Substituted alkyl pyrimidin-4-one derivatives

1. A compound of formula (I):

wherein:

X represents a methylene, NH, or a nitrogen atom substituted by a C(O)—O—(C 1-6 -alkyl) group;

R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine 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 hydrogen atom, a C 1-6 alkyl group or a halogen atom;

R3 represents a C 1-6 alkyl group which is optionally substituted by 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-6 alkoxy group, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group, C 1-6 alkyl group, and an aromatic group, wherein the aromatic group is optionally substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, a C 1-6 alkoxy group, and a C 1-6 alkyl group;

R4 represents a hydrogen atom, a halogen atom, a hydroxyl group, or a C 1-6 alkyl group; and

m represents 1 to 2 when X is a methylene or

m represents 2 when X is NH or a nitrogen atom substituted by a C(O)—O—(C 1-6 -alkyl) group;

or an acid addition salt thereof.

2. The compound of formula (I) according to claim 1 :

wherein

X represents a methylene, NH, or a nitrogen atom substituted by a C(O)—O—(C 1-6 -alkyl) group;

R1 represents an unsubstituted 4-pyridine ring or an unsubstituted 4-pyrimidine ring;

R2 represents a hydrogen atom;

R3 represents a C 1-6 alkyl group which is optionally substituted by 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, a C 1-2 perhalogenated alkyl group, C 1-6 alkyl group, and a phenyl group wherein the phenyl group is optionally substituted by 1 to 4 substituents selected from a halogen atom and a C 1-6 alkoxy group;

R4 represents a hydrogen atom;

m represents 1 to 2 when X is a methylene, or

m represents 2 when X is NH or a nitrogen atom substituted by a C(O)—O—(C 1-6 -alkyl) group;

or an acid addition salt thereof.

3. The compound according to claim 1 selected from the group consisting of:

(+/−)-9-[2-(2-Methoxy-phenyl)-ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-α]pyrimidin-4-one;

(+/−)-9-(3-Chloro-benzyl)-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-α]pyrimidin-4-one;

(+/−)-9-(4-Fluoro-benzyl)-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-α]pyrimidin-4-one;

(+/−)-9-(5-Bromo-2-methoxy-benzyl)-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-α]pyrimidin-4-one;

(+/−)-10-Methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-Methyl-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-Ethyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-Ethyl-2-pyridin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(2-(Phenyl-ethyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-Benzyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(3-Phenyl-propyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-[(4-Fluoro-2-methoxy-phenyl)-hydroxy-methyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-[Fluoro-(4-fluoro-2-methoxy-phenyl)methyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-[2-(4-Methoxy-phenyl)ethyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-[2-(2-Methoxy-phenyl)-ethyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(2-Methyl-2-phenyl-propyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-Isobutyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-[2-(4-Fluoro-2-methoxy-phenyl)-ethyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-[2-(2,4-Difluoro-phenyl)-ethyl]-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(1-Hydroxy-2-phenyl-ethyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-Cyclopentyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(1-Fluoro-2-phenyl-ethyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-Cyclopropyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-2-Pyrimidin-4-yl-10-[2,2,2-trifluoro-1-hydroxy-1-(4-methoxy-benzyl)-ethyl]-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(1-Hydroxy-ethyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(1-Fluoro-ethyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(4-Fluoro-benzyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-10-(1-Hydroxy-2-phenyl-ethyl)-10-methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+)-10-(4-Fluoro-benzyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(−)-10-(4-Fluoro-benzyl)-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-α]azepin-4-one;

(+/−)-9-Ethyl-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

(+/−)-9-Ethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-5H-1,4-a,7-triaza-benzocyclohepten-4-one;

(+/−)-9-(2-Phenyl-ethyl)-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-5H-1,4-a,7-triaza-benzocyclohepten-4-one; and

(+/−)-9-(4-Fluoro-benzyl)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

or an acid addition salt thereof.

4. A compound of formula (II) or formula (V):

wherein:

X represents NH or a nitrogen atom substituted by a C(O)—O—(C 1-6 -alkyl) group;

R1 represents an 4-pyridine ring or an 4-pyrimidine ring;

R2 represents a hydrogen atom; and

Y represents a halogen.

5. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof and one or more pharmaceutical additives.

6. A pharmaceutical composition comprising a compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt, hydrate or solvate thereof and one or more pharmaceutical additives.

7. A pharmaceutical composition comprising a compound according to claim 3 or a pharmaceutically acceptable salt, hydrate or solvate thereof and one or more pharmaceutical additives.

8. 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) according to claim 1 or a pharmaceutically acceptable salt thereof.

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

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

11. A process for the synthesis of the compound of formula (I):

according to claim 2 , comprising reacting a compound of formula (II)

with R4-L and then R3-A, wherein R3 and R4 are as defined in claim 2 ; L represents a tosyl, mesyl or bromine, A represents a tosyl, mesyl or halogen, R1 represents an 4-pyridine ring or an 4-pyrimidine ring; and R2 represents a hydrogen atom.