7-aza-spiro [3.5]nonane-7-carboxylate derivatives,
preparation thereof and therapeutic use thereof
The subject of the invention is 7-aza-spiro[3.5] nonane-
7-carboxylate derivatives, the preparation thereof and
the therapeutic use thereof.
There is still a need to find and develop products
which inhibit the enzyme FAAH (Fatty Acid Amide
Hydrolase) . The compounds of the invention meet this
purpose.
The compounds of the invention correspond to the
general formula (I):

in which
R2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trif luoromethyl, Cx-6-alkyl, Cx-6-alkoxy or NR8R9
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
S 5;
A represents a covalent bond, an oxygen atom, a C!_6-
alkylene group or an -0-C1-6-a.lkylene group in which the
end represented by an oxygen atom is linked to the
group R1 and the end represented by an alkylene group is
linked to the carbon of the bicyclic system;
Ri represents a group R5 optionally substituted with one
or more groups R6 and/or R7;
R5 represents a group selected from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl,

quinazolinyl, quinoxalinyl, cinnolinyl or naphthyrid-
iny1 group;
R6 represents a halogen atom, a cyano, -CH2CN, nitro,
hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-g-thioalkyl, C1-6-
haloalkyl, C1-6-haloalkoxy, C1-6-halothioalkyl, C3.7-
cycloalkyl, Ca-v-cycloalkyl-Qi^-alkylene, C3-7-cyclo-
alkyl-C1-3-alkylene-O-, NR8R9, NR8COR9, NR8C02R9, NR8S02R9,
NR8S02NR8R9, COR8, C02R8, C0NR8R9, S02R8, S02NR8R9 or
-0- (Cj.-3-alkylene) -0 group;
R7 represents a group selected from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl group,
the group or group(s) R7 possibly being substituted with
one or more groups R6 which are identical to or
different from one other;
R3 represents a hydrogen or fluorine atom, a C1-6-alkyl
group or a trifluoromethyl group;
R4 represents a 5-membered heterocycle selected from a
furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl,
oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thia-
diazolyl, imidazolyl, triazolyl or tetrazoyl group;
this heterocycle optionally being substituted with one
or more substituents selected from a halogen atom, or a
Ca-s-alkyl, Cx-6-haloalkyl, C3.7-cycloalkyl, C3_7-
cycloalkyl-
C1_3-alkylene, Ci^-haloalkoxy, cyano, NR8R9, NR8COR9,
NR8C02R9, NR8S02R9, NR8S02NR8R9; COR8, C02R8, CONR8R9,
C0N(R8) (C^-alkylene-NRioRn) , S02R8, S02NR8R9, or -0-(Ci_3-
alkylene)-0- group;
Rs and R9 independently of each other represent a
hydrogen atom or a C1-6-alkyl group;
or with the atom or atoms which bear them form,
in the case of NR8R9, a ring selected from the
azetidine, pyrrolidine, piperidine, morpholine, thio-
morpholine, azepine, oxazepine or piperazine rings,
this ring possibly being substituted with a C1-6-alkyl
or benzyl group;
in the case of NR8COR9, a lactam ring; in the case of
NR8C02R9, an oxazolidinone, oxazinone or oxazepinone

ring; in the case of NR8S02R9, a sultam ring; and in the
case of NR8S02NRBRs, a thiazolidine dioxide or thia-
diazinane dioxide ring; and
Rio and Rxl independently of one another represent a
hydrogen atom or a C1-6-alkyl group.
Among the compounds of general formula (I) , a first
subgroup of compounds is made up of compounds for which
R2 represents a hydrogen atom.
Among the compounds of general formula (I) , a second
subgroup of compounds is made up of compounds for which
ra, n, o and p have the value 1 or 2.
Among this subgroup, another group of compounds is made
up of the compounds for which m and n have the value 1
or 2 and o and p have the value 1.
Among the compounds of general formula (I) , a third
subgroup of compounds is made up of compounds for which
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.
Among the compounds of general formula (I) , a fourth
subgroup of compounds is made up of compounds for which
A represents an oxygen atom.
Among the compounds of general formula (I) , a fifth
subgroup of compounds is made up of compounds for which
Rx represents a group R5, unsubstituted or substituted
with one or more groups R6 and/or R7;
R5 represents a phenyl, naphthalenyl or
isoquinolinyl group;
R5 represents a halogen atom, more particularly a
fluorine or chlorine atom, or a C1-6-haloalkyl,
more particularly trifluoromethyl, group or a C1-6-

alkoxy group, more particularly an ethoxy group;
and
R7 represents a phenyl which may be substituted
with one or more groups R6 which are identical to
or different from one another.
Among the compounds of general formula (I) , a sixth
subgroup of compounds is made up of compounds for which R1 represents a group R5 substituted with one or more
groups R6 and/or R7;
R5 represents a phenyl group;
R6 represents a halogen atom, more particularly a
fluorine or chlorine atom, or a Ci_5-haloalkyl,
more particularly trifluoromethyl, group; and
R7 represents a phenyl which may be substituted
with one or more groups R6 which are identical to
or different from one another, selected from a
halogen atom, more particularly a fluorine atom.
Among the compounds of general formula (I) , an eighth
subgroup of compounds is made up of compounds for which R1 represents a group R5 substituted with one or more
groups R6;
R5 represents a naphthalen-2-yl group; and
R6 represents a C1-6-alkoxy group, more particularly
an ethoxy group.
Among the compounds of general formula (I) , a ninth
subgroup of compounds is made up of compounds for which R1 represents a group R5 substituted with one or more
groups R6 ;
R5 represents a naphthalen-1-yl group; and
R6 represents a halogen atom, more particularly a
chlorine atom.
Among the compounds of general formula (I) , a tenth
subgroup of compounds is made up of compounds for which

Ri represents an unsubstituted group R5 and R5
represents an isoquinolin-7-yl group.
Among the compounds of general formula (I), an eleventh
subgroup of compounds is made up of compounds for which
R3 represents a hydrogen atom.
Among the compounds of general formula (I) , a twelfth
subgroup of compounds is made up of 'compounds for which
R4 represents a group selected from a thiazolyl, a
triazolyl, an oxazolyl or an isoxazolyl;
this group being unsubstituted or substituted with one
or more C1-6 alkyl or CONR8R9 groups;
R8 and R9 independently of one another represent a
hydrogen atom or a C1-6-alkyl group. More particularly,
the Ci.6-alkyl group is a methyl.
Among the compounds of general formula (I) , a
thirteenth subgroup of compounds is made up of
compounds for which R4 represents a thiazol-4-yl group,
this group being unsubstituted.
Among the compounds of general formula (I) , a
fourteenth subgroup of compounds is made up of
compounds for which R4 represents a thiazol-2-yl group,
this group being substituted with one or more CONR8R9
groups;
R8 and R9 independently of one another represent a
hydrogen atom or a C1-6 alkyl group. More particularly,
the C1-6-alkyl group is a methyl.
Among the compounds of general formula (I), a fifteenth
subgroup of compounds is made up of compounds for which
R4 represents an isoxazol-5-yl group;
this group being substituted with one or more C0NRSR9
groups;

R8 and R9 independently of one another represent a
hydrogen atom or a C1-6-alkyl group. More particularly,
the C1-s-alkyl group is a methyl.
Among the compounds of general formula (I), a sixteenth
subgroup of compounds is made up of compounds for which
R4 represents a group selected from any 1H-1,2,4-
triazol-5-yl group; this group being substituted with
one or more C1-6-alkyl groups.
Among the compounds of general formula (I) , a
seventeenth subgroup of compounds is made up of
compounds for which R4 represents a group selected from
any oxazol-2-yl;
this group being substituted with one or more CONR8R9
groups ,-
R8 and R9 independently of one another represent a
hydrogen atom or a C1-6-alkyl group. More particularly,
the C^g-alkyl group is a methyl.
Among the compounds of general formula (I) , an
eighteenth subgroup of compounds is made up of
compounds of general formula (I) in which at the same
time R1 and/or R2 and/or R3 and/or R4 and/or n and/or m
and/or o and/or p and or A are as defined in the above
groups.
Among the compounds of general formula (I) , the
following compounds can be cited (IUPAC nomenclature
generated by the software AutoNom):
1. Thiazol-4-ylmethyl 2-(4-chlorophenoxy)-7-aza-spiro-
[3.5]nonane- 7 -carboxylate.
2. 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. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
phenoxy) -7-aza-spiro[3.5]nonane-7-carboxylate.

4. 3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chlorophenoxy)-
7-aza-spiro[3.5]nonane-7-carboxylate.
5. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(3-tri-
fluoromethylphenoxy)-7-aza-spiro[3.5]nonane-7-
carboxylate.
6. 3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-
methylphenoxy) -7-aza-spiro[3.5]nonane-7-carboxylate.
7. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate .
8. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(7-ethoxy-
naphthalen-2-yloxy)-7-aza-spiro[3.5]nonane-7-carb-
oxylate.
9. 3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro [3.4]octane-6-carboxylate and
the hydrochloride thereof (isomers I + II).
10. 3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro[3.4]octane-6-carboxylate
(isomer I of compound No.9).
11. 3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro[3.4]octane-6-carboxylate
(isomer II of compound No.9).
12. 3-carbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-3-yloxy)-7-aza-spiro[3.5] nonane-7-carboxylate.
13. 3-carbamoyl-isoxazol-5-ylmethyl 2-(7-ethoxynaphth-
alen-2-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate.
14. 4-carbamoyl-oxazol-2-ylmethyl 2-(3-trifluoromethyl-
phenoxy) -6-aza-spiro[3.4]octane-6-carboxylate (isomers
I + II) .
15. 4-methylcarbamoyl-oxazol-2-ylmethyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro[3.4]octane-6-carboxylate
(isomers I + II).
16. 3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloronaphth-
alen-1-yloxy)-7-aza-spiro[3.5]nonane- 7-carboxylate.

17. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
naphthalen-1-yloxy)-7-aza-spiro[3.5] nonane-7-carbox-
ylate.
18. 3-carbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-4-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate .
19. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-4-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate.
20. 4-methylcarbamoyl-thiazol-2-ylmethyl 2-(4'-fluoro-
biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate.
21. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(isoquin-
olin-7-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate.
22. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
3-fluorophenoxy)-7-aza-spiro[3.5] nonane-7-carboxylate.
23. 3-methylcarbamoyl-isoxazol-5-ylmethyl S-(4-chloro-
3-fluorophenoxy)-2-aza-spiro[3.3] heptane-2-carboxylate.
24. 3-carbamoyl-isoxazol-5-ylmethyl 6-(4-chloro-3-
fluorophenoxy)-2-aza-spiro[3.3]heptane-2-carboxylate.
25. 3-methylcarbamoyl-isoxazol-5-ylmethyl 6-(4 ' -fluoro-
biphenyl-4-yloxy)-2-aza-spiro[3.3]heptane-2-carbox-
ylate.
26. 3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-3-
fluorophenoxy)-6-aza-spiro[3.4]octane-5-carboxylate
(isomers I + II).
27. 3-methylcarbamoyl-isoxazol-5-ylraethyl 2-(4-chloro-
phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate (isomers
I + II) .
28. 3-carbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4] octane-6-carboxylate
(isomers I + II).
29. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4 '-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4] octane-6-carboxylate
(isomers I + II).

30. 3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloronaphth-
alen-1-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomers I + II).
31. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
naphthalen-1-yloxy)-6-aza-spiro[3.4]octane-6-carbox-
ylate (isomers I + II).
32. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4 '-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomer I of compound 29).
33. 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4 '-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4] octane-6-carboxylate
(isomer II of compound 29).
The compounds of general formula (I) can contain one or
more asymmetric carbons. They can exist in the form of
enantiomers or diastereoisomers. The compounds of
general formula (I) can also exist in the form of cis
or trans stereoisomers. These stereoisomers,
enantiomers and diastereoisomers, and mixtures thereof,
including racemic mixtures, are part of the invention.
The compounds of formula (I) can exist in the state of
bases or of acid addition salts. Such addition salts
are part of the invention.
These salts are advantageously prepared with pharma-
ceutically acceptable acids, but the salts of other
acids useful, for example, for the purification or the
isolation of the compounds of formula (I) are also part
of the invention.
In the context of the invention, the following meanings
are understood:
- Ct-z where t and z can take values from 1 to 8, a
carbon chain which can have from t to z carbon atoms,
for example C1-3/ a carbon chain which can have from 1
to 3 carbon atoms;

- alkyl, a saturated, linear or branched aliphatic
group, for example a C1-6-alkyl group represents a
linear or branched carbon chain of 1 to 6 carbon
atoms, more particularly a methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, fcert-butyl, pentyl or
hexyl;
- alkylene, a divalent saturated, linear or branched,
alkyl group, for example a Ci.3-alkylene group
represents a divalent, linear or branched carbon
chain of 1 to 3 carbon atoms, more particularly a
methylene, ethylene, 1-methylethylene or propylene;
- cycloalkyl, a cyclic alkyl group, for example a C3-7-
cycloalkyl group represents a cyclic carbon group of
3 to 7 carbon atoms, more particularly a cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
- alkoxy, an -O-alkyl group with a saturated, linear or
branched aliphatic chain;
- thioalkyl, an -S-alkyl group with a saturated, linear
or branched aliphatic chain;
- haloalkyl, an alkyl group one or more hydrogen atoms
whereof have been replaced by a halogen atom;
- haloalkoxy, an alkoxy group one or more hydrogen
atoms whereof have been replaced by a halogen atom;
- halothioalkyl, a thioalkyl group one or more hydrogen
atoms whereof have been replaced by a halogen atom;
- halogen atom, a fluorine, chlorine, bromine or
iodine;
- TFA: trifluoroacetic acid;
- ACN: acetonitrile.
The compounds of the invention can be prepared by
different methods, illustrated by the following
schemes. These methods, and the intermediate compounds
used, are a subject of the present invention.
Scheme 1


Thus a first preparation method (scheme 1) consists in
reacting an amine of general formula (II), in which A,
Ri, R2, m, n, o and p are as defined in the general
formula (I) defined above, with a carbonate of general
formula (III), in which Z represents a hydrogen atom or
a nitro group, and R3 and R4 are as defined in the
general formula (I) defined above, in presence of a
base such as triethylamine, pyridine, N,N-dimethyl-
aminopyridine or N,N-diisopropylethylamine, in a
solvent such as toluene, acetonitrile or dichloroethane
at a temperature lying between ambient temperature and
the reflux temperature of the solvent.

A second preparation method (scheme 2) for obtaining
the compounds of general formula (I) in which A more
particularly represents an oxygen atom or an -0-C1-6-
alkylene group, consists in reacting, in a first step,
an alcohol of general formula (Ila), in which R2, m, n,
o and p are as defined in the general formula (I)
defined above, G represents a part of the group A as
defined in the general formula (I) namely either a
covalent bond or the CVg-alkylene part of the -O-Cx 6-

alkylene group and GP represents a protective group
such as a Boc (tert-butyloxycarbonyl), Cbz
(benzyloxycarbonyl), benzyl or benzhydryl;
- either with an alcohol derivative of general
formula (IV) , in which Rx is as defined above
using the Mitsunobu reaction conditions
(Synthesis, 1981, 1-28),
- or with a halogen derivative of general formula
(IVa) , in which R1 is as defined above and X
represents a fluorine, chlorine, bromine or
iodine atom, using aromatic or heteroaromatic
nucleophilic substitution, or O-arylation or
Buchwald O-heteroarylation reactions, for
example by means of a palladium- or copper-
containing catalyst;
followed by a deprotection reaction, for example in
presence of trifluoroacetic acid or a solution of
hydrochloric acid in isopropanol or dioxan, to result
in the amine of the general formula (lib) , in which G,
R2, m, n, o and p are as defined in the above amine of
formula (Ila) and R1 is as defined in the general
formula (I) defined above. An alternative to the
Mitsunobu reaction consists in reacting an alcohol
derivative of general formula (IV) with the compounds
of general formula (lie) obtained by activation of the
alcohol function of the compounds of general formula
(Ila) by a tosylate group. The derivative of general
formula (lib) thus obtained is then transformed into a
compound of general formula (I) by a condensation
reaction with a carbonate of general formula (III) as
defined above, under the conditions described above
(Scheme 1).
An alternative for obtaining compounds of general
formula (I) (Scheme 2) in which A more particularly
represents an oxygen atom or an -0-C1-6-alkylene group,
consists in deprotecting an alcohol of general formula

(Ila) as defined above, by a deprotection reaction as
defined above in order to obtain an amino alcohol of
general formula (lie) , then in reacting this amino
alcohol of general formula (lie), in which R2, m, n, o
and p are as defined in the general formula (I) defined
above, and G represents a part of the group A as
defined in the general formula (I) namely either a
covalent bond or the C1-6-alkylene part of the -0-C1-6-
alkylene group, with a carbonate of general formula
(III) as defined above, under the conditions described
above (Scheme 1), to result in the carbamate derivative
of general formula (la) , in which R2, R3, R4, m, n, o
and p are as defined in the general formula (I) defined
above and G represents a part of the group A as defined
in the general formula (I) namely either a covalent
bond or the C1-6-alkylene part of the -0-C1-6-alkylene
group. The carbamate derivative (la) thus obtained is
then transformed into a compound of general formula (I)
by the action of an alcohol of general formula RiOH (IV)
as defined above, using the Mitsunobu reaction
conditions or by the action of a halogenated derivative
of general formula RiX (IVa) as defined above, using
aromatic or heteroaromatic nucleophilic substitution,
or O-arylation or Buchwald O-heteroarylation reactions,
for example by means of a palladium- or copper-
containing catalyst.

A third method (Scheme 3) was developed as regards the
synthesis of compounds of general formula (I) , in which R1 represents a group R5 substituted in particular with

a group R6 of the C1-5-alkyl, C3_7-cycloalkyl or C3.7-
cycloalkyl-C1-3-alkylene type, or with a group R7 as
defined in the general formula (I) defined above. Thus,
the first stage consists in reacting an amine of
general formula (lid) , in which A, R2, R5, m, n, o and p
are as defined in the general formula (I) defined above
and Ui represents a chlorine, bromine or iodine atom or
a triflate group, with a carbonate of general formula
(III) as defined above, under the conditions defined
above (Scheme 1), to result in the carbamate derivative
of general formula (lb), in which A, R2, R3, R4, R5, m,
n, o and p are as defined in the general formula (I)
defined above and Ui is as defined above. The coupling
reaction catalysed by means of a transition metal such
as palladium (0) is then performed on the key
intermediate of general formula (lb) as defined above,
U-! being in the position where it is desired to
introduce the group R6 or R7 (Scheme 3) :
- 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 derivative
- or by a Negishi type reaction, for example using an
alkyl, cycloalkyl, aryl or heteroaryl halide zincate
derivative.
Another subject of the present invention relates to the
compounds of formula (III)
in which Z represents a hydrogen atom or a nitro group,
R3 is as defined in the formula (I) and R4 represents a
4-(methylcarbamoyl)-oxazol-2-yl group.
Another subject of the present invention relates to the
compounds of general formula (la):


in which R2, R3, R4, m, n, o and p are as defined in the
general formula (I) and G represents a part of the
group A as defined in the general formula (I) namely
either a covalent bond or the C1-6-alkylene part of the
-0-C1-6-alkylene group.
Among these compounds, thiazol-4-ylmethyl 2-hydroxy-7-
aza-spiro[3.5]nonane-7-carboxylate may be cited.
Another subject of the present invention relates to the
compounds of general formula (lb):

in which A, R2, R3, R4, R5, m, n, o and p are as defined
in the general formula (I) according to claim 1 and Ui
represents a chlorine, bromine or iodine atom or a
triflate group.
Another subject of the present invention relates to the
compounds of general formula (II):

in which Rlr R2, m, n, o and p are as defined in the
general formula (I) and A represents an oxygen atom, it
being given that Rx is not a fluorophenyl group.
Among these compounds, the following can be cited:
2-(4-chlorophenoxy)-7-aza-spiro[3.5]nonane;
2-(4'-fluorobiphenyl-3-yloxy)-7-aza-spiro[3.5]nonane;
2-(4'-fluorobiphenyl-4-yloxy)-7-aza-spiro[3.5]nonane
^H NMR (DMSO) 5 (ppm) : 8.80 (broad s, 2H) , 7.65
(t, 2H) ; 7.60 (d, 2H) ; 7.30 (t, 2H) ; 6.95 (d, 2H) ; 4.80

(qt, 1H) ; 3.00 (broad d, 4H) ; 2.55 (m, 2H) ; 1.90 (m,
2H); 1.80 (dt, 4H));
2-(4-chloronaphthalen-l-yloxy)-7-aza-spiro[3.5]nonane;
2-(4-chloronaphthalen-l-yloxy)-6-aza-spiro[3.4]octane;
2- (3-trifluoromethylphenoxy)-6-aza-spiro[3.4]octane;
2-(4'-fluoro-biphenyl-4-yloxy)-6-aza-spiro[3.4]octane;
6-(4-chloro-3-fluorophenoxy)-2-aza-spiro[3.3]heptane;
6-(4'-fluorobiphenyl-4-yloxy)-2-aza-spiro[3.3]heptane;
2-(7-ethoxynaphthalen-2-yloxy)-7-aza-spiro[3.5]nonane
^H NMR (DMSO) 5 (ppm) : 8.90 (broad s, 2H) , 7.75
(d, 2H); 7.20 (s, 1H); 7.10 (s, 1H); 7.00 (d, 1H); 6.95
(d, 1H) ; 4.85 (qt, 1H) ; 4.15 (qd, 2H) ; 3.00 (broad d,
4H) ; 2.55 (m, 2H) ; 1.95 (m, 2H) ; 1.80 (dt, 4H) ; 1.40
(t, 3H));
6- (7-aza-spiro[3.5]non-2-yloxy)isoquinoline
(XH NMR (DMSO) 5 (ppm): 9.20 (s, 1H) , 8.35 (d, 1H) ;
7.90 (d, 1H) ; 7.65 (d, 1H) ; 7.40 (t, 2H) ; 4.90 (qt,
1H) ; 2.65 (broad d, 4H) ; 2.50 (m, 2H) ; 1.85 (m, 2H) ;
1.55 (dt, 4H));
2-(4-chlorophenoxy)-6-aza-spiro[3.4]octane
Cu NMR (DMSO) 5 (ppm): 8.80 (broad s, 2H) , 7.35
(d, 1H) ; 6.90 (t, 2H) ; 4.75 (qt, 1H) ; 3.20 (m, 4H) ;
2.60 (m, 2H); 2.15 (m, 2H); 2.00 (m, 2H)).
Another subject of the present invention relates to the
compounds of general formula (Ila):

in which R2 is as defined in the general formula (I), o
and p represent 1, and m and n represent 1 or 2, but m
and n do not together represent the value 2, G
represents a part of the group A as defined in the
general formula (I) , namely either a covalent bond or
the C1-6-alkylene part of the -0-C1-6-alkylene group, and
GP represents a protective group such as a Boc (tert-
butyloxycarbonyl), Cbz (benzyloxycarbonyl), benzyl or
benzhydryl.

Among these compounds, the following can be cited:
tert-butyl 2-hydroxy-6-aza-spiro[3.4]octane-6-carbox-
ylate
(XH NMR (DMSO) 5 (ppm): 4.7 (t, 1H); 4.1 (m, 1H);
3.2 (m, 4H); 2.2 (m, 2H); 1.8 (m, 4H); 1.4 (s, 9H) ) ;
tert-butyl 6-hydroxy-2-aza-spiro[3.3]heptane-2-carb-
oxylate
(^ NMR (DMSO) 5 (ppm): 5.00 (d, 1H); 3.95 (hex,
1H); 3.75 (d, 4H); 2.40 (ra, 2H); 1.95 (m, 2H); 1.40 (s,
9H)) .
Another subject of the present invention relates to the
compounds of general formula (lie):

in which R2 is as defined in the general formula (I) , o
and p represent 1, m and n represent 1 or 2, but m and
n do not together represent the value 2, G represents a
part of the group A as defined in the general formula
(I) , namely either a covalent bond or the C1-6-alkylene
part of the -0-C1-6-alkylene group and GP represents a
protective group such as a Boc (tert-butyloxycarbonyl),
Cbz (benzyloxycarbonyl), benzyl or benzhydryl.
Among these compounds, the following can be cited:
tert-butyl 2-(toluene-4-sulphonyloxy)-6-aza-spiro[3.4]-
octane-6 -carboxylate
(XH NMR (DMSO) 6 (ppm): 7.80 (d, 2H) , 7.50 (d, 2H) ;
4.90 (m, 1H) ; 3.15 (m, 4H) ; 2.45 (s, 3H) ; 2.20 (m, 2H) ;
2.10 (m, 2H); 1.80 (t, 2H); 1.40 (s, 9H) ) ;
tert-butyl 2-(toluene-4-sulphonyloxy)-6-aza-spiro [3.4] -
octane-6-carboxylate (isomer 2a)
^H NMR (DMSO) 5 (ppm): 7.80 (d, 2H) , 7.50 (d, 2H) ;
4.90 (qt, 1H) ; 3.15 (m, 4H) ; 2.45 (s, 3H) ; 2.25 (t,
2H); 2.05 (t, 2H); 1.80 (m, 2H); 1.40 (s, 9H));
tert-butyl 2-(toluene-4-sulphonyloxy)-6-aza-spiro[3.4]-
octane-6-carboxylate (isomer 2b)

(XH NMR (DMSO) 5 (ppm) : 7.80 (d, 2H) , 7.50 (d, 2H) ;
4.90 (qt, 1H) ; 3.20 (m, 4H) ; 2.45 (s, 3H) ; 2.20 (t,
2H); 2.10 (t, 2H); 1.80 (m, 2H); 1.40 (s, 9H)).
The other compounds of general formulae (II), (Ila),
(lib), (He), (lid), (III), (IV) and (IVa) and the
other reagents are commercially available or described
in the literature, or else can be prepared by the
methods which are described there and which are known
by the person skilled in the art.
The examples that follow illustrate the preparation of
some compounds of the invention. These examples are not
limiting and only illustrate the invention. The micro-
analyses, the IR and NMR spectra and/or the LC-MS
(Liquid Chromatography coupled to Mass Spectrometry)
confirm the structures and the purities of the
compounds obtained.
MP (°C) represents the melting point in degrees
Celsius.
RE indicates the retention time obtained by TLC (thin
layer chromatography) analysis.
The numbers shown in brackets in the titles of the
examples correspond to those in the first column in the
tables below.
The IUPAC (International Union of Pure and Applied
Chemistry) nomenclature was used for the naming of the
compounds in the examples below.
Compound No. 9 is a mixture of isomers. Compound No. 10
is isomer I of compound No. 9 and compound No. 11 is
isomer II of compound No.9.
Compound No.2 9 is a mixture of isomers. Compound No. 32
is isomer I of compound No.29 and compound No.33 is
isomer II of compound No.29.
Compounds 14, 15, 26, 27, 28, 30 and 31 are mixtures of
isomers.

Example 1 (Compound No.l)
Thiazol-4-ylmethyl 2-(4-chlorophenoxy)-7-aza-spiro-
[3.5]nonane-7 -c arboxylat e
1.1 7-Aza-spiro[3.5]non-2-yl acetate, hydrobromide
0.800 g (2.91 mmoles) of benzyl 2-hydroxy-7-aza-spiro-
[3.5]nonane-7-carboxylate (WO 9222550) is slowly added
to 5 ml of a 5. 7N solution of hydrobromic acid in
acetic acid cooled to 0°C. After stirring for 1 hr at
0°C, 50 ml of diethyl ether are added and the medium is
stirred for 1 hr. The precipitate formed is filtered on
a fritted filter and copiously rinsed with diethyl
ether. After drying overnight under vacuum at 80 °C,
0.3 80 g of the expected product are obtained in the
form of a white solid.
1.2 Thiazol-4-ylmethyl 2-acetoxy-7-aza-spiro [3.5]-
nonane-7 -carboxylate
0.280 g (1.06 mmoles) of 7-aza-spiro[3.5]non-2-yl
acetate, hydrobromide, obtained in stage 1.1, is
dissolved in 3 ml of methanol. 0.20 ml (1.17 mmoles) of
N,N-diisopropylethylamine is added at ambient
temperature. The medium is stirred for 3 minutes then
0.297 g (1.06 mmoles) of thiazole-4-ylmethyl (4-nitro-
phenyl)carbonate (WO 2008013834) in solution in 3 ml of
dichloromethane is added. After stirring for 14 hrs at
ambient temperature, the medium is diluted with
dichloromethane and a IN aqueous solution of caustic
soda. After separation of the aqueous phase, the
organic phase is washed twice with a IN aqueous
solution of caustic soda then three times with a
saturated aqueous solution of ammonium chloride, dried
over sodium sulphate, filtered and concentrated to
dryness. 0.33 g of the expected product are obtained in
the form of a powder, used as such in the following
stage.
Melting point (°C) = 94-96°C

XH NMR (CDCI3) 5 (ppm): 8.85 (s, 1H), 7.40 (s, 1H); 5.35
(s, 2H) ; 5.10 (qt, 1H) ; 3.50 (m, 4H) ; 2.40 (m, 2H) ;
2.10 (s, 3H); 1.90 (m, 2H); 1.65 (m, 4H).
1.3 Thiazol-4-ylmethyl 2-hydroxy-7-aza-spiro[3.5]-
nonane- 7 -carboxylate
0.267 g (0.82 mmole) of the thiazol-4-ylmethyl
2-acetoxy-7-aza-spiro[3.5]nonane-7-carboxylate obtained
in stage 1.2 is dissolved in 2 ml of methanol then
0.5 ml of water and 0.114 g (0.82 mmole) of potassium
carbonate are added. After stirring for 1 hr at ambient
temperature, the medium is concentrated under vacuum
then taken up in water. The aqueous solution is
extracted twice with dichloromethane then the organic
phases are combined, dried over sodium sulphate,
filtered and concentrated to dryness. 0.222 g of the
expected product are obtained in the form of a colour-
less oil.
XH NMR (CDCI3) 5 (ppm): 8.75 (s, 1H) , 7.30 (s, 1H) ; 5.20
(s, 2H) ; 4.25 (qt, 1H) ; 3.35 (m, 4H) ; 2.20 (m, 2H) ;
1.65 (m, 2H) ; 1.45 (m, 4H) .
1.4 Thiazol-4-ylmethyl 2-(4-chlorophenoxy)-7-aza-spiro-
3.5] nonane-7-carboxylate
Under an inert atmosphere, 0.11 g (0.39 mmole) of
thiazol-4-ylmethyl 2-hydroxy-7-aza-spiro[3.5]-nonane-7-
carboxylate, obtained in stage 1.3, is dissolved in
4 ml of toluene. 0.160 g (0.61 mmole) of triphenyl-
phosphine and 0.060 g (0.47 mmole) of 4-chlorophenol
are added. The medium is cooled to 0°C and a solution
of 0.096 g (0.48 mmole) of diethylazodicarboxylate in 1
ml of toluene is added. The medium is stirred for
14 hrs at ambient temperature then concentrated under
vacuum. The residue obtained is taken up in water and
extracted twice with ethyl acetate. The combined
organic phases are dried over sodium sulphate, filtered
and concentrated under vacuum. The residue obtained is
purified by silica gel chromatography eluting with a

mixture of 50/50 to 80/20 of cyclohexane and ethyl
acetate. 0.04 g of the expected product are obtained in
the form of a solid.
Melting point (°C): 86-88°C
LC-MS: M+H = 393
XH NMR (CDC13) 5 (ppm) : 8.85 (s, 1H) , 7.40 (s, 1H) ; 7.30
(t, 2H) ; 6.80 (d, 2H) ; 5.35 (s, 2H) ; 4.70 (qt, 1H) ;
3.35 (m, 4H) ; 2.45 (m, 2H) ; 2.00 (s, 2H) ; 1.65 (m, 4H) .
Example 2 (Compound No.2)
2-Methyl-2H-[1,2,4]triazol-3-ylmethyl 2-(4-chloro-
phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate hydro-
chloride
2.1 Tert-butyl 2-(4-chlorophenoxy)-7-aza-spiro[3.5]-
nonane- 7-carboxylate
Under an inert atmosphere, 0.60 g (2.49 mmoles) of
tert-butyl 2-hydroxy-7-aza-spiro[3.5]-nonane-7-carbox-
ylate (WO 2003084948) is dissolved in 25 ml of toluene.
1.024 g (3.90 mmoles) of triphenylphosphine and 0.384 g
(2.98 mmoles) of 4-chlorophenol are added. The medium
is cooled to 0°C, then a solution of 0.528 g (3.03
mmoles) of diethylazodicarboxylate in 3 ml of toluene
is added. The medium is stirred for 14 hrs at ambient
temperature then concentrated under vacuum. The residue
obtained is taken up in a saturated aqueous solution of
sodium carbonate and extracted twice with dichloro-
methane. The combined organic phases are washed once
with a saturated aqueous solution of sodium chloride,
dried over sodium sulphate, filtered and concentrated
under vacuum. 0.874 g of a residue is obtained, which
is used as such in the following stage.
2.2 2-(4-chlorophenoxy)-7-aza-spiro[3.5]-nonane
0.874 g (2.49 mmoles) of tert-butyl 2-(4-chlorophen-
oxy) -7-aza-spiro-[3.5]nonane-7-carboxylate, obtained in
stage 2.1, is taken up in 5 ml of dioxan and 9.32 ml
(37.29 mmoles) of a 4N solution of hydrochloric acid in
dioxan are added slowly with stirring. After stirring

for 3 hrs at ambient temperature, the medium is
concentrated under vacuum and the residue is taken up
in a IN aqueous solution of hydrochloric acid. The
aqueous phase is extracted twice with ethyl acetate
then slowly basified to pH 10 by addition of 35%
caustic soda solution. The aqueous phase is extracted
three times with dichloromethane. These three organic
extracts are combined, washed once with a saturated
aqueous solution of sodium chloride, dried over sodium
sulphate, filtered and concentrated under vacuum.
0.460 g of the expected product are obtained in the
form of a yellow oil.
2H NMR (DMSO) 5 (ppm): 7.30 (d, 2H), 6.85 (d, 2H) ; 4.70
(qt, 1H) ; 2.65 (dt, 4H) ; 2.40 (m, 2H) ; 1.75 (m, 2H) ;
1.50 (dt, 4H).
2.3 2-Methyl-2H-[1,2,4]triazol-3-ylmethyl 2-(4-chloro-
phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate
0.100 g (0.40 mmole) of (2-methyl-2H-[1,2,4]triazol-3-
yl)methanol and 0.15 ml (0.83 mmole) of N,N-diiso-
propylethylamine are dissolved in 4 ml of 1,2-dichloro-
ethane. The medium is cooled to 0°C then 0.08 g (0.40
mmole) of p-nitrophenyl chloroformate in solution in 2
ml of 1,2-dichloroethane is added. The mixture is
stirred for 15 mins at ambient temperature then 0.100 g
(0.40 mmole) of 2-(4-chlorophenoxy)-7-aza-spiro [3 . 5] -
nonane, obtained in stage 2.2, is added. The mixture is
heated at 6 0 °C for 15 hrs. After return to ambient
temperature, the medium is diluted with a IN aqueous
solution of caustic soda, and the product is extracted
with dichloromethane. The combined organic phases are
then successively washed three times with a 1M aqueous
solution of caustic soda, twice with a saturated
aqueous solution of ammonium chloride and once with a
saturated aqueous solution of sodium chloride, dried
over sodium sulphate, filtered and evaporated to
dryness. After purification on a silica gel column
eluting with dichloromethane then with a 99/1/0.1 then

98/2/0.2 and 97/3/0.3 mixture of dichloromethane,
methanol and 30% aqueous ammonia, 0.100 g of expected
product are obtained in the form of a colourless oil
which is taken up in a 5-6N solution of hydrochloric
acid in propan-2-ol. The white solid formed is taken up
in diethyl ether, filtered off and dried under vacuum.
0.8 0 g of the hydrochloride of the expected product are
obtained in the form of a white powder.
Melting point (°C): 163-165°C
LC-MS: M + H = 391
XH NMR (DMSO) 5 (ppm) : 7.95 (s, 1H) ; 7.30 (d, 2H) , 6.85
(d, 2H) ; 5.20 (s, 2H) ; 4.75 (qt, 1H) ; 3.90 (s, 3H) ;
3.35 (broad d, 4H) ; 2.45 (m, 2H) ; 1.80 (m, 2H) ; 1.55
(dt, 4H).
Example 3 (Compound No.3)
3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate
3.1 3-ethoxycarbonyl-isoxazol-5-ylmethyl 2-(4-chloro-
phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate
0.172 g (1.00 mmole) of ethyl 5-hydroxymethyl-
isoxazole-3-carboxylate and 0.33 ml (1.92 mmoles) of
N,N-diisopropylethylamine are dissolved in 9 ml of
1,2-dichloroethane then cooled to 0°C. 0.184 g
(0.91 mmole) of p-nitrophenyl chloroformate in solution
in 2 ml of 1,2-dichloromethane are added. The mixture
is stirred for 20 mins at ambient temperature, then
0.230 g (0.91 mmole) of 2-(4-chlorophenoxy)-7-aza-
spiro [3 . 5] -nonane, obtained in stage 2.2, is added. The
mixture is heated at 60°C for 15 hrs. After return to
ambient temperature, a IN aqueous solution of caustic
soda is added, and the product is extracted with
dichloromethane. The combined organic phases are then
successively washed three times with a IN aqueous
solution of caustic soda, twice with a saturated
aqueous solution of ammonium chloride and once with a
saturated aqueous solution of sodium chloride, dried
over sodium sulphate, filtered and evaporated to

dryness. 0.447 g of the expected product are obtained
in the form of a colourless oil which is used as such
in the following stage.
3.2 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
phenoxy)-7-aza-spiro[3.5]nonane-7-carboxylate
In a sealed tube, 0.18 0 g (0.40 mmole) of 3-ethoxy-
carbonyl-isoxazol-5-ylmethyl 2-(4-chlorophenoxy)-7-aza-
spiro [3 . 5] nonane- 7 -carboxylate, obtained in stage 3.1,
is dissolved in 5 ml of methanol. 0.5 ml (4.00 mmoles)
of an 8N solution of methylamine in ethanol is added,
then the medium, with the tube sealed, is heated at
60°C with stirring for 3 hrs. After returning to
ambient temperature, the medium is concentrated under
vacuum and the residue obtained is chromatographed on
silica gel preparative plates eluting with a 95/5/0.5
mixture of dichloromethane, methanol and 3 0% aqueous
ammonia. 0.073 g of the expected product are thus
obtained in the form of a white powder.
Melting point (°C): 147-149°C
LC-MS: M+H = 434
2H NMR (DMSO) 5 (ppm): 8.85 (s, 1H); 7.35 (d, 2H), 6.90
(d, 2H) ; 6.80 (s, 1H) ; 5.25 (s, 2H) ; 4.75 (qt, 1H) ;
3.35 (broad d, 4H) ; 2.80 (s, 3H) ; 2.45 (m, 2H) ; 1.80
(m, 2H); 1.55 (dt, 4H).
Example 4 (Compound No.4)
3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chlorophenoxy)-7-
aza-spiro[3.5]nonane-7-carboxylate
4.1 3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chlorophen-
oxy) -7-aza-spiro[3.5]nonane-7-carboxylate
In a sealed tube, 0.190 g (0.42 mmole) of 3-ethoxy-
carbonyl-isoxazol-5-ylmethyl 2-(4-chlorophenoxy)-7-aza-
spiro [3 . 5] nonane- 7 -carboxylate, obtained in stage 3.1,
is dissolved in 5 ml of methanol. 0.91 ml (6.36 mmoles)
of a 7N solution of ammonia in methanol is added, and
the medium is heated at 50°C for 15 hrs. After
returning to ambient temperature, the medium is

concentrated under vacuum and the residue obtained is
chromatographed on silica gel preparative plates
eluting with a 95/5/0.5 mixture of dichloromethane,
methanol and 30% aqueous ammonia. An oil is obtained
which crystallises in pentane. The solid obtained is
filtered off and dried under vacuum at 60°C. 0.104 g of
the expected product are obtained in the form of a
white powder.
Melting point (°C): 70-72°C
LC-MS: M+H = 420
XH NMR (DMSO) 5 (ppm): 8.15 (s, 1H); 7.85 (s; 1H); 7.30
(d, 2H) , 6.90 (d, 2H) ; 6.80 (s, 1H) ; 5.25 (s, 2H) ; 4.75
(qt, 1H) ; 3.35 (broad d, 4H) ; 2.45 (t, 2H) ; 1.80 (t,
2H); 1.55 (d, 4H).
Example 5 (Compound No.20)
4-methylcarbamoyl-thiazol-2-ylmethyl 2-(4'-fluoro-
biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate
5.1 2-(4'-fluorobiphenyl-3-yloxy)-7-aza-spiro[3.5]-
nonane
The procedure described in Example 2 stages 2.1 and 2.2
is followed. From 0.500 g (2.07 mmoles) of tert-butyl
2-hydroxy-7-aza-spiro[3.5]-nonane-7-carboxylate (WO
2003084948), 0.468 g (2.49 mmoles) of 4'-fluoro-
biphenyl-3-ol, 0.440 g (2.53 mmoles) of diethyl
azodicarboxylate, 0.853 g (3.25 mmoles) of triphenyl-
phosphine and 7.77 ml of a 4N solution of hydrochloric
acid in dioxan, 0.645 g of the expected product are
obtained in the form of a wax used as such in the
following stage.
5.2 Methyl 2-hydroxymethyl-thiazole-4-carboxylate
5.2.1 Ethyl 2-[(acetyloxy)methyl]-1,3-thiazole-4-carb-
oxylate
2.7 g (10.80 mmoles) of ethyl 2-(bromomethyl) thiazole-
4-carboxylate are dissolved in 108 ml of acetonitrile.
2.225 g (22.67 mmoles) of potassium acetate are added

and the mixture is stirred for 14 hrs at ambient
temperature.
It is concentrated under reduced pressure. The residue
obtained is taken up in a saturated aqueous solution of
sodium chloride and extracted twice with dichloro-
methane. The combined organic phases are dried over
sodium sulphate, filtered and concentrated to dryness.
2.347 g of the expected product are obtained in the
form of a wax.
2H NMR (CDCI3) 5 (ppm) : 8.15 (s, 1H) ; 5.35 (s, 2H) ; 4.35
(qd, 2H); 2.10 (s, 3H); 1.35 (t, 3H).
5.2.2 Methyl 2-hydroxymethyl-thiazole-4-carboxylate
2.347 g (10.24 mmoles) of ethyl 2-acetoxymethyl-
thiazole-4-carboxylate, obtained in stage 5.2.1, are
dissolved in 100 ml of a 5/1 mixture of dichloromethane
and methanol. 2.58 ml (11.26 mmoles) of a 4.37N
solution of sodium methanolate in methanol are added
and the medium is stirred for two hrs at ambient
temperature before being concentrated under reduced
pressure. The residue obtained is taken up in a
saturated aqueous solution of sodium chloride and
extracted three times with dichloromethane. The
combined organic phases are washed once with a
saturated aqueous solution of sodium chloride, dried
over sodium sulphate, filtered and concentrated to
dryness. The residue obtained is purified by silica gel
chromatography eluting with a 98/2/0.2 mixture of
dichloromethane, methanol and 30% aqueous ammonia.
0.92 g of the expected product are obtained in the form
of a white powder.
Melting point (°C): 158-160°C
XH NMR (CDCI3) 5 (ppm): 8.10 (s, 1H) ; 4.95 (s, 2H) ; 3.90
(s, 3H); 2.50 (broad s, 1H).

5.3 4-methoxycarbonyl-thiazol-2-ylmethyl 2-(4 ' -fluoro-
biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate
The procedure described in Example 2 stage 2.3 is
followed. From 0.19 g (0.61 mmole) of 2-(4' -fluoro-
biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane, obtained in
stage 5.1, 0.127 g (0.73 mmole) of methyl 2-hydroxy-
methyl-thiazole-4-carboxylate, obtained in stage 5.2.2,
0.135 g (0.67 mmole) of para-nitrophenyl chloroformate
and 0.265 ml (1.53 mmoles) of N,N-diisopropylethylamine
and after silica gel chromatography eluting with a 99/1
mixture of dichloromethane and methanol, 0.161 g of the
expected product are obtained in the form of a wax.
XH NMR (CDC13) 5: 8.10 (s, 1H) ; 7.45 (t, 2H) ; 7.25 (t,
1H) , 7.05 (m, 3H) ; 6.90 (d, 1H) ; 6.70 (d, 1H) ; 5.35 (s,
2H) ; 4.70 (qt, 1H) ; 3.90 (s, 3H) ; 3.40 (m, 4H) ; 2.35
(m, 2H) ; 1.95 (m, 2H) ; 1.60 (m, 4H) .
5.4 4-methylcarbamoyl-thiazol-2-ylmethyl 2-( 4'-fluoro-
biphenyl-3-yloxy)-7-aza-spiro[3.5]nonane-7-carboxylate
In a sealed tube, 0.15 5 g (0.30 mmole) of 4-methoxy-
carbonyl-thiazol-2-ylmethyl 2-(4' -fluoro-biphenyl-3-yl-
oxy)-7-aza-spiro[3.5]nonane-7-carboxylate, obtained in
stage 5.3, is dissolved in 6 ml of ethanol. 1 ml (8.00
mmoles) of an 8N solution of methylamine in ethanol is
added and the medium is stirred for 15 hrs at ambient
temperature. After concentration of the medium under
vacuum, the residue obtained is purified by silica gel
chromatography eluting with dichloromethane, then with
a 99/1/0.1 mixture of dichloromethane, methanol and 30%
aqueous ammonia. A wax is obtained which crystallises
in diisopropyl ether to give, after filtration and
drying under vacuum at 60°C, 0.087 g of the expected
product in the form of a white powder.
Melting point (°C): 130-132°C
LC-MS: M+H = 510
XH NMR (DMSO) 5 (ppm): 8.35 (broad s, 1H); 8.25 (s, 1H);
7.70 (t, 2H) ; 7.35 (t, 1H) ; 7.30 (t, 2H) ; 7.20 (d, 1H) ;
7.05 (s, 1H) ; 6.85 (d, 1H) ; 5.35 (s, 2H) ; 4.90 (qt,

1H) ; 3.40 (broad d, 4H) ; 2.80 (s, 3H) ; 2.50 (m, 2H) ;
1.85 (m, 2H); 1.60 (dt, 4H).
Example 6 (Compound No.17)
3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
naphthalen-1-yloxy)-7-aza-spiro[3.5]nonane-7-carb-
oxylate
6.1 3-methylcarbamoyl-isoxazol-5-ylmethyl 4-nitrophenyl
carbonate
2.58 g (12.81 mmoles) of .4-nitrophenyl chloroformate
are added in small portions to a solution of 2.00 g
(12.81 mmoles) of 3-methylcarbamoyl-isoxazol-5-yl-
methanol (commercial), 1.52 g (19.21 mmoles) of
pyridine and 0.157 g (1.28 moles) of N,N-dimethylamino-
pyridine in 15 ml of dichloromethane, cooled to about
0°C. The medium is maintained with stirring for 1 hr at
0°C then for 1 hr at ambient temperature. The
precipitate formed is filtered off, then copiously
rinsed with diisopropyl ether. After drying under
vacuum at about 60°C, 2.6 g of pure product are
obtained in the form of a white powder.
Melting point (°C): 166-168°C
XH NMR (CDC13) 5 (ppm): 8.40 (d, 2H); 7.50 (d, 2H); 7.0
(s, 1H) ; 6.90 (broad s, 1H) ; 5.50 (s, 2H) ; 3.10 (d,
3H) .
6.2 2-(4-chloronaphthalen-l-yloxy)-7-aza-spiro[3.5]-
nonane hydrochloride.
Under an inert atmosphere, 1.00 g (4.14 mmoles) of
tert-butyl 2-hydroxy-7-aza-spiro[3.5] -nonane-7-carbox-
ylate (WO 2003084948) is dissolved in 41 ml of toluene.
1.250 g (4.77 mmoles) of triphenylphosphine and 0.888 g
(4.97 mmoles) of 4-chloronaphthalen-l-ol (commercial)
are added. The medium is cooled to 0°C and a solution
of 0.7 94 g (4.56 mmoles) of diethyl azodicarboxylate in
3 ml of toluene is added. The medium is stirred for
14 hrs at ambient temperature, then concentrated under
vacuum. The residue obtained is taken up in a IN

aqueous solution of caustic soda and extracted twice
with dichloromethane. The combined organic phases are
washed once with a saturated aqueous solution of sodium
chloride, dried over sodium sulphate, filtered and
concentrated under vacuum. The crude residue is taken
up in 20 ml of dichloromethane and 10 ml (40 mmoles) of
a 4N solution of hydrochloric acid in dioxan are added
slowly with stirring. After stirring for 3 hrs at
ambient temperature, the medium is concentrated under
vacuum and the residue is taken up in a IN aqueous
solution of hydrochloric acid. The aqueous phase is
extracted twice with ethyl acetate then slowly basified
to pH 10 by addition of 35% caustic soda solution. The
aqueous phase is extracted three times with dichloro-
methane. These three organic extracts are combined,
washed once with a saturated aqueous solution of sodium
chloride, dried over sodium sulphate, filtered and
concentrated under vacuum. The expected product is
obtained in the form of a wax which is taken up in 2 ml
of a 4N solution of hydrochloric acid in dioxan. The
medium is diluted with diethyl ether and the
precipitate formed is filtered off, rinsed with diethyl
ether and dried under vacuum. 1.10 g of the
hydrochloride of the expected product is obtained in
the form of a white powder.
Melting point (°C): 272-274°C
LC-MS: M+H = 302
2H NMR (DMSO) 5 (ppm) : 8.75 (broad s, 2H) ; 8.25 (d, 1H) ;
8.15 (d, 1H) , 7.75 (t, 1H) ; 7.65 (t, 1H) ; 7.60 (d, 1H) ;
6.80 (d, 1H) ; 4.95 (qt, 1H) ; 3.00 (broad d, 4H) ; 2.60
(m, 2H) ; 2.05 (ttl, 2H) ; 1.85 (dt, 4H) .
6.3 3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
naphthalen-1-yloxy)-7-aza-spiro[3.5]nonane-7-carbox-
ylate
In a reaction tube, a mixture of 0.300 g (0.89 mmole)
of 2-(4-chloronaphthalen-l-yloxy)-7-aza-spiro[3.5]-
nonane hydrochloride, obtained in stage 6.2, 0.34 2 g

(1.06 mmoles) of 3-methylcarbamoyl-isoxazol-5-ylmethyl
4-nitrophenyl carbonate, obtained in stage 6.1, 0.54 ml
(3.10 mmoles) of N,N-diisopropylethylamine and 0.011 g
(0.09 mmole) of N,N-dimethylaminopyridine is dissolved
in 5 ml of 1,2-dichloroethane. The medium is then
heated to 70°C for 14 hrs. After return to ambient
temperature, the medium is diluted with a IN aqueous
solution of caustic soda and extracted twice with
dichloromethane. The combined organic phases are then
successively washed twice with a IN aqueous solution of
caustic soda, once with a saturated aqueous solution of
ammonium chloride and once with a saturated aqueous
solution of sodium chloride. After drying over sodium
sulphate, filtration and evaporation to dryness, the
residue obtained is purified by silica gel chromato-
graphy eluting with dichloromethane, then with a
99/1/0.1 mixture of dichloromethane, methanol and 30%
aqueous ammonia. 0.363 g of the expected product are
obtained in the form of a white powder.
Melting point (°C): 62-64°C
LC-MS: M+H = 484
xti NMR (DMSO) 5 (ppm): 8.70 (s, 2H); 8.25 (d, 1H); 8.15
(d, 1H) , 7.75 (t, 1H) ; 7.65 (t, 1H) ; 7.60 (d, 1H) ; 6.80
(d, 2H) ; 5.25 (s, 2H) ; 4.95 (qt, 1H) ; 3.40 (broad d,
4H) ; 2.80 (s, 3H) ; 2.55 (m, 2H) ; 1.95 (m, 2H) ; 1.60
(dt, 4H).
Example 7 (Compound No.30)
3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloronaphthalen-
1-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
7.1 Tert-butyl 2-hydroxy-6-aza-spiro[3.4]octane-6-
carboxylate
0.89 g (23.57 mmoles) of sodium borohydride is added in
portions at 0°C to a solution of 3.54 g (15.71 mmoles)
of tert-butyl 2-oxo-6-aza-spiro[3.4] octane-6-carboxyl-
ate (WO 9806720) diluted in 40 ml of methanol. The
reaction mixture is stirred for 1 hr and 3 0 mins at
ambient temperature. After evaporation of the solvent,

water is added to the reaction mixture, the aqueous
phase is separated, it is extracted several times with
diethyl ether, and the combined organic phases are
washed with a saturated aqueous solution of sodium
chloride, they are dried over sodium sulphate and the
filtrate is concentrated under reduced pressure. After
evaporation of the solvent, 3.10 g of product are
obtained in the form of a brown oil used as such in the
following stage.
1ti NMR (DMSO) 5 (ppm): 4.7 (t, 1H); 4.1 (m, 1H); 3.2 (m,
4H), 2.2 (m, 2H); 1.8 (m, 4H); 1.4 (s, 9H).
7.2 Tert-butyl 2-(4-chloronaphthalen-l-yloxy)-6-aza-
spiro [3.4]octane-6-carboxylate
The procedure described in Example 2, stage 2.1, is
followed. From 3.50 g (15.40 mmoles) of tert-butyl 2-
hydroxy-6-aza-spiro[3.4]octane-6-carboxylate, obtained
in stage 7.1, 3.30 g (18.48 mmoles) of 4-chloro-
naphthalen-1-ol (commercial), 3.08 g (17.71 mmoles) of
diethyl azodicarboxylate and 4.846 g (18.48 mmoles) of
triphenylphosphine and after silica gel chromatography
eluting with a 70/30, 60/40 then 50/50 mixture of
cyclohexane and ethyl acetate, 6.14 g of the expected
product are obtained in the form of an oil, used as
such in the following stage.
7.3 2-(4-chloronaphthalen-l-yloxy)-6-aza-spiro[3.4]-
octane trifluoroacetate
6.14 g of tert-butyl 2-(4-chloronaphthalen-l-yloxy)-6-
aza-spiro[3.4]octane-6-carboxylate, obtained in stage
7.2, are dissolved in 100 ml of dichloromethane. The
medium is cooled to 0°C then 20 ml of trifluoroacetic
acid are added slowly. After stirring for 2 hrs at
ambient temperature, the medium is diluted with 100 ml
of toluene and concentrated under vacuum. The residue
obtained is taken up in diethyl ether to give a powder
which is filtered off, rinsed with diethyl ether and

dried under vacuum. 4.19 g of the expected product are
obtained in the form of a pink powder.
Melting point (°C): 129-131°C
1H NMR (DMSO) 5 (ppm) : 8.85 (broad s, 2H) ; 8.25 (d, 1H) ;
8.15 (d, 1H) , 7.75 (t, 1H) ; 7.65 (t, 1H) ; 7.60 (d, 1H) ;
6.85 (dd, 1H) ; 5.00 (qt, 1H) ; 3.25 (m, 4H) ; 2.75 (m,
1H); 2.65 (m, 1H); 2.30 (m, 2H); 2.10 (m, 2H).
7.4 3-carbamoyl-isoxazol-5-ylmethyl 4-nitrophenyl
carbonate
2.84 g (14.07 mmoles) of 4-nitrophenyl chloroformate
are added in small portions to a solution of 2.0 g
(14.07 mmoles) of 3-methylcarbamoyl-isoxazol-5-yl-
methanol (commercial), 1.71 ml (21.11 mmoles) of
pyridine and 0.17 g (1.41 moles) of N,N-dimethylamino-
pyridine in 15 ml of dichloromethane, cooled to about
0°C. The medium is maintained with stirring for 1 hr at
0°C then for 1 hr at ambient temperature. The
precipitate formed is filtered off then copiously
rinsed with diisopropyl ether. After drying under
vacuum at about 6 0°C, 3.12 g of the expected product
are obtained in the form of a white solid used as such
in the following stage.
Melting point (°C): 143-145°C
XH NMR (DMSO) 5 (ppm): 8.40 (d, 2H) ; 8.25 (broad s, 1H) ;
7.90 (broad s, 1H), 7.65 (d, 2H); 7.0 (s, 1H); 5.50 (s,
2H) .
7.5 3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloronaphth-
alen-1-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
In a reaction tube, a mixture of 1.000 g (2.49 mmoles)
of 2-(4-chloronaphthalen-l-yloxy)-6-aza-spiro[3.4]-
octane trifluoroacetate, obtained in stage 7.3, 0.841 g
(2.74 mmoles) of 3-methylcarbamoyl-isoxazol-5-ylmethyl
4-nitrophenyl carbonate, obtained in stage 7.4, 1.3 0 ml
(7.47 mmoles) of N,N-diisopropylethylamine and 0.032 g
(0.25 mmole) of N,N-dimethylaminopyridine is dissolved
in 8 ml of 1,2-dichloroethane. The medium, with the

tube sealed, is heated to 70°C with stirring for
14 hrs. After return to ambient temperature, the medium
is diluted with a IN aqueous solution of caustic soda
and extracted twice with dichloromethane. The combined
organic phases are then successively washed twice with
a IN aqueous solution of caustic soda, once with a
saturated aqueous solution of ammonium chloride and
once with a saturated aqueous solution of sodium
chloride. After drying over sodium sulphate, filtration
and evaporation to dryness, the residue is purified by
silica gel chromatography eluting with a 99/1/0.1, then
98/2/0.2 mixture of dichloromethane, methanol and 30%
aqueous ammonia. 1.15 g of the expected product are
obtained in the form of a white powder.
Melting point (°C): 149-150°C
LC-MS: M+H = 456
xti NMR (DMSO) 5 (ppm) : 8.25 (d, 1H) ; 8.15 (d, 2H) , 7.85
(broad s, 1H) ; 7.75 (t, 1H) ; 7.65 (t, 1H) ; 7.55 (d,
1H) ; 6.85 (d, 1H) ; 6.80 (s, 1H) ; 5.25 (d, 2H) ; 5.00 (m,
1H) ; 3.40 (m, 4H) ; 2.65 (m, 2H) ; 2.20 (m, 2H) ; 2.00 (m,
2H) .
Example 8 (Compound Nos.10 and 11)
3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-
phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate (isomers
I and II)
8.1 Tert-butyl 2-(3-trifluoromethylphenoxy)-6-aza-
spiro [3.4]octane-6-carboxylate (isomers la and lb)
0.910 g (4.00 mmoles) of tert-butyl 2-hydroxy-6-aza-
spiro [3.4]octane-6-carboxylate, obtained in stage 7.1,
is dissolved in 14 ml of dimethylformamide. 0.24 0 g
(6.01 mmoles) of sodium hydride is added in portions,
then 0.821 g (5.00 mmoles) of 1-fluoro-3-trifluoro-
methylbenzene (commercial) is added to the medium.
After heating for 14 hrs at 90°C, the medium is allowed
to return to ambient temperature then diluted in water
and ethyl acetate. After decantation and separation,
the aqueous phase is extracted a second time with ethyl

acetate, then the combined organic phases are washed
twice with water and once with a saturated aqueous
solution of sodium chloride, dried over sodium sulphate
and concentrated to dryness. 1.2 8 g of the expected
isomers _la and 3Jo is obtained in the form of an oil.
0.130 g (0.35 mmole) of the mixture of isomers is
separated by chromatography on preparative silica gel
plates eluting with a 70/30 mixture of cyclohexane and
ethyl acetate.
0.042 g of the isomer la (Rf = 0.55) and 0.045 g of the
isomer ^Lb (Rf = 0.65) are thus obtained in the form of
colourless oils.
Isomer ILa
Rf = 0.55 (ethyl acetate/cyclohexane: 70/30)
2H NMR (DMSO) 5 (ppm) : 7.55 (t, 1H) ; 7.30 (d, 1H) , 7.20
(d, 1H) ; 7.15 (s, 1H) ; 4.90 (qt, 1H) ; 3.35 (d, 2H) ;
3.25 (m, 2H) ; 2.55 (m, 2H) ; 2.05 (m, 2H) ; 1.90 (m, 2H) ;
1.45 (s; 9H).
Isomer lb
Rf = 0.65 (ethyl acetate/cyclohexane: 70/30)
1H NMR (DMSO) 5 (ppm): 7.55 (t, 1H) ; 7.30 (d, 1H) , 7.20
(d, 1H) ; 7.15 (s, 1H) ; 4.85 (qt, 1H) ; 3.35-3.20 (m,
4H); 2.50 (m, 2H); 2.10 (m, 2H); 1.95 (m, 2H); 1.40 (s,
9H) .
8.2 2-(3-trifluoromethylphenoxy)-6-aza-spiro[3.4]octane
hydrochloride
8.2a 2-(3-trifluoromethylphenoxy)-6-aza-spiro [3.4]-
octane hydrochloride (obtained from isomer la)
0.042 g (0.11 mmole) of tert-butyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro [3.4]octane-6-carboxylate,
isomer la, obtained in stage 8.1, is taken up in 3 ml
of dioxan and 0.43 ml (1.71 mmoles) of a 4N solution of
hydrochloric acid in dioxan is added slowly with
stirring. After stirring for 14 hrs at ambient
temperature, the medium is concentrated to dryness

under reduced pressure. 0.035 g of the hydrochloride of
the expected product is obtained in the form of a
yellow oil.
8.2b 2-(3-trifluoromethylphenoxy)-6-aza-spiro[3.4]-
octane hydrochloride (obtained from isomer lb)
0.045 g (0.12 mmole) of tert-butyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro[3.4]octane-6-carboxylate,
isomer lb, obtained in stage 8.1, is taken up in 3 ml
of dioxan and 0.45 ml (1.82 mmoles) of a 4N solution of
hydrochloric acid in dioxan is added slowly with
stirring. After stirring for 14 hrs at ambient
temperature, the medium is concentrated to dryness
under reduced pressure. 0.037 g of the hydrochloride of
the expected product is obtained in the form of a
yellow oil.
8.3 3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro[3.4]octane-6-carboxylate
8.3a 3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro[3.4]octane-6-carboxylate
(isomer I) (compound No.10)
The procedure described in Example 6, stage 6.3, is
followed. From 0.035 g (0.11 mmole) of 2-(3-trifluoro-
methylphenoxy) -6-aza-spiro[3.4] -octane hydrochloride,
obtained in stage 8.2a, 0.042 g (0.14 mmole) of
3-carbamoyl-isoxazol- 5-ylmethyl 4-nitrophenyl
carbonate, obtained in stage 7.4, 0.060 ml (0.34 mmole)
of N,N-diisopropylethylamine and 0.007 g (0.06 mmole)
of N,N-dimethylaminopyridine, and after purification by
chromatography on preparative silica gel plates eluting
with a 90/10/1 mixture of dichloromethane, methanol and
3 0% aqueous ammonia, a colourless oil is obtained which
crystallises in pentane. After filtration and drying
under vacuum at 60°C, 0.050 g of the expected product
is obtained in the form of a white powder.
LC-MS: M+H = 440
Melting point (°C): 97-99°C

lH NMR (DMSO) 6 (ppm): 8.15 (s, 1H); 7.85 (s, 1H); 7.55
(t, 1H); 7.30 (d, 1H), 7.20 (d, 1H); 7.15 (s, 1H); 6.85
(d, 1H) ; 5.25 (S, 2H) ; 4.90 (qt, 1H) ; 3.45 (s, 2H) ;
3.30 (m, 2H) ; 2.55 (m, 2H) ; 2.05 (m, 2H) ; 1.95 (m, 2H) .
8.3b 3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoro-
methylphenoxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomer II) (compound No.11)
The procedure described in Example 6, stage 6.3, is
followed. From 0.037 g (0.12 mmole) of 2-(3-trifluoro-
methylphenoxy)-6-aza-spiro [3.4]-octane hydrochloride,
obtained in stage 8.2b, 0.042 g (0.14 mmole) of
3-carbamoyl-isoxazol- 5-ylmethyl 4-nitrophenyl
carbonate, obtained in stage 7.4, 0.060 ml (0.36 mmole)
of N,N-diisopropylethylamine and 0.007 g (0.06 mmole)
of N,N-dimethylaminopyridine, and after purification by
chromatography on preparative silica gel plates eluting
with a 90/10/1 mixture of dichloromethane, methanol and
3 0% aqueous ammonia, a colourless oil is obtained which
crystallises in pentane. After filtration of the solid
and drying under vacuum at 60°C, 0.029 g of the
expected product is obtained in the form of a wax.
LC-MS: M+H = 440
1H NMR (DMSO) 5 (ppm): 8.10 (s, 1H) ; 7.85 (s, 1H) ; 7.55
(t, 1H) ; 7.30 (d, 1H) , 7.20 (d, 1H) ; 7.15 (s, 1H) ; 6.80
(s, 1H) ; 5.25 (s, 2H) ; 4.85 (qt, 1H) ; 3.45-3.25 (m,
5H); 2.50 (m, 2H); 2.10 (m, 2H); 1.95 (m, 2H).
Example 9 (Compound Nos.32 and 33)
3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomers I and II)
9.1 Tert-butyl 2-(toluene-4-sulphonyloxy)-6-aza-spiro-
[3.4]octane-6-carboxylate (isomers 2a and 2b)
10.00 g (43.99 mmoles) of tert-butyl 2-hydroxy-6-aza-
spiro-[3.4]octane-6-carboxylate, obtained in stage 7.1,
and 9.15 ml (65.9 8 mmoles) of triethylamine are
dissolved in 400 ml of dichloromethane and 13.07 g

(65.98 mmoles) of tosyl chloride are added. After
stirring for 14 hrs at ambient temperature, the medium
is extracted once with a saturated aqueous solution of
ammonium chloride then once with a saturated aqueous
solution of sodium chloride, dried over sodium
sulphate, filtered and concentrated under reduced
pressure. The residue obtained is purified by silica
gel chromatography eluting with cyclohexane, then with
a 95/5 mixture of cyclohexane and ethyl acetate. 11.9 g
of expected product are obtained in the form of an oil.
LC-MS: M+H = 382
XH NMR (DMSO) 5 (ppm): 7.80 (d, 2H); 7.50 (d, 2H); 4.90
(m, 1H); 3.15 (m, 4H); 2.45 (s, 3H); 2.20 (m, 2H); 2.10
(m, 2H) ; 1.80 (t, 2H) ; 1.40 (s, 9H) .
11.5 g (3.01 mmoles) of tert-butyl 2-(toluene-4-
sulphonyloxy)-6-aza-spiro-[3.4]octane-6-carboxylate,
obtained in stage 9.1, are separated by preparative
chiral chromatography (Macherey-Nagel Nucleosil 50-10 /
50 x 220 mm) eluting with a 13/87 mixture of ethyl
acetate and cyclohexane, to give 5.15 g of isomer 2a
and 4.69 g of isomer 2b in the form of white powders.
Isomer 2a.
Tr = 33 mins
Melting point (°C): 83.7°C
LC-MS: M+H = 382
1H NMR (DMSO) 5 (ppm): 7.80 (d, 2H); 7.50 (d, 2H); 4.90
(qt, 1H) ; 3.15 (m, 4H) ; 2.45 (s, 3H) ; 2.25 (t, 2H) ;
2.05 (t, 2H); 1.80 (m, 2H); 1.40 (s, 9H).
Isomer 2b_
Tr = 43 mins
Melting point (°C): 94.9°C
LC-MS: M+H = 3 82
1ti NMR (DMSO) 5 (ppm): 7.80 (d, 2H) ; 7.50 (d, 2H) ; 4.90
(qt, 1H) ; 3.20 (m, 4H) ; 2.45 (s, 3H) ; 2.20 (t, 2H) ;
2.10 (t, 2H); 1.80 (m, 2H); 1.40 (s, 9H).

60/40 mixture of cyclohexane and ethyl acetate. 2.4 g
of the expected product are obtained in the form of a
brown gum.
aH NMR (DMSO) 5 (ppm): 4.05 (s, 4H); 3.30 (s, 4H); 1.40
(s, 9H).
10.3 Tert-butyl 6-hydroxy-2-aza-spiro[3.3]heptane-2-
carboxylate
0.4 94 g (13.06 mmoles) of sodium borohydride is added
in portions at 0°C to a solution of 2.30 g
(10.89 mmoles) of tert-butyl 6-oxo-2-aza-spiro [3.3] -
heptane-2-carboxylate, obtained in stage 10.2, in 55 ml
of methanol. The reaction mixture is stirred for 1 hr
at ambient temperature. After evaporation of the
solvent, water is added to the reaction mixture, the
aqueous phase is separated, it is extracted several
times with dichloromethane, and the combined organic
phases are washed with a saturated aqueous solution of
sodium chloride, dried over sodium sulphate and the
filtrate is concentrated under reduced pressure. After
crystallisation of the residue in diisopropyl ether,
filtration of the solid obtained and drying under
vacuum at 60°C, 2.24 g of product are obtained in the
form of a beige powder.
XH NMR (DMSO) 5 (ppm): 5.00 (d, 1H) ; 3.95 (hex, 1H) ;
3.75 (d, 4H); 2.40 (m, 2H); 1.95 (m, 2H); 1.40 (s, 9H).
10.4 Tert-butyl 6-(4-chloro-3-fluorophenoxy)-2-aza-
spiro[3.3]-heptane-2-carboxylate
The procedure described in Example 2, stage 2.1, is
followed. From 1.50 g (7.03 mmoles) of tert-butyl 6-
hydroxy-2-aza-spiro[3.3]heptane-2-carboxylate, obtained
in stage 10.3, 1.237 g (8.44 mmoles) of 4-chloro-3-
fluorophenol, 1.409 g (8.09 mmoles) of diethyl azo-
dicarboxylate and 2.121 g (8.09 mmoles) of triphenyl-
phosphine and after silica gel chromatography eluting
with a 95/5, then 90/10 mixture of cyclohexane and

ethyl acetate, 1.73 g of the expected product are
obtained in the form of a beige powder.
Melting point (°C): 110-112°C
LC-MS: M+H = 342
XH NMR (DMSO) 5 (ppm) : 7.45 (t, 1H) ; 6.95 (d, 1H) ; 6.75
(d, 1H) ; 4.65 (qt, 1H) ; 3.90 (broad d, 4H) ; 2.75 (m,
2H); 2.20 (m, 2H); 1.40 (s, 9H).
10.5 6-(4-chloro-3-fluorophenoxy)-2-aza-spiro [3.3]-
heptane trifluoroacetate
1.70 g (4.97 mmoles) of tert-butyl 6-(4-chloro-3-
fluorophenoxy)-2-aza-spiro[3.3]heptane-2-carboxylate,
obtained in stage 10.4, are dissolved in 40 ml of
dichloromethane. The medium is cooled in an ice bath,
then 8 ml (105.24 mmoles) of trif luoroacetic acid are
added slowly. After stirring for 2 hrs at ambient
temperature, the medium is diluted with 100 ml of
toluene and concentrated under reduced pressure. The
residue obtained is crystallised in diethyl ether to
give a powder which is filtered off, rinsed with
diethyl ether and dried under vacuum. 1.675 g of the
expected product are obtained in the form of a hygro-
scopic pink powder.
LC-MS: M+H = 242
1H NMR (DMSO) 5 (ppm): 8.75 (broad s, 2H) ; 7.45 (t,
1H) ; 6.95 (d, 1H) ; 6.75 (d, 1H) ; 4.65 (qt, 1H) ; 4.00
(broad d, 4H); 2.80 (m, 2H); 2.25 (m, 2H).
10.6 3-carbamoyl-isoxazol-5-ylmethyl 6-(4-chloro-3-
fluorophenoxy)-2 -aza-spiro[3.3]heptane-2 -carboxylate
The procedure described in example 7, stage 7.5, is
followed. From 0.600 g (1.69 mmoles) of 6-(4-chloro-3-
fluorophenoxy)-2-aza-spiro[3.3]heptane trifluoroacetate
obtained in stage 10.5, 0.622 g (2.02 mmoles) of
3-carbamoylisoxazol-5-ylmethyl 4-nitrophenyl carbonate,
obtained in stage 7.4, 1.03 ml (5.90 mmoles) of N,N-
diisopropylethylamine and 0.021 g (0.17 mmole) of N,N-
dimethylaminopyridine, and after silica gel chromato-

graphy eluting with a 99/1/0.1 then 98/2/0.2 mixture of
dichloromethane, methanol and 30% aqueous ammonia.
0.6 02 g of the expected product are obtained in the
form of a white powder.
Melting point (°C): 135-137°C
LC-MS: M+H = 410
XH NMR (DMSO) 5 (ppm): 8.15 (s, 1H); 7.85 (s, 1H); 7.45
(t, 1H) ; 6.95 (d, 1H) ; 6.80 (s, 1H) ; 6.75 (d, 1H) ; 5.20
(s, 2H) ; 4.65 (qt, 1H) ; 4.10-3.90 (broad d, 4H) ; 2.75
(m, 2H); 2.25 (m, 2H).
Example 11 (Compound No.25}
3-methylcarbamoyl-isoxazol-5-ylmethyl 6-(4'fluoro-
biphenyl-4-yloxy)-2-aza-spiro[3.3]heptane-2-carboxylate
11.1 Tert-butyl 6-(4'fluorobiphenyl-4-yloxy)-2-aza-
spiro [3.3]heptane-2-carboxylate
The procedure described in Example 2, stage 2.1, is
followed. From 0.900 g (4.22 moles) of tert-butyl 6-
hydroxy-2-aza-spiro[3.3]heptane-2-carboxylate, obtained
in stage 10.3, 0.953 g (5.06 mmoles) of 4'-fluoro-
biphenyl-4-ol, 0.845 g (4.85 mmoles) of diethyl azo-
dicarboxylate and 1.328 g (5.06 mmoles) of triphenyl-
phosphine, and after silica gel chromatography eluting
with a 95/5, then 90/10 mixture of cyclohexane and
ethyl acetate, 1.44 g of the expected product are
obtained in the form of a beige powder used as such in
the following stage.
11.2 6-(4'fluorobiphenyl-4-yloxy)-2-aza-spiro[3.3]-
heptane trifluoroacetate
The procedure described in Example 10, stage 10.5, is
followed. From 1.44 g (3.76 mmoles) of tert-butyl
6- (4'fluorobiphenyl-4-yloxy)-2-aza-spiro[3.3]heptane-2-
carboxylate, obtained in stage 11.1, and 8 ml
(105.24 mmoles) of trifluoroacetic acid, 1.04 g of the
expected product are obtained in the form of a
hygroscopic powder.
LC-MS: M+H = 284

1tt NMR (DMSO) 5 (ppm) : 8.60 (broad S, 1H) ; 7.65 (t, 2H) ;
7.60 (d, 2H) ; 7.25 (t, 2H) ; 6.90 (d, 2H) ; 4.70 (qt,
1H); 4.05 (broad d, 4H); 2.85 (m, 2H); 2.30 (m, 2H).
11.3 3-methylcarbamoyl-isoxazol-5-ylmethyl 6-(4'fluoro-
biphenyl-4-yloxy)-2-aza-spiro[3.3]-heptane-2-carbox-
ylate
The procedure described in Example 7, stage 7.5, is
followed. From 0.500 g (1.26 mmoles) of 6-(4'fluoro-
biphenyl-4-yloxy)-2-aza-spiro[3.3]heptane trifluoro-
acetate, obtained in stage 11.2, 0.485 g (1.51 mmoles)
of 3-methylcarbamoyl-isoxazol-5-ylmethyl 4-nitrophenyl
carbonate, obtained in stage 6.1, 0.77 ml (4.40 mmoles)
of N,N-diisopropylethylamine and 0.015 g (0.13 mmole)
of N,N-dimethylaminopyridine, and after silica gel
chromatography eluting with a 99/1/0.1 mixture of
dichloromethane, methanol and 3 0% aqueous ammonia.
0.538 g of the expected product is obtained in the form
of a white powder.
Melting point (°C): 163-165°C
LC-MS: M+H = 466
XH NMR (DMSO) 5 (ppm): 8.70 (qd, 1H) ; 7.65 (t, 2H) ; 7.55
(d, 2H); 7.25 (t, 2H); 6.90 (d, 2H); 6.80 (s, 1H); 5.20
(s, 2H) ; 4.65 (qt, 1H) ; 4.10-3.90 (broad d, 4H) ; 2.80
(d, 3H); 2.75 (m, 2H); 2.25 (m, 2H).
Table 1 below illustrates the chemical structures and
the physical properties of some compounds according to
the invention. In this table, the compounds are in free
base or salt form.

Table 3 below shows the relative proportions and
retention times of the isomers of the compounds 9, 14,
15, 26, 27, 28, 29, 30 and 31, obtained from one of the
two chromatographic analysis methods below:
Method 1:
HPLC / ZQ - Gradient 10 min
Mobile phases: Phase A: CH3COONH4 + 3% ACN
Phase B: ACN
Stationary phase / column: Kromasil C18 column,
Dimensions: 50 x 2.1 mm ; 3.5 urn
Flow rate: D = 0.8 ml/min
Column temperature: T = 4 0°C
Injection volume: V = 5 ul
Gradient: T = 0 min: 100% A; from T = 5.5 mins to
T = 7 mins: 100% B; from T = 7.1 mins to T = 10 mins:
100% A
Method 2:
UPLC / TOF - Gradient 3 min
Mobile phases: Phase A: H20 + 0.05% of TFA
Phase B: ACN + 0.035% of TFA
Stationary phase / column: Acquity BEH C18 column,
Dimensions: 50 x 2.1 mm ; 1.7 um
Flow rate: D = 1.0 ml/min

Column, temperature: T = 40°C
Injection volume: V = 2 ul
Gradient: T = 0 min: 98% A and 2% B; from T = 1.6 mins
to T = 2.1 mins: 10 0% B; from T = 2.5 mins to T =
3 mins: 98% A and 2% B.
Table 3

The compounds of the invention were subjected to
pharmacological tests to determine their inhibitory
effect on the enzyme FAAH (Fatty Acid Amide Hydrolase) .
Protocol 1
The inhibitory activity was demonstrated in a radio-
enzymatic test based on measurement of the product of
hydrolysis of [1-3H ethanolamine] anandamide by FAAH
[Life Sciences (1995), 56, 1999-2005 and Journal of
Biochemical and Biophysical Methods (2004), 60(2), 171-
177) . Thus, mouse brains (minus the cerebellum) are
removed and stored at -80°C. The membrane homogenates
are prepared extemporaneously by homogenizing the
tissues using a Precellys® machine in the reaction
buffer (10 mM Tris-HCl, pH = 8, 150 mM NaCl and 1 mM
ethylenediaminetetraacetic acid (EDTA)). The enzymatic
reaction is performed in 96-well Multiscreen filtration
plates in a final volume of 70 ul. Reaction buffer
supplemented with fatty acid-free bovine serum albumin
(BSA, 1 mg/ml) is used for the enzymatic reaction and
the dilution of the compounds and the [1-3H ethanol-
amine] anandamide. The reaction buffer containing BSA

(43 iil/well), the diluted test compounds at different
concentrations (7 ul/well containing 1% DMSO) and the
membrane preparation (10 ul/well, i.e. 200 pg of tissue
per test) are successively added to the wells. After
preincubation of the compounds with the enzyme at 2 5°C
for 2 0 mins, the reaction is started by adding
[1-3H ethanolamine] anandamide. (Specific activity 15-
20 Ci/mmol) diluted with cold anandamide (10 ul/well,
final concentration 10 /xM, 0.01 jxCi per test). After
incubation for 20 mins at 25°C, the enzymatic reaction
is stopped by addition of a 5M solution of active
charcoal prepared in 1. 5M NaCl and 0. 5M HC1 buffer
(50 /xl/well) . The mixture is stirred for 10 mins and
the aqueous phase containing the [1-3H] ethanolamine is
then recovered by filtration under vacuum and counted
by liquid scintillation.
Protocol 2
The inhibitory activity was demonstrated by the
fluorescence technique in an enzymatic test based on
measurement of the fluorescent product of hydrolysis of
arachidonyl 7-amino 4-methyl coumarin amide (AAMC) by
FAAH (Analytical Biochemistry (2005), 343: 143-151, J.
of Biomolecular Screening (2006), 11(5): 519-527 and J.
of Neurosciences Methods (2007), 161: 47-54). Thus,
mouse brains (minus the cerebellum) are removed and
stored at -80°C. The brain homogenates are prepared
extemporaneously by homogenizing the tissues using a
Precellys machine in the reaction buffer (10 mM Tris-
HC1, pH = 8, 150 mM NaCl and 1 mM ethylenediamine-
tetraacetic acid (EDTA)). The enzymatic reaction is
performed in black polystyrene 384-well plates in a
final volume of 50 ul. Reaction buffer supplemented
with fatty acid-free bovine serum albumin (BSA,
1 mg/ml) is used for the enzymatic reaction, dilution
of the compounds and dilution of the AAMC. The reaction
buffer containing BSA (25 ul/well), the diluted test
compounds at different concentrations (5 ul/well

containing 1% DMSO) and the membrane preparation (10
ul/well, i.e. 200 ug of tissue per test) are
successively added to the wells. After preincubation of
the compounds with the enzyme for
20 mins at 25°C, the reaction is started by addition of
10 ul of substrate per well (AAMC, final concentration
10 fiM) . After incubation for 40 mins at 37°C, the
aminomethyl coumarin (AMC) produced is measured by
fluorescent counting (Envision plate reader).
Under the conditions of protocol 1, the most active
compounds of the invention have IC50 (concentration
inhibiting 50% of the control enzymatic activity of
FAAH) values lying between 0.001 and 1 (M; for example,
compounds 7, 29, 32 and 33 have respective IC50 values
of 19 nM 5.3 nM, 3 nM and 19 nM.
Under the conditions of protocol 2, the most active
compounds of the invention have IC50 (concentration
inhibiting 50% of the control enzymatic activity of
FAAH) values lying between 0.001 and 1 /xM; for example,
compounds 19 and 25 have respective IC50 values of
1.7 nM and 0.46 nM.
It thus appears that the compounds according to the
invention have inhibitory activity on the enzyme FAAH.
The in vivo activity of the compounds of the invention
was evaluated in a test of analgesia.
Thus, the intraperitoneal (i.p.) administration of PBQ
(phenylbenzoquinone, 2 mg/kg in 0.9% sodium chloride
solution containing 5% ethanol) to male OF1 mice
weighing 25 to 30 g causes abdominal stretching, on
average 3 0 torsions or contractions during the period
of 5 to 15 mins after injection. The test compounds are
administered orally (p.o.) or intraperitoneally (i.p.)
suspended in Tween 80 at 0.5%, 60 mins or 120 mins

before the administration of PBQ. Under these
conditions, the most powerful compounds reduce by 35%
to 8 0% the number of stretches induced by the PBQ, in a
dosage range lying between 1 and 3 0 mg/kg. For example,
compound 25 of Table 1 reduces by 50% the number of
stretches induced by the PBQ, at a dose of 30 mg/kg
p.o. at 120 mins.
The enzyme FAAH (Chemistry and Physics of Lipids,
(2000), 108, 107-121) catalyses the hydrolysis of the
endogenous amide and ester derivatives of various fatty
acids such as N-arachidonoylethanolamine (anandamide),
N-palmitoylethanolamine, N-oleoylethanolamine, oleamide
or 2-arachidonoylglycerol. These derivatives exert
different pharmacological activities by interacting,
inter alia, with the cannabinoid and vanilloid
receptors.
The compounds of the invention block this degradation
pathway and increase the tissue levels of these
endogenous substances. Hence, they can be used in the
prevention and treatment of pathologies in which the
endogenous cannabinoids and/or any other substrates
metabolized by the enzyme FAAH are involved. The
following diseases and complaints can for example be
cited:
pain, especially acute or chronic pain of neurogenic
type: migraine, neuropathic pain including the forms
associated with the herpes virus and diabetes and with
chemotherapy, acute or chronic pain associated with
inflammatory diseases: arthritis, rheumatoid arthritis,
osteoarthritis, spondylitis, gout, vascularitis,
Crohn's disease, irritable bowel syndrome, acute or
chronic peripheral pain, vertigo, vomiting, nausea, in
particular post-chemotherapy nausea, eating disorders,
in particular anorexia and cachexia of diverse nature,
neurological and psychiatric disorders: tremor,
dyskinaesia, dystonia, spasticity, compulsive and

obsessive behaviour, Tourette's syndrome, all forms of
depression and anxiety of any nature or origin, mood
disorders, psychoses, acute and chronic neuro-
degenerative diseases: Parkinson's disease, Alzheimer's
disease, senile dementia, Huntington's chorea, lesions
associated with cerebral ischaemia and cranial and
medullary trauma, epilepsy, sleep disorders, including
sleep apnoea, cardiovascular diseases, in particular
hypertension, cardiac arrhythmia, arteriosclerosis,
heart attack, cardiac ischaemia, renal ischaemia,
cancers: benign skin tumours, papillomas and cerebral
tumours, prostate tumours, cerebral tumours
(glioblastomas, medullo-epitheliomas, medullo-
blastomas, neuroblastomas, tumours of embryonic origin,
astrocytomas, astroblastomas, ependyomas, oligodendro-
gliomas, plexus tumour, neuroepitheliomas, pineal gland
tumours, ependymoblastomas, malignant meningiomas,
sarcomatoses, malignant melanomas, schwannomas), immune
system disorders, especially autoimmune diseases:
psoriasis, lupus erythematosus, connective tissue
diseases or connectivitis, Sjogrer's syndrome,
ankylosing spondylitis, undifferentiated spondylitis,
Behcet's disease, haemolytic autoimmune anaemias,
multiple sclerosis, amyotrophic lateral sclerosis,
amylosis, graft rejection, diseases affecting the
plasmocytic line, allergic diseases: immediate or
delayed hyper-sensitivity, allergic rhinitis or
allergic conjunctivitis, contact dermatitis, parasitic,
viral or bacterial infectious diseases: AIDS,
meningitis, inflammatory diseases, especially articular
diseases: arthritis, rheumatoid arthritis,
osteoarthritis, spondylitis, gout, vascularitis,
Crohn's disease, irritable bowel syndrome,
osteoporosis, ocular complaints: ocular hypertension,
glaucoma, pulmonary complaints: respiratory tract
diseases, bronchospasm, cough, asthma, chronic
bronchitis, chronic obstruction of the respiratory
tract, emphysema, gastrointestinal diseases: irritable

bowel syndrome, intestinal inflammatory disorders,
ulcers, diarrhoea, urinary incontinence and
inflammation of the bladder.
The use of the compounds according to the invention, in
the form of the base, pharmaceutically acceptable acid
addition salt, hydrate or solvate, for the preparation
of a medicinal product for treating the pathologies
mentioned above forms an integral part of the
invention.
Also a subject of the invention are medicinal products
which contain a compound of formula (I) , or a
pharmaceutically acceptable acid addition salt or
hydrate or solvate of the compound of formula (I) .
These medicinal products are used in therapy, in
particular in the treatment of the pathologies
mentioned above.
According to another of its aspects, the present
invention relates to pharmaceutical compositions
containing as the active principle at least one
compound according to the invention. These
pharmaceutical compositions contain an effective dose
of a compound according to the invention, or a
pharmaceutically acceptable acid addition salt, hydrate
or solvate of the said compound, and possibly one or
more pharmaceutically acceptable excipients.
The said excipients are selected, depending on the
pharmaceutical form and the desired administration
form, from the usual excipients known to the person
skilled in the art.
In the pharmaceutical compositions of the present
invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, local, intra-
thecal, intranasal, transdermal, pulmonary, ocular or

rectal administration, the active principle of formula
(I) above, or the possible acid addition salt, solvate
or hydrate thereof, can be administered to animals and
human beings in a unit administration form, mixed with
standard pharmaceutical excipients, for the prophylaxis
or treatment of the above disorders or diseases.
The appropriate unit administration forms comprise oral
forms such as tablets, soft or hard gel capsules,
powders, granules, chewing gums and oral solutions or
suspensions, sublingual, buccal, intratracheal, intra-
ocular, intranasal administration forms, forms for
administration by inhalation, subcutaneous, intra-
muscular or intravenous administration forms and rectal
or vaginal administration forms. For topical
administration, the compounds according to the
invention may be used in creams, ointments or lotions.
By way of example, a unit administration form of a
compound according to the invention in the form of a
tablet can comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscarmellose 6.0 mg
Corn starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said unit forms are dosed to allow daily admin-
istration of 0.01 to 20 mg of active principle per kg
of body weight, depending on the presentation form.
There may be particular cases in which higher or lower
dosages are suitable, and such dosages also form part
of the invention. According to normal practice, the
dosage appropriate for each patient is determined by
the doctor depending on the mode of administration and
the weight and response of the said patient.

According to another of its aspects, the invention also
relates to a method for treating the pathologies
mentioned above which comprises the administration of
an effective dose of a compound according to the
invention, or one of the pharmaceutically acceptable
acid addition salts thereof or a solvate or a hydrate
of the said compound.

Claims
1. Compound corresponding to the formula (I):

in which
R2 represents a hydrogen or fluorine atom or a hydroxyl,
cyano, trifluoromethyl, C±.6 alkyl, C1-6 alkoxy or NR8R9
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 2 5 and that
2 < o+p < 5;
A represents a covalent bond, an oxygen atom, a C1-6
alkylene group or an -0-C1-6 alkylene group in which the
end represented by an oxygen atom is linked to the
group R1 and the end represented by an alkylene group is
linked to the carbon of the bicyclic system;
Ri represents a group R5 optionally substituted with one
or more groups R6 and/or R7;
R5 represents a group selected from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
naphthalenyl, quinolinyl, isoquinolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, cinnolinyl or naphthyrid-
inyl group;
R6 represents a halogen atom, a cyano, -CH2CN, nitro,
hydroxyl, d-g-alkyl, C1-6-alkoxy, C1-6- thioalkyl, C1-6-
haloalkyl, d.g-haloalkoxy, C1-6-halothioalkyl, C3.7-
cycloalkyl, C3.7-cycloalkyl-C1-3-alkylene, C3.7-cyclo-
alkyl-C1-3-alkylene-O-, NR8R9, NR8COR9, NR8C02R9, NR8S02R9,
NR8S02NR8R9, COR8, C02RB, CONR8R9, S02R8, S02NR8R9 or
-0- (C1-3-alkylene) -0- group;
R7 represents a group selected from a phenyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl group,
the group or group(s) R7 possibly being substituted with

one or more groups R6 which are identical to or
different from one other;
R3 represents a hydrogen or fluorine atom, a C1-6-alkyl
group or a trifluoromethyl group;
R4 represents a 5-membered heterocycle selected from a
furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl,
oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thia-
diazolyl, imidazolyl, triazolyl or tetrazoyl group;
this heterocycle optionally being substituted with one
or more substituents selected from a halogen atom, a Ci_
6-alkyl, Cx-e-haloalkyl, C3.7-cycloalkyl, C3-7-cycloalkyl-
Cx-3-alkylene, C1-6-haloalkoxy, cyano, NR8R9, NR8COR9,
NR8C02R9, NR8S02R9, NR8S02NR8R9, COR8, C02R8, CONR8R9,
CON(R8) (C1-3-alkylene-NRioRii) , S02R8, S02NR8R9, or -0-(C1-
3-alkylene)-0 group;
R8 and R9 independently of each other represent a
hydrogen atom or a C1-6-alkyl group;
or with the atom or atoms which bear them form,
in the case of NR8R9, a ring selected from the
azetidine, pyrrolidine, piperidine, morpholine, thio-
morpholine, azepine, oxazepine or piperazine rings,
this ring possibly being substituted with a C1-6-alkyl
or benzyl group;
in the case of NR8COR9, a lactam ring; in the case of
NR8C02R9, an oxazolidinone, oxazinone or oxazepinone
ring; in the case of NR8S02R9, a sultam ring; and in the
case of NR8S02NR8R9, a thiazolidine dioxide or thia-
diazinane dioxide ring; and
Rio and Ru independently of one another represent a
hydrogen atom or a Cx-6-alkyl group;
in the form of the base or an acid addition salt.
2. Compound of formula (I) according to Claim 1,
characterized in that R2 represents a hydrogen atom;
in the form of the base or an acid addition salt.
3. Compound of formula (I) according to Claim 1 or 2,
characterized in that 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 the base or an acid addition salt.
4. Compound of formula (I) according to any one of
Claims 1 to 3, characterized in that A represents an
oxygen atom, in the form of the base or an acid
addition salt.
5. Compound of formula (I) according to any one of
Claims 1 to 4, characterized in that R1 represents a
group R5, unsubstituted or substituted with one or more
groups R6 and/or R7;
R5 represents a phenyl, naphthalenyl or
isoquinolinyl group;
R6 represents a halogen atom, more particularly a
fluorine or chlorine atom, or a Cx-g-haloalkyl,
more particularly trifluoromethyl, group or a C1-6-
alkoxy group, more particularly an ethoxy group;
and
R7 represents a phenyl which may be substituted
with one or more groups R6 which are identical to
or different from one another, in the form of the
base or an acid addition salt.
6. Compound of formula (I) according to any one of
Claims 1 to 5, characterized in that R3 represents a
hydrogen atom, in the form of the base or an acid
addition salt.
7. Compound of formula (I) according to any one of
Claims 1 to 6, characterized in that R4 represents a
group selected from a thiazolyl, triazolyl, oxazolyl or
isoxazolyl, this group being unsubstituted or
substituted with one or more Cj.-6-alkyl or CONR8R9
groups, and R8 and R9 independently of one another

represent a hydrogen atom or a C1-6-alkyl group, in the
form of the base or an acid addition salt.
8. Compound of formula (I) 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-carbox-
ylate;
3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-
phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate and the
hydrochloride thereof (isomers I + II) ;
3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-
phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate (isomer I
of compound No.9);
3-carbamoyl-isoxazol-5-ylmethyl 2-(3-trifluoromethyl-
phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate (isomer
II of compound No.9);
3-carbamoyl-isoxazol-5-ylmethyl 2-(A' -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-aza-spiro[3.4]octane-6-carboxylate (isomers
I + ID ;
4-methylcarbamoyl-oxazol-2-ylmethyl 2-(3-trifluoro-
methylphenoxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomers I + II) ;
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-2-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 (isomers
I + ID ;

3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
phenoxy)-6-aza-spiro[3.4]octane-6-carboxylate (isomers
I + ID ;
3-carbamoyl-isoxazol-5-ylmethyl 2-(4' -fluorobiphenyl-4-
yloxy)-6-aza-spiro[3.4]octane-6-carboxylate (isomers I
+ ID ;
3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomers I + II) ;
3-carbamoyl-isoxazol-5-ylmethyl 2-(4-chloronaphthalen-
1-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate (isomers
I + ID ;
3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4-chloro-
naphthalen-1-yloxy)-6-aza-spiro[3.4]octane-6-carbox-
ylate (isomers I + II) ;
3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomer I of compound 29) ;
3-methylcarbamoyl-isoxazol-5-ylmethyl 2-(4'-fluoro-
biphenyl-4-yloxy)-6-aza-spiro[3.4]octane-6-carboxylate
(isomer II of compound 29).
9. Process for preparation of a compound of formula (I)
according to any one of Claims 1 to 8, characterized in
that it comprises the stage consisting in reacting
either an amine of general formula (II),

in which A, R1# R2, 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,
R3 and R4 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. Process for preparation of a compound of formula
(I) according to any one of Claims 1 to 8,
characterized in that it comprises the stage consisting
in reacting a compound of general formula (la)

in which R2, R3, R4, 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 C1-6-alkylene part of the -O-C1-6-alkylene group;
with either an alcohol derivative of general formula
R1OH (IV) , in which R1 is as defined in the general
formula (I) according to Claim 1, using the Mitsunobu
reaction conditions;
or with a halogenated derivative of general formula RXX
(IVa) in which R1 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. Process for preparation of a compound of formula
(I) according to any one of Claims 1 to 8, in which R1
represents a group R5 substituted in particular with a
group R6 of the C1-6-alkyl, C3-7-cycloalkyl or C3-7-
cycloalkyl-C1-3-alkylene type, or with a group R7 as
defined in the general formula (I) according to Claim
1, characterized in that it comprises the stage
consisting in performing a coupling reaction, catalysed

by means of a transition metal, on the compound of
general formula (lb),

in which A, R2, R3, R4, R5, m, n, o and p are as defined
in the general formula (I) according to Claim 1 and Ux
represents a chlorine, bromine or iodine atom or a
triflate group, Ui being in the position where it is
desired to introduce the group Rs or R7 :
- 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 derivative
- or by a Negishi type reaction, for example using an
alkyl, cycloalkyl, aryl or heteroaryl halide zincate
derivative.
12. Compound of formula (III)

in which Z represents a hydrogen atom or a nitro group,
R3 is as defined in the formula (I) and R4 represents a
4- (methylcarbamoyl)-oxazol-2-yl group.
13. Compound of general formula (la):

in which R2, R3, R4, m, n, o and p are as defined in
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 C1-6-alkylene part of the -0-C1-6-
alkylene group.

14. Compound of general formula (Ila):
in which R2 is as defined in the general formula (I) of
Claim 1, o and p represent 1, m and n represent 1 or 2,
but m and n do not together represent the value 2, G
represents a part of the group A as defined in the
general formula (I) , namely either a covalent bond or
the C1-6-alkylene part of the -0-C1-6-alkylene group, and
GP represents a protective group such as a Boc (terfc-
butyloxycarbonyl), Cbz (benzyloxycarbonyl), benzyl or
benzhydryl.
15. Compound of general formula (II):

in which Rlt R2, m, n, o and p are as defined in Claim
1, and A represents an oxygen atom, it being given that R1 is not a fluorophenyl group.
16. Compound of general formula (lie):

in which R2 is as defined in Claim 1, o and p represent
1, m and n represent 1 or 2, but m and n do not
together represent the value 2, G represents a part of
the group A as defined in the general formula (I) ,
namely either a covalent bond or the C1-5-alkylene part
of the -0-C1-6-alkylene group and GP represents a
protective group such as a Boc (tert-butyloxycarbonyl),
Cbz (benzyloxycarbonyl), benzyl or benzhydryl.
17. Compound of general formula (I) according to any
one of Claims 1 to 8, in the form of the base or

addition salt to a pharmaceutically acceptable acid,
for the use thereof as a medicament.
18. Pharmaceutical composition containing at least one
compound of formula (I) according to any one of Claims
1 to 8, in the form of the base or addition salt to a
pharmaceutically acceptable acid, and optionally one or
more pharmaceutically acceptable excipients.
19. Use of a compound of formula (I) according to any
one of Claims 1 to 8, in the form of the base or
addition salt to a pharmaceutically acceptable acid,
for the preparation of a medicament intended to prevent
or to treat a pathology in which the endogenous
cannabinoids and/or any other substrates metabolized by
the enzyme FAAH are involved.
20. Use of a compound of formula (I) according to any
one of Claims 1 to 8, in the form of the base or
addition salt to a pharmaceutically acceptable acid,
for the preparation of a medicament intended to prevent
or to treat acute or chronic pain of neurogenic type,
acute or chronic pain associated with inflammatory
diseases, acute or chronic peripheral pain, vertigo,
vomiting, nausea, eating disorders, neurological and
psychiatric pathologies, acute and chronic neuro-
degenerative diseases, epilepsy, sleep disorders,
cardiovascular diseases, renal ischaemia, cancers,
immune system disorders, allergic diseases, parasitic,
viral or bacterial infectious diseases, osteoporosis,
ocular complaints, gastrointestinal diseases, urinary
incontinence or inflammation of the bladder.

The invention relates to compounds of the general formula (I) where: R2 is a hydrogen or fluorine atom or a
hydroxyl, cyano, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy, or NR8R9 group; m, n, o and p independently are a number from 0 to 3,
provided that m+n ≤ 7 and that o+p ≤ 7; A is a covalent bond, an oxygen atom, a C1-6-alkylene group or a -O-C1-6-alkylene group
in which the end that is an oxygen atom is bonded to the R1 group and the end that is an alkylene group is bonded to the carbon of
the bicyclic compound; R1 is an optionally substituted aryl or heteroaryl group; R3 is a hydrogen or fluorine atom or a C1-6-alkyl or
trifluoromethyl group; R4 is an optionally substituted 5-membered heterocyclic compounds; wherein the compounds can be in the
state of a base or an acid addition salt. The invention can be used in therapeutics.