C 1- (2,4-Dichloro-3-fluoro-phenyl) -5- (4-hydroxy-phenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid C-piperidin-1-yl-amide dissolves 1 - (2,4-dichloro-3-fluoro-phenyl) -5- (4-methyloxy-phenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid piperidin-1-ylide (0.79) g, 1.66 mmol) in 40 ml of dichloromethane at 0 ° C. Boron bromide (0.32 ml, 3.31 mmol) is added, the cooling bath is removed and stirring is continued for 2 hours at room temperature before it is poured into ice water and extracted with DCM (x 3). The combined extracts are dried (Na2SO4), filtered and concentrated. Flash chromatography (EtOAc) afforded 0.36 g (47%) of the title compound as a colorless solid.

Step D Ester 4- [2- (2,4-dichloro-3-fluoro-phenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-n-phenyl of propan- 1-sulfonic acid To a solution of piperidin-1-yl-amide of 1- (2,4-dichloro-3-fluoro-phenyl) -5- (4-hydroxy-phenyl) -4-methyl-1 H -pyrazole-3-carboxylic acid (0.36 g, 0.78 mmol) in dichloromethane (10 ml). Triethylamine (0.22 ml, 1.56 mmol) is added and the reaction mixture is cooled to 0 ° C. 1-Propanesulfonyl chloride (0.22 g, 1.56 mmol) is added, the cooling bath is removed and the reaction mixture is stirred at room temperature for 2 hours. Water is added, the product is extracted with DCM (x2), the combined organic extracts are washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (gradient of hexane.EtOAc) allows to obtain 100 mg (23%) of the title compound as a colorless solid. HPLC 80% purity. Preparative HPLC allows obtaining 40 mg of the title compound. 1 H NMR (CDCl 3): d 7.50-7.20 (7 H, m), 3.57-3.23 (6H, m), 2.37 (3H, s), 2.10-1.80 (6H, m), 1.70-1 50 (2H, m), 1 .10 (3H, t) MS: 591 (M + Na) HPLC: 97.1% or EXAMPLE 21 Ester 4-r2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazole-3-in-phenyl 5-chlorothiophen-2-sulfonic acid 1 - (2,4-Dichloro-phenyl) -5- (4-hydroxy-phenyl) -4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-yl-amide is dissolved, which is prepared as described in Example 1, Step F (100 mg, 0.22 mmol) in dry dichloromethane (3 ml) under nitrogen atmosphere and triethylamine (0.09 ml) is added. Then add 5-chlorothiophen-2-sulfonyl chloride (0.54 mg, 0.24 mmol), dissolved in dry dichloromethane (2 ml). The reaction mixture is stirred over the weekend at room temperature. The reaction mixture is diluted with dichloromethane to 20 ml and then washed with water (2 x 5 ml) and brine (5 ml). The organic layer is concentrated under reduced pressure to obtain an oil. The crude material is purified by reverse phase HPLC, Kromasil C8, 5-100%) of MeCN in water with 0.1 M ammonium acetate. The product fraction is concentrated under reduced pressure and the residue is dissolved in dichloromethane and washed with water and brine. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to obtain the title compound as a yellow solid. 1 H NMR (CDCl 3): d 1 .42-1.50 (m, 2H), 1 .73-1.81 (m, 4H), 2.39 (s, 3H), 2.84-2.92 (m, 4H), 6.95 (d, 1 H), 7.04-7.14 (m, 4H), 7.30-7.36 (m, 3H), 7.44 (d, 1 H), 7.63 (s, 1 H). MS: 625 (M + 1). H PLC: purity > 99%

Claims (10)

CLAIMS 1 .- A compound of the formula (I) and pharmaceutically acceptable salts thereof, wherein R1 represents a) a C1-3 alkoxy group substituted with one or more of the following i) fluoro ii) a group NRcRd in which Rc and Rd independently represent H, a C 1-6 alkyl group or a C 1-6 alkoxycarbonyl group with the proviso that one of Rc and Rd is different from H or iii) a 1,3-dioxolan-2-yl group, b) R 1 represents an alkoxy group of C4-6 optionally substituted with one or more of the following i) fluoro ii) a group NRcRd in which Rc and Rd independently represent H, an alkyl group of -6 or an alkoxycarbonyl group of C? -6 with the proviso that one of Rc and Rd is different from H or iii) a 1,3-dioxolan-2-yl group; c) a group of the formula in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, d) a group R5S (O) 2O or R5S (O) 2NH wherein R 5 represents a C 1-6 alkyl group optionally substituted by one or more fluoro, or R 5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z; e) a group of the formula (R6) 3 Si in which R6 represents an alkyl group of d-6 which may be the same or different of) a group of the formula RbO (CO) O in which Rb represents a group d_6 alkyl optionally substituted with one or more fluoro; Ra represents halogen, an alkyl group of d.3 or an alkoxy group of C? _3; m is 0, 1, 2 or 3; R 2 represents an alkyl group of d-3, a C 1 -3 alkoxy group, hydroxy, nitro, cyano or halogen n is 0, 1, 2 or 3; R3 represents a) a group X-Y-NR7R8 in which X is CO or SO2, Y is absent or represents NH optionally substituted by an alkyl group of C? -3; and R7 and R8 independently represent: an alkyl group of C6-6 optionally substituted with 1, 2, or 3 groups represented by W; a C3-15 cycloalkyl group optionally substituted with 1, 2, or 3 groups represented by W; a cycloalkyl (C3-i5) -alkylene group of C1-3 optionally substituted with 1, 2, or 3 groups represented by W; a group - (CH2) r (phenyl) s in which r is 0, 1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and phenyl groups, independently, they are optionally substituted with one, two or three groups represented by Z; a saturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen in which the heterocyclic group is optionally substituted with one or more alkyl groups of d-3, hydroxy or benzyl; a group - (CH 2) t Het in which t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted with one or more C? _3 alkyl groups and Het represents an aromatic heterocycle optionally substituted with one , two or three groups that are selected from C 1-5 alkyl group, a C 1-5 alkoxy group or halogen in which the alkyl and alkoxy group are optionally substituted, independently, with one or more fluoro; or R7 represents H and R8 is as defined above; or R7 and R8 together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5- to 8-membered heterocyclic group containing a nitrogen and optionally one of the following: oxygen, sulfur or additional nitrogen; wherein the heterocyclic group is optionally substituted with one or more alkyl groups of d.3, hydroxy, fluoro or benzyl; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazole, tetrazolyl, thienyl, furyl or oxazolinyl, each optionally substituted with 1, 2 or 3 Z groups; R4 represents H, halogen, hydroxy, cyano, an alkyl group of C -? - 6, an alkoxy group of d-6 or an alkoxy (d-6) -alkylene group of which contains a maximum of 6 carbon atoms , of which, each of said groups is optionally substituted with one or more fluoro or cyano; Z represents a C1-3 alkyl group, a C1-3 alkoxy group, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, monoalkylamino or dialkylamino C1.3, alkylsulfonyl of d.3, alkoxycarbonyl of C1-3, carboxy, cyano, carbamoyl, monoalkyl (C? -3) -carbamoyl or dialkyl (C1.3) carbamoyl and acetyl; and W represents hydroxy, fluoro, an alkyl group of d-3, an alkoxy group of d-3, amino, monoalkylamino of C1-3 or dialkylamino of d3, an alkoxycarbonyl group of C6-6 or a heterocyclic amine which is selected from morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl in which the heterocyclic amine is optionally substituted with a C1-3 alkyl or hydroxyl group; but excluding [2- [4 ~ [3 - [(ethylmethylamino) carbonyl] -1- (4-methoxyphenyl) -1 H -pyrazol-5-yl] phenoxy] ethyl] carbamate 1,1-dimethylethyl and [2- [4- [1 - (methoxyphenyl) -3- (1-piperidinylcarbonyl) -1-pyrazol-5-yl] phenoxy] ethyl] carbamic acid 1,1-dimethylethyl ester. 2. A compound according to claim 1, wherein R3 represents a group a group as described in paragraph a) above. 3. A compound according to claim 1, as represented by the formula IA
1. IA in which R1 is a) a C4.6 alkoxy group optionally substituted with one or more fluoro, b) a group of the formula phenyl (CH2) pO- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or three groups represented by Z, c) a group R5S (O) 2O or RS (O) 2NH in which R5 represents an alkyl group of d6 optionally substituted with one or more fluoro, or R5 represents phenyl or a heteroaryl group of which each is optionally substituted with 1, 2 or 3 groups represented by Z in which Z is as previously defined, d) a group of the formula (R6) 3 Si in which R6 represents a alkyl group of d-6 which may be the same or different or, e) a group of the formula RO (CO) O in which Rb represents a C 1-6 alkyl group optionally substituted by one or more fluoro; Ra represents halogen and m is 0, 1 or 2; R2a represents chlorine; R2b represents chlorine; R2 ^ represents H or fluoro; R3 represents a group CONHNR7R8 in which NR7R8 represents piperidino or morpholino or R3 represents a group
2. CONHR8 in which R8 represents a C7 cycloalkyl group optionally substituted with an alkoxycarbonyl group of d.6 or R8 represents an optionally substituted pyridyl; and R4 represents H, an alkyl group of d3 or halogen. 4. A compound in accordance with the claim 1, as represented by the formula IB
3. IB in which R1 is a) a C4-6 alkoxy group optionally substituted with one or more fluoro, b) a group of the formula phenyl (CH2) PO- in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, c) a group R5S (O) 2O or R5S (O) 2NH in which R5 represents an alkyl group of d-6 optionally substituted with one or more fluoro, or R 5 represents phenyl or a heteroaryl group each of which is optionally substituted with 1, 2 or 3 groups represented by Z or d) a group of the formula (R 6) 3 Si in which R 6 represents an alkyl group of C 6 -6 which can be the same or different; Ra1 represents halogen or H; Ra2 represents halogen or H; R2a represents chlorine; R2b represents chlorine; R2c represents halogen or H; R3 represents a group CONHNR7R8 in which NR7R8 represents piperidino; and R 4 represents an alkyl group of d 3. 5. A compound according to claim 1, as represented by the formula IC wherein R1 is a) a C4_6 alkoxy group optionally substituted with one or more fluoro, b) a R5S (O) 2O group in which R5 represents a C1_6 alkyl group optionally substituted with one or more fluoro; R2a represents chlorine; R2b represents chlorine; R3 represents a group CONHNR7R8 in which NR7R8 represents piperidino or morpholino; and R 4 represents a C 1-3 alkyl group or halogen. 6. A compound according to any of the preceding claims in which R1 is a group R5S (O) 2O in which R5 represents an alkyl group of d.6 optionally substituted with one or more fluoro. 7. A compound according to any of claims 1 to 5 wherein R1 is a C4-6 alkyl group substituted with one or more fluoro. 8. A compound that is selected from one or more of the following: Ester 4- [2- (2,4-dichloropheni) -4-methyl-5- (piperidin-1-l-carbamoyl) -2H -pyrazol-3-yl] phenyl of butan-1-sulfonic acid; 1 - (2,4-Dichlorophenyl) -4-methyl-5- [4- (4,4,4-trifluorobutoxy) phenyl] -1H-pyrazole-3-carboxylic acid piperidin-1-alamide; 4- (2- (2,4-Dichloro-phenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-yl] -phenyl ester of propan-1-sulfonic acid;
4. 4- (2- (2,4-Dichlorophenyl) -4-methyl-
5. 5- (morpholin-4-yl-carbamoyl) -2H-pyrazol-3-yl] phenyl ester of propan-1-sulfonic acid; Ester 4-3- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-yl] -phenyl acid of 3,3,3-trifluoropropan- 1-sulfonic; 4-4- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-yl] -phenyl ester of 4,4,4-trifluorobutan- 1-sulfonic; Ester [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-yl-carbamoyl) -2H-pyrazol-3-yl] -2,
6. 6-difluoro-phenyl of propan-1 acid sulfonic; 4- (2- (2,4-Dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester of propan-1-sulfonic acid; Ester 4- [4-bromo-2- (2,4-dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl] -propan-1-sulfonic acid; 1 -. { [(1 - (2,4-dichlorophenyl) -4-methyl-5. {4 - [(propylsulfonyl) oxy] f -yl-phenyl] -1- H-pyrazol-3-yl) carbonyl] amino} methylcyclopentanecarboxylate; Propyl ester of the 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester of carbonic acid; 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} phenyl thiophene-2-sulfonate; 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} phenyl-pyridine-3-sulfonate; [2- (4-. {1 - (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-yl-amino) carbonyl] -1 H -pyrazol-5-yl}. Phenoxy ) ethyl butyl tert-butyl carbamate; 1- (2,4-dichlorophenyl) -5-. { 4- [2- (ethylamino) ethoxy] phenyl} -4-methyl-N-piperidin-1-yl-1 H-pyrazole-3-carboxamide; 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} phenyl 3-methylbutan-1-sulfonate; 3,3-dimethylbutan-1-sulfonate of 4-. { 1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) -carbonyl] -1H-pyrazol-5-yl} f enyl; 3, 3- [1 - (2,4-dichloro-phenyl) -4-methyl-3- (- {[[5- (trifluoromethyl) pyridin-2-yl] amino] -3,3-trifluoropropane-1-sulfonate .}. carbonyl) -1H-pyrazol-5-yl] phenyl; 1- (2,4-dichlorophenyl) -5-. { 4- [2- (1, 3-dioxolan-2-yl) ethoxy] phenyl} -4-methyl-N-piperidin-1-yl-1 H-pyrazole-3-carboxamide; 4- (2- (2,4-Dichloro-3-fluorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester of propan-1-sulfonic acid; 5-Chloro-thiophene-2-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazolo-3-yl] -phenyl ester; as well as pharmaceutically acceptable salts thereof. 9. A compound of the formula I according to any of claims 1 to 8 for use as a medicament. 10. A pharmaceutical formulation comprising a compound of the formula I according to any of claims 1 to 8 and a pharmaceutically acceptable adjuvant, diluent or vehicle. 1 - The use of a compound of the formula I according to any of claims 1 to 8 in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety , anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, and neurological disorders, Parkinson's disease, Huntington's chorea and Alzheimer's, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems and indications of widespread abuse, addiction and / or relapse. 12.- A method to treat obesity, psychiatric disorders, psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders , epilepsy, and related conditions, and neurological disorders, Parkinson's disease, Huntington's chorea and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems and indications of widespread abuse , addiction and / or relapse, which comprises administering a pharmacologically effective amount of a compound of the formula I according to any of claims 1 to 8 to a patient in need of the same. 3. A compound according to any of claims 1 to 8 for use in the treatment of obesity. 14. A process for the preparation of compounds of the formula I in which R1 represents a) a d-3 alkoxy group substituted with one or more fluoro or C4-6 alkoxy group optionally substituted with one or more fluoro or b) a group of the formula phenyl (CH2) pO- in which p is 1, 2 or 3, and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, or c) a group R5S (O) 2O , which comprises reacting a compound of the formula III wherein Ra, R2, R3, R4, m and n are as previously defined with any of a) an alkylating agent of the formula R9X in which R9 represents a C1-3 alkyl group substituted with one or more fluoro or alkyl group of C4-6 optionally substituted with one or more fluoro and X represents a leaving group in an inert solvent, in the presence of a base at a temperature in the range of -25 ° C to 150 ° C; or b) an alkylating agent of the formula R9X in which R9 represents a group of the formula phenyl (CH2) - in which p is 1, 2 or 3 and the phenyl ring is optionally substituted with 1, 2 or 3 groups represented by Z, and X represents a leaving group, for example chlorine, bromine or iodine, in an inert solvent in the presence of a base at a temperature in the range of -25 ° C to 150 ° C; or c) an agent for sulfonation of the formula R5SO2L in which R5 is as previously defined and L represents a leaving group, for example chlorine, in an inert solvent in the presence of a base at a temperature in the range of -25 ° C up to 150 ° C; respectively.