BRPI0614626A2 - compound, pharmaceutical formulation, use of a compound, and method for treating disease - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL FORMULATION, USE OF A COMPOUND, AND METHOD FOR TREATING DISEASES. Salts of 1,5-diarylpyrazole-3-carboxamides and processes for preparing such compounds, their use in the treatment of obesity, neurological and psychiatric disorders, methods for their therapeutic use and the pharmaceutical compositions containing them are described.

Description

"COMPOUND, PHARMACEUTICAL FORMULATION, USE OF A COMPOUND, AND METHOD FOR TREATING DISEASES"

FIELD OF THE INVENTION The present invention concerns certain salts of 1,5-diarylpyrazol-3-carboxamides, processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, methods for their therapeutic use and compositions. pharmaceutical products containing them.

BACKGROUND OF THE INVENTION Certain CBi modulators (known as antagonists or inverse agonists) are known to be used in the treatment of obesity, psychiatric and neurological disorders (W001 / 70700 EP 658.546 and EP 656.354). However, there is a need for CB1 modulators with physicochemical properties and / or DMPK properties and / or improved pharmacodynamic properties. Pyrazoles with anti-inflammatory activity are disclosed in WO 95/15316, WO96 / 38418, WO97 / 11704, WO99 / 64415, EP 418 845 and WO2004050632. WO2004050632 discloses 1,1-dimethylethyl [2- [4- [3 - [(ethylmethylamino) carbonyl] -1- (4-methoxyphenyl) -1H-pyrazol-5-yl] phenoxy] ethyl] carbamate, 5- [4- (2-aminoethoxy) phenyl] -N-ethyl-1- (4-methoxyphenyl) -N-methyl-1H-pyrazol-3-carboxamide, 1 - [[5- [4- (2-aminoethoxy) phenyl] -1 - (4-methoxyphenyl) -1H-pyrazol-3-yl] carbonyl] piperidine and 1,1-dimethylethyl [2- [4 - [- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H -pyrazol-5-yl] phenoxy] ethyl] carbamate. All compounds exemplified in WO2004050632 and their salts are excluded from the scope of the claims of the compound of the present invention. 1,5-Diarylpyrazol-3-carboxamide derivatives are disclosed to have CB1 modulating activity in US 5,624,941, W001 / 29007, W02004 / 052864, W003 / 020217, US 2004/0119972, Journal of Medicinal 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), 769-776 1999 and US Pat. Appl. PubL US 2003199536.

Co-pending PCT Application No. PCT / GB2005 / 000534 discloses compounds of formula A

<formula> formula see original document page 3 </formula>

and pharmaceutically acceptable salts thereof, wherein

R1 represents a) a C1-3 alkoxy group substituted by one or more of the following i) fluorine ii) an NRcRd group in which Rc and Rd independently represent H, a C1-6 alkyl group or C1-6 alkoxycarbonyl group provided one of Rc and Rd is other than H or iii) a 1,3-dioxolan-2-yl group b) R1 represents a C1-6 alkoxy group optionally substituted by one or more of the following i) fluorine ii) an NRcRd group in which Rc and Rd independently represent H, a C 1-6 alkyl group or C 1-6 alkoxycarbonyl group provided that one of R c and R d is other than H or iii) a 1,3-dioxolan-2-yl group c) a group of the formula phenyl (CH 2) p O in where ρ is 1, 2 or 3 and the phenyl ring is optionally substituted by 1, 2 or 3 groups represented by Z, d) a group R 5 S (O) 2 O or R 5 S (O) 2 NH where R 5 represents a C 1-6 alkyl group optionally substituted by one or more fluorine, or R 5 represents phenyl group or a heteroaryl each of which is optionally substituted by 1, 2 or 3 groups represented by R e is a group of the formula (R 6) 3 Si in which R 6 represents a C 1-6 alkyl group which may be the same or different or f) a group of the formula RbO (CO) O wherein R b represents an optionally substituted C 1-6 alkyl group for one or more fluorine; Ra represents halo, a C1-3 alkyl group or a C1-3 alkoxy group; m is Ο, 1, 2 or 3; R2 represents a C1-3 alkyl group, a C1-3 alkoxy, hydroxy, nitro, cyano or halo group η is O, 1,2 or 3; R 3 represents a) an X-Y-NR 7 R 8 group in which X is CO or SO 2, Y is absent or represents NH optionally substituted by a C 1-3 alkyl group; and R and R independently represent: a C1-6 alkyl group optionally substituted by 1, 2, or 3 groups represented by W;

a C3-15 cycloalkyl group optionally substituted by 1, 2, or 3 groups represented by W;

a (C3-15 cycloalkyl) C1-3 alkylidene group optionally substituted by 1, 2, or 3 groups represented by W;

a group - (CH2) r (phenyl) s wherein 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 independently substituted by one. , two or three groups represented by

a nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen wherein the heterocycle group is optionally substituted by one or more C1-3 alkyl, hydroxy or benzyl groups; a - (CH 2) t Het group in which t is 0, 1, 2, 3 or 4, and the alkylidene chain is optionally substituted by one or more C 1-3 alkyl groups and Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a C1-5 alkyl group, a C1-5 alkoxy or halo group wherein the alkyl and alkoxy group are optionally independently substituted by one or more fluorine; a 5- to 8-membered saturated heterocyclic group containing OR R 7 represents H and R 8 is as defined above;

or R7 and R8 together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5-8 membered heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen; wherein the heterocycle group is optionally substituted by one or more C1-3 alkyl, hydroxy, fluorine or benzyl groups;

or (b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl, each optionally substituted by 1, 2 or 3 groups Z;

R 4 represents H, halo, hydroxy, cyano, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 alkoxyalkylene group containing a maximum of 6 carbon atoms, each of which is optionally substituted by one or more fluorine or cyano;

Z represents a C1-3 alkyl group, a C1-6 alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, mono or dialkylaminoC1-3 alkylsulfonylC1-3 alkoxycarbonylcarboxycarbonylcarboxycarbonyl mono or diC 1-3 alkylcarbamoyl and acetyl; and

W represents hydroxy, fluorine, a C 1-3 alkyl group, a C 1-3 alkoxy group, amino, mono or diC 1-3 alkylamino, a C 6 alkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic amine is optionally substituted by a C1-3 alkyl or hydroxyl group;

but excluding 1,1-dimethylethyl [2- [4- [3 - [(ethylmethylamino)

carbonyl] -1- (4-methoxyphenyl) -1H-pyrazol-5-yl] phenoxy] ethyl] carbamate and 1,1-dimethylethyl [2- [4- [1- (4-methoxyphenyl) -3- (1- piperidinylcarbonyl) -1H-pyrazol-5-yl] phenoxy] ethyl] carbamate. Salts are mentioned in general terms in PCT / GB2005 / 000534 as follows: "pharmaceutically acceptable salt", where such salts are possible, including both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically acceptable salt of a compound of Formula A is, for example, an acid addition salt of a compound of Formula A which is sufficiently basic, for example, an acid addition salt with an inorganic or organic acid such as hydrochloric acid. hydrobromic, sulfuric, trifluoroacetic, citric or maleic; or, for example, a salt of a compound of Formula A which is sufficiently acidic, for example an alkaline or alkaline earth metal salt such as a 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.

Only 2 specific salts of compounds of Formula A are disclosed in PCT / GB2005 / 000534. These are: pyridine-3-sulfonate hydrochloride 4- 1- (2,4-dichlorophenyl) -4-methyl-3 - [(piperidin-lilamino) carbonyl] -1H-pyrazol-5-yl} phenyl and dihydrohydrochloride 1- (2,4-dichlorophenyl) -5- {4- [2- (ethylamino) ethoxy] phenyl} -4-methyl-N-piperidin-1-yl-1H-pyrazol-3-carboxamide both of which are excluded from the claims of the present invention.

Additional salts with properties suitable for pharmaceutical formulation have recently been found.

In formulating drug compositions, it is important that the drug substance is in a form in which it can be conveniently handled and processed. This is of importance not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound.

Additionally, in the manufacture of drug compositions, it is important that a reliable, reproducible and constant drug plasma concentration profile is provided after administration to a patient.

Chemical stability, solid state stability, and "shelf life" of the active ingredients are also very important factors. The drug substance and compositions containing them should preferably be capable of being effectively stored for appreciable periods of time, without presenting a significant change in the physicochemical characteristics of the active component (e.g. chemical composition, density, hygroscopicity and solubility).

In addition, it is also important to be able to provide the drug in a form that is as chemically pure as possible.

Those of skill in the art have observed that, typically, if a drug can be readily obtained stably, such as a stable crystalline form, advantages can be obtained in terms of ease of handling, ease of preparation of suitable pharmaceutical formulations, and a profile. more reliable solubility.

DESCRIPTION OF THE INVENTION The present invention provides a compound selected from: 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester butane-1-sulfonic acid; piperidin-1-ylamide 1- (2,4-dichlorophenyl) -4-methyl-5- [4- (4,4,4-trifluorobutoxy) phenyl] -1H-pyrazol-3-carboxylic acid; propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) 2H-pyrazol-3-yl] phenyl ester; 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl] propane-1-sulfonic acid ester; 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl] 3,3,3-trifluorpropane-1-sulfonic ester; 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ester)

4,4,4-trifluorobutane-1-sulfonic acid ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

propan-1-sulfonic acid [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester;

propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester;

4- [4-bromo-2- (2,4-dichlorophenyl) -5- (piperidin-1-

propane-1-sulfonic acid ylcarbamoyl) -2H-pyrazol-3-yl] phenyl; Methyl 1 - {[(1- (2,4-dichlorophenyl) -4-methyl-5- {4 [(propylsulfonyl) oxy] phenyl} -1H-pyrazol-3-yl) carbonyl] amino} cyclopentanecarboxylate;

carbonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester propyl ester;

4- {1- (2,4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenylthiophene-2-sulfonate;

4- {1- (254-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-ylamino)

tert-butyl carbonyl] -1H-pyrazol-5-yl} phenoxy) ethyl] ethylcarbamate;

4- {1- (254-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino)

carbonyl] -1H-pyrazol-5-yl} phenyl 3-methylbutane-1-sulfonate;

4- {1- (2,4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenyl 3,3-dimethylbutane-1-sulfonate;

1- (2,4-dichlorophenyl) -5- {4- [2- (13-dioxolan-2-yl) ethoxy] phenyl} -4-methyl-N-piperidin-1-yl-1H-pyrazol-3-one carboxamide;

propan-1-sulfonic acid 4- [2- (2,4-dichloro-3-fluorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester; and

4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ester)

5-chlorothiophene-2-sulfonic acid ylcarbamoyl) -2H-pyrazol-3-yl] phenyl; in the form of a methanesulfonate salt (mesylate salt), a semi-1,5-naphthalenedisulfonate salt, a 1,2-ethanedisulfonic acid salt, a hydrochloride salt or a hydrogen sulfate salt but excluding pyridine hydrochloride 4- {1- (2,4-Dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenyl -3-sulfonate.

In a particular aspect the present invention provides one or more of the following: 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-ester hydrochloride butane-1-sulfonic acid phenyl;

4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl semi-1,5-naphthalenedisulfonate ;

propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride

propane-1-ester 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl semi-1,5-naphthalenedisulfonate sulfonic;

4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester propane-1-sulfonic acid mesylate;

4,4,4-trifluorobutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-lilcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride 4,4,4-trifluorobutane-1-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester mesylate - sulfonic

4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate 4,4 4-trifluorobutane-1-sulfonic; 4- [2- (2,4-dichlorophenyl) -4-methyl ester hydrogen sulfate

4,4,4-Acid 5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl

trifluorobutane-1-sulfonic;

4- [2- (2,4-dichlorophen) -4-methyl-5- ester ester hydrochloride

(piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenylic acid

propane-1-sulfonic;

propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5-piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester mesylate ;

4- [2- (2,4-dichlorophenyl) ester ester semi-1,5-naphthalenedisulfonate

4-Methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl

propane-1-sulfonic acid;

3,3,3-Trifluorpropane-1-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride sulfonic;

3,3,3-Trifluorpropane-1-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester mesylate - sulfonic;

4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate 3,3 , 3-

trifluorpropane-1-sulfonic;

3-4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-lilcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester hydrogen sulfate

trifluorpropane-1-sulfonic; 4- [2- (2,4-dichlorophenyl) -4-methyl-5- ester ester hydrochloride

3-methylbutane-1-sulfonic acid (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

3-methylbutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl mesylate; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (4-pyridm-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate

methylbutane-1-sulfonic;

4- [2- (2,4-dichlorophenyl) -4-methyl-5- ester ester hydrochloride

3,3-Dimethylbutane-1-sulfonic acid (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

3,3-dimethylbutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl mesylate ;

4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate 3,3 -

dimethylbutane-1-sulfonic;

4- [2- (2,4-dichlorophenyl) -4-methyl-5- ester ester hydrochloride

propane-1-sulfonic acid (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-2-ester) mesylate

propane-1-sulfonic acid 1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

4- [2- (2,4-dichlorophenyl) ester ester semi-1,5-naphthalenedisulfonate

Propane-1-sulfonic acid 4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

4- [2- (2,4-dichlorophenyl) -4-methyl ester hydrogen sulfate

Propane-1-sulfonic acid 5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl propyl ester hydrochloride;

4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl propyl ester;

4- [2- ester ester semi-1,5-naphthalenedisulfonate propyl ester

Carbonic acid (2,4-dichlorophenyl) -4-methyl-5-piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl;

pyridine-3-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5-piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl mesylate;

4- [2- (2,4-Dichlorophenyl> 4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate sulfonic.

It is to be understood that the present invention includes one or any combination of more than one of the foregoing salts.

We note that certain compounds of the invention have the advantage that they can be prepared in crystalline form.

According to a further aspect of the invention there is provided a compound of the invention in substantially crystalline form.

Although we have observed that it is possible to produce compounds of the invention in forms which are above 80% crystalline, by "substantially crystalline" we include above 20%, preferably above 30%, and more preferably above 40% (e.g. above any of 50, 60, 70, 80 or 90%) crystalline.

According to a further aspect of the invention there is also provided a compound of the invention in partially crystalline form. By "partially crystalline" we include 5% or between 5% and 20% crystalline.

The degree (%) of crystallinity can be determined by those skilled in the technology using X-ray powder diffraction (XRPD). Other techniques such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry can also be used.

Compounds of the invention, and particularly crystalline compounds of the invention, may have better stability as compared to compounds disclosed in PCT / GB2005 / 000534.

The term "stability" as defined herein includes chemical stability and solid state stability.

By "chemical stability" we include that it may be possible to store compounds of the invention in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (for example, in an oral dosage form). , such as a tablet, capsule, etc.) under normal storage conditions with an insignificant degree of chemical degradation or decomposition.

By "solid state stability" we include that it may be possible to store compounds of the invention in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (for example, in a oral dosage form, such as a tablet, capsule, etc.), under normal storage conditions, with an insignificant degree of solid state transformation (e.g., crystallization, recrystallization, solid state phase transition, hydration, dehydration, solvation or desolvation).

Examples of "normal storage conditions" include temperatures between minus 80 and plus 50 ° C (preferably between 0 and 40 ° C and more preferably ambient temperatures such as 15 to 30 ° C), pressures between 0.1 and 2 bar (preferably at atmospheric humidity), relative humidity between 5 and 95% (preferably 10 to 60%), and / or exposure to visible light / UV of 460 lux for extended periods (i.e. greater than or equal to six months). Under such conditions, compounds of the invention may be considered less than 15%, more preferably less than 10%, and especially less than 5%, chemically degraded / decomposed, or solid state transformed, as appropriate. Technology-savvy have noted that the upper and lower limits mentioned above for temperature, pressure and relative humidity represent extremes of normal storage conditions, and that certain combinations of these extremes will not be observed during normal storage (eg a temperature of 50 ° C and a pressure of 0.1 bar).

It may be possible to crystallize salts of compounds of the present invention with or without the presence of a solvent system (e.g. crystallization may be from a fusion under supercritical conditions or obtained by sublimation). However, it is preferable for crystallization to occur from an appropriate solvent system.

According to a further aspect of the invention, there is provided a process for the preparation of a crystalline compound of the invention comprising crystallizing a compound of the invention from an appropriate solvent system.

Crystallization temperatures and crystallization times depend on the salt to be crystallized, the concentration of that salt in solution, and the solvent system that is used.

Crystallization may also be initiated and / or effected by standard techniques, for example with or without crystal seeding of the appropriate crystalline compound of the invention.

Different crystalline forms of the compounds of the invention can be easily characterized using X-ray powder diffraction (XRPD) methods, for example as described below.

In order to ensure that a particular crystalline form is prepared in the absence of other crystalline forms, crystallizations are preferably performed by seed and / or seed crystals of the desired crystalline form in the substantially complete absence of nucleus and / or seed crystals of other crystalline forms. . Seed crystals of the appropriate compound may be prepared, for example, by slowly evaporating solvent from a portion of the appropriate salt solution.

Compounds of the invention may be isolated using techniques which are well known to those skilled in the art, for example by decanting, filtering or centrifuging.

Compounds can be dried using standard techniques.

Further purification of compounds of the invention may be effected using techniques which are well known to those skilled in the art. For example, impurities may be removed by recrystallization from an appropriate solvent system. Suitable temperatures and times for recrystallization depend on the concentration of the salt in solution and the solvent system that is used.

When the compounds of the invention are crystallized or recrystallized in the manner described herein, the resulting salt may be in a form which has greater chemical and / or solid state stability as mentioned above.

Compounds of the invention have the advantage that they can be more effective, be less toxic, have greater action, have a broad range of activity, be more potent, produce fewer side effects, be more easily absorbed and / or have a better pharmacokinetic profile. (e.g., higher oral bioavailability and / or lower release) and / or have other pharmacological, physical, or chemical properties used with respect to compounds known in the prior art.

Compounds of the invention may have the additional advantage that they may be administered less frequently than compounds known in the prior art.

Compounds of the invention may also have the advantage that they are in a form that provides improved ease of handling. Additionally, compounds of the invention have the advantage that they can be produced in forms that may have greater chemical and / or solid state stability (including for example because of low hygroscopicity). Thus, such compounds of the invention may be stable when stored for extended periods.

Compounds of the invention may also have the advantage that they can be crystallized in good yield, in high purity, quickly, conveniently and at low cost.

It is also to be understood that the compounds of the present invention may exist in solvated, for example hydrated as well as unsolvated, forms. It is to be understood that the present invention encompasses all such solvated and unsolvated forms.

PREPARATION METHODS

The compounds of the invention may be prepared as described below. However, the invention is not limited to these methods.

Salts may be prepared by reacting a compound prepared in the manner described in PCT / GB2005 / 000534 and in the examples section of this application with the appropriate acid, for example methanesulfonic acid, naphthalene-1,5-disulfonic acid, 1,2- ethanedisulfonic acid, sulfuric acid or hydrochloric acid in an inert solvent, for example, butanone at a temperature in the range 0-100 ° C and isolating the solid salt. The salt may be isolated by cooling the reaction solution and optionally seeding the solution with the desired product and / or concentrating the solution. Optionally the product may be isolated by adding an anti-solvent to a solution of the product in an inert solvent. The solid may be collected by methods known to those skilled in the art, for example filtration or centrifugation.

Particularly one molar equivalent of acid with respect to free base is used for methanesulfonic acid and hydrochloric acid, whereas for sulfuric acid, 1,5-naphthalene disulfonic acid and 1,2-ethanedisulfonic acid is used with respect to free base. It is noted that a slight excess of both the basic compound and the acid may be employed. For example, with sulfuric acid a ratio of 1 molar equivalent to 0.5 molar equivalent of base may be employed.

The term "inert solvent" refers to a liquid that dissolves or partially dissolves the free base and / or the acid and / or salt of the product, but does not react with the starting materials, reagents, intermediates or products in a manner adversely affects the yield of the desired product.

In another aspect the present invention provides the compound obtainable by reacting one of the following:

butane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester;

propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester;

4,4,4-trifluorobutane-1-methyl-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-25-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester sulfonic;

propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester;

3,3,3-Trifluorpropane-4- [2- (2,4-dichloro-phenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester 1-sulfonic;

3-methyl-butan-1-sulfonic acid 442- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-lilcarbamoyl) -2H-pyrazol-3-yl] phenyl ester;

3,3-dimethylbutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester;

propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester;

4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester carbonic acid propyl ester; and 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ester)

pyridine-3-sulfonic acid ylcarbamoyl) -2H-pyrazol-3-yl] phenyl; both with

(a) one molar equivalent of hydrochloric acid, as

(b) one molar equivalent of methanesulfonic acid as

(c) one half of a molar equivalent of sulfuric acid as

(d) one half of a molar equivalent of 1,5-naphthalenedisulfonic acid as

e) one half a molar equivalent of 1,2-ethanedisulfonic acid in butanone.

Those skilled in the art should understand that the molar equivalents used are within the experimental error range and may include a slight excess of one of the reagents. For example, about 10% of the equivalent theoretical weight.

In another aspect the present invention provides a compound of formula I

<formula> formula see original document page 18 </formula>

in which

R 1 represents a) a C 1-3 alkoxy group substituted by one or more of the following i) fluorine ii) an NR c R d group wherein R 0 and R d independently represent H, a C 1-6 alkyl group or C 1-4 alkoxycarbonyl group provided that one of R c and R d is other than H or iii) a 1,3-dioxolan-2-yl group b) R1 represents a C4-6 alkoxy group optionally substituted by one or more of the following i) fluorine ii) a NRcRd group in which Rc and Rd independently represent H, a group C 1-6 alkyl or C 1-6 alkoxycarbonyl group provided that one of Re and Rd is other than H or iii) a 1,3-dioxolan-2-yl group c) a group of the formula (CH 2) p O- wherein ρ is 1,2 or 3 and the phenyl ring is optionally substituted by 1, 2 or 3 groups represented by Z, d) a group R 5 S (O) 2 O or R 5 S (O) 2 NH where R 5 represents a C 1-6 alkyl group optionally substituted by one or more fluorine, or R5 represents phenyl group or a heteroaryl each of which is optionally substituted by 1, 2 or 3 groups represented by Z e) a group of the formula (R 6) 3 Si in which R 6 represents a C 1-6 alkyl group which may be the same or different or f) a group of the formula RbO (CO) O wherein R b represents a C 1-6 alkyl group optionally substituted by one or more fluorine;

Ra represents halo, a C1-3 alkyl group or a C1-3 alkoxy group;

m is 0, 1,2 or 3;

R2 represents a C1-3 alkyl group, a C1-3 alkoxy, hydroxy, nitro, cyano or halo group η is 0, 1.2 or 3; R3 represents a) a group X-Y-NR7R8 wherein X is CO or SO2,

Y is absent or represents NH optionally substituted by a C1-3 alkyl group; and R7 and R8 independently represent:

a C1-6 alkyl group optionally substituted by 1, 2, or 3 groups represented by W; a C3-15 cycloalkyl group optionally substituted by 1,2,

or 3 groups represented by W; a (C3-15 cycloalkyl) C1-3 alkylidene group optionally substituted by I2, or 3 groups represented by W;

a - (CH 2) r (phenyl) group, where 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 independently substituted by one. , two or three groups represented by Z;

a saturated 5- to 8-membered saturated heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more C1-3 alkyl, hydroxy or benzyl groups; a - (CH 2) t Het group in which t is 0, 1, 2, 3 or 4, and the alkylidene chain is optionally substituted by one or more C 1-3 alkyl groups and Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a C1-5 alkyl group, a C1-5 alkoxy group or halo wherein the alkyl and alkoxy group are optionally independently substituted by one or more fluorine;

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 5-8 membered heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen; wherein the heterocyclic group is optionally substituted by 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 by 1, 2 or 3 groups Z;

R4 represents H, halo, hydroxy, cyano, a C1-6 alkyl group, a C1-6 alkoxy group or a C1-6 alkylidene C1-6 alkoxy group which contains a maximum of 6 carbon atoms, each of the groups optionally substituted by one or more fluorine or cyano;

Z represents a C1-3 alkyl group, a C1-3 alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, mono or dialkylaminoC3-3 alkylsulfonylC1-3 alkoxycarbonyl, carboxycarbonyl, halo or diC 1-3 alkylcarbamoyl and acetyl; and

W represents hydroxy, fluorine, a C1-3 alkyl group, a C1-3 alkoxy group, amino, mono or diC1-3 alkylamino group, a C1-6 alkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic amine is optionally substituted a C1-3 alkyl or hydroxyl group;

but excluding 1,1-dimethylethyl [2- [4- [3 - [(ethylmethylamino) carbonyl] -1- (4-methoxyphenyl) -1H-pyrazol-5-yl] phenoxy] ethyl] carbamate and 1,1- dimethylethyl [2- [4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl] phenoxy] ethyl] carbamate;

in the form of a methanesulfonate salt, a semi-1,5-naphthalenedisulfonate salt, or a 1,2-ethanedisulfonic acid salt. PHARMACEUTICAL PREPARATIONS

The compounds of the invention will normally be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or in 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 patient to be treated and the route of administration, the compositions may be administered in varying doses.

Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg / kg body weight, preferably 0.01-1 mg / kg body weight.

Oral formulations are preferred, particularly tablets or capsules, which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range 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.

According to a further aspect of the invention there is also provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and / or carriers.

PHARMACOLOGICAL PROPERTIES The compounds of formula (I) are used for the treatment of obesity or overweight, (e.g., weight loss promotion and maintenance of weight loss), prevention of weight gain (eg, induced by medication or subsequent smoking cessation) for appetite and / or satiety modulation, meal disorders (eg, voracious meal, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or food items non-essential), for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorders, anxiety, antidepressant disorders, depression, mania, obsessive compulsive disorders, impulse control disorder (eg Gilles de la Tourette syndrome), attention disorders such as ADD / ADHD, stress, and neurological disorders such as dementia and cognitive dysfunction and / or memory (eg, amnesia, Alzheimer's disease, Pick's dementia, aging dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild aging dementia), neurological and / or neurodegenerative disorders (eg multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelination-related disorders, neuroinflammatory disorders (eg Guillain-Barre syndrome).

The compounds are also potentially used for the prevention or treatment of addiction and addictive disorders and behaviors (eg, alcohol and / or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (eg, alcohol withdrawal with or no perception disorders; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disorders; sedative, hypnotic or anxiolytic withdrawal delirium and symptoms of withdrawal due to other substances), alcohol and / or drug-induced mood, anxiety and / or sleep disorder with onset of action during withdrawal, and alcohol and / or drug relapse.

The compounds are also potentially used for the prevention or treatment of neurological disorders such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal injury, neuropathy, migraine, surveillance disorders, sleep disorders (eg disturbed sleep, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, head trauma.

The compounds are also potentially used for the treatment of immune cardiovascular disorders, (eg, atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythm, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemia attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, stroke, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, disorders metabolic disorders (eg, conditions showing lower metabolic activity or a decrease in resting energy expenditure as a percentage of total fat free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, tolerance impaired glucose, altered fasting glucose, 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, low adiponectin levels), reproductive and endocrine disorders (eg, male hypogonadism treatment, infertility or contraceptive treatment, menstrual amenopathy / abnormalities, polycystic ovary disease, sexual and reproductive dysfunction in women and men) (erectile dysfunction), GH deficient subjects, female hirsutism, normal variant short stature) and respiratory-related diseases (eg asthma and chronic obstructive pulmonary disease) and gastrointestinal (eg gastrointestinal mobility dysfunction or intestinal propulsion, diarrhea) , vomiting, nausea, gallbladder disease, cholelithiasis, reflux gas -esophageal disease related to obesity, ulcers).

The compounds are also potentially used for treating dermatological disorders, cancers (eg, colon, rectum, prostate, breast, ovarian, endometrium, cervic, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (eg, deforming arthritis, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds are also potentially used as agents in the treatment of achalasia (esophageal).

In another aspect, the present invention provides a compound of the invention as previously defined for use as a medicament.

In a further aspect, the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of obesity or overweight (e.g., promoting weight loss and maintaining weight loss). prevention of weight gain (eg, medication-induced or subsequent smoking cessation), for appetite and / or satiety modulation, meal disorders (eg, voracious, anorexia, bulimia and compulsive meal), cravings (by drugs) , tobacco, alcohol, any appetizing macronutrients or nonessential food items), for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorders, anxiety, antidepressant disorders, depression, mania, obsessive disorders -compulsive disorders, impulse control disorder (eg Gilles de la Tourette syndrome), attention disorders such as ADD / ADHD, stress, and neurological disorders such as dementia and cognitive dysfunction and / or memory (eg, amnesia, Alzheimer's disease, Pick dementia, aging dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild aging dementia), neurological and / or neurodegenerative disorders (eg multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelination-related disorders, neuroinflammatory disorder (eg Guillain-Barre).

In a further aspect the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of addiction and addictive disorders and behaviors (e.g., alcohol and / or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (eg, alcohol withdrawal with or without perception disorders; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without without perception disorders, sedative, hypnotic or anxiolytic delirium withdrawal, and withdrawal symptoms due to other substances), alcohol and / or drug-induced mood, anxiety and / or sleep disorder with onset of action during withdrawal, and relapse of alcohol and / or drugs.

In a further aspect the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of neurological disorders such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal injury, neuropathy, migraine. , vigilance disorders, sleep disturbances (eg, disturbed sleep architecture, sleep apnea, obstrutirva sleep apnea, sleep apnea syndrome), pain disorders, head trauma.

In a further aspect, the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of immune cardiovascular disorders, (e.g., atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemia attack, peripheral vascular disease, systemic vasculature inflammation, septic shock, stroke, stroke cerebrovascular infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (eg, conditions that exhibit lower metabolic activity or a decrease in resting energy expenditure as a percentage of total fat free mass, diabetes mellitus, dyslipidemia fat liver drop hi percolesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, hypoventilation obesity syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL and / or high LDL cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (eg treatment of male hypogonadism, treatment of infertility or as a contraceptive, amenopathy / menstrual abnormalities, ovarian disease polycystic disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH deficient subjects, hirsutism in females, normal variant short stature) and respiratory system-related diseases (eg asthma and chronic obstructive pulmonary disease) and gastrointestinal (eg example, gastrointestinal or functional mobility dysfunction Intestinal injury, diarrhea, vomiting, nausea, gallbladder disease, cholelithiasis, obesity-related gastroesophageal reflux, ulcers).

In a further aspect the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast, ovarian, endometrium, cervical, gallbladder). , bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (eg, deforming arthritis, 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 invention to a patient in need thereof for the prophylaxis or treatment of obesity or overweight, (e.g., weight loss promotion). and maintenance of weight loss), prevention of weight gain (eg, medication induced or subsequent smoking cessation), for appetite and / or satiety modulation, meal disorders (eg, voracious meal, anorexia, bulimia and cravings), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or nonessential food items), for the treatment of psychiatric disorders such as psychotic and / or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorders, anxiety, antidepressants, depression, mania, obsessive-compulsive disorders, impulse control disorder (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, mild cognitive impairment, age-related cognitive decline, and mild aging dementia), neurological and / or neurodegenerative disorders (eg, multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea, and Alzheimer's disease) , demyelination-related disorders, neuroinflammatory disorders (eg Guillain-Barre syndrome).

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for prophylaxis or treatment of addiction and addictive disorders and behaviors (e.g., alcohol and / or drug abuse , pathological gambling, kleptomania), drug withdrawal disorders (eg, alcohol withdrawal with or without perception disorders; delirium of alcohol withdrawal; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic with or without perception disorders; delirium of sedative, hypnotic or anxiolytic withdrawal; and withdrawal symptoms due to other substances), alcohol and / or drug-induced mood, anxiety disorder and / or sleep with onset of action during withdrawal, and alcohol and / or drug relapse.

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of neurological disorders such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal injury, neuropathy, migraine, vigilance disorders, sleep disturbances (eg, disturbed sleep architecture, sleep apnea, obstrutirva sleep apnea, sleep apnea syndrome), pain disorders, head trauma.

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of immune cardiovascular disorders (e.g. atherosclerosis, atherosclerosis, angina pectoris, rhythms heart failure, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemia attack, peripheral vascular disease, systemic inflammation of the vasculature, shock sepsis, stroke, stroke, stroke, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral haemorrhage, metabolic disorders (eg, conditions that exhibit lower metabolic activity or a decrease in resting energy expenditure as a percentage of ma total fat-free ssa, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, syndrome hypoventilation obesity (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL and / or high LDL cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (eg treatment of male hypogonadism, treatment infertility or as a contraceptive, ameniopathy / menstrual abnormalities, polycystic ovary disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH deficient subjects, female hirsutism, normal variant short stature) and respiratory system-related diseases ( eg asthma and chronic obstructive pulmonary disease) and gastrin (eg, gastrointestinal mobility dysfunction or intestinal propulsion, diarrhea, vomiting, nausea, gallbladder disease, cholelithiasis, obesity-related gastroesophageal reflux, ulcers).

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of dermatological disorders, cancers (e.g., colon, rectum, prostate, breast, ovarian, endometrium, cervic, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (eg, deforming arthritis, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders.

The compounds of the present invention are particularly suitable for treating obesity or overweight, (e.g., promoting weight loss and maintaining weight loss), preventing or reversing weight gain (e.g., recovery, induced medication or subsequent smoking cessation), for appetite and / or satiety modulation, meal disorders (eg, voracious meal, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrient or items food products).

The compounds of formula (I) are used for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, antidepressant 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 (eg, multiple sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea, and Alzheimer's disease. The compounds are also potentially used for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock, and respiratory and gastrointestinal disorders (eg, diarrhea). The compounds are also potentially used as agents in the treatment of prolonged abuse, indications of addiction and / or relapse, for example drug related dependence (nicotine, ethanol, cocaine, opiates, etc.) and / or withdrawal symptoms. related (nicotine, ethanol, cocaine, opiates, etc.). The compounds may also eliminate the weight gain that normally accompanies smoking cessation.

In another aspect the present invention provides a compound of the invention as previously defined for use as a medicament.

In a further aspect the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, antidepressant 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), Parkinson's disease, Huntington's chorea, and malaria. Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, respiratory and gastrointestinal disorders (eg, diarrhea), and prolonged abuse, addiction and / or relapse indications, eg, drug-related dependence (nicotine, cocaine, opiates, etc.) and / or syn withdrawal of the related drug (nicotine, ethanol, cocaine, opiates, etc.).

In a still further aspect the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, antidepressant 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), 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 system (eg diarrhea), and prolonged abuse, addiction and / or relapse indications, eg drug related dependence (nicotine, ethanol, cocaine, opiates, etc.) and / or symptoms of drug withdrawal related (nicotine, ethanol, cocaine, opioid acts, etc.) comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof.

The compounds of the present invention are particularly suitable for treating obesity, for example by reducing appetite and body weight, maintaining weight reduction and preventing recovery.

The compounds of the present invention may also be used to prevent or reverse medication-induced weight gain, for example, weight gain caused by antipsychotic (neuroleptic) treatment (s). The compounds of the present invention may also be used to prevent or reverse weight gain associated with smoking cessation.

The compounds of the present invention are suitable for use in treating the above indications in a young or adolescent patient population.

The compounds of the present invention may also be suitable for use in regulating bone mass and bone loss and therefore used in the treatment of osteoporosis and other bone diseases.

COMBINATION THERAPY

The compounds of the invention may be combined with another therapeutic agent which is used in the treatment of obesity such as other anti-obesity drugs, which affect energy expenditure, glycolysis, gluconeogenesis, glycogenolysis, lipolysis, lipogenesis, fat absorption, fat storage. fat excretion, hunger and / or satiety and / or craving mechanisms, appetite motivation, food intake, or GI motility.

The compounds of the invention may be further combined with another therapeutic agent which is used in the treatment of disorders associated with obesity such as hypertension, hyperlipidemias, dyslipidemias, diabetes, sleep apnea, asthma, heart disorders, atherosclerosis, macro and micro vascular diseases. , steatos and liver disease, 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 decreases the LDL: HDL ratio or an agent that causes a decrease in LDL cholesterol circulation levels. In patients with diabetes mellitus, the compounds of the invention may also be combined with therapeutic agents used to treat microangiopathy-related complications.

The compounds of the invention may be used in parallel with other therapies for the treatment of obesity and its complications associated with metabolic syndrome and type 2 diabetes. These drugs include biguanide, insulin (synthetic insulin analogues) and oral antihyperglycemic drugs (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors).

In another aspect of the invention, the compound of the invention, or a pharmaceutically acceptable salt thereof may be administered in combination with a PPAR modulating agent. PPAR modulating agents include, but are not limited to, a PPAR alpha and / or gamma agonist, or salts, solvates, solvates of such pharmaceutically acceptable salts or prodrugs thereof. Suitable PPAR alpha and / or gamma agonists, salts, solvates, solvates of such pharmaceutically acceptable salts or prodrugs thereof are well known in the art.

In addition, the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol lowering agent. Cholesterol lowering agents referred to in this application include, but are not limited to, HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitors. The suitable HMG-CoA reductase inhibitor is a statin.

In the present application, the term "cholesterol lowering agent" also includes chemical modifications of HMG-CoA reductase inhibitors such as esters, prodrugs and metabolites, either active or inactive.

The present invention also includes a compound of the present invention in combination with an ileal bile acid transport system inhibitor (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin.

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 colestagel.

According to a further further aspect of the present invention, a combination treatment is provided comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with simultaneous, sequential or separate administration of one or more of the following selected agents from:

a CETP (cholesteryl ester transfer protein) inhibitor;

a cholesterol absorption antagonist; an MTP (microsomal transfer protein) inhibitor; 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 antihypertensive compound for example, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor II antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha adrenergic blocker, a adrenergic stimulant, calcium channel blocker, an AT-1 blocker, a uretic salt, a diuretic or a vasodilator;

a melanin concentration hormone (MCH) modulator;

an NPY receptor modulator; a uridine receptor modulator;

a phosphoinositide dependent protein kinase (PDK) modulator; or

nuclear receptor modulators for example, LXR5 FXR5 RXR, GR, ERRa5 β5 PPARa5 β, y and RORalfa;

a monoamine transmission modulating agent, for example, a selective serotonin reuptake inhibitor (SSRI), a norepinephrine recapitation inhibitor (NARI) 5 a noradrenaline serotonin reuptake inhibitor (SNRI) 5 a monoamine oxidase inhibitor ( MAGI), a tricyclic antidepressant agent (TCA), a specific noradrenergic and serotonergic antidepressant (NaSSA);

an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptinleptin receptor modulator; a ghrelin / ghrelin receptor modulator; a DPP-IV inhibitor;

or a pharmaceutically acceptable salt, solvate, solvate of a salt such as this or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier for a warm-blooded animal such as man in need of such therapeutic treatment.

According to a further aspect of the present invention, a combination treatment is provided comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low calorie diets (LCD).

Therefore, in a further feature of the invention there is provided a method for treating obesity and its associated complications in a warm-blooded animal, such as man, which requires such treatment which comprises administering to said animal an effective amount of a compound. of the invention, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of a salt such as this one. or such a prodrug.

Therefore, in a further feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, which needs such treatment which comprises administering to said animal an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound of one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof . According to a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a compound of one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt solvate. solvate of a salt such as this or a prodrug thereof in combination with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention, there is provided a kit comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a compound of one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate such a salt or a prodrug thereof.

According to a further aspect of the present invention, a kit is provided comprising:

a) a compound of the invention, or a pharmaceutically acceptable salt thereof, in a first unit dosage form;

b) a compound of one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and

c) container device for containing said first and second dosage form.

According to a further aspect of the present invention, a kit is provided comprising:

a) a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form;

b) a compound of one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in a second unit dosage form; and

c) container device for containing said first and second dosage form.

According to another feature of the invention, there is provided the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of a salt such as this or such a prodrug in the manufacture of a medicament for use in treating obesity and its associated complications in a warm-blooded animal such as man.

According to another feature of the invention, there is provided the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of a salt such as this or such a prodrug in the manufacture of a medicament for use in treating hyperlipidemic conditions in a warm-blooded animal such as man.

According to a further aspect of the present invention, a combination treatment is provided comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier with simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a diluent or pharmaceutically acceptable carrier for a warm-blooded animal, such as man, in need of such therapeutic treatment.

In addition, a compound of the invention may also be combined with therapeutic agents which are used to treat disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, nonalcoholic steatoepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.

It should be understood that there are medically accepted definitions of obesity and overweight. A patient can be identified by, for example, measuring body mass index (BMI), which is calculated by dividing weight in kilograms by height in square meters, and comparing the result with the definitions.

PHARMACOLOGICAL ACTIVITY

Compounds of the present invention are active against the CB 1 gene receptor product. The affinity of the compounds of the invention for central cannabinoid receptors is demonstrable in methods described in Devane et al, Molecular Pharmacology, 1988, 34,605 or those described in WOO1 / 70700. or EP 656354. Alternatively the assay may be performed as follows.

10 μg of prepared stable cells transfected with the CB1 gene were suspended in 200 μΐ of 100 mM NaCl, 5 mM MgCl2, 1 mM EDTA, 50 mM HEPES (pH 7.4), IMT DTT, 0.1% BSA and GDP 100 μΜ. To this was added an agonist EC80 concentration (CP55940), the required concentration of test compound and 0.1 μα [35SJ-GTPyS. The reaction proceeded naturally at 0 ° C for 45 minutes. Samples were then transferred to GFIB filters using a cell harvester and washed with cleaning buffer (50 mM Tris (pH 7.4), 5 mM MgCl2, 50 mM NaCl). Filters were then covered with scintillant and counted by the amount of [35SJ-GTPyS retained by the filter.

Activity is measured in the absence of all ligands (minimum activity) or in the presence of an EC80 concentration of CP55940 (maximum activity). These activities are set at 0% and 100% of the activity respectively. At various unpublished binder concentrations, activity is calculated as a percentage of the maximum activity and plotted. Data are adjusted using the equation y = A + ((B-A) / 1 + ((C / x) LTD)) and the IC50 value determined as the concentration required to give half of the maximum inhibition of GTPyS binding under the conditions used.

The compounds of the present invention are active at the CB 1 receptor (IC50 <1 micromolar). Most preferred compounds have IC50 <200 nanomolar.

The compounds of the invention are believed to be selective CB 1 antagonists or inverse agonists. The potency, selectivity profile and side effect propensity may limit the clinical utility of the compounds hitherto known with supposed CB 1 antagonistic / inverse agonistic properties. In this regard, preclinical evaluation of compounds of the present invention in models of gastrointestinal and / or cardiovascular function indicates that it offers significant advantages compared with representative reference of CB 1 antagonist / inverse agonist agents.

The compounds of the present invention may provide additional benefits in terms of potency, selectivity profile, bioavailability, plasma half-life, blood brain permeability, plasma protein binding (e.g., higher drug free fraction) or solubility compared with representative reference. CB1 antagonist / inverse agonist agents.

The utility of the compounds of the present invention in the treatment of obesity and related conditions is demonstrated by an increase in body weight in obese diet-induced mice. Female C57B1 / 6J mice had ad libitum access to the calorie-dense "restaurant" diet (soft chocolate / butter cake, chocolate, greasy and sweet cheese) and standard laboratory food for 8-10 weeks. Compounds to be tested were then systematically administered (iv, ip, sc or po) once daily for a minimum of 5 days, and mouse body weights monitored on a daily basis. Simultaneous adiposity assessment was performed by baseline DEXA imaging and study termination. Blood sampling was also performed to test for changes in obesity-related plasma markers. Examples of the invention Abbreviations

AcOH Acetic Acid

DCM dichloromethane

Dimethylformamide DMF

DEA diethylamine

DIEA N, N-diisopropylethylamine 41

DMAP 4-dimethylaminopyridine

EtOAc ethyl acetate

Et3N triethylamine Ex or EX Example

5LiHMDS lithium hexamethyldisilazide

LiHMDSA Lithium bis (trimethylsilyl) amide bis (trimethylsilyl) amide

MEK Methyl Ethyl Ketone

Methanol MeOH

MeCN acetonitrile

10 NMM 4-methylmorpholine

NMP N-methylpyrrolidone

rt or RT room temperature

TBTU 0- (benzotriazol-1-yl) -N, N, N ', N-tertamethyluronium

TEA triethylamine

15 TFA Trifluoroacetic acid

THF tetrahydrofuran

triplet t

s singlet

d doublet

20 q quartet

qvint quintet

m multiplet

br broad

bs broad singlet

25 dm multiplet doublet

bt broad triplet

dd doublet of doublet

General Experimental Procedures

Mass spectra were recorded on either a single quadruple Micromass ZQ mass spectrometer or a single quadruple Micromass LCZ mass spectrometer, both equipped with a pneumatically assisted electrospray (LC-MS) interface. 1H NMR measurements were performed on both a Varian Mercury 300 and a Varian Inova 500, operating at 300 and 500 MHz IH frequencies, respectively. Chemical shifts are given in ppm with CDCl3 as internal standard. CDCl3 is used as the solvent for NMR unless otherwise stated. Purification was performed on a semipreparative HPLC (High Performance Liquid Chromatography) with a mass triggered fraction collector, Shimadzu QP 8000 single quadruple mass spectrometer equipped with a 19 χ 100 mm C8 column. The mobile phase used was, if not further established, acetonitrile and buffer (ammonium acetate: 0.1 M acetonitrile 95: 5). For isolation of isomers, a Kromasil CN E9344 column (250 χ 20 mm i.d.) was used. Heptane: ethyl acetate: DEA 95: 5: 0.1 was used as the mobile phase (1 m / min). Fraction collection was conducted using a UV detector (330 nm).

Typical HPLC parameters for purity analysis:

HPLC system: Agilent 1100

Column: Zorbax Eclipse XDB-C8 150 χ 4.6 mm

Analysis time: 15 min

Flow rate: 1.5 mL / min

Mobile phase: A: water, 5% MeOH

B: MeOH

Temperature: 40 0C

Detector: UV 240 nm

Examples

General salt preparation procedure

The free base (usually 15-30 mg) was dissolved in butanone (For example, 0.08 to 0.2 mL usually 0.8-2 mL) and if necessary together with methanol (usually less than 1 mL). The solution was optionally placed in an ultrasonic bath (Decon FS200b). Acid (1 molar equivalent (equiv.) HCl or 1 equiv methanesulfonic acid or 0.5 equiv naphthalene-1,5-disulfonic acid) or 1 equiv. or 0.5 equiv. of sulfuric acid dissolved in methanol (usually 0.1-0.2 mL) was added. Heptane (usually 0.5-2 mL) was added dropwise and the resulting mixture was left in the ultrasonic bath. The solid formed was collected by filtration and dried under high vacuum.

Melting points were determined on a Reichert melting point microscope and are incorrect. Those skilled in the art realize that the heating rate may affect the obtained melting point and that certain salts, for example hydrochloride salts, may dissociate under slow heating so that in the end the obtained melting point may be that of the free base or that of a mixture of free base and hydrochloride salt. In such cases combustion analysis may be used to confirm the identity of the salt. Those skilled in technology will also appreciate that the drying temperature cannot be too high, for example above 45 ° C, otherwise salt decomposition may occur. Vacuum drying is preferred.

The following salts were formed as described in the general procedure using appropriate acid.

Example 1: Butan-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester

Hydrochloride: mp 106-112 ° C.

Semi-1,5-naphthalenedisulfonate: mp 160-163 ° C.

Example 2: Propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester

Hydrochloride: mp 220-223 ° C.

Semi-1,5-naphthalenedisulfonate: mp 270-274 ° C.

Mesylate: mp 218-223 ° C. Example 3: 4,4,4-Trifluorobutane-4- (2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester 1 - sulfonic

Hydrochloride: melting point: 100-105 ° C

Mesylate: mp 169-174 ° C.

Semi-1,5-naphthalenedisulfonate: mp 260-265 ° C.

Hydrogen sulphate: mp 203-207 ° C.

Example 4: Propane-1-Acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester - sulfonic

Hydrochloride: melting point: 104-108 ° C.

Mesylate: mp 141-145 ° C.

Semi-1,5-naphthalenedisulfonate: mp 271-274 ° C.

Example 5: 3,3,3-Trifluoropropane-4- (2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester l- sulfonic

Hydrochloride: melting point: 101-107 ° C.

Mesylate: mp 168-173 ° C.

Semi-1,5-naphthalenedisulfonate: mp 159-164 ° C.

Hydrogen sulphate: mp 205-209 ° C.

Example 6: 3-Methyl-butan-1-methyl-4- (2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester sulfonic

Hydrochloride: melting point: 110-115 ° C.

Mesylate: mp 122-127 ° C.

Semi-1,5-naphthalenedisulfonate: mp 161-164 ° C.

Example 7: 3,3-Dimethyl-butane-4- (2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester l- sulfonic

Hydrochloride: melting point: 112-119 ° C. Mesylate: mp 160-167 ° C. Semi-1,5-naphthalenedisulfonate: mp 276-279 ° C. Example 8: Propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester Hydrochloride: dot mp 185-189 ° C. Mesylate: mp 111-114 ° C. Semi-1,5-naphthalenedisulfonate: mp 156-161 ° C. Hydrogen sulphate: mp 203-209 ° C. Example 9: Carbonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl propyl ester Hydrochloride: melting: 99-108 ° C. Mesylate: mp 110-115 ° C. Semi-1,5-naphthalenedisulfonate: mp 175-180 ° C. Example 10: Pyridine-3-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5-piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester

Semi-1,5-naphthalenedisulfonate: melting point 168-172 ° C Preparation of Free Bases

1) 4- (2- (2,4-Dichlorophenin-4-methyl-5-) -piperidin-1-ylcarbamoyl-2-pyrazol-2-ester

Propane-1-sulfonic acid 3-phenylphenyl Step A 1- (4-benzyloxyphenyl) propan-1-one

4-Hydroxypropiophenone (15.0 g, 50 mol) was dissolved in acetone (200 mL) along with potassium carbonate (13.8 g, 10 mol). Benzyl bromide (17.1 g, 0.10 mol) was added and the reaction mixture heated at reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated on the rotary evaporator to afford 24.0 g (100%) of the title compound as a white solid.

Step B 1- (4-Benzyloxyphenyl V2-bromopropan-1-one

1- (4-benzyloxyphenyl) propan-1-one (4.80 g, 20.0 mmol) was suspended in acetic acid (25 mL) and cooled to 0 ° C. Bromine (3.20 g, 20.0 mmol) was added dropwise and the reaction mixture stirred two hours at room temperature at which point the reaction mixture was a pale yellow solution. After cooling, water (100 mL) was added and the product extracted with ether (2 x 100 mL). The combined organic extracts were washed with water, sodium hydrogen carbonate and brine. The organic phase was dried (Na 2 SO 4), filtered and evaporated leaving the title compound as a faded yellow solid (6.17 g, 97%). Step C 2- (2- (4-Benzyloxy-phenyl) -2-oxo-ethyl-3-oxobutyric acid ethyl ester

A sodium ethoxide solution was generated from sodium metal (0.53 g, 23.0 mmol) and methanol 30 mL abs. To this solution was added ethyl acetoacetate (3.00 g, 23.0 mmol) at 0 ° C. After 30 minutes this solution was added to a solution of 1- (4-benzyloxyphenyl) -2-bromo-propan-1-one (6.17 g, 19.0 mmol) in ethanehtoluene (30:15 mL) and the mixture from the stirring reaction all night long. Acid development with 1 M HCl, extraction with ethyl acetate (3 x), brine washing, drying (Na 2 SO 4), filtration and evaporation left a crude product purified by flash flash chromatography (hexane: EtOAc 95: 5-70: 30 ) providing 5.18 g of the title compound as a faded yellow oil.

Step D 5-R4-Benzyloxyphenyl-N-carboxylic acid

A solution of sodium ethoxide was generated from sodium metal (0.19 g, 8.26 mmol) in ethanol 20 mL abs. To this solution was added 2- [2- (4-benzyloxyphenyl acid ethyl ester). ) -2-oxo-ethyl] -3-oxobutyric (2.13 g, 6.00 mmol) and the reaction mixture stirred at room temperature for 30 minutes. A previously prepared solution of 2,4-dichlorophenyldiazonium chloride (prepared from 2,4-dichloroaniline (1.19 g, 7.30 mmol) in 3 mL 24% HCl and sodium nitrite (0.52 g 7.50 mmol) in 3 mL of water at 0 ° C) was added in 5 portions leaving the temperature below 50 ° C. After stirring at room temperature for 2.5 hours, Water was added, and the product extracted with EtOAc (3 x). The combined organic extracts were dried (Na 2 SO 4), filtered and evaporated. The residue was dissolved in ethanol (40 mL) and sodium hydroxide (0.80 g, 20.0 mmol) in 10 mL of water was added. After 2 hours boiling under reflux the reaction mixture was cooled, acidified with HCl and the product extracted with EtOAc (3 x). After washing, drying (Na 2 SO 4), filtration and concentration, the residue was purified by flash chromatography (70:30 - 50:50 hexane: EtOAc) affording 1.84 g (68%) of the title compound as a solid. Faded yellow.

Step E Piperidin-1-ylamide 5- (4-benzyloxyphenyl] -1,2,4-dichlorophenyl) -4 · methyl-1H-pyrazol-3-carboxylic acid

5- (4-Benzyloxyphenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (1.84 g, 4.07 mmol) was suspended in dichloromethane and a few drops of DMF added followed by the addition of oxalyl chloride (1.03 g, 8.14 mmol). The reaction mixture was refluxed for two hours. After cooling to room temperature, the solvent was removed and the crude hydrochloric acid redissolved in dichloromethane and cooled to 0 ° C. Triethylamine (1.15 mL, 8.20 mmol) was added followed by 1-aminopiperidine (0.5 mL, 4.50 mmol). The cooling bath was removed and the reaction mixture stirred at room temperature for 2 hours. Water was added and the product extracted with dichloromethane (3x). The combined extracts were dried (Na 2 SO 4), filtered and evaporated. Flash chromatography (80:20 - 70:30 hexane: EtOAc) provided 1.13 g (52%) of the title compound as a solid.

Step F Piperidin-1-yl amide 1-, 2,4-dichlorophenin-5'-4-hydroxyphenyl-4-methyl-1H-pyrazol-3-carboxylic acid Piperidin-1-ylamide- (4-benzyloxyphenyl) -1 - ( 2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (1.00 g, 1.87 mmol) was dissolved in 25 mL of abs ethanol. together with 100 mg palladium on charcoal (10% Pd). The reaction was hydrogenated with a flask overnight. Filtration, concentration and flash chromatography (50:50 hexane: EtOAc - EtOAc) provided 0.83 g (100%) of the title compound as a solid.

Step G Propane-1-Sulfonic Acid 4-r2-r2,4-dichlorophenin-4-methyl-5- (piperidin-lilcarbamoin2H-pyrazol-3-yl-phenyl ester)

Piperidin-1-yl amide 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (222 mg, 0.50 mmol) was dissolved in dichloromethane ( 10 mL) and triethylamine (0.07 mL, 0.50 mmol) was added. Propanesulfonyl chloride (71 mg, 0.50 mmol) was added at 0 ° C, the cooling bath removed and the reaction stirred at room temperature for 2 hours. Water was added and the product was extracted with dichloromethane, dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (hexane: EtOAc 70:30 - 50: 50) provided a product which was recrystallized from hexane: EtOAc to give 135 mg (49%) of the title compound as a white solid m.p. 190 ° C. 1H NMR (CDCl3): δ 7.66 (1H, 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)

2) Piperidin-1-ylamide 1- (Z4-dichlorophenyl-V4-methyl-5-4-4A4-trifluorobutoxy) -phenyl-1H-pyrazol-3-carboxylic acid

Piperidin-1-yl amide 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid from 1, Step F (250 mg, 0.56 mmol) was dissolved in acetone (10 mL) and potassium carbonate (77 mg, 0.56 mmol) was added followed by 1-iodo-4,4,4-trifluorobutane (140 mg, 0.56 mmol). The reaction mixture was boiled under reflux overnight, concentrated and purified by flash chromatography (70:30 - 60:40 hexane: EtOAc) afforded 130 mg (42%) of a white solid which was triturated with hexane: 95: 5 EtOAc and filtered.

1H NMR (CDCl3): δ 7.63 (1H, broad s), 7.43 (1H, 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, wk), 2.15-1.97 ( 2H, m), 25 1.78 (4H, m), 1.45 (2H, m), MS m / z 577 (M + Na), HPLC: 98.4%

3) Butane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl ') -4-methyl-5- (piperidin-1-ylcarbamoyl) 2H-pyrazol-3-yl-phenyl ester

Piperidin-1-yl amide 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid prepared as in 1, Step F (350 mg, 0.78 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.11 mL, 0.78 mmol) was added. Butanesulfonyl chloride (0.12 g, 0.78 mmol) was added at 0 ° C, the cooling bath removed and the reaction stirred at room temperature overnight. Water was added, the product extracted with dichloromethane, dried (Na2 SO4), filtered and concentrated. Flash vapor chromatography (hexane: EtOAc 70:30 - 50:50) provided a product which was recrystallized from hexane: EtOAc to give 200 mg (45%) of the title compound as a solid.

1H NMR (CDCl3): δ 7.48-7.19 (8H, m), 3.29 (2H, m), 2.96 (4H, em), 2.41 (3H, s), 2.09 -1.97 (2H, m), 1.81 (4H, m), 1.64-1.50 (4H, m), 1.02 (3H, t)

4) propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl] -4-methyl-5- (morpholin-4-ylcarbamoyl] 2H-pyrazol-3-ylphenyl ester

Step A 5- (4-Benzyloxyphenyl-1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid morpholin-4-ylamide

To a solution of 5- (4-benzyloxyphenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid prepared as in 1, Step D (1.18 g, 2, 6 mmol) in 25 mL of CH 2 Cl 2 was added 2 drops of DMF followed by oxalyl chloride (0.44 mL, 5.2 mmol). The mixture was boiled under reflux for 2 hours, cooled to room temperature and evaporated to dryness. The residue was dissolved in 25 mL of CH 2 Cl 2 and cooled to 0 ° C. Triethylamine (0.73 mL, 5.2 mmol) was added followed by 1-aminopiperidine (0.28 mL, 2.9 mmol) and the mixture was stirred at room temperature for 3 hours. Water (100 mL) was added and the mixture was extracted with CH 2 Cl 2 (3 x 50 mL), dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (silica, hexanorEtOAc 1: 2, EtOAc) provided 215 mg (15%) of the title compound as a white solid.

Step B Morpholin-4-ylamide 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid

Morpholin-4-ylamide 5- (4-benzyloxyphenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (215 mg, 0.40 mmol) was dissolved in 20 mL of CH 2 Cl 2 and cooled to 0 ° C. Boron tribromide (78 μΐ, 0.80 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2.5 hours. Water (50 mL) was added and the solution extracted with EtOAc (3 x 50 mL). The combined organic phases were dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (silica, hexane: EtOAc 1: 2, EtOAc) provided 180 mg (99%) of the title compound as a white solid.

Step C Propane-1-Sulfonic Acid 4-R 2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoin-2H-pyrazol-3-yl-phenyl ester

A solution of morpholin-4-ylamide 1- (2,4-dichlorophenyl) 5- (4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (180 mg, 0.40 mmol) in 10 mL of CH 2 Cl 2 was cooled to 0 ° C. Triethylamine (56 μΐ, 0.40 mmol) was added followed by 1-propanesulfonyl chloride (45 μΐ, 0.40 mmol) and the reaction mixture was stirred at room temperature for 5 hours. Water was added and the mixture was extracted with CH 2 Cl 2 (3 x 20 mL), dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (silica, hexane: EtOAc 1: 2) afforded 82 mg (46%) of the title compound as a white solid.

1H NMR (CDCl3): δ 7.7 (1H, s), 7.5-7.4 (1H, 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%. .5) 4-R2 - (, 2,4-Dichlorophenyl] -4-methyl-5-piperidin-1-ylcarbamoyl-2H-ester

3,3,3-trifluorpropane-1-sulfonic acid phenyl pyrazol-3-yl Step A Piperidin-1-yl-amide 1- (2,4-dichlorophenyl) -5-hydroxyphenyl) -4-methyl-1H-pyrazol-3-yl carboxylic

Piperidin-1-ylamide- (4-benzyloxyphenyl) -1- (2,4-

dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic, prepared as in 5, Step E (330 mg, 0.62 mmol) was dissolved in 20 mL of CH 2 Cl 2 and cooled to 0 ° C. Boron tribromide (120 μΐ, 1.24 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) was added and the solution extracted with EtOAc (3 x 20 mL). The combined organic phases were dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (silica, hexane: EtOAc 1: 3, EtOAc) provided 130 mg (47%) of the title compound as a white solid.

Step B 3,3-Trifluorpropane-1-sulfonic acid 4-2- (2,4-dichlorophenyl-4-methyl-5- (pberidin-1-ylcarbamoyl-2-pyrazol-3-ylphenyl ester)

A solution of piperidin-1-yl amide 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl> 4-methyl-1H-pyrazol-3-carboxylic acid, (130 mg, 0.30 mmol) in 10 mL of CH 2 Cl 2 was cooled to 0 ° C. Triethylamine (42 μΐ, 0.30 mmol) was added followed by 3,3,3-trifluorpropane-1-sulfonyl chloride (59 mg, 0.30 mmol), purchased from Manchester Organics ( but may also be prepared in a manner analogous to the method described in WO0200010968 for 4,4,4-trifluorobutane-1-sulfonyl chloride), and the reaction mixture was stirred at room temperature for 2 hours. extracted with CH 2 Cl 2 (3 x 20 mL), dried (Na 2 SO 4), filtered and concentrated Flash Flash Chromatography (silica, hexane: EtOAc 7: 3, 6: 4) afforded 150 mg (82%) of the title compound as of a white solid mp 160 ° C.

1H NMR (CDCl3): δ 7.7 (1H, broad s), 7.5-7.2 (7H, em), 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%.

.6) 4 A4-Trifluorobutane-1-sulfonic acid 4- (2- (2,4-dichlorophenin-4-methyl-5- (r) iperidm-1-ylcarbamoyl-2-pyrazol-3-yl) phenyl ester

Piperidin-1-yl amide 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid prepared as in 5, Step A (0.49 g, 1.20 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 ° C and triethylamine (0.67 mL, 4.8 mmol) added followed by 4,4,4-trifluorobutane-1-sulfonyl chloride prepared from as described in WO0200010968, (0.38 g, 1.80 mmol). The reaction mixture was stirred at room temperature overnight. Water was added, the product extracted with dichloromethane, dried (Na 2 SO 4), filtered and concentrated. Flash chromatography (1: 1-EtOAc hexane: EtOAc) followed by recrystallization (hexane: EtOAc) afforded 0.32 g (43%) of the title compound as a colorless solid.

1H NMR (CDCl3): δ 7.80 (1H, broad s), 7.50-7.19 (7H, m), 3.40 (2H, m), 3.05-2.90 (4H, m ), 2.50-2.20 (7H, if em), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m), MS m / z 641 (M + Na) HPLC: 96.5%

7) Propane-1-sulfonic acid [2- (2'4-dichlorophenin-4-methyl-5- (piperidin-ylcarbamoyl) -2H-pyrazol-3-yl-2,6-difluorophenyl ester)

Step A 1- (4-Benzyloxy-3,5-difluorophenyl) propane-1-one

1- (3,5-difluoro-4-hydroxyphenyl) propane-1-one (5.00 g, 26.9 mmol) was dissolved in acetone (100 mL) along with potassium carbonate (3.90 g, 28, 2 mmol). Benzyl bromide (4.82 g, 28.2 mmol) was added and the reaction mixture was boiled under reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated on a rotary evaporator to afford 7.43 g (100%) of the title compound as a white solid. Step B 1-4-Benzyloxy-3,5-difluorophenin-2-bromopropan-1-one

1- (4-Benzyloxy-3,5-difluorophenyl) propane-1-one (7.43 g, 26.9 mmol) was suspended in acetic acid (35 mL). Bromine (4.28 g, 26.8 mmol) was added dropwise and the reaction mixture stirred two hours at room temperature at which point the reaction mixture was a pale yellow solution. After cooling, ice water (100 mL) was added and the product extracted with ether (2 x 100 mL). The combined organic extracts were washed with water, sodium hydrogen carbonate solution and brine. The organic phase was dried (Na 2 SO 4), filtered and evaporated leaving 9.30 g (98%) of the title compound as a faded yellow oil. Step C 2-Acetyl-4-4-benzyloxy-3, S-difluorophenyl V.3-methyl-4-oxobutyric acid ethyl ester

A solution of sodium ethoxide was generated from sodium metal (0.74 g, 32.0 mmol) in 40 mL of absolute ethanol. To this solution was added ethyl acetoacetate (4.16 g, 32.0 mmol) at 0 ° C. After 30 minutes this solution was added to a solution of 1- (4-benzyloxy-3,5-difluorophenyl) -2-bromopropan-1-one (9.30 g, 26.2 mmol) in ethanehtoluene (40:20 mL ) and the reaction mixture stirred overnight. Acid development with 1 M HCl, extraction with ethyl acetate (3 x), brine washing, drying (Na 2 SO 4), filtration and evaporation left a crude product purified by flash flash chromatography (hexane: EtOAc 95: 5-70: 30 ) providing 6.95 g (66%) of the title compound as an oil. Step 4 S-N-benzyloxy-S.S-difluorophenyl-N-4H-dichlorophenin-methyl-1H: pyrazol-3-carboxylic acid

A solution of sodium ethoxide was generated from sodium metal (0.53 g, 22.0 mmol) in 60 mL of absolute ethanol. To this solution was 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. stirred at room temperature for 30 minutes. A previously prepared solution of 2,4-dichlorophenyldiazonium chloride (prepared from 2,4-dichloroaniline (3.39 g, 21.0 mmol) in 9 mL of 24% HCl and sodium nitrite 1. (48 g, 21.0 mmol) in 3 mL of water at 0 ° C) was added in 5 portions leaving the temperature below 5 ° C. After stirring at 0 ° C for 2 hours the reaction mixture naturally reached room temperature and was stirred overnight. Water was added, the product extracted with EtOAc (3x). The combined organic extracts were dried (Na 2 SO 4), filtered and evaporated, leaving 9.20 g of crude ethyl ester as an oil.

The residue (9.20 g) was dissolved in ethanol (120 mL) and sodium hydroxide (2.30 g, 57.5 mmol) in 15 mL of water was added. After 2 hours of boiling under reflux the reaction mixture was cooled, acidified with HCl and the product extracted with EtOAc (3 x). After washing, drying (Na 2 SO 4), filtration and concentration, the residue was purified by flash flash chromatography (hexane: EtOAc: AcOH 80: 20: 2 hexane: EtOAc: AcOH 50: 50: 2) affording 5.46 g ( 65%, two steps) of the title compound as a solid.

ETAPA E pjperidin-1-ylamide 5-r4-benzyloxy-3,5-difluorophenyl [1,2-dichlorophenin-4-methyl-1H-pyrazol-3-carboxylic acid]

5- (4-Benzyloxy-3,5-difluorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (5.46 g, 11.2 mmol) was suspended in dichloromethane (60 mL) and a few drops of DMF added followed by the addition of oxalyl chloride (4.70 mL, 55.8 mmol). The reaction mixture was boiled under reflux for 1.5 hours. After cooling to room temperature the solvent was removed and crude hydrochloric acid redissolved in dichloromethane, cooled to 0 ° C, Et 3 N (3.10 mL, 22.2 mmol) was added followed by 1-aminopiperidine (1.2 mL, 11.2 mmol). The cooling bath was removed and the reaction mixture stirred at room temperature overnight. Water was added and the product extracted with dichloromethane (3x), the combined extracts dried (Na 2 SO 4), filtered and evaporated. Flash vapor chromatography (hexane: EtOAc 80:20 - 70:30) afforded 1.86 g (30%) of the title compound as a yellow solid. Step F Piperidin-1-ylamide 5- (4-hydroxy-3,5-difluorophenyl) 1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid

Piperidin-1-ylamide 5- (4-benzyloxy-3,5-difluorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (1.86 g, 3.25 mmol) was dissolved in 50 mL of dichloromethane and cooled to -78 ° C. BBr 3 (0.60 mL, 6.50 mmol) was slowly added and the reaction mixture stirred at 0 ° C for 30 minutes. Water was added and the product extracted with CH 2 Cl 2 (x3). The combined organic extracts were dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (50:50 hexane: EtOAc) provided 0.64 g (41%) of the title compound as a faded yellow solid.

Step G-2- (2,4-Dichlorophenyl-4-methyl · 5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl1-2,6-difluorophenyl ester of propane-1-sulfonic acid

Piperidin-1-ylamide 5- (4-hydroxy-3,5-difluorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (0.64 g, 1.32 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 ° C and triethylamine (0.18 mL, 1.32 mmol) added followed by propanesulfonyl chloride (0.19 g, 1.31 mmol). The reaction mixture was stirred at room temperature overnight. Water was added, the product extracted with dichloromethane, dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (hexane: EtOAc 70:30 - 50:50) afforded 410 mg (53%) of the title compound as a faded yellow solid.

1H NMR (CDCl3): δ 7.66 (1H, broad s), 7.60-7.24 (4 Hi m), 6.97-6.78 (1H, 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 ( 4 H, m), 1.60-1.40 (2 H, m), 1.08 (3H, t), MS m / z 609 (M + Na), HPLC: 97.5%.

.8) Propane-4-R2-R2.4-dichlorophenyl-V- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-ylphenyl ester of propane-1-sulfonic acid

Step A 4-4-Benzyloxyphenyl-2-4-dioxobutyric acid ethyl ester

To a solution of LiHMDS (88 mL, IM in THF) in ether (50 mL) under nitrogen at -78 ° C was added for 1 hour a suspension of 1- (4-benzyloxyphenyl) ethanone (20 g, 88.4 mmol) dissolved in ether (150 mL) and THF (50 mL). The resulting mixture was stirred at -78 ° C for 1 hour and then diethyl ester oxalic acid (14.2 g, 97.2 mmol) was added. The resulting mixture was slowly warmed to warm to room temperature and then left overnight. The reaction mixture was diluted with pentane (90 mL) and the crude product precipitated as its lithium salt. The collected solid (27.2 g) was dried under vacuum and used directly in the next step. Step B 5- (4-Benzyloxyphenyl-N'-2,4'-dichlorophenin-1H-pyrazol-3-carboxylic acid ethyl ester

4- (4-Benzyloxyphenyl) -2,4-dioxobutyric acid ethyl ester (27.2 g, as Li salt from the previous step) was suspended in ethanol (350 mL) and 2,4-dichlorophenylhydrazine (17 , 8 g, 83.3 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solvent was then removed under low pressure and the residue was dissolved in acetic acid and the resulting mixture was refluxed for 24 hours. The reaction mixture was diluted with ethyl acetate (IL) and then washed with saturated NaHCO3 (6 x 250). mL) and brine (100 mL). The organic layer was dried (MgSO 4), filtered and concentrated under low pressure to give an oil. The oil was purified by flash chromatography (SiO 2, 20% EtOAc in heptane). The product fraction was concentrated under low pressure and the remaining material was then further purified by recrystallization (ethyl acetate / heptane) to give a white solid (19.6.57% over 2 steps).

1H-NMR (CDCl3): δ 1.42 (t, 3H), 4.45 (q, 2H), 5.03 (s, 2H), 6.88 (d, 2H), 7.01 (s, 1H), 7.11 (d, 2H), 7.3-7.45 (m, 8H). MS: 467 (M + 1). EtaPa C 1- (2,4-Dichlorophenin-5-β-hydroxyphenyl-1H-pyrazol-3-carboxylic acid ethyl ester

To a solution of 5- (4-benzyloxyphenyl) -1- (2,4-dichlorophenyl) -1 H -pyrazol-3-carboxylic acid ethyl ester (735 mg, 1.57 mmol) and (CH3) 2S (0 58 mL, 7.86 mmol) in dichloromethane (30 mL) under nitrogen was added dropwise diethyl BF3-etherate (1.0 mL, 7.86 mmol). The resulting mixture was stirred overnight at room temperature. More (CH 3) 2 S (0.58 mL, 7.86 mmol) and diethyl BF3-etherate (1.0 mL, 7.86 mmol) was then added and the resulting mixture was stirred for a further 3 days. The reaction mixture was diluted with dichloromethane to 80 mL and washed with water (3 x 30 mL) and brine (40 mL). The organic layer was dried (MgSO 4), filtered and concentrated under low pressure to give a white solid (573 mg, 96%). The raw material was used directly.

1H-NMR (CDCl3): δ 1.41 (t, 3H), 4.44 (q, 2H), 6.74 (d, 2H), 7.00 (s, 1H), 7.06 (d, 2H), 7.3-7.45 (m, 3H). MS: 375 (M-1). 1-F2,4-dichlorophen-5-R4-Cpropane-1-sulfonyloxy-phenyl-1H-pyrazol-3-carboxylic acid ethyl ester

1- (2,4-Dichlorophenyl) -5- (4-hydroxyphenyl) -1H-pyrazol-3-carboxylic acid ethyl ester (510 mg, 1.35 mmol) was suspended in dichloromethane (20 mL) under nitrogen and Triethylamine (0.75 mL, 5.4 mmol) was added. The resulting mixture was cooled to 0 ° C and 1-propanesulfonyl chloride (0.30 mL, 2.7 mmol) was added dropwise. The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then diluted to 40 mL with dichloromethane and then washed with saturated NaHCO 3 (3 x 20 mL) and brine (20 mL). The organic layer was dried (MgSO 4), filtered and concentrated under low pressure to give an oil (0.64 g, 98%). The crude material was used as such without further purification.

1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.43 (t, 3H), 2.01 (m, 2H), 3.23 (m, 2H), 4.46 (q, 2H), 7.07 (s, 1H), 7.19-7.46 (m, 7H),

MS: 483 (M + 1).

EtaPa E 4-r2-r2,4-dichlorophenin-5 - ('uiperidin-1-ylcarbamoin-2H-pyrazol-3-infenyl ester of propane-1-sulfonic acid

1-Aminopiperidine hydrochloride (36 mg, 0.26 mmol) was dissolved in toluene (1.0 mL) under a nitrogen atmosphere. Trimethyl aluminum (2 M in toluene, 0.17 mL) was added dropwise at room temperature. The resulting mixture was then stirred at room temperature for 40 minutes. This mixture was then added to a stirred suspension of 1- (2,4-dichloro-phenyl) -5- [4- (propane-1-sulfonyloxy) phenyl] -1H-pyrazol-3-carboxylic acid ethyl ester ( 42 mg, 0.087 mmol) in DCM (1.0 mL) and the resulting mixture was heated at 60 ° C overnight. The reaction was terminated by addition of water and then partitioned between water (20 mL) and DCM (20 mL). The organic layer was washed with water (3 x 10 mL) and then concentrated under low pressure. The residue was purified by reverse phase HPLC, column C8, 5-100% acetonitrile in water (buffer: 0.1 am ammonium acetate). The product fraction was diluted with ethyl acetate and washed with water several times. The organic layer was concentrated under low pressure and the residue was freeze-dried to give a white solid (26 mg, 55%).

1H-NMR (CDCl3): 1.11 (t, 3H), 1.43 (m, 2H), 1.76 (m, 4H), 2.00 (m, 2H), 2.85 (m, 4H ), 3.22 (m, 2H), 7.11 (m, 1H), 7.20 (m, 4H), 7.37 (m, 2H), 7.49 (m, 1H). MS: 537 (M + 1). 9) 4-R4-Bromo-2- (2,4-dichlorophenyl-V5- (p -Deridin-1-carbamin-2R-ester)

propane-1-sulfonic acid pyrazol-3-ylphenyl

Step A 4-Bromo-1- (2,4-dichlorofemn-5-R-4-propane-1-sulfonyloxy) phenyl-1H-pyrazol-3-carboxylic acid ethyl ester

1- (2,4-Dichlorophenyl) -5- [4- (propane-1-sulfonyloxy) phenyl] -1H-pyrazol-3-carboxylic acid ethyl ester prepared as in 8, Step D (597 mg, 1, 23 mmol) was dissolved in dichloromethane (15 mL) and bromine (0.06 mL, 1.23 mmol) in dichloromethane (1 mL) was added and the resulting mixture was stirred at room temperature overnight. Extra bromine (0.06 mL, 1.23 mmol) was added and the mixture was stirred for a further 20 hours.

The reaction mixture was diluted to 80 mL with dichloromethane and was then washed with saturated NaHCO 3 (40 mL), 20% Na 2 S 2 O 5 (40 mL), saturated NaHCO 3 (2 x 40 mL) and brine (40 mL). The organic layer was dried (MgSO 4), filtered and concentrated under low pressure to give an orange oil (0.598, 73%). The crude material was used without further purification.

1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.44 (t, 3H), 2.01 (m, 2H), 3.24 (m, 2H), 4.48 (q, 2H), 7.2-7.46 (m, 7H). MS: 561 StepB Propane-1-sulfonic acid 4-R4-bromo-2- (2,4-dichlorophenyl) -5- (piperidin-1-ylcarbamoin-2H-pyrazol-3-yl) propane-1-sulfonic ester

This compound was prepared in a similar manner to that described in Step E. Reacting 4-bromo-1- (2,4-dichlorophenyl) -5- [4- (propane-1-sulfonyloxy) phenyl] -1-acid ethyl ester H-pyrazol-3-carboxylic acid with 1-aminopiperidine hydrochloride to give 26 mg of the title compound as a white solid. Yield: 25%

1H-NMR (CDCl3): 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. 10) Methyl 1- (II-1,2,4-dichlorophenyl] -4-methyl-5- (4-propylsulfoninoxylphenyl} - 1H-pyrazol-3-dcarbonillaminol cyclopentanecarboxylate Step A Methyl 1-aminocyclopentanecarboxylate hydrochloride

Thionyl chloride (1.5 mL) was dissolved in methanol (15 mL) and poured into 1-aminocyclopentanecarboxylic acid (100 mg, 0.744 mmol). The mixture was refluxed for 1 hour. The solvent was evaporated to afford the product (107 mg, 77%).

1H NMR (399.964 MHz) δ 9.00-8.60 (br, 3H), 3.79 (s, 3H), 2.23 (s, 4H), 2.14-2.00 (m, 2H) 1.90-1.76 (em, 2H). Step B Methyl 1 - ((Γ5-r4-benzyloxy) phenyl-1-1,2,4-dichlorophenyl] -4-methyl-1H-pyrazol-3-yl carbonyl} amino) cyclopentanecarboxylate

A solution of 5- [4-benzyloxy) phenyl] -1- (2,4-dichlorophenyl) -4-methyl-1H-pyrazol-3-carboxylic acid prepared as in 1, Step D (59 mg, 0.130 mmol) in DCM (2 mL) was mixed with a solution of oxalyl chloride (2 mL) in DCM (20 mL). A drop of DMF was added and the reaction continued at room temperature in the dark for 1 hour. The solvent was evaporated, DCM (2 mL) was added and the hydrochloric acid mixture added to a mixture of 1-aminocyclopentanecarboxylate methyl hydrochloride (23 mg, 0.130 mmol) in DCM (2 mL) and K 2 CO 3 (aq, 10 wt% 2 mL). The reaction continued at room temperature for 3 hours. The phases were separated and the organic phase washed with water and dried by MgSO4 to afford the product (71 mg, 94%).

1H NMR (399.964 MHz) δ 7.43-7.23 (m, 9H), 7.06-7.00 (m, 2H), 6.93-6.87 (m, 2H), 5.02 s (s, 2H), 3.75 (s, 3H), 2.40-2.30 (em, 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 Methyl 1-mi-1,2-dichlorophenin-5- (4-h-3-ylcarbonyl} amino) cyclopentanecarboxylate

Boron trifluoride etherate (156 μΐ, 1.23 mmol) was added to a mixture of methyl 1 - ({[5- [4- (benzyloxy) phenyl] -1- (2,4-dichlorophenyl) -4-methyl -1 H-pyrazol-3-yl] carbonyl} amino) cyclopentanecarboxylate (51 mg, 0.088 mmol) and dimethyl sulfide (90 μΐ, 1.23 mmol) in DCM (2 mL). The reaction continued at room temperature in the dark for 46 hours. Water and DCM were added, the phases separated and the organic phase washed with water and dried over MgSO4 (39 mg, 90%).

1H NMR (399.964 MHz) δ 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 Methyl-1- {β- (1- (2,4-dichlorophenyl-4-methyl-5- (4- [propylsulfonyloxyphenyl] -1H-pyrazol-3-ylcarboninamino] cyclopentanecarboxylate,

TEA (100 μΐ) and then 1-propanesulfonyl chloride (30 μl, 0.268 mmol) were added to a mixture of methyl 1 - ({[1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) - 4-methyl-1H-pyrazol-3-yl] carbonyl} amino) cyclopentanecarboxylate (39 mg, 0.080 mmol) in dry DCM (1.5 mL) at -78 ° C. The reaction continued at -78 ° C under N 2 (g) for 1.5 hours. Water and DCM were added and the temperature was raised to room temperature. The phases were separated and the organic phase washed with water and dried over MgSO4. The product was purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, product became about 88% acetonitrile) to give the product as an off-white powder (17 mg, 35%).

1H-RAlN (399.964 MHz) δ 7.45-7.39 (br, 1H), 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 by [C 27 H 29 Cl 2 N 3 O 6 S + • +: 594.123, Found: 594.121.

11) carbonic acid 4- (2- (2,4-dichloro-phenyl) -4-methyl-5-pyridin-1-ylcarbamoyl-2-pyrazol-3-in-phenyl propyl ester propyl ester

Carbonic acid 4-r2-2,4-dichlorophenin-4-methyl-5-piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl-phenyl propyl ester

Piperidin-1-yl-amide-1- (2,4-dichloro-phenyl) -5- (4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid prepared as in Is Step F (0, 44 g, 1.00 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.28 mL, 2.24 mmol) was added. Propyl chloroformate (0.14 mL, 1.24 mmol) was added at 0 ° C, and the reaction stirred for 40 minutes, concentrated and the product purified by flash chromatography (hexane: EtOAc 70: 30 - 50:50 ) to provide 345 mg (65%) of the title compound. Further purification by preparative HPLC gave 239 mg of the title compound.

1H NMR (CDCl3): δ 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%

12α- (1- (Z4-dichlorophenyl) -4-methyl-3-f (piperidin-1-ylamino) carbonyl-1 H-

pyrazol-5-yl] phenylthiophene-2-sulfonate

Thiophene-2-sulfonyl chloride (433 mg, 2.37 mmol) in DCM (2.5 mL) was added to a mixture of 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4- methyl-N-piperidin-1-yl-1H-pyrazol-3-carboxamide prepared as in 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 N 2 (g). The reaction continued at -78 ° C for 2 hours and then at room temperature for 19 hours. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO4. The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, the product became 100% acetonitrile) to give an off-white powder (158 mg, 60%).

1H NMR (399.964 MHz) δ 7.71-7.67 (m, 1H), 7.67-7.57 (br, 1H), 7.50-7.46 (m, 1H), 7.35 ( s, 1H), 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, 303H), 1.73-1.65 (m, 4H), 1.42-1.33 (m, 2Η),

HRMS Calculated by [C 26 H 24 Cl 2 N 4 O 4 S 2 + H] +: 591.069, Found: 591.067.

13) 4- (1- (2,4-dichlorophen-4-methyl-3-ylpiperidin-1-ylamino) carbonyl-1H-pyrazol-5-yl} phenyl pyridin-3-sulfonate

Step A: 4- {1- (2,4-Dichlorophenyl-4-methyl-1H-pyrazol-5-yl] phenylpyridine-3-sulfonate

A suspension of pyridine-3-sulfonyl chloride (144 mg, 0.67 mmol) in DCM (10 mL) was added to a mixture of 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4 -methyl-N-piperidin-1-yl-1H-pyrazol-3-one

carboxamide, prepared as Ex 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 N 2 (g) . The reaction continued at -78 ° C for 1.5 hours and then at room temperature for 30 minutes. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO4. The product was further purified by flash chromatography (SiO 2, toluene: ethyl acetate, the product became 42% ethyl acetate) to give the title compound as a powder (216 mg, 82%).

1H NMR (399.964 MHz) δ 8.95-8.85 (m, 2H), 8.10-8.04 (m, 1H), 7.64 (s, 1H), 7.50-7.45 ( m, 1H), 7.44-7.40 (m, 1H), 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 by [C 27 H 25 Cl 2 N 5 O 4 S · H] +: 586.108. Found: 586.111.

14) tert-Butyl? 2- (4- (1-r2,4-dichlorophenyl? 4-methyl-3 - ((piperidin-1-

ylamino) carbonyl "[-1H-pyrazol-5-yl) phenoxytetyl ethyl carbamate Step A: tert-butyl ethyl 2-hydroxyethylcarbamate

Di-tert-butyl dicarbonate (3.19 g, 14.6 mmol) in THF (10 mL) was added to 2- (ethylamino) ethanol (1.00 g, 11.2 mmol) and reacted at room temperature by 3 hours. The solvent was evaporated at low pressure to give crude product (2.28 g).

1H NMR (499.961 MHz) δ 3.71-3.65 (br, 2H), 3.55-3.35 (br, 1H), 3.35-3.30 (br, 2H), 3.30- 3.20 (br, 2H), 1.43 (s, 9H), 1.07 (t, 3H).

Step B: tert-Butyl r2-4-yl-r2t4-dichlorophenyl-4-methyl-3-r ('uiperidm-1-ylamino >> carbonill-1 H-pyrazol-5-yl phenoxyethylethyl ethyl carbamate

1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-N-piperidin-1-yl-1H-pyrazol-3-carboxamide prepared as 1, Step F (151.6 mg 0.34 mmol) and tert-butyl ethyl (2-hydroxyethyl) carbamate (408.6 mg, 1.73 mmol) were mixed in toluene (1 mL) and reacted repeatedly in a single node microwave oven at 180 ° C. 0C. The total reaction time was 2 hours. Cyanomethylene-N-butylphosphorane was added before each heating (total amount 925 mg, 3.83 mmol). The solvent was then evaporated and the product purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, the product became 100% acetonitrile) and flash chromatography (SiO2, toluene : ethyl acetate, the product became 30% ethyl acetate) to give an off-white powder (125 mg, 60%).

1H NMR (399.964 MHz) δ 7.62 (s, 1H), 7.37 (s, 1H), 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) +.

15) 4- (2,4-dichlorophenyl, 4-methyl-3-ylpiperidin-1-ylamino) carbonyl-1H-pyrazol-5-yl} phenyl 3-methylbutane-1-sulfonate

3-Methylbutane-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-1H-pyrazol-3-carboxamide, prepared as in 1, Step F (100 mg, 0.23 mmol) and TEA (0.5 mL, 3.59 mmol) in DCM ( 2 mL) at -78 ° C under N 2 (g). The reaction continued at -78 ° C for 1 hour. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO4. The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, the product became 100% acetonitrile) to give an off-white powder (94 mg, 72%).

1H NMR (399.964 MHz) δ 7.85-7.45 (br, 1H), 7.38 (s, 1H), 7.29-7.25 (m, 2H), 7.23-7.18 ( m, 2H), 7.16-7.11 (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 by [C 27 H 32 Cl 2 N 4 O 4 S · H] +: 579.160, Found: 579.159.

reads) —4- {1- (2,4-dichlorophenyl] -4-methyl-3-pyriperidin-1-ylamino) carbonyl-1H-pyrazol-5-yl} phenyl 3,3-dimethylbutane-1-sulfonate

3,3-Dimethylbutane-1-sulfonyl chloride (59 mg, 0.32 mmol) in DCM (2 mL) was added to a mixture of 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) - 4-Methyl-N-piperidin-1-yl-1H-pyrazol-3-carboxamide, prepared as in 1, Step F (103 mg, 0.23 mmol) and TEA (0.5 mL, 3.59 mmol) in DCM (2 mL) at -78 ° C under N 2 (g). The reaction continued at -78 ° C for 1 hour. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO4. The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, the product became 100% acetonitrile) to give an off-white powder (94 mg, 68%).

1H NMR (399.964 MHz) δ 8.20-7.40 (br, 1H), 7.36 (s, 1H), 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 (em, 2H), 1.73-1.65 (m, 4H), 1.43-1.32 (m, 2H), 0.89 (s, 9H) HRMS Calculated by [C 28 H 34 Cl 2 N 4 O 4 S + H] +: 593.176, Found: 593.176.

17) 1- (2,4-Dichlorophenin-5-4-2- (1,3-dioxolan-2-yethoxyphenyl-M-methyl-N-piperidin-1-yl-1H-pyrazol-3-carboxamide

2- (2-bromoethyl) -1,3-dioxolane (60 mg, 0.33 mmol), 1- (2,4-dichlorophenyl) -5- (4-hydroxyphenyl) -4-methyl-N-piperidin-1 -1H-pyrazol-3-carboxamide prepared as in 1, step F (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) were refluxed in acetonitrile (25 mL) for 15 hours . The solvent was evaporated, water and DCM were added, the phases separated and the organic phase washed with water and dried (MgSO4). The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, the product became 100% acetonitrile) to give an off-white powder (60 mg, 49%).

1H NMR (399.964 MHz) δ 7.80-7.50 (br, 1H), 7.36 (s, 1H), 7.21 (s, 2H), 7.00-6.94 (m, 2H) 6.80-6.74 (m, 2H), 5.02 (t, 1H), 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 by [C 27 H 30 Cl 2 N 4 HCV] +: 545.172. Found: 545.172.

18) 4-R2- (2,4-Dichloro-3-fluorophenyl-4-methyl-5- (dimidin-1-ylcarbamoyl) 2H-pyrazol-3-ylphenyl ester of propane-1-sulfonic acid Step A: 1f, 2.4 -dichloro-3-fluorophenyl-5- (4-methoxyphenin-4-methyl-1H-pyrazol-3-carboxylic acid)

A solution of sodium ethoxide was generated from sodium metal (0.18 g, 7.89 mmol) in 20 mL of abs. Ethanol. To this solution was added 2-acetyl-4- acid ethyl ester (4 -methoxy-phenyl) -3-methyl-4-oxobutyric acid (1.73 g, 5.92 mmol) and the reaction mixture stirred at room temperature for 30 minutes. A previously prepared solution of 2,4-dichloro-3-fluorodiazonium chloride (prepared from 2,4-dichloro-3-fluoraniline (1.30 g, 7.22 mmol) in 3 mL 24% HCl and nitrite NaCl (0.51 g, 7.39 mmol) in 3.5 mL of water at 0 ° C) was added in 5 portions leaving the temperature below 5 ° C. After stirring at room temperature for 2.5 hours water was added, the product extracted with EtOAc (3 x). The combined organic extracts were dried (Na 2 SO 4), filtered and evaporated. The residue was dissolved in ethanol (40 mL) and sodium hydroxide (1.00 g, 25.0 mmol) in 5 mL of water was added. After 2 hours boiling under reflux the reaction mixture was cooled, acidified with HCl and the product extracted with EtOAc (3 x). After washing, drying (Na 2 SO 4), filtration and concentration, the residue was purified by flash chromatography (70:30 - 50:50 hexane: EtOAc) affording 1.37 g (31%) of the title compound as a solid. light brown.

Step B: Piperidin-1-ylamide 1- (2,4-dichloro-3-fluorophenyl-5- (4-methoxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid

1- (2,4-Dichloro-3-fluorophenyl) -5- (4-methoxy-phenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (1.37 g, 3.43 mmol) was suspended in dichloromethane (20 mL) and a few drops of DMF added followed by the addition of oxalyl chloride (0.87 g, 6.86 mmol). The reaction mixture was refluxed for two hours. After cooling to room temperature the solvent was removed and crude hydrochloric acid redissolved in dichloromethane (20 mL), cooled to 0 ° C, Et 3 N (0.96 mL, 6.94 mmol) was added followed by 1-aminopiperidine (0.37 mL, 3.62 mmol). The cooling bath was removed and the reaction mixture stirred at room temperature overnight. Water was added and the product extracted with dichloromethane (3x), the combined extracts dried (Na 2 SO 4), filtered and evaporated. Flash vapor chromatography (50:50 hexane: EtOAc) provided 0.79 g (48%) of the title compound as a light brown solid.

Step C: Piperidin-1-ylamide 1- (Z4-dichloro-3-fluorophenyl-V-4-hydroxyphenyl) -4-methyl-1H-pyrazol-3-carboxylic acid

Piperidin-1-ylamide 1- (2,4-dichloro-3-fluorophenyl) -5- (4-methoxy-phenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (0.79 g, 1.66 mmol) was dissolved in 40 mL of dichloromethane at 0 ° C. Boron tribromide (0.32 mL, 3.31 mmol) was added, the cooling bath was removed and stirring was continued for 2 hours at room temperature before pouring into ice water and extracting with DCM (x 3). The combined extracts were dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (EtOAc) provided 0.36 g (47%) of the title compound as a colorless solid.

Step Da: 4-2- [2,4-Dichloro-3-fluorophenyl] -4-methyl-5- (1-piperidin-1-ylcarbamoyl) 2H-pyrazol-3-yl] phenyl ester of propane-1-sulfonic acid

To a solution of piperidin-1-ylamide 1- (2,4-dichloro-3-fluorophenyl) -5- (4-hydroxy-phenyl) -4-methyl-1H-pyrazol-3-carboxylic acid (0.36 g, 0.78 mmol) in dichloromethane (10 mL) was added triethylamine (0.22 mL, 1.56 mmol) and the reaction mixture cooled to 0 ° C. 1-Propanesulfonyl chloride (0.22 g, 1.56 mmol) was added, the cooling bath removed and the reaction mixture stirred at rt for 2 hours. Water was added, the product extracted with DCM (x 2), the combined organic extracts washed with water, dried (Na 2 SO 4), filtered and concentrated. Flash vapor chromatography (hexane: EtOAc gradient) provided 100 mg (23%) of the title compound as a colorless solid. HPLC purity 80%. Preparative HPLC provided 40 mg of the title compound.

1H NMR (CDCl3): δ 7.50-7.20 (7 δ, 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%

19) Chlorothiophene-2-sulfonic acid 5-ester 4-r2-r2,4-dichlorophenin-4-methyl-5-rpiperidin-1-ylcarbamoyl-2H-pyrazol-3-infenyl

Piperidin-1-ylamide 1- (2,4-dichloro-phenyl) -5- (4-hydroxy-phenyl) -4-methyl-1H-pyrazol-3-carboxylic acid prepared as in 1, Step F (100 mg 0.22 mmol) was dissolved in dry dichloromethane (3 mL) under nitrogen atmosphere and triethylamine (0.09 mL) was added. 5-Chlorothiophene-2-sulfonyl chloride (0.54 mg, 0.24 mmol), dissolved in dry dichloromethane (2 mL), was then added. The reaction mixture was stirred over the weekend at room temperature. The reaction mixture was diluted with dichloromethane to 20 mL and was then washed with water (2 x 5 mL) and brine (5 mL). The organic layer was concentrated under low pressure to give an oil. The crude material was purified by reverse phase HPLC, Kromasil C8, 5-100% MeCN in water with 0.1% ammonium acetate. The product fraction was concentrated under low pressure and the residue was dissolved in dichloromethane and washed with water and brine. The organic layer was dried (MgSO 4 filtered and concentrated under low pressure to give the title compound as a yellow solid.

1H-NMR (CDCl3): δ 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, 1H), 7.04-7.14 (m, 4H), 7.30-7.36 (m, 3H), 7.44 (d, 1H), 7.63 (s, 1H), MS: 625 (M + 1). HPLC:> 99% purity.

GENERAL FREE BASE SYNTHESIS METHOD

Method A

<formula> formula see original document page 70 </formula> <formula> formula see original document page 71 </formula>

Claims (8)

A compound characterized in that it is selected from: 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester butane-1-sulfonic acid; piperidin-1-ylamide 1- (2,4-dichlorophenyl) -4-methyl-5- [4- (4,4,4-trifluorobutoxy) phenyl] -1H-pyrazol-3-carboxylic acid; propane-1-sulfonic acid 4- [2- (2,4-dichloro-phenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) 2H-pyrazol-3-yl] -phenyl ester; propane-1-sulfonic acid 4- [2- (2S4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester; 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl] 3,3,3-trifluorpropane-1-sulfonic ester; 4,4,4-trifluorobutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester ; propan-1-sulfonic acid [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester; propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester; propan-1-sulfonic acid 4- [4-bromo-2- (2,4-dichlorophenyl) -5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester; methyl 1 - {[(1- (2,4-dichlorophenyl) -4-methyl-5- {4 [(propylsulfonyl) oxyphenyl} -1H-pyrazol-3-yl) carbonyl] amino} cyclopentanecarboxylate; carbonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester propyl ester; 4- {1- (2-4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenylthiophene-2-sulfonate; 4- {1- (2-4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenyl pyridin-3-sulfonate; tert-butyl [2- (4- {1- (2,4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenoxy) ethyl] ethylcarbamate ; 4- {1- (2-4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenyl 3-methylbutane-1-sulfonate; 4- {1- (2,4-dichlorophenyl) -4-methyl-3 - [(piperidin-1-ylamino) carbonyl] -1H-pyrazol-5-yl} phenyl 3,3-dimethylbutane-1-sulfonate; 1- (2,4-dichlorophenyl) -5- {4- [2- (1,3-dioxolan-2-yl) ethoxy] phenyl} -4-methyl-N-piperidin-1-yl-1H-pyrazole -3-carboxamide; propan-1-sulfonic acid 4- [2- (2S4-dichloro-3-fluorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester; and 5-chlorothiophene-2-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester; in the form of a methanesulfonate salt, a semi-1,5-naphthalenedisulfonate salt, a 1,2-ethanedisulfonic acid salt, a hydrochloride salt or a hydrogen sulfate salt but excluding 4- [2-] ester hydrochloride Pyridine-3-sulfonic acid (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl. Compound, characterized in that it is one or more of the following: 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-ester hydrochloride Butane-1-sulfonic acid 3-yl] phenyl; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate - sulfonic; propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride; propane-1-ester 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl semi-1,5-naphthalenedisulfonate - sulfonic; propan-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (morpholin-4-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl mesylate; 4,4,4-trifluorobutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-lilcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride ; 4,4,4-trifluorobutane-1-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester mesylate - sulfonic; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate 4,4 4-trifluorobutane-1-sulfonic; 4,4,4-trifluorobutane-1-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-lilcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester hydrogen sulfate sulfonic; propane-1-methyl-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester hydrochloride sulfonic; propane-1-ester 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester mesylate sulfonic; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -2,6-difluorophenyl ester semi-1,5-naphthalenedisulfonate propane-1-sulfonic acid; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride 3,3,3-ίπί1υοφΓορ3ηο-1 sulfonic; 3,3,3-Trifluorpropane-1-4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester mesylate - sulfonic; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate 3,3 3-trifluorpropane-1-sulfonic; 3,3,3-trifluorpropane 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrogen sulfate -1-sulfonic; 3-methylbutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride; 3-methylbutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl mesylate; 4- [2- (2,4-Dichlorophenyl) -1,4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-irazol-3-yl] ester ester semi-1,5-naphthalenedisulfonate -1-sulfonic; 3S3-dimethylbutane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester hydrochloride; 3,3-dimethylbutane-1-sulfonic mesylate 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-lilcarbamoyl) -2H-pyrazol-3-yl] -phenyl ester; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate 3,3 dimethylbutane-1-sulfonic; propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl hydrochloride; propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl mesylate; propane-1-ester 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl semi-1,5-naphthalenedisulfonate sulfonic; propane-1-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl hydrogen sulfate; carbonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl propyl ester hydrochloride; carbonic acid 4- [2- (2,4-dichlorophenyl> 4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl] propyl ester mesylate; propyl ester 4- [2- (2,4-dichlorophenyl) -4-methyl-5-ylperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phen-propyl ester-naphthalenedisulfonate; pyridine-3-sulfonic acid 4- [2- (2,4-dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl mesylate; 4- [2- (2,4-Dichlorophenyl) -4-methyl-5- (piperidin-1-ylcarbamoyl) -2H-pyrazol-3-yl] phenyl ester semi-1,5-naphthalenedisulfonate -sulfonic. A compound wherein R1 is a) a) a C1-3 alkoxy group substituted by one or more of the following i) fluorine ii) an NRcRd group in which Re and Rd independently represent Η a C1-6 alkyl or C1-6 alkoxycarbonyl group provided that one of Rc and Rd is other than H or iii) a 1,3-dioxolan-2-yl group b) R1 represents a C1-6 alkoxy group optionally substituted by one or more of the following i) (ii) a NRc R d group wherein R c and R d independently represent H, a C 1-6 alkyl group or an alkoxycarbonyl group provided that one of R c and R d is other than H or iii) a 1,3-dioxolane-2-group. ila c) a group of the formula (CH 2) p O- wherein ρ is 1, 2 or 3 and the phenyl ring is optionally substituted by 1, 2 or 3 groups represented by Z, d) a group R 5 S (O) 2 O or R5S (O) 2NH wherein R5 represents a C1-6 alkyl group optionally substituted by one or more fluorine, or R5 represents phenyl group or a heteroaryl each of which al is optionally substituted by 1, 2 or 3 groups represented by Z e) a group of the formula (R 6) 3 Si in which R 6 represents a C 1-6 alkyl group which may be the same or different or f) a group of the formula RbO (CO) Wherein Rb represents a C1-6 alkyl group optionally substituted by one or more fluorine; Ra represents halo, a C1-4 alkyl group or a C1-3 alkoxy group; m is 0,1,2 or 3; R represents a C1-3 alkyl group, a C1-3 alkoxy, hydroxy, nitro, cyano or halo group η is 0, 1, 2 or 3; R represents a) an X-Y-NR 7 R 8 group in which X is CO or SO 2, Y is absent or represents NH optionally substituted by a C 1-3 alkyl group; and R7 and R8 independently represent: a C1-6 alkyl group optionally substituted by 1, 2, or 3 groups represented by W; a C3-15 cycloalkyl group optionally substituted by 1, 2, or 3 groups represented by W; a (C3-15 cycloalkyl) C1-3 alkylidene group optionally substituted by 1, 2, or 3 groups represented by W; a - (CH 2) r (phenyl) group, where r is 0, 1, 2, 3 or 4, s is 1 when r is O otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one. , two or three groups represented by Z; a saturated 5- to 8-membered saturated heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more C1-3 alkyl, hydroxy or benzyl groups; a - (CH 2) t Het group wherein t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more C 1-3 alkyl groups and Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a C1-5 alkyl group, a C1-5 alkoxy or halo group wherein the alkyl and alkoxy group are optionally independently substituted by one or more fluorine; or R7 represents HeR is as defined above; OR R7 and R8 together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 5-8 membered heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulfur or an additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more C1-3 alkyl, hydroxy, fluorine or benzyl groups; or (b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl, each optionally substituted by 1, 2 or 3 groups Z; R4 represents hal, halo, hydroxy, cyano, a C1-6 alkyl group, a C1-6 alkoxy group or a C1-6 alkoxyalkylidene group containing a maximum of 6 carbon atoms, each of the groups optionally substituted by one or more fluorine or cyano; Z represents a C1-3 alkyl group, C1-4 alkoxy, hydroxy, halo, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl, nitro, amino, mono or dialkylaminoC1-3 alkylsulfonyl, C1-3 alkoxycarbonyl, carbamoyl, and acetyl; and W represents hydroxy, fluorine, a C1-4 alkyl group, a C1-3 alkoxy group, amino, mono or diC1-3 alkylamino group, a C1-4 alkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic amine is optionally substituted by C1-3 alkyl or hydroxyl group; but excluding 1,1-dimethylethyl [2- [4- [3 - [(ethylmethylamino) carbonyl] -1- (4-methoxyphenyl) -1H-pyrazol-5-yl] phenoxy] ethyl] carbamate and 1,1-dimethylethyl [2- [4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl] phenoxy] ethyl] carbamate; in the form of a methanesulfonate salt, a semi-1,5-naphthalenedisulfonate salt, or a 1,2-ethanedisulfonic acid salt. A compound according to any one of claims 1 to 3, characterized in that it is for use as a medicament. Pharmaceutical formulation, characterized in that it comprises a compound as defined in any one of claims 1 to 3 and a pharmaceutically acceptable adjuvant, diluent or carrier. Use of a compound as defined in any one of claims 1 to 3, characterized in that it is in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety disorders antidepressants, 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 disorders, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems, and prolonged abuse, indications of addiction and / or relapse. 7. A method for treating diseases, said diseases being obesity, psychiatric disorders, psychotic disorders, schizophrenia and bipolar disorders, anxiety, antidepressant disorders, depression, cognitive disorders, memory disorders, obsessive compulsive disorders, anorexia, bulimia, attention disorders. , epilepsy and related conditions, neurological disorders, Parkinson's disease, Huntington's chorea and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, respiratory and gastrointestinal disorders, and prolonged abuse, indications of addiction and / or relapse, characterized in that it comprises administering a pharmacologically effective amount of a compound as defined in any one of claims 1 to 3 to a patient in need thereof. A compound according to any one of claims 1 to 3, characterized in that it is for use in the treatment of obesity.