Heteroarylamide pyrimidone derivatives

1. A compound of the formula (I) or a salt thereof:

wherein:

X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1-2 alkyl group and a hydrogen atom;

Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C 1-3 alkyl group, a sulfur atom, a methylene group optionally substituted by one or two groups chosen from a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-2 perhalogenated alkyl group or an amino group;

R1 represents a 2, 4 or 5-pyrimidine ring or a 4-pyridine ring, the ring being optionally substituted by a C 1-6 alkyl group, a C 1-6 alkoxy group or a halogen atom;

R2 represents a 4-15 membered heterocyclic group, this group being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-6 halogenated alkyl group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-2 perhalogenated alkoxy group, a C 1-6 halogenated alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group, a C 2-12 dialkylamino group, a S—(C 1-6 -alkyl) group, an heterocyclic group, an aryl group, an heteroaryl group, a O-aryl group or a S-aryl group, the above-mentioned groups being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group, a C(O)O (C 1-6 -alkyl) or a C(O)O (aryl) group, the aryl optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group;

R3 represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom;

R4 represents a hydrogen atom or a C 1-6 alkyl group;

R5 represents a hydrogen atom, a C 1-6 alkyl group;

R6 represents a hydrogen atom, a C 1-6 alkyl group;

R7 represents a hydrogen atom or a C 1-6 alkyl group; and

n represents 0 to 3 and m represents 0.

2. The compound according to claim 1 , wherein R1 represents an unsubstituted 4-pyrimidine ring.

3. The compound according to claim 1 , wherein:

R1 represents a 4- or 5-pyrimidine ring or 4-pyridine ring; the ring being optionally substituted by a C 1-2 alkyl group, a C 1-2 alkoxy group or a halogen atom;

R2 represents a 6-10 membered heterocyclic group, this group being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-6 halogenated alkyl group, a hydroxyl group, a C 1-6 alkoxy group, a C 1-2 perhalogenated alkoxy group, a C 1-6 halogenated alkoxy group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group, a C 2-12 dialkylamino group, a S—(C 1-6 -alkyl) group, an heterocyclic group, an aryl group, an heteroaryl group, a O-aryl group or a S-aryl group, the above-mentioned groups being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group, a C(O)O (C 1-6 -alkyl) or a C(O)O (phenyl) group, the phenyl optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group;

R3 represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom;

R4 represents a hydrogen atom or a C 1-6 alkyl group;

R5 represents a hydrogen atom, a C 1-6 alkyl group;

R6 represents a hydrogen atom, a C 1-6 alkyl group;

R7 represents a hydrogen atom or a C 1-6 alkyl group;

X represents two hydrogen atoms, an oxygen atom or a C 1-2 alkyl group and a hydrogen atom;

Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a C 1-3 alkyl group, a methylene group optionally substituted by one or two groups chosen from a C 1-3 alkyl group, a hydroxyl group, a C 1-3 alkoxy group, a C 1-2 perhalogenated alkyl group or an amino group; and

n represents 0 to 3; or a salt thereof.

4. The compound according to claim 1 , wherein:

R1 represents an unsubstituted 4-pyrimidine ring;

R2 represents a benzodioxine ring, a pyrimidine ring, a pyridazine ring, naphthyridine ring, pyridine ring, dihydrobenzodioxine, benzofuran, dihydrobenzofuran ring, benzothiazole ring, benzothiophene ring, benzodioxole, dihydrobenzodioxole ring, imidazopyridine ring; the rings being optionally partially or fully saturated and or being optionally substituted by 1 to 4 substituents selected from hydroxyl group, an amino, a C 1-6 alkyl group, a S—(C 1-6 alkyl) group, a halogen atom, a C 1-2 perhalogenated alkyl group, C 1-6 alkoxy group, a C 1-2 perhalogenated alkoxy group or an aryl group optionally substituted by a halogen atom; and/or

R3 represents a hydrogen atom;

R4 represents a methyl;

R5 represents a hydrogen atom or a methyl;

R6 represents a hydrogen atom;

R7 represents a hydrogen atom;

X represents an oxygen atom;

Z represents a bond, or a nitrogen atom substituted by a hydrogen atom;

n and m represent 0; or a salt thereof.

5. The compound according to claim 1 which is selected from the group consisting of:

8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

5-Chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

3,6-Dimethoxy-pyridazine-4-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

[1,5]Naphthyridine-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-ylmethyl)-amide;

2-Methoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-nicotinamide;

Pyridine-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

[1,6]Naphthyridine-5-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-ylmethyl)-amide;

N-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-nicotinamide;

6-Chloro-pyridine-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-ylmethyl)-amide;

2,3-Dihydro-benzofuran-7-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

5-Bromo-benzofuran-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

Benzothiazole-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

Benzo[b]thiophene-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

2,2-Difluoro-benzo[1,3]dioxole-4-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

(+/−) [1,5]Naphthyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

3-Hydroxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

(+/−) 6-Chloro-pyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

(+/−) 5-Chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

4-Methoxy-pyridine-2-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

(+/−) Pyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

(+/−) 6-(2-Fluoro-phenyl)-pyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

(+/−) 3-Methoxy-pyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

(+/−) 2-Methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-nicotinamide;

(+/−) Benzo[b]thiophene-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

3H-Imidazo[4,5-b]pyridine-6-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-amide;

(+/−) 4-Methoxy-pyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-yl)-ethyl]-amide;

(+)-4-Methoxy-pyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-yl)-ethyl]-amide;

(−)-4-Methoxy-pyridine-2-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-yl)-ethyl]-amide;

6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4]bipyrimidinyl-2-yl)-ethyl]-amide;

8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

5-Bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid [1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-amide;

(+)-2-Methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-nicotinamide;

(−)-2-Methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-nicotinamide; and

2,6-Dimethoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-nicotinamide; or a salt thereof.

6. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and at least one pharmaceutically acceptable excipient.

7. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 2 and at least one pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3 and at least one pharmaceutically acceptable excipient.

9. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 and at least one pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5 and at least one pharmaceutically acceptable excipient.

11. A method of treating a disease in a patient, said disease selected from the group consisting of Alzheimer's disease, Parkinson's disease and taupathies, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

12. A method of treating a disease in a patient, said disease selected from the group consisting of non-insulin dependent diabetes, obesity, manic depressive illness and schizophrenia, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

13. A method of treating a disease in a patient, said disease selected from the group consisting of breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus-induced tumors, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

14. A method of treating malaria in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

15. A method of treating a bone disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

16. A method of treating pemphigus vulgaris in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

17. A method for the treatment of neutropenia induced by cancer chemotherapy in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

18. A method for the treatment of a disease caused by cognitive and memory deficits in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

19. A method of inhibiting the activity of glycogen synthase kinase 3-beta (GSK3-β), which comprises administering to a patient in need of said inhibition a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .

20. A process for the preparation of a compound of formula (I) according to claim 1 comprising:

reacting a compound of formula (III):

with a compound of formula (II):

wherein X, Z, R1, R2, R3, R4, R5, R6, m and n are as defined in claim 1 .