Title of Invention

N-(HETEROARYL)-1H-INDOLE-2-CARBOXAMIDE DERIVATIVES AND THEIR USE AS VANILLOID TRPV 1 RECEPTOR LIGANDS.

Abstract The invention concerns compounds of general formula (I), wherein: n is equal to 0,1,2 or 3; X1, X2 X3, X4. Z1 Z2, Z3, Z4, and Z5 represent a hydrogen atom or certain specific substituents; W represents a fused bicyclic group of formula (a), bound to the nitrogen atom by positions 1,2,3 or 4; A represents a 5 to 7-membered optionally substituted heterocycle comprising one to three heteroatoms selected among O, S or N. Said compounds are ligands of the TRPV1 vanilloid receptor useful for treating pain and inflammation.
Full Text The invention relates to N-(heteroaryl)-1H-indole-2-carboxamide-based compounds,
which show in vitro and in vivo antagonist or agonist activity for receptors of TRPV1 (or
VR1)type.
A first subject of the invention relates to compounds corresponding to the general
formula (I) below.
Another subject of the invention relates to processes for preparing the compounds of
general formula (I).
Another subject of the invention relates to the use of the compounds of general
formula (I) especially in medicaments or in pharmaceutical compositions.
The compounds of the invention correspond to the general formula (I):

in which
n is equal to 0, 1, 2 or 3;
X1, X2, X3, X4, Z1, Z2, Z3, Z4 and Z5 represent, independently of each other, a hydrogen or
halogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2, nitro, NR1R2,
C1-C6-thioalkyl, -S((O)-C1-C6-alkyl, -S(O)2-C1-C6-alkyl, SO2-NR1R2, NR3COR4, NR3SO2R5
or aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro or cyano group;
R1 and R2 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3 ralkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,

azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;
A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;
the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C3-Crcycloalkyl, C3-C7cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is
adjacent to a carbon atom substituted with an oxo group, or with R7 in the other cases;
R6 represents a hydrogen atom or a C1-C6-alkyl, C3-C7 cycloalkyl, C3-C7-cycloalkyl-C1-C3
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C3-C7-cycloalkyl-C1-C3-
alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-C7cydoalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6-
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2-l C3-C7 -cycloalkyl-S(O)2-,
C3-C7-cycloalkyl-C1-C3-alkylene-S(O)2-, aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2- or aryl
group; and
W is other than indolyl.
In the case of the compounds of general formula (I):
- the sulfur atom(s) of the heterocycle A may be in oxidized form (S(O) or S(O)2);
- the nitrogen atom(s) of the heterocycle A may be in oxidized form (N-oxide).
Among the compounds of general formula (I) that are subjects of the invention, a first
subgroup of compounds consists of the compounds for which n is equal to 0 or 1.

Among the compounds of general formula (I) that are subjects of the invention, a second
subgroup of compounds consists of the compounds for which X1, X2, X3, X4, Z1, Z2, Z3, Z4
and Z5 represent, independently of each other, a hydrogen or halogen atom, more
particularly a fluorine, or a C1-C6-alkyl group, more particularly a methyl, or a
C1-C6-fluoroalkyl group, more particularly a CF3, or a C1-C6-alkoxy group, more
particularly a methoxy.
Among the compounds of general formula (I) that are subjects of the invention, a third
subgroup of compounds consists of the compounds for which W is chosen from indolinyl,
isoindolinyl, benzofuryl, dihydrobenzofuryl, benzothiophenyl, dihydrobenzothiophenyl,
benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuryl, dihydroisobenzofuryl,
benzimidazolyl, dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl,
dihydroisobenzothiazolyl, benzotriazolyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl,
isoquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzoxazinyl, dihydrobenzoxazinyl,
benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl, dihydroquinazolinyl,
tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl,
phthalazinyl, dihydrophthalazinyl, tetrahydrophthalazinyl, tetrahydrobenz[jb]azepinyl,
tetrahydrobenz[c]azepinyl, tetrahydrobenz[d]azepinyl, tetrahydrobenzo[b][1,4]diazepinyl,
tetrahydrobenzo[e][1,4]diazepinyl, tetrahydrobenzo[b)][1,4]oxazepinyl and
tetrahydrobenzo[b][1,4]thiazepinyl groups;
the carbon and/or nitrogen atom(s) of the said group W being optionally substituted as
defined in the general formula (I).
Among the compounds of the third subgroup, a fourth subgroup of compounds consists
of the compounds for which W is chosen from isoquinolyl, dihydroquinolyl,
tetrahydroquinolyl, benzoxazinyl, dihydrobenzoxazinyl, benzofuryl, indolinyl,
benzoxazolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, quinolyl and
quinoxalinyl groups;
the carbon atom(s) of the said group W being optionally substituted with one or more
groups chosen from an oxo group, C1-C6-alkyl, more particularly methyl or ethyl, or aryl,
more particularly phenyl, as defined in the general formula (I) in relation with A; and/or
the nitrogen atom(s) of the said group W being optionally substituted with R6 when the
nitrogen is adjacent to a carbon atom substituted with an oxo group, or with R7 in the
other cases, R6 and R7 being as defined in the general formula (I) in relation with A,
with R6 representing a hydrogen atom or a C1-C6-alkyl group, more particularly a methyl,
with R7 representing a hydrogen atom or a C1-C6-alkyl group, more particularly a methyl,
or a C1-C6-alkyl-S(O)2-, more particularly a methylsulfonyl.

A fifth subgroup of compounds consists of the compounds of general formula (I):

in which
5 n is equal to 0, 1, 2 or 3;
X1, X2, X3, X4, Z1 Z2, Z3, Z4 and Z5 represent, independently of each other, a hydrogen or
halogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2 nitro, NR1R2,
C1-C6-thioalkyl, -S(O)-C1-C6-alkyl, -S(O)2-C1-C6-alkyl, SO2NR1R2, NR3COR4, NR3SO2R5
or aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen and a C1-C6-alkyl, C3-C7-cycloalkyl, C1-C7cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro or cyano group;
R1 and R2 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-C7cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a C1-C6-alkyl, C3-Crcycloalkyl, C3-C7 cycloalkyl-C1-C3
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alky! or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;
A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;

the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is adjacent to a carbon atom substituted with an oxo group, or with R7 in the other cases;
R6 represents a hydrogen atom or a C1-C6-alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C1-C6-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C3-C7cycloalkyl-C1-C3- alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-C7-cycloalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2-, C3-C7-cycloalkyl-S(O)2-,
C3-C7-cycloalkyl-C1-C3-alkylene-S(O)2-, aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2- or aryl
group; and
W is other than indolyl;
on condition that when Z1, Z2, Z3, Z4 and Z5 simultaneously represent hydrogen atoms,
then n = 2 or 3.
Among the compounds of general formula (I) that are subjects of the invention, a sixth
subgroup of compounds consists of compounds for which W is other than quinolyl,
dihydroquinolyl, tetrahydroquinolyl, isoquinolyl, dihydroisoquinolyl or tetrahydroisoquinolyl
groups.
Among the compounds of general formula (I) that are subjects of the invention, a seventh
subgroup of compounds consists of ail of the compounds of general formula (I):

in which
n is equal to 0,1, 2 or 3;
X1 X3, X4, Z1,Z3,.Z4 and Z5 represent hydrogen atoms, X2 represents a hydrogen atom, a
fluorine atom or a CF3 group and Z2 represents a hydrogen atom or a fluorine atom;

R1 and R2 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;
A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;
the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3ralkylene,
C1-C6-fluoroalkyl, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is
adjacent to a carbon atom substituted with an oxo group, or with R7 in the other cases;
Re represents a hydrogen atom or a C,-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-Cr
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C1-C7-cycloalkyl-C1-C3-
alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-C7-cycloalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6-
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2,-, C3-C7-cycloalkyl-S(O)2-,
C3-C7-cycloalkyl-C1-C3-alkylene-S(O)2-, aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2- or aryl
group; and
W is other than indolyl.
Among the compounds of general formula (I) that are subjects of the invention, an eighth
subgroup of compounds consists of the compounds for which W is as defined in the sixth
subgroup above and X1, X2 X3, X4, Z1, Z2, Z3, Z4 and Z5 are as defined in the seventh
subgroup above.

Among the compounds of general formula (I) that are subjects of the invention, a ninth
subgroup of compounds consists of all of the compounds of general formula (I):

in which
n is equal to 0, 1, 2 or 3;
X1 X2 X3, X4, Z1 Z2 Z3, Z4 and Z5 represent, independently of each other, a hydrogen or
halogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-Cz-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2 nitro, NR1R2,
C1-C6-thioalkyl, -S(O)-C1-C6-alkyI, -S(O)2-C1-C6-alkyl, SO2NR1R2, NR3COR4, NR3SO2R5
or aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen and a C1-C6-alkyl, C3-Crcycloalkyl, C3-C7cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro or cyano group;
R1 and R2 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;

A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;
the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C3-C7-cycloalkyl, C1-CVcycloalkyl-C1-C3-alkylene,
C1-C6-fiuoroalkyl, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is
adjacent to a carbon atom substituted with an oxo group, or with R7 in the other cases;
Re represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C3-C7-cycloalkyl-C1-C3
alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-C7-cycloalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6-
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2-, C3-C7cycloalkyl-S(O)2-,
C3-C7-cycloalkyl-C1-C3-alkylene-S(O)2-, aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2- or aryl
group; and
W is other than indolyl,
the following compounds being excluded: N-(quinol-7-yl)-1-benzyl-6-bromo-1H-indole-2-
carboxamide, N-(quinol-7-yl)-1-benzyl-5-bromo-1H-indole-2-carboxamide and N-(quinol-
7-yl)-6-bromo-1-(4-(trifluoromethyl)benzyl)-1 H-indole-2-carboxamide. These three
compounds are described in document US 2005/0165049.
Among the compounds of general formula (I) that are subjects of the invention, a tenth
subgroup of compounds consists of all of the compounds of general formula (I):

in which
n is equal to 0, 1, 2 or 3;
X1, X2, X3, X4, Z1 Z2, Z3, Z4 and Z5 represent, independently of each other, a hydrogen or
halogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2, nitro, NR1R2,

C1-C6-thioalkyl, -S(O)-C1-C6-alkyl, -S(O)2-C1-C6-alkyl, SOzNR1R2, NR3COR4, NR3SO2R5
or aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro or cyano group;
R1 and R2 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a CfC6-alkyl, C3-C7-cycloalkyl, C1-C^cycloalkyl-C1-C6-
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;
A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;
the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is
adjacent to a carbon atom substituted with an oxo, or with R7 in the other cases;
Re represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C^cycloalkyl-C1-C6-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C3-d-cycloalkyl-C1-C3-
alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-Crcycloalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6-
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2-, C1-CVcycloalkyl-SCCOr,
C1-C7-cycloalkyl-C1-C3-alkylene-S(O)2-, aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2- or aryl
group; and
W is other than indolyl;

on condition that when W is a benzimidazolyl, benzothiazolyl or benzoxazolyl group, then
Z1, Z2, Z3, Z4 and Z5 represent a C1-C6-alkyl, C3-Crcycloalkyl, C1-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2, -S(O)-C1-C6-alkyl,
SO2NR.,R2, NR3COR4, NR3SO2R5 or aryl group.
i
Among the compounds of general formula (I) that are subjects of the invention, an
eleventh subgroup of compounds consists of all of the compounds of general formula (I):

in which
n is equal to 0, 1, 2 or 3;
X1, X2, X3, X4, Z1f Z2, Z3, Z4 and Z5 represent, independently of each other, a hydrogen or
halogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-d-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2, nitro, NR1R2,
C1-C6-thioalkyl, -S(O)-C1-C6-alkyl, -S(O)2-C1-C6-alkyl, SO2NR1R2, NR3COR4, NRsSO2R5
or aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro or cyano group;
R1 and R2, represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C6-alkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:


linked to the nitrogen atom via the positions 1, 2, 3 or 4;
A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;
the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C3-Crcycloalkyl, C3-d-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is
adjacent to a carbon atom substituted with an oxo group, or with R7 in the other cases;
Re represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C3-C7-cycloalkyl-C1-C3-
alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-C7-cycloalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6-
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2-, C3-C7-cycloalkyl-S(O)2-,
C3-C7-cycloalkyl-C1-C3-alkylene-S(O)2-> aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2- or aryl
group; and
W is other than indolyl
on condition that when A is a 5-membered heterocycle, then it is unsaturated.
Among the compounds of general formula (I) that are subjects of the invention, a twelfth
subgroup of compounds consists of all of the compounds of general formula (I):

in which
n is equal to 0, 1, 2 or 3;

XL X2, X3> X4, Z1; Z2, Z3, Z4 and Z5 represent, independently of each other, a hydrogen or
halogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2, nitro, NR1R2,
C1-C6-thioalkyl, -S(O)-C1-C6-alkyl, -S(O)2-C1-C6-alkyl, SOzNR1Rz, NR3COR4, NR3SO2R5
or aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen and a C1-C6-alkyl, C3-C7-cycloalkyl, QrC^cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro or cyano group;
Rt and R2 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-d-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a C1-C6-alkyl, C3-C7-cycloalkyl, C1-Cr-cycloalkyl-C1-C6-
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:

linked to the nitrogen atom via positions 1, 2, 3 or 4;
A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;
the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C1-Cr-cycloalkyl, C1-Crcycloalkyl-C1-C6-alkylene,
C1-C6-fluoroalkyl, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is
adjacent to a carbon atom substituted with an oxo group, or with R7 in the other cases;
Re represents a hydrogen atom or a C1-C6-alkyl, C3-Crcycloalkyl, C3-d-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C1-C6-cycloalkyl-C1-C6-
alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-C7-cycloalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6-
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2-, C3-d-cycloalkyl-S(O)2-,

C3-C7-cycloalkyl-C1-C3-alkylene-S(O)2-, aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2- or aryl
group; and
W is other than indolyl
on condition that A is other than an unsaturated 5-membered heterocycle.
The compounds for which n, X-,, X2, X3l X4, Zu Z2, Z3, Z4, Z5 and W are as defined in the
above subgroups of compounds form a thirteenth subgroup.
Among the compounds of general formula (I) that are subjects of the invention, a
fourteenth subgroup of compounds consists of the following compounds:
A/-(isoquinol-5-yl)-5-fiuoro-1-[((3-trifluoromethyl)phenyl)methyl]-1H-indole-2-carboxamide,
A/-(1 -methyl-1,2,3,4-tetrahydroquinol-7-yl)-1 -[3-(trifluoromethyl)phenyl]-1 H-indole-2-
carboxamide,
/V-(1 -methyl-1,2,3,4-tetrahydroquinol-7-yl)-1-((3-5-dimethyl)phenyl)-1tf-indole-2-
carboxamide,
A/-(1,2,3,4-tetrahydroquinol-7-yl)-1 -[3-(trifluoromethyl)phenyl]-1 H-indole-2-carboxamide,
A/-(4-methyl-3-oxo-2/7-benzoxazin-7-yl)-1 -[3-(trifluoromethyl)phenyl]-1 H-indole-2-
carboxamide,
A/-(4-methyl-3-oxo-2H-benzoxazin-6-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-
carboxamide,
A/-(2-oxo-3,4-dihydroquinol-7-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,
A/-(benzofuran-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,
/V-(1 -methylindolin-5-yl)-1 -[3-(trifluoromethyl)phenyl]-1 H-indole-2-carboxamide,
A/-(2,3-dihydrobenzoxazin-6-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,
A/-(3-oxo-2H-benzoxazin-7-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,
A/-(1 -methylindolin-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 W-indole-2-carboxamide,
A/-(1 -methyl-1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
A/-(1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
/V-(isoquinol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(1,2,3,4-tetrahydroquinol-8-yl)-1 -[3-(trifluoromethyl)phenyl]-1 H-indole-2-carboxamide,
/V-(benzoxazol-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,
A/-(2-methylbenzoxazol-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide,
/V-(1 -methyl-1 H-indazol-5-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 /-/-indole-2-
carboxamide,

A/-(2-oxo-3,4-dihydroquinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(benzofuran-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(2,3-dihydrobenzoxazin-6-yl)-5-fIuoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(3-oxo-2H-benzoxazin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
/V-(1,2,3,4-tetrahydroquinol-7-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 /-/-indole-2-
carboxamide,
A/-(2-oxoindolin-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1/-/-indole-2-
carboxamide,
A/-(1 -methylbenzimidazol-5-yl)-5-trifIuoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
A/-(1 -methyl-1,2,3,4-tetrahydroquinol-7-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-
indole-2-carboxamide,
A/-(benzothiazol-6-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(2-methylbenzoxazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(2-methylbenzothiazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(1 -methylsulfonylindolin-5-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
A/-(isoquinol-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
/V-(1 -methylbenzimidazol-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
A/-(1-methylbenzimidazol-4-yl)-5-fluoro-1-[(3-fIuorophenyl)methyl]-1H-indole-2-
carboxamide,
N-( 7H-benzotriazol-5-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
A/-(quinol-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(1 -methylindazol-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide,
A/-(2-methylbenzoxazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(benzothiazol-6-yl)-5-fluoro-1-[(3-fIuorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(2-methylbenzothiazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,

A/-(2-oxo-3,4-dihydroquinol-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(2-oxoindolin-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
N-( 7H-benzotriazol-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide,
A/-(1 -methylsulfonylindolin-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
A/-(1,2-dimethylbenzimidazol-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide,
A/-(2-ethylbenzoxazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(2-phenylbenzoxazol-5-yl)-5-trifIuoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(quinoxalin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(quinol-7-yl)-5-fIuoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(isoquinol-7-yl)-5-fIuoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(2-methylbenzimidazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide,
A/-(benzimidazol-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide,
A/-(2-oxo-3,4-dihydroquinol-7-yl)-6-methoxy-1-[(4-fIuorophenyl)methyl]-1/-/-indole-2-
carboxamide and
A/-(1-methylbenzimidazol-6-yl)-5-fIuoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide.
In the context of the present invention, the following meanings apply:
- Ct-C2 in which t and z may take the values from 1 to 7: a carbon-based chain possibly
containing from t to z carbon atoms, for example C,-C3 is a carbon-based chain that
may contain from 1 to 3 carbon atoms;
- an alkyl: a saturated, linear or branched aliphatic group. Examples that may be
mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,
etc. groups;
- an alkylene: a saturated, linear or branched divalent alkyl group, for example a C1.3-
alkylene group represents a linear or branched divalent carbon-based chain of 1 to
3 carbon atoms, more particularly a methylene, ethylene, 1-methylethylene or
propylene;
- a cycloalkyl: a cyclic carbon-based group. Examples that may be mentioned include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. groups;
- a fluoroalkyl: an alkyl group of which one or more hydrogen atoms have been

replaced with a fluorine atom;
- an alkoxy: a radical -O-alkyl in which the alkyl group is as defined above;
- a fluoroalkoxy: an alkoxy group of which one or more hydrogen atoms have been
replaced with a fluorine atom;
- a thioalkyl: a radical -S-alkyl in which the alkyl group is as defined above;
- an aryl: a cyclic aromatic group containing between 6 and 10 carbon atoms.
Examples of aryl groups that may be mentioned include phenyl and naphthyl groups;
a heterocycle: a saturated, partially unsaturated or aromatic 5- to 7-membered cyclic
group comprising from one to three heteroatoms chosen from O, S and N. Examples of
groups W that may be mentioned include indolinyl, isoindolinyl, benzofuryl,
dihydrobenzofuryl, benzothiophenyl, dihydrobenzothiophenyl, benzoxazolyl,
dihydrobenzoxazolinyl, isobenzofuryl, dihydroisobenzofuryl, benzimidazolyl,
dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl,
dihydroisobenzothiazolyl, benzotriazolyl, quinolyl, dihydroquinolyl, tetrahydroquinolyl,
isoquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzoxazinyl, dihydrobenzoxazinyl,
benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl, dihydroquinazolinyl,
tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl,
phthalazinyl, dihydrophthalazinyl, tetrahydrophthalazinyl, tetrahydrobenz[b]azepinyl,
tetrahydrobenz[c]azepinyl, tetrahydrobenz[c/]azepinyl, tetrahydrobenz[c(]azepinyl,
tetrahydrobenzo[/>][1,4]diazepinyl, tetrahydrobenzo[e][1,4]diazepinyl,
tetrahydrobenzo[b][1,4]oxazepinyl and tetrahydrobenzo[b][1,4]thiazepinyl groups;
- a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
"oxo" means "=0";
- "thio" means "=S".
The compounds of formula (I) may comprise one or more asymmetric carbon atoms.
They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers
and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of
the invention.
The compounds of formula (I) may exist in the form of bases or of acid-addition salts.
Such addition salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, but the
salts of other acids that are useful, for example, for purifying or isolating the compounds
of formula (I) also form part of the invention.
The compounds of general formula (I) may be in the form of hydrates or solvates, i.e. in

the form of associations or combinations with one or more water molecules or with a
solvent. Such hydrates and solvates also form part of the invention.
In the text hereinbelow, the term "leaving group" means a group that can be readily
cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This
group may thus be readily replaced with another group, for example during a substitution
reaction. Such leaving groups are, for example, halogens or an activated hydroxyl group
such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc.
Examples of leaving groups and references for preparing them are given in "Advances in
Organic Chemistry", J. March, 5th Edition, Wiley Interscience, 2001.
In accordance with the invention, the compounds of general formula (I) may be prepared
according to the process illustrated in scheme 1 below.
According to scheme 1, the compounds of general formula (IV) may be obtained by
reacting a compound of general formula (II) in which X1t X2, X3 and X* are as defined in
the general formula (I) above and B represents a C1-C6-alkoxy or hydroxyl group, with a
compound of general formula (III), in which Z1t Z2, Z3, Z4, Z5 and n are as defined in the
general formula (I) above and R' represents a bromine or iodine atom, a tosylate group or
any other leaving group.
When n = 1, 2 or 3, the compound of general formula (III) may be an alkyl halide, such as
a benzyl bromide (n = 1: Kolasa T., Bioorg.Med.Chem. 1997, 5 (3) 507) or a phenethyl
iodide (n = 2: Abramovitch R., Synth. Commun., 1995, 25 (1), 1), and the reaction may be
performed in the presence of a base such as sodium hydride or potassium carbonate, in
a polar solvent such as dimethyiformamide, dimethyl sulfoxide or acetone.



When n = 0, the compound of general formula (III) is an aryl iodide or bromide and the
reaction may be performed at a temperature of between 80°C and 250°C, in the presence
of a copper-based catalyst such as copper bromide or copper oxide and also a base such
as potassium carbonate (Murakami Y., Chem. Pharm. Bull., 1995, 43 (8), 1281). The
milder conditions described in S.L. Buchwald, J. Am. Chem. Soc. 2002, 124, 11684 may
also be used.
Alternatively, the compounds of general formula (IV), in which n = 0, may be obtained by
reacting the compound of general formula (II) with a compound of general formula (III) of
boronic acid type (n = 0, R' = B(OH)2), in the presence of a base such as triethylamine or
pyridine and also copper diacetate, by analogy with protocols described in
W.W.K.R. Mederski, Tetrahedron, 1999, 55,12757.
The compounds of general formula (II) are commerically available or prepared according
to many processes described in the literature (for example D. Knittel Synthesis 1985, 2,
186; T.M. Williams J. Med. Chem. 1993, 36 (9), 1291; JP2001151771A2).
In the case of the indoles of general formula (IV), in which B represents a C^Ce-alkoxy
group, the compound of general formula (I) is obtained by reacting a compound of
general formula (IV), as obtained above, with an amide of the compound of general
formula (V), in which W is as defined in the general formula (I) above, at the reflux point
of a solvent such as toluene. The amide of the compound of general formula (V) is
prepared by the prior action of trimethylaluminium on the amines of general formula (V).
In the case of the indoles of general formula (IV), in which B represents a hydroxyl group,
the carboxylic acid function may be converted beforehand into an acid halide such as an
acid chloride via the action of thionyl chloride, at the reflux point of a solvent such as
dichloromethane or dichloroethane. The compound of general formula (I) is then obtained
by reacting the compound of general formula (IV), in which B represents a chlorine atom,
with the compound of general formula (V), in the presence of a base such as
triethylamine or sodium carbonate.
Alternatively, the indole of general formula (IV), in which B represents a hydroxyl group,
may be coupled with the compound of general formula (V) in the presence of a coupling
agent such as a dialkyl carbodiimide, benzotriazol-l-yloxytris(pyrrolidinophosphonium)
hexafluorophosphate, diethyl cyanophosphonate or any other coupling agent known to
those skilled in the art, in the presence of a base such as triethylamine, in a solvent such
as dimethylformamide.
In scheme 1, the compounds of formula (II), (III) and (V) and the other reagents, when
their preparation method is not described, are commercially available or described in the

literature (for example WO 2003/049702 or WO 2003/068749).
The compounds of general formulae (II), (IV) and (I), in which X-,, X2, X3, X4, Zu Z2, Z3, Z4
and/or Z5 represent a cyano group or an aryl, may be obtained via a coupling reaction,
catalysed with a metal such as palladium, performed on the corresponding compounds of
general formula (II), (IV) or (I), in which X1( X2, X3, X4, Zif Z2, Z3, Z4 and/or Z5 represents a
bromine atom.
The compounds of general formulae (II), (IV) and (I), in which X1, X2, X3, X4, Z1t Z2, Z3, Z4
and/or Z5 represent a group C(O)NR1R2, may be obtained from the corresponding
compounds of general formula (II), (IV) or (I), in which X1, X2, X3, X4, Z1, Z2) Z3> Z4 and/or
Z5 represents a cyano group, according to methods that are described in the literature or
that are known to those skilled in the art.
The compounds of general formulae (II), (IV) and (I), in which X1, X2, XJ, X4, Zu Z2, Z3, Z4
and/or Zs represent a group -S(O)-alkyl or -S(O)2-alkyl, may be obtained by oxidation of
the corresponding compounds of general formula (II), (IV) or (I), in which X1, X2, X3, X4,
Zy, Z2, Z3, Z4 and/or Z5 represents a C1-C6-thioalkyl group, according to methods that are
described in the literature or that are known to those skilled in the art.
The compounds of general formulae (II), (IV) and (I), in which X1( X2, X3, X4, ZL Z2, Z3, Z>
and/or Z5 represent a group NR.,R2, NR3C0R4 or NR3SO2R5, may be obtained from the
corresponding compounds of general formula (II), (IV) or (I), in which X1, X2, X3, X4, Z1t
Z2) Z3, Z4 and/or Zs represents a nitro group, for example by reduction, followed by
acylation or sulfonylation, according to methods that are described in the literature or that
are known to those skilled in the art.
The compounds of general formulae (II), (IV) and (I), in which X1t X2, X3, X4, Z1, Z2, Z3, Z4
and/or Z5 represent a group SO2NR1R2, may be obtained via a method analogous to that
described in Pharmazie 1990, 45, 346, or according to methods that are described in the
literature or that are known to those skilled in the art.
The compounds of general formula (I) in which R7 represents a hydrogen atom may be
obtained from compounds of general formula (I) in which R7 represents a phenylmethyl
group, by hydrogenation, for example catalysed with palladium, or by any method
described in the literature or known to those skilled in the art.
The examples that follow describe the preparation of certain compounds in accordance
with the invention. These examples are not limiting and serve merely to illustrate the
present invention. The numbers of the compounds given as examples refer to those
given in Table 1. The elemental microanalyses, the LC-MS (liquid chromatography
coupled to mass spectrometry) analyses and the IR and NMR spectra confirm the
structures of the compounds obtained.

Example 1 (compound 12)
/V-(1 -methyl-1 H-indolin-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide
1.1. Ethyl 5-fluoro-1 -[(3-fIuorophenyl)methyl]-1 H-indole-2-carboxylate
A suspension of 0.207 g (1 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.173 g (1.2
mmol) of 3-fluorobenzyl chloride and 0.276 g (2 mmol) of potassium carbonate in 10 ml of
dimethylformamide is stirred for 24 hours at 60°C. The reaction mixture is then cooled
and poured into a mixture of ice-water and ethyl acetate. After allowing the phases to
separate by settling, the organic phase is separated out and then washed with twice
50 ml of water and then with 50 ml of saturated sodium chloride solution. The solution is
dried over magnesium sulfate and filtered, and the filtrate is then concentrated under
reduced pressure. 0.195 g of an oil is obtained, which is used without further purification
in the following step.
1.2 /V-(1 -methyl-1 H-indolin-5-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide (compound 12)
0.089 g (0.6 mmol) of 5-amino-1-methyl-1 H-indoline (WO 2003/049702) and 0.5 ml of
trimethylaluminium (2M in toluene) are added to 2 ml of toluene under argon. The mixture
is heated for 2 hours at 50°C and 0.157 g (0.5 mmol) of ethyl 5-fluoro-1-[(3-
fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1, is added. The
reaction medium is refluxed for 10 minutes and left at room temperature overnight. It is
poured onto ice and 1 ml of 1N hydrochloric acid is added. The resulting mixture is
extracted with ethyl acetate and the organic phase is dried with magnesium sulfate and
concentrated under reduced pressure. The residue is purified by preparative
chromatography. 0.066 g of solid is obtained.
Melting point: 145-147°C
1H NMR (DMSO D6), 5 (ppm): 2.65 (s, 3H); 2.85 (t, 2H); 3.2 (t, 2H); 5.85 (s, 2H); 6.45 (d,
1H); 6.9 (m, 2H); 7.1 (m, 2H); 7.3 (m, 3H); 7.5 (m, 3H);
Example 2 (compound 13)
/V-(1 -methyl-1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide
The process is performed according to the method described in step 1.2 of Example 1,
starting with 0.185 g of 7-amino-1-methyl-1,2,3,4-tetrahydroquinol (WO 2003/049702),
0.95 ml of trimethylaluminium (2M in toluene) and 0.3 g of ethyl 5-fluoro-1-[(3-

fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1 of Example 1. 0.122 g
of product is obtained.
Melting point: 159-160°C
1H NMR (DMSO D6): 5 (ppm): 1.85 (m, 2H); 2.65 (t, 2H); 2.8 (s, 3H); 3.15 (t, 2H); 5.85 (s,
2H); 7 (m, 7H); 7.3 (m, 2H); 7.5 (m, 2H); 10.1 (s, 1H)
Example 3 (compound 14)
/V-(1,2,3,4-tetrahydroquinol-7-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide
The process is performed according to the method described in step 1.2 of Example 1,
starting with 0.169 g of 7-amino-1,2,3,4-tetrahydroquinol (WO 2003/049702), 0.95 ml of
trimethylaluminium (2M in toluene) and 0.3 g of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-
1H-indole-2-carboxylate, obtained in step 1.1 of Example 1. 0.033 g of product is
obtained.
Melting point: 149-151°C
1H NMR (DMSO D6): 5 (ppm): 1.75 (m, 2H); 2.6 (t, 2H); 3.1 (t, 2H); 5.85 (s, 2H); 6.95 (m,
7H); 7.3 (m, 2H); 7.5 (m, 2H); 10.1 (s, 1H)
Example 4 (compound 18)
A/-(2-methyl-benzoxazol-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide
0.091 ml (0.6 mmol) of diethylcyanophosphonate, 0.168 ml (0.6 mmol) of triethylamine
and 0.111 g (0.6 mmol) of 5-amino-2-methylbenzoxazole hydrochloride are added to a
solution of 0.152 g (0.5 mmol) of 1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxylic acid
(JP2001151771A2) in 3 ml of dimethylformamide. The mixture is stirred overnight at room
temperature and concentrated under reduced pressure, and the residue is taken up in
water and dichloromethane. After separation of the phases by settling, the organic phase
is dried and evaporated under reduced pressure. The residue is purified by preparative
chromatography. 0.102 g of solid is obtained.
Melting point: 223 - 225°C
1H NMR (DMSO D6): 8 (ppm): 2.55 (s, 3H); 7.2 (m, 3H); 7.6 (m, 3H); 7.75 (m, 5H); 7.95
(s, 1H);10.5(s, 1H)
Example 5 (compound 19)
/V-(1 -methyl-1 H-indazol-5-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide

5.1 Ethyl 5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-carboxylate
A solution of 2.88 g (11.2 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate
(obtained by Fisher indole synthesis from 4-(trifluoromethyl)phenylhydrazine) in 50 ml of
dimethylformamide is added dropwise to a suspension of 0.58 g (14.56 mmol) of sodium
hydride in 5 ml of dimethylformamide cooled in an ice bath. The mixture is stirred for 2
hours at room temperature and a solution of 2.54 g (13.44 mmol) of 3-fluorobenzyl
bromide in 20 ml of dimethylformamide is then added. Stirring is continued for 24 hours.
2.44 mmol of 3-fluorobenzyl bromide are added and the mixture is stirred for a further 4
hours. The solvent is evaporated off under reduced pressure and the residue is taken up
in water and ethyl acetate. After separation of the phases by settling, the organic phase is
separated out and then washed with twice 50 ml of water and then with 50 ml of
saturated sodium chloride solution. The solution is dried over magnesium sulfate and
filtered, and then the filtrate is concentrated under reduced pressure. The residue is
purified by chromatography on silica gel. 2.74 g of product are obtained.
5.2. /V-(1-methyl-1H-indazol-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-
indole-2-carboxamide
A solution of 0.34 g (2.3 mmol) of 5-amino-1-methyl-1H-indazole (IT. Forbes, J. Med.
Chem. 1993, 36 (8), 1104) in 10 ml of toluene is added, on an ice bath, to a solution of
1.92 ml (3.83 mmol) of trimethylaluminium (2M in toluene) in 5 ml of toluene. The reaction
medium is maintained at 50°C for 30 minutes. 1.92 mmol of ethyl 5-trifluoromethyl-1-[(3-
fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained in step 5.1, dissolved in 10 ml of
toluene, is then added. The mixture is refluxed for 3 hours and allowed to cool to room
temperature. 20 ml of water and 30 ml of ethyl acetate are added. The aqueous phase is
extracted with ethyl acetate; the organic phases are combined and washed with water
and then with saturated sodium chloride solution. The solution is dried over magnesium
sulfate and filtered, and the filtrate is then concentrated under reduced pressure. The
residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl
acetate and dichloromethane. The residue is taken up in petroleum ether, filtered, rinsed
and dried under reduced pressure. 0.71 g of solid is obtained.
Melting point: 198-199°C
1H NMR (CDCI3): 5 (ppm): 4 (s, 3H); 5.9 (s, 2H); 6.9 (m, 2H); 7 (m, 1H); 7.3 (m, 1H); 7.6
(m, 4H); 7.8 (d, 1H); 8 (s, 1H); 8.2 (d, 2H); 10.6 (s, 1H).
Example 6 (compound 20)

A/-(1 H-2-oxo-3,4-dihydroquinol-7-yl)-5-fiuoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide
0.097 g (0.6 mmol) of 7-amino-1H-3,4-dihydroquinol-2-one (WO 2003/049702) and 0.5 ml
i of trimethylaluminium (2M in toluene) are added to 2 ml of toluene under argon. The
mixture is heated for 2 hours at 50°C and 0.157 g (0.5 mmol) of ethyl 5-fluoro-1-[(3-
fluorophenyl)methyl]-1/-/-indole-2-carboxylate, obtained in step 1.1 of Example 1,
dissolved in 1 ml of toluene, is added. The reaction medium is refluxed for 2 hours and
left at room temperature overnight. It is poured onto ice and 2 ml of 1N hydrochloric acid
> are added. The resulting mixture is extracted with ethyl acetate and the organic phase is
dried with magnesium sulfate and concentrated under reduced pressure. The residue is
purified by preparative chromatography. 0.047 g of solid is obtained.
Melting point: 277- 279°C
1H NMR (DMSO D6): 8 (ppm): 2.4 (t, 2H); 2.8 (t, 2H); 5.85 (s, 2H); 6.9 (m, 2H) ; 7.1 (m,
5H); 7.4 (m, 2H); 7.5 (m, 2H); 10.05 (s, 1H); 10.4 (s, 1H)
Example 7 (compound 22)
A/-(2,3-dihydrobenzoxazin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide
The process is performed according to the method described in Example 6, starting with
0.090 g of 6-amino-2,3-dihydrobenzoxazine (WO 2003/049702), 0.5 ml of
trimethylaluminium (2M in toluene) and 0.157 g of ethyl 5-fluoro-1-[(3-
fluorophenyl)methyl]-1/-/-indole-2-carboxylate, obtained in step 1.1 of Example 1. 0.061 g
of product is obtained.
Melting point: 216-217°C
1H NMR (DMSO D6): 5 (ppm): 3.25 (t, 2H); 4.1 (t, 2H); 5.85 (s, 2H+1H); 6.55 (d, 1H); 6.9
(m, 3H); 7.1 (m, 3H); 7.3 (m, 2H); 7.5 (m, 2H); 10.1 (s, 1H)
Example 8 (compound 23)
A/-(3-oxo-2H-benzoxazin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxamide
The process is performed according to the method described in Example 6, starting with
0.107 g of 6-amino-3-oxo-2H-benzoxazine (WO 2003/049702), 0.5 ml of
trimethylaluminium (2M in toluene) and 0.157 g of ethyl 5-fluoro-1-[(3-

fluorophenyl)methyl]-1/-/-indole-2-carboxylate, obtained in step 1.1 of Example 1. 0.053 g
of product is obtained.
LC-MS: M+H = 434
1H NMR (DMSO D6): 5 (ppm): 4.5 (s, 2H); 5.85 (s, 2H); 6.9 (m, 3H); 7.1 (m, 4H); 7.4 (s,
1H); 7.5 (m, 3H); 10.4 (s, 1H); 10.7 (s, 1H)
Example 9 (compound 24)
A/-(1 ,2,3,4-tetrahydroquinol-7-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 /-/-indole-2-
carboxamide
A solution of 0.24 g (1.64 mmol) of 7-amino-1,2,3,4-tetrahydroquinol (WO 2003/049702)
in 5 ml of toluene is added, at 0°C on an ice bath, to a solution of 1.37 ml (2.74 mmol) of
trimethylaluminium (2M in toluene) in 5 ml of toluene. The reaction medium is maintained
at 50°C for 2 hours. 0.5 g (1.37 mmol) of ethyl 5-trifluoromethyl-1-[(3-
fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained in step 5.1 of Example 5,
dissolved in 10 ml of toluene, is then added. The mixture is refluxed for 3 hours and
allowed to cool to room temperature. 20 ml of ice-water, 20 ml of ethyl acetate and 20 ml
of 1N hydrochloric acid are added. After filtering the mixture and separation of the phases
by settling, the organic phase is washed with an alkaline solution and then with saturated
sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered,
and the filtrate is then concentrated under reduced pressure. The residue is taken up in
petroleum ether, collected by filtration and dried under reduced pressure. The product is
purified by chromatography on a column of silica, eluting with a mixture of heptane and
dichloromethane. The residue is recrystallized from ethanol. 0.29 g of solid is obtained.
Melting point: 203 - 204°C
1H NMR (DMSO): 5 (ppm): 1.7 (m, 2H); 2.6 (m, 2H); 3.1 (m, 2H); 5.7 (t, 1H); 5.9 (s, 2H);
6.7 (m, 2H); 6.95 (m, 4H); 7.3 (m, 1H); 7.45 (s, 1H); 7.5 (d, 1H); 7.75 (d, 1H); 8.1 (s, 1H);
10.2 (s,1H).
Example 10 (compound 26)
/V-(1 -methyl-benzimidazol-5-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-
carboxamide
10.1 5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 /-/-indole-2-carboxylic acid
A solution of 0.7 g (1.92 mol) of ethyl 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-
indole-2-carboxylate, obtained in step 5.1 of Example 5, and 0.21 g (3.83 mmol) of
potassium hydroxide in 10 ml of methanol is heated to reflux. The mixture is concentrated

under reduced pressure and the residue is taken up in water and acidified with
hydrochloric acid. The precipitate is collected by filtration, rinsed with water and dried
under reduced pressure. 0.69 g of solid is obtained, and is used without further
purification in the following step.
10.2 A/-(1 -methyl-benzimidazol-5-yl)-5-trifluoromethyl-1 -[(3-fluorophenyl)methyl]-1 H-
indole-2-carboxamide
A solution of 0.32 g (0.95 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-
2-carboxylic acid, obtained in step 10.1, and 0.69 ml (9.49 mmol) of thionyl chloride in
25 ml of dichloromethane is refluxed for 2 hours. The mixture is concentrated under
reduced pressure, the residue is taken up in 20 ml of diethyl ether, and 0.17 g (1.14
mmol) of 5-amino-1-methylbenzimidazole and a solution of 0.2 g (1.9 mmol) of sodium
carbonate in 2 ml of water are added. The mixture is stirred for 24 hours at room
temperature, the organic phase is evaporated under reduced pressure and the resulting
phase is extracted with ethyl acetate and dichloromethane. The organic phases are
washed with water and with saturated sodium chloride solution, dried over sodium sulfate
and concentrated under reduced pressure. The residue is taken up in petroleum ether,
collected by filtration, washed and dried under reduced pressure. It is then purified by
chromatography on a column of silica gel, eluting with a mixture of dichloromethane and
ethyl acetate. The residue is taken up in petroleum ether, collected by filtration, washed
and dried under reduced pressure. 0.3 g of solid is obtained.
Melting point: 223 - 224°C
1H NMR (DMSO), 8 (ppm): 5.9 (s, 2H); 7 (m, 3H); 7.3 (m, 1H); 7.55 (m, 4H); 7.8 (d, 1H);
8.05 (s, 1H); 8.1 (d, 2H); 10.5 (s, 1H).
Example 11 (compound 49)
A/-(quinol-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide
11.1 5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-carboxylic acid
A solution of 8.3 g (26.3 mmol) of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-
carboxylate, obtained in step 1.1 of Example 1, and 5.2 g (79 mmol) of potassium
hydroxide in a solution of 140 ml of ethanol and 14 ml of water is refluxed for 2 hours.
The mixture is concentrated under reduced pressure and the residue is taken up in water
and acidified with hydrochloric acid. The precipitate is collected by filtration, rinsed with
water and dried under reduced pressure. 7.4 g of solid are obtained, and are used
without further purification in the following step.
Melting point: 205 - 206°C

11.2 A/-(quinol-7-yl)-5-fluoro-1 -[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide
1 g (1.9 mmol) of benzotriazol-1-yloxytris(pyrrolidine)phosphonium hexafluorophosphate
is added, with stirring and under nitrogen, to a suspension of 0.5 g (1.74 mmol) of 5-
fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, obtained in step 11.1, in
10 ml of dry dimethylformamide. After 5 minutes, 0.4 g (1.83 mmol) of 7-aminoquinoline
hydrochloride (WO 2003/049702) and 0.9 g (7 mmol) of diisopropylethylamine are added.
After stirrihg for 2 hours at room temperature and for 2 hours at 60°C, the reaction
medium is poured into 100 ml of water and 50 ml of ethyl acetate. After separation of the
phases by settling and extraction of the aqueous phase, the organic phases are
combined, washed with water and dried over sodium sulfate. The residue is purified by
chromatography on a column of silica gel, eluting with a mixture of dichloromethane and
acetone. The solid obtained is recrystallized from isopropyl alcohol. 0.26 g of solid is
obtained.
Melting po nt: 222 - 223°C
1H NMR (I)MSO), 8 (ppm): 5.95 (s, 2H); 6.95 (t, 2H); 7.05 (m, 1H); 7.2 (t, 1H); 7.35 (q,
1H); 7.45 im, 1H); 7.55 (s, 1H); 7.65 (m, 2H); 8 (s, 2H); 8.3 (d, 1H); 8.55 (s, 1H); 8.9 (m,
1H); 11 (s, 1H).
Table 1 below illustrates the chemical structures and the physical properties of a number
of compounds of general formula (I) according to the invention. In this table, the "m.p."
column gi"es the melting points of the products in degrees Celsius (°C). When the
products were isolated in the form of an amorphous solid or an oil, they are characterized
in this column by their mass ([MH]+). Moreover, in the "salt" column, "-" represents a
compound in free base form, whereas "HCI" represents a compound in hydrochloride
form, and trie ratio in parentheses is the (acid:base) ratio





The compounds of the invention were subjected to in vitro and in vivo pharmacological
tests that demonstrated their value as substances with therapeutic activities.
Test of inhibition of the current induced with capsaicin on rat DRGs
- Primary culture of rat dorsal root ganglion (DRG) cells:
The neurons of the DRG naturally express the TRPV1 receptor.
The primary cultures of newborn rat DRGs are prepared using 1-day-old rats. Briefly,
after dissection, the ganglions are trypsinized and the cells dissociated by mechanical
trituration. The cells are resuspended in an Eagle basal culture medium containing 10%
foetal calf serum, 25 mM KCI, 2 mM glutamine, 100 //g/ml gentamicin and 50 ng/ml of
NGF, and then deposited on glass slides coated with laminin (0.25 x 106 cells per slide),
which are then placed in Corning 12-well dishes. The cells are incubated at 37°C in a
humidified atmosphere containing 5% C02 and 95% air. Cytosine 3-D-arabinoside (1 //M)
is added 48 hours after culturing, to prevent the growth of non-neuronal cells. The slides
are transferred into experimental chambers for the patch-clamp studies after 7-10 days of
culturing.
- Electrophysiology
The measuring chambers (volume 800 //I) containing the cell preparation are placed on
the platform of an inverted microscope (Olympus IMT2) equipped with Hoffman optics
(Modulation Contrast, New York) and observed at a magnification of 400X. The
chambers are continuously gravity-influxed (2.5 ml/min) using a solution distributor
accepting 8 inlets and whose sole outlet, consisting of a polyethylene tube (aperture
500 //m), is placed less than 3 mm from the cell under study. The "whole cell"
configuration of the patch-clamp technique was used. The borosilicate-glass pipettes
(resistance 5-10 MOhms) are brought to the cell by means of a 3D piezoelectric
micromanipulator (Burleigh, PC1000). The overall currents (membrane potential set at
-60 mV) are recorded with an Axopatch 1D amplifier (Axon Instruments, Foster city,
California), connected to a PC running the Pclamp8 software (Axon Instrument). The
current plots are recorded on paper and simultaneously digitized (sampling frequency 15
to 25 Hz) and acquired on the hard drive of the PC.
The application of a 300 nM capsaicin solution induces on the DRG cells (voltage set at
-70 mV) an entering cationic current. In order to minimize the desensitization of the
receptors, a minimum interval of 1 minute between two applications of capsaicin is
observed. After a control period (stabilization of the capsaicin response alone), the test
compounds are applied alone at a given concentration (concentration of 10 nM or 1 nM)
for a time of 4 to 5 minutes, during which several capsaicin + compound tests are

performed (to obtain the maximum inhibition). The results are expressed as a percentage
of inhibition of the control capsaicin response.
The percentages of inhibition of the capsaicin response (300 nM) are between 20% and
100% for the most active antagonist compounds of the invention tested at a
concentration of 10 nM or 1 nM (see selected examples in Table 2).

The intrinsic agonist effect of the compounds may be evaluated by measuring the
current induced at various compound concentrations on the rat DRG, in the presence or
absence of capsazepine.
Test of mouse corneal irritation
The irritant nature of capsaicin is readily assessed on the cornea since this organ is one
of the organs most densely innervated with C fibres. In this context, from preliminary
experiments, the application of a very small amount of capsaicin (2 //I at a concentration
of 160 //M) to the surface of the cornea of an animal leads to a certain number of
stereotypic behavioural traits associated with irritation, which are easy to detect. Among
these, the following are noted: blinking of the eye, rubbing of the instilled eye with the
ipsilateral front paw, rubbing of the face with both front paws, scratching of the ipsilateral
face with the hind paw. The duration of this behaviour does not exceed the 2 minutes of
observation, and the animal then resumes its normal activity. This aspect is moreover
also normal. The mouse is not recluse in a corner with raised hackles and does not
develop any observable sign of suffering. It may be concluded that the duration of action
of capsaicin at these doses is less than 2 minutes.
Summary of the methodology:
The principle of the series of experiments is to determine whether the compounds of the
invention can influence the behavioural response induced with a given amount of
capsaicin. The capsaicin is initially diluted to 25 mM in DMSO and diluted, for its final
use, in Tween 80 to 10% in physiological saline. It appears, from control studies, that,
under these conditions, the solvent has no effect.

In practice, the test product is administered orally and, with a delay (pretreatment time: t)
that depends on the pharmacokinetic data, the animal receives an ocular instillation of
2 JJ\ of a 160 //M capsaicin solution prepared as indicated above. During a 2-minute
observation following the instillation, the number of times the instilled eye is rubbed with
5 the ipsilateral front paw is recorded.
For a given animal, the percentage of protection is calculated as follows:
P= 100 - ((number of scratching actions observed/mean number of scratching actions
for the group treated with the solvent) x 100)
This percentage of protection is averaged for each group of animals (n = number of
) animals tested with the compound of the invention).
The percentages of protection evaluated in this model for the most active compounds of
the invention, used at a dose of 1 mg/kg (po), are between 20% and 100% (see selected
examples in Table 3):

The results of these tests show that the compounds may have agonist or antagonist
effects on the TRPV1 receptor. The most active antagonist compounds of the invention
block the effects induced by stimulation of the TRPV1 receptors.
The compounds of the invention may thus be used for the preparation of medicaments,
especially for the preparation of a medicament for preventing or treating pathologies in
which the TRPV1 receptors are involved.
Thus, according to another of its aspects, a subject of the invention is medicaments that
comprise a compound of formula (I), or a pharmaceutically acceptable salt, or
alternatively a hydrate or a solvate of the said compound.
These medicaments find therapeutic use especially in the prevention and/or treatment of
pain and inflammation, chronic pain, neuropathic pain (trauma-related, diabetic,
metabolic, infection-related or toxic pain, or pain induced by an anticancer or iatrogenic
treatment), (osteo)arthritic pain, rheumatic pain, fibromyalgia, back pain, cancer-related
pain, facial neuralgia, headaches, migraine, dental pain, burns, sunburn, animal bites or
insect bites, post-herpetic neuralgia, muscular pain, trapped nerves (central and/or

peripheral), spinal column and/or brain trauma, ischaemia (of the spinal column and/or
the brain), neurodegeneration, haemorrhagic strokes (of the spinal column and/or of the
brain) and post-stroke pain.
The compounds of the invention may be used for the preparation of a medicament for
preventing and/or treating urological disorders such as hyperactivity of the bladder,
vesical hyperreflexia, vesical instability, incontinence, urgent micturition, urinary
incontinence, cystitis, nephritic colic, pelvic hypersensitivity and pelvic pain.
The compounds of the invention may be used to prepare a medicament for preventing
and/or treating gynaecological disorders, for instance vulvodynia and pain associated
with salpingitis or with dysmenorrhoea.
These products may also be used for the preparation of a medicament for preventing
and/or treating gastrointestinal disorders such as gastrooesophageal reflux disorder,
stomach ulcers, duodenal ulcers, functional dyspepsia, colitis, IBS, Crohn's disease,
pancreatitis, oesophagitis and biliary colic.
Similarly, the products of the present invention may be useful in the prevention and/or
treatment of respiratory disorders such as asthma, coughing, COPD,
bronchoconstriction and inflammatory disorders. These products may also be used for
preventing and/or treating psoriasis, pruritus, dermal, ocular or mucous irritation, herpes
and zona.
According to another of its aspects, the present invention relates to pharmaceutical
compositions comprising a compound according to the invention as active principle.
These pharmaceutical compositions contain an effective dose of at least one compound
according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of
the said compound, and also at least one pharmaceutically acceptable excipient.
The said excipients are chosen, according to the pharmaceutical form and the desired
mode of administration, from the usual excipients known to those skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active principle of formula (I) above, or the
possible salt, solvate or hydrate thereof, may be administered in a unit administration
form, as a mixture with standard pharmaceutical excipients, to man and animals for the
prophylaxis or treatment of the disorders or diseases mentioned above.
The appropriate unit forms of administration include oral forms such as tablets, soft or
hard gel capsules, powders, granules and oral solutions or suspensions, sublingual,

buccal, intratracheal, intraocular and intranasal administration forms, forms for
administration by inhalation, topical, transdermal, subcutaneous, intramuscular or
intravenous administration forms, rectal administration forms and implants. For topical
application, the compounds according to the invention may be used in creams, gels,
pomades or lotions.
By way of example, a unit form of administration of a compound according to the
invention in tablet form may comprise the fo lowing components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscaramellose 6.0 mg
Cornstarch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said unit forms are dosed to allow a deiily administration of from 0.001 to 30 mg of
active principle per kg of body weight, according to the galenical form.
There may be particular cases in which hie her or lower dosages are appropriate: such
dosages do not depart from the scope of the invention. According to the usual practice,
the dosage that is appropriate for each patient is determined by the doctor according to
the mode of administration, the weight and the response of the said patient.
According to another of its aspects, the present invention also relates to a method for
treating the pathologies indicated above, wh ch comprises the administration to a patient
of an effective dose of a compound according to the invention, or a pharmaceutically
acceptable salt, or hydrate or solvate thereof.

WE CLAIM :
1. Compound corresponding to formula (I)

in which
n is equal to 0, 1, 2 or 3;
X1, X2, X3, X4, Z1, Z2 ,Z3, Z4and Z5 represent, independently of each other, a hydrogen or
halogen atom or a C1-C6-alkyI, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-fluoroalkoxy, cyano, C(O)NR1R2, nitro, NR1R2,
C1-C6-thioalkyl, -S(O)-C1-C6-alkyl, -S(O)2-C1-C6-alkyl, SO2NR1R2, NR3COR4, NR3SO2R5 or
aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyI, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro or cyano group;
R1 and R2 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene or aryl group; or R1 and R2 form,
together with the nitrogen atom that bears them, an azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group
being optionally substituted with a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene or aryl group;
R3 and R4 represent, independently of each other, a hydrogen atom or a C1-C6-alkyl or
aryl group;
R5 represents a C1-C6-alkyl or aryl group;
W represents a fused bicyclic group of formula:


linked to the nitrogen atom via positions 1, 2, 3 or 4;
A represents a 5- to 7-membered heterocycle comprising from one to three heteroatoms
chosen from O, S and N;
the carbon atom(s) of A being optionally substituted with one or more groups chosen from
a hydrogen atom and a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-alkylene,
C1-C6-fluoroalkyI, aryl, aryl-C1-C6-alkylene, oxo or thio group;
the nitrogen atom(s) of A being optionally substituted with R6 when the nitrogen is
adjacent to a carbon atom substituted with an oxo group, or with R7 in the other cases;
R6 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl group;
R7 represents a hydrogen atom or a C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3-
alkylene, C1-C6-fluoroalkyI, aryl-C1-C6-alkylene, C1-C6-alkyl-C(O)-, C3-C7-cycloalkyl-C1-C3-
alkylene-(CO)-, C1-C6-fluoroalkyl-C(O)-, C3-C7-cycloalkyl-C(O)-, aryl-C(O)-, aryl-C1-C6-
alkylene-C(O)-, C1-C6-alkyl-S(O)2-, C1-C6-fluoroalkyl-S(O)2-, C3-C7-cycloalkyl-S(O)2-,
C3-C7-cycloalkyl-C1-C3-alkylene-S(O)2-, aryl-S(O)2- or aryl-C1-C6-alkylene-S(O)2 or aryl
group; and
W is other than indolyl;
the sulfur atom(s) of the heterocycle A possibly being in oxidized form;
the nitrogen atom(s) of the heterocycle A possibly being in oxidized form;
in the form of base or of acid-addition salt, and also in the form of hydrate or solvate.
2. Compound of formula (I) as claimed in Claim 1, wherein n is equal to 0 or 1, in the form
of base or of acid-addition salt, and also in the form of hydrate or solvate.
3. Compound of formula (I) as claimed in Claim 1 or 2, wherein X1, X2, X3, X4, Z1, Z2, Z3, Z4
and Z5 represent, independently of each other, a hydrogen or halogen atom or a C1-C6-
alkyl, C1-C6-fluoroalkyI or C1-C6-alkoxy group, in the form of base or of acid-addition salt,
and also in the form of hydrate or solvate.
4. Compound of formula (I) as claimed in any one of Claims 1 to 3, wherein W is chosen
from indolinyl, isoindolinyl, benzofuryl, dihydrobenzofuryl, benzothiophenyl,
dihydrobenzothiophenyl, benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuryl,
dihydroisobenzofuryl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, benzothiazolyl,
isobenzothiazolyl, dihydroisobenzothiazolyl, benzotriazolyl, quinolyl, dihydroquinolyl,
tetrahydroquinolyl, isoquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzoxazinyl,
dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl,
dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl,

tetrahydroquinoxalinyl, phthalazinyl, dihydrophthalazinyl, tetrahydrophthalazinyl,
tetrahydrobenz[b]azepinyl, tetrahydrobenz[c]azepinyl, tetrahydrobenz[c(]azepinyl,
tetrahydrobenzo[b][1,4]diazepinyl, tetrahydrobenzo[e][1,4]diazepinyl, tetrahydrobenzo[b]
[1,4]oxazepinyl and tetrahydrobenzo[b][1,4]thiazepinyl groups;
the carbon and/or nitrogen atom(s) of the said group W optionally being substituted as
defined in the general formula (I) as claimed in Claim 1;
in the form of base or of acid-addition salt, and also in the form of hydrate or solvate.
5. Compound of formula (I) as claimed in Claim 4, wherein W is chosen from isoquinolyl,
dihydroquinolyl, tetrahydroquinolyl, benzoxazinyl, dihydrobenzoxazinyl, benzofuryl,
indolinyl, benzoxazolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, quinolyl,
quinoxalinyl groups;
the carbon atom(s) of the said group W being optionally substituted with one or more
groups chosen from an oxo, C1-C6-alkyl or aryl group, as defined in the general formula (I)
in relation with A; and/or
the nitrogen atom(s) of the said group W being optionally substituted with R6 when the
nitrogen is adjacent to a carbon atom substituted with an oxo group, or with R7 in the
other cases, R6 and R7 being as defined in the general formula (I) as claimed in Claim 1 in
relation with A,
with R6 representing a hydrogen atom or a C1-C6-alkyl group,
with R7 representing a hydrogen atom or a C1-C6-alkyl or C1-C6-alkyl-S(O)2 group;
in the form of base or of acid-addition salt, and also in the form of hydrate or solvate.





in which X1, X2, X3, X4, Z1, Z2, Z3, Z4, Z5 and n are as defined in the general formula (I) as
claimed in Claim 1 and B represents a C1-C4-alkoxy group,
is reacted with an amide of the compound of general formula (V)

in which W is as defined in the general formula (I) as claimed in Claim 1, at the reflux
point of a solvent, the amide of the compound of general formula (V) being prepared via
the prior action of trimethylaluminium on the compounds of general formula (V).
8. Process for preparing a compound of formula (I) as claimed in any one of Claims 1 to
6, wherein a compound of general formula (IV)

in which X1, X2, X3, X4, Z1, Z2, Z3, Z4, Z5 and n are as defined in the general formula (I) as
claimed in Claim 1 and B represents a hydroxyl group,
is converted into the acid chloride via the action of thionyl chloride at the reflux point of a
solvent,
and the compound of general formula (IV) obtained, in which X1, X2, X3, X4, Z1, Z2, Z3, Z4,
Z5 and n are as defined in the general formula (I) as claimed in Claim 1, and B represents
a chlorine atom, is then reacted, in the presence of a base, with the compound of general
formula (V)

in which W is as defined in the general formula (I) as claimed in Claim 1,

or alternatively a coupling reaction is performed between a compound of general formula
(IV) in which X1, X2, X3, X4, Z1, Z2, Z3, Z4, Z5 and n are as defined in the general formula (I)
as claimed in Claim 1 and B represents a hydroxyl group,
and the compound of general formula (V), in which W is as defined in the general formula
(I) as claimed in Claim 1, in the presence of a coupling agent and a base, in a solvent.
9. Medicament, comprising a compound of formula (I) as claimed in any one of Claims 1
to 6, or a pharmaceutically acceptable salt, or a hydrate or a solvate of the compound of
formula (I).
10. Pharmaceutical composition, comprising a compound of formula (I) as claimed in any
one of Claims 1 to 6, or a pharmaceutically acceptable salt, a hydrate or a solvate of this
compound, and also at least one pharmaceutically acceptable excipient.


(54) Title: N- (HETEROARYL) -1H-INDOLE-2-CARB0XAMIDE DERIVATIVES AND THEIR USE AS VANILLOID TRPV1
RECEPTOR LIGANDS


(57) Abstract: The invention concerns compounds
of general formula (I), wherein: n is equal to 0,1,2 or
3; X1, X2 X3, X4. Z1 Z2, Z3, Z4, and Z5 represent a hydrogen atom or certain specific substituents; W represents a fused bicyclic group of formula (a), bound
to the nitrogen atom by positions 1,2,3 or 4; A represents a 5 to 7-membered optionally substituted heterocycle comprising one to three heteroatoms selected
among O, S or N. Said compounds are ligands of the
TRPV1 vanilloid receptor useful for treating pain and
inflammation.

Documents:

02579-kolnp-2007-abstract.pdf

02579-kolnp-2007-claims.pdf

02579-kolnp-2007-correspondence others.pdf

02579-kolnp-2007-description complete.pdf

02579-kolnp-2007-form 1.pdf

02579-kolnp-2007-form 3.pdf

02579-kolnp-2007-form 5.pdf

02579-kolnp-2007-gpa.pdf

02579-kolnp-2007-international publication.pdf

02579-kolnp-2007-international search report.pdf

02579-kolnp-2007-others.pdf

02579-kolnp-2007-pct request form.pdf

02579-kolnp-2007-priority document.pdf

2579-KOLNP-2007-(19-10-2011)-ABSTRACT.pdf

2579-KOLNP-2007-(19-10-2011)-AMANDED CLAIMS.pdf

2579-KOLNP-2007-(19-10-2011)-DESCRIPTION (COMPLETE).pdf

2579-KOLNP-2007-(19-10-2011)-FORM 1.pdf

2579-KOLNP-2007-(19-10-2011)-FORM 13.pdf

2579-KOLNP-2007-(19-10-2011)-FORM 2.pdf

2579-KOLNP-2007-(19-10-2011)-OTHERS.pdf

2579-KOLNP-2007-(19-10-2011)-PETITION UNDER RULE 137.pdf

2579-KOLNP-2007-(30-08-2011)-ENGLISH TRANSLATION.pdf

2579-KOLNP-2007-ASSIGNMENT-1.1.pdf

2579-KOLNP-2007-ASSIGNMENT.pdf

2579-KOLNP-2007-CORRESPONDENCE-1.1.pdf

2579-KOLNP-2007-CORRESPONDENCE.pdf

2579-KOLNP-2007-EXAMINATION REPORT-1.1.pdf

2579-KOLNP-2007-EXAMINATION REPORT.pdf

2579-KOLNP-2007-FORM 13.pdf

2579-KOLNP-2007-FORM 18-1.1.pdf

2579-kolnp-2007-form 18.pdf

2579-KOLNP-2007-FORM 3-1.1.pdf

2579-KOLNP-2007-FORM 3.pdf

2579-KOLNP-2007-FORM 5-1.1.pdf

2579-KOLNP-2007-FORM 5.pdf

2579-KOLNP-2007-GPA-1.1.pdf

2579-KOLNP-2007-GPA.pdf

2579-KOLNP-2007-GRANTED-ABSTRACT.pdf

2579-KOLNP-2007-GRANTED-CLAIMS.pdf

2579-KOLNP-2007-GRANTED-DESCRIPTION (COMPLETE).pdf

2579-KOLNP-2007-GRANTED-FORM 1.pdf

2579-KOLNP-2007-GRANTED-FORM 2.pdf

2579-KOLNP-2007-GRANTED-SPECIFICATION.pdf

2579-KOLNP-2007-OTHERS-1.1.pdf

2579-KOLNP-2007-OTHERS.pdf

2579-KOLNP-2007-REPLY TO EXAMINATION REPORT-1.1.pdf

2579-KOLNP-2007-REPLY TO EXAMINATION REPORT.pdf

2579-KOLNP-2007-SPECIFICATION.pdf

2579-KOLNP-2007-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

abstract-02579-kolnp-2007.jpg


Patent Number 253754
Indian Patent Application Number 2579/KOLNP/2007
PG Journal Number 34/2012
Publication Date 24-Aug-2012
Grant Date 22-Aug-2012
Date of Filing 10-Jul-2007
Name of Patentee SANOFI AVENTIS
Applicant Address 174 , AVENUE DE FRANCE PARIS, 75013, FRANCE
Inventors:
# Inventor's Name Inventor's Address
1 DUBOIS, LAURENT 132, AVENUE DE LA RESISTANCE 92350, LE PLESSIS-ROBINSON, FRANCE
2 MALANDA, ANDRE 13 HAMEAU DES COUDRAYES, 91140, VILLEJUST
3 EVANNO, YANNICK 12 RUE DE COURANCES, 91490, DANNEMOIS
PCT International Classification Number C07D 209/42
PCT International Application Number PCT/FR2006/000008
PCT International Filing date 2006-01-04
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 05/50,068 2005-01-07 France