Arylamide 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 benzene ring, a naphthalene ring or a benzyl group; the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 3-7 cycloalkyl-C 1-6 alkyl group, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, an heteroaryl group optionally substituted by a C 1-6 alkyl group, C 3-7 cycloalkyl group, a C 3-7 cycloalkyl-C 1-6 alkyl group, C 1-6 alkoxy group optionally substituted by a C 3-7 cycloalkyl group, a C 1-2 perhalogenated alkoxy group, a C 1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-12 dialkylamino group, an acetoxy group or an aminosulfonyl 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 or a C 1-6 alkyl group;

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

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

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 a 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 benzene ring, a naphthalene ring or a benzyl group; the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, C 3-7 cycloalkyl group, a C 3-7 cycloalkyl-C 1-6 alkyl group, a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, a hydroxyl group, an heteroaryl group optionally substituted by a C 1-6 alkyl group, C 3-7 cycloalkyl group, a C 3-7 cycloalkyl-C 1-6 alkyl group, C 1-6 alkoxy group optionally substituted by a C 3-5 cycloalkyl group, a C 1-2 perhalogenated alkoxy group, a C 1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C 1-3 monoalkylamino group or a C 2-6 dialkylamino group, an acetoxy group or an aminosulfonyl group; and/or

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 or a C 1-6 alkyl group;

R6 represents a hydrogen atom or 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 benzene ring, a naphthalene ring or a benzyl group; the rings being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, an amino group, a C 1-2 perhalogenated alkyl group, a C 1-6 alkoxy group, a C 1-2 perhalogenated alkoxy group or an oxadiazole group optionally substituted by a C 1-6 alkyl group;

R3 represents a hydrogen atom;

R4 represents a methyl;

R5 represents a hydrogen atom or a methyl;

R6 represents a hydrogen atom or a methyl;

R7 represents a hydrogen atom;

X represents an oxygen atom;

Z represents a bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom; and

n represents 0, or a salt thereof.

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

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

5-Chloro-2-methoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

4-Fluoro-2-methoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyly)-benzamide;

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

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

(−)-4-Fluoro-2-methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-benzamide;

4-Fluoro-2-methoxy-N-[1-methyl-1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-benzamide;

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

1-(4-Fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-urea;

1-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-3-phenyl-urea;

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

3-Fluoro-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

4-Amino-5-chloro-2-methoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

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

2-Fluoro-6-methoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

2-Chloro-5-fluoro-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

5-Bromo-2-methoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

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

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

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

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

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

2,3-Dimethoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

2,5-Dimethoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

2-Methoxy-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-benzamide;

(+/−) 2-Methoxy-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-benzamide;

(+/−) 5-Bromo-2-methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-benzamide;

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

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

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

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

(+/−) 4-Amino-5-chloro-2-methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-benzamide;

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

(+/−) [1-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-carbamic acid benzyl ester;

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

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

(+)-4-Chloro-2-methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-benzamide; and

(−)-4-Chloro-2-methoxy-N-[1-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-ethyl]-benzamide; 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 compound of the formula (III):

wherein:

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;

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 or a C 1-6 alkyl group;

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

m represents 0.