1-oxo-isoindoline-4-carboxamide and 1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide derivatives, preparation and therapeutic use thereof

1. A compound of formula (I):

wherein:

R1 is hydrogen, (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (CH 2 ) n —(C 1 -C 6 )alkenyl, (CH 2 ) n —(C 1 -C 6 )alkynyl, (C 1 -C 6 )alkyl-Z—(C 1 -C 6 )alkyl, COOR, S(O) m R, aryl or aralkyl, wherein the (C 1 -C 10 )alkyl, (C 3 -C 7 )cycloalkyl, (CH 2 ) n —(C 1 -C 6 )alkenyl, (CH 2 ) n —(C 1 -C 6 )alkynyl, (C 1 -C 6 )alkyl-Z—(C 1 -C 6 )alkyl, aryl and aralkyl are optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, NR7R8, nitro, cyano, OR, COOR, CONR7R8, S(O) m NR7R8 and aryl, wherein the aryl is optionally substituted with halogen;

R2 is one or more groups chosen from hydrogen, halogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 1 -C 6 )alkyl-Z—(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, hydroxy, nitro, cyano, amino, NR7R8, COOR, CONR7R8, OCO(C 1 -C 6 )alkyl, S(O) m —NR7R8 and aryl, wherein the aryl is optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, NR7R8, OR, nitro, cyano, COOR, CONR7R8 and S(O) m NR7R8;

R3 is trifluoromethyl;

R4 and R5 are hydrogen, or

R4 and R5 taken together with the carbon atom to which they are attached form a saturated ring containing from 3 to 6 carbon atoms and optionally containing from 0 to 1 heteroatom, chosen from O, N and S;

R6 is hydrogen, halogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, nitro, amino, NR7R8, COOR, NR7(SO 2 )R8, CONR7R8, aryl, or heterocycle, wherein the aryl and heterocycle are optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and cyano;

R, R7 and R8 are, independently of one another, hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl group, aryl or aryl(C 1 -C 6 )alkylene, or

R7 and R8 taken together with the nitrogen atom to which they are attached form a saturated, partially unsaturated or unsaturated ring containing from 5 to 7 carbon atoms and optionally containing, in addition, a heteroatom chosen from O, N and S(O) m ;

X is (C 1 -C 2 )alkylene optionally substituted with one or more (C 1 -C 6 )alkyl;

Z is O, N or S(O) m ,

m is 0, 1 or 2; and

n is 1, 2, 3, 4, 5 or 6;

provided that the carbon bearing the benzyl group substituted by R2 is of S absolute configuration; and

the carbon bearing the hydroxyl group is of R absolute configuration;

or an addition salt with an acid thereof.

2. The compound according to claim 1 or an addition salt with an acid of said compound, wherein X is methylene optionally substituted with one or more (C 1 -C 6 )alkyl.

3. The compound according to claim 1 or an addition salt with an acid with said compound, wherein X is ethylene substituted with one or more (C 1 -C 6 )alkyl.

4. The compound according to claim 1 or an addition salt with an acid with said compound, wherein R6 is hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, NR7SO 2 R8, aryl or heterocycle, wherein the aryl is optionally substituted with a cyano group.

5. The compound according to claim 1 or an addition salt with an acid with said compound, wherein R6 is hydrogen, chlorine, fluorine, methyl, trifluoromethyl, NMeSO 2 Me, phenyl or oxazole, wherein the phenyl is substituted with a cyano group.

6. The compound according to claim 1 or an addition salt with an acid with said compound, wherein:

R1 is (C 1 -C 10 )alkyl optionally substituted with one or more (C 1 -C 6 )alkyl groups,

aryl optionally substituted with halogen,

(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, or

aralkyl optionally substituted with halogen;

R2 is one or more groups chosen from hydrogen and halogen;

R4 and R5 are hydrogen atom, or

R4 and R5 taken together with the carbon atom to which they are attached form a cyclopropyl group;

R6 is hydrogen, halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, NR7SO 2 R8, aryl or heterocycle, wherein the aryl is optionally substituted with a cyano group;

R7 is hydrogen or (C 1 -C 6 )alkyl; and

R8 is (C 1 -C 6 )alkyl.

7. The compound according to claim 1 or an addition salt with an acid with said compound, which is selected from:

N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}-propyl]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-benzyl-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclo-propyl}amino)propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroiso-quinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetra-hydroisoquinoline-5 -carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}-propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

2-benzyl-N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-1,2,3,4-tetrahydroiso-quinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-2-pentyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5 -carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-2-[1-(4-fluorophenyl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-6-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)isoindoline-3-methyl-4-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-6-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-trifluoromethyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-[(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-(2-oxazolyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide hydrochloride (1:1);

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-(3-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-methyl-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-chloro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof;and

N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-fluoro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof.

8. A pharmaceutical composition, comprising the compound according to claim 1 or an addition salt with an acid with said compound, and at least one pharmaceutically acceptable excipient.

9. A pharmaceutical composition, comprising the compound according to claim 2 or an addition salt with an acid of said compound, and at least one pharmaceutically acceptable excipient.

10. A pharmaceutical composition, comprising the compound according to claim 3 or an addition salt with an acid with said compound, and at least one pharmaceutically acceptable excipient.

11. A pharmaceutical composition, comprising the compound according to claim 4 or an addition salt with an acid with said compound, and at least one pharmaceutically acceptable excipient.

12. A pharmaceutical composition, comprising the compound according to claim 5 or an addition salt with an acid with said compound, and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition, comprising the compound according to claim 6 or an addition salt with an acid with said compound, and at least one pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising the compound according to claim 7 or an addition salt with an acid with said compound, and at least one pharmaceutically acceptable excipient.

15. The compound according to claim 7 wherein the compound is N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}-propyl]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxamide or the 1:1 hydrochloride salt thereof.

16. The compound according to claim 7 wherein the compound is N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof.

17. The compound according to claim 7 wherein the compound is N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-(3-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof.

18. The compound according to claim 7 wherein the compound is N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)-phenyl]cyclopropyl}amino)propyl]-7-(2-cyanophenyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide or the 1:1 hydrochloride salt thereof.