3-heteroaryl-3, 5-dihydro-4-oxo-4H-pyridazino[4, 5-b]indole-1-carboxamide derivatives their preparations and therapeutic use

1. A compound of formula (I)

wherein

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 –C 4 )alkyl group,

R 2 and R 3 each represent, independently of one another, a hydrogen atom or a (C 1 –C 4 )alkyl group or else R 2 and R 3 form, with the nitrogen atom which carries them, a pyrrolidinyl, piperidinyl, morpholinyl or 4-alkylpiperazinyl group, and Het represents a heteroaryl group selected from pyridinyl, 1-oxidopyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl and pyridazinyl, optionally substituted with one or more halogen atoms and/or one or more (C 1 –C 4 )alkyl or (C 1 –C 4 )alkoxy groups, or

a hydrate, or acid addition salt thereof.

2. A compound according to claim 1 wherein

X represents a halogen atom;

R 1 represents a (C 1 –C 4 )alkyl;

R 2 and R 3 each represent, independently of one another, a hydrogen atom or a (C 1 –C 4 )alkyl group, or else R 2 and R 3 form, with the nitrogen atom which carries them, a pyrrolidinyl, piperidinyl, morpholinyl or 4-alkylpiperazinyl group;

Het represents a heteroaryl group selected from pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl and pyridazinyl, optionally substituted with one or more halogen atoms, and/or one or more (C 1 –C 4 )alkyl groups or (C 1 –C 4 )alkoxy groups.

3. A compound according to claim 2 wherein

X represents a chlorine atom; and

R 1 represents a methyl group.

4. A compound of formula (III)

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 –C 4 )alkyl group,

Het represents a heteroaryl group selected from pyridinyl, 1-oxidopyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl and pyridazinyl, optionally substituted with one or more halogen atoms and/or one or more (C 1 –C 4 )alkyl or (C 1 –C 4 )alkoxy groups, and

R″ represents a (C 1 –C 4 )alkyl group.

5. A compound of the formula

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 –C 4 )alkyl group,

Het represents a heteroaryl group selected from pyridinyl, 1-oxidopyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl and pyridazinyl, optionally substituted with one or more halogen atoms and/or one or more (C 1 –C 4 )alkyl or (C 1 –C 4 )alkoxy groups.

6. A compound of formula (IV)

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 –C 4 )alkl group, and

R″ represents a (C 1 –C 4 )alkyl group.

7. A compound of the formula

in which

X represents a hydrogen or halogen atom, and

R 1 represents a hydrogen atom or a (C 1 –C 4 )alkyl group.

8. A compound of formula (V)

in which

X represents a hydrogen or halogen atom,

R 1 represents a hydrogen atom or a (C 1 –C 4 )alkyl group, and

R 2 and R 3 each represent, independently of one another, a hydrogen atom or a (C 1 –C 4 )alkyl group or else R 2 and R 3 form, with the nitrogen atom which carries them, a pyrrolidinyl, piperidinyl, morpholinyl or 4-alkylpiperazinyl group.

9. A compound according to claim 2 wherein

R 2 and R 3 are independently hydrogen, methyl or ethyl, or R 2 and R 3 together with the nitrogen atom to which they are bound are pyrrolidinyl, piperidinyl, morpholinyl or 4-alkylpiperazinyl, and

Het is pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl or pyridazinyl, optionally substituted with bromine, methyl or methoxy.

10. A compound according to claim 9 wherein X is chlorine and R 1 is methyl.

11. A compound selected from the group consisting of

7-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide hydrochloride (1:1),

7-fluoro-N,N,5-trimethyl-4-oxo-3-(2-methoxypyridin-5-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-fluoro-N,N,5-trimethyl-4-oxo-3-(quinolin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

1-[[7-fluoro-5-methyl-3-(pyrimidin-2-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-yl]carbonyl]pyrrolidine,

4-methyl-1-[[7-fluoro-5-methyl-3-(pyridin-3-yl)4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]piperazine hydrochloride (1:1),

1-[[7-fluoro-5-methyl-3-(pyridin-3-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]pyrrolidine,

7-fluoro-N,5-dimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-fluoro-5-methyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro4H-pyridazino[4,5-b]indole-1-carboxamide hydrochloride (1:1),

7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(pyridin4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide hydrochloride (1:1),

7-chloro-N,N,5-trimethyl-4-oxo-3-(5-methylpyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(2-methoxypyridin-5-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(2-methylpyridin-5-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(2-bromopyridin-5-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(quinolin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(isoquinolin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(6-methylpyridazin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(pyrimidin-5-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(pyrimidin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(pyrazin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

1-[[7-chloro-5-methyl-3-(pyridin-3-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]-pyrrolidine hydrochloride (1:1),

4-methyl-1-[[7-chloro-5-methyl-3-(pyridin-3-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]piperazine hydrochloride (1:1),

1-[[7-chloro-5-methyl-3-(pyridin-4-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]-pyrrolidine,

7-chloro-N,5-dimethyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-5-methyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(4-methoxypyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

1-[[7-chloro-5-methyl-3-(pyridin-4-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]morpholine,

7-chloro-N,N,-diethyl-5-methyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N-ethyl-N,5-dimethyl-4-oxo-3-(pyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

1-[[7-chloro-5-methyl-3-(pyridin-4-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]-piperidine,

7-chloro-N,N,5-trimethyl-4-oxo-3-(2-methylpyridin-4-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

1-[[7-chloro-5-methyl-3-(2-methylpyridin-4-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indol-1-yl]carbonyl]pyrrolidine,

7-chloro-N,N,5-trimethyl-3-(1-oxidopyridin-4-yl)-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-3-(2-methoxypyridin-4-yl)-N,N,5-triethyl-4oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide, and

3-(2-bromopyridin-4-yl)-7-chloro-N,N,5-trimethyl-4-oxo-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

or a hydrate, or acid addition salt thereof.

12. A process for preparing a compound according to claim 1 which comprises reacting a compound of formula (III)

with an amine HNR 2 R 3 , or

saponifying the compound of formula (III) and coupling the acid obtained with the amine HNR 2 R 3 , wherein X, R 1 , R 2 , R 3 , and Het in the above formulas are as defined in claim 1 and R″ is (C 1 –C 4 ) alkyl.

13. A process according to claim 12 wherein the compound of formula (III) is obtained by reacting a compound of formula (II)

with a heteroarylhydrazine HetNHNH 2 in a polar solvent in the presence of acid at the reflux temperature, wherein in formula II, X, R 1 and R″ are as defined in claim 12 and R′ is (C 1 –C 4 ) alkyl.

14. A process for preparing a compound according to claim 1 which comprises the N-heteroarylation of a compound of formula (V)

wherein X, R 1 , R 2 , and R 3 , are as defined in claim 1 .

15. A process according to claim 14 wherein the compound of formula (V) is obtained by reacting a compound of formula (IV)

with an amine HNR 2 R 3 , or by saponifying the compound of formula (IV) and coupling the acid obtained with the amine HNR 2 R 3 , wherein X, R 1 , R 2 , and R 3 , are as defined in claim 14 and R″ is (C 1 –C 4 ) alkyl.

16. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a compound according to claim 2 together with a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound according to claim 11 together with a pharmaceutically acceptable excipient.

19. A compound according to claim 1 selected from the group consisting of:

7-chloro-N,N,5-trimethyl-4-oxo-3-(2-methoxypyridin-5-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

7-chloro-N,N,5-trimethyl-4-oxo-3-(2-methylpyridin-5-yl)-3,5-dihydro-4H-pyridazino[(4,5-b]indole-1-carboxamide, and

7-chloro-N,N,5-trimethyl-4-oxo-3-(2-bromopyridin-5-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxamide,

or a hydrate, or acid addition salt thereof.

20. A pharmaceutical composition comprising a compound according to claim 19 together with a pharmaceutically acceptable excipient.