7-aza-spiro[3.5]nonane-7-carboxylate derivatives, preparation thereof and therapeutic use thereof

1. A compound corresponding to the formula (I):

in which R 2 represents a hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl, C 1 , 6 alkyl, C 1 - 6 alkoxy or NR 8 R 9 group;

m, n, o and p independently of one another represent a number ranging from 0 to 3;

it being understood that 2 <m+n<5 and that 2<o+p<5;

A represents a covalent bond, an oxygen atom, a C 1 , 6 alkylene group or an —O—C 1 , 6 alkylene group in which the end represented by an oxygen atom is linked to the group R 1 and the end represented by an alkylene group is linked to the carbon of the bicyclic system;

R 1 represents a group R 5 optionally substituted with one or more groups R 6 and/or R 7 ;

R 5 represents a group selected from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl group;

R 6 represents a halogen atom, a cyano, —CH 2 CN, nitro, hydroxyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1 - 6 -thioalkyl, C 1-6 -haloalkyl, C 1-6 -haloalkoxy, C 1-6 -halothioalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkylene, C 3-7 -cyclo-alkyl-C 1-3 -alkylene-O—, NR 8 R 9 , NR 8 COR 9 , NR 8 CO 2 R 9 , NR 8 SO 2 R 9 , NR 8 SO 2 NR 8 R 9 , COR 8 , CO 2 R 8 , CONR 8 R 9 , SO 2 R 8 , SO 2 NR 8 R 9 or —O—(C 1-3 -alkylene)-O— group;

R 7 represents a group selected from a phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl group, the group or group(s) R 7 possibly being substituted with one or more groups R 6 which are identical to or different from one other;

R 3 represents a hydrogen or fluorine atom, a C 1-6 -alkyl group or a trifluoromethyl group;

R 4 represents a 5-membered heterocycle selected from a furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl or tetrazoyl group;

this heterocycle optionally being substituted with one or more substituents selected from a halogen atom, a C 1-6 -alkyl, C 1-6 -haloalkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkylene, C 1-6 -haloalkoxy, cyano, NR 8 R 9 , NR 8 COR 9 , NR 8 CO 2 R 9 , NR 8 SO 2 R 9 , NR 8 SO 2 NR 8 R 9 , COR 8 , CO 2 R 8 , CONR 8 R 9 , CON(R 8 ) (C 1-3 -alkylene-NR IO R II ), SO 2 R s , SO 2 NR 8 R 9 , or —O—(C 1-3 -alkylene)-O group;

R 8 and R 9 independently of each other represent a hydrogen atom or a C 1-6 -alkyl group;

or with the atom or atoms which bear them form,

in the case of NR 8 R 9 , a ring selected from the azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, azepine, oxazepine or piperazine rings, this ring possibly being substituted with a C 1-6 -alkyl or benzyl group;

in the case of NR 8 COR 9 , a lactam ring; in the case of NR 8 CO 2 R 9 , an oxazolidinone, oxazinone or oxazepinone ring; in the case of NR 8 SO 2 R 9 , a sultam ring; and in the case of NR 8 SO 2 NR 8 R 9 , a thiazolidine dioxide or thiadiazinane dioxide ring; and

R 10 and R 11 independently of one another represent a hydrogen atom or a C 1-6 -alkyl group;

in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

2. The compound of Claim 1 , wherein R 2 represents a hydrogen atom;

in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

3. The compound of Claim 1 , wherein m, n, o and p have the value 1, or else p and o have the value 1, and n and m have the value 2, or else n, o and p have the value 1 and m has the value 2;

in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

4. The compound of claim 1 , wherein A represents an oxygen atom, in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

5. The compound of claim 1 , wherein R 1 represents a group R 5 , unsubstituted or substituted with one or more groups R 6 and/or R 7 ;

R 5 represents a phenyl, naphthalenyl or isoquinolinyl group;

R 6 represents a halogen atom, more particularly a fluorine or chlorine atom, or a C 1-6 -haloalkyl, more particularly trifluoromethyl, group or a C 1-6 -alkoxy group, more particularly an ethoxy group; and

R 7 represents a phenyl which may be substituted with one or more groups R 6 which are identical to or different from one another, in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

6. The compound of claim 1 , wherein R 3 represents a hydrogen atom, in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

7. The compound of claim 1 ,wherein R 4 represents a group selected from a thiazolyl, triazolyl, oxazolyl or isoxazolyl, this group being unsubstituted or substituted with one or more C 1-6 -alkyl or CONR 8 R 9 groups, and R 8 and R 9 independently of one another represent a hydrogen atom or a C 1-6 -alkyl group, in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

8. The compound of claim 1 selected from:

Thiazol-4-ylmethyl 2-(4-chlorophenoxy)-7-aza-spiro-[3.5]nonane-7-carboxylate;

2-methyl-2H-[1,2,4]-triazol-3-ylmethyl 2-(4-chloro-phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate and the hydrochloride thereof;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chlorophenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-methylphenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4′-fluoro-biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(7-ethoxy-naphthalen-2-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate and the hydrochloride thereof;

3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(4′-fluorobiphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(7-ethoxynaphthalen-2-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

4-carbamoyl-oxazol-2-ylmethyl 2-(3-trifluoromethyl-phenoxy)-6-azo-spiro[3.4]octane-6-carboxylate;

4-methylcarbamoyl-oxazol-2-ylmethyl 2-(3-trifluoro-methylphenoxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloronaphthalen-1-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-naphthalen-1-yloxy)-7-aza-spiro[3.5]nonane-7-carb-oxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(4′-fluorobiphenyl-4-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4′-fluoro-biphenyl-4-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

4-methylcarbamoyl-thiazol-7-ylmethyl 2-(4′-fluoro-biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(isoquinolin-7-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-3-fluorophenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 6-(4-chloro-3-fluorophenoxy)-2-aza-spiro[3.3]heptane-2-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 6-(4-chloro-3-fluoro-phenoxy)-2-aza-spiro[3.3]heptane-2-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 6-(4′-fluoro-biphenyl-4-yloxy)-2-aza-spiro[3.3]heptane-2-carbox-ylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-3-fluoro-phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(4′-fluorobiphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4′-fluoro-biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloronaphthalen-1-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-naphthalen-1-yloxy)-6-aza-spiro[3.4]octane-6-carbox-ylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4′-fluoro-biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4′-fluoro-biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate;

in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof.

9. A process for preparing the compound of claim 1 , comprising reacting an amine of general formula (II),

in which A, R 1 , R 2 , m, n, o and p are as defined in the general formula (I) according to claim 1 , with a carbonate of general formula (III),

in which Z represents a hydrogen atom or a nitro group, R 3 and R 4 are as defined in the general formula (I) according to claim 1 ,

in the presence of a base, in a solvent at a temperature lying between ambient temperature and the reflux temperature of the solvent.

10. A process for preparing the compound of claim 1 , comprising reacting a compound of general formula (Ia)

in which R 2 , R 3 , R 4 , m, n, o and p are as defined in the general formula (I) according to claim 1 and G represents a part of the group A as defined in the general formula (I) namely either a covalent bond or the C 6 -alkylene part of the —O—C 1-6 -alkylene group;

with either an alcohol compound of general formula R 1 OH (IV), in which R 1 is as defined in the general formula (I) according to claim 1 , using the Mitsunobu reaction conditions;

or with a halogenated compound of general formula R 1 X (IVa) in which R 1 is as defined in the general formula (I) according to claim 1 , and X represents a fluorine, chlorine, bromine or iodine atom using aromatic or heteroaromatic nucleophilic substitution, or O-aryl-ation or Buchwald O-heteroarylation reactions.

11. A process for preparing the compound of claim 1 , in which R 1 represents a group R 5 substituted in particular with a group R 6 of the C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 3 -alkylene type, or with a group R 7 as defined in the general formula (I) according to claim 1 , comprising performing a coupling reaction, catalysed by means of a transition metal, on the compound of general formula (Ib),

in which A, R 2 , R 3 , R 4 , R 5 , m, n, o and p are as defined in the general formula (I) according to claim 1 and U 1 represents a chlorine, bromine or iodine atom or a triflate group, U 1 being in the position where it is desired to introduce the group R 6 or R 7 :

either by a Suzuki type reaction, for example by means of an alkyl, cycloalkyl, aryl or heteroaryl boronic acid,

or by a Stille type reaction, for example using an aryl or heteroaryl tri-alkyltin compound

or by a Negishi type reaction, using an alkyl, cycloalkyl, aryl or heteroaryl halide zincate compound.

12. A pharmaceutical composition comprising the compound of claim 1 , in the form of a base or an acid addition salt and stereoisomers, enantiomers, diastereoisomers, and mixtures thereof to a pharmaceutically acceptable acid.

13. The pharmaceutical composition of claim 12 , comprising one or more pharmaceutically acceptable excipients.