4-cyanopyrazole-3-carboxamide derivatives, preparation, and application thereof
View Patent ↗The invention relates to 4-cyanopyrazole-3-carboxamide derivatives of formula (I): in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as described herein. Also disclosed and claimed are the method of preparation and therapeutic application of compound of formula (I).
1. A compound of formula (I):
in which:
R 1 represents hydrogen or a (C 1 -C 4 )alkyl;
R 2 represents:
an NR 9 R 10 group;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 represent, each independently of the other, a hydrogen, halogen, a (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or trifluoromethyl; provided that at least one of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is different from hydrogen;
R 9 represents a hydrogen atom;
R 10 represents a (C 3 -C 6 )alkyl;
or R 9 and R 10 together with the nitrogen atom to which they are attached constitute a saturated or unsaturated heterocyclic radical of 5 to 10 atoms, optionally containing a second heteroatom chosen from O or N, said radical being unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl, hydroxyl, (C 1 -C 4 )alkoxy, methoxy(C 1 -C 2 )alkylene, (C 1 -C 4 )alkanoyl group or substituted with a spirocyclobutane, a spirocyclopentane or a spirocyclohexane; or
a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof.
2. The compound of formula (I), as set forth in claim 1 , wherein:
R 1 represents hydrogen or a (C 1 -C 4 )alkyl;
R 2 represents an NR 9 R 10 group in which R 9 and R 10 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is unsubstituted or disubstituted with a 4,4-dimethyl group or substituted at the 4-position with a spirocyclopentane group;
at least one of the substituents R 3 , R 4 or R 5 represents a halogen atom, a methyl or methoxy; and
at least one of the substituents R 6 , R 7 or R 8 represents a halogen atom or a methyl; or
a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof.
3. The compound of formula (I), as set forth in claim 1 , wherein:
R 1 represents hydrogen;
R 2 represents an NR 9 R 10 group in which R 9 and R 10 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is unsubstituted or disubstituted with a 4,4-dimethyl group or substituted at the 4-position with a spirocyclopentane group;
R 3 is at the 4-position and represents chlorine, bromine or methoxy;
R 4 and R 5 are hydrogen;
R 6 and R 7 are at the 2,4-position and represent 2 chlorine atoms; and
R 8 is hydrogen; or
a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof.
4. The compound, as set forth in claim 1 , chosen from:
5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide and
5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide; or
a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof.
5. A method for preparing a compound of formula (I) as set forth in claim 1 , comprising reacting 4-cyano-1,5-diphenylpyrazole-3-carboxylic acid of formula II or a functional derivative thereof:
in which R 3, R 4 , R 5 , R 6 , R 7 , R 8 are as defined in claim 1 , with an amine of formula HNR 1 R 2 (III) in which R 1 and R 2 are as defined in claim 1 .
6. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, a hydrate or a solvate thereof, in combination with at least one pharmaceutically acceptable excipient:
in which:
R 1 represents hydrogen or a (C 1 -C 4 )alkyl;
R 2 represents:
an NR 9 R 10 group;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 represent, each independently of the other, a hydrogen, halogen, a (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or trifluoromethyl; provided that at least one of the substituents R 3 , R 4 , R 5 , R 6 , R 7 , R 8 is different from hydrogen;
R 9 represents a hydrogen atom;
R 10 represents a (C 3 -C 6 )alkyl;
or R 9 and R 10 together with the nitrogen atom to which they are attached constitute a saturated or unsaturated heterocyclic radical of 5 to 10 atoms, optionally containing a second heteroatom chosen from O or N, said radical being unsubstituted or substituted once or several times with a (C 1 -C 4 )alkyl, hydroxyl, (C 1 -C 4 )alkoxy, methoxy(C 1 -C 2 )alkylene, (C 1 -C 4 )alkanoyl group or substituted with a spirocyclobutane, a spirocyclopentane or a spirocyclohexane.
7. The composition as set forth in claim 6 wherein:
R 1 represents hydrogen or a (C 1 -C 4 )alkyl;
R 2 represents an NR 9 R 10 group in which R 9 and R 10 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is unsubstituted or disubstituted with a 4,4-dimethyl group or substituted at the 4-position with a spirocyclopentane group;
at least one of the substituents R 3 , R 4 or R 5 represents a halogen atom, a methyl or methoxy; and
at least one of the substituents R 6 , R 7 or R 8 represents a halogen atom or a methyl.
8. The composition as set forth in claim 6 , wherein:
R 1 represents hydrogen;
R 2 represents an NR 9 R 10 group in which R 9 and R 10 together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is unsubstituted or disubstituted with a 4,4-dimethyl group or substituted at the 4-position with a spirocyclopentane group;
R 3 is at the 4-position and represents chlorine, bromine or methoxy;
R 4 and R 5 are hydrogen;
R 6 and R 7 are at the 2,4-position and represent 2 chlorine atoms; and
R 8 is hydrogen.
9. The composition as set forth in claim 6 , wherein said compound is chosen from:
5-(4-chlorophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide and
5-(4-bromophenyl)-4-cyano-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-pyrazole-3-carboxamide; or
a pharmaceutically acceptable salt thereof or a hydrate or a solvate thereof.