Benzimidazole derivatives, preparation and therapeutic use thereof

1. A compound of formula (I)

in which

R1 represents a hydrogen atom, a (C1-C4)alkyl group, a halogen atom, a nitro group or a (C1-C4)alkoxy group,

R2, R2′, R9 and R9′ represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group,

X represents a nitrogen atom or a carbon atom,

m is equal to 1 or 2,

and when X represents a nitrogen atom:

R3 represents a hydrogen atom or a (C1-C4)alkyl group, or alternatively, R3 is not present,

R4 represents

a hydrogen atom, or

a (C1-C6)alkyl group, or

a (C3-C7)cycloalkyl group, or

a 4-piperidyl group optionally substituted on a carbon atom or on the nitrogen atom with a (C1-C4)alkyl group, or

a group —(CH 2 ) p —NR5R6, —(CH 2 ) p —CONR5R6 or —CO—(CH 2 ) p —NR5R6, in which p may range from 0 to 4 and in which

R5 and R6 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group, or

a group —(CH 2 ) p -phenyl, in which p may range from 0 to 4 and in which the phenyl radical is optionally substituted with one to three groups chosen, independently of each other, from: a (C1-C4)alkyl group, a nitro group, a hydroxyl group, an amino group, a halogen atom, a trifluoromethyl group, a (C1-C4)alkoxy group, a (C1-C4)alkylamino group, a (C1-C4)dialkylamino group, a —NHCHO group, a group —NHCOR and a group —NHSO 2 R, in which

R represents a (C1-C4)alkoxy group or a (C1-C4)alkyl group, wherein the (C1-C4)alkyl group is optionally substituted with a dimethylamino group, or

a group —(CH 2 ) p -morpholinyl, —(CH 2 ) p -pyrrolidinyl or —(CH 2 ) p -tetrahydroisoquinoline, in which p may range from 0 to 4, or

a group —(CH 2 ) p -heteroaryl, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from pyridyl, aminopyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl and pyrazolyl groups,

wherein said heteroaryl group is optionally substituted on a carbon atom, on a nitrogen atom, or on both a carbon atom and a nitrogen atom, with one to three groups chosen from a (C1-C4)alkyl group and a phenyl group,

wherein the phenyl group is optionally substituted with one to three groups chosen from halogen atoms and (C1-C4)alkyl groups, or

a heteroarylcarbonyl group, wherein the heteroaryl part of the heteroarylcarbonyl group is chosen from furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and imidazolyl groups, or

a phenylcarbonyl group, wherein the phenyl part of the phenylcarbonyl group is optionally substituted with a halogen atom, or

a (C1-C6)alkylcarbonyl group, or

a group —(CH 2 ) p —COOR′ in which p may range from 0 to 4 and in which R′ represents a hydrogen atom or a (C1-C6)alkyl group, or

a phenylsulphonyl group, optionally substituted on the phenyl radical with a halogen atom, a trifluoromethyl group, a (C1-C4)alkyl group, a nitro group or a (C1-C4)alkoxy group;

and when X represents a carbon atom:

R3 represents a hydrogen atom, a group —NR5R6, a group —NHCOR7, a group —CONHR5, a group —COR7, an —NHCONH 2 group, an —OH group or a —CH 2 OH group,

R4 represents:

a hydrogen atom, or

a group —(CH 2 ) p -phenyl, in which p may range from 0 to 4 and in which the phenyl radical is optionally substituted with one to three groups chosen, independently of each other, from: a (C1-C4)alkyl group, a nitro group, a hydroxyl group, an amino group, a halogen atom, a trifluoromethyl group, a (C1-C4)alkoxy group, a (C1-C4)alkylamino group, a (C1-C4)dialkylamino group, an —NHCHO group, a group —NHCOR and a group —NHSO 2 R, in which

R represents a (C1-C4)alkoxy group or a (C1-C4)alkyl group, wherein the (C1-C4)alkyl group is optionally substituted with a dimethylamino group, or

a group —(CH 2 ) p -heteroaryl, in which p may range from 0 to 4 and in which the heteroaryl group is chosen from pyridyl, aminopyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl and pyrazolyl groups,

wherein said heteroaryl group is optionally substituted on a carbon atom, on a nitrogen atom, or on both a carbon atom and a nitrogen atom, with one to three groups chosen from a (C1-C4)alkyl group and a phenyl group,

wherein the phenyl group is optionally substituted with one to three groups chosen from halogen atoms and (C1-C4)alkyl groups, or

a group —(CH 2 ) t NR7R8, in which t is equal to 0 or 1,

R5 and R6 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group,

R7 and R8 represent, independently of each other, a (C1-C4)alkyl or

(C1-C4)alkoxy group, or R7 and R8 together form a 5- to 7-membered saturated ring optionally having an additional nitrogen atom,

wherein the ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached,

or an enantiomer or diastereolsomer of a compound of formula I, or a mixture thereof, including a racemic mixture, or a base or addition salt of a compound of formula I with a pharmaceutically acceptable acid.

2. A compound according to claim 1 , wherein

R1, R2 and R9 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group,

R2′ and R9′ each represents a hydrogen atom,

X represents a nitrogen atom,

m is equal to 1 or 2,

R3 represents a (C1-C4)alkyl group, or alternatively, R3 is not present,

R4 represents

a hydrogen atom, or

a (C1-C6)alkyl group, or

a (C3-C7)cycloalkyl group, or

a 4-piperidyl group, optionally substituted on a carbon atom or on the nitrogen atom with a (C1-C4)alkyl group, or

a group —(CH 2 ) p —NR5R6, —(CH 2 ) p —CONR5R6 or —CO—(CH 2 ) p —NR5R6, in which p may range from 0 to 4 and in which

R5 and R6 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group, or

a group —(CH 2 ) p -phenyl, in which p may range from 0 to 4 and in which the phenyl radical is optionally substituted with one to three groups chosen, independently of each other, from a nitro group, a halogen atom and a trifluoromethyl group, or

a group —(CH 2 ) p -morpholinyl, —(CH 2 ) p -pyrrolidinyl or —(CH 2 ) p -tetrahydroisoquinoline, in which p may range from 0 to 4, or

a group —(CH 2 ) p -pyrazolyl, in which p may range from 0 to 4 and in which the pyrazolyl group is optionally substituted on a carbon atom, on a nitrogen atom, or on both a carbon atom and a nitrogen atom, with one to three groups chosen from a (C1-C4)alkyl group and a phenyl group, or

a group —(CH 2 ) p -pyridyl, in which p may range from 0 to 4, or

a heteroarylcarbonyl group, wherein the heteroaryl part of the heteroarylcarbonyl group is chosen from a furyl group or a pyridyl group, or

a phenylcarbonyl group, wherein the phenyl part of the heteroarylcarbonyl group is optionally substituted with a halogen atom, or

a (C1-C6)alkylcarbonyl group, or

a group —(CH 2 ) p —COOR′ in which p may range from 0 to 4 and in which R′ represents a (C1-C6)alkyl group, or

a phenylsulphonyl group;

or where

R1, R2′ and R9′, each represents a hydrogen atom,

R2 and R9 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group,

X represents a carbon atom,

m is equal to 1,

R3 represents a hydrogen atom, a group —NR5R6, a group —NHCOR7, a group —CONHR5, a group —COR7, an —NHCONH 2 group, an —OH group or a —CH 2 OH group,

R4 represents

a hydrogen atom, or

a phenyl group, or

a heteroaryl group chosen from:

an imidazolyl group, optionally substituted with a (C1-C4)alkyl group,

a pyridyl group, optionally substituted on a nitrogen atom or on a carbon atom with a phenyl group, wherein the phenyl group is optionally substituted with one to three groups chosen from halogen atoms and (C1-C4)alkyl groups, and

a pyrazolyl group, optionally substituted on a nitrogen atom or on a carbon atom with a phenyl group, wherein the phenyl group is optionally substituted with one to three groups chosen from halogen atoms and (C1-C4)alkyl groups, or

a group —NR7R8,

R5 and R6 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group,

R7 and R8 represent, independently of each other, a (C1-C4)alkyl or (C1-C4)alkoxy group, or R7 and R8 together form a saturated 5- to 7-membered ring optionally having an additional nitrogen atom,

wherein the ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or on a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached.

3. A compound according to claim 1 , wherein

R1, R2 and R9 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group,

R2′ and R9′, each represents a hydrogen atom,

X represents a nitrogen atom,

m is equal to 1 or 2,

R3 represents a (C1-C4)alkyl group, or alternatively, R3 is not present,

R4 represents

a hydrogen atom, or

a (C1-C4)alkyl group, or

a (C3-C7)cycloalkyl group, or

a 4-piperidyl group optionally substituted on the nitrogen atom with a (C1-C4)alkyl group, or

a group —(CH 2 ) p —NR5R6, —(CH 2 ) p —CONR5R6 or —CO—(CH 2 ) p —NR5R6, in which p is between 1 and 3 and in which R5 and R6 represent, independently of each other, (C1-C4)alkyl groups, or

a group —(CH 2 ) p -phenyl, in which p may range from 0 to 4 and in which the phenyl radical is optionally substituted with one to three groups chosen, independently of each other, from a nitro group, a halogen atom and a trifluoromethyl group, or

a group —(CH 2 ) p -morpholinyl, —(CH 2 ) p -pyrrolidinyl or —(CH 2 ) p -tetrahydroisoquinoline, in which p is equal to 2 or 3, or

a group —(CH 2 ) p -pyrazolyl, in which p may range from 0 to 4 and in which the pyrazole group may be substituted on a carbon atom, on a nitrogen atom, or on both a carbon atom and a nitrogen atom, with one to three groups chosen from a (C1-C4)alkyl group and a phenyl group, or

a group —(CH 2 ) p -heteroaryl, in which p is equal to 0 or 1 and in which the heteroaryl group is a 4-pyridyl or a 2-pyridyl group, or

a (C1-C4)alkylcarbonyl group, or

a group —COOR′ in which R′ represents a (C1-C4)alkyl group;

or where

R1, R2′ and R9′, each represents a hydrogen atom,

R2 and R9 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group,

X represents a carbon atom,

m is equal to 1,

R3 represents a hydrogen atom, a —NH 2 group or a group —NHCOR7,

R4 represents

a phenyl group, or

a heteroaryl group chosen from:

an imidazolyl group optionally substituted with a (C1-C4)alkyl group, and

a pyrazolyl group optionally substituted, on a carbon atom, with a phenyl group, wherein the phenyl group is optionally substituted with one to three groups chosen from halogen atoms and (C1-C4)alkyl groups, or

a group —NR7R8, in which R7 and R8 represent, independently of each other, a (C1-C4)alkyl or (C1-C4)alkoxy group, or R7 and R8 together form a saturated 5- to 7-membered ring,

wherein the ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or on a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached.

4. A compound according to claim 1 , wherein

when X represents a nitrogen atom:

R4 represents:

a 4-piperidyl group substituted, on a carbon atom or on the nitrogen atom, with a (C1-C4)alkyl group, or

a group —(CH 2 ) p —NR5R6 or —(CH 2 ) p —CONR5R6, in which p may range from 1 to 4 and in which

R5 and R6 represent, independently of each other, a (C1-C4)alkyl group, or

a group —CO—(CH 2 ) p —NR5R6, in which p may range from 0 to 4 and in which

R5 and R6 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group; or

a group —(CH 2 ) p -phenyl, in which p may range from 1 to 4 and in which the phenyl radical is optionally substituted with one to three groups chosen, independently of each other, from: a (C1-C4)alkyl group, a nitro group, a hydroxyl group, an amino group, a halogen atom, a trifluoromethyl group, a (C1-C4)alkoxy group, a (C1-C4)alkylamino group, a (C1-C4)dialkylamino group, an —NHCHO group and a group —NHCOR, in which

R represents a (C1-C4)alkoxy group or a (C1-C4)alkyl group, wherein the (C1-C4)alkyl group is optionally substituted with a dimethylamino group, or

a group —(CH 2 ) p -morpholinyl, —(CH 2 ) p -pyrrolidinyl or —(CH 2 ) p -tetrahydroisoquinoline, in which p may range from 1 to 4, or

a group —(CH 2 ) p -heteroaryl, in which p may range from 1 to 4 and in which the heteroaryl group is chosen from pyridyl, aminopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl and pyrazolyl groups,

wherein said heteroaryl group is optionally substituted on a carbon atom, on a nitrogen atom, or on both a carbon atom and a nitrogen atom, with one to three groups chosen from a (C1-C4)alkyl group or a phenyl group, or

a heteroarylcarbonyl group, wherein the heteroaryl part of the heteroarylcarbonyl group is chosen from furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and imidazolyl groups, or

a phenylcarbonyl group, wherein the phenyl part of the phenylcarbonyl group is optionally substituted with a halogen atom, or

a (C1-C6)alkylcarbonyl group, or

a group —(CH 2 ) p —COOR′ in which p may range from 0 to 4 and in which R′ represents a hydrogen atom or a (C1-C6)alkyl group, or

a phenylsulphonyl group optionally substituted on the phenyl radical with a halogen atom, a trifluoromethyl group, a (C1-C4)alkyl group, a nitro group or a (C1-C4)alkoxy group, or

a group —CO—(CH 2 ) p —NR5R6, in which p may range from 0 to 4 and in which

R5 and R6 represent, independently of each other, a hydrogen atom or a (C1-C4)alkyl group; or

when X represents a carbon atom:

R3 represents

a group —NR5R6, in which R5 and R6 represent, independently of each other, a (C1-C4)alkyl group; or

a group —NHCOR7, in which R7 represents a (C1-C4)alkoxy group; or

a group —CONHR5, in which R5 represents a hydrogen atom or a (C1-C4)alkyl group; or

a group —COR7, in which R7 represents a (C1-C4)alkyl or (C1-C4)alkoxy group; or

a —NHCO NH 2 group,

or, alternatively, when X represents a carbon atom:

R4 represents:

a phenyl group substituted with one to three groups chosen, independently of each other, from: a (C1-C4)alkyl group and a trifluoromethyl group, or

an imidazolyl group substituted with a (C1-C4)alkyl group, or

a pyrazolyl group substituted, on a nitrogen atom or on a carbon atom, with a phenyl group wherein the phenyl group is optionally substituted with one to three groups chosen from halogen atoms and (C1-C4)alkyl groups, or

a group —CH 2 —NR7R8, or

a group —NR7R8,

in which R7 and R8 represent, independently of each other, a (C1-C4)alkyl group or R7 and R8 together form a saturated 5- to 7-membered ring optionally having an additional nitrogen atom, wherein the ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or on a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached.

5. A process for preparing a compound according to claim 1 , comprising reacting a compound of formula (II)

in which A represents a leaving group, with an amine of formula (III)

to obtain a compound of formula (I), and optionally reacting the compound of formula (I) with a pharmaceutically acceptable acid to form an addition salt of a compound of formula (I).

6. A pharmaceutical composition, comprising at least one compound as claimed in claim 1 , and one or more suitable pharmaceutical excipients.

7. A compound as claimed in claim 1 , wherein, when X represents a carbon atom and when R4 represents a —NR7R8 group, R7 and R8 together form a saturated 5- to 7-membered ring chosen from a 1-piperidyl group, a 1-pyrrolidinyl group and a 1-piperazinyl group, and

wherein the ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached.

8. A compound as claimed in claim 2 , wherein, when X represents a carbon atom and when R4 represents a —NR7R8 group, R7 and R8 together form a saturated 5-to 7-membered ring chosen from a 1-piperidyl group, a 1-pyrrolidinyl group and a 1-piperazinyl group, and

wherein the ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached.

9. A compound as claimed in claim 3 , wherein, when X represents a carbon atom and when R4 represents a —NR7R8 group, R7 and R8 together form a 1-piperidyl group, and

wherein the piperidyl ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached.

10. A compound as claimed in claim 4 , wherein, when X represents a carbon atom and when R4 represents a —NR7R8 group, R7 and R8 together form a saturated 5- to 7-membered ring chosen from a 1-piperidyl group, a 1-pyrrolidinyl group and a 1-piperazinyl group, and

wherein the ring is optionally substituted with a (C1-C4)alkyl group on a carbon atom or a nitrogen atom, including on the nitrogen atom to which the groups R7 and R8 are attached.

11. A process according to claim 5 , wherein the reaction of a compound of formula (II) with a compound of formula (III) takes place in a solvent chosen from an alcohol, an ether, dimethylformamide and a hydrocarbon.

12. A process according to claim 5 , wherein the reaction of a compound of formula (II) with a compound of formula (III) takes place in the presence of a base, in the presence of alkali metal halide, or in the presence of palladium-based or nickel-based catalysts.

13. A process according to claim 5 , wherein the leaving group A is a halogen.