FGF receptor (FGFR) agonist dimeric compounds, process for the preparation thereof and therapeutic use thereof

1. FGF receptor agonist compounds corresponding to the general formula:

M 1 -L-M 2

in which M 1 and M 2 , which may be identical or different, each represent, independently of one another, a monomer unit M and L represents a linker group which links M 1 and M 2 covalently, characterized in that said monomer unit corresponds to the general formula M which follows:

in which:

the asterisk * indicates the site of linkage between the monomer and the linker L, said linkage site of each monomer unit M 1 and M 2 being located on one of the substituents R or R 2 ,

R represents a hydrogen atom (in which case the site of linkage of L with M is located on R 2 ) or a group —CONH*,

R 1 represents a hydrogen atom or a linear (C 1 -C 3 )alkyl group,

R 2 represents a group —CONH 2 (in which case the site of linkage of L with M is located on R) or —CONH*,

R 3 represents a group —CO 2 R 4 , where R 4 represents a hydrogen atom or a linear (C 1 -C 4 )alkyl group, and

X is a halogen atom chosen from fluorine, chlorine and bromine atoms,

in the form of a base or of an addition salt with an acid or with a base.

2. FGF receptor agonist compounds according to claim 1 , characterized in that R 1 represents a hydrogen atom, in the form of a base or of an addition salt with an acid or with a base.

3. FGF receptor agonist compounds according to claim 1 , characterized in that R 3 represents a group —CO 2 R 4 , with R 4 representing a hydrogen atom, in the form of a base or of an addition salt with an acid or with a base.

4. FGF receptor agonist compounds according to claim 1 , characterized in that X represents a fluorine atom, in the form of a base or of an addition salt with an acid or with a base.

5. FGF receptor agonist compounds according to claim 1 , characterized in that:

R represents a group —CONH*, where the asterisk * indicates the site of linkage of L, firstly, with the monomer unit M 1 and, secondly, with the monomer unit M 2 ,

R 1 represents a hydrogen atom or a linear (C 1 -C 3 )alkyl group and advantageously a hydrogen atom, in the form of a base or of an addition salt with an acid or with a base.

6. FGF receptor agonist compounds according to claim 1 , characterized in that R is located in the meta or para position, in the form of a base or of an addition salt with an acid or with a base.

7. FGF receptor agonist compounds according to claim 1 , characterized in that:

R represents a hydrogen atom,

R 2 represents a group —CONH*, where the asterisk * indicates the site of linkage of L, firstly, with the monomer unit M 1 and, secondly, with the monomer unit M 2 ,

in the form of a base or of an addition salt with an acid or with a base.

8. FGF receptor agonist compounds according to claim 1 , characterized in that the linker group L can be more particularly chosen from the following PEG radicals:

in which

the asterisk * indicates the atom for linkage of L with the monomer unit M on the substituent R* or R 2 *;

n represents an integer from 2 to 6, in the form of a base or of an addition salt with an acid or with a base.

9. FGF receptor agonist compounds according to claim 1 , characterized in that n is an integer of 3 or 4, in the form of a base or of an addition salt with an acid or with a base.

10. Compound according to claim 1 , characterized in that it is chosen from:

Compound No. 1: 3,3′-{ethane-1,2-diylbis[oxypropane-3,1-diylcarbamoyl(3-phenyl-1H-pyrazolo[3,4-b]pyridine-4,6-diyl)]}bis(6-fluorobenzoic acid);

Compound No. 2: 5-[4-({15-[6-(3-carboxy-4-fluorophenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-15-oxo-4,7,10-trioxa-14-azapentadec-1-yl}carbamoyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-2-fluorobenzoic acid;

Compound No. 3: 5-[4-({16-[6-(3-carboxy-4-fluorophenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-16-oxo-3,6,9,12-tetraoxa-15-azahexadec-1-yl}carbamoyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-2-fluorobenzoic acid;

Compound No. 4: 5-[4-({19-[6-(3-carboxy-4-fluorophenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-19-oxo-3,6,9,12,15-pentaoxa-18-azanonadec-1-yl}carbamoyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-2-fluorobenzoic acid;

Compound No. 5: 5-[4-({21-[6-(3-carboxy-4-fluorophenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-21-oxo-4,7,10,13,16-pentaoxa-20-azahenicos-1-yl}carbamoyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-2-fluorobenzoic acid;

Compound No. 6: 5-(4-carbamoyl-3-{3-[(15-{3-[4-carbamoyl-6-(3-carboxy-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]phenyl}-15-oxo-4,7,10-trioxa-14-azapentadec-1-yl)carbamoyl]phenyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorobenzoic acid;

Compound No. 7: 3,3′-{ethane-1,2-diylbis[oxyethane-2,1-diylcarbamoylbenzene-3,1-diyl(4-carbamoyl-1H-pyrazolo[3,4-b]pyridine-3,6-diyl)]}bis(6-fluorobenzoic acid);

Compound No. 8: 5-(4-carbamoyl-3-{4-[(15-{4-[4-carbamoyl-6-(3-carboxy-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]phenyl}-15-oxo-4,7,10-trioxa-14-azapentadec-1-yl)carbamoyl]phenyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorobenzoic acid; and

Compound No. 9: 3,3′-{ethane-1,2-diylbis[oxyethane-2,1-diylcarbamoylbenzene-4,1-diyl(4-carbamoyl-1H-pyrazolo[3,4-b]pyridine-3,6-diyl)]}bis(6-fluorobenzoic acid).

11. Process for preparing an FGF receptor agonist compound according to claim 1 , comprising the reaction of at least one monomer comprising at least one carboxylic acid group with a reactant of formula H 2 N-L-NH 2 after activation.

12. A pharmaceutical composition comprising an FGF receptor agonist compound according to claim 1 , or an addition salt of this compound with a pharmaceutically acceptable acid or base of this compound.

13. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt of this compound, and also at least one pharmaceutically acceptable excipient.