Substituted arylamide diazepinopyrimidone derivatives

1. A compound of formula (I):

wherein:

Y represents two hydrogen atoms, a sulphur 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 sulphur 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, 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 benzene ring or a naphthalene ring; the rings 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 1-3 halogenated alkyl group, a hydroxyl group, a C 1-6 alkoxy 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, a C 2-12 dialkylamino group, an acetoxy group or an aminosulfonyl group, a 4-15 membered heterocyclic group, this group being optionally substituted by a 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, or a C 1-6 alkoxy group;

R4 represents a hydrogen atom; a C 1-6 alkyl group; a benzyl group, a phenethyl group, a benzyloxycarbonyl group, a C 1-4 alkoxy carbonyl group, a benzene group, a naphthalene group, a 5,6,7,8-tetrahydronaphthalene group, a benzenesulfonyl group, a benzoyl group, a 4-15 membered heterocyclic group, the above-mentioned group being optionally substituted by 1 to 4 substituents selected from a halogen atom, a hydroxyl group, a C 1-4 alkoxy group, a C 1-2 perhalogenated alkyl group, a C 1-6 alkyl group, a benzene group, a halogen atom, a C 1-3 halogenated alkyl group, a nitro, a cyano, an amino, a C 1-6 monoalkylamino group or a C 2-10 dialkylamino group;

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

n represents 0 to 3;

or a salt thereof.

2. The compound according to claim 1 , wherein

Y represents an oxygen atom or two hydrogen atoms;

z represents a bond;

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

R2 represents an hydrogen atom;

R3 represents a benzene group optionally substituted by 1 to 4 substituents selected from a halogen atom, a C 1-2 perhalogenated alkyl group, a C 1-6 alkoxy group, an amino, a pyrazole group, and an oxadiazole group, the oxadiazole group and the pyrazole group being optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group;

R4 represents an hydrogen atom, a C 1-6 alkyl group, a COO(C 1-4 -alkyl) group, or a phenyl group, these group being eventually substituted by 1 to 3 halogen; and

n represents 0;

or a salt thereof.

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

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

(+/−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-4-Chloro-2-methoxy-N-(7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-4-Chloro-N-[7-(4-fluoro-phenyl)-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl]-2-methoxy-benzamide;

(+/−)-4-Chloro-N-(7-cyclopropylmethyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-methoxy-benzamide;

(+/−)-4-Chloro-N-(7-isopropyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-methoxy-benzamide;

(+/−)-4-Chloro-N-(7-cyclopentyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-methoxy-benzamide;

(+/−)-4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-2,4-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

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

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

(−)-4-Chloro-2-methoxy-N-(7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+)-4-Chloro-2-methoxy-N-(7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-9-(2,3-Dimethoxy-benzoylamino)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

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

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

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

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

(+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-5-Bromo-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-2,3-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

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

(+/−)-2,3-Dimethoxy-N-(7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

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

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

(+/−)-4-Amino-5-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-5-Bromo-2-methoxy-N-(7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-5-Chloro-2-methoxy-N-(7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-5-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

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

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

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

(+/−)-9-[(4-Chloro-2-methoxy-benzoyl)-methyl-amino]-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

(+/−)-2-Methoxy-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-2-Methoxy-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-N-(7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-4-Fluoro-2-methoxy-N-(7-methyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-N-(7-Isopropyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-methoxy-benzamide;

(+/−)-2-Methoxy-N-(4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-4-Chloro-N-(7-cyclopropylmethyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-methoxy-benzamide;

(+/−)-2-Methoxy-N-(4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-4-trifluoromethyl-benzamide;

(+/−)-N-(7-Isopropyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-methoxy-4-trifluoromethyl-benzamide;

(+/−)-N-(7-Cyclopropylmethyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2,5-dimethoxy-benzamide;

((+/−)-2,5-Dimethoxy-N-(4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-4-Fluoro-N-(4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-trifluoromethyl-benzamide;

(+/−)-5-Chloro-2-methoxy-N-(4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide;

(+/−)-4-Fluoro-N-(7-methyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-2-trifluoromethyl-benzamide; and

(+/−)-N-(7-Benzyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-5-chloro-2-methoxy-benzamide;

or a salt thereof.

4. A pyrimidone derivative represented by formula (III) (XI), or (XII):

wherein R1, R2, and R4 are as defined for the compound of formula (I) according to claim 1 .

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

7. A pharmaceutical composition comprising a compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical additives.

8. A method of treating a neurodegenerative disease 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; wherein said neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, tauopathies, vascular dementia; acute stroke, traumatic injuries; cerebrovascular accidents, brain cord trauma, spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma.

9. 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; schizophrenia; and cancers, wherein said cancer is 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) according to claim 1 or a pharmaceutically acceptable salt thereof.

10. 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.

11. 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.

12. 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 z, R1, R2, R3, R4, Y and n are as defined in claim 1 , and L represents a leaving group.