CN1918129B - therapeutic agent - Google Patents

Abstract

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

Description

therapeutic agent

field of invention

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

Background of the invention

Certain _CB1 modulators (known as antagonists or inverse agonists) are known to be effective in the treatment of obesity, psychiatric and neurological disorders (WO01/70700 EP 658,546 and EP 656,354). However, there is a need for _CB1 modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.

Pyrazoles with anti-inflammatory activity are disclosed in WO 95/15316, WO 96/38418, WO 97/11704, WO 99/64415, EP418845 and WO 2004050632. WO2004050632 discloses [2-[4-[3-[(ethylmethylamino)carbonyl]-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy]ethyl ] 1,1-dimethylethyl carbamate, 5-[4-(2-aminoethoxy)phenyl]-N-ethyl-1-(4-methoxyphenyl)-N-methyl Base-1H-pyrazole-3-carboxamide, 1-[[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole- 3-yl]carbonyl]piperidine and [2-[4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]phenoxy Base] ethyl]-1,1-dimethylethyl carbamate. All the compounds and their salts exemplified in WO 2004050632 are not included in the scope of the protected compounds of the present invention. the

1,5-diarylpyrazole-3-carboxamide derivatives in US 5,624,941, WO 01/29007, WO 2004/052864, WO 03/020217, 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), 769-7761999 and US Patent Application Publication Disclosed in US 2003199536 to have CB ₁ modulating activity.

Contents of the invention

The present invention relates to compounds of formula (I)

and its pharmaceutically acceptable salts, wherein

R ¹ represents a) C _1-3 alkoxy i) fluorine ii) group NR ^c R ^d substituted by one or more of the following groups, wherein R ^c and R ^d independently represent H, C _1-6 alkane or C _1-6 alkoxycarbonyl, with the proviso that one of R ^c and R ^d is not H or iii) 1,3-dioxolan-2-yl; b) ^R represents optionally replaced by one or C _4-6 alkoxy i) fluorine ii) group NR ^c R ^d substituted by a plurality of the following groups, wherein R ^c and R ^d independently represent H, C _1-6 alkyl or C _2-6 alkane Oxycarbonyl, with the proviso that one of R ^{and R} is not H or iii) 1,3-dioxolan-2-yl; c) a group of the formula phenyl (CH ₂ ) _p O—, wherein p is 1, 2 or 3 and the benzene ring is optionally substituted by 1, 2 or 3 groups represented by Z; d) R ⁵ S(O) ₂ O or R ⁵ S(O) ₂ NH, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines, or ^R represents phenyl or heteroaryl optionally substituted by 1, 2 or 3 groups represented by Z respectively; e) the formula A group of (R ⁶ ) ₃ Si, wherein R ⁶ represents C _1-6 alkyl, which is the same or different or f) a group of formula R ^b O(CO)O, wherein R ^b represents optionally replaced by one or Multiple fluorine-substituted C _1-6 alkyl groups;

^R represents halogen, C _1-3 alkyl or C _1-3 alkoxy;

m is 0, 1, 2 or 3;

R ² represents C _1-3 alkyl, C _1-3 alkoxy, hydroxyl, nitro, cyano or halogen;

n is 0, 1, 2 or 3;

R ³ represents a) a group XY-NR ⁷ R ⁸ , wherein X is CO or SO ₂ , Y is absent or represents NH optionally substituted with C _1-3 alkyl; and R ⁷ and R ⁸ independently represent : C _1-6 alkyl optionally substituted by 1, 2 or 3 groups represented by W;

(C _3-15 cycloalkyl)C _1-3 alkylene optionally substituted by 1, 2 or 3 groups represented by W;

-(CH ₂ ) _r (phenyl) _s , 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 group is independently and optionally substituted by 1, 2 or 3 groups represented by Z;

A saturated 5-8 membered heterocyclic group containing one nitrogen and optionally containing one of the following: oxygen, sulfur or additional nitrogen, wherein the heterocyclic group is optionally surrounded by one or more C _1-3 alkyl groups, Hydroxy or benzyl substitution;

-(CH ₂ ) _t Het, 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 means optionally substituted by 1 , 2 or 3 aromatic heterocycles selected from C _1-5 alkyl, C _1-5 alkoxy or halogen substituted, wherein the alkyl and alkoxy are independently and optionally substituted by one or more fluorines;

Or R ⁷ represents H and R ⁸ are as defined above;

Or R ⁷ and R ⁸ 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 additional Nitrogen; wherein the heterocyclic group is optionally substituted by one or more C _1-3 alkyl, hydroxyl, fluorine or benzyl; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolinyl, each optionally replaced by 1, 2 or 3 The group Z is substituted;

R ⁴ represents H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy C _1-6 alkylene, which contains up to 6 carbon atoms, Each group is optionally substituted with one or more fluoro or cyano groups;

Z represents C _1-3 alkyl, C _1-3 alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl , nitro, amino, one or two C _1-3 alkylamino, C _1-3 alkylsulfonyl, C _1-3 alkoxycarbonyl, carboxyl, cyano, carbamoyl, one or two C _{1- 3} alkylcarbamoyl and acetyl; and

W represents hydroxyl, fluorine, C _1-3 alkyl, C _1-3 alkoxy, amino, one or two C _1-3 alkylamino, C _1-6 alkoxycarbonyl or heterocyclic amine selected from morpholine Base, pyrrolidinyl, piperidinyl or piperazinyl, wherein the heterocyclic amine is optionally substituted by C _1-3 alkyl or hydroxyl; but not including [2-[4-[3-[(ethylmethyl Amino)carbonyl]-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy]ethyl]carbamate 1,1-dimethylethyl ester and [2-[4 -[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]phenoxy]ethyl]carbamic acid 1,1-dimethyl ethyl ester.

In one embodiment the present invention relates to compounds of formula (I)

and its pharmaceutically acceptable salts, wherein

R ¹ represents a) C _1-3 alkoxy substituted by one or more fluorine or C _4-6 alkoxy optionally substituted by one or more fluorine, b) phenyl (CH ₂ ) _p O - a group where p is 1, 2 or 3 and the benzene ring is optionally substituted by 1, 2 or 3 groups represented by Z, c) R ⁵ S(O) ₂ O or R ⁵ S(O ) ₂ NH, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines, or R ⁵ represents phenyl or heteroaryl, each of which is optionally represented by 1, 2 or 3 Z d) a group of (R ⁶ ) ₃ Si, wherein R ⁶ represents C _1-6 alkyl, which may be the same or different or e) a group of formula R ^b O(CO)O, wherein R ^b represents C _1-6 alkyl optionally substituted by one or more fluorines;

^R represents halogen, C _1-3 alkyl or C _1-3 alkoxy;

m is 0, 1, 2 or 3;

R ² represents C _1-3 alkyl, C _1-3 alkoxy, hydroxyl, nitro, cyano or halogen;

n is 0, 1, 2 or 3;

R ³ means

a) Group XY-NR ⁷ R ⁸

Wherein X is CO or SO ₂ , Y is absent or represents NH optionally substituted by C _1-3 alkyl;

and R ⁷ and R ⁸ independently represent:

C _1-6 alkyl optionally substituted by 1, 2 or 3 groups represented by W;

C _3-15 cycloalkyl optionally substituted by 1, 2 or 3 groups represented by W;

Optionally substituted (C _3-15 cycloalkyl)C _1-3 alkylene optionally substituted by 1, 2 or 3 groups represented by W;

-(CH ₂ ) _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 group is optionally replaced by 1, 2 Or substituted by 3 groups represented by Z;

A saturated 5-8 membered heterocyclic group containing one nitrogen and optionally containing one of the following: oxygen, sulfur or additional nitrogen, wherein the heterocyclic group is optionally surrounded by one or more _C1-3 alkyl groups, Hydroxy or benzyl substitution;

The group -(CH ₂ ) _t Het, 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 optionally Aromatic heterocycles substituted by 1, 2 or 3 selected from C _1-5 alkyl, C _1-5 alkoxy or halogen;

Or R ⁷ represents H and R ⁸ are as defined above;

Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a saturated 5-8 membered heterocyclic group that is saturated or partially free of a nitrogen and optionally contains one of the following: oxygen, sulfur or additional nitrogen; wherein the hetero The ring group is optionally substituted by one or more C _1-3 alkyl, hydroxy, fluoro or benzyl; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, Thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolyl, each optionally substituted by 1, 2 or 3 groups Z;

^R represents H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy C _1-6 alkylene, which contains up to 6 carbon atoms, each of which is optionally substituted with one or more fluoro or cyano groups;

Z represents C _1-3 alkyl, C _1-3 alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl , nitro, amino, one or two C _1-3 alkylamino, C _1-3 alkylsulfonyl, C _1-3 alkoxycarbonyl, carboxyl, cyano, carbamoyl, one or two C _{1- 3} alkylcarbamoyl and acetyl; and

W represents hydroxyl, fluorine, C _1-3 alkyl, C _1-3 alkoxy, amino, one or two C _1-3 alkylamino, C _1-6 alkoxycarbonyl or heterocyclic amine selected from morpholine Base, pyrrolidinyl, piperidinyl or piperazinyl, wherein the heterocyclic amine is optionally substituted by C _1-3 alkyl or cyano.

In another embodiment the present invention relates to compounds of formula (I)

and its pharmaceutically acceptable salts, wherein

R ¹ represents a) a C _1-3 alkoxy group substituted by one or more fluorines or a C _4-6 alkoxy group optionally substituted by one or more fluorines, b) the formula phenyl (CH ₂ ) _p O - a group wherein p is 1, 2 or 3 and the benzene ring is optionally substituted by 1, 2 or 3 groups represented by Z, c) the group R ⁵ S(O) ₂ O or R ⁵ S (O) ₂ NH, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines, or R ⁵ represents phenyl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 A group represented by Z replaces or, d) a group of (R ⁶ ) ₃ Si, wherein R ⁶ represents a C _1-6 alkyl group, which may be the same or different;

R ^a represents halogen, C _1-3 alkyl or C _1-3 alkoxy

m is 0, 1, 2 or 3;

R ² represents C _1-3 alkyl, C _1-3 alkoxy, hydroxyl, nitro, cyano or halogen

n is 0, 1, 2 or 3;

R ³ represents a) group XY-NR ⁷ R ⁸ ,

where X is CO or SO ₂ ,

Y is absent or represents NH optionally substituted by C _1-3 alkyl;

and R ⁷ and R ⁸ independently represent:

C _1-6 alkyl optionally substituted by 1, 2 or 3 groups represented by W;

C _3-15 cycloalkyl optionally substituted by 1, 2 or 3 groups represented by W;

Optionally substituted (C _3-15 cycloalkyl)C _1-3 alkylene optionally substituted by 1, 2 or 3 groups represented by W;

Group -(CH ₂ ) _r (phenyl) _s , wherein r is 0, 1, 2, 3 or 4, when r is 0, s is 1 otherwise s is 1 or 2 and the phenyl group is optionally replaced by 1 , 2 or 3 groups represented by Z are substituted;

A saturated 5-8 membered heterocyclic group containing one nitrogen and optionally containing one of the following: oxygen, sulfur or additional nitrogen, wherein the heterocyclic group is optionally surrounded by one or more _C1-3 alkyl groups, Hydroxy or benzyl substitution;

The group -(CH ₂ ) _t Het, 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 optionally Aromatic heterocycles substituted by 1, 2 or 3 selected from C _1-5 alkyl, C _1-5 alkoxy or halogen;

Or R ⁷ represents H and R ⁸ are as defined above;

Or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached represent a saturated or partially saturated 5-8 membered heterocyclic group which does not contain a nitrogen and optionally contains one of the following: oxygen, sulfur or additional nitrogen; wherein the hetero The ring group is optionally substituted by one or more C _1-3 alkyl, hydroxy, fluoro or benzyl; or b) oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, Thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl or oxazolyl, each optionally substituted by 1, 2 or 3 groups Z;

R ⁴ represents H, C _1-6 alkyl, C _1-6 alkoxy or C alkoxy C _1-6 alkylene, which contains up to 6 carbon atoms, each of which is optionally replaced by one or more Fluorine or cyano substitution;

Z represents C _1-3 alkyl, C _1-3 alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulfonyl , nitro, amino, one or two C _1-3 alkylamino, C _1-3 alkylsulfonyl, C alkoxycarbonyl, carboxyl, cyano, carbamoyl, one or two C _1-3 alkyl Carbamoyl and acetyl; and W represents hydroxyl, fluorine, C _1-3 alkyl, C _1-3 alkoxy, amino, one or two C _1-3 alkylamino, or heterocyclic amine selected from morpholine Base, pyrrolidinyl, piperidinyl or piperazinyl, wherein the heterocyclic amine is optionally substituted by C _1-3 alkyl or hydroxyl.

In the specific group of compounds of formula I described in the above three embodiments, R ³ represents a group as described in the above paragraph a). In another specific group of these embodiments above, wherein R ³ represents compounds as described in the above paragraph a), excluding wherein R ³ represents N,N-diC _1-6 alkylcarbamoyl or R ³ represents Compounds of the group XY- ^NR7R8 , in which X is CO, Y is absent and ^R7 and ^R8 together with ^the nitrogen atom to which they are attached represent saturation or partly containing no nitrogen and optionally containing one of 5-8 membered heterocyclic group: oxygen, sulfur or additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more C _1-3 alkyl, hydroxyl, fluorine or benzyl. In another particular group of compounds of formula I in the first three above-mentioned embodiments, R ³ represents piperidin-1-ylcarbamoyl.

It is understood that when a substituent Z is present on more than one group, these substituents are independently selected and may be the same or different. So does W. Likewise when m is 2 or 3 then R ^{a are} independently selected such that they may be the same or different, and likewise when n is 2 or 3 then the groups ^R are independently selected such that they may be the same or different.

The term C _3-15 cycloalkyl includes monocyclic, bicyclic, tricyclic and spiro ring systems such as cyclopentyl, cyclohexyl and adamantyl.

The term heteroaryl refers to an aromatic 5-, 6- or 7-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to 5 ring heteroatoms selected from oxygen, nitrogen and sulfur. Suitable aromatic heteroaryl groups include, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl , triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuryl, indolyl, benzothienyl, benzo Oxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl . Preferably furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxazolylthiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, Tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5-triazenyl and more preferably pyrrolyl, thienyl, imidazolyl, oxazolyl or pyridyl. the

Suitable saturated or partially unsaturated 5-8 membered heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen or sulfur include, for example, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro- 1,3-thiazolyl, 1,3-thiazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, 1-oxotetrahydrothiophenyl, 1,1 -Dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl or tetrahydro Pyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, more preferably tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidinyl-3 -yl, morpholino, piperidino, piperidin-4-yl or piperazin-1-yl. the

Suitable groups wherein R ¹ represents the group R ⁵ S(O) ₂ O, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines include methanesulfonyloxy, ethylsulfonyl Oxygen, n-propylsulfonyloxy, n-butylsulfonyloxy, 3-methylbutane-1-sulfonyloxy, 3,3-dimethylbutane-1-sulfonyloxy, fluoromethyl Sulfonyloxy, difluoromethylsulfonyloxy, trifluoromethylsulfonyloxy, one, two or three (fluoroethyl)sulfonyloxy, 3,3,3-trifluoropropyl- 1-sulfonyloxy, or 4,4,4-trifluorobutyl-1-sulfonyloxy,

Suitable groups wherein R ¹ represents C _1-3 alkoxy substituted by one or more fluorine or C _4-6 alkoxy optionally substituted by one or more fluorine include butoxy, pentyloxy radical, hexyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy and 6,6 , 6-trifluorohexyloxy.

Suitable groups wherein R ¹ represents R ⁵ S(O) ₂ O, wherein R ⁵ represents phenyl and heteroaryl, each optionally substituted by 1, 2 and 3 groups represented by Z, include optionally phenylsulfonyloxy, thienylsulfonyloxy or pyridylsulfonyloxy substituted with 1, 2 and 3 groups represented by Z.

In a particular group of compounds of formula I, R ¹ represents a) a C _1-3 alkoxy i) fluoro ii) group NR ^c R ^d substituted by one or more of the following groups, where R ^c and R ^d independently represents H, C _1-6 alkyl or C _1-6 alkoxycarbonyl, provided that one of ^R and ^R is not H or iii) 1,3-dioxolan-2-yl b) R ¹ represents C _4-6 alkoxy i) fluorine ii) group NR ^c R ^d optionally substituted by one or more of the following groups, wherein R ^c and R ^d independently represent H, C _1-6 alkyl or _C2-6 alkoxycarbonyl, provided that one of R ^{and R} is not H or iii) 1,3-dioxolan-2-yl; c) phenyl of the formula ( CH ₂ ) a group of _p O-, wherein p is 1, 2 or 3 and the benzene ring is optionally substituted by 1, 2 or 3 groups represented by Z; d) R ⁵ S(O) ₂ O or R ⁵ S(O) ₂ NH, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines, or R ⁵ represents optionally substituted by 1, 2 or 3 groups represented by Z respectively phenyl or heteroaryl; e) a group of formula (R ⁶ ) ₃ Si, wherein R ⁶ represents a C _1-6 alkyl group, which is the same or different or f) a group of formula R ^b O(CO)O , ^wherein R represents C _1-6 alkyl optionally substituted by one or more fluorines;

R ^a represents halogen;

m is 0, 1, 2 or 3;

R ² represents halogen;

n is 0, 1, 2 or 3;

R ³ represents a group CONR ⁷ R ⁸ , wherein R ⁷ represents H and R ⁸ represents a C _3-15 cycloalkyl optionally substituted by a group represented by W or R ⁸ represents a group -(CH ₂ ) _t Het , wherein t is 0 and Het represents pyridyl optionally _{substituted by 1, 2 or 3 groups selected from C 1-5 alkyl} independently optionally replaced by one or more Fluorine substitution; or

R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents piperidino or morpholino; and R ⁴ represents H, halogen or C _1-6 alkyl, which is optionally replaced by one or more fluorine Substitution; Z represents halogen; and W represents C _1-6 alkoxycarbonyl-

A specific group of compounds of formula I is represented by formula IA

where ^R1 is

a) a C _4-6 alkoxy group optionally substituted by one or more fluorines, b) a group of the formula phenyl (CH ₂ ) _p O—, wherein p is 1, 2 or 3 and the phenyl ring is optionally is optionally substituted by 1, 2 or 3 groups represented by Z, c) a group R ⁵ S(O) ₂ O or R ⁵ S(O) ₂ NH, wherein R ⁵ represents optionally substituted by one or more fluorine C _1-6 alkyl, or R ⁵ represents phenyl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 groups represented by Z, wherein Z is as defined above, d) (R ⁶ ) ₃ A group of Si, wherein R ⁶ represents C _1-6 alkyl which may be the same or different, or e) a group of formula R ^b O(CO)O, wherein R ⁶ represents optionally substituted by one or more fluorine C _1-6 alkyl;

R ^a represents halogen and m is 0, 1 or 2;

R ^2a represents chlorine;

R ^2b represents chlorine;

R ^2c represents H or fluorine;

R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents piperidino or morpholino or R ³ represents a group CONHR ⁸ , wherein R ⁸ represents optionally substituted by C _1-6 alkoxycarbonyl C _5-7 cycloalkyl or R ⁸ represents optionally substituted pyridyl; and

R ⁴ represents H, C _1-3 alkyl or halogen.

A particular group of compounds of formula I is represented by formula IA, wherein R ¹ is a) C _4-6 alkoxy optionally substituted by one or more fluorines, b) a group of formula phenyl(CH ₂ ) _p O- wherein p is 1, 2 or 3 and the benzene ring is optionally substituted by 1, 2 or 3 groups represented by Z, c) the group R ⁵ S(O) ₂ O or R ⁵ S(O) ₂ NH, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines, or R ⁵ represents phenyl or heteroaryl each optionally substituted by 1, 2 or 3 groups represented by Z d) a group of (R ⁶ ) ₃ Si, wherein R ⁶ represents a C _1-6 alkyl group, which may be the same or different; or e) a group of the formula R ^b O(CO)O, wherein R ^b represents One or more C _1-6 alkyl optionally substituted by fluorine;

R ^a represents halogen and m is 0, 1 or 2;

R ^2a represents chlorine;

R ^2b represents chlorine;

R ^2c represents H;

R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents piperidino or morpholino or R ³ represents a group CONHR ⁸ , wherein R ⁸ represents C optionally substituted by C _1-6 alkoxycarbonyl _5-7 cycloalkyl; and

R ⁴ represents C _1-3 alkyl or halogen.

Another particular group of compounds of formula I is represented by formula IB

where ^R1 is

a) a C _4-6 alkoxy group optionally substituted by one or more fluorines, b) a group of the formula phenyl (CH ₂ ) _p O—, wherein p is 1, 2 or 3 and the phenyl ring is optionally is optionally substituted by 1, 2 or 3 groups represented by Z, c) a group R ⁵ S(O) ₂ O or R ⁵ S(O) ₂ NH, wherein R ⁵ represents optionally substituted by one or more fluorine C _1-6 alkyl, or R ⁵ represents phenyl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 groups represented by Z or d) a group of (R ⁶ ) ₃ Si, Wherein ^R represents C _1-6 alkyl which may be the same or different;

b) R ^a 1 represents halogen or H;

R ^a2 represents halogen or H;

R ^2a represents chlorine;

R ^2b represents chlorine;

R ^2c represents halogen or H;

R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents a piperidino group; and

R ⁴ represents a C _1-3 alkyl group.

In a particular group of compounds of formula I, formula IA or formula IB, R ¹ represents C _4-6 alkoxy optionally substituted by one or more fluorine.

In another particular group of compounds of formula I, formula IA or formula IB, R ¹ represents a group R ⁵ S(O) ₂ O or R ⁵ S(O) ₂ NH, wherein R ⁵ represents a group represented by one or more C _1-6 alkyl optionally substituted by fluorine, or R ⁵ represents heteroaryl optionally substituted by 1, 2 or 3 groups represented by Z. In a further group R ¹ represents a group R ⁵ S(O) ₂ O, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorine.

In another particular group of compounds of formula I, IA or IB, R ¹ represents a group of (R ⁶ ) ₃ Si, wherein R ⁶ represents a C _1-6 alkyl group which may be the same or different.

A particular group of compounds of formula I is represented by formula IC

where ^R1 is

a) C _4-6 alkoxy optionally substituted by one or more fluorines, b) a group R ⁵ S(O) ₂ O, wherein R ⁵ represents C _1- optionally substituted by one or more fluorines ₆ alkyl;

R ^2a represents chlorine;

R ^2b represents chlorine;

R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents piperidino or morpholino; and R ⁴ represents C _1-3 alkyl or halogen.

In a particular group of compounds of formula IC, R ¹ is a group R ⁵ S(O) ₂ O, wherein represents C _1-6 alkyl substituted by one or more fluorines. More particularly R ¹ is a group R ⁵ S(O) ₂ O, wherein R ⁵ represents C _3-6 alkyl substituted by one or more fluorines.

Other values of R ¹ , R ² , R ³ , R ⁴ and R ^a in compounds of formula I, formula LA, formula IB or formula IC are as follows. It is to be understood that such values may take any values given in the definitions, claims or contextual embodiments where appropriate.

R ¹ represents 4,4,4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsulfonyloxy, 4,4,4-trifluorobutyl-1-sulfonyloxy, 3 , 3,3-trifluoropropyl-1-sulfonyloxy, propoxycarbonyloxy, 2-(1,3-dioxolan-2-yl)ethoxy, N-ethyl -2-aminoethoxy, N-tert-butoxycarbonyl-N-ethyl-2-aminoethoxy, 3-methylbutane-1-sulfonyloxy, 3,3-dimethylbutane- 1-sulfonyloxy, 5-chloro-2-thienylsulfonyloxy, 2-thienylsulfonyloxy or 3-pyridylsulfonyloxy.

R ¹ represents a C _4-6 alkoxy group substituted by one or more fluorines. R ¹ represents 4,4,4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsulfonyloxy, 4,4,4-trifluorobutyl-1-sulfonyloxy, 3 , 3,3-trifluoropropyl-1-sulfonyloxy, propoxycarbonyloxy, 2-(1,3-dioxolan-2-yl)ethoxy, N-ethyl -2-aminoethoxy, or N-tert-butoxycarbonyl-N-ethyl-2-aminoethoxy.

R ¹ represents 4,4,4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsulfonyloxy, 4,4,4-trifluorobutyl-1-sulfonyloxy, 3 , 3,3-trifluoropropyl-1-sulfonyloxy or propoxycarbonyloxy.

R ¹ represents 4,4,4-trifluorobutoxy, n-butylsulfonyloxy or n-propylsulfonyloxy.

^R2 represents chlorine or fluorine and n is 2 or 3.

R ³ represents N-(piperidin-1-yl)carbamoyl, 5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl, morpholin-4-ylcarbamoyl or N-(1- Methoxycarbonyl-1-cyclopentyl)carbamoyl.

R ⁴ represents C1-4 alkyl or halogen. R ⁴ represents methyl or bromine. m is 0 or R ^a represents fluorine when m is 1 or 2.

In another particular group of compounds of formula I, formula IA, formula IB or formula IC or any embodiment thereof, R ³ represents N-(piperidin-1-yl)carbamoyl.

"Pharmaceutically acceptable salts", when such salts are practicable, include both pharmaceutically acceptable acid and base addition salts. Suitable pharmaceutically acceptable salts of compounds of formula I are, for example, acid addition salts of compounds of formula I which are sufficiently basic, for example with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoro Acetic acid, citric acid or maleic acid; or, for example, a salt of a compound of formula I which is sufficiently acidic, for example an alkali metal or alkaline earth metal salt, for example sodium, calcium or magnesium, or an ammonium salt, or a salt with an organic base, for example Methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. the

Throughout the specification and appended claims, given chemical formulas and names shall include all stereo and optical isomers and their racemates as well as mixtures of individual enantiomers in varying proportions, where such Isomers and enantiomers, where they exist, as well as their pharmaceutically acceptable salts and their solvates, eg hydrates. Isomers may be separated using conventional techniques such as chromatography or fractional crystallization. Enantiomers may be separated by separation of racemates, for example by fractional crystallization, resolution or HPLC. Diastereoisomers can be separated by separation of isomeric compounds using fractional crystallization, HPLC or flash chromatography. Additional stereoisomers may be prepared by chiral synthesis from chiral starting materials under conditions which do not initiate racemization or epimerization, or by derivatization with chiral reagents. All stereoisomers are within the scope of this invention. Where possible, all tautomers are within the scope of the invention. The present invention also includes compounds containing one or more isotopes such as ¹⁴ C, ¹¹ C or ¹⁹ F and their use as isotopically labeled compounds for pharmacological and metabolic studies.

The present invention also includes prodrugs of compounds of formula I, which are compounds which are converted to compounds of formula I in vivo. the

The following definitions shall apply to the entire specification and appended claims. the

Unless otherwise stated or indicated, the term "alkyl" represents a straight or branched chain alkyl group. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl , hexyl and isohexyl. the

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and t-butyl. the

Unless otherwise stated or indicated, the term "alkoxy" denotes the group O-alkyl, wherein alkyl is as defined above. the

Unless stated or indicated otherwise, the term "halogen" shall mean fluoro, chloro, bromo or iodo. the

Specific compounds of the present invention are one or more of the following compounds:

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

1-(2,4-diaminophenyl)-4-methyl-5-[4-(4,4,4-trifluorobutoxy)phenyl]-1H-pyrazole-3-carboxylic acid piperidine Pyridine-1-ylamide;

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

Propane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-ylcarbamoyl)-2H-pyrazol-3-yl] Phenyl esters;

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

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

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

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

4-{1-(2,4-Diaminophenyl)-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}phenylpyridine-3 - sulfonate;

[2-(4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}benzene Oxygen) ethyl] tert-butyl ethyl carbamate;

1-(2,4-dichlorophenyl)-5-{4-[2-(ethylamino)ethoxy]phenyl}-4-methyl-N-piperidin-1-yl-1H- Pyrazole-3-carboxamide;

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

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

4-[1-(2,4-Dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-1H-pyrazole- 5-yl]phenyl 3,3,3-trifluoropropane-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;

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

5-Chloro-thiophene-2-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-2H-pyrazole- 3-base] phenyl ester;

and pharmaceutically acceptable salts thereof. the

The process for the preparation of compounds of formula I wherein R ^a , R ² , R ³ , R ⁴ , m and n are as defined above and R ¹ represents a group R ⁵ S(O) ₂ NH can be achieved by a compound of formula II

wherein R ^a , R ² , R ³ , R ⁴ , m and n are as defined above, and a sulfonating reagent of the formula R ⁵ SO ₂ L, wherein R ⁵ is as defined above and L represents a leaving group such as chlorine, in an inert solvent such as In difluoromethane, it is produced by reacting in the presence of a base such as triethylamine at a temperature ranging from -25°C to 150°C.

wherein R ¹ represents a) C _1-3 alkoxy substituted by one or more fluorine or C _4-6 alkoxy optionally substituted by one or more fluorine or b) phenyl (CH ₂ ) _p A group of O-where p is 1, 2 or 3 and the phenyl ring is optionally substituted by 1, 2 or 3 groups represented by Z, or c) the formula I of the group R ⁵ S(O) ₂ O The compound can be obtained by making the compound of formula III

wherein R ^a , R ² , R ³ , R ⁴ , m and n are as defined above, respectively and a) an alkylating agent of the formula R ⁹ X, wherein R ⁹ represents a C _1-3 alkyl group substituted by one or more fluorines Or C _4-6 alkyl optionally substituted by one or more fluorines and X represents a leaving group such as chlorine, bromine or iodine, in an inert solvent such as acetone, in the presence of a base such as potassium carbonate, at -25 ℃ to 150 ℃ temperature range; or b) with an alkylating agent of formula R ⁹ X, wherein R ⁹ represents a group of formula phenyl (CH ₂ ) _p -, wherein p is 1, 2 or 3 and the benzene ring is optionally substituted by 1, 2 or 3 groups represented by Z, and X represents a leaving group such as chlorine, bromine or iodine, in an inert solvent such as acetone, in the presence of a base such as potassium carbonate or c) with a sulfonated reagent of formula R ⁵ SO ₂ L, wherein R ⁵ is as defined above and L represents a leaving group such as chlorine, in an inert It is prepared by reacting in a solvent such as difluorohexane in the presence of a base such as triethylamine at a temperature ranging from -25°C to 150°C.

wherein R ^a , R ¹ , R ² , R ⁴ , m and n are as defined above and R ³ represents the group XY-NR ⁷ R ⁸ wherein X is CO, Y is absent or represents optionally substituted by C _1-3 alkyl NH and R ⁷ and R ⁸ as defined above for the compound of formula I can also be obtained by the compound of formula IV

wherein R ^a , R ¹ , R ² , R ⁴ , m and n are as defined above and R ¹ represents a C _1-6 alkyl group, reacted with a compound of formula V

R ⁷ R ⁸ YNH ₂ V

wherein Y, R ⁷ and R ⁸ are as defined above or salts thereof, prepared by reacting in an inert solvent such as toluene in the presence of a Lewis acid such as trimethylaluminum at a temperature ranging from -25°C to 150°C;

R ³ of formula I represents a group XY-NR ⁷ R ⁸ , wherein X is SO ₂ , Y is absent or represents NH optionally substituted by C _1-3 alkyl and R ⁷ and R ⁸ are defined as above compounds can also be Through the compound of formula VI

wherein R ^a , R ¹ , R ² , R ⁴ , m and n are as defined above and A represents a leaving group such as halogen such as chlorine, and a compound of formula V wherein Y, R ⁷ and R ⁸ are as defined above or a salt thereof Prepared by reacting in an inert solvent such as THF or difluoromethane in the presence of a base such as potassium carbonate, triethylamine or pyridine at a temperature ranging from -25°C to 150°C.

Compounds of formula III, IV and VI can be prepared by methods analogous to those described above. the

Certain intermediate compounds are believed to be novel and form part of the present invention. Those skilled in the art will appreciate that in this reaction scheme certain functional groups will need to be protected and subsequently deprotected with appropriate borrowing, see "Protective Groups in Organic Synthesis" by Greene and Wuts, 3rd edition (1999). the

pharmacological properties

The compounds of the present invention are generally administered orally, parenterally, intravenously, intramuscularly, subcutaneously or by other injectable routes, buccally, rectally, vaginally, transdermally and/or intranasally and/or by inhalation, using in A pharmaceutically acceptable dosage form containing the active ingredient or a pharmaceutically acceptable addition salt thereof in the form of a pharmaceutical preparation. The composition can be administered in different doses depending on the disease and patient to be treated and the route of administration. the

A suitable daily dose of a compound of the invention in therapeutically treated humans is about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight. the

Oral formulations are particularly preferably tablets or capsules, which can be supplemented by methods known to those skilled in the art to provide dosages of the active compound in the range of 0.5 mg to 500 mg, for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250mg. the

According to another aspect of the present invention there is provided a pharmaceutical formulation comprising any compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable adjuvant, diluent and/or carrier. the

pharmacological properties

Compounds of formula (I) are effective in treating obesity or overweight, (for example, promoting weight loss and maintaining weight loss), preventing weight gain (for example, drug-induced or induced after smoking cessation), regulating appetite and/or satiety, diet Disorders (e.g. binge eating, anorexia, bulimia and compulsiveness), addiction (to drugs, tobacco, alcohol, any palatable macronutrient or non-essential food), treatment disorders Psychotic disorders such as psychotic and/or mood disorders, mental Schizophrenia and schizoaffective disorder, bipolar disorder, anxiety, anxiety-depressive disorder, depression, mania, obsessive-compulsive disorder, impulse control disorder (eg, Tourette's syndrome), attention disorders such as DD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (eg, amnesia, Alzheimer's disease, Pick's dementia, senile dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild senile dementia), psychiatric and/or neurodegenerative disorders (such as multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease, and Alzheimer's disease), demyelination-related diseases, neuroinflammatory diseases (eg, Guillain-Barr syndrome). the

The compounds of the present invention are also effective in the prevention or treatment of dependence and addiction disorders and behaviors (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol abstinence with or without perceptual disturbance ; alcohol withdrawal slander; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opiate withdrawal; and other substance-induced withdrawal symptoms), alcohol and/or drug-induced mood, anxiety, and/or sleep disturbances and episodes during withdrawal, and alcohol and/or drug-induced relapse. the

Said compounds are also effective in the prevention or treatment of psychiatric disorders such as dystonia, dyskinesia, akathisia, tremor and rigidity, treatment of spinal cord injuries, neuropathy, migraine, insomnia disorders, sleep disorders (e.g., disorders of the sleep system, sleep apnea , obstructive sleep apnea, sleep apnea syndrome), pain disorders, traumatic trauma. the

The compounds are also effective in the treatment of immune, vascular diseases (such as atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrythmias), congestive heart failure, coronary artery disease, heart disease, hypertension, prophylaxis and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, vascular eluting systemic inflammation, septic blockage, stroke, stroke, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral Embolism, cerebral hemorrhage, metabolic disorders (such as conditions showing reduced metabolic activity or resting energy consumption as a percentage of total free fat mass), diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hypercholesterolemia Lipids, hypertriglyceridemia, hyperureaemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity - lung hypoventilation syndrome (Pickwickian syndrome), type 1 diabetes, type 2 diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (eg, treatment of hypogonadism in men, treatment Infertility or as a contraceptive, menstrual abnormalities/menstrual disorders, polycystic ovary disease, sexual and reproductive dysfunction (erectile dysfunction) in women and men, GH-deficiency subjects, female hirsutism, normal variant short stature) and Diseases related to breathing (such as asthma and chronic obstructive pulmonary disease) and diseases of the gastrointestinal system (such as dysfunction of gastrointestinal motility or bowel propulsion, diarrhea, vomiting, nausea, gallbladder disease, gallstones, obesity-related gastric - esophageal reflux, ulcer).

Said compounds are also effective as a treatment for skin diseases, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), cranial smoke duct tumors, Prader-Willi syndrome, Turner syndrome syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract diseases and inflammatory diseases (such as osteoarthritis, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic diseases. The compound is also effective as a drug for the treatment of (esophageal) achalasia. the

In another aspect the invention provides a compound of formula I as defined above for use as a medicament. the

In another aspect the present invention provides the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of obesity or overweight, (for example, promoting weight loss and maintaining weight loss), preventing weight gain (for example, drug-induced or subsequent to smoking cessation) development), regulation of appetite and/or satiety, eating disorders (such as binge eating, anorexia, bulimia, and compulsiveness), addiction (for drugs, tobacco, alcohol, any palatable high-nutrient or non-essential food), Treatment of psychotic disorders such as psychosis and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety, anxiety-depressive disorder, depression, mania, obsessive-compulsive and behavioral disorders, impulse control disorders (eg , Tourette's syndrome), attention disorders such as ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick dementia, senile dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild senile dementia), psychiatric and/or neurodegenerative disorders (eg, multiple sclerosis, Raynaud's syndrome , Parkinson's disease, Huntington's disease and Alzheimer's disease), demyelination-related diseases, neuroinflammatory diseases (eg, Guillain-Barr syndrome). the

On the other hand the present invention provides compounds of formula I in the preparation for the treatment or prevention of dependence and addiction diseases and behaviors (for example, alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal diseases (for example, Alcohol withdrawal with or without perceptual disturbance; alcohol withdrawal slander; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opiate withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbance; sedatives , hypnotic or anxiolytic withdrawal slander; and other substance-induced withdrawal symptoms), alcohol- and/or drug-induced mood, anxiety, and/or sleep disturbances accompanying withdrawal episodes, and alcohol and/or drug-induced psychosis Drug use in relapse. the

On the other hand, the present invention provides compounds of formula I in the preparation for the treatment or prevention of psychiatric disorders such as dystonia, dyskinesia, akathisia, tremor and rigidity, treatment of spinal cord injuries, neuropathy, migraine, insomnia disorders, sleep disorders (e.g. , sleep system disorders, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, traumatic drug application. the

In another aspect the invention provides the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of: immunity, vascular diseases (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythm, and arrhythmia, hyperemia Heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, vascular eluting systemic inflammation, septic occlusion, stroke, cerebral Stroke, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (e.g. conditions exhibiting decreased metabolic activity or decreased resting energy consumption as a percentage of total free fat mass), diabetes mellitus, lipid abnormalities hyperlipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperureaemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance sexual syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels) , reproductive and endocrine disorders (such as treatment of hypogonadism in men, treatment of infertility or as a contraceptive, menstrual abnormalities/menstrual disorders, polycystic ovarian disease, sexual and reproductive dysfunction (erectile dysfunction) in women and men, GH-deficient subjects, female hirsutism, normal variant short stature) and diseases related to respiratory (such as asthma and chronic obstructive pulmonary disease) and gastrointestinal system (such as dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, vomiting , nausea, gallbladder disease, gallstones, obesity-related gastroesophageal reflux, ulcers).

On the other hand, the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prevention of the following diseases: skin diseases, cancer (such as colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, cholangiocarcinoma), cranial smoked duct tumors, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract diseases and inflammatory diseases (such as osteoarthritis, inflammation, inflammation of viral encephalitis sexual sequelae, osteoarthritis) and orthopedic diseases. the

In yet another aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prevention or treatment of obesity or overweight, (e.g., promoting weight loss and maintaining weight loss), Prevention of weight gain (eg, drug-induced or secondary to smoking cessation), regulation of appetite and/or satiety, eating disorders (eg, binge eating, anorexia, bulimia, and compulsion), addiction to drugs, tobacco, alcohol, Any palatable high-nutrient or non-essential food), treatment of psychotic disorders such as psychosis and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety, anxiety-depressive disorder, depression, mania, obsessive-compulsive disorder Perceptual and behavioral disorders, impulse control disorders (eg, Tourette's 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, senile dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild senile dementia), psychiatric and/or neurodegenerative disorders (e.g., multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease, and Alzheimer's disease), demyelination-related diseases, neuroinflammatory diseases (e.g., Guillain-Barr syndrome sign). the

In yet another aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prevention or treatment of: dependence and addiction disorders and behaviors (e.g., alcohol and/or or substance abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbance; alcohol withdrawal slander; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opiate withdrawal ; sedative, hypnotic, or anxiolytic withdrawal with or without perceptual disturbance; sedative, hypnotic, or anxiolytic withdrawal slander; and other substance-induced withdrawal symptoms), alcohol and/or drug-induced mood, anxiety, and And/or sleep disturbances associated with onset of withdrawal, and relapses of alcohol and/or drug slumps. the

In a further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prevention or treatment of psychiatric dysfunction such as dystonia, dyskinesia, akathisia, tremor and rigidity , for the treatment of spinal cord injuries, neuropathy, migraine, insomnia disorders, sleep disorders (eg, sleep system disorders, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, traumatic trauma. the

In yet another aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for preventing or treating the following diseases: immunity, vascular diseases (e.g. atherosclerosis, arteriosclerosis, angina pectoris, Abnormal heart rhythm, and arrhythmia, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, vascular washout system Inflammation, septic blockage, stroke, cerebral apoplexy, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disorders (such as manifested by decreased metabolic activity or resting energy consumption as a percentage of total free fat mass Reduced conditions, diabetes, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperureaemia, impaired glucose tolerance, impaired fasting glucose , insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation 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 hypogonadism in men, treatment of infertility or as birth control pills, menstrual abnormalities/menstrual disorders, polycystic ovarian disease, sexual and Reproductive dysfunction (erectile dysfunction), GH-deficient subjects, female hirsutism, normal variant short stature) and diseases related to the respiratory (such as asthma and chronic obstructive pulmonary disease) and gastrointestinal system (such as gastrointestinal motility or Bowel propulsion dysfunction, diarrhea, vomiting, nausea, gallbladder disease, gallstones, obesity-related gastro-oesophageal reflux, ulcers).

In yet another aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for preventing or treating the following diseases: skin disease, cancer (e.g. colon, rectum, prostate, breast, ovarian , endometrium, cervix, gallbladder, bile ducts), cranioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract diseases and inflammatory diseases (such as osteoarthritis , inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic diseases. the

The compounds of the 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., rebound, drug-induced or secondary to smoking cessation), regulating appetite and/or satiety Insensitivity, eating disorders (such as binge eating, anorexia, bulimia and compulsions), addictions (for drugs, tobacco, alcohol, any tasty high nutrient or non-essential food). the

Compounds of formula (I) are effective in the treatment of obesity, psychotic disorders such as psychotic disorders, schizophrenia, bipolar disorder, anxiety, anxiety-depressive disorder, depression, cognitive impairment, memory impairment, obsessive-compulsive attitude and behavior disorder, anorexia, Hyperphagia, attention disorders such as ADHD, epilepsy and related disorders, and neurological disorders such as dementia, neurological disorders (such as multiple sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's disease and Alzheimer's disease. The compounds are also effective in the treatment of immune, cardiovascular, reproductive and endocrine diseases, septic shock and diseases related to the respiratory and gastrointestinal system (eg diarrhea). Said compounds are also effective in the treatment of long-term abuse, addiction and/or relapse indications such as treatment of drug (nicotine, ethanol, cocaine, opiates, etc.) dependence and/or treatment of drug (nicotine, ethanol, cocaine, opiates, etc.) withdrawal symptoms. The compounds also abolish the weight gain that normally accompanies smoking cessation. the

In another aspect the invention provides a compound of formula I as defined above for use as a medicament. the

In another aspect the invention provides the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of: obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxiety-depressive disorders, depression , cognitive impairment, memory impairment, obsessive-compulsive and behavioral disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders such as multiple sclerosis, Kinson's disease, Huntington's disease, and Alzheimer's disease, immune, cardiovascular, reproductive, and endocrine disorders, septic shock, conditions related to the respiratory and gastrointestinal systems (such as diarrhea), and chronic abuse, Indications of addiction and/or relapse, such as treatment drug (nicotine, ethanol, cocaine, opiates, etc.) dependence and/or treatment drug (nicotine, ethanol, cocaine, opiates, etc.) withdrawal syndrome. the

In another aspect the invention provides a method for the treatment of obesity, psychotic disorders such as psychotic disorders such as schizophrenia and bipolar disorder, anxiety, anxiety-depressive disorder, depression, cognitive impairment, memory impairment, obsessive-compulsive Perceptual and behavioral disorders, anorexia, bulimia, attention disorders such as ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders such as multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, disorders related to the respiratory and gastrointestinal system (e.g. diarrhea), and long-term abuse, addiction and/or relapse indications , such as treating drug (nicotine, ethanol, cocaine, opiates, etc.) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc.) withdrawal syndrome, the method comprising administering a pharmacologically effective amount of the formula The compound of I is given to patients in need thereof. the

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

The compounds of the invention are also useful for preventing or reversing drug-induced weight gain, for example weight gain induced by neuroleptic treatment. The compounds of the invention may also be used to prevent or reverse weight gain associated with smoking cessation. the

combination therapy

The compounds of the invention may be combined with another therapeutic agent effective in the treatment of obesity, such as other anti-obesity drugs that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat Absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/actuation, food intake or G-I movement. the

The compounds of the present invention may further be combined with another therapy effective in the treatment of obesity-related diseases such as hypertension, hyperlipidemia, dyslipidemia, diabetes, sleep apnea, asthma, heart disease, atherosclerosis, Macrovascular and microvascular disease, hepatic steatosis, cancer, joint disease, and gallbladder disease. For example, a compound of the invention may be administered in combination with another drug that lowers blood pressure or lowers the LDL:HDL ratio, or with a drug that causes a decrease in circulating levels of LDL-cholesterol. Compounds of the invention may also be used in combination with therapeutic agents for the treatment of complications associated with macrovascular disease in patients with diabetes. the

The compounds of the present invention may be combined with other therapies for the treatment of obesity and its mutual complications metabolic syndrome and type 2 diabetes, these include biguanide biguanide drugs, insulin (synthetic insulin analogs) and oral antihyperglycemic drugs (these are divided into dietary glucose regulators and α-glucose inhibitors). the

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

Furthermore the combinations according to the invention can be combined with sulfonylureas. The present invention also includes the compounds of the present invention in combination with cholesterol-lowering drugs. Cholesterol-lowering drugs are referred to in this application including but not limited to inhibitors of HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase). Suitable HMG-CoA reductase inhibitors are statins. the

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

The present invention also includes the compounds of the invention in combination with inhibitors of the ileal bile acid transport system (IBAT inhibitors). The present invention also includes compounds of the present invention in combination with bile acid binding resins. the

The present invention also includes a compound of the present invention in combination with a bile acid sequestrant such as colestipol or cholestyramine or cholestagel. the

According to another aspect of the present invention, a combination therapy is provided, comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable diluent or carrier, and one or more selected from the following Drugs:

CETP (cholesteryl ester transfer protein) inhibitors;

Cholesterol absorption antagonists;

MTP (microsomal transfer protein) inhibitors;

Niacin derivatives, including extended-release and combination products;

Phytosterol compounds;

Probucol;

anticoagulants;

Omega-3 fatty acids;

Another anti-obesity compound such as sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine;

Antihypertensive compounds such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, adrenergic blocking agents, alpha adrenergic blocking agents, beta adrenergic blocking agents, mixed Type alpha/beta adrenergic blockers, adrenergic stimulants, calcium channel blockers, AT-1 blockers, chlorothiazide (saluretic), diuretics or vasodilators;

Melanin-concentrating hormone (MCH) modulator;

NPY receptor modulators;

Orexin receptor modulators;

Phosphoinositide-dependent protein kinase (PDK) modulators; or

Nuclear receptor modulators such as LXR, FXR, RXR, GR, ERRα, β, PPARα, β, γ, and RORα;

Monoamine transport modulators, such as selective serotonin uptake inhibitors (SSRI), norepinephrine uptake inhibitors (NARI), norepinephrine-serotonin uptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI), Tricyclic antidepressants (TCA), noradrenergic and specific serotonergic antidepressants (NaSSA);

Antipsychotic medications such as olanzapine and clozapine;

Serotonin receptor modulators;

Leptin/leptin receptor modulators;

ghrelin/ghrelin receptor modulators;

DPP-IV inhibitors;

or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of said salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier for simultaneous, sequential or separate administration to a warm-blooded animal, such as in need of such treatment people. the

According to another aspect of the present invention, there is provided a composition comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable diluent or carrier, and a very low calorie diet (VLCD) Or a low-calorie diet (LCD) administered simultaneously, sequentially or separately. the

Thus, in another aspect of the present invention, there is provided a method of treating obesity and its complications in a warm-blooded animal in need of such treatment, such as a human, comprising administering to the animal an effective amount of a compound of formula I or a pharmaceutically acceptable compound thereof The salt is administered simultaneously, sequentially or separately with an effective amount of a compound selected from other classes of compounds described in the combination section or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof. the

Therefore, another aspect of the present invention provides a method for treating hyperlipidemia in a warm-blooded animal in need of the treatment, such as a human, comprising giving the animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with an effective Amounts of one compound selected from the other classes of compounds described in the combination section or pharmaceutically acceptable salts, solvates, solvates of said salts or prodrugs thereof are administered simultaneously, sequentially or separately. the

According to another aspect of the present invention there is provided a pharmaceutical composition, the composition contains a compound of formula I or a pharmaceutically acceptable salt thereof, and a compound or a pharmaceutically acceptable salt thereof in the other types of compounds described in the combination section , a solvate, a solvate of the salt or a prodrug thereof, and a pharmaceutically acceptable diluent or carrier. the

According to another aspect of the present invention, there is provided a kit, which contains a compound of formula I or a pharmaceutically acceptable salt thereof, and a compound or a pharmaceutically acceptable salt or solvate thereof in other types of compounds described in the combination section , A solvate of said salt or a prodrug thereof. the

According to another aspect of the present invention there is provided a kit, which contains:

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

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

c) A container containing the first and second dosage forms described above. the

According to another aspect of the present invention there is provided a kit, which contains:

a) in a first unit dosage form, a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier;

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

c) A container containing the first and second dosage forms described above. the

According to another aspect of the present invention there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, and one of the other compounds described in the Combination section or a pharmaceutically acceptable salt, solvate, solvate of said salt or a prodrug thereof Use in the manufacture of a medicament for the treatment of obesity and its associated complications in warm-blooded animals such as humans. the

According to another aspect of the present invention there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, and one of the other compounds described in the Combination section or a pharmaceutically acceptable salt, solvate, solvate of said salt or a prodrug thereof Use in the manufacture of a medicament for the treatment of hyperlipidemic disorders in warm-blooded animals such as humans. the

According to another aspect of the present invention there is provided a combination therapy comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable diluent or carrier, and an effective amount of one of the Other compounds described above or pharmaceutically acceptable salts, solvates, solvates of said salts or prodrugs thereof, optionally together with pharmaceutically acceptable diluents or carriers, are administered to literature animals simultaneously, sequentially or separately, for example, as required The person who should be treated therapeutically. the

In addition, the compounds of the present invention can also effectively treat obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, nonalcoholic steatohepatitis, osteoarthritis) Combinations of therapeutic agents for diseases or conditions associated with certain cancers) and psychosis and psychiatric disorders. the

Medically acceptable definitions of obesity and overweight should be understood. Patients can be identified by providing, for example, a measurement of body mass index (BMI), which is weight in kilograms divided by height in square metres, and a comparison result defined thereby. the

pharmacological activity

The compounds of the present invention have antagonistic activity against the receptor product of the CB ₁ gene. The affinity of the compounds of the invention for the central cannabinoid receptors is determined according to those methods described by Devane et al. in Molecular Pharmacology, 1988, 34,605 or WO01/70700 or EP 656354. Alternatively the test can be performed as follows.

10 μg of membranes prepared from cells stably transfected with the CB ₁ gene were suspended in 200 μl of 100 mM NaCl, 5 mM MgCl ₂ , 1 mM EDTA, 50 mM HEPES (pH 7.4), 1 mM DTT, 0.1% BSA and 100 11 M GDP. To this was added an agonist (CP55940) at an EC80 concentration, a test compound at a desired concentration and 0.1 µCi of [ ³⁵ S]-GTPyS. The reaction was allowed to proceed at 30°C for 45 minutes. Samples were then transferred to GF/B filters using a cell harvester and washed with wash buffer (50 mM Tris (pH 7.4), 5 mM _MgCl2 , 50 mM NaCl). The filters were then covered with scintillant and the amount of [ ³⁵ S]-GTPγS retained on the filters was counted.

Activity was measured in the absence of all ligands (minimum activity) or in the presence of an EC80 concentration of CP55940 (maximal activity). These activities were set as 0% and 100% activity, respectively. At different concentrations of the new ligand, the activity was calculated as a percentage of the maximal activity and plotted. Data were fitted using the following formula y=A+((B-A)/l+((C/x)UD)) and IC50 values were determined as the concentration required to achieve half-maximal inhibition of GTPyS binding under the conditions used. the

The compounds of the present invention are active at the _CB1 receptor (IC50 < 1 micromolar). Most preferred compounds have IC50 < 200 nanomolar. For example, the IC50 of Example 10 is 6.0 nM and that of Example 11 is 6.4 nM.

The compounds of the present invention are believed to be selective _CB1 antagonists or inverse agonists. Potency, selectivity and side effect propensity may limit the clinical utility of hitherto known compounds with established CB ₁ antagonistic/inverse agonistic properties. In this regard, preclinical evaluation of compounds of the invention in models of gastrointestinal and/or cardiovascular function demonstrates that they possess significant advantages over representative reference _CB1 antagonists/inverse agonists.

Compounds of the present invention are comparable to representative reference _CB1 antagonists/reverse agents in potency, selectivity, bioavailability, plasma half-life, blood-brain permeability, plasma protein binding (e.g., higher free fraction of drug) or solubility. Agonists may offer additional advantages over agonists.

The utility of the compounds of the present invention in the treatment of obesity and related disorders was demonstrated by self-food-induced weight loss in obese mice. Female C57B1/6J mice received ad libitum high-calorie 'self-service' chow (soft chocolate/cocoa pastry, chocolate, fatty cheese and nougat) and standard laboratory chow for 8-10 weeks. The compounds tested were then administered systemically once daily (iv, ip, sc or po) for a minimum of 5 days, and the body weight of the mice was monitored daily for inositol. Concurrent assessment of obesity was performed by DEXA imaging modality at baseline and at the end of the study. Blood was collected for analysis of changes in obesity-related plasma markers. the

Example

abbreviation

AcOH Acetic acid

DCM Difluoromethane

DMF Dimethylformazan

Amide

DEA Diethylamine

DIEA N, N-diisopropylethylamine

DMAP 4-Dimethylaminopyridine

EtOAc Ethyl acetate

Et ₃ N Triethylamine

Ex or EX Example

LiHMDS Lithium hexamethyldisilazide

MeOH Methanol

MeCN

rt or RT room temperature

TEA Triethylamine

THF Tetrahydrofuran

t triplet

s singlet

d double peak

q quartet

qvint quintet

m multiplet

br broad peak

bs broad singlet

dm double multiplet

bt broad triplet

dd double doublet

General implementation method

Mass spectra were recorded on a ZQ single quadrupole or Micromass LCZ single quadrupole mass spectrometer equipped with a gas-filled assisted electrospray interface (LC-MS). ¹ H NMR measurements were performed on a Varian Mercury 300 or Varian Inova 500 at ¹ H frequencies of 300 and 500 MHz, respectively. Chemical shifts are in ppm relative to _CDCl3 as internal standard. CDCl ₃ was used as solvent in NMR unless otherwise stated. Purification was performed on a Shimadzu QP 8000 single quadrupole mass spectrometer with a 19 x 100 mm C8 column with semi-preparative HPLC (High Performance Liquid Chromatography) and mass triggered fractionation collector. If not stated, the mobile phase was acetonitrile and buffer (0.1M ammonium acetate:acetonitrile 95:5). For the separation of isomers, a Kromasil CN E9344 (250×20 mm id) column was used. Heptane:ethyl acetate:DEA 95:5:0.1 was used as mobile phase (1 ml/min). Fraction collection was guided with a UV-detector (330mn).

Typical HPLC-parameters for purity analysis:

HPLC system: Agilent 1100

Column: Zorbax EclipseXDB-C8150×4.6mm

Analysis time: 15 minutes

Flow: 1.5ml/min

Mobile phase: A: water, 5% MeOH

B: MeOH

Temperature: 40°C

Detector: Uv240nm

Embodiments of the invention

Example 1

Step A 1-(4-Benzyloxyphenyl)propan-1-one

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

Step B 1-(4-Benzyloxyphenyl)-2-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 was stirred at room temperature for 2 hours, at which point the reaction mixture was a clear, yellow solution. After cooling, water (100ml) was added and the product was extracted with ether (2x100ml). The combined organic extracts were washed with water, sodium bicarbonate and brine. The organic phase was dried ( _Na2SO4 ), filtered and evaporated to give the title compound as _a yellow solid (6.17 g, 97%).

Step C 2-[2-(4-Benzyloxyphenyl)-2-oxo-ethyl]-3-oxo-butanoic acid ethyl ester

A solution of sodium ethoxide was prepared from sodium metal (0.53 g, 23.0 mmol) in 30 ml absolute ethanol. To this solution was added ethyl acetoacetate (3.00 g, 23.0 mmol) at 0°C. After 30 minutes, a solution of 1-(4-benzyloxyphenyl)-2-bromo-propan-1-one (6.17 g, 19.0 mmol) in ethanol:toluene (30:15 ml) was added to the solution and The reaction mixture was stirred overnight. Acidic work-up with 1M HCl, extraction with ethyl acetate (3x), washing with brine, drying ( _{Na2SO4 )} , filtration and evaporation afforded the crude product by flash chromatography (hexane:EtOAc 95:5-70:30) 5.18 g of the title compound were obtained as a pale yellow oil.

Step D 5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

A solution of sodium ethoxide was prepared from sodium metal (0.19 g, 8.26 mmol) in 20 ml absolute ethanol. To this solution was added 2-[2-(4-benzyloxyphenyl)-2-oxo-ethyl]-3-oxo-butanoic acid ethyl ester (2.13 g, 6.00 mmol) and the reaction mixture Stir at room temperature for 30 minutes. A solution of 2,4-dichlorophenyldiazide chlorine prepared previously (from 2,4-dichloroaniline (1.19g, 7.30mmol) in 3ml 24% HCl and sodium nitrite (0.52g, 7.50mmol) prepared in 3 ml of water at 0°C) was added in 5 portions maintaining the temperature below 5°C. After stirring at room temperature for 2.5 hours water was added and the product was extracted with EtOAc (3x). _The combined organic extracts were dried ( _Na2SO4 ), filtered and evaporated. The residue was dissolved in ethanol (40ml) and sodium hydroxide (0.80g, 20.0mmol) in 10ml of water was added. After boiling at reflux for 2 hours, the reaction mixture was cooled, acidified with HCl and the product extracted with EtOAe (3x). After washing, drying ( _Na2SO4 ), filtration and concentration, the residue was purified by flash chromatography (Hex:EtOAc 70:30-50: ₅₀ ) to give 1.84 g (68%) of the title compound as a yellow solid.

Step E 5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide

5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1.84 g, 4.07 mmol) was suspended in di chloride and added a few drops of DMF followed by oxalyl chloride (1.03 g, 8.14 mmol). The reaction mixture was refluxed for 2 hours. After cooling to room temperature, the solvent was removed and the crude acid chloride was redissolved in dichloromethane and cooled to 0 °C. Triethylamine (1.15ml, 8.20mmol) was added followed by 1-aminopiperidine (0.5ml, 4.50mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the product was extracted with dichloromethane (3x). _The combined extracts were dried ( _Na2SO4 ), filtered and evaporated. Flash chromatography (Hex:EtOAc 80:20-70:30) afforded 1.13 g (52%) of the title compound as a solid.

Step F 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide

5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (1.00g , 1.87 mmol) was dissolved in 25 ml of absolute ethanol containing 100 mg of palladium on carbon (10% Pd). The reaction was balloon hydrogenated overnight. Filtration, concentration and flash chromatography (Hex:EtOAc 50:50-EtOAc) afforded 0.83 g (100%) of the title compound as a solid. the

Step G Propane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)2H-pyrazol-3-yl -Phenyl ester

1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (222mg, 0.50mmol) Dissolve in dichloromethane (10ml) and add triethylamine (0.07ml, 0.50mmol). Propanylsulfonyl chloride (71 mg, 0.50 mmol) was added at 0°C, the cooling bath was removed and the reaction was stirred at room temperature for 2 hours. Water was added and the product was extracted with _{dichloromethane} , dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (Hexane:EtOAc 70:30-50:50) gave the product which was recrystallized from Hexane:EtOAc to give 135 mg (49%) of the title compound as a white solid mp 190°C.

¹ H NMR (CDCl ₃ ): δ 7.66 (1H, broad peak s), 7.44-7.17 (7H, m), 3.25 (2H, t), 2.90 (4H, m), 2.39 (3H, s), 2.09- 1.97(2H,m), 1.78(4H,m), 1.45(2H,m), 1.17(3H,t) MS m/z 573(M+Na)

Example 2

1-(2,4-Dichlorophenyl)-4-methyl-5-[4-(4,4,4-trifluorobutoxy)-phenyl]-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide

1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine-1 from Ex 1, Step F Amylamide (250mg, 0.56mmol) was dissolved in acetone (10ml) and potassium carbonate (77mg, 0.56mmol) was added followed by 1-iodo-4,4,4-trifluorobutane (140mg, 0.56mmol). The reaction mixture was boiled at reflux overnight, concentrated and purified by flash chromatography (hexane:EtOAc 70:30-60:40) to give 130 mg (42%) of a white solid which was triturated with hexane:EtOAc 95:5 and filter. the

¹ H NMR (CDCl ₃ ): δ7.63 (1H, broad peak 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(SH, s and m), 2.15-1.97(2H, m), 1.78(4H, m), 1.45(2H, m)

MSm/z 577(M+Na).HPLC: 98.4%

Example 3

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

The 1-(2,4-dichlorophenyl)-5-(4-hydroxyl-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine-1- Dichloromethane (350mg, 0.78mmol) was dissolved in dichloromethane (10ml) and triethylamine (0.11ml, 0.78mmol) was added. Butanesulfonyl chloride (0.12 g, 0.78 mmol) was added at 0°C, the cooling bath was removed and the reaction was stirred overnight at room temperature. Water was added and the product was extracted with _{dichloromethane} , dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (Hexane:EtOAc 70:30-50:50) gave the product, which was recrystallized from Hexane:EtOAc to give 200 mg (45%) of the title compound as a solid.

¹ H NMR (CDCl ₃ ): δ7.48-7.19 (8H, m), 3.29 (2H, m), 2.96 (4H, m), 2.41 (3H, s), 2.09-1.97 (2H, m), 1.81 (4H, m), 1.64-1.50 (4H, m), 1.02 (3H, t)

Example 4

Propane-1-sulfonic acid 4-r2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-ylcarbonyl)-2H-pyrazol-3-yl]phenyl ester

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

To 5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole in 25 ml _CH2Cl2 prepared in _Ex1 , Step D -3-Carboxylic acid (1.18g, 2.6mmol) was added with 2 drops of DMF, followed by oxalyl chloride (0.44ml, 5.2mmol). The mixture was boiled at reflux for 2 hours, cooled to room temperature and evaporated to dryness. The residue _was dissolved in 25ml _CH2Cl2 and cooled to 0°C. Triethylamine (0.73ml, 5.2mmol) was added followed by 1-aminopiperidine (0.28ml, 2.9mmol) and the mixture was stirred at room temperature for 3 hours. _Water (100ml) was _added and the mixture was extracted with _CH2Cl2 (3x50ml), dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (silica gel, hexanes:EtOAc 1:2, EtOAc) gave 215 mg (15%) of the title compound as a white solid.

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

5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide (215mg, 0.40 _mmol ) was dissolved in 20 ml _CH2Cl2 and cooled to 0°C. Boron tribromide (78 μl, 0.80 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2.5 hours. Water (50ml) was added and the solution was extracted with EtOAc (3 x 50ml). _The combined organic phases were dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (silica gel, hexane:EtOAc 1:2, EtOAc) afforded 180 mg (99%) of the title compound as a white solid.

Step C Propane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-ylcarbamoyl)-2H-pyrazole-3- base]-phenyl ester

1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide (180mg, 0.40mmol ) in 10 ml _CH2Cl2 was cooled _to 0°C. Triethylamine (561, 0.40 mmol) was added followed by 1-propanesulfonyl chloride (45 μl, 0.40 mmol) and the reaction mixture was stirred at room temperature for 5 hours. Water was added and the mixture was extracted with _CH2Cl2 (3 _x 20ml), dried ( _Na2SO4 ), _filtered and concentrated. Flash chromatography (silica gel, hexane:EtOAc 1:2) gave 82 mg (46%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ7.7 (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%. the

Example 5

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

Step A 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide

5-(4-benzyloxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine- The 1-ylamide (330mg, _0.62mmol ) was dissolved in 20ml _CH2Cl2 and cooled to 0°C. Boron bromide (120 μl, 1.24 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. Water (50ml) was added and the solution was extracted with EtOAc (3 x 20ml). The combined organic phases were dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (silica gel, hexane:EtOAc ₁ :3, EtOAc) gave 130 mg (47%) of the title compound as a white solid.

Step B 3,3,3-Trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl) -2H-pyrazol-3-ylphenyl ester

1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide, (130mg, 0.30 A solution _of mmol) in 10 ml _CH2Cl2 was cooled to 0°C. Triethylamine (42 μl, 0.30 mmol) was added followed by 3,3,3-trifluoropropane-1-sulfonyl chloride (59 mg, 0.30 mmol), purchased from Manchester Organics (but also in a manner similar to that described in WO 200010968). 4,4,4-trifluorobutane-1-sulfonyl chloride) was prepared and the reaction mixture was stirred at room temperature for 2 hours. Water was added and _the mixture was extracted with _CH2Cl2 (3x20ml), dried ( _Na2SO4 ), _filtered and concentrated. Flash chromatography (silica gel, hexane:EtOAc 7:3, 6:4) gave 150 mg (82%) of the title compound as a white solid mp 160°C.

¹ H NMR (CDCl ₃ ): δ7.7 (1H, broad peak s), 7.5-7.2 (7H, m), 3.6-3.5 (2H, m), 3.0-2.7 (6H, m), 2.4 (3H, s), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m).

MS m/z 628 (M+Na). HPLC: 92.5%. the

Example 6

4,4,4-Trifluorobutane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl(piperidin-1-ylcarbamoyl)-2H-pyridine Azol-3-yl]phenyl ester

The 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide prepared in Ex5 step A (0.49g, 1.20mmol) in dichloromethane (20ml), cooled to 0°C and added triethylamine (0.67ml, 4.8mmol) followed by 4,4,4-trifluorobutane prepared according to WO 200010968 - 1-sulfonyl chloride (0.38 g, 1.80 mmol). The reaction mixture was stirred overnight at room temperature. Water was added and the product was extracted with _{dichloromethane} , dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (hexanes:EtOAc 1:1-EtOAc) followed by recrystallization (hexanes:EtOAc) afforded 0.32 g (43%) of the title compound as a colorless solid.

¹ H NMR (CDCl ₃ ): δ7.80 (1H, broad peak s), 7.50-7.19 (7H, m), 3.40 (2H, m), 3.05-2.90 (4H, m), 2.50-2.20 (7H, sand m), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m).

MS m/z 641(M+Na)HPLC: 96.5%

Example 7

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

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

1-(3,5-Difluoro-4-hydroxyphenyl)propan-1-one (5.00 g, 26.9 mmol) was dissolved in acetone (100 mL) containing potassium carbonate (3.90 g, 28.2 mmol). Benzyl bromide (4.82 g, 28.2 mmol) was added and the reaction mixture was boiled at 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. the

Step B 1-[4-Benzyloxy-3,5-difluorophenyl)-2-bromopropan-1-one

1-(4-Benzyloxy-3,5-difluorophenyl)propan-1-one (7.43g, 26.9mmol) was suspended in acetic acid (35ml). Bromine (4.28 g, 26.8 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours, at which point the reaction mixture was a clear, yellow solution. After cooling, ice water (100ml) was added and the product was extracted with ether (2x100ml). The combined organic extracts were washed with water, sodium bicarbonate solution and brine. The organic phase was dried ( _Na2SO4 ), filtered and evaporated to give 9.30 g (98%) of _the title compound as a pale yellow oil.

Step C 2-Acetyl-4-(4-benzyloxy-3,5-difluorophenyl)-3-methyl-4-oxobutanoic acid ethyl ester

A solution of sodium ethoxide was prepared from sodium metal (0.74 g, 32.0 mmol) in 40 ml 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 1-(4-benzyloxy-3,5-difluorophenyl)-2-bromopropan-1-one (9.30 g, 26.2 mmol) in ethanol:toluene (40: 20 ml) and the reaction mixture was stirred overnight. Acidic treatment with 1M HCl, extraction with ethyl acetate (3x), washing with brine, drying ( _Na2SO4 ), filtration and evaporation afforded crude product which was purified by flash chromatography (Hex:EtOAc 95:5-70 _: 30 ) afforded 6.95 g (66%) of the title compound as an oil.

Step D 5-(4-Benzyloxy-3,5-difluorophenyl)-1-(2,4-dichlorobenzene-4-methyl-1H-pyrazole-3-carboxylic acid

A solution of sodium ethoxide was made up of sodium metal (0.53 g, 22.0 mmol) in 60 ml absolute ethanol. To this solution was added ethyl 2-acetyl-4-(4-benzyloxy-3,5-difluorophenyl)-3-methyl-4-oxobutanoate (6.95 g, 17.2 mmol) and The reaction mixture was stirred at room temperature for 30 minutes. Pre-prepared 2,4-dichlorophenyldiazide chloride (made from 2,4-dichloroaniline (3.39g, 21.0mmol) in 9ml 24% HCl and sodium nitrite 1. (48g, 21.0mmol) in 3 ml of water at 0°C) was added in 5 portions keeping the temperature below 5°C. After stirring at 0°C for 2 hours the reaction mixture was warmed to room temperature and stirred overnight. Water was added and the product was extracted with EtOAc (3x). _The combined organic extracts were dried ( _Na2SO4 ), filtered and evaporated to give 9.20 g of the 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 boiling at reflux for 2 hours, the reaction mixture was cooled, acidified with HCl and the product was extracted with EtOAc (3x). After washing, drying ( _Na2SO4 ), filtration and concentration, the residue was purified by flash chromatography (hexane:EtOAc:AcOH 80 _: 20:2-hexane:EtOAc:AcOH 50:50:2) to give 5.46 g (65 %, 2 steps) of the title compound as a solid.

Step E 5-(4-Benzyloxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine -1-yl amides

5-(4-benzyloxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (5.46g, 11.2mmol) was suspended in dichloromethane (60ml) and a few drops of DMF were added followed by oxalyl chloride (4.70ml, 55.8mmol). The reaction mixture was boiled at reflux for 1.5 hours. After cooling to room temperature, the solvent was removed, the crude acid chloride was redissolved in dichloromethane, cooled to 0°C, Et ₃ N (3.10ml, 22.2mmol) was added, and 1-aminopiperidine (1.2ml, 11.2mmol) was added. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. Water was added and the product was extracted with dichloromethane (3x), the combined extracts were dried ( _Na2SO4 ), filtered and evaporated _. Flash chromatography (hexanes:EtOAc 80:20-70:30) afforded 1.86 g (30%) of the title compound as a yellow solid.

Step F 5-(4-Hydroxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole 3-carboxylic acid piperidine-1- Amide

5-(4-Benzyloxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine-1- Amylamide (1.86 g, 3.25 mmol) was dissolved in 50 ml of dichloromethane and cooled to -78°C. BBr3 (0.60ml, 6.50mmol) was added slowly and the reaction mixture was stirred at 0°C for 30 minutes. Water was added and _the product was extracted with _CH2Cl2 (x3). The combined organic extracts were dried ( _Na2SO4 ), filtered and concentrated _. Flash chromatography (hexanes:EtOAc 50:50) gave 0.64 g (41%) of the title compound as a yellow solid.

Step G Propane-1-sulfonic acid-[2-(2,4-dichlorophenyl)-4-methyl-5-(pyridin-1-ylcarbamoyl)-2H-pyrazol-3-yl] -2,6-difluorophenyl ester

5-(4-hydroxy-3,5-difluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine-1- Dichloromethane (0.64g, 1.32mmol) was dissolved in dichloromethane (20ml), cooled to 0°C and triethylamine (0.18ml, 1.32mmol), followed by propanesulfonyl chloride (0.19g, 1.31mmol). The reaction mixture was stirred overnight at room temperature. Water was added and the product was extracted with _{dichloromethane} , dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (Hexane:EtOAc 70:30-50:50) afforded 410 mg (53%) of the title compound as a pale yellow solid.

¹ H NMR (CDCl ₃ ): δ7.66 (1H, broad peak s), 7.60-7.24 (4H, 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 (4H, m), 1.60-1.40 (2H, m), 1.08 (3H, t).

MS m/z 609 (M+Na). HPLC: 97.5%. the

Example 8

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

Step A Ethyl 4-(4-benzyloxyphenyl)-2,4-dioxobutanoate

To a solution of LiHMDS (88ml, 1M in THF) in ether (50ml) was added 1-(4-benzyloxyphenyl)ethanone (20g, 88.4mmol) under nitrogen at -78°C over 1 hour The suspension was dissolved in ether (150ml) and THF (50ml). The resulting mixture was stirred at -78°C for 1 hour and then diethyl oxalate (14.2 g, 97.2 mmol) was added. The resulting mixture was slowly warmed to room temperature and then left overnight. The reaction mixture was diluted with pentane (90ml) and the crude product precipitated as lithium salt. The collected solid (27.2 g) was dried under vacuum and used directly in the next step. the

Step B 5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

Ethyl 4-(4-benzyloxyphenyl)-2,4-dioxobutyrate (27.2 g, the Li salt from the previous step) was suspended in ethanol (350 ml) and 2,4-dichloro Phenylhydrazine (17.8 g, 83.3 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was then removed under reduced 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 (1 L) and then washed with saturated NaHCO ₃ (6×250 ml) and brine (100 ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated under reduced pressure to an oil. The oil was purified by flash chromatography ( _SiO2 , 20% EtOAc in heptane). The product fractions were concentrated under reduced pressure and the residual material was then further purified by recrystallization (ethyl acetate/heptane) to give a white solid (19.6, 57% over 2 steps).

¹ H-NMR (CDCl ₃ ): δ1.42(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). the

Step C 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxylic acid ethyl ester

5-(4-Benzyloxyphenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (735 mg, 1.57 mmol) and (CH3)2S (0.58 ml, 7.86 mmol) in dichloromethane (30 ml) was added BF3-diethyl etherate (1.0 ml, 7.86 mmol) dropwise under nitrogen. The resulting mixture was stirred overnight at room temperature. More (CH3)2S (0.58ml, 7.86mmol) and BF3-diethyletherate (1.0ml, 7.86mmol) were added and the resulting mixture stirred for a further 3 days. The reaction mixture was diluted to 80ml with difluoromethane and washed with water (3 x 30ml) and brine (40ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated under reduced pressure to give a white solid (573mg, 96%). The crude product was used directly.

¹ H-NMR (CDCl ₃ ): δ1.41(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).

Step D 1-(2,4-Dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)-phenyl]-1H-pyrazole-3-carboxylic acid ethyl ester

1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (510mg, 1.35mmol) was suspended in dichloromethane (20ml ) and added triethylamine (0.75ml, 5.4mmol). The resulting mixture was cooled to 0°C or it was added dropwise with 1-propanesulfonyl chloride (0.30ml, 2.7mmol). The mixture was stirred at 0°C for 1 hour. The reaction mixture was then diluted to 40ml with dichloromethane, then washed with saturated _NaHCO3 (3 x 20ml) and brine (20ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated under reduced pressure to give an oil (0.64g, 98%). The crude product was used without further purification.

¹ H-NMR (CDCl ₃ ): δ1.12(t, 3H), 1.43(t, 3H), 2.01(m, 2H), 3.23(m, 2H), 4.46(q, 2H), 7.07(s, 1H), 7.1 9-7.46 (m, 7H).

MS: 483 (M+1). the

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

1-Aminopiperidine hydrochloride (36mg, 0.26mmol) was dissolved in toluene (1.0ml) under nitrogen atmosphere. Trimethylaluminum (2M in toluene, 0.17ml) was added dropwise at room temperature. The resulting mixture was then stirred at room temperature for 40 minutes. This mixture was then added to ethyl 1-(2,4-dichloro-phenyl)-5-[4-(propane-1-sulfonyloxy)phenyl]-1H-pyrazole-3-carboxylate (42mg, 0.087mmol) was in a stirred solution in DCM (1.0ml) and the resulting mixture was heated at 60°C overnight. The reaction was quenched by adding water and then partitioned between water (20ml) and DCM (20ml). The organic layer was washed with water (3 x 10 ml), then concentrated under reduced pressure. The residue was purified by reverse phase HPLC, C8 column, 5-100% acetonitrile in water (buffer: 0.1M ammonium acetate). The product fractions were diluted with ethyl acetate and washed several times with water. The organic layer was concentrated under reduced pressure and the residue was lyophilized to give a white solid (26 mg, 55%). the

¹ H-NMR (CDCl ₃ ): 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). the

Example 9

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

Step A 4-Bromo-1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)phenyl]-1H-pyrazole-3-carboxylic acid ethyl ester

The 1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)phenyl]-1H-pyrazole-3-carboxy Ethyl acetate (597mg, 1.23mmol) was dissolved in dichloromethane (15ml) and bromine (0.06ml, 1.23mmol) in dichloromethane (1ml) was added and the resulting mixture was stirred at room temperature overnight. Excess bromine (0.06ml, 1.23mmol) was added and the mixture was stirred for a further 20 hours. The reaction mixture was diluted to 80ml with dichloromethane, then washed with saturated _NaHCO3 (40ml), 20% Na2S2O5 (40ml), saturated _NaHCO3 (2 x 40ml) and brine (40ml). The organic layer was dried ( _MgSO4 ), filtered and concentrated under reduced pressure to give an orange oil (0.598, 73%). The crude product was used without further purification. ¹ H-NMR (CDCl ₃ ): δ1.12(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

Step B Propane-1-sulfonic acid 4-[4-bromo-2-(2,4-dichlorophenyl)-5-(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl ] phenyl ester

This compound was passed through 4-bromo-1-(2,4-dichlorophenyl)-5-[4-(propane-1-sulfonyloxy)phenyl in a manner similar to that described in Step E of Ex.8 ]-1H-Pyrazole-3-carboxylic acid ethyl ester was prepared by reaction with 1-aminopiperidine hydrochloride to give 26 mg of the title compound as a white solid. Yield: 25% ¹ H-NMR (CDCl ₃ ): 1.12(t, 3H), 1.43(m, 2H), 1.74(m, 4H), 2.01(m, 2H), 2.90(m, 4H), 3.24 (m, 2H), 7.21-7.45 (m, 7H) MS: 615.

Example 10

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

Step A Methyl 1-aminocyclopentanecarboxylate hydrochloride

Thionyl chloride (1.5ml) was dissolved in methanol (15ml) and poured into 1-aminocyclopentanecarboxylic acid (100mg, 0.774mmol). The mixture was refluxed for 1 hour. Evaporation of the solvent gave the product (107 mg, 77%). the

¹ H NMR (399.964 MHz): δ9.00-8.60 (br, 3H), 3.79 (s, 3H), 2.23 (s, 4H), 2.14-2.00 (m, 2H), 1.90-1.76 (m, 2H) .

Step B 1-({[5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl} Amino) methyl cyclopentanecarboxylate

5-[4-benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ( A solution of 59 mg, 0.130 mmol) in DCM (2 ml) was mixed with a solution of oxalyl chloride (2 ml) in DCM (20 ml). 1 drop of DMF was added and the reaction proceeded for 1 hour at room temperature in the dark. The solvent was evaporated, DCM (2ml) was added and the acid chloride mixture was added to methyl 1-aminocyclopentanecarboxylate hydrochloride (23mg, 0.130mmol) in DCM (2ml) and _K2CO3 (aq, 10wt% _, 2ml) in the mixture. The reaction was carried out at room temperature for 3 hours. The phases were separated and the organic phase was washed with water and dried over _MgSO4 to give the product (71 mg, 94%).

¹ H NMR (399.964MHz): δ7.43-7.23(m, 9H), 7.06-7.00(m, 2H), 6.93-6.87(m, 2H), 5.02(s, 2H), 3.75(s, 3H) , 2.40-2.30 (m, 2H), 2.34 (s, 3H), 2.14-2.04 (m, 2H), 1.87-1.77 (m, 4H).

MS m/z 578, 580, 582 (M+H)+. the

Step C 1-{[1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}amino)cyclopentane methyl carboxylate

Boron trifluoride etherate (156 μl, 1.23 mmol) was added to 1-({[5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4- A mixture of methyl-1H-pyrazol-3-yl]carbonyl}amino)cyclopentanecarboxylate (51 mg, 0.088 mmol) and dimethylsulfide (90 μl, 1.23 mmol) in DCM (2 ml) . The reaction was carried out at room temperature in the dark for 46 hours. Water and DCM were added, the phases were separated and the organic phase was washed with water and dried over _MgSO4 (39mg, 90%).

¹ H NMR (399.964MHz): δ1.60-6.60(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)+. the

Step D 1-{[1-(2,4-dichlorophenyl)-4-methyl-5-{4[(propylsulfonyl)oxy]phenyl)-1H-pyrazol-3-yl ]carbonyl}amino)cyclopentanecarboxylate methyl ester

TEA (100 μl) and 1-propanesulfonyl chloride (30 μl, 0.268 mmol) were added to 1-{[1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)- Methyl 4-methyl-1H-pyrazol-3-yl]carbonyl}amino)cyclopentanecarboxylate (39mg, 0.090mmol) in a mixture in dry DCM (1.5ml). the

The reaction was continued at -78°C under Na(g) for 1.5 hours. Water and DCM were added and the temperature was allowed to rise to room temperature. The phases were separated and the organic phase was 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 was obtained at 88% acetonitrile) to give the product as an off-white powder (17 mg, 35%).

¹ H NMR (399.964MHz): δ7.45-7.39(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 Calcd} . [ _{C27H29Cl2N3O6S} +H]+: _{594.123 .} Found: 594.121.

Example 11

Carbonic acid 4-[2-(2,4-dichloro-phenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl-phenyl ester propane base ester

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

The 1-(2,4-dichloro-phenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine-1- Dichloromethane (0.44g, 1.00mmol) was dissolved in dichloromethane (10ml) and triethylamine (0.28ml, 2.24mmol) was added. Propyl chloroformate (0.14ml, 1.24mmol) was added at 0°C, and the reaction was stirred for 40 minutes, concentrated and the product was purified by flash chromatography (Hexane:EtOAc 70:30-50:50) to give 345mg (65% ) of the title compound. Further purification by preparative HPLC afforded 239 mg of the title compound. the

¹ H NMR (CDCl ₃ ): δ7.71-7.18 (8H, m), 4.24 (2H, t), 2.93 (4H, m), 2.40 (3H, s), 1.78 (6H, m), 1.46 (2H , m), 1.03(3H, t)

MS m/z 553(M+Na)

HPLC: 94.15%

Example 12

4-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}phenylthiophene-2-sulfonic acid ester

Thiophene-2-sulfonyl chloride (433 mg, 2.37 mmol) in DCM (2.5 ml) was added to 1-(2,4-dichlorobenzene prepared in Ex 1, Step F at -78 °C under N2 (g) Base)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-yl-1H-pyrazole-3-carboxamide (200mg, 0.45mmol) and TEA (0.5ml, 3.59mmol ) in a mixture in DCM (2.5ml). The reaction was continued at -78°C for 2 hours, followed by 19 hours at room temperature. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq., 0.1 M): acetonitrile, product was obtained at 100% acetonitrile) to give an off-white powder (158 mg, 60%).

¹ H 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, 3H), 1.73-1.65(m, 4H), 1.42-1.33(m, 2H) .

_{HRMS Calcd} . [ _{C26H24Cl2N4O4S2} + _{H ]} +: 591.069 _. Found: 591.067.

Example 13:

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

Step A : 4-{-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-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 1-(2,4-dichloro prepared in Ex 1, step F) at -78°C under N2 (gas) Phenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-yl-1H-pyrazole-3-carboxamide (200mg, 0.45mmol) and TEA (0.5ml, 3.59 mmol) in a mixture in DCM (2.5ml). The reaction was continued for 1.5 hours at -78°C and then for 30 minutes at room temperature. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by flash chromatography ( _SiO2 , toluene:ethyl acetate, product was obtained at 42% ethyl acetate) to give an off-white powder (216 mg, 82%).

¹ H NMR (399.964MHz) δ8.95-8.85(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 for} [ _{C27H25Cl2N5O4S} +H]+: _586.108 . Found: 586.111.

Step B: 4-{1-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}phenyl Pyridine-3-sulfonate hydrochloride

4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}phenylpyridine- 3-Sulphonate (150 mg, 0.26 mmol) was dissolved in 0.1 M HCl in acetic acid (10 ml) and lyophilized to give the salt as a white powder (159 mg, 99.8%). the

Example 14

[2-(4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}benzene Oxy)ethyl]tert-butyl carbamate

Step A: tert-Butyl Ethyl(2-Hydroxyethyl)carbamate

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 for 3 hours. The solvent was evaporated under reduced pressure to obtain a crude product (2.28 g). the

¹ H NMR (499.961MHz) δ3.71-3.65(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: [2-(4-{1-(2,4-Dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-pyrazol-5-yl} phenoxy)ethyl]carbamate tert-butyl ester

The 1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-yl-1H-pyrazole-3 prepared in Ex1, step F -Carboxamide (151.6mg, 0.34mmol) and tert-butyl ethyl(2-hydroxyethyl)carbamate (408.6mg, 1.73mmol) were mixed with toluene (1ml) and reacted repeatedly at 180°C in a single-section microwave oven. The total reaction time was 2 hours. Cyanomethylenetri-N-butylphosphine was added before each heat (total 925 mg, 3.83 mmol). The solvent was evaporated and the product was purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1M): acetonitrile, product was obtained at 100% acetonitrile) and flash chromatography ( _SiO2 , toluene: ethyl acetate, in 30% acetic acid Ethyl ester) to give an off-white powder (125 mg, 60%).

¹ H NMR (399.964 MHz) δ7.62(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)+. the

Example l5

1-(2,4-dichlorophenyl)-5-{4-[2-(ethylamino)ethoxy]phenyl}-4-methyl-N-piperidin-1-yl-1H- Pyrazole-3-carboxamide dihydrochloride

Thionyl chloride (1 ml, 13.71 mmol) in methanol (10 ml) was added to [2-(4-{1-(2,4-dichlorophenyl)-4-methyl -3-[(Piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}phenoxy)ethyl]ethylcarbamate (137mg, 0.22mmol) in methanol (2ml ) in suspension. After 2.5 hours the solvent was evaporated and the product was lyophilized. The compound was purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq., 0.1 M): acetonitrile, product was obtained at 72% acetonitrile), lyophilized and finally dissolved in 0.1 M HCl in acetic acid (15 ml) and re-frozen Drying afforded an off-white powder (53 mg, 40%). the

¹ H NMR (399.964MHz) δ7.54-7.47(m, 2H), 7.44-7.39(m, 1H), 7.19-7.14(m, 2H), 7.01-6.96(m, 2H), 4.24(t, 2H ), 3.41(t, 2H), 3.18-3.06(m, 6H), 2.27(s, 3H), 1.87-1.78(m, 4H), 1.57-1.48(m, 2H), 1.32(t, 3H).

_HRMS calcd for [ _{C26H31Cl2N5O2} + _H ] ₊ : _516.193 . Found: 516.195.

Example 16

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

3-Methylbutane-1-sulfonyl chloride (84 mg, 0.49 mmol) in DCM (2 ml) was added to 1-(2,4 -dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-yl-1H-pyrazole-3-carboxamide (100mg, 0.23mmol) and TEA (0.5 ml, 3.59 mmol) in a mixture in DCM (2 ml). The reaction was 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 MgSO ₄ . The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1M): acetonitrile, product yield in 100% acetonitrile) to give an off-white powder (94 mg, 72%).

¹ H NMR (399.964MHz) δ7.85-7.45(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 for} [ _{C27H32Cl2N4O4S} +H _] +: 579.160. _Found : 579.159.

Example 17

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

To 1-( 2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-1-yl-1H-pyrazole-3-carboxamide (103mg, 0.23mmol) and TEA (0.5ml, 3.59mmol) was in a mixture in DCM (2ml). The reaction was 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 MgSO ₄ . The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq, 0.1 M): acetonitrile, product yielded in 100% acetonitrile) to give an off-white powder (94 mg, 68%).

¹ H NMR (399.964MHz) δ8.20-7.40(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(m, 2H), 1.73-1.65(m, 4H), 1.43-1.32(m , 2H), 0.89(s, 9H).

_HRMS Calcd. [ _{C28H34Cl2N4O4S} +H _] +: 593.176 _{. Found} : 593.176.

Example 18

4-[1-(2,4-Dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-1H-pyrazole- 5-yl]phenyl 3,3,3-trifluoropropane-1-sulfonate

Step A: 5-[4-(Benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-N-[5-(trifluoromethylpyridin-2-yl ]-1H-pyrazole-3-carboxamide

Oxalyl chloride (1 ml) in DCM (4 ml) was added to 5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4 prepared in step D of Example 1 - Methyl-1H-pyrazole-3-carboxylic acid (202mg, 0.45mmol) in suspension in DCM (4ml). 1 drop of DMF was added and the reaction was continued at room temperature for 1 hour. DCM and excess oxalyl chloride were removed under reduced pressure, the acid chloride _was suspended in _DCM (4 ml) and added to 5-(trifluoro Methyl)pyridin-2-amine (87.6 mg, 0.54 mmol). The reaction was continued at room temperature for 24 hours, then 50 mg DMAP was added and the reaction was continued at room temperature for 1 hour. The phases were separated and the organic phase was washed with water and dried over _MgSO4 . The product was further purified by flash chromatography ( _SiO2 , toluene) (108 mg, 41%).

¹ H NMR (399.964MHz) δ 9.66(s, 1H), 8.58-8.48(m, 2H), 7.95-7.90(m, 1H), 7.44-7.14(m, 8H), 7.10-7.04(m, 2H) , 6.94-6.90 (m, 2H), 5.02 (s, 2H), 2.42 (s, 3H).

MS m/z 597,599,601 (M+H)+. the

Step B: 1-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-[5-( trifluoromethylpyridinium )-2-yl]- 1H-pyrazole-3-carboxamide

5-[4-(benzyloxy)phenyl]-1-(2,4-dichlorophenyl)-4-methyl-N-[5-(trifluoromethyl)pyridin-2-yl] -1H-pyrazole-3-carboxamide (108mg, 0.18mmol) was suspended in 4.1M HBr in acetic acid solution (10ml) and reacted at room temperature for 6 hours. Ethanol (95%, 75ml) was added and the solvent was evaporated under reduced pressure. Methanol was added and the product was neutralized with _NaHCO3 (1M, aq). The solvent was evaporated and the mixture was dissolved in DCM and water. The phases were separated and the organic phase was washed with water and dried over _MgSO4 (87mg, 95%).

¹ H NMR (399.964MHz) δ9.64(s, 1H), 8.58-8.48(m, 2H), 7.97-7.91(m, 1H), 7.45-7.41(m, 1H), 7.32-7.23(m, 2H ), 7.03-6.98 (m, 2H), 6.80-6.75 (m, 2H), 5.50-5.30 (br, 1H), 2.40 (s, 3H).

MS m/z 507, 509, 511 (M+H)+. the

Step C: 4-[1-(2,4-Dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-1H- Pyrazol-5-yl]phenyl

3,3,3-Trifluoropropane-1-sulfonate 3,3,3-trifluoropropane-1-sulfonyl chloride (105 mg, 0.53 mmol) was added to 1- (2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-3 - Carboxamide (87mg, 0.17mmol) and TEA (0.5ml, 3.59mmol) in a mixture in DCM (3ml). The reaction was continued for 2 hours at -78°C and then overnight at room temperature. Water was added and the phases were separated. The organic phase was washed with water and dried over MgSO ₄ . The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq., 0.1 M): acetonitrile, product yielded in 100% acetonitrile) to give an off-white powder (86 mg, 75%).

¹ H NMR (399.964MHz) δ9.70(s, 1H), 8.57-8.48(m, 2H), 7.99-7.92(m, 1H), 7.43(s, 1H), 7.32(s, 2H), 7.28- 7.19 (m, 4H), 3.53-3.44 (m, 2H), 2.85-2.71 (m, 2H), 2.42 (s, 3H).

_{HRMS calculated} for [ _{C26H28Cl2F6N4O4S} +H _] +: _667.041 . _Found : 667.031.

Example 19

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

2-(2-bromoethyl)-1,3-dioxolane (60mg, 0.33mmol), Ex.1, 1-(2,4-dichlorophenyl)-5 -(4-Hydroxyphenyl)-4-methyl-N-piperidin-1-yl-1H-pyrazole-3-carboxamide (100 mg, 0.22 mmol) and potassium carbonate (150 mg, 1.09 mmol) in acetonitrile ( 25ml) was refluxed for 15 hours. The solvent was evaporated, water and DCM were added, the phases were separated and the organic phase was washed with water and dried ( _MgSO4 ). The product was further purified by preparative HPLC (kromasil C8 column, ammonium acetate (aq., 0.1 M): acetonitrile, product yielded in 100% acetonitrile) to give an off-white powder (60 mg, 49%).

¹ H NMR (399.964MHz) δ7.80-7.50(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} for [ _{C27H30Cl2N4O4} +H]+: _545.172 . Found _: 545.172.

Example 20

Propane-1-sulfonic acid 4-[2-(2,4-dichloro-3-fluorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-2H-pyrazole- 3-yl]phenyl ester

Step A: 1-(2,4-Dichloro-3-fluorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid

A solution of sodium ethoxide was prepared from sodium metal (0.18 g, 7.89 mmol) in 20 ml absolute ethanol. To this solution was added ethyl 2-acetyl-4-(4-methoxy-phenyl)-3-methyl-4-oxo-butanoate (1.73 g, 5.92 mmol) and the reaction mixture was Stir at room temperature for 30 minutes. Pre-prepared 2,4-dichloro-3-fluorochlorodiazide (from 2,4-dichloro-3-fluoroaniline (1.30g, 7.22mmol) in 3ml 24% HCl and sodium nitrite (0.51g , 7.39 mmol) in 3.5 ml of water prepared at 0°C) was added in 5 portions keeping the temperature below 5°C. After stirring at room temperature for 2.5 hours water was added and the product was extracted with EtOAc (3x). _The combined organic extracts were dried ( _Na2SO4 ), filtered and evaporated. The residue was dissolved in ethanol (40ml) and sodium hydroxide (1.00g, 25.0mmol) in 5ml of water was added. After boiling at reflux for 2 hours the reaction mixture was cooled, acidified with HCl and the product extracted with EtOAc (3x). After washing, drying ( _Na2SO4 ), filtration and concentration, the residue was purified by flash chromatography (Hex:EtOAc 70:30-50: ₅₀ ) to give 1.37 g (31%) of the title compound as a beige solid .

Step B: 1-(2,4-Dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine -1-yl amides

1-(2,4-Dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1.37g, 3.43mmol) was suspended in dichloromethane (20ml) and a few drops of DMF were added followed by oxalyl chloride (0.87g, 6.86mmol). The reaction mixture was refluxed for 2 hours. After cooling to room temperature the solvent was removed and the crude acid chloride was redissolved in dichloromethane (20ml), cooled to 0°C, _Et3N (0.96ml, 6.94mmol) was added followed by 1-aminopiperidine (0.37ml, 3.62 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Water was added and the product was extracted with dichloromethane (3x), the combined extracts were dried ( _Na2SO4 ), filtered and evaporated _. Flash chromatography (hexanes:EtOAc 50:50) gave 0.79 g (48%) of the title compound as a beige solid.

Step C: 1-(2,4-Dichloro-3-fluoro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine-1 -yl amides

1-(2,4-dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidine Pyridin-1-ylamide (0.79g, 1.66mmol) was dissolved in 40ml of difluoromethane. Boron bromide (0.32ml, 3.31mmol) was added, the cooling bath was removed and stirring was continued at room temperature for 2 hours before being poured into ice-water and extracted with DCM (x3). _The combined extracts were dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (EtOAc) gave 0.36 g (47%) of the title compound as a colorless solid.

Step D: Propane-1-sulfonic acid 4-[2-(2,4-dichloro-3-fluoro-phenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-2H -pyrazol-3-yl]-phenyl ester

To 1-(2,4-dichloro-3-fluoro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-yl To a solution of the amide (0.36g, 0.78mmol) in dichloromethane (10ml) was added triethylamine (0.22ml, 1.56mmol) and the reaction mixture was cooled to 0°C. 1-Propanesulfonyl chloride (0.22 g, 1.56 mmol) was added, the cooling bath was removed and the reaction mixture was stirred at rt for 2 hours. _Water was added, the product was extracted with DCM (x2), the combined organic extracts were washed with water, dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (hexane:EtOAc gradient) gave 100 mg (23%) of the title compound as a colorless solid. HPLC 80% purity. Preparative HPLC gave 40 mg of the title compound.

¹ H NMR (CDCl ₃ ): δ7.50-7.20 (7H, 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%

Example 21

5-Chlorothiophene-2-sulfonic acid 4-[2-(2,4-difluorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl Base)-2H-pyrazol-3-yl]phenyl ester

1-(2,4-dichloro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid prepared in Ex 1, step F under nitrogen atmosphere Piperidin-1-ylamide (100mg, 0.22mmol) was dissolved in dry dichloromethane (3ml) and triethylamine (0.09ml) was added. 5-Chlorothiophene-2-sulfonyl chloride (0.54mg, 0.24mmol) dissolved in dry dichloromethane (2ml) was added. The reaction mixture was stirred at room temperature over weekend. The reaction mixture was diluted to 20ml with difluoromethane and then washed with water (2 x 5ml) and brine (5ml). The organic layer was concentrated under reduced pressure to obtain an oil. The crude product was purified by reverse phase HPLC, Kromasil C8, 5-100% MeCN in water with 0.1 M ammonium acetate. The product fractions were concentrated under reduced pressure and the residue was dissolved in dichloromethane and washed with water and brine. The organic layer was dried ( _MgSO4 ), filtered and concentrated under reduced pressure to afford the title compound as a yellow solid.

¹ H-NMR (CDCl ₃ ): δ1.42-1.50 (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% pure. the

Claims (6)

1. The compound shown in formula IA: and pharmaceutically acceptable salts thereof, wherein R ¹ is a group R ⁵ S(O) ₂ O, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines; R ^a represents halogen and m is 0, 1 or 2; R ^2a represents chlorine; R ^2b represents chlorine; R ^2c represents H or fluorine; R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents piperidino or morpholino or R ³ represents a group CONHR ⁸ , wherein R ⁸ represents optionally substituted by C _1-6 alkoxycarbonyl C _5-7 cycloalkyl or R ⁸ represents pyridyl optionally substituted by one C _1-5 alkyl, wherein said alkyl is optionally substituted by one or more fluorines; and R ⁴ represents H, C _1-3 alkyl or halogen. 2. The compound of claim 1, as shown in formula IB

wherein R ¹ is a group R ⁵ S(O) ₂ O, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines; R ^a1 represents halogen or H; R ^a2 represents halogen or H; R ^2a represents chlorine; R ^2b represents chlorine; R ^2c represents halogen or H; R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents a piperidino group; and R ⁴ represents a C _1-3 alkyl group. 3. The compound of claim 1, as shown in formula IC

wherein R ¹ is a group R ⁵ S(O) ₂ O, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorines; R ^2a represents chlorine; R ^2b represents chlorine; R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents piperidino or morpholino; and R ⁴ represents C _1-3 alkyl or halogen. 4. The compound of claim 1, selected from one or more of the following compounds: 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-(piperidin-1-ylcarbamoyl)2H-pyrazol-3-yl]benzene base ester; Propane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(morpholin-4-ylcarbamoyl)-2H-pyrazol-3-yl] Phenyl esters; 3,3,3-Trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-2H -pyrazol-3-yl]phenyl 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; Propane-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; Propane-1-sulfonic acid 4-[4-bromo-2-(2,4-dichlorophenyl)-5-(piperidin-1-ylcarbamoyl)-2H-pyrazol-3-yl]benzene base ester; 1-{[(1-(2,4-dichlorophenyl)-4-methyl-5-{4[(propylsulfonyl)oxy]phenyl}-1H-pyrazol-3-yl) Methyl carbonyl]amino}cyclopentanecarboxylate; 4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}phenyl 3-methyl Butane-1-sulfonate; 4-{1-(2,4-dichlorophenyl)-4-methyl-3-[(piperidin-1-ylamino)carbonyl]-1H-pyrazol-5-yl}phenyl 3,3 - Dimethylbutane-1-sulfonate; 4-[1-(2,4-Dichlorophenyl)-4-methyl-3-({[5-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)-1H-pyrazole- 5-yl]phenyl 3,3,3-trifluoropropane-1-sulfonate; Propane-1-sulfonic acid 4-[2-(2,4-dichloro-3-fluorophenyl)-4-methyl-5-(piperidin-1-ylcarbamoyl)-2H-pyrazole- 3-yl]phenyl ester; or a pharmaceutically acceptable salt thereof. 5. Use of a compound according to any one of claims 1-4 for the manufacture of a medicament for the treatment of obesity. 6. A pharmaceutical preparation for the treatment of obesity, which contains the compound according to any one of claims 1-4 and a pharmaceutically acceptable adjuvant, diluent or carrier.