Indazolecarboxamide derivatives, preparation and use thereof as CDK1, CDK2 and CDK4 inhibitors

1. A compound corresponding to general formula (I):

in which,

R 1 represents

a heteroaromatic group optionally substituted with one or two substituents selected from a halogen atom, a hydroxyl, a heteroaromatic group, C 1-6 alkyl, NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 and CH 2 XR 2 where X represents an atom selected from O, NH and S; and

Ar represents

a heteroaromatic group, optionally substituted with one or two substituents selected from a halogen atom, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, NH 2 , NHR 2 , NR 2 R 3 , NHSO 2 R 2 , CN, SO 2 R 2 , SO 2 NH 2 , SO 2 NHR 2 , COOH, COOR 2 , CONH 2 , CONHNH 2 , CONHR 2 , CH 2 NHR 2 and CH 2 NR 2 R 3 ; and wherein

R 2 and R 3 represent, independently of each other, a C 1-6 alkyl optionally substituted with a CONH 2 group, with a phenyl or with a heteroaromatic group; or R 2 and R 3 represent, independently of each other, a phenyl or a heteroaromatic group; and

n represents 0, 1, 2 or 3; or a salt thereof, or a hydrate or a solvate thereof.

2. The compound according to claim 1 , wherein:

R 1 represents

a heteroaromatic group optionally substituted with one or two substituents selected from a halogen atom, a hydroxyl, a heteroaromatic group, C 1-6 alkyl, NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 and CH 2 XR 2 where X represents an atom selected from O, NH and S;

Ar represents

a heteroaromatic group, optionally substituted with one or two substituents selected from a halogen atom, C 1-6 thioalkyl, C 1-6 alkoxy, CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, NH 2 , NHR 2 , NR 2 R 3 , NHSO 2 R 2 , CN, SO 2 R 2 , SO 2 NH 2 , SO 2 NHR 2 , COOH, COOR 2 , CONH 2 , CONHNH 2 , CONHR 2 , CH 2 NHR 2 and CH 2 NR 2 R 3 ; and wherein

R 2 and R 3 represent, independently of each other, a C 1-6 alkyl optionally substituted with a CONH 2 group, with a phenyl or with a heteroaromatic group; or R 2 and R 3 represent, independently of each other, a phenyl or a heteroaromatic group; and

n represents 0, 1, or 2; or a salt thereof, or a hydrate or a solvate thereof.

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

when R 1 represents

a heteroaromatic group optionally substituted with one or two substituents selected from a halogen atom, a hydroxyl, a heteroaromatic group, C 1-6 alkyl, NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 and CH 2 XR 2 where X represents an atom selected from O, NH and S;

then Ar represents

a heteroaromatic group, optionally substituted with one or two substituents selected from a halogen atom, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, NH 2 , NHR 2 , NR 2 R 3 , NHSO 2 R 2 , CN, SO 2 R 2 , SO 2 NH 2 , SO 2 NHR 2 , COOH, COOR 2 , CONH 2 , CONHNH 2 , CONHR 2 , CH 2 NHR 2 and CH 2 NR 2 R 3 ; and wherein

R 2 and R 3 represent, independently of each other, a C 1-6 alkyl optionally substituted with a CONH 2 group, with a phenyl or with a heteroaromatic group; or R 2 and R 3 represent, independently of each other, a phenyl or a heteroaromatic group; and

n represents 0 or 1; or a salt thereof, or a hydrate or a solvate thereof.

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

when R 1 represents

a heteroaromatic group chosen from pyrazolyl, tetrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl or pyrrolo [2,3-c]pyridinyl, optionally substituted with one or two substituents chosen from a chlorine or a fluorine, a hydroxyl, a pyridinyl, a methyl, NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 and CH 2 OR 2 ;

then Ar represents

pyridinyl, optionally substituted with a C 1-6 alkoxy; and wherein

R 2 represents a methyl, an ethyl or a 2-methylpropyl, optionally substituted with a group CONH 2 or with a phenyl; or R 2 represents a phenyl or a heteroaromatic group chosen from a pyridinyl or a pyrimidinyl; and

n represents 0 or 1;

or a salt thereof, or a hydrate or a solvate thereof.

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

R 1 represents a heteroaromatic group optionally substituted with one or two substituents chosen from a halogen atom, a hydroxyl, a heteroaromatic group, C 1-6 alkyl, NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 and CH 2 XR 2 where X represents an atom chosen from O, NH and S;

Ar represents

a heteroaromatic group, optionally substituted with one or two substituents chosen from fluorine, chlorine, methoxy, CH 2 OH, phenoxy, morpholinyl, —CH 2 -morpholinyl, NH 2 , NHSO 2 CH 3 , CN, SO 2 CH 3 , SO 2 NH 2 , SO 2 NH-pyrimidinyl, COOH, CONH 2 , CONHNH 2 , CH 2 NHC 2 H 5 and CH 2 N(CH 2 H 5 ) 2 ; and

n represents 0, 1, 2 or 3;

or a salt thereof, or a hydrate or a solvate thereof.

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

R 1 represents a heteroaromatic group chosen from pyrazolyl, thiazolyl, oxazolyl, pyridinyl, isoquinolinyl or pyrrolo[2,3-c]pyridinyl, optionally substituted with one or two substituents chosen from a chlorine,

a pyridinyl, methyl, NH 2 and CONHR 2 ;

Ar represents

a pyridinyl, optionally substituted with a methoxy;

R 2 represents a methyl or an ethyl, optionally substituted with a group CONH 2 , or with a phenyl; or R 2 represents a pyridinyl or a pyrimidinyl; and

n represents 0 or 1;

or a salt thereof, or a hydrate or a solvate thereof.

7. The compound of formula (I) according to claim 1 , which is selected from the group consisting of:

—N-(pyridin-4-yl)-5-pyridin-3-yl-1H-indazole-3-carboxamide hydrochloride;

—N-(pyridin-4-yl)-5-(4-methyl-[3,4′]bipyridinyl-5-yl)-1H-indazole-3-carboxamide hydrochloride;

—N-(pyridin-4-yl)-5-isoquinolin-4-yl-1H-indazole-3-carboxamide;

—N-(pyridin-3-ylmethyl)-5-isoquinolin-4-yl-1H-indazole-3-carboxamide;

—N-(pyridin-4-yl)-5-[4-methyl-5-(pyridin-3-ylcarbamoyl)pyridin-3-yl]-1H-indazole-3-carboxamide;

—N-(pyridin-4-yl)-5-(4-methyl-[3,3′]bipyridinyl-5-yl)-1H-indazole-3-carboxamide;

—N-(pyridin-4-yl)-5-(1,3-thiazol-5-yl)-1H-indazole-3-carboxamide;

—N-(pyridin-4-yl)-5-(1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-indazole-3-carboxamide;

-5-(1H-pyrazol-4-yl)-N-(pyridin-4-yl)-1H-indazole-3-carboxamide;

—N-(pyridin-4-yl)-5-[(2-chloro)pyridin-5-yl]-1H-indazole-3-carboxamide;

-5-(1,3-oxazol-5-yl)-N-(pyridin-4-yl)-1H-indazole-3-carboxamide;

-5-(5-amino-4-methylpyridin-3-yl)-N-(pyridin-4-yl)-1H-indazole-3-carboxamide;

—N-(pyridin-4-yl)-5-(3-(N-aminoketomethyl)carboxamide)pyridin-4-yl-1H-indazole-3-carboxamide;

—N-(pyridin-3-ylmethyl)-5-(1,3-thiazol-5-yl)-1H-indazole-3-carboxamide;

—N-(pyridin-3-ylmethyl)-5-pyridin-3-yl-1H-indazole-3-carboxamide;

-5-(4-hydroxy-3-methylpyridin-2-yl)-N-pyridin-4-yl-1H-indazole-3-carboxamide;

—N-(2-methoxypyridin-5-yl)-5-(1,3-oxazol-5-yl)-1H-indazole-3-carboxamide;

or a salt thereof, or a hydrate or a solvate thereof.

8. A method for preparing a compound of general formula (I) of claim 1 , comprising the step consisting in deprotecting a compound of general formula (VII)

in which R 1 , Ar and n are as defined in general formula (I) according to claim 1 and PG represents a protecting group of the trimethylsilylethoxymethyl (SEM) or mesitylenesulphonyl (Mts) type,

either by the action of a base such as sodium hydroxide, or in the presence of tetrabutylammonium fluoride (TBAF) and ethylenediamine, or alternatively in the presence of trifluoroacetic acid followed by heating with ethylenediamine.

9. The method of preparation according to claim 8 , wherein the compound of general formula (VII),

in which R 1 , Ar and n are as defined in general formula (I) according to claim 1 and PG represents a protecting group of the trimethylsilylethoxymethyl (SEM) or mesitylenesulphonyl (Mts) type,

is prepared by coupling a compound of general formula (V)

in which R 1 is as defined in general formula (I) according to claim 1 and PG represents a protecting group of the trimethylsilylethoxymethyl (SEM) or mesitylenesulphonyl (Mts) type,

with an amine of general formula Ar(CH 2 )nNH 2 (VI) in which Ar and n are as defined in general formula (I) according to claim 1 , it being possible for the coupling reaction to be carried out by activating the compound of general formula (V) with coupling reagents, such as carbonyldiimidazole or isopropyl or isobutyl chloroformate.

10. A compound of general formula (V)

in which

R 1 represents

a heteroaromatic group optionally substituted with one or two substituents selected from a halogen atom, a hydroxyl, a heteroaromatic group, C 1-6 alkyl, NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 and CH 2 XR 2 where X represents an atom selected from O, NH and S; and

PG represents a protecting group of the trimethylsilylethoxymethyl (SEM) or mesitylenesulphonyl (Mts) type.

11. A compound of general formula (VII)

in which

R 1 represents

a heteroaromatic group optionally substituted with one or two substituents selected from a halogen atom, a hydroxyl, a heteroaromatic group, C 1-6 alkyl, NH 2 , NHR 2 , NHCOR 2 , COOR 2 , CONH 2 , CONHR 2 and CH 2 XR 2 where X represents an atom selected from O, NH and S;

Ar represents

a heteroaromatic group, optionally substituted with one or two substituents selected from a halogen atom, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, CH 2 OH, phenoxy, morpholinyl, NH 2 , NHR 2 , NR 2 R 3 , NHSO 2 R 2 , CN, SO 2 R 2 , SO 2 NH 2 , SO 2 NHR 2 , COOH, COOR 2 , CONH 2 , CONHNH 2 , CONHR 2 and CH 2 NHR 2 ; and wherein

R 2 and R 3 represent, independently of each other, a C 1-6 alkyl optionally substituted with a CONH 2 , a phenyl or a heteroaromatic group; or R 2 and R 3 represent, independently of each other, a phenyl or a heteroaromatic group;

n represents 0, 1, 2 or 3; and

PG represents a protecting group of the trimethylsilylethoxymethyl (SEM) or mesitylenesuiphonyl (Mts) type.

12. A compound of general formula (X)

in which

Ar represents

a heteroaromatic group, optionally substituted with one or two substituents selected from a halogen atom, C 1-6 alkyl, C 1-6 thioalkyl, C 1-6 alkoxy, CH 2 OH, phenoxy, morpholinyl, NH 2 , NHR 2 , NR 2 R 3 , NHSO 2 R 2 , CN, SO 2 R 2 , SO 2 NH 2 , SO 2 NHR 2 , COOH, COOR 2 , CONH 2 , CONHNH 2 , CONHR 2 and CH 2 NHR 2 ; and wherein

R 2 and R 3 represent, independently of each other, a C 1-6 alkyl optionally substituted with a CONH 2 , a phenyl or a heteroaromatic group; or R 2 and R 3 represent, independently of each other, a phenyl or a heteroaromatic group;

n represents 0, 1, 2 or 3;

SEM represents a protecting group of trimethylsilylethoxymethyl type; and

X represents a bromine or iodine atom.

13. A pharmaceutical composition comprising at least one compound of general formula (I) according to claim 1 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with one or more pharmaceutically acceptable excipients.