5,6-bisaryl-2-pyridine-carboxamide derivatives, preparation thereof and therapeutic application thereof as urotensin II receptor antagonists

1. A compound corresponding to formula (I)

in which:

X is a nitrogen atom and Y is —CR4—, in which R4 represents a hydrogen atom or a (C1-C4) alkyl or alkoxy group;

A represents an unfused aryl group, said unfused aryl group optionally substituted with one or more groups selected from halogen atom, hydroxyl group, (C1-C4) alkyl, (C3-5) cycloalkyl, (C1-C4) alkoxy optionally substituted with a (C1-C4) alkoxy, haloalkyl or haloalkoxy group, and nitrile group;

W represents a halogen atom or a haloalkyl group;

Z represents a (C1-C4) alkylene group optionally substituted with one or more groups selected from halogen atom, (C1-C4) alkyl, hydroxyl, and (C1-C4) alkoxy groups;

B represents a group —NR4R5, in which R4 and R5 represent, independently of each other, a (C1-C4) alkyl group;

either, R1 represents a hydrogen atom and R2 represents a (C1-C4) alkyl group,

or R1 and R2 form, together with the carbon atom to which they are attached, a monocyclic or polycyclic system selected from a (C3-C8) cycloalkyl group, a bridged bicyclic group, and a bridged tetracyclic group, wherein said monocyclic or polycyclic system is optionally substituted with one or more hydroxyl groups;

either R3 represents a group C(O)R5 with R5 representing a (C1-C4) alkoxy group optionally substituted with a (C1-C4) alkoxy group or a group NR6R7, with R6 and R7, independently of each other, representing a hydrogen atom or a (C1-C4) alkyl, (C3-5) cycloalkyl, (C1-C4) alkylsulfonyl or haloalkyl group,

or R3 represents a group CH 2 XR8 in which:

X represents an oxygen atom and R8 represents a hydrogen atom or a (C1-C4) alkyl group,

or X represents an NH group and R8 represents a (C1-C4) alkylcarbonyl, (C1-C4) alkylcarboxyl or (C1-C4)alkylsulfonyl group,

or R3 represents a nitrile group (CN);

p represents an integer equal to 0 or 1,

wherein the compound can be in the form of a base or an addition salt with an acid or a base, and enantiomers and diastereoisomers thereof, including racemic mixtures thereof.

2. The compound of claim 1 , wherein:

R4 represents a hydrogen atom;

said unfused aryl group is optionally substituted with one or more groups selected from halogen atom, hydroxyl group, (C1-C4) alkyl, (C3-5) cycloalkyl, and (C1-C4) alkoxy optionally substituted with a (C1-C4) alkoxy, haloalkyl or haloalkoxy group;

W represents a halogen atom;

Z represents a (C1-C4) alkylene group;

either, R1 represents a hydrogen atom and R2 represents a (C1-C4) alkyl group,

or R1 and R2 form, together with the carbon atom to which they are attached, a monocyclic or polycyclic system selected from a (C3-C8) cycloalkyl group and a bridged tetracyclic group, wherein said monocyclic or polycyclic system is optionally substituted with one or more hydroxyl groups.

3. The compound of claim 1 wherein:

R4 represents a hydrogen atom;

said unfused aryl group is optionally substituted with one or more groups selected from halogen atom, (C1-C4) alkyl, (C3-5) cycloalkyl, (C1-C4) alkoxy and haloalkoxy;

W represents a halogen atom;

Z represents a (C1-C4) alkylene group;

either, R1 represents a hydrogen atom and R2 represents a (C1-C4) alkyl group,

or R1 and R2 form, together with the carbon atom to which they are attached, a (C3-C8) cycloalkyl group, optionally substituted with one or more hydroxyl groups, or an adamantyl group;

either R3 represents a group C(O)R5 with R5 representing a (C1-C4) alkoxy group optionally substituted with a (C1-C4) alkoxy group or a group NR6R7 with R6 representing a hydrogen atom and R7 representing a hydrogen atom or a (C1-C4) alkyl, (C3-C5) cycloalkyl, (C1-C4) alkylsulfonyl or haloalkyl group,

or R3 represents a group —CH 2 XR8 with X representing an oxygen atom and R8 representing a hydrogen atom or a (C1-C4) alkyl group.

4. A compound of claim 1 selected from:

methyl 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-phenyl) pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(2-methoxyethoxy)-2-methylphenyl)pyridin-2-yl)carbonyl}amino)cyclohexanecarboxylate;

methyl 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-cyclopropyl-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-isopropoxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-propoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethoxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylate;

methyl 1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(difluoromethoxy)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate;

methyl 1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)-5-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate;

methyl (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoate;

methyl (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoate;

methyl 2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-phenyl) pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylate;

2-methoxyethyl (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoate;

methyl (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoate;

ethyl (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoate;

isopropyl (3S)-3-({[6-}4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoate;

methyl (3S)-3({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoate;

N-[(1S)-1-(2-amino-2-oxoethyl)-2,2-dimethylpropyl]-6- {4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxamide;

6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-{(1S)-2,2-dimethyl- 1-[2-(methylamino)-2-oxoethyl]propyl}-5-(2-methylphenyl)pyridine-2-carboxamide;

6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1 S)-2,2-dimethyl- 1-{2-[(methylsulfonyl)amino]-2-oxoethyl}propyl]-5-(2-methylphenyppyridine-2-carboxamide;

6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-1-{2-[(1,1,1-trifluoroethyl)amino]-2-oxoethyl}-2,2-dimethylpropyl]-5-(2-methylphenyl)pyridine-2-carboxamide;

6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-1-{2-[cyclo-propyl (methyl)amino]-2-oxoethyl}-2,2-dimethylpropyl]-5-(2-methylphenyl)pyridine-2-carboxamide;

6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-1-(2-hydroxyethyl)-2,2-dimethylpropyl]-5-(2-methylphenyl)pyridine-2-carboxamide;

6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)- 1(2-methoxyethyl)-2,2-dimethylpropyl]-5-(2-methylphenyl)pyridine-2-carboxamide;

6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(2S)-1-cyano-3,3-dimethylbutan-2-yl]-5-(2-methylphenyl)pyridine-2-carboxamide;

methyl cis-1-({[6-{4-chloro-3-[3- (dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylate;

methyl cis-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-phenyl) pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylate; and

methyl cis-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethoxy-2-methylphenyl)pyridin-2-yl]carbonyllamino)-4-hydroxycyclohexanecarboxylate.

5. A process for preparing a compound of formula (I) of claim 1 comprising the step of reacting a compound of formula (II):

in which X, Y, Z, W, A and B are as defined in claim 1 , with a compound of formula (III):

in which R1, R2, R3, and p are as defined in claim 1 .

6. A process for preparing a compound of formula (I) of claim 1 comprising the step of reacting a compound of formula (IV):

in which X, Y, Z, W, A B, R1, R2, and p are as defined in claim 1 , with a compound of formula R5H wherein R5 is as defined in claim 1 .

7. A process for preparing a compound of formula (I) of claim 1 comprising the step of reacting a compound of formula (IV):

in which A, Y, X, R1, R2, p, W, Z and B are as defined in claim 1 , with a reducing agent.

8. A medicament comprising a compound of formula (I) as claimed in claim 1 , or an addition salt of said compound with a pharmaceutically acceptable acid or base, or alternatively an enantiomer, a diastereoisomer or a racemic mixture of said compound.

9. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 , or an addition salt of this compound with a pharmaceutically acceptable acid or base, an enantiomer, a diastereoisomer or a racemic mixture of this compound, and at least one pharmaceutically acceptable excipient.