Substituted heteroarylamide 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 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(O)O (C 1-6 -alkyl) group, a C(O)O (aryl) 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, a 4-15 membered heterocyclic group, an aryl 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, and a (C 1-6 ) alcoxy 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;

z represents a bond;

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

R2 represents a hydrogen atom;

R3 represents a naphthyridine group, a pyridine group, a dihydrobenzofuran group, a tetrahydroisoquinoline group, a pyridazine group, a dihydrobenzodioxine group or a benzodioxine group, wherein the above-mentioned groups are optionally substituted by 1 to 4 substituents selected from a C 1-6 alkyl group, a halogen atom, a C 1-6 alkoxy group, an amino, and a C(O)O (C 1-6 -alkyl) group;

R4 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-4 alkoxy carbonyl group, or a benzyl group;

R5 represents a hydrogen atom; and

n represents 0;

or a salt thereof.

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

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

(+/−)-4-Oxo-9-[(pyridine-2-carbonyl)-amino]-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

(+/−)-9-[(2,2-Dimethyl-2,3-dihydro-benzofuran-7-carbonyl)-amino]-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

(+/−)-Pyridine-2-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-amide;

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

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

(+/−)-4-Methoxy-pyridine-2-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-9-[(2,3-Dihydro-benzofuran-7-carbonyl)amino]-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

(+/−)-9-[(2-tert-Butoxycarbonyl-1,2,3,4-tetrahydro-isoquinoline-7-carbonyl)-amino]-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxyl is acid ethyl ester;

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

(+/−)-2,3-Dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-amide;

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

(+/−)-2,3-Dihydro-benzofuran-7-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-amide;

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

(+/−)-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)-nicotinamide;

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

(+/−)-5-Bromo-2,3-dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-5-Bromo-2,3-dihydro-benzofuran-7-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-4-Oxo-2-pyridin-4-yl-9-[(1,2,3,4-tetrahydro-isoquinoline-7-carbonyl)-amino]-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester;

(+/−)-8-Amino-7-chloro-2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

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

(+/−)-5-Chloro-2,3-dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-5-Chloro-2,3-dihydro-benzofuran-7-carboxylic acid (7-methyl-4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid (4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (7-methyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

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

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

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

(+/−)-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-nicotinamide;

(+/−)-Pyridine-2-carboxylic acid (4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-amide;

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

(+/−)-2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid (7-benzyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (7-isopropyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

(+/−)-6-Fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (7-benzyl-4-oxo-2-pyridin-4-yl-4,5,6,7,8,9-hexahydro-1,4-a,7-triaza-benzocyclohepten-9-yl)-amide;

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

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

or a salt thereof.

4. A compound of formula (III), (VI) or (VII):

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.