2-amino-3-(imidazol-2-yl)-pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors

1. A compound of formula (I):

in which:

W represents a nitrogen atom or a group CH;

Y represents a group C 2 -C 3 -alkynylene or a 1,4-phenylene optionally substituted with R 7 which represents one or more halogen atom(s);

Z represents a bond or a group CR 1 R 2 ;

R 1 and R 2 , independently of each other, represent a group chosen from a hydrogen atom, a group C 1 -C 6 -alkyl, a trifluoromethyl group, a group (CH 2 ) n OR 6 , C 3 -C 7 -cycloalkyl, an heteroaryl or an aryl optionally substituted with one or more halogen atom(s);

or R 1 and R 2 can form together, with the carbon atom which bear them, a C 3 -C 7 -cycloalkyl;

R 3 represents a hydrogen atom;

R 4 represents a group chosen from a group C 1 -C 6 -alkyl, a group (CH 2 ) n OR 6 , C 3 -C 7 -cycloalkyl or C 1 -C 6 -alkyl optionally substituted by a C 3 -C 7 -cycloalkyl;

R 5 represents a group chosen from a hydrogen atom or a group C 1 -C 6 -alkyl;

R 6 represents a group chosen from a hydrogen atom or a group C 1 -C 6 -alkyl;

n is equal to 1, 2 or 3;

in the form of the base or of an acid-addition salt.

2. The compound according to claim 1 , wherein W represents a a group CH, in the form of the base or of an acid-addition salt.

3. The compound according to claim 1 , wherein W represents a nitrogen atom, in the form of the base or of an acid-addition salt.

4. The compound according to claim 1 , wherein Y represents a group C 2 -C 3 -alkynylene in the form of the base or of an acid-addition salt.

5. The compound according to claim 1 , wherein

R 1 represents a group chosen from a hydrogen atom, a group C 1 -C 6 -alkyl, a group (CH 2 ) n OR 6 , C 3 -C 7 -cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl;

R 2 represents a group chosen from a hydrogen atom, a group C 1 -C 6 -alkyl or a trifluoromethyl;

in the form of the base or of an acid-addition salt.

6. The compound according to claim 1 , wherein

Z represents a group CR 1 R 2 ;

R 1 represents a group chosen from a hydrogen atom, a group C 1 -C 6 -alkyl, a group (CH 2 ) n OR 6 , C 3 -C 7 -cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl;

R 2 represents a group chosen from a hydrogen atom, a group C 1 -C 6 -alkyl or a trifluoromethyl;

in the form of the base or of an acid-addition salt.

7. The compound according to claim 1 , wherein R 4 represents a group chosen from a group (CH 2 ) n OR 6 , C 3 -C 7 -cycloalkyl or C 1 -C 6 -alkyl optionally substituted by a C 3 -C 7 -cycloalkyl, in the form of the base or of an acid-addition salt.

8. The compound according to claim 1 , wherein R 4 represents a group C 1 -C 6 -alkyl, in the form of the base or of an acid-addition salt.

9. The compound according to claim 1 , wherein R 5 represents a group C 1 -C 6 -alkyl, in the form of the base or of an acid-addition salt.

10. The compound according to claim 1 , wherein R 5 represents a hydrogen atom, in the form of the base or of an acid-addition salt.

11. The compound according to claim 1 , wherein

Y represents a group C 2 -C 3 -alkynylene or a 1,4-phenylene optionally substituted with R 7 which represents a halogen atom;

R 1 represents a group chosen from a hydrogen atom, a group C 1 -C 6 -alkyl, a group (CH 2 ) n OR 6 , C 3 -C 7 -cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl optionally substituted with a halogen atom;

R 2 represents a group chosen from a hydrogen atom, a group C 1 -C 6 -alkyl or a trifluoromethyl;

in the form of the base or of an acid-addition salt.

12. The compound according to claim 1 , wherein R 1 and R 2 form together, with the carbon atom which bear them, a C 3 -C 7 -cycloalkyl, in the form of the base or of an acid-addition salt.

13. The compound according to claim 1 , in the form of the base or of an acid-addition salt, chosen from the group consisting of:

2-Amino-1-ethyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-propyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-7-(3,4-dihydroxy-3-methyl-but-1-ynyl)-1-ethyl-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(-3-hydroxy-3-pyridin-2-yl-but-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methyl-but-1-ynyl]-3-(4-methyl-1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-(cyclopropylmethyl)-7-(3-hydroxy-pent-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methyl-but-1-ynyl]-3-(1H-imidazol-2-yl)-1H-quinolin-4-one;

2-Amino-7-(3-chloro-4-hydroxy-phenyl)-1-ethyl-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-[3-(2-fluorophenyl)-3-hydroxy-but-1-ynyl]-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-cyclopentyl-7-(3-hydroxy-pent-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-7-(3-hydroxy-pent-1-ynyl)-3-(1H-imidazol-2-yl)-1-(3-methoxypropyl)-1H-[1,8]naphthyridin-4-one;

2-Amino-7-(3-hydroxy-pent-1-ynyl)-3-(1H-imidazol-2-yl)-1-(2-methoxyethyl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-[(1-hydroxycyclobutyl)ethynyl]-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-[(1-hydroxycyclopentyl)ethynyl]-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-3-methyl-pent-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-3-phenyl-but-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-[3-(3-fluorophenyl)-3-hydroxy-but-1-ynyl]-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-3-(1H-imidazol-2-yl)-7-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but-1-ynyl)-1H-[1,8]naphthyridin-4-one;

2-Amino-7-(3-cyclopropyl-3-hydroxy-but-1-ynyl)-1-ethyl-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-[3-hydroxy-3-(thiophen-2-yl)but-1-ynyl]-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-but-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-pent-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-hex-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-4-methyl-pent-1-ynyl)-3-(1H-imidazol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-1-ethyl-7-(3-hydroxy-3-phenyl-prop-1-ynyl)-3-(1H-imidaz ol-2-yl)-1H-[1,8]naphthyridin-4-one;

2-Amino-7-((3R)3,4-dihydroxy-3-methyl-but-1-ynyl)-1-ethyl-3-(1H-imidazol-2-yl)-1,8-naphthyridin-4(1H)-one;

2-Amino-7-((3S)3,4-dihydroxy-3-methyl-but-1-ynyl)-1-ethyl-3-(1H-imidazol-2-yl)-1, 8-naphthyridin-4(1H)-one; and

2-Amino-1-ethyl-7-((3S)-3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-3-(1H-imidazol-2-yl)-1,8-naphthyridin-4(1H)-one.

14. A process for preparing the compound according to claim 1 , comprising reacting a compound of formula (VII):

in which X is a chlorine or a bromine and R 4 and R 5 are as defined in claim 1 with a compound of general formula (XVa):

in which R 1 , R 2 and R 3 are as defined in claim 1 ,

or with a compound of general formula (XVb):

in which R3 and R7 are as defined in claim 1 ,

and carrying out a conventional stage of deprotection before or after reacting the compound of formula (VII) with the compound of general formula (XVa) or the compound of general formula (XVb).

15. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt, or an enantiomer or a diastereoisomer, or a mixture thereof.

16. The pharmaceutical composition of claim 15 further comprising at least one pharmaceutically acceptable excipient.

17. The combination of the compound according to claim 1 with at least one therapeutic agent selected from:

alkylating agents,

intercalating agents,

antimicrotubule agents,

antimitotics,

antimetabolites,

antiproliferative agents,

antibiotics,

immunomodulatory agents,

anti-inflammatories,

kinase inhibitors,

anti-angiogenic agents,

antivascular agents,

oestrogenic and androgenic hormones.

18. The compound according to claim 4 , wherein said C 2 -C 3 -alkynylene is ethynylene.

19. The compound according to claim 8 , wherein said group C 1 -C 6 alkyl is an ethyl.