Diphenyl-pyrazolopyridine derivatives, preparation thereof, and use thereof as nuclear receptor not modulators
The invention relates to a formula (I), in which R is a hydrogen or halogen atom or a (C1-C6)alkyl group; X is one or more substituents selected from a hydrogen or halogen atom, a (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, cyano, hydroxy, or hydroxy(C1-C6)alkyl group; Y is a hydrogen or halogen atom or a (C1-C6)alkyl group; R1 is an NR2R3 or OR4 group; R2 and R3 independently are a hydrogen atom, a (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl group or R2 and R3, together with the nitrogen atom supporting the same, form a heterocycle optionally substituted by a (C1-C6)alkyl, hydroxy or oxo group; and R4 is a (C1-C6)alkyl, hydroxy(C1-C6)alkyl, or oxo(C1-C6)alkyl group, in the base or acid addition salt state. Said formula can be used therapeutically for treating or preventing diseases linked to the nuclear receptors Nurr-1, also known as NR4A2, NOT, TINUR, RNR-1, and HZF3.
1. A compound of formula (I):
in which:
R represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
X represents one or more substituents chosen from a hydrogen or halogen atom and a group (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, cyano, hydroxyl or hydroxy(C1-C6)alkyl;
Y represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
R1 represents a group NR2R3 or OR4;
R2 and R3 represent, independently of each other, a hydrogen atom or a group (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl, or alternatively R2 and R3 form, with the nitrogen atom that bears them, a heterocycle optionally substituted with a group (C1-C6)alkyl, hydroxyl or oxo,
R4 represents a group (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl, in the form of base or of acid-addition salt.
2. The compound according to claim 1 , wherein
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a halogen atom and a group (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
R1 represents a group OR4,
R4 represents a methyl group, in the form of base or of acid-addition salt.
3. The compound according to claim 1 , wherein
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
Y represents a hydrogen, chlorine or fluorine atom or a methyl group,
R1 represents a group OR4,
R4 represents a methyl group, in the form of base or of acid-addition salt.
4. The compound according to claim 1 , wherein
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a halogen atom and a group (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
R1 represents a group NR2R3,
R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl, isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl group, in the form of base or of acid-addition salt.
5. The compound according to claim 1 , wherein
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl, trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
Y represents a hydrogen or chlorine atom or a methyl group,
R1 represents a group NR2R3,
R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl, isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl group, in the form of base or of acid-addition salt.
6. The compound according to claim 1 corresponding to the following formulae:
Methyl 3-[2-(4-chlorophenyl)pyrazolo[1,5-α]pyridin-5-yl]benzoate
3-[2-(4-Chlorophenyl)pyrazolo[1,5-α]pyridin-5-yl]benzamide
3-[2-(4-Chlorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N,N-dimethylbenzamide
3-[2-(4-Chlorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
Methyl 3-[2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]benzoate
3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-isopropylbenzamide
3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N,N-dimethylbenzamide
{3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]phenyl}morpholin-4-yl-methanone
3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-2,N-dimethylbenzamide
2-Chloro-5-[2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
4-Chloro-3-[2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-4,N-dimethylbenzamide
2-Fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
N-Cyclopropyl-3-[2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]benzamide
{3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]phenyl}pyrrolidin-1-ylmethanone
3-[2-(2,6-Difluorophenyl)pyrazolo[1,5-α]pyridin-5-yl-methylbenzamide
3-[2-(2-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
N-Methyl-3-[2-(4-trifluoromethylphenyl)pyrazolo[1,5-α]pyridin-5-yl]benzamide
4-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
2-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
{3-[2-(4-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]phenyl}-(3-hydroxypyrrolidin-1-yl)methanone
3-[2-(2,4-Difluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
N-Methyl-3-[2-(4-trifluoromethoxyphenyl)pyrazolo[1,5-α]pyridin-5-yl]benzamide
3-[2-(3,4-Difluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
3-[2-(3,5-Difluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
3-[2-(3-Fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
N-Methyl-3-(2-p-tolylpyrazolo[1,5-α]pyridin-5-yl)benzamide
3-[2-(4-Methoxyphenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
3-[2-(3,4-Dimethylphenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
3-[2-(4-Cyanophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
3-[2-(2,3-Difluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide
N-Methyl-3-(2-o-tolylpyrazolo[1,5-α]pyridin-5-yl)benzamide
3-[3-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-yl]-N-methylbenzamide.
7. A pharmaceutical composition comprising the compound of claim 1 , or an addition salt of said compound with a pharmaceutically acceptable acid.
8. The pharmaceutical composition of claim 7 further comprising at least one pharmaceutically acceptable excipient.