N-azabicyclic carboxamide derivatives, preparation thereof and therapeutic use thereof

1. A compound corresponding to formula (I):

wherein:

X 1 , X 2 , X 3 and X 4 represent, independently of each other, a nitrogen atom or a group C—R 1 ; wherein when one from among X 1 , X 2 , X 3 and X 4 represents a nitrogen atom, the others correspond to a group C—R 1 ;

W represents an oxygen or sulfur atom;

n is equal to 0, 1, 2 or 3;

Y represents an aryl or a heteroaryl optionally substituted with one or more groups chosen from a halogen atom and a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, hydroxyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkylene-O—, C 1 -C 6 -fluoroalkoxy, cyano, C(O)NR 3 R 4 , nitro, NR 3 R 4 , C 1 -C 6 -thioalkyl, thiol, —S(O)—C 1 -C 6 -alkyl, —S(O) 2 —C 1 -C 6 -alkyl, SO 2 NR 3 R 4 , NR 5 C(O)R 6 ; NR 5 SO 2 R 7 , C(O)NR 3 R 4 , OC(O)NR 3 R 4 , —Si—(C 1 -C 6 -alkyl) 3 , —SF 5 , aryl-C 1 -C 5 -alkylene or aryl, heteroaryl-C 1 -C 5 -alkylene or heteroaryl; the groups C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy and C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkylene-O— being optionally substituted with a hydroxyl, C 1 -C 6 -alkoxy or NR 3 R 4 group; the aryl and heteroaryl groups being optionally substituted with one or more substituents R 8 , which may be identical to or different from each other;

A represents a bicyclic heteroaryl of formula:

wherein:

Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom, a nitrogen atom or a group C—R 2a ;

Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;

Z 8 represents a carbon atom;

wherein three, at most, from among Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom; one from among Z 1 , Z 2 , Z 3 and Z 4 , corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I);

R 1 is chosen from a hydrogen atom, a halogen atom, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, aryloxy-C 1 -C 6 -alkyl, heteroaryloxy-C 1 -C 6 -alkyl, aryl-C 1 -C 3 -alkylenoxy-C 1 -C 6 -alkyl, heteroaryl-C 1 -C 3 -alkylenoxy-C 1 -C 6 -alkyl, arylthio-C 1 -C 6 -alkyl, heteroarylthio-C 1 -C 6 -alkyl, aryl-C 1 -C 3 -alkylenethio-C 1 -C 6 -alkyl, heteroaryl-C 1 -C 3 -alkylenethio-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -fluoroalkoxy, cyano, C(O)NR 3 R 4 , nitro, NR 3 R 4 , C 1 -C 6 -thioalkyl, C 3 -C 7 -cycloalkylthio, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenethio, —S(O)—C 1 -C 6 -alkyl, —S(O)—C 3 -C 7 -cycloalkyl, —S(O)—C 1 -C 3 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 6 -alkyl-S(O) 2 —, C 1 -C 6 -fluoroalkyl-S(O) 2 —, C 3 -C 7 -cycloalkyl-S(O) 2 —, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene-S(O) 2 —, SO 2 NR 3 R 4 , (C 1 -C 6 -alkyl) 3 -Si—, —SF 5 , NR 5 C(O)R 6 , NR 5 SO 2 R 7 , C(O)NR 3 R 4 , OC(O)NR 3 R 4 , aryl, heteroaryl, aryl-C 1 -C 5 -alkylene, heteroaryl-C 1 -C 5 -alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio; the heteroaryl or aryl groups being optionally substituted with one or more substituents R 8 , which may be identical to or different from each other;

R 2a represents a hydrogen atom, a halogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene-O—, hydroxyl, thiol or C 1 -C 6 -fluoroalkoxy;

R 2b represents a hydrogen atom, a halogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, hydroxyl, thiol, oxo, thio, C 3 -C 7 -cycloalkyloxy, C 1 -C 6 -fluoroalkoxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -alkoxy-C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyloxy-C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy-C 1 -C 3 -alkylene, C 1 -C 6 -alkyl-C(O)—O—C 1 -C 3 -alkylene, C 1 -C 6 -alkyl-C(O)—O—, C 3 -C 7 -cycloalkyl-C(O)—O—C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyl-C(O)—O—, C 1 -C 6 -fluoroalkyl-C(O)—O—C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl-C(O)—O—, C(O)NR 3 R 4 , C(O)O—C 1 -C 6 -alkyl, cyano, CHO, CO 2 H, —C(O)—C 1 -C 6 -alkyl, —C(O)—C 3 -C 7 -cycloalkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 1 -C 6 -fluoroalkoxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -alkoxy-C 1 -C 3 -alkylene, C 3 -C 7 -cycloalkyloxy-C 1 -C 3 -alkylene and C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy-C 1 -C 3 -alkylene optionally being substituted with a hydroxyl, C 1 -C 6 -alkoxy or NR 3 R 4 group;

R 3 and R 4 represent, independently of each other, a hydrogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 5 -alkylene or aryl, or R 3 and R 4 together form, with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group; the group NR 3 R 4 being optionally substituted with a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 6 -alkylene, aryl, heteroaryl, aryl-S(O) 2 —, C 1 -C 6 -alkyl-S(O) 2 —, C 1 -C 6 -fluoroalkyl-S(O) 2 , C 3 -C 7 -cycloalkyl-S(O) 2 —, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene-S(O) 2 —, aryl-C(O)—, C 1 -C 6 -alkyl-C(O)—, C 3 -C 7 -cycloalkyl-C(O)—, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene-C(O)—, C 1 -C 6 -fluoroalkyl-C(O)—, hydroxyl, C 1 -C 6 -alkyloxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -fluoroalkyl, aryloxy-C 1 -C 6 -alkylene, aryloxy, heteroaryloxy-C 1 -C 6 -alkylene or heteroaryloxy;

R 5 and R 6 represent, independently of each other, a hydrogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 6 -alkylene or aryl; the aryl group being optionally substituted with one or more substituents chosen from a halogen atom and a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -fluoroalkoxy, nitro or cyano;

or R 5 and R 6 together form a 4- to 7-membered lactam comprising the nitrogen atom and the C(O) group that bear them;

R 7 represents a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, aryl-C 1 -C 6 -alkylene or aryl; the aryl group being optionally substituted with one or more substituents chosen from a halogen atom and a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -fluoroalkoxy, nitro or cyano;

or R 5 and R 7 together form a 4- to 7-membered sultam comprising the nitrogen atom and the S(O) 2 group that bear them;

R 8 represents a halogen atom or a group C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy, C 1 -C 6 -fluoroalkoxy, nitro, cyano, NR 3 R 4 , —C(O)—C 1 -C 6 -alkyl or —C(O)—C 3 -C 7 -cycloalkyl; the groups C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylene, C 1 -C 6 -fluoroalkyl, C 1 -C 6 -alkoxy, C 3 -C 7 -cycloalkyloxy and C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkylenoxy possibly being substituted with a group OH, C 1 -C 6 -alkoxy or NR 3 R 4 ;

the sulfur atom(s) of the compound of formula (I) optionally being in oxidized form; the nitrogen atom(s) of the compound of formula (I) optionally being in oxidized form; or an acid-addition salt thereof.

2. The compound of formula (I) according to claim 1 , wherein:

X 1 , X 2 , X 3 and X 4 represent, independently of each other, a group C—R 1 ; and

R 1 is as defined in formula (I) according to claim 1 ;

or an acid-addition salt thereof.

3. The compound of formula (I) according to claim 1 , wherein:

X 1 , X 2 and X 3 represent a group C—R 1 ; X 4 represents a nitrogen atom; and

R 1 is as defined in formula (I) according to claim 1 ;

or an acid-addition salt thereof.

4. The compound of formula (I) according to claim 1 , wherein R 1 is chosen from a hydrogen atom, a halogen atom and a group C 1 -C 6 -fluoroalkyl;

or an acid-addition salt thereof.

5. The compound of formula (I) according to claim 1 , wherein n is equal to 1;

or an acid-addition salt thereof.

6. The compound of formula (I) according to claim 1 , wherein Y represents an aryl optionally substituted with one or more halogen atoms;

or an acid-addition salt thereof.

7. The compound of formula (I) according to claim 1 , wherein W represents an oxygen atom;

or an acid-addition salt thereof.

8. The compound of formula (I) according to claim 1 , wherein:

A represents a bicyclic heteroaryl of formula:

wherein:

Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom or a nitrogen atom;

Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;

Z 8 represents a carbon atom;

wherein two, at most, from among Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom;

one from among Z 1 , Z 2 , Z 3 and Z 4 , corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I); and

R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, C(O)O—C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl optionally being substituted with a hydroxyl or C 1 -C 6 -alkoxy group;

or an acid-addition salt thereof.

9. The compound of formula (I) according to claim 1 , wherein:

A represents the group:

R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, C(O)O—C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl possibly being substituted with a hydroxyl or C 1 -C 6 -alkoxy group;

or an acid-addition salt thereof.

10. The compound of formula (I) according to claim 1 , wherein:

A represents the group:

R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl optionally being substituted with a hydroxyl or C 1 -C 6 -alkoxy group;

or an acid-addition salt thereof.

11. The compound of formula (I) according to claim 1 , wherein:

X 1 , X 2 , X 3 and X 4 represent, independently of each other, a group C—R 1 ; or alternatively X 1 , X 2 and X 3 represent a group C—R 1 ; X 4 represents a nitrogen atom;

R 1 is chosen from a hydrogen atom, a halogen atom or a group C 1 -C 6 -fluoroalkyl;

n is equal to 1;

Y represents an aryl optionally substituted with one or more halogen atoms;

W represents an oxygen atom;

A represents a bicyclic heteroaryl of formula:

wherein:

Z 1 , Z 2 , Z 3 and Z 4 represent, independently of each other, a carbon atom or a nitrogen atom;

Z 5 , Z 6 and Z 7 represent, independently of each other, a nitrogen atom or a group C—R 2b ;

Z 8 represents a carbon atom;

wherein two, at most, from among Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 represent a nitrogen atom;

one from among Z 1 , Z 2 , Z 3 and Z 4 , corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I); and

R 2b represents a hydrogen atom or a group C 1 -C 6 -alkyl, C(O)O—C 1 -C 6 -alkyl, phenyl or thienyl; the groups C 1 -C 6 -alkyl optionally being substituted with a hydroxyl or C 1 -C 6 -alkoxy group;

or an acid-addition salt thereof.

12. The compound of formula (I) according to claim 1 , chosen from:

N-(2,3-Dimethylimidazo[1,2-c]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2,3-Dimethylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-[2-(Hydroxymethyl)imidazo[1,2-a]pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(3-Methyl-2-phenylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-Ethylimidazo[1,2-c]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl-1H-indole-2-carboxamide;

N-[2-(Thien-2-yl)imidazo[1,2-a]pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-tert-Butylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-Methoxymethylimidazo[1,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-[2-(Hydroxymethyl)imidazo[1,2-a]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-Methyl-3-phenylimidazo[1,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-[2-(Thien-2-ylimidazo[1,2-c]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-Ethylimidazo[1,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl-1H-indole-2-carboxamide;

N-(2-tert-Butylimidazo[1,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2,3-Dimethylimidazo[1,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-Ethylimidazo[1,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

N-(2,3-Dimethylimidazo[1,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

N-[2-(Hydroxymethyl)imidazo[1,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-[2-(Hydroxymethyl)imidazo[1,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

N-(2-Methylimidazo[1,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-Methylpyrazolo[1,5-a]pyrimidin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-[2-(Ethyloxycarbonyl)imidazo[1,2-b]pyridazin-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-[(2-(Ethyloxycarbonyl)imidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

N-(2-Methylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide; and

N-([1,2,4]Triazolo[1,5-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide;

or an acid-addition salt thereof, or a hydrate or solvate thereof.

13. A process for preparing a compound of formula (I) according to claim 1 , comprising reacting a compound of formula (II):

in which X 1 , X 2 , X 3 , X 4 , n, Y and W are as defined in formula (I) according to claim 1 , with a compound of formula (III):

in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are as defined in formula (I) according to claim 1 : and

when B represents an NH 2 group and D represents a leaving group,

either in the presence of a copper salt in catalytic amount, a copper ligand in catalytic amount and a base, in a solvent; or in the presence of a catalytic amount of a palladium derivative, a catalytic amount of a palladium ligand and a base, in a refluxing solvent;

when B represents a hydroxyl group and D represents an NH 2 group, in the presence of a coupling agent in a solvent; or

when B is a chlorine atom and D represents an NH 2 group, in a solvent.

14. A process for preparing a compound of formula (I) according to claim 1 , in which W represents an oxygen atom and A represents a group:

comprising reacting a compound of formula (V):

in which X 1 , X 2 , X 3 , X 4 , n and Y are as defined in formula (I) according to claim 1 and PG represents a hydrogen atom,

with a compound of formula (IV):

in which X represents a leaving group and R 2b is as defined in formula (I) according to claim 1 .

15. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable acid addition salt thereof, in combination with at least one pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising a compound of formula (I) according to claim 9 , or a pharmaceutically acceptable acid addition salt thereof, in combination with at least one pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a compound of formula (I) according to claim 12 , or a pharmaceutically acceptable acid addition salt thereof, in combination with at least one pharmaceutically acceptable excipient.