CN1964948A - Therapeutic agents - Google Patents

Abstract

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

Description

medicine

field of invention

The present invention relates to certain 1,2-diarylimidazole-4-carboxamide compounds of formula I, processes for the preparation of such compounds, their use in the treatment of obesity, psychiatric and neurotic disorders, their therapeutic use Methods and pharmaceutical compositions containing these compounds.

Background of the invention

Certain _CB1 modulators (considered antagonists or inverse agonists) are known to be useful in the treatment of obesity, psychiatric and neurological disorders (WO 01/70700 and EP 656354).

Certain diarylimidazoles and triazoles are disclosed in WO04/60367 and WO2004/099130 as COX-1 inhibitors for the treatment of inflammation. The compounds exemplified in these applications are disclaimed from the claims of the present invention.

DD 140966 discloses the use of certain N-imidazolecarboxanilides as plant growth regulators. The compounds exemplified in these applications are disclaimed from the claims of the present invention.

Certain 4,5-diarylimidazole-2-carboxamides useful as CB ₁ modulators are disclosed in WO03/007887 and WO03/075660.

Certain 1,2-diarylimidazole-4-carboxamides are disclosed as CB ₁ modulators in WO 03/27076 and WO 03/63781. The compounds exemplified in these applications are disclaimed from the claims of the present invention.

1,2-Diarylimidazole-4-carboxamides for the treatment of obesity and obesity-related diseases are disclosed in WO03/40107.

However, there is a need for _CB1 modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.

Description of the invention

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof,

in:

R ¹ represents a) a C ^1-6 alkoxy group 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 phenyl The 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 groups, wherein R ⁵ represents optionally substituted by one or more C _1-10 alkyl substituted by fluorine, or R ⁵ represents phenyl or heteroaryl each optionally substituted by 1, 2 or 3 groups represented by Z, or d) formula (R ⁶ ) ₃ Si A group, wherein R ⁶ represents C _1-6 alkyl that may be the same or different;

^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 stands for

a) XY-NR ⁷ R ⁸ group

where X is CO or SO ₂ ,

Y does not exist or represents NH optionally substituted by C _1-3 alkyl;

and ^R7 and ^R8 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 group, wherein r is 0, 1, 2, 3 or 4, when r is 0, s is 1, otherwise s is 1 or 2, and optionally the phenyl independently substituted by one, two or three groups represented by Z;

A 5-8 membered saturated heterocyclic group containing one nitrogen and optionally one of oxygen, sulfur or another nitrogen, wherein the heterocyclic group is optionally substituted with one or more of: C _1-3 Alkyl, hydroxy or benzyl;

-(CH ₂ ) _t Het group, wherein t is 0, 1, 2, 3 or 4, the alkylene chain is optionally substituted by one or more C _1-3 alkyl groups, and Het represents optionally substituted by one , two or three heteroaryl substituted by groups selected from C _1-5 alkyl, C _1-5 alkoxy or halogen, wherein the alkyl and alkoxy are optionally independently replaced by one or more fluorine replace;

Or R ⁷ represents H, and R ⁸ is as defined above;

Or R ⁷ and R ⁸ , together with the nitrogen atom to which they are attached, represent a 5-8 membered saturated or partially unsaturated heterocyclic group containing one nitrogen and optionally the following: one of oxygen, sulfur or another nitrogen; wherein the heterocyclic The group is optionally substituted by one or more of the following groups: 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 substituted by 1, 2 or 3 Z groups;

R ⁴ represents H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy C _1-6 alkylene containing up to 6 carbon atoms, each group is optionally replaced by one or Multiple fluorine or cyano substitutions;

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, or selected from morpholinyl, pyrrolidinyl, piperidinyl or piperidinyl The heterocyclic amine of azinyl, wherein the heterocyclic amine is optionally substituted by C _1-3 alkyl or hydroxyl;

With the proviso that when n is 1, then ^R2 is not methoxy at the 2- or 4-position of the benzene ring, and with the further proviso that ^R1 is not methanesulfonylamino, methoxy or _CF3O- .

In a particular group of compounds of formula (I) and pharmaceutically acceptable salts thereof,

in

R ¹ represents a) a C _1-6 alkoxy group 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 phenyl The 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 groups, wherein R ⁵ represents optionally substituted by one or more C _1-6 alkyl substituted by fluorine, or R ⁵ represents phenyl or heteroaryl each optionally substituted by 1, 2 or 3 groups represented by Z, or d) formula (R ⁶ ) ₃ Si A group, wherein R ⁶ represents C _1-6 alkyl that may be the same or different;

^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 stands for

a) XY-NR ⁷ R ⁸ group

where X is CO or SO ₂ ,

Y does not exist or represents NH optionally substituted by C _1-3 alkyl;

and ^R7 and ^R8 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 group, wherein r is 0, 1, 2, 3 or 4, when r is 0, s is 1, otherwise s is 1 or 2, and optionally the phenyl independently substituted by one, two or three groups represented by Z;

A 5-8 membered saturated heterocyclic group containing one nitrogen and optionally one of oxygen, sulfur or another nitrogen, wherein the heterocyclic group is optionally substituted with one or more of: C _1-3 Alkyl, hydroxy or benzyl;

-(CH ₂ ) _t Het group, wherein t is 0, 1, 2, 3 or 4, the alkylene chain is optionally substituted by one or more C _1-3 alkyl groups, and Het represents optionally substituted by one , two or three heteroaryl groups substituted by groups selected from C _1-5 alkyl, C _1-5 alkoxy or halogen;

Or R ⁷ represents H, and R ⁸ is as defined above;

Or R ⁷ and R ⁸ , together with the nitrogen atom to which they are attached, represent a 5-8 membered saturated or partially unsaturated heterocyclic group containing one nitrogen and optionally the following: one of oxygen, sulfur or another nitrogen; wherein the heterocyclic The group is optionally substituted by one or more of the following groups: 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 substituted by 1, 2 or 3 Z groups;

R ⁴ represents H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy C _1-6 alkylene containing up to 6 carbon atoms, each group is optionally replaced by one or Multiple fluorine or cyano substitutions;

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, or selected from morpholinyl, pyrrolidinyl, piperidinyl or piperidinyl The heterocyclic amine of azinyl, wherein the heterocyclic amine is optionally substituted by C _1-3 alkyl or hydroxyl;

With the proviso that when n is 1, then ^R2 is not methoxy at the 2- or 4-position of the benzene ring, and with the further proviso that ^R1 is not methanesulfonylamino, methoxy or _CF3O- .

In a particular group of compounds of formula (I) and pharmaceutically acceptable salts thereof,

R ¹ represents a) a C _3-6 alkoxy group substituted by one or more fluorines, or b) a phenyl (CH ₂ ) _p O- group, wherein p is 1, 2 or 3, and the phenyl ring is optionally optionally substituted by 1, 2 or 3 groups represented by Z, or c) a R ⁵ S(O) ₂ O group, wherein R ⁵ represents a C _1-6 alkyl optionally substituted by one or more fluorine , or ^R represents phenyl or heteroaryl each optionally substituted by 1, 2 or 3 groups represented by Z;

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

m is 0, 1, 2 or 3;

^R represents halogen;

n is 0, 1, 2 or 3;

R ³ stands for

a) XY-NR ⁷ R ⁸ group

where X is CO;

Y does not exist or represents NH optionally substituted by C _1-3 alkyl;

and ^R7 and ^R8 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 group, wherein r is 0, 1, 2, 3 or 4, when r is 0, s is 1, otherwise s is 1 or 2, and optionally the phenyl independently substituted by one, two or three groups represented by Z;

Containing one nitrogen and optionally the following: a 5-8 membered saturated heterocyclic group of one of oxygen, sulfur or another nitrogen, wherein the heterocyclic group is optionally replaced by one or more C _1-3 alkyl, hydroxyl or Benzyl substitution;

-(CH ₂ ) _t Het group, wherein t is 0, 1, 2, 3 or 4, the alkylene chain is optionally substituted by one or more C _1-3 alkyl groups, and Het represents optionally substituted by one , two or three heteroaryl groups substituted by groups selected from C _1-5 alkyl, C _1-5 alkoxy or halogen;

Or R ⁷ represents H, and R ⁸ is as defined above;

Or R ⁷ and R ⁸ , together with the nitrogen atom to which they are attached, represent a 5-8 membered saturated or partially unsaturated heterocyclic group containing one nitrogen and optionally the following: one of oxygen, sulfur or another nitrogen; wherein the heterocyclic The group is optionally substituted by one or more of the following groups: C _1-3 alkyl, hydroxyl, fluorine or benzyl;

R ⁴ represents H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy C _1-6 alkylene containing up to 6 carbon atoms, each group is optionally replaced by one or Multiple fluorine or cyano substitutions;

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, or selected from morpholinyl, pyrrolidinyl, piperidinyl or piperidinyl An azinyl heterocyclic amine, wherein the heterocyclic amine is optionally substituted by C _1-3 alkyl or hydroxyl.

In a particular group of compounds of formula I, R ¹ represents a R ⁵ S(O) ₂ O group, wherein R ⁵ represents C _1-6 alkyl, especially C _2-6 alkyl, each optionally replaced by one or Multiple fluorine substitutions, and wherein R ² , R ³ , R ⁴ , R ^a , m and n are as defined above.

In a particular group of compounds of formula I, R ³ represents a CONHNR ⁷ R ⁸ group, wherein NR ⁷ R ⁸ represents a piperidino group, and R ¹ , R ² , R ⁴ , R ^a , m and n are as previously described definition.

It is understood that when substituent Z is present in more than one group, or when more than one substituent Z is present in the same group, these substituents are independently selected and may be the same or different. The same is true for W. Similarly, when m is 2 or 3, then ^the R groups are independently selected so that they may be the same or different, and similarly, when n is 2 or 3, then ^the R groups are independently selected such that They can be the same or different. Similarly, when ^R5 and ^R7 and/or ^R8 contain heteroaryl groups, such heteroaryl groups and their optional substituents 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 or 9- or 10-membered bicyclic ring having up to five ring heteroatoms selected from oxygen, nitrogen and sulfur. Suitable aromatic heteroaryl groups include, for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazole Base, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, benzofuranyl, indolyl, benzothienyl, benzo oxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl . Preferred are furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxazolylthiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, Tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5-triazenyl, more preferably pyrrolyl, thienyl, imidazolyl, oxazolyl or pyridyl.

Suitable 5-8 membered saturated or partially unsaturated 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 tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, more preferably tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, pyrrolidinyl-3-yl, Morpholino, piperidino, piperidin-4-yl or piperazin-1-yl.

wherein R ¹ represents a R ⁵ S(O) ₂ O group, and wherein R ⁵ represents a C _1-6 alkyl group optionally substituted by one or more fluorines, suitable groups include: methanesulfonyloxy, ethanesulfonyl Acyloxy, n-propylsulfonyloxy, n-butylsulfonyloxy, 3-methylbutane-1-sulfonyloxy, 3,3-dimethylbutane-1-sulfonyl Oxygen, fluoromethylsulfonyloxy, 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 represents _C1-6 alkoxy optionally substituted by one or more fluorines include: butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy , trifluoroethoxy, 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy and 6,6,6-trifluorohexyloxy.

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

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

where ^R1 is

a) a C _3-6 alkoxy group 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 replaced by 1, 2 or 3 are substituted by groups represented by Z, c) R ⁵ S(O) ₂ O group, wherein R ⁵ represents C _1-10 alkyl optionally substituted by one or more fluorine, or R ⁵ represents Thienyl or pyridyl, each optionally substituted by one or more halogens;

R ^2a represents H or chlorine;

R ^2b represents H or chlorine;

R ³ represents a CONHNR ⁷ R ⁸ group, wherein NR ⁷ R ⁸ represents a piperidino group, or R ³ represents a CONR ⁷ R ⁸ group, wherein R ⁷ is H, and R ⁸ is optionally halogen or trifluoromethyl Substituted pyridyl; and

R ⁴ represents a C _1-3 alkyl group.

Additional values for R ^2a , R ^2b , R ⁴ , R ⁵ , R ⁷ and R ⁸ in compounds of formula I and formula IA are described below. It is understood that such values may be used together with any definition, claim or embodiment defined above or below, where appropriate.

In particular in the compound of formula IA just mentioned above, R ¹ represents a group R ⁵ S(O) ₂ O, wherein R ⁵ represents a C _2-7 alkyl group optionally substituted by one or more fluorines. In particular in the compounds of formula IA just mentioned above, R ¹ represents the group R ⁵ S(O) ₂ O, wherein R ⁵ represents 2-thienyl optionally substituted by chlorine, or R ⁵ represents 3-pyridyl. In particular in the compounds of formula IA just mentioned above, R ^2a represents chlorine, and R ^2b represents chlorine. In particular in the compound of formula IA just mentioned above, R ³ represents a group CONHNR ⁷ R ⁸ , wherein NR ⁷ R ⁸ represents a piperidino group. In particular in the compound of formula IA just mentioned above ^{, R3} represents a group ^CONR7R8 , wherein ^R7 is H and ^R8 is pyridyl optionally substituted by trifluoromethyl. Especially in the compound of formula IA just above, R ⁴ is methyl.

Another special group of compounds of formula I is represented by formula IA

where ^R1 is

a) a C _3-6 alkoxy group 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 replaced by 1, 2 or 3 are substituted by groups represented by Z, c) R ⁵ S(O) ₂ O group, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorine;

R ^2a represents H or chlorine;

R ^2b represents H or chlorine;

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

R ⁴ represents a C _1-3 alkyl group.

Additional values for R ¹ in compounds of formula I and formula IA are described below. It is understood that such values may be used together with any definition, claim or embodiment defined above or below, where appropriate.

In a group of compounds of formula I or formula IA, R ¹ is C _3-6 alkoxy substituted by one or more fluorines. In the second group of compounds of formula I or formula IA, R ¹ is C _4-6 alkoxy optionally substituted with one or more fluorine. In the third group of compounds of formula I or formula IA, R ¹ is C _4-6 alkoxy substituted with one or more fluorines. In a fourth group of compounds of formula I or formula IA, R ¹ is a group of formula phenyl(CH ₂ ) _p O—, wherein p is 1, 2 or 3. In the fifth group of compounds of formula I or formula IA, R ¹ is an R ⁵ S(O) ₂ O group, wherein R ⁵ represents a C _1-6 alkyl group optionally substituted by one or more fluorines.

In particular R ^is 4,4,4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsulfonyloxy, n-ethylsulfonyloxy, benzyloxy, 4, 4,4-trifluorobutyl-1-sulfonyloxy or 3,3,3-trifluoropropyl-1-sulfonyloxy. More particularly ^R1 is 4,4,4-trifluorobutoxy, n-butylsulfonyloxy, n-propylsulfonyloxy, ethylsulfonyloxy or benzyloxy.

Another special group of compounds of formula I is represented by formula IA

where ^R1 is

a) a C _3-6 alkoxy group substituted by one or more fluorines, or b) a R ⁵ S(O) ₂ O group, wherein R ⁵ represents a C _1-6 optionally substituted by one or more fluorines Alkyl, or ^R represents phenyl or heteroaryl, each optionally substituted by 1, 2 or 3 groups represented by Z;

R ^2a represents chlorine;

R ^2b represents chlorine;

R ³ represents a CONHNR ⁷ R ⁸ group, 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 IA, R ¹ represents a R ⁵ S(O) ₂ O group, wherein R ⁵ represents a C _1-6 alkyl group optionally substituted by one or more fluorines;

R ^2a represents chlorine;

R ^2b represents chlorine;

R ³ represents a CONHNR ⁷ R ⁸ group, 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 IA, R ¹ represents C _4-6 alkoxy optionally substituted by one or more fluorines;

R ^2a represents chlorine;

R ^2b represents chlorine;

R ³ represents a CONHNR ⁷ R ⁸ group, 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 IA, ^R represents C _4-6 alkoxy substituted by one or more fluorines;

R ^2a represents chlorine;

R ^2b represents chlorine;

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

R ⁴ represents a C _1-3 alkyl group.

"Pharmaceutically acceptable salts", where such salts may include 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, trifluoroacetic acid, citric acid or Acid addition salts formed with maleic acid; or, for example, salts of compounds of formula I having sufficient acidity, for example alkali metal or alkaline earth metal salts such as sodium, calcium or magnesium salts, or ammonium salts, or with organic bases such as methylamine, Salts of dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Throughout the specification and claims, a given chemical formula or name shall include all stereoisomers and optical isomers and their racemates, as well as mixtures of individual enantiomers in varying proportions, where such Isomers and enantiomers, as well as pharmaceutically acceptable salts and solvates, such as hydrates, thereof. Isomers may be separated by conventional techniques such as chromatography or fractional crystallization. Enantiomers may be separated by, for example, fractional crystallization, resolution or HPLC separation of racemates. Diastereoisomers may be separated by separation of isomeric mixtures eg by fractional crystallization, HPLC or flash chromatography. Alternatively, stereoisomers may be prepared by chiral synthesis from chiral starting materials under conditions which do not cause racemization or epimerization, or by derivatization with chiral reagents. All stereoisomers are included within the scope of the present invention. All tautomers, where possible, are included within the scope of the present invention. The invention also includes compounds containing one or more isotopes, such as14C, ^{11C or19F} , and their use as isotopically ^labeled compounds in pharmacological and metabolic studies.

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

The following definitions shall apply throughout the specification and claims.

Unless otherwise stated or indicated, the term "alkyl" means straight or branched chain alkyl. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl and t-butyl.

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

Unless stated or indicated otherwise, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.

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

1) N-piperidin-1-yl-1-(4-benzyloxy-phenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide ;

2) 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidazol-1-yl]phenyl ethanesulfonic acid ester;

3) propane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidazol-1-yl]- Phenyl esters;

4) Butane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidazol-1-yl]- Phenyl esters;

5) N-piperidin-1-yl-2-(2,4-dichloro-phenyl)-5-methyl-1-[4-(4,4,4-trifluorobutoxy)phenyl ]-1H-imidazole-4-carboxamide;

6) 3,3,3-trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl) Imidazol-1-yl]phenyl ester;

7) 4,4,4-trifluorobutane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl ) imidazol-1-yl] phenyl ester;

8) Thiophene-2-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H-imidazole-1- Base} phenyl ester;

9) Pyridine-3-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H-imidazole-1- Base} phenyl ester;

10) Pyridine-3-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H-imidazole-1- Base} phenyl ester;

11) 3-methylbutane-1-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H -imidazol-1-yl}phenyl ester;

12) 3,3-Dimethylbutane-1-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl ]-1H-imidazol-1-yl}phenyl ester;

13) 3,3,3-trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-({[5-(trifluoromethyl) Pyridin-2-yl]amino}carbonyl)-1H-imidazol-1-yl]phenyl ester;

14) 3-methylbutane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-({[5-(trifluoromethyl)pyridine-2 -yl]amino}carbonyl)-1H-imidazol-1-yl]phenyl ester;

and pharmaceutically acceptable salts thereof.

Preparation

Compounds of the present invention may be prepared according to any of the following methods, as outlined below. However, the present invention is not limited to these methods and these compounds can also be prepared as described in the prior art for structurally related compounds.

A compound of formula I, wherein: R ¹ represents a) a C _3-6 alkoxy group substituted by one or more fluorines, or b) a phenyl (CH ₂ ) _p O-group, wherein p is 1, 2 or 3. The benzene ring is optionally substituted by 1, 2 or 3 groups represented by Z, or c) the R ⁵ S(O) ₂ O group, which can be passed at a temperature in the range of -25-150° C. In the presence of an inert solvent such as dichloromethane, and optionally in the presence of a base such as triethylamine or pyridine, the compound of formula II

wherein R ² , R ³ , R ⁴ , R ^a , m and n are as defined above,

Prepared by reaction with a R ^1A -X group, wherein R ^1A represents a group such that R ^1A O represents R ¹ , and X represents a leaving group such as a halogen.

A compound of formula I, wherein: R ^a , R ¹ , R ² , R ⁴ , m and n are as defined above, R ³ represents a group XY-NR ⁷ R ⁸ , wherein X is CO, and Y, R ⁷ and R ⁸ As previously defined, the compound of formula III can be

Wherein R ^a , R ¹ , R ² , R ⁴ , m and n are as defined above, R ¹⁰ represents H or C _1-6 alkyl,

Prepared by reacting with formula IV compound or its salt

R ⁷ R ⁸ YNH ² IV

Wherein Y, R ⁷ and R ⁸ are as defined above,

When R ¹⁰ is C _1-6 alkyl, the reaction is carried out in an inert solvent such as toluene, in the presence of a Lewis acid such as trimethylaluminum, at a temperature in the range of -25°C to 150°C; or when R ¹⁰ When it is H, the compound of formula III is reacted with a chlorinating agent such as oxalyl chloride, and then the resulting acid chloride is reacted with the amine of formula IV in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine, at -25°C- React at temperatures in the range of 150°C.

The compound of formula I, wherein: R ^a , R ¹ , R ² , R ⁴ , m and n are as defined above, R ³ represents a group XY-NR ⁷ R ⁸ , wherein X is SO ₂ , which can be obtained in an inert solvent such as In THF or dichloromethane, in the presence of a base such as potassium carbonate, triethylamine or pyridine, at a temperature in the range of -25 ° C to 150 ° C, the compound of formula V

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,

Prepared by reacting with a compound of formula IV or a salt thereof wherein Y, R ⁷ and R ⁸ are as defined above.

The compound of formula I, wherein: R ^a , R ² , R ³ , R ⁴ , m and n are as defined above, R ¹ represents R ⁵ S(O) ₂ NH group, which can be obtained in an inert solvent such as dichloromethane , in the presence of a base such as triethylamine, at a temperature ranging from -25°C to 150°C, the compound of formula VI

wherein R ^a , R ² , R ³ , R ⁴ , m and n are as defined above,

Prepared by reacting with a sulfonating agent of formula R ⁵ SO ₂ L, wherein R ⁵ is as defined above, and L represents a leaving group, such as chlorine.

Certain intermediate compounds are considered novel and form part of the present invention, in particular compounds of formula III as defined above and including each and all of the definitions given above for R ¹ .

Compounds of formula II, III, V and VI can be prepared by the general synthetic routes shown at the end of the examples and their modifications, or by analogous methods known to those skilled in the art. Those skilled in the art will recognize that certain functional groups require protection during the reaction sequence, followed by deprotection at appropriate stages, see "Protective Groups in Organic Synthesis", 3rd Edition (1999), Greene and Wuts.

drug preparation

The compounds of the present invention will generally be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or by other means of injection, buccal, rectal, vaginal, transdermal and/or nasal routes and/or by inhalation, to contain the active ingredient or pharmaceutically. The pharmaceutical preparation form of salt addition is acceptable and administered in a pharmaceutically acceptable dosage form. The compositions can be administered in different dosages depending on the disease, the patient treated and the route of administration.

Suitable daily dosages of the compounds of the invention in human therapy are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight.

Particularly preferred oral formulations are tablets or capsules which may be formulated by methods known to those skilled in the art, providing doses of active compound in the range 0.5 mg to 500 mg, for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250mg.

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

pharmacological properties

The compounds of formula (I) are useful in the treatment of obesity or overweight (e.g. promoting and maintaining weight loss), preventing weight gain (e.g. drug-induced or following cessation of smoking), for regulating appetite and/or satiety, eating Disorders (such as binge eating disorder, anorexia, bulimia, and compulsive eating), addiction (addiction to drugs, tobacco, alcohol, any appetite-stimulating macronutrient, or nonessential food), for the treatment of: Psychotic disorders such as psychotic and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety disorders, anxiety-depressive disorders, depression, mania, obsessive-compulsive disorder, impulse control disorder ( such as Gilles de la Tourette syndrome), attention disorders such as ADD/ADHD, stress disorders; and neurological disorders such as dementia and cognitive and/or memory dysfunction (such as amnesia, Alzheimer's Alzheimer's disease, Pick's dementia, senile dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild senile dementia), neurological and/or neurodegenerative diseases (such as multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease, and Alzheimer's disease), demyelination-related diseases, neuroinflammatory diseases (such as Guerrilla-Barr syndrome).

These compounds are also potentially useful in the prophylaxis or treatment of: dependence and addiction disorders and behaviors (e.g. alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g. presence or absence of Disordered alcohol withdrawal disorder; alcohol withdrawal delirium; amphetamine withdrawal disorder; cocaine withdrawal disorder; nicotine withdrawal disorder; opioid withdrawal disorder; sedative, hypnotics, or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety, and/or sleep disorder.

These compounds are also potentially useful in the prophylaxis or treatment of neurological disorders such as dystonia, movement disorders, akathisia, tremors and spasms, in the treatment of spinal cord injuries, neuropathies, migraines, insomnia, sleep disorders (e.g. sleep system disorders, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), painful conditions, traumatic trauma.

These compounds are also potentially useful in the treatment of immune, cardiovascular diseases (such as atherosclerosis, arteriosclerosis, angina pectoris, cardiac arrhythmias and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and Treatment of left ventricular hypertrophy, myocardial infarction, transient ischemic attack, peripheral vascular disease, systemic vasculature inflammation, septic shock (chock), stroke, stroke, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, Cerebral hemorrhage, metabolic disease (eg, a condition in which reduced metabolic activity or resting energy expenditure is shown by the percentage of total fat-free mass), diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hyperlipidemia Triglyceridemia, hyperuricemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwick syndrome) , type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g. treatment of male hypogonadism, treatment of infertility or As a contraceptive, menstrual abnormalities/menstrual disorders, polycystic ovary disease, sexual and reproductive dysfunction in men (erectile dysfunction) and women, GH-deficiency patients, female hirsutism, normal variant short stature) and in relation to respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal system (e.g. gastrointestinal motility or bowel propulsion dysfunction, diarrhea, vomiting, nausea, cholecystopathy, cholelithiasis, obesity-related gastroesophageal reflux, ulcers) disease.

These compounds are also potentially useful as drugs for the treatment of skin diseases, cancers (such as colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, gallbladder cancer, bile duct cancer), Craniopharyngioma, Pr-Will syndrome, Turner syndrome, Frölich syndrome, glaucoma, infectious diseases, urinary tract diseases, and inflammatory conditions (e.g., osteoarthritis, inflammation, inflammatory sequelae, osteoarthritis) and orthopedic disease. These compounds are also potentially useful as drugs for the treatment of (esophageal) achalasia.

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

In another aspect, the present invention provides the use of the compound of formula I in the preparation of medicaments, which can be used to treat or prevent obesity or overweight (such as promoting weight loss and maintaining weight loss), preventing weight gain (such as drug-induced or cessation of smoking) subsequent weight gain), for regulation of appetite and/or satiety, eating disorders (e.g., binge eating disorder, anorexia, bulimia, and compulsive eating), addiction (response to drugs, tobacco, alcohol, nutritional or non-essential food addiction), for the treatment of psychotic disorders such as psychotic and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety disorders, anxiety-depressive disorders, depression , mania, obsessive-compulsive disorders, impulse control disorders (such as Gilles de la Tourette syndrome), attention disorders such as ADD/ADHD, stress disorders, and neurological disorders such as dementia and cognitive and/or or memory dysfunction (such as amnesia, Alzheimer's disease, Pick's dementia, senile dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild senile dementia), neurological and/or or neurodegenerative diseases (such as multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease, and Alzheimer's disease), demyelination-related diseases, neuroinflammatory diseases (such as Gerbera-Barr syndrome sign).

In another aspect, the present invention provides the use of compounds of formula I in the preparation of medicaments, which can be used to treat or prevent dependence and addiction diseases and behaviors (such as alcohol and/or drug abuse, pathological gambling, kleptomania) , drug withdrawal disorder (e.g. alcohol withdrawal disorder with or without perceptual disturbance; alcohol withdrawal delirium; amphetamine withdrawal disorder; cocaine withdrawal disorder; nicotine withdrawal disorder; opioid withdrawal disorder; sedative, hypnotic, or anxiolytic withdrawal disorder; sedative, hypnotic, or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), episodes during withdrawal, and alcohol and/or drug relapse and/or drug-induced mood, anxiety, and/or sleep disturbances.

In another aspect, the present invention provides the use of the compound of formula I in the preparation of medicaments, which can be used for the treatment or prevention of neurological dysfunction such as dystonia, dyskinesia, akathisia, tremor and spasm, for the treatment of spinal cord injury, neuropathy, Migraine, Insomnia, Sleep Disorders (eg, Sleep System Disorders, Sleep Apnea, Obstructive Sleep Apnea, Sleep Apnea Syndrome), Painful Conditions, Traumatic Trauma.

In another aspect, the present invention provides the purposes of the compound of formula I in the preparation of medicines, and these medicines can be used for the treatment or prevention of immunity, cardiovascular diseases (such as atherosclerosis, arteriosclerosis, angina pectoris, arrhythmia 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, inflammation of systemic vasculature, septic shock, stroke, cerebral apoplexy, cerebral Infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic disease (such as a condition showing reduced metabolic activity or reduced resting energy expenditure as a percentage of total fat-free mass), diabetes, dyslipidemia, fatty liver, Gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, decreased fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity - Hypoventilation syndrome (Pickwick syndrome), type 1 diabetes, type 2 diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (eg, male gonadism Treatment of hypogonadism, treatment of infertility or as a contraceptive, menstrual abnormalities/menstrual disorders, polycystic ovary disease, sexual and reproductive dysfunction in men (erectile dysfunction) and women, GH-deficient patients, hirsutism in women , normal variant short stature) and those associated with respiratory (such as asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (such as gastrointestinal motility or bowel propulsion dysfunction, diarrhea, vomiting, nausea, gallbladder disease, gallstone disease, obesity) Gastroesophageal reflux, ulcer) related diseases.

In another aspect, the present invention provides the purposes of the compound of formula I in the preparation of medicines, and these medicines can be used for the treatment or prevention of skin diseases, cancer (such as colon cancer, rectal cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer) , cervical cancer, gallbladder cancer, cholangiocarcinoma), craniopharyngioma, Pr-Way syndrome, Turner syndrome, Frölich syndrome, glaucoma, infectious diseases, urinary tract diseases, and inflammatory conditions (such as deformed joints inflammation, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disease.

In yet another aspect, the present invention provides a method comprising administering to a patient in need thereof a pharmacologically effective amount of a compound of formula I for: preventing or treating obesity or overweight (e.g. promoting weight loss and maintaining weight loss), preventing weight loss Gain (such as drug-induced or weight gain after smoking cessation), regulation of appetite and/or satiety, eating disorders (such as binge eating disorder, anorexia, bulimia, and compulsive eating), addiction (response to drugs, tobacco , alcohol, any appetite-stimulating macronutrient, or addiction to non-essential food) for the treatment of psychotic disorders such as psychotic and/or mood disorders, schizophrenia and schizoaffective disorder, bipolar disorder, anxiety disorders, Anxiety-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (eg, Gilles de la Tourette syndrome), attention disorders such as ADD/ADHD, stress disorders, and neurological disorders Examples include dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, senile dementia, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild geriatric dementia), neurological and/or neurodegenerative diseases (such as multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease, and Alzheimer's disease), demyelination-related diseases, neuroinflammatory Diseases (such as Guerrilla-Barr Syndrome).

In yet another aspect, the present invention provides a method for preventing or treating diseases, the method comprising administering to a patient in need a pharmacologically effective amount of a compound of formula I, said diseases including: dependence and addiction diseases and behaviors (such as Alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal disorder with or without perceptual disturbance; alcohol withdrawal delirium; amphetamine withdrawal disorder; cocaine withdrawal disorder; nicotine withdrawal disorder opioid withdrawal disorder; sedative, hypnotic, or anxiolytic withdrawal disorder with or without perceptual disturbance; sedative, hypnotic, or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), Alcohol and/or drug-induced mood, anxiety, and/or sleep disturbances with onset during withdrawal and alcohol and/or drug relapse.

In yet another aspect, the present invention provides a method for preventing or treating diseases comprising administering to a patient in need a pharmacologically effective amount of a compound of formula I, said diseases comprising: neurological disorders such as dystonia, movement disorders, akathisia Incapacity, tremors, and spasms, for the treatment of spinal cord injuries, neuropathy, migraine, insomnia, sleep disorders (e.g., sleep system disorders, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), painful conditions, cranial trauma.

In yet another aspect, the present invention provides a method for preventing or treating a disease, the method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need, the disease comprising: immunity, cardiovascular disease (such as atherosclerosis , arteriosclerosis, angina pectoris, arrhythmia 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, systemic arterial Inflammation of the vascular system, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhage, metabolic diseases (such as decreased metabolic activity or resting energy expenditure as shown by the percentage of total fat-free mass Reduced conditions, diabetes, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, impaired glucose tolerance, decreased fasting glucose, insulin resistance, Insulin resistance syndrome, metabolic syndrome, syndrome X, obesity-hypoventilation syndrome (Pickwick syndrome), type 1 diabetes, type 2 diabetes, low H-DL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (eg, treatment of male hypogonadism, treatment of infertility or as a contraceptive, menstrual abnormalities/menstrual disorders, polycystic ovarian disease, men (erectile dysfunction) and women Sexual and reproductive dysfunction, GH-deficiency patients, female hirsutism, normal variant short stature) and 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, cholelithiasis, obesity-related gastro-oesophageal reflux, ulcer) related diseases.

In yet another aspect, the present invention provides a method for preventing or treating a disease, the method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need, the disease comprising: skin disease, cancer (such as colon cancer, rectal cancer , prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, gallbladder cancer, cholangiocarcinoma), craniopharyngioma, Prudential syndrome, Turner syndrome, Fröhlich syndrome, glaucoma, Infectious diseases, urinary tract diseases and inflammatory disorders (eg osteoarthritis, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic diseases.

The compounds of the invention are particularly useful in the treatment of obesity or overweight (e.g. promoting weight loss and maintaining weight loss), preventing or reversing weight gain (e.g. rebound, drug-induced or following smoking cessation), for regulating appetite and/or satiety eating disorders (eg, binge eating disorder, anorexia, bulimia, and compulsive eating), addiction (addiction to drugs, tobacco, alcohol, any appetite-stimulating macronutrient, or nonessential food).

The compounds of formula (I) are useful in the treatment of obesity, psychotic disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety disorders, anxiety-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders , anorexia, bulimia, attention disorders such as ADHD, epilepsy and related conditions, and neurological disorders such as dementia, neurological disorders such as multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's disease and Alzheimer's disease Alzheimer's disease. These compounds are also potentially useful in the treatment of immune, cardiovascular, reproductive and endocrine diseases, septic shock, and diseases related to the respiratory and gastrointestinal system (such as diarrhea). These compounds are also potentially useful as drugs for 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, Alcohol, cocaine, opiates, etc.) withdrawal symptoms. These compounds also counteract the weight gain that usually accompanies smoking cessation.

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

In another aspect, the present invention provides the use of the compound of formula I in the preparation of a medicament, which can be used for the treatment or prevention of obesity, psychiatric disorders such as psychosis, schizophrenia, bipolar disorder, anxiety, anxiety- Depressive disorders, depression, cognitive impairment, memory impairment, obsessive-compulsive disorder, 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 disease and Alzheimer's disease, immune, cardiovascular, reproductive and endocrine diseases, septic shock, diseases related to the respiratory and gastrointestinal system (such as diarrhea), and chronic abuse, addiction Addiction and/or relapse indications, such as treatment of drug (nicotine, alcohol, cocaine, opiates, etc.) dependence and/or treatment of drug (nicotine, alcohol, cocaine, opiates, etc.) withdrawal symptoms.

In yet a further aspect, the present invention provides a method for the treatment of obesity; psychotic disorders such as schizophrenia and bipolar disorders, anxiety disorders, anxiety-depressive disorders, depression, cognitive disorders , memory impairment, obsessive-compulsive disorder, 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 disease 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 relapsing indications, such as treatment Drug (nicotine, ethanol, cocaine, opiates, etc.) dependence and/or treatment of drug (nicotine, ethanol, cocaine, opiates, etc.) withdrawal symptoms, the method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need .

The compounds of the invention are particularly useful in the treatment of obesity, for example by reducing appetite and body weight, maintaining weight loss and preventing weight regain.

The compounds of the invention are also useful for preventing or reversing drug-induced weight gain, for example weight gain resulting from antipsychotic (neuroleptic) treatment. The compounds of the invention are also useful for preventing or reversing weight gain associated with smoking cessation.

The compounds of the invention are suitable for use in the treatment of the aforementioned indications in adolescent or adult patients.

combination therapy

The compounds of the present invention may be combined with other therapeutic agents useful in the treatment of obesity, such as other weight loss drugs that affect energy expenditure, glycolysis, gluconeogenesis, glycolysis, lipolysis, lipogenesis, fat absorption, fat storage , fat excretion, hunger and/or satiety and/or addiction mechanisms, appetite/impulse, food intake or G-I exercise.

The compounds of the invention may also be combined with additional therapeutic agents useful in the treatment of obesity-related diseases such as hypertension, hyperlipidemia, dyslipidaemias, diabetes, sleep apnea, asthma , heart disease, atherosclerosis, macrovascular and microvascular disease, hepatic steatosis, cancer, joint disease and gallbladder disease. For example, the compounds of the present invention may be used in combination with other therapeutic agents that lower blood pressure or lower the LDL:HDL ratio, or that cause a decrease in circulating levels of LDL-cholesterol. In diabetic patients, the compounds of the invention may also be used in combination with therapeutic agents for the treatment of complications associated with macrovascular disease.

The compounds of the present invention may be used in conjunction with other therapies for the treatment of obesity and its associated complications metabolic syndrome and type 2 diabetes, including biguanides, insulin (synthetic insulin analogs) and oral hypoglycemic agents (these are divided into dietary Glucose regulators and alpha-glucosidase inhibitors).

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, solvates of such salts or prodrugs thereof are well known in the art.

In addition, the combination drug of the present invention can be used in combination with sulfonylurea drugs. The invention also includes compounds of the invention used in combination with cholesterol-lowering drugs. In this application, cholesterol-lowering drugs include, but are not limited to, HMG-CoA reductase inhibitors (3-hydroxy-3-methylglutaryl-CoA reductase). Suitable HMG-CoA reductase inhibitors are statins.

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

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

The invention also includes compounds of the invention in combination with a bile acid sequestrant, such as colestipol, cholestyramine or cholestyr gum.

According to yet another aspect of the present invention, combined therapy is provided, which comprises administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a warm-blooded animal in need thereof, such as a human, optionally with a pharmaceutically An acceptable diluent or carrier, and simultaneously, sequentially or separately administer one or more drugs selected from the following, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, optionally with Pharmaceutically acceptable diluent or carrier:

CETP (cholesteryl ester transfer protein) inhibitors;

Cholesterol absorption antagonists;

MTP (microsomal transport protein) inhibitors;

Niacin derivatives, including extended-release and combination products;

Phytosterol compounds;

Probucol;

Anticoagulants;

Omega-3 fatty acids;

Another weight loss 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 α/β-adrenergic blockers, adrenergic stimulants, calcium channel blockers, AT-1 blockers, saluretics, diuretics or vasodilators;

Melanin-concentrating hormone (MCH) modulators;

NPY receptor modulators;

Orexin receptor modulators;

A phosphoinositide-dependent protein kinase (PDK) modulator; or

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

Monoamine transmission modulators, such as selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NARIs), norepinephrine-serotonin reuptake inhibitors (SNRIs), monoamine oxidase inhibitors antidepressant (MAOI), tricyclic antidepressant (TCA), noradrenergic and specific serotonergic antidepressant (NaSSA);

antipsychotics, such as olanzapine and clozapine;

Serotonin receptor modulators;

Leptin/leptin receptor modulators;

ghrelin/ghrelin receptor modulators;

DPP-IV inhibitors.

According to yet another aspect of the present invention, a combination therapy is provided, which comprises administering 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) was administered simultaneously, sequentially or separately.

Thus, in a further feature of the invention, there is provided a method of treating obesity and its associated complications in a warm-blooded animal in need thereof, such as a human, the method comprising administering to said animal an effective amount of a compound of formula I, or A pharmaceutically acceptable salt, and simultaneously, sequentially or separately administering an effective amount of a compound of one of the other classes of compounds described in this combination therapy section, or a pharmaceutically acceptable salt, solvate, or solvent of this salt compounds or prodrugs.

Therefore, in another feature of the present invention, there is provided a method of treating hyperlipidemia in a warm-blooded animal in need of such treatment, the method comprising administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable Accepted salts, and simultaneously, sequentially or separately administer an effective amount of a compound of one of the other classes of compounds described in the Combination Therapy section, or a pharmaceutically acceptable salt, solvate, solvate of this salt, or precursor thereof medicine.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a compound of one of the other classes of compounds described in the combination therapy section, or A pharmaceutically acceptable salt, solvate, solvate or prodrug of the salt, and a pharmaceutically acceptable diluent or carrier for combined use.

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

According to still another aspect of the present invention, a kind of medicine box is provided, and this medicine box comprises:

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

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

c) a container containing said first and second dosage forms.

According to still another aspect of the present invention, a kind of medicine box is provided, and this medicine box comprises:

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

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

c) a container containing said first and second dosage forms.

According to another feature of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, and a compound or a pharmaceutically acceptable salt, solvate, or a compound of one of the other compounds described in this combination therapy section. Use of a solvate or a prodrug of a salt in the preparation of a medicament for treating obesity in warm-blooded animals such as humans and related complications.

According to another feature of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, and a compound or a pharmaceutically acceptable salt, solvate, or a compound of one of the other compounds described in this combination therapy section. Use of a solvate or a prodrug of a salt in preparing a medicine for treating hyperlipidemia in warm-blooded animals such as humans.

According to yet another aspect of the present invention, there is provided a combination therapy comprising administering to a warm-blooded animal in need thereof, such as a human, an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable an acceptable diluent or carrier; and simultaneously, sequentially or separately administer an effective amount of one of the other compounds described in the Combination Therapy section, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or precursor thereof drug, optionally with a pharmaceutically acceptable diluent or carrier.

In addition, the compounds of the present invention can also be used for the treatment of obesity-related diseases or disorders (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, nonalcoholic steatohepatitis, Osteoarthritis and certain cancers), and drug combinations for the treatment of psychiatric and neurological conditions.

It should be understood that there are medically accepted definitions of obesity and overweight. Patients can be identified by, for example, determining body mass index (BMI), which is calculated by dividing weight in kilograms by height in meters squared, and comparing the result to a definition.

pharmacological activity

The compounds of the present invention have activity against the receptor product of the CB1 gene. The affinity of the compounds of the invention for the central cannabinoid receptors can be demonstrated by the methods described in Devane et al., Molecular Pharmacology, 1988, 34,605 or WO 01/70700 or EP 656354. Or the test can be carried out as follows.

10 μg of membrane prepared from cells stably transfected with CB1 gene was suspended in 200 μl of 100 mM NaCl, 5 mM MgCl ₂ , 1 mM EDTA, 50 mM HEPES (pH 7.4), 1 mM DTT, 0.1% BSA and 100 μM GDP. Thereto were added an EC80 concentration agonist (CP55940), a desired concentration of a test compound and 0.1 μCi of [ ³⁵ S]-GTPγS.

The reaction was allowed to proceed for 45 minutes at 30°C. 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 [ ^35S ]-GTPyS retained by the filters was counted.

Activity was determined in the absence of all ligands (minimal activity) or in the presence of EC80 concentration CP55940 (maximal activity). These activities were set as 0% and 100% activity, respectively. Activity was calculated and plotted as a percentage of maximal activity at various concentrations of neoligand. put the data in the equation Fitting, the _IC50 values determined were the concentration required to produce a half-maximal inhibition of GTPyS binding under the conditions used.

The compounds of the invention are active at the CB1 receptor ( _IC50 < 1 micromolar). Most preferred compounds have an _IC50 < 200 nanomolar. For example, the IC ₅₀ of the compound of Example 1 is 18 nM, and the IC ₅₀ of the compound of Example 2 is 28 nM.

The compounds of the present invention are believed to be selective CB1 antagonists or inverse agonists. Its potency, selectivity profile and side-effect propensity may limit the clinical use of compounds known to date with proven CB1 antagonist/inverse agonist properties. In this regard, preclinical evaluation of the compounds of the invention in models of gastrointestinal and/or cardiovascular function demonstrates that they exhibit clear advantages over representative control CB1 antagonists/inverse agonists.

Compounds of the present invention are comparable to representative control CB1 antagonists/inverse agonists in terms of potency, selectivity profile, bioavailability, plasma half-life, blood-brain permeability, plasma protein binding (for example, increasing the free component of the drug) or solubility. can provide additional benefits compared to other agents.

The utility of the compounds of the present invention in the treatment of obesity and related disorders is demonstrated by buffet-induced body weight loss in obese mice. Female C5781/6J mice were given a high-calorie "buffet" (soft chocolate/cocoa-type treats, chocolate, fatty cheese and nougat) and standard laboratory chow ad libitum for 8-10 weeks. Then, the compound to be tested (iv, ip, sc or po) is administered systemically once a day for a minimum of 5 consecutive days and the body weight of the mice is monitored daily. Simultaneously, obesity assessment was performed by DEXA imaging at the beginning and at the end of the study. Blood samples were also assayed for obesity-associated changes in plasma markers.

Example

abbreviation

DMF Dimethylformamide

DEA diethylamine

EtOAc ethyl acetate

THF Tetrahydrofuran

TLC thin layer chromatography

t triplet

s unimodal

d doublet

q quartet

qvint quintet

m multiplet

br broad peak

bs broad singlet

dm double multiplet

bt broad triplet

dd double doublet

General Experimental Method

Mass spectra were recorded with a Micromass ZQ single quadrupole mass spectrometer or a Micromass LCZ single quadrupole mass spectrometer, both equipped with a gas-assisted electrospray interface (LC-MS). ¹ H NMR measurements were performed on a Varian Mercury 300 or Varian Inova 500 operating at ¹ H frequencies of 300 and 500 MHz, respectively. Chemical shifts are given in ppm with _CDCl3 as internal standard. Unless otherwise stated, _CDCl3 was used as solvent for NMR. Purification was performed on a semi-preparative HPLC with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with a 19 x 100 mm C8 column. If not stated otherwise, the mobile phase used was acetonitrile and buffer (0.1M _NH4Ac :acetonitrile 95:5).

For the separation of isomers, a Kromasil CN E9344 (250×20 mm i.d.) column was used.

Use heptane:ethyl acetate:DEA 95:5:0.1 as mobile phase (1ml/min). Fraction collection was guided by a UV detector (330 nm).

Embodiment of the invention

Example 1

step 1

N-(4-Benzyloxyphenyl)-2,4-dichloro-benzamidine

Under a nitrogen atmosphere, 4-benzyloxyaniline hydrochloride (5.0 g, 21.2 mmol) was added dropwise to a solution of ethylmagnesium bromide in 25 ml of anhydrous THF (44.5 ml, 1M in THF, 44.5 mmol). After stirring for 20 minutes, a solution of 2,4-dichlorobenzonitrile (3.65 g, 21.2 mmol) in 25 mL THF was added. The reaction mixture was stirred at room temperature for 20 hours. Water (50ml) was added carefully. Extraction with EtOAc (2x100ml) _, dried ( _Na2SO4 ), filtered and evaporated to dryness afforded 7.7g (98%) of the title compound.

step 2

1-(4-Benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester

Potassium carbonate (2.56 g, 18.5 mmol) was added to N-(4-benzyloxyphenyl)-2,4-dichlorobenzamidine (6.88 g, 18.5 mmol), the product of step 1 of Example 1 dissolved in 50 ml THF , and the suspension was stirred for 10 min. Ethyl 3-bromo-2-oxobutanoate (4.65 g, 22.2 mmol) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 66 hours. The solution was filtered and evaporated to dryness. The residue was dissolved in acetic acid and refluxed for 1 hour. The mixture was cooled to room temperature, 100ml of water was added and the product was extracted with EtOAc (2 x 200ml). The combined organic phases were _washed with saturated sodium bicarbonate, dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (silica gel, hexane:EtOAc 70:30, 60:40) afforded 5.75 g (65%) of the title compound as a pale yellow solid.

¹ H NMR (CDCl ₃ ): δ7.5-7.2 (8H, m), 7.1-6.9 (4H, m), 5.1 (2H, s), 4.5 (2H, q), 2.5 (3H, s), 1.5 (3H,t), MSm/z 504(M+Na), 985(2M+Na)

step 3

1-(4-Benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid

To Example 1 step 2 product 1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester (3.62g, A solution of potassium hydroxide (4.05 g, 72 mmol) in water (20 ml) was added to a suspension of 7.5 mmol) in 60 ml of methanol, and the reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature, acidified to pH~2 with 1M HCl, and extracted with ethyl acetate (2 x 200ml). The combined organic phases were dried ( _Na2SO4 ), filtered and concentrated to afford 3.38 g (99%) of _the title compound.

step 4

N-piperidin-1-yl-1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole- 4-formamide

To Example 1 step 3 product 1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid (3.38g, 7.5mmol ) in 60ml _{of CH2Cl2} was added 3 drops of DMF, followed by oxalyl chloride (1.3ml, 14.9mmol). The mixture was refluxed for 2 hours, cooled to room temperature, and evaporated to dryness. The residue was dissolved _in 50ml _CH2Cl2 and cooled to 0°C. Triethylamine (2.1 ml, 14.9 mmol) was added followed by 1-aminopiperidine (0.9 ml, 8.2 mmol), and the mixture was stirred at room temperature for 2 hours. _Water (300ml) was _added and the mixture was extracted with _CH2Cl2 (3 x 100ml), dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (silica gel, hexanes:EtOAc 1:2, EtOAc) gave 2.94 g (74%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ7.5-7.2 (8H, m), 7.1-6.9 (4H, m), 5.1 (2H, s), 3.0-2.7 (4H, m), 2.5 (3H, s) , 1.9-1.7 (4H, m), 1.6-1.4 (2H, m). MSm/z 558 (M+Na). HPLC: 96.5%.

Example 2

step 1

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4- Formamide

N-piperidin-1-yl-1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole- 4-Carboxamide (2.78 g, _5.2 mmol) was dissolved in 80 ml _CH2Cl2 and cooled to 0°C. Boron tribromide solution (1M _CH2Cl2 solution, _10.4ml , 10.4mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. Water (200ml) was added and the solution was extracted with EtOAc (3 x 200ml). _The combined organic phases were dried ( _Na2SO4 ), filtered and concentrated. Flash chromatography (silica gel, hexanes:EtOAc 1:3, EtOAc) gave 1.34 g (58%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ8.6 (1H, bs), 7.4-7.1 (3H, m), 7.0-6.9 (4H, m), 3.0-2.8 (4H, m), 2.5 (3H, s) , 1.8-1.6(4H, m), 1.5-1.3(2H, m).

step 2

4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidazole ethanesulfonic acid -1-yl]-phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4- A solution _of formamide (321 mg, 0.72 mmol) in 10 ml _CH2Cl2 was cooled to 0°C. Triethylamine (101 μl, 0.72 mmol) was added followed by ethanesulfonyl chloride (69 μl, 0.72 mmol), and the reaction mixture was stirred at room temperature overnight. _Water was added and the mixture was extracted with _CH2Cl2 (3 x 20ml), dried _{( Na2SO4} ), filtered and concentrated. Flash chromatography (silica gel, hexane:EtOAc 1:3) afforded 230 mg (60%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ7.9 (1H, broad s), 7.4-7.1 (7H, m), 3.3 (2H, q), 3.0-2.8 (4H, m), 2.5 (3H, s), 1.9-1.7 (4H, m), 1.5 (3H, t), 1.5-1.4 (2H, m). MSm/z 560 (M+Na). HPLC: 97.0%.

Example 3

Propan-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidium Azol-1-yl]phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4- A solution of formamide (320mg, _0.72mmol ) in 10ml of _CH2Cl2 was cooled to 0°C. Triethylamine (100 μl, 0.72 mmol) was added followed by 1-propanesulfonyl chloride (81 μl, 0.72 mmol), and the reaction mixture was stirred at room temperature overnight. _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 220 mg (56%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ7.9 (1H, broad s), 7.4-7.1 (7H, m), 3.3 (2H, m), 3.0-2.8 (4H, m), 2.5 (3H, s), 2.1-1.9 (2H, m), 1.9-1.7 (4H, m), 1.5-1.4 (2H, m), 1.2 (3H, t). MSm/z 574 (M+Na). HPLC: 97.0%.

Example 4

Butan-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidium Azol-1-yl]phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4- A solution of formamide (320mg, ^0.72mmol ) in 10ml of ^CH2Cl2 was cooled to 0°C. Triethylamine (100 μl, 0.72 mmol) was added followed by 1-butanesulfonyl chloride (93 μl, 0.72 mmol) and the reaction mixture was stirred at room temperature overnight. _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 230 mg (57%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ7.9 (1H, bs), 7.4-7.1 (7H, m), 3.3 (2H, m), 3.0-2.8 (4H, m), 2.5 (3H, s), 2.1 -1.9 (2H, m), 1.9-1.7 (4H, m), 1.6-1.4 (4H, m), 1.0 (3H, t) MSm/z 588 (M+Na). HPLC: 96.0%.

Example 5

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-5-methyl-1-[4-(4,4,4-trifluorobutoxy)-benzene Base] -1H-imidazole-4-carboxamide

Add 1-iodo-4,4,4-trifluorobutane (376mg, 1.58mmol) dropwise to N-piperidin-1-yl-2-(2,4-dichlorophenyl )-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxamide (351mg, 0.79mmol) and K ₂ CO ₃ (218mg, 1.58mmol) in 50ml acetone suspension. The reaction mixture was refluxed overnight, cooled, filtered and concentrated. Flash chromatography (silica gel, hexane:EtOAc 1:2) gave 200 mg (46%) of the title compound as a white solid.

¹ H NMR (CDCl ₃ ): δ8.0 (1H, broad s), 7.4-7.2 (3H, m), 7.1-7.0 (2H, m), 6.9-6.8 (2H, m), 4.1-4.0 (2H , m), 3.0-2.9(4H, m), 2.5-2.2(5H, m), 2.2-2.0(2H, m), 1.9-1.7(4H, m), 1.6-1.4(2H, m).MSm /z 578 (M+Na). HPLC: 99.4%.

Example 6

3,3,3-Trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylamino Formyl) imidazol-1-yl] phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4- Formamide (0.89g, 2.00mmol) was dissolved in dichloromethane (20ml), cooled to 0°C, and triethylamine (0.35ml, 2.4mmol) was added followed by 3,3,3-trifluoropropanesulfonyl chloride (Prepared in analogy to the butyl homologue described in WO00/010968) (0.35ml, 2.40mmol). The reaction mixture was stirred overnight at room temperature. TLC showed starting material remaining, so another portion of triethylamine and 3,3,3-trifluoropropanesulfonyl chloride were added and the reaction mixture was stirred for an additional 2 hours. Water was added and the product was extracted with dichloromethane, dried ( _Na2SO4 ), filtered and concentrated _. Flash chromatography (hexane:EtOAc 1:3-EtOAc) followed by recrystallization (hexane:EtOAc) gave 700 mg (59%) of the title compound as a colorless solid.

¹ H NMR (CDCl ₃ ): δ7.40-7.10 (8H, m), 3.60-3.43 (2H, m), 3.02-2.70 (6H, m), 2.50 (3H, s), 1.92-1.70 (4H, m), 1.57-1.40 (2H, m). MSm/z 627 (M+Na). HPLC: 97.8%

Example 7

4,4,4-Trifluorobutane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylamino Formyl)imidazol-1-yl]-phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4- Formamide (0.49g, 1.20mmol) was dissolved in dichloromethane (20ml), cooled to 0°C, and triethylamine (0.67ml, 4.8mmol) was added, followed by 4,4,4-trifluorobutane- 1-Sulphonyl chloride (prepared as described in WO00/010968) (0.38 g, 1.80 mmol). The reaction mixture was stirred at room temperature for 3 hours. TLC showed starting material remaining, so another portion of triethylamine and 4,4,4-trifluorobutane-1-sulfonyl chloride were added and the reaction mixture was stirred overnight. Water was added and the product was extracted with dichloromethane, dried ( _Na2SO4 ), filtered and concentrated _. Flash chromatography (hexane:EtOAc 1:3-EtOAc) followed by recrystallization (hexane:EtOAc) afforded 0.45 g (61%) of the title compound as a colorless solid.

¹ H NMR (CDCl ₃ ): δ7.35-7.19 (8H, m), 3.40 (2H, m), 3.05-2.90 (4H, m), 2.78-2.20 (7H, sand m), 1.92-1.70 (4H , m), 1.57-1.40 (2H, m). MSm/z 641 (M+Na). HPLC: 98.6%

Example 8

Thiophene-2-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]- 1H-Imidazol-1-yl}phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole- A solution of 4-carboxamide (100mg, 0.22mmol) and triethylamine (0.31ml, 2.25mmol) in dichloromethane (2.5ml) was cooled to -78°C. To the reaction mixture was carefully added 2-thiophenesulfonyl chloride (287mg, 1.57mmol) dissolved in dichloromethane (2.5ml). The resulting mixture was stirred at -78 °C for 1 h, then at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase was washed with water and dried. The solvent was removed under reduced pressure and separation by preparative HPLC gave the title compound as a solid (110 mg, 83%).

¹ H NMR (400MHz) δ7.89(s, NH), 7.75-7.74(m, 1H), 7.55-7.54(m, 1H), 7.35-7.34(m, 1H), 7.30-7.25(m, 2H) , 7.13-7.11(m, 1H), 7.07(d, 4H), 2.90-2.86(m, 4H), 1.80-1.75(m, 4H), 1.48-1.42(m, 2H).MSm/z 591(M +H) ⁺ .

Example 9

Pyridine-3-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]- 1H-Imidazol-1-yl}phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole- A solution of 4-carboxamide (100mg, 0.22mmol) and triethylamine (0.31ml, 2.25mmol) in dichloromethane (5.0ml) was cooled to -78°C. To the reaction mixture was added 3-pyridinesulfonyl chloride (144 mg, 0.67 mmol) in small portions. The resulting mixture was stirred at -78 °C for 1 h, then at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase was washed with water and dried. The solvent was removed under reduced pressure and separation by preparative HPLC gave the title compound as a solid (110 mg, 84%).

¹ H NMR (400MHz) δ8.96(s, 1H), 8.92(s, 1H), 8.09-8.06(m, 1H), 7.89(s, 1H), 7.51-7.49(m, 1H), 7.36(d , 1H), 7.30-7.25(m, 2H), 7.06(s, 4H), 2.88-2.84(m, 4H), 2.48(s, 3H), 1.79-1.74(m, 4H), 1.47-1.41(m , 2H).MSm/z 586(M+H) ⁺ .

Example 10

5-chlorothiophene-2-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl Base]-1H-imidazol-1-yl}phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole- A solution of 4-carboxamide (100mg, 0.22mmol) and triethylamine (0.16ml, 1.12mmol) in dichloromethane (2.5ml) was cooled to -78°C. To the reaction mixture was carefully added a solution of 5-chlorothiophene-2-sulfonyl chloride (244mg, 1.12mmol) in dichloromethane (2.5ml). The resulting mixture was stirred at -78 °C for 1 h, then at room temperature overnight. Water was added to the reaction, the phases were separated and the organic phase was washed with water and dried. The solvent was removed under reduced pressure and separation by preparative HPLC gave the title compound as a solid (84 mg, 60%).

¹ H NMR (400MHz) δ7.90(s, NH), 7.34-7.26(m, 4H), 7.10(d, 4H), 6.96(d, 1H), 2.88-2.85(m, 4H), 2.49(s , 3H), 1.79-1.74(m, 4H), 1.47-1.42(m, 2H). MSm/z 625(M+H) ⁺ .

Example 11

3-Methylbutane-1-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino) Carbonyl]-1H-imidazol-1-yl}phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole- 4-Formamide (50 mg, 0.11 mmol) was dissolved in dichloromethane (3.0 ml), cooled to 0°C, and triethylamine (20 μl, 0.13 mmol) was added to the mixture. The resulting mixture was cooled to -78°C, and 3-methylbutane-1-sulfonyl chloride (23 mg, 0.13 mmol) was carefully added. The reaction was stirred at -78 °C for 1.5 h. Water was added to the reaction, and the product was extracted with dichloromethane and dried. The solvent was removed under reduced pressure and separation by preparative HPLC gave the title compound as a solid (46 mg, 71%).

¹ H NMR (400MHz) δ7.86(s, NH), 7.30-7.20(m, 5H), 7.12-7.09(m, 2H), 3.26-3.22(m, 2H), 2.86-2.80(m, 4H) , 2.46(s, 3H), 1.86-1.80(m, 3H), 1.77-1.69(m, 4H), 1.45-1.37(m, 2H), 0.93(d, 6H).MSm/z 579(M+H ) ⁺ .

Example 12

3,3-Dimethylbutane-1-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-yl Amino)carbonyl]-1H-imidazol-1-yl}phenyl ester

N-piperidin-1-yl-2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole- 4-Formamide (50 mg, 0.11 mmol) was dissolved in dichloromethane (3.0 ml), cooled to 0°C, and triethylamine (20 μl, 0.13 mmol) was added to the mixture. The resulting mixture was cooled to -78°C, and 3,3-dimethylbutane-1-sulfonyl chloride (25 mg, 0.13 mmol) was carefully added. The reaction was stirred at -78 °C for 2 h. Water was added to the reaction, and the product was extracted with dichloromethane and dried. The solvent was removed under reduced pressure and separation by preparative HPLC gave the title compound as a solid (46 mg, 69%).

¹ H NMR (400MHz) δ7.85(s, NH), 7.30-7.20(m, 5H), 7.13-7.09(m, 2H), 3.24-3.18(m, 2H), 2.86-2.81(m, 4H) , 2.46(s, 3H), 1.86-1.80(m, 2H), 1.76-1.69(m, 5H), 1.44-1.37(m, 2H), 0.92(s, 9H)..MSm/z 593(M+ H) ⁺ .

Example 13

step 1

1-[4-(Benzyloxy)phenyl]-2-(2,4-dichlorophenyl)-5-methyl-N-[5-(trifluoromethyl)pyridine -2-yl]-1H-imidazole-4-carboxamide

2-Amino-5-(trifluoromethyl)pyridine (404 mg, 2.49 mmol) was dissolved in dichloromethane (2.5 ml) under argon, and trimethylaluminum (1.25 ml, 2.0 M toluene solution, 2.5 mmol). The solution was stirred at room temperature for 1.5 h, as a result, a 0.66 M solution of the aminating reagent was obtained. 3.75 ml (2.5 mmol) of this stock solution were added to 1-[4-(benzyloxy)phenyl]-2-(2,4-dichlorophenyl)-5 -methyl-1H-imidazole-4-carboxylic acid ethyl ester (400mg, 0.83mmol), and the reaction solution was stirred at 45°C overnight. The reaction solution was cooled to 0°C and quenched with aqueous HCl (2M, 7.5ml). The mixture was diluted with dichloromethane and neutralized by the addition of aqueous KOH (2M). The organic phase was separated and the aqueous phase was re-extracted with dichloromethane. The collected organic phases were washed with _H2O and _dried over _Na2SO4 . The solvent was removed under reduced pressure and purified by preparative HPLC to give the title compound as a solid (319 mg, 64%).

¹ H NMR (400MHz) δ9.89(s, NH), 8.54(s, 1H), 8.50(d, 1H), 7.92-7.88(m, 1H), 7.40-7.33(m, 5H), 7.27-7.20 (m, 3H), 7.03-6.91(m, 4H), 5.02(s, 2H), 2.50(s, 3H). MSm/z 597(M+H) ⁺ .

Step 2:

2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-[5-(trifluoromethyl)pyridine-2- Base] -1H-imidazole-4-carboxamide

1-[4-(benzyloxy)phenyl]-2-(2,4-dichlorophenyl)-5-methyl-N-[5-(trifluoromethyl)pyridin-2-yl] -1H-imidazole-4-carboxamide (319mg, 0.53mmol) was dissolved in hydrogen bromide (7.5ml, 4.1M acetic acid solution, 30.75mmol), and the reaction mixture was stirred at room temperature for 4h. Acetic acid was co-evaporated with ethanol, and the residue was neutralized with ammonia and dissolved in methanol. Purification by flash chromatography afforded the title compound (266 mg, 98%).

¹ H NMR (400MHz) δ10.36(s, NH el.OH), 10.09(s, NH el.OH), 8.89(s, 1H), 8.69(d, 1H), 8.48-8.43(m, 1H) , 7.87-7.80(m, 2H), 7.67(d, 1H), 7.41(d, 2H), 7.06(d, 2H), 2.65(s, 3H). MSm/z 507(M+H) ⁺ .

Step 3:

3,3,3-Trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-({[5-(trifluoromethyl Base) pyridin-2-yl] amino}carbonyl)-1H-imidazol-1-yl]phenyl ester

2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]-1H-imidazole - A solution of 4-carboxamide (136 mg, 0.27 mmol) and triethylamine (40 μl, 0.32 mmol) in dichloromethane (4.0 ml) was cooled to -78°C. To the reaction mixture was carefully added 3,3,3-trifluoropropane-1-sulfonyl chloride (63 mg, 0.32 mmol). The resulting mixture was stirred at -78 °C for 1 h, then allowed to reach room temperature. Water was added to the reaction, and the phases were separated. _The organic phase was washed with _NaHCO3 , brine and dried over _Na2SO4 . The solvent was removed under reduced pressure and separation by preparative HPLC gave the title compound as a solid (88 mg, 49%).

¹ H NMR (400MHz) δ9.87(s, NH), 8.55(s, 1H), 8.49(d, 1H), 7.93-7.89(m, 1H), 7.34-7.18(m, 7H) 3.53(m, 2H), 2.85-2.73(m, 2H), 2.54(s, 3H). MSm/z 667 (M+H) ⁺ .

Example 14

3-Methylbutane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-({[5-(trifluoromethyl) Pyridin-2-yl]amino}carbonyl)-1H-imidazol-1-yl]phenyl ester

The 2-(2,4-dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-[5-(trifluoromethyl)pyridine prepared in step 3 of Example 13- A solution of 2-yl]-1H-imidazole-4-carboxamide (139 mg, 0.27 mmol) and triethylamine (46 μl, 0.33 mmol) in dichloromethane (4.0 mL) was cooled to -78°C. To the reaction mixture was carefully added 3-methylbutane-1-sulfonyl chloride (56 mg, 0.33 mmol). The resulting mixture was stirred at -78 °C for 1 h, then allowed to reach room temperature. Water was added to the reaction, and the phases were separated. _The organic phase was washed with _NaHCO3 , brine and dried over _Na2SO4 . The solvent was removed under reduced pressure and separation by preparative HPLC gave the title compound as a solid (81 mg, 46%).

¹ H NMR (400MHz) δ9.87(s, NH), 8.55(s, 1H), 8.49(d, 1H), 7.93-7.89(m, 1H), 7.34-7.14(m, 7H), 3.29-3.24 (m, 2H), 2.53(s, 3H), 1.88-1.81(m, 2H), 1.79-1.69(m, 1H), 0.95(d, 6H). MSm/z 641(M+H) ⁺ .

General synthetic route

Claims (17)

1. A compound of formula (I) and pharmaceutically acceptable salts thereof,

in R ¹ represents: a) a C _1-10 alkoxy group 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 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 groups, wherein R ⁵ represents optionally substituted by one or A plurality of fluorine-substituted C _1-10 alkyl groups, or R ⁵ represents a phenyl or heteroaryl group each optionally substituted by 1, 2 or 3 groups represented by Z, or d) the formula (R ⁶ ) ₃ Si group, wherein R ⁶ represents the same or different C _1-6 alkyl; ^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; ^R3 stands for: a) XY-NR ⁷ R ⁸ group where X is CO or SO ₂ , Y does not exist or represents NH optionally substituted by C _1-3 alkyl; and ^R7 and ^R8 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 group, wherein r is 0, 1, 2, 3 or 4, when r is 0, s is 1, otherwise s is 1 or 2, and optionally the phenyl independently substituted by one, two or three groups represented by Z; A 5-8 membered saturated heterocyclic group containing one nitrogen and optionally one of oxygen, sulfur or another nitrogen, wherein the heterocyclic group is optionally substituted with one or more of: C _1-3 Alkyl, hydroxy or benzyl; -(CH ₂ ) _t Het group, wherein t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more C _1-3 alkyl groups; and Het represents optionally Heteroaryl substituted by one, two or three groups selected from the group consisting of C _1-5 alkyl, C _1-5 alkoxy or halogen, wherein the alkyl and alkoxy are optionally independently replaced by one or multiple fluorine substitutions; or R ⁷ represents H, and R ⁸ is as defined above; or ^R7 and ^R8 together with the nitrogen atom to which they are attached represent a 5-8 membered saturated or partially unsaturated heterocyclic group containing one nitrogen and optionally the following: one of oxygen, sulfur or another nitrogen ; Wherein the heterocyclic group is optionally substituted by one or more of the following groups: 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 substituted by 1, 2 or 3 Z groups; R ⁴ represents H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy C _1-6 alkylene containing up to 6 carbon atoms, each group is optionally replaced by one or Multiple fluorine or cyano substitutions; 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 or a heterocyclic amino group selected from the following: morpholinyl, pyrrolidinyl , piperidinyl or piperazinyl, wherein the heterocyclic amino group is optionally substituted by C _1-3 alkyl or hydroxyl; With the proviso that when n is 1, then ^R2 is not methoxy at the 2- or 4-position of the benzene ring, and with the further proviso that ^R1 is not methanesulfonylamino, methoxy or _CF3O- . 2. The compound of claim 1, wherein R ¹ represents: a) a C _3-6 alkoxy group substituted by one or more fluorines, or b) a phenyl (CH ₂ ) _p O- group, wherein p is 1, 2 or 3, and the phenyl The ring is optionally substituted by 1, 2 or 3 groups represented by Z, or c) a R ⁵ S(O) ₂ O group, wherein R ⁵ represents C _1-6 optionally substituted by one or more fluorine Alkyl, or ^R represents phenyl or heteroaryl, each optionally substituted by 1, 2 or 3 groups represented by Z; ^R represents halogen, C _1-3 alkyl or C _1-3 alkoxy; m is 0, 1, 2 or 3; ^R represents halogen; n is 0, 1, 2 or 3; ^R3 stands for: a) XY-NR ⁷ R ⁸ group where X is CO; Y does not exist or represents NH optionally substituted by C _1-3 alkyl; and ^R7 and ^R8 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 group, wherein r is 0, 1, 2, 3 or 4, when r is 0, s is 1, otherwise s is 1 or 2, and optionally the phenyl independently substituted by one, two or three groups represented by Z; A 5-8 membered saturated heterocyclic group containing one nitrogen and optionally one of oxygen, sulfur or another nitrogen, wherein the heterocyclic group is optionally substituted with one or more of: C _1-3 Alkyl, hydroxy or benzyl; -(CH ₂ ) _t Het group, wherein t is 0, 1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more C _1-3 alkyl groups, and Het represents optionally Heteroaryl substituted by one, two or three groups selected from: C _1-5 alkyl, C _1-5 alkoxy or halogen; or R ⁷ represents H, and R ⁸ is as defined above; or ^R7 and ^R8 together with the nitrogen atom to which they are attached represent a 5-8 membered saturated or partially unsaturated heterocyclic group containing one nitrogen and optionally the following: one of oxygen, sulfur or another nitrogen ; Wherein the heterocyclic group is optionally substituted by one or more of the following groups: C _1-3 alkyl, hydroxyl, fluorine or benzyl; R ⁴ represents H, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy C _1-6 alkylene containing up to 6 carbon atoms, each group is optionally replaced by one or Multiple fluorine or cyano substitutions; 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, or a heterocyclic amino group selected from the following: morpholinyl, pyrrolidine Base, piperidinyl or piperazinyl, wherein the heterocyclic amine group is optionally substituted by C _1-3 alkyl or hydroxyl. 3. A compound of formula I represented by formula IA

where ^R1 is: a) a C _3-6 alkoxy group substituted by one or more fluorines, b) a phenyl (CH ₂ ) _p O- group, wherein p is 1, 2 or 3, and the phenyl ring is optionally replaced by 1 , 2 or 3 substituted by groups represented by Z, c) R ⁵ S(O) ₂ O group, wherein R ⁵ represents C _1-10 alkyl optionally substituted by one or more fluorine, or R ⁵ represents thienyl or pyridyl, each optionally substituted by one or more halogens; R ^2a represents H or chlorine; R ^2b represents H or chlorine; R ³ represents a CONHNR ⁷ R ⁸ group, wherein NR ⁷ R ⁸ represents a piperidino group, or R ³ represents a CONR ⁷ R ⁸ group, wherein R ⁷ is H, and R ⁸ is optionally halogenated or trifluoromethyl Base substituted pyridyl; and R ⁴ represents a C _1-3 alkyl group. 4. A compound of formula I represented by formula IA

where ^R1 is: a) a C _3-6 alkoxy group substituted by one or more fluorines, b) a phenyl (CH ₂ ) _p O- group, wherein p is 1, 2 or 3, and the phenyl ring is optionally replaced by 1 , 2 or 3 substituted by groups represented by Z, c) R ⁵ S(O) ₂ O group, wherein R ⁵ represents C _1-6 alkyl optionally substituted by one or more fluorine; R ^2a represents H or chlorine; R ^2b represents H or chlorine; R ³ represents a CONHNR ⁷ R ⁸ group, wherein NR ⁷ R ⁸ represents a piperidino group; and R ⁴ represents a C _1-3 alkyl group. 5. A compound of formula I represented by formula IA where ^R1 is: a) a C _3-6 alkoxy group substituted by one or more fluorines, or b) a R ⁵ S(O) ₂ O group, wherein R ⁵ represents a C _1-6 optionally substituted by one or more fluorines Alkyl, or ^R represents phenyl or heteroaryl, each optionally substituted by 1, 2 or 3 groups represented by Z; R ^2a represents chlorine; R ^2b represents chlorine; R ³ represents a CONHNR ⁷ R ⁸ group, wherein NR ⁷ R ⁸ represents a piperidino group; and R ⁴ represents a C _1-3 alkyl group. 6. The compound according to any one of the preceding claims, wherein ^R1 represents a ^R5S (O) _2O group, wherein ^R5 represents a _C1-6 alkyl group optionally substituted by one or more fluorines. 7. The compound of any one of claims 1-5, wherein R ¹ is C _4-6 alkoxy substituted with one or more fluorines. 8. The compound according to any one of claims 1-5, wherein ^R1 is a group of formula phenyl( _CH2 ) _pO- , wherein p is 1, 2 or 3. 9. ^The compound according to any one of claims 1-3, wherein ^R3 represents a ^CONHNR7R8 group, wherein ^NR7R8 represents a piperidino group ^. 10. The compound according to any one of the preceding claims, wherein R ⁴ represents C _1-6 alkyl. 11. A compound selected from one or more of the following compounds: 1) N-piperidin-1-yl-1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide; 2) 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidazol-1-yl]phenyl ethanesulfonic acid ester; 3) propane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidazol-1-yl]benzene base ester; 4) Butane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl)-imidazol-1-yl]benzene base ester; 5) N-piperidin-1-yl-2-(2,4-dichlorophenyl)-5-methyl-1-[4-(4,4,4-trifluorobutoxy)phenyl] -1H-imidazole-4-carboxamide; 6) 3,3,3-trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl) Imidazol-1-yl]phenyl ester; 7) 4,4,4-trifluorobutane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-(piperidin-1-ylcarbamoyl ) imidazol-1-yl] phenyl ester; 8) Thiophene-2-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H-imidazole-1- Base} phenyl ester; 9) Pyridine-3-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H-imidazole-1- Base} phenyl ester; 10) Pyridine-3-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H-imidazole-1- Base} phenyl ester; 11) 3-methylbutane-1-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl]-1H -imidazol-1-yl}phenyl ester; 12) 3,3-Dimethylbutane-1-sulfonic acid 4-{2-(2,4-dichlorophenyl)-5-methyl-4-[(piperidin-1-ylamino)carbonyl ]-1H-imidazol-1-yl}phenyl ester; 13) 3,3,3-trifluoropropane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-({[5-(trifluoromethyl) Pyridin-2-yl]amino}carbonyl)-1H-imidazol-1-yl]phenyl ester; and 14) 3-methylbutane-1-sulfonic acid 4-[2-(2,4-dichlorophenyl)-5-methyl-4-({[5-(trifluoromethyl)pyridine-2 -yl]amino}carbonyl)-1H-imidazol-1-yl]phenyl ester; and pharmaceutically acceptable salts thereof. 12. Compounds of formula I according to any one of claims 1 to 11 for use as medicaments. 13. A pharmaceutical formulation comprising a compound of formula I according to any one of claims 1-11 and a pharmaceutically acceptable adjuvant, diluent or carrier. 14. Use of the compound of formula I according to any one of claims 1-11 in the preparation of a medicament, wherein the medicament is used for the treatment or prevention of: obesity; psychotic disorders, such as psychotic disorders, schizophrenia and bipolar disorder disorders, anxiety disorders, anxiety-depressive disorders, depression, cognitive impairment, memory impairment, obsessive-compulsive disorder, anorexia, bulimia, attention disorders, epilepsy, and related disorders; and neurological disorders such as dementia, neurological disorders, Parkinson's disease, Huntington's disease, and Alzheimer's disease; immune, cardiovascular, reproductive, and endocrine disorders; septic shock; disorders related to the respiratory and gastrointestinal systems; and chronic abuse, addiction, and/or Indications for recurrence. 15. A method for the treatment of obesity; psychotic disorders, psychotic disorders, schizophrenia and bipolar disorders, anxiety disorders, anxiety-depressive disorders, depression, cognitive impairment, memory impairment, obsessive-compulsive Nervous disorders, anorexia, bulimia, attention disorders, epilepsy and related conditions; neurological disorders, neurological disorders, Parkinson's disease, Huntington's disease and Alzheimer's disease; immune, cardiovascular, reproductive and endocrine diseases; septic shock; diseases associated with the respiratory and gastrointestinal systems; and chronic abuse, addiction and/or relapse indications, the method comprising administering to a patient in need thereof a pharmacologically effective amount of any one of claims 1-11 The compound of formula I. 16. A compound as defined in any one of claims 1-11 for use in the treatment of obesity. 17. A process for the preparation of a compound according to any one of claims 1-11, said process comprising making the formula II compound wherein R ² , R ³ , R ⁴ , R ^a , m and n are as defined above; Reaction with a R ^1A -X group, where R ^1A represents a group such that R ^1A O represents R ¹ and X represents a leaving group.