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(21)Application Number:     KElP/ 2010/001112       
       
(22) Filing Date: 20/0112009       
       
(30) Priority data: 08/00,310  22/0112008  FR   
       
(86)  PCT data PCT/FR09/000053    20/0112009 wo 2009/112679    17/09/2009   

(73) Owner: SANOFI-AVENTIS of 174 Avenue de France, 75013 Paris, France

(72) Inventors: EV ANNO, Yannick of c/o Sanofi-Aventis Departement Brevets 174, avenue de France F-75013 Paris, France; LECLERC, Odile of c/o Sanofi-Aventis Departement Brevets 174, avenue de France F-75013 Paris, France; DUBOIS. Laurent of c/o Sanofi-Aventis Departement Brevets 174, avenue de France F-75013 Paris,  Franceand MALANDA, Andre of c/o Sanofi-AventisDepartement Brevets 174, avenue de France F-7501Paris, France

(74) Agent/address for correspondence:Kaplan & Stratton Advocates, P.O. Box 40111-00100,Nairobi   

(54)    Title: AZABICYCLIC CARBOXAMIDE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

(57)    Abstract: The invention relates to the compounds of general formula (I) in which XI, X2, X3 and X4 are, independently of one another, a nitrogen atom or a C-Rl group; W is an oxygen or sulphur atom; n is equal to 0, 1, 2 or 3; Y is an optionally substituted aryl or heteroaryl; A is a bicyclic heteroaryl of formula (II) where Zl, Z2, Z3 and Z4 are, independently of one another, a carbon atom, a nitrogen atom or a C-R2a group; Z5, Z6 and Z7 are, independently of one another, a nitrogen atom or a C-Rb group; Z8 is a carbon atom; in the form of a base or of an addition salt with an acid, and also in the form of a hydrate or of a solvate. Process for preparation thereof and therapeutic use.
 
N-Azabicyclic carboxamide derivatives, preparation thereof and therapeutic use thereof.

Documents W02006/024 776, W02006/072 736, W02007/010 144 and W02007/010 138 describe bicyclic carboxamide derivatives with in vitro and in vivo

5    antagonist or agonist activity on receptors of TRPV1 (or VR1) type.

There is still a need to find novel ligands for receptors of TRPV 1 type, which are improved in terms of functional activity, metabolic profile and/or safety profile.

10    The present invention satisfies this need by providing azabicyclic carboxamide derivatives that have in vitro and in vivo antagonist or agonist activity on receptors of TRPV1 (or VR1) type.

A first subject of the invention concerns the compounds corresponding to the general

15    formula (I) hereinbelow.

Another subject of the invention concerns processes for preparing the compounds of general formula (I).

20    Another subject of the invention concerns 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 (1):


(I)
25

in which:

X1, X2, ~and ~represent, independently of each other, a nitrogen atom or a group C-
 

it being understood that when one from among X, X2, X3 and ~represents a nitrogen atom, the others correspond to a group C-R,;

W represents an oxygen or sulfur atom;

5

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

Y represents an aryl or a heteroaryl optionally substituted with one or more groups chosen from a halogen atom and a group C,-Ce-alkyl, C3-C7-cycloalkyl, C3-C7-

10    cycloalkyi-C1-C3-alkylene, C1-Ce-fluoroalkyl, hydroxyl, C1-Ce-alkoxy, C3-C 7-cycloalkyloxy, C3-C7-cycloalkyi-C,-Ce-alkylene-O-, C,-Ce-fluoroalkoxy, cyano, C(O)

N~~, nitro,  NR3~,  C1-Ce-thioalkyl,  thiol,  -S(O}-C1-C6-alkyl,  -S(0)2-C1-C6-alkyl,

S02N~~, NRsC(O)Re, NRsS02R1, C(O)NR3~, OC(O)NR3~, -Si-(C,-Ce-alkyl)3, -SF5 ,

aryi-C1-C5-alkylene or aryl, heteroaryi-C,-C5-alkylene or heteroaryl; the groups C1-C6-
15    alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyi-C,-C3-alkylene, C1-Ce-fluoroalkyl, C1-C6-alkoxy,
C3-C7-cycloalkyloxy and C3-C7-cycloalkyi-C1-Ca-alkylene-O- possibly being substituted with a hydroxyl, C1-C6-alkoxy or NR3~ group; the aryl and heteroaryl groups being optionally substituted with one or more substituents Re, which may be identical to or different from each other;

20

A represents a bicyclic heteroaryl of formula:

in which
25    Z1,  Z2, Z3 and Zt represent, independently of each other, a carbon atom, a nitrogen

atom or a group C-R2a;
Z5, Ze and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b;

Z8 represents a carbon atom;
three, at most, from among Z1, Z2, Z3, Zt, Z5, Ze and Z7 represent a nitrogen atom;

30    one from among z,, Z2, Z3 and Zt, corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I);

R1  is chosen from a hydrogen atom, a halogen atom, C1-C6-alkyl, C3-Crcycloalkyl,

C3-Crcycloalkyi-C1-C3-alkylene, C1-Ca-fluoroalkyl, aryloxy-C1-Ca-alkyl, heteroaryloxy-C1-C6-alkyl, aryi-C1-C3-alkylenoxy-C1-Ca-alkyl, heteroaryi-C1-C3-alkylenoxy-C1-C6-alkyl, arylthio-C1-Ca-alkyl, heteroarylthio-C1-Cs-alkyl, aryi-C1-C3-alkylenethio-C1-C6-alkyl, heteroaryi-C1-C3-alkylenethio-C,-Ca-alkyl, C1-Ca-alkoxy, C3-C7-cycloalkyloxy, C3-C7-
5    cycloalkyi-C1-C3-alkylenoxy, C1-Ca-fluoroalkoxy, cyano, C(O)N~~. nitro, NR3~. C1-C6-th ioalkyl, C3-C7-cycloalkylthio, C3-Crcycloalkyi-C1-C3-alkylenethio, -S( 0 )-C1-C6-alkyl, -S(O)-C3-C7-cycloalkyl, -S(O)-C1-C3-alkylene-C3-C7-cycloalkyl, C1-Ca-alkyi-S(0)2-, C1-C6-fluoroalkyi-S(0)2-, C3-C7-cycloalkyi-S(0)2-, C3-Crcycloalkyi-C1-C3-alkylene-

S(Oh-,  S02NR3~. (C1-Ca-alkyi)J-Si-,  -SFs,  NRsC(O)Rs,  NRsS02R7,  C(O)NR3~.

10    OC(O}NR3~, aryl, heteroaryl, aryi-C1-Cs-alkylene, heteroaryi-C1-C5-alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio; the heteroaryl or aryl groups being optionally substituted with one or more substituents R8 , which may be identical to or different from each other;

15    R2a represents a hydrogen atom, a halogen atom or a group C1-C6-alkyl, C3-Cr cycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C1-Ca-fluoroalkyl, C1-C6-alkoxy, C3-Cr cycloalkyloxy, C3-Crcycloalkyi-C1-C3-alkylene-O-, hydroxyl, thiol or C1-C6-fluoroalkoxy;

R2b  represents  a  hydrogen  atom,  a  halogen  atom  or a  group  C1-C6-alkyl,  C3-C7-

20    cycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl, C1-C6-alkoxy, hydroxyl, thiol, oxo, thio, C3-C7-cycloalkyloxy, C1-Ca-fluoroalkoxy, C3-C?-cycloalkyi-C1-C3-alkylenoxy, C1-Cs-alkoxy-C1-C3-alkylene, C3-C?-cycloalkyloxy-C1-C3-alkylene, C3-Cr cycloalkyi-C1-C3-alkylenoxy-C1-C3-alkylene, C1-Ca-alkyi-C(0)-0-C1-C3-alkylene, C1-C6-alkyi-C(O}-O-, C3-C7-cycloalkyi-C(O)-O-C1-C3-alkylene, C3-C7-cycloalkyi-C(O)-O-, C1-

25    C6-fluoroalkyi-C(O)-O-C1-C3-alkylene, C1-Ca-fluoroalkyi-C(O)-O-, C(O)N~~. C(O)O-C1-C6-alkyl, cyano, CHO, C02H, -C(O)-C1-Ca-alkyl, -C(O)-C3-C7-cycloalkyl, phenyl or thienyl; the groups C,-Ca-alkyl, C3-C7-cycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl, C1-Ca-alkoxy, C3-C,cycloalkyloxy, C1-Cs-fluoroalkoxy, C3-C7-
cycloalkyi-C1-C3-alkylenoxy,  C1-Cs-alkoxy-C1-C3-alkylene,  C3-C1  cycloalkyloxy-C1-C3-

30    alkylene and CTC?-cycloalkyi-C1-C3-alkylenoxy-C1-C3-alkylene possibly being substituted with a hydroxyl, C1-C6-alkoxy or NR3~ group;
 

~ and ~ represent, independently of each other, a hydrogen atom or a group C1-C6-alkyl, C3-C7-cycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, aryi-C1-Cs-alkylene or aryl, or
35    ~ and  ~ together form,  with  the  nitrogen  atom  that  bears  them,  an  azetidine,
pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group; the group NR3~ being optionally substituted with a group C1-C6-alkyl, C3-C7-cycloalkyt, C3-Crcycloalkyi-C1-C3-alkylene, aryi-C1-C6-alkylene, aryl, heteroaryl, aryi-S(0)2-, C1-Cs-alkyi-S(0)2-, C1-C6-fluoroalkyi-S(0)2, C3-Crcycloalkyl-

5    S(Oh-, C3-Crcycloalkyi-C1-C3-alkylene-S(Oh-, aryi-C(O)-, C1-Cs-alkyi-C(O}-, C3-Cr cycloalkyi-C(O)-, C3-C7-cycloalkyi-C1-C3-alkylene-C(O)-, C1-Cs-fluoroalkyi-C(O)-,

hydroxyl, C1-Cs-alkyloxy, C3-C1-cycloalkyloxy, C3-Crcycloalkyi-C1-C3-alkylenoxy, C1-Cs-fluoroalkyl, aryloxy-C1-Cs-alkylene, aryloxy, heteroaryloxy-C1-C6-alkylene or heteroaryloxy;

10
R5 and R6 represent, independently of each other, a hydrogen atom or a group C1-C6-alkyl, C3-C1-cycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, aryi-C1-Cs-alkylene or aryl; the aryl group being optionally substituted with one or more substituents chosen from a halogen atom and a group C1-Cs-alkyl, C3-C1-cycloalkyl, C3-C7-cycloalkyi-C1-C3-

15    alkylene, C1-Cs-fluoroalkyl, C1-Cs-alkoxy, C3-Crcycloalkyloxy, C3-Crcycloalkyi-C1-C3-alkylenoxy, C1-C6-fluoroalkoxy, nitro or cyano;

or Rs and Rs together form a 4- to ?-membered lactam comprising the nitrogen atom and the C(O) group that bear them;

20    R7 represents a group C1-Cs-alkyl, C3-Crcycloalkyl, C3-C1-cycloalkyi-C1-C3-alkylene, aryi-C1-C6-alkylene or aryl; the aryl group being optionally substituted with one or more substituents chosen from a halogen atom and a group C1-C6-alkyl, C3-C7-cycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, C1-Cs-fluoroalkyl, C1-Cs-alkoxy, C3-C1-cycloalkyloxy, C3-
Crcycloalkyi-C1-C3-alkylenoxy, C1-C6-fluoroalkoxy, nitro or cyano;

25    or R5 and R7 together fonm a 4- to 7-membered sultam comprising the nitrogen atom and the S(0)2 group that bear them;

R6   represents  a  halogen  atom  or  a  group  C1-C6-alkyl,  C3-Crcycloalkyl,  C3-Cr
cycloalkyi-C1-C3-alkylene, C1-Cs-fluoroalkyl, C1-Cs-alkoxy,  C3-C1-cycloalkyloxy,  C3-Cr

30    cycloalkyi-C1-C3-alkylenoxy, C1-Cs-fluoroalkoxy, nitro, cyano, N~~. -C(O)-CrC6 -alkyl or -C(O}-C3-Crcycloalkyl; the groups C1-C6-alkyl, CTCrcycloalkyl, ~-Crcycloalkyi-C1-C3-alkylene, C1-Cs-ftuoroalkyl, C1-Cs-alkoxy, C3-Crcycloalkyloxy and C3-C7-cycloalkyi-C1-C3-alkylenoxy possibly being substituted with a group OH, CrC6-alkoxy or NR3~.
 

35    In the compounds of general formula (1):
 
the sulfur atom(s) may be in oxidized form (S(O) or S(0)2);

the nitrogen atom(s) may optionally be in oxidized form (N-oxide).

The compounds of formula (I) may comprise one or more asymmetric carbon atoms.

5    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. 1 0 Such addition salts form part of the invention.

These solvents may be 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.
15

The compounds of formula (I) may also exist 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.

20 In the context of the present invention, the following definitions apply: a halogen atom: a fluorine, a chlorine, a bromine or an iodine;

Ct-Cz: a carbon-based chain possibly containing from t to z carbon atoms in which t and z may take values from 1 to 7; for example, C1-C3 is a carbon-based chain possibly containing from 1 to 3 carbon atoms;

25    an alkyl: a linear or branched saturated aliphatic group. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terl-butyl, pentyl, etc.;

an alkylene: a linear or branched saturated divalent alkyl group, for example a group C1•3-alkylene represents a linear or branched divalent carbon-based chain of

30    1 to 3 carbon atoms, more particularly a methylene, ethylene, 1-methylethylene or propylene;

a cycloalkyl: a saturated or partially unsaturated cyclic alkyl group. Examples that may be mentioned include the groups cyclopropyl, cyclobutyl, cyclopentyl,

cyclohexyl, etc.;

35    a cycloalkyloxy: a radical -0-cycloalkyl in which the cycloalkyl group is as defined

previously;

a fluoroalkyl: an alkyl group, one or more hydrogen atoms of which have been

replaced with a fluorine atom;

an alkoxy: a radical -0-alkyl in which the alkyl group is as defined previously;

5    a fluoroalkoxy: an alkoxy group, one or more hydrogen atoms of which have been replaced with a fluorine atom;

a thioalkyl or alkylthio: a radical -S-alkyl in which the alkyl group is as defined

previously;

an  aryl:  a monocyclic or bicyclic aromatic group containing  between 6 and  10

10 carbon atoms. Examples of aryl groups that may be mentioned include phenyl and naphthyl groups;
a heteroaryl: a monocyclic or bicyclic aromatic group 5- to 12-membered containing from 1 to 5 heteroatoms chosen from 0, Sand N.

15    Examples of monocyclic heteroaryls that may be mentioned include imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, fury!, thiophenyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

Examples of bicyclic heteroaryls that may be mentioned include indolyl,  isoindolyl,

20    benzofuryl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzofuryl, isobenzothiazolyl, pyrrolo[2,3-c]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3.2-b]pyridyl, pyrrolo[3.2-c]pyridyl, pyrrolo[1 ,2-a]pyridyl, quinolyl, isoquinolyl, cinnolinyl,

quinazolinyl,  quinoxalinyl,  pyrrolo[1 ,2-a]imidazolyl, imidazo[1 ,2-a]pyridyl,  imidazo[1 ,5-a]pyridyl, imidazo[1 ,2-b]pyridazinyl, imidazo[1 ,2-c]pyrimidinyl, imidazo[1 ,2-a]pyrimidinyl, 25    imidazo[1 ,5-a]pyrimidinyl,      imidazo[1 ,5-c]pyrimidinyl,      imidazo[1 ,2-a]pyrazinyl, imidazo[1 ,5-a]pyrazinyl, imidazo[1 ,5-b]pyridazinyl, imidazo[4.5-b]pyrazinyl, imidazo[4.5-b]pyridyl,   imidazo[4.5-c]pyridyl,   pyrazolo[1 ,5-a]pyridyl,   pyrazolo[1 ,5-a]pyrimidinyl, pyrazolo[1 ,5-c]pyrimidinyl,     pyrazolo[1 ,5-a]pyrazinyl,     pyrazolo[1 ,5-b]pyridazinyl, indolizinyl,  pyrrolo[1 ,2-b]pyridazinyl,  pyrrolo[1 ,2-c]pyrimidinyl,  pyrrolo[1 ,2-a]pyrazinyl,

30    pyrrolo[1 ,2-a]pyrimidinyl, [1 ,2,4]triazolo[4.3-a]pyridyl, [1 ,2,4]triazolo[2,3-a]pyridyl, [1 ,2,4]triazolo[1 ,5-a]pyridyl, [1.2.3]triazolo[1 ,5-a]pyridyl, [1 ,2,4]triazolo[1 ,5-b]pyridazinyl,
    triazolo[1 ,2-a]pyrimidinyl, triazolo[1 ,2-c]pyrimidinyl, triazolo[1 ,2-a]pyrazinyl, triazolo[1 ,2-
    b]pyridazinyl,    [1 ,2,4]triazolo[1 ,5-b]pyridazinyl,    [1 ,2,4]triazolo[1 ,5-c]pyrimidinyl,
    [1 ,2,4]triazolo[1 ,2-a]pyrazinyl,    [1 ,2,4]triazolo[1 ,5-a]pyrimidinyl,    [1.2.3]triazolo[1 ,5-
35    b]pyridazinyl,    [1.2.3]triazolo[1 ,5-c]pyrimidinyl,    [1.2.3]triazolo[1 ,2-a]pyrazinyl,
 


[1.2.3]triazolo[1,5-a]pyrimidinyl, imidazo[1,2-d][1,2,4]triazinyl, imidazo[2.1-f][1,2,4]triazinyl, imidazo[1,2-b][1,2,4]triazinyl, imidazo[1,2-a][1.3.5]triazinyl, imidazo[2.1-c][1,2,4]triazinyl, imidazo[5.1-c][1,2,4]triazinyl, imidazo[1,5-a][1.3.5]triazinyl, imidazo[1,5-b][1,2,4]triazinyl, imidazo[5.1-m1,2,4]triazinyl, imidazo[1,5-d][1,2,4]triazinyl,

5    imidazo[1,5-c][1.2.3]triazinyl, pyrazolo[5.1-c][1,2,4]triazinyl, pyrazolo[1,5-a][1.3.5]triazinyl, pyrazolo[1,5-b][1,2,4]triazinyl, pyrazolo[5.1-f][1,2,4]triazinyl, pyrazolo[1,5-d][1,2,4]triazinyl and pyrazolo[1,5-c][1.2.3]triazinyl groups;
"oxo" means "=0"; "thio" means "=S".
10

Among the compounds of general formula (I) that are subjects of the invention, a first subgroup of compounds is constituted by the compounds for which
Xt. X2, X3 and~ represent, independently of each other, a group C-Rt; Rt being as defined in the general formula (I).

15

Among the compounds of general formula (I) that are subjects of the invention, a second subgroup of compounds is constituted by the compounds for which
Xt. X2, X3 and~ represent, independently of each other, a nitrogen atom or a group C-

Rt;

20    it being understood that one from among Xt. X2, ~ and ~ represents a nitrogen atom, the others corresponding to a group C-Rt;

Rt being as defined in the general formula (1).

Among the compounds of general formula (I) that are subjects of the invention, a third

25    subgroup of compounds is constituted by the compounds for which Xt. X2 and X3 represent a group C-Rt; X4 represents a nitrogen atom; Rt being as defined in the general formula (1).

Among the compounds of general formula (I) that are subjects of the invention, a fourth

30    subgroup of compounds is constituted by the compounds for which

Rt is chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom, and a group C1-C6-fluoroalkyl, more particularly a trifluoromethyl group.

Among the compounds of general formula (I) that are subjects of the invention, a fifth

35    subgroup of compounds is constituted by the compounds for which n is equal to 1.
 

Among the compounds of general formula (I) that are subjects of the invention, a sixth subgroup Y represents an aryl, more particularly a phenyl, optionally substituted with one or more halogen atoms, more particularly fluorine atoms.

5

Among the compounds of general formula (I) that are subjects of the invention, a seventh subgroup of compounds is constituted by the compounds for which W represents an oxygen atom.

10    Among the compounds of general formula (I) that are subjects of the invention, an eighth subgroup of compounds is constituted by the compounds for which

A represents a bicyclic heteroaryl of formula:

15    in which
z, Z2,  Z3  and ~ represent, independently of each other, a carbon atom or a nitrogen

atom;
Z5,  Z6 and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b;

Zs represents a carbon atom;

20    two, at most, from among Z1. Z2. Z3, Z4, Zs. Ze and Z1 represent a nitrogen atom;

one from among Z1, Z2, Zs and ~. corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I);
R2b being as defined in the general formula (1).

25    Among the compounds of general formula (I) that are subjects of the invention, a ninth subgroup of compounds is constituted by the compounds for which

A represents a bicyclic heteroaryl of formula:


Z1, Z2, Z3 and ~ represent, independently of each other, a carbon atom or a nitrogen

atom;
Z5, Z6 and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b;

Za represents a carbon atom;
5    two, at most, from among Z1, Z2, Z3, ~. Zs, Za and Z7 represent a nitrogen atom;
one from among Z1, Z2, Z3 and ~. corresponding to a carbon atom, being bonded to

the nitrogen atom of the amide or thioamide of formula (I);
R2b represents a hydrogen atom or a group C1-Cs-alkyl, C(O)O-C1-Cs-alkyl, phenyl or thienyl; the groups C1-Cs-alkyl possibly being substituted with a hydroxyl or C1-C6-

10    alkoxy group.

Among the compounds of general formula (I) that are subjects of the invention, a tenth subgroup of compounds is constituted by the compounds for which

A represents a bicyclic heteroaryl of formula:


in which

Z1o Z2, ~ and ~ represent, independently of each other, a carbon atom or a nitrogen atom;

20    Z5, Za and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b; Z8 represents a carbon atom;

two, at most, from among Z1, Z2, ~. ~. Zs. Za and Zr represent a nitrogen atom;
one from among Z1, Z2, Z3 and ~. corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I);

25    R2b represents a hydrogen atom or a methyl, ethyl, terl-butyl, C(O)O-ethyl, phenyl or thienyl group; the methyl groups possibly being substituted with a hydroxyl or methoxy group.

Among the compounds of general formula (I) that are subjects of the invention, an

30    eleventh subgroup of compounds is constituted by the compounds for which A represents the group

R2b being as defined in the general formula (1).

Among the compounds of general formula (I) that are subjects of the invention, a

5    twelfth subgroup of compounds is constituted by the compounds for which A represents the group
R2b represents a hydrogen atom or a group C1-Cs-alkyl, C(O)O-C1-Ca-alkyl, phenyl or thienyl; the groups C1-Ca-alkyl possibly being substituted with a hydroxyl or C1-C6-

1 0    alkoxy group.

Among the compounds of general formula (I) that are subjects of the invention, a thirteenth subgroup of compounds is constituted by the compounds for which

A represents the group


R2b represents a hydrogen atom or a methyl, ethyl, terl-butyl, C(O)O-ethyl, phenyl or
 



11


thienyl group; the methyl groups possibly being substituted with a hydroxyl or methoxy

group.

Among the compounds of general formula (I) that are subjects of the  invention, a

5    fourteenth subgroup of compounds is constituted by the compounds for which A represents the group
~~b
W-?-R, ~[:>-R,

R2b

R2b being as defined in the general formula (I).

10    Among the compounds of general formula (I) that are subjects of the invention, a fifteenth subgroup of compounds is constituted by the compounds for which

A represents the group

~b
~N    f'N'

~N=-r-R2b /vN-..N   R2b

R2b

R2b represents a hydrogen atom or a group CrCa-alkyl, phenyl or thienyl; the groups

15    C1-C6-alkyl possibly being substituted with a hydroxyl or C1-C6-alkoxy group.

Among the compounds of general formula (I) that are subjects of the invention, a sixteenth subgroup of compounds is constituted by the compounds for which

A represents the group






20

R2b represents a hydrogen atom or a methyl, ethyl, terl-butyl, phenyl or thienyl group; the methyl groups possibly being substituted with a hydroxyl or methoxy group.

Among the compounds of general formula (I) that are subjects of the invention, a

seventeenth subgroup of compounds is constituted by the compounds for which the

definitions of X1 , X2 , X3, ~. n, Y, Wand A given above are combined.

5    Among the compounds of general formula (I) that are subjects of the invention, an eighteenth subgroup of compounds is constituted by the compounds for which
X1, X2 , Xs and~ represent, independently of each other, a group C-R1; or alternatively X1, X2 and Xs represent a group C-R,; ~represents a nitrogen atom;

R, is chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom,

10    and a group C1-C6-fluoroalkyl, more particularly a trifluoromethyl group; n is equal to 1;

Y represents an aryl, more particularly a phenyl, optionally substituted with one or more halogen atoms, more particularly fluorine atoms;

W represents an oxygen atom;

15    A represents a bicyclic heteroaryl of formula:






in which
Z1,  Z2, Z3 and ~ represent, independently of each other, a carbon atom or a nitrogen

20    atom;

Z5 ,  Zs and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b;

Z8  represents a carbon atom;

two, at most, from among z, Z2, Z3, ~. Z5, Zs and Z1 represent a nitrogen atom;
one from among z,, Z2. Z3 and ~. corresponding to a carbon atom, being bonded to

25    the nitrogen atom of the amide or thioamide of formula (I);

R2b represents a hydrogen atom or a group C,-Cs-alkyl, C(O)O-C1-Cs-alkyl, phenyl or thienyl; the groups C,-Cs-alkyl possibly being substituted with a hydroxyl or C1-C6-alkoxy group.

30    Among the compounds of general formula (I) that are subjects of the invention, mention may be made especially of the following compounds:

1• N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide;
 



13


2•    N-(2,3-Dimethylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide;

3•    N-[2-(Hydroxymethyl)imidazo[1 ,2-a] pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide;

5    4• N-(3-Methyl-2-phenylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide;
5• N-(2-Ethylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl-1 H-indole-

2-carboxamide;

6•    N-[2-(Thien-2-yl)imidazo[1,2-a]pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

1 0    indole-2-carboxamide;

7 • N-(2-terl-Butylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide;

8•    N-(2-Methoxymethylimidazo[1,2-a]pyrid-7 -yl)-5-fluoro-1-[ (3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide;

15    9• N-[2-(Hydroxymethyl)imidazo[1,2-a]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide;

10• N-(2-Methyl-3-phenylimidazo[1,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide;
11• N-[2-(Thien-2-yl)imidazo[1,2-a]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

20    indole-2-carboxamide;

12• N-(2-Ethylimidazo[1,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl-1 H-indole-

2-carboxamide;

13•    N-(2-terl-Butylimidazo[1,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide;

25    14• N-(2,3-Dimethylimidazo[1,2-a]pyrid-7 -yl)-5-trifluoromethyl-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide;
15• N-(2-Ethylimidazo[1 ,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-

1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

16•    N-(2,3-Dimethylimidazo[1,2-a]pyrid-7 -yl)-5-trifluoromethyl-1-[(3-fluorophenyl)-

30    methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide;

17. N-[2-(Hydroxymethyl)imidazo[1,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1 H-indole-2-carboxamide;
18• N-[2-(Hydroxymethyl)imidazo[1,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1 H-pyrrolo[2 ,3-b]pyridine-2-carboxamide;
 



14


19•    N-(2-Methylimidazo[1 ,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide;

20•    N-(2-Methylpyrazolo[1 ,5-a]pyrimidin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-

1H-indole-2-carboxamide;

5    21• N-[2-(Ethyloxycarbonyl)imidazo[1 ,2-b]pyridazin-6-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1 H-indole-2-carboxamide;

22• N-[(2-(Ethyloxycarbonyl)imidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide;

23• N-(2-Methylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

10    indole-2-carboxamide;

24•    N-([1 ,2,4]Triazolo[1 ,5-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-

2-carboxamide.

Among the compounds of general formula (I) that are subjects of the invention, one

15    subfamily is represented by the compounds of general formula (I')for which:
R2b represents a hydrogen atom, a halogen atom or a group C,-Ce-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyi-C,-C3-alkylene, C,-Ce-fluoroalkyl, C,-Ce-alkoxy, hydroxyl, thiol, oxo, thio, C3-C7-cycloalkyloxy, C1-Ce-fluoroalkoxy, C3-C7-cycloalkyi-C1-C3-
alkylenoxy,  C1-C6-alkoxy-CrC3-alkylene,  C3-Cr-cycloalkyloxy-C1-C3-alkylene,  C3-C7-

20    cycloalkyi-C1-C3-alkylenoxy-C,-C3-alkylene, C,-C6-alkyi-C(O)-O-C,-C3-alkylene, C1-C6-alkyi-C(O)-O-, C3-C7-cycloalkyi-C(O)-O-C1-C3-alkylene, C3-C7-cycloalkyi-C(O)-O-, C1-C6-fluoroalkyi-C(O)-O-C,-C3-alkylene, C1-C6-fluoroalkyi-C(O)-O-, C(O)NR3~, C(O)O-C1-C6-alkyl, cyano, CHO, COzH, -C(O)-CrCe-alkyl or -C(O)-C3-Crcycloalkyl; the
groups C1-C6-alkyl, C3-C7-cycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl,

25    C1-C6-alkoxy, C3-C7-cycloalkyloxy, C,-Ce-fluoroalkoxy, C3-C7-cycloalkyi-C1-C3-alkylenoxy, C1-C6-alkoxy-C1-C3-alkylene, C3-Crcycloalkyloxy-C1-C3-alkylene and C3-

C7-cycloalkyi-C1-C3-alkylenoxy-C,-C3-alkylene possibly being substituted with a hydroxyl, C1-C6-alkoxy or NR3~ group;

~ and ~ being as defined in the general formula (I).

30

Among the compounds of general formula (I')that are subjects of the invention, a first subgroup of compounds is constituted by the compounds for which X1 , X2 , X3 and~ represent, independently of each other, a group C-R1 ; and R1 is chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom, and a group
35    C1-C6-fluoroalkyl, more particularly a trifluoromethyl group.
 

Among the compounds of general formula (I')that are subjects of the invention, a second subgroup of compounds is constituted by the compounds for which n is equal to 1 and Y represents an aryl, more particularly a phenyl, optionally substituted with

5    one or more halogen atoms, more particularly fluorine atoms.

Among the compounds of general formula (I')that are subjects of the invention, a third subgroup of compounds is constituted by the compounds for which W represents an oxygen atom.

10

Among the compounds of general formula (I')that are subjects of the invention, a fourth subgroup of compounds is constituted by the compounds for which A represents the group




15    this group being optionally substituted as defined in the general formula (I) above.

Among the compounds of general formula (I')that are subjects of the invention, a fifth subgroup of compounds is constituted by the compounds for which
X1,  X2,  X3  and ~ represent, independently of each other, a group C-R1 ;  and R1  is

20    chosen from a hydrogen atom, a halogen atom, more particularly a fluorine atom, and a group C1-C6-fluoroalkyl, more particularly a trifluoromethyl group;

n is equal to 1;

Y represents an aryl, more particularly a phenyl, optionally substituted with one or more

halogen atoms, more particularly fluorine atoms;

25    W represents an oxygen atom; A represents the group





this group being optionally substituted as defined in the general formula (I) above.

30
 

In the text hereinbelow, the term "leaving group" means a group that can be readily
 

16


cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group may thus be readily replaced by another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfate,
5    trifluoromethanesulfonate, acetate, etc. Examples of leaving groups and references for preparing them are given in "Advances in Organic Chemistry", J. March, 5th Edition, Wiley lnterscience, 2001.

In  the  text  hereinbelow,  the term  "protecting  group" means  a group  that  can  be

10 momentarily incorporated into a chemical structure for the purpose of temporarily inactivating a part of the molecule during a reaction, and which may be readily removed in a subsequent synthetic step. Examples of protecting groups and references concerning their properties are given in T.W. Greene, P.G.M. Wutz, 3rd Edition, Wiley lnterscience 1999.

15

In accordance with the invention, the compounds of general formula (I) may be prepared according to the process illustrated by the general schemes 1 and 2 below:

Scheme 1

20

D

According to scheme 1, compounds (I) may be obtained by reacting a compound of general formula (II}, in which B represents an NH2 group and X, X2 , X3 , ~. n, Y and W

25    are as defined in the general formula (I) above, with a compound of general formula (Ill}, in which z, Z2, Z3, ~. Zs, Za, Z7 and Z8 are as defined in the general formula (I) above and D represents a leaving group, as defined above, for instance a bromine or iodine atom or a trifluoromethanesulfonate group,

-    for example according to a method similar to that described in J.  Am.  Chern.  Soc.

30    2001,  123 (31), 7727, or according to methods described in the literature or known to
 



17


those skilled in the art, in the presence of a copper salt in catalytic amount, in the

presence of a catalytic amount of a copper ligand, such as a diamine, the whole in the

presence of a base such as potassium carbonate, in a solvent such as dioxane;

- for example according to a method similar to that described in J.  Am.  Chern.  Soc.

5    2002, 124 (21 ), 6043, or according to methods described in the literature or known to those skilled in the art, in the presence of a catalytic amount of a palladium derivative, such as palladium diacetate, in the presence of a catalytic amount of a palladium ligand, such as a diphosphine, the whole in the presence of a base such as caesium carbonate, at reflux in a solvent such as dioxane.
10

The compounds of general formula (I) may also be obtained by reacting a compound of general formula (II), in which B represents a hydroxyl group and X1, X2, X3, ~. n, Y and W are as defined in the general formula (I) above, with a compound of general formula (Ill), in which Z1. Z2, Zs. 4, Zs, Za. Z7 and Zs are as defined in the general formula (I)

15    above and D represents an NH2 group, in the presence of a coupling agent such as diethyl cyanophosphonate or N-(3-dimethylaminopropyi)-N~ethylcarbodiimide, optionally in the presence of a base such as triethylamine, in a solvent, for instance dimethylformamide.

20    The compounds of general formula (I) may also be obtained by reacting a compound of general formula (II), in which B is a chlorine atom and X1, X2, X3, ~. n, Y and W are as defined in the general formula (I) above, with a compound of general formula (Ill), in

which Z1, Z2, Zs. 4. Zs. Za, Z7 and Zs are as defined in the general formula (I) above and D represents an NH2 group, in a solvent such as dichloroethane, toluene or

25    tetrahydrofuran.


The compounds of general formula (II), for which B represents a group C1-C6-alkoxyl, may be converted into compounds of general formula (II), in which B represents a hydroxyl group, via the action of a base such as sodium hydroxide or potassium

30    hydroxide in solution in a solvent such as ethanol. The compounds of general formula (II), in which B represents a hydroxyl group may, thereafter, be converted into compounds of general formula (II), in which B represents a chlorine atom, via the action of a chlorinating agent such as thionyl chloride in a solvent such as dichloromethane.
 


Alternatively, according to scheme 2, the compounds of general formula (1), in which W represents an oxygen atom and A represents a group:


may be obtained by reacting a compound of general formula (V) in which X1 ,  X2 ,  X3,  ~.

5    n and Y are as defined in the general formula (I) above and PG represents a hydrogen atom, with a compound of general formula (IV), in which X represents a leaving group,

as defined above, for instance a bromine or chlorine atom and R2b is as defined in the general formula (I) above, for example according to a method similar to those described in J. Org. Chern. 1965, 30 (7), 2403 and Organometallics 2008, 27(8),

1 0 1936 or according to methods described in the literature or known to those skilled in the art.

15

The compounds of general formula (V), in which PG represents a hydrogen atom, may be obtained from compounds of general formula (V), in which PG represents a protecting group, for example an acetyl group, according to deprotection methods

20    described in the literature or known to those skilled in the art.
 



19


The compounds of general formula (V) in which PG represents a protecting group, for example an acetyl group, may be obtained by reacting a compound of general formula (II), in which 8 represents an NH2 group and X1, X2 , )(;, ~. nand Yare as defined in the general formula (I) above, with a compound of general formula (VI), in which PG
5    represents a protecting group, for example an acetyl group, and D represents a leaving group, as defined above, for instance a bromine atom or a trifluoromethanesulfonate group, for example according to a method similar to that described in J. Am. Chern. Soc. 2001, 123 (31), 7727, or according to methods described in the literature or

known to those skilled in the art, in the presence of a copper salt in catalytic amount, in 1 0 the presence of a catalytic amount of a copper ligand, such as a diamine, the whole in
the presence of a base, such as potassium carbonate, in a solvent such as dioxane.

The compounds of general formula (V) may also be obtained by reacting a compound of general formula (II), in which 8 represents a hydroxyl group and X1, X2, X3, ~. nand

15    Y are as defined in the general formula (I) above, with a compound of general formula (VI), in which PG represents a protecting group, for example an acetyl group, and D represents an amino group, according to any coupling method known to those skilled in the art.

20    According to another of its aspects, a subject of the invention is also the compounds of formulae (lila), (lllb), (lllc), (llld), (llle) and (lllf). These compounds are useful as synthetic intermediates for the preparation of the compounds of formula (I).
    BrY"J-'N o_j
25    ~...i:J---{0
    (I lie)
    Br'(J_}---;0-
(llle)    (IIIf)
30   

The compounds of formulae (lila), (lllb), (lllc), (llld), (I lie) and (lllf) may be prepared, for example, according to the processes described in Examples 1, 8 and 14.

In schemes 1 and 2, the compounds of general formulae (II), (Ill), (IV) and (VI) the

35    other reagents, when their preparation is not described, are commercially available,
 



20


described in the literature or prepared by analogy with processes described in the literature (US 6 737 435; US 6 673 797; WO 2006/101 455; Synthesis 1985, 2, 186; J.G. Lombardino J. Org. Chern. 1965, 30 (7), 2403; T.M. Williams J. Med. Chern. 1993,
36  (9),  1291;  J.  Med.  Chern.  2008,  51  (19),  6044;  JP  2001-151  771  A2.;  WO

5    2006/024 776; WO 2006/072 736; WO 2007/010 144; WO 2007/010 138, for example). The compounds of general formula (1), for which one from among X1, X2, X3 and ~

corresponds to a carbon atom substituted with an alkyl group, may be obtained via a coupling reaction, catalysed with a metal such as palladium or iron, performed on the

10    corresponding compounds of general formula (I), substituted with a halogen atom, such as a chlorine, in the presence, for example, of an alkylmagnesium halide or an alkylzinc halide, according to methods described in the literature (A. Furstner et al., J. Am. Chern. Soc. 2002, 124(46), 13856; G. Qw§guiner et al., J. Org. Chern. 1998, 63(9), 2892), for example, or known to those skilled in the art.
15

The compounds of general formula (1), for which one from among1 , X2 , X3 and ~ corresponds to a carbon atom substituted with a cyano, aryl or heteroaryl group, may be obtained via a coupling reaction, catalysed with a metal such as palladium, performed on the corresponding compounds of general formula (1), substituted, for

20    example, with a bromine atom, in the presence of trimethylsilyl cyanide, an arylboronic acid or a heteroarylboronic acid, or via any other method described in the literature or known to those skilled in the art.

The compounds of general formula (I) substituted with a group C(O)N~~ may be

25    obtained from the corresponding compounds of general formula (I) substituted with a cyano group, according to methods described in the literature or known to those skilled in the art.

The compounds of general formula (I) substituted with a group -S(O)-alkyl or -S(Oh-

30    alkyl may be obtained by oxidation of the corresponding compounds of general formula (1), substituted with a group thioalkyl, according to methods described in the literature or known to those skilled in the art.

The compounds of general formula (1),  substituted with a group NR3~, NR5COR6  or

35    NR5S02R7  may be obtained from the corresponding compounds of general formula (1),
 


substituted with a nitro group, for example via reduction, followed by acylation or sulfonylation, according to methods described in the literature or known to those skilled in the art.

5    The compounds of general formula (I) in which W represents a sulfur atom may be obtained, for example, by reacting the corresponding compounds of general formula (I), in which W represents an oxygen atom, with a reagent such as Lawesson'sreagent.

The compounds of general formula (I) for which R2b corresponds to a hydroxyalkyl

10    group may be obtained from compounds of general formula (I) for which R2b corresponds, for example, to an acetoxyalkyl or pivaloyloxyalkyl group, according to chemical methods known to those skilled in the art, such as reaction with a base such

as an aqueous sodium hydroxide solution, or reaction with an alkoxide, for example methoxide, of a salt such as lithium or sodium, in an alcoholic solvent such as

15    methanol or ethanol.

The compounds of general formula (I) for which R2b corresponds to a hydroxymethyl group may also be obtained from compounds of general formula (I) for which R2b

corresponds, for example, to an ethyl carboxylate group, by reaction with a reducing

20    agent such as sodium borohydride, in a solvent such as tetrahydrofuran.

The compounds of general formula (II), for which one from among1. X2, X3 and ~ corresponds to a carbon atom substituted with a group NR3~, NR5CORa or NR5S02R7 and B represents a group C1-Ce-alkoxy, C3-C7-cycloalkyloxy, C3-C7-cycloalkyi-C1-C3-

25    alkylenoxy or aryi-C1-C3-alkylenoxy, may be obtained from the corresponding compounds of general formula (II), substituted, for example, with a bromine atom, via a coupling reaction with an amine, an amide or a sulfonamide, respectively, in the presence of a base, a phosphine and a palladium-based catalyst, according to methods described in the literature or known to those skilled in the art.
30

The compounds of general formula (II), for which one from among1, X2, X3 and ~ corresponds to a carbon atom substituted with a group S02N~~ and B represents a group CrCe-alkoxy, C3-Crcycloalkyloxy, C3-Crcycloalkyi-C1-C3-alkylenoxy or aryi-C1-C3-alkylenoxy, may be obtained via a method similar to that described in Pharmazie

35    1990, 45, 346, or according to methods 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

5    present invention. The numbers of the illustrated compounds refer to those in Table 1. The elemental microanalyses, the LC-MS analyses (liquid chromatography coupled to mass spectrometry) and the IR or NMR spectrum confirm the structures of the compounds obtained.

10    Example 1 (Compound 1)

N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

1.1    5-Fiuoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxylic acid

15    An aqueous sodium hydroxide solution, prepared from 1.15 g (28.92 mmol) of sodium hydroxide pellets in 50 mL of water, is added to a solution of 7.6 g (24.1 0 mmol) of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxylate (WO 2006/024 776) in 241 mL of ethanol. The mixture is heated for two hours and then concentrated under reduced pressure. The resulting solid is taken up in 200 mL of water. The solution is

20    washed with twice 100 mL of ethyl ether, acidified by successive addition of small amounts of concentrated hydrochloric acid and then extracted with 200 ml of ethyl acetate. The organic phase is finally washed twice with 100 mL of water, once with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. After drying at 50°C under reduced pressure,

25    6.4 g of the expected product are obtained in the form of a solid, which is used without further purification in the rest of the synthesis.

1.2    5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

To a suspension, stirred at 20°C, of 2 g (6.96 mmol) of 5-fluoro-1-[(3-fluorophenyl)-

30    methyl]-1 H-indole-2-carboxylic acid, prepared in step 1.1, in 80 mL of dry toluene are added 5.08 ml (69.62 mmol) of thionyl chloride. The reaction mixture is refluxed for 2 hours with stirring and is then concentrated under reduced pressure. The resulting product is taken up in 10 mL of dichloromethane, and this solution is poured dropwise

into a solution of 9.12 mL (69.62 mmol) of 30% aqueous ammonia. The reaction 35 mixture is stirred for 14 hours at 20°C. After this time, a solid is collected by filtration,
 




23


and is triturated in 50 ml of diisopropyl ether. After filtering off and drying under reduced pressure, 0.58 g of the expected product is collected.

1H NMR (DMS0-06}, cS ppm: 8.11 (broad peak, 1H); 7.5 (m, 3H); 7.32 (m, 1H); 7.25 (s, 1 H); 7.09 (m, 2H); 6.89 (m, 2H); 5.91 (s, 2H).

5

1.3    7-Bromo-2,3-dimethylimidazo[1 ,2-a)pyridine (Compound lila}

3 ml (19.86 mmol) of 3-bromobutan-2-one are added to a mixture, stirred at 20°C, of 1.5 g (8.67 mmol) of 2-amino-4-bromopyridine and 1.45 g (17.34 mmol) of sodium hydrogen carbonate in 50 ml of ethanol. The mixture is stirred at reflux for 12 hours

10    and then concentrated under reduced pressure. The mixture obtained is taken up in 20 ml of water. The pH of the solution is basified by successive addition of potassium carbonate. A precipitate is collected by filtration, and is washed with water and then dried under reduced pressure. 0.79 g of the expected product is thus isolated, and is used without further purification in the rest of the synthesis.

15    1 H NMR (DMSO-Ds), cS ppm: 8.15 (d, 1H); 7.71 (s, 1H); 7.01 (d, 1H); 2.39 (s, 3H); 2.31

(s, 3H}.

1.4    N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide (compound 1)

20    0.0134 g (0.07 mmol) of copper iodide, 0.2 g (0.7 mmol) of 5-fluoro-1-[(3-fluorophenyl}-methyl]-1 H-indole-2-carboxamide, obtained in step 1.2, 132 mg (0.56 mmol) of 7-bromo-2,3-dimethylimidazo[1 ,2-a)pyridine, obtained in step 1.3, 193 mg (1.4 mmol) of potassium carbonate and 5 ml of dioxane are mixed together in a pressure tube, under
an inert atmosphere at 20°C. The suspension is degassed for a few minutes, 0.01 ml

25    (0.08 mmol) of trans-1 ,2-cyclohexanediamine is then added and the tube is closed. The reaction mixture is stirred for 20 hours at 11 o•c. After this time, the cooled suspension is filtered through a pad of silica, eluting with a mixture of dichloromethane and methanol. The filtrate is concentrated under reduced pressure. The resulting product is triturated in a mixture of 90 ml of isopropanol and 10 ml of isopropyl ether. A solid is

30    collected by filtration, and is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 27 mg of the expected product are thus obtained.
m.p.: 251 - 253•c
 

1H NMR (DMSO-Ds), cS ppm: 10.82 (s, 1H); 8.41 (broad peak, 1H); 8.19 (broad peak, 35 1H); 7.62 (dxd, 1H); 7.58 (dxd, 1H); 7.51 (s, 1H); 7.45 (d, 1H); 7.32 (m, 1H); 7.19 (txd,
 



24


1 H); 7.4 (txd, 1H); 6.5 (m, 2H); 5.89 (s, 2H); 2.5 (s, 6H).

Example 2 (Compound 2)

N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-

5    2-carboxamide

2.1    6-Bromo-2,3-dimethylimidazo[1 ,2-a]pyridine

13.53    mL (130.06 mmol) of 3-bromobutan-2-one are added to a mixture, stirred at 20°C, of 5 g (28.90 mmol) of 2-amino-5-bromopyridine and 4.85 g (57.80 mmol) of

10    sodium hydrogen carbonate in 100 mL of ethanol. The mixture is refluxed for 12 hours and then concentrated under reduced pressure. The mixture obtained is taken up in 100 mL of water. The pH of the solution is basified by successive additions of

potassium carbonate. The mixture is then extracted with 3x50 mL of ethyl acetate. The

combined organic phases are washed with water (50 mL), dried over sodium sulfate

15    and then concentrated under reduced pressure. An oil is obtained, which is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 1.1 g of the expected product are thus isolated.
1H NMR (DMS0-06 ),  8 ppm: 8.5 (s, 1H); 7.4 (d, 1H); 7.25 (d, 1H); 2.4 (s, 3H); 2.31 (s,

3H).

20    LC-MS: 225 ([M+H]+, Rt =0.52 min.).

2.2    N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide (compound 2)

0.054 g (0.28 mmol) of copper iodide, 0.8 g (2.79 mmol) of 5-fluoro-1-[(3-fluorophenyl)-

25    methyl]-1 H-indole-2-carboxamide, obtained in step 1.2, 0.5 g (2.24 mmol) of 6-bromo-2,3-dimethylimidazo[1 ,2-a]pyridine, obtained in step 2.1, 0.77 g (5.59 mmol) of potassium carbonate and 25 mL of dioxane are mixed together in a pressure tube, under an inert atmosphere at 20°C. The suspension is degassed for a few minutes,

0.4    mL (0.31 mmol) of trans-1,2-cyclohexanediamine is then added and the tube is

30    closed. The reaction mixture is stirred for 20 hours at 11 0°C. After this time, the reaction mixture is diluted with 50 mL of water and 50 mL of ethyl acetate. The aqueous phase is extracted with 2x50 mL of ethyl acetate. The combined organic phases are washed with water (50 mL), dried over sodium sulfate and then concentrated under reduced pressure. The resulting product is triturated in a boiling

35    mixture of 30 mL of isopropyl ether and 10 mL of water. 0.63 g of the expected product
 



25


is collected by filtration while hot, in the form of a white solid. m.p.: 220- 242°C

1H NMR (DMSO-D6 ), 8 ppm: 11.0 (s, 1H); 9.2 (s, 1H); 8.1 (m, 1H); 7.95 (m, 1H); 7.6 (m, 2H); 7.55 (s, 1H); 7.35 (m, 1H); 7.2 (m, 1H); 7.15 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 2.5
5    (s, 3H); 2.45 (s, 3H).

Example 3 (Compound 3)

N-[2-(Hydroxymethylimidazo[ 1,2-a] pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide

10 20 mg (0.1 mmol) of copper iodide, 0.3 g (1.05 mmol) of 5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide, obtained in step 1.2, 0.23 g (0.84 mmol) of 6-iodoimidazo[1 ,2-a]pyrid-2-ylmethanol, 0.29 g (2.1 mmol) of potassium carbonate and 10 mL of dioxane are mixed together in a pressure tube, under an inert atmosphere at 20°C. The suspension is degassed for a few minutes, 0.01 mL (0.12 mmol) of trans-
15 1,2-cyclohexanediamine is then added and the tube is closed. The reaction mixture is stirred for 15 hours at 110°C. After this time, the suspension, cooled to room

temperature and is poured into 20 mL of water and 20 mL of ethyl acetate. The aqueous phase is extracted with 2x 10 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure.

20    The resulting product is triturated in a boiling mixture of 10 mL of dichloromethane and 30 mL of isopropyl ether and then filtered while hot. After drying, 0.31 g of the expected product is collected in the form of a beige-coloured solid.

m.p.: 247- 249°C

1H NMR (DMSO-D6 ),  8 ppm: 10.6 (s, 1H); 9.3 (s, 1H); 7.9 (s, 1H); 7.6 (m, 2H); 7.5 (m,

25    2H); 7.35 (m, 2H); 7.2 (m, 1H); 7.1 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 5.1 (t, 1 H); 4.6 (d, 2H).
LC-MS: 433 ([M+H]+, Rt = 4.12 min.).

Example 4 (Compound 4)

30    N-(3-Methyl-2-phenylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

4.1 N-[6-(Acetylamino )pyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-

carboxamide

35    To a solution, stirred at 20°C under an inert atmosphere, of 2 g (6.96 mmol) of 5-fluoro-
 



26


1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxylic acid, prepared according to the protocol described in step 1.1, in 40 mL of DMF are added 1.72 g (8.35 mmol) of dicyclohexylcarbodiimide (DCC) and 1.13 g (8.35 mmol) of 1-hydroxybenzotriazole hydrate (HOST). The reaction mixture is stirred at room temperature for 30 minutes.

5 2.1 g (13.92 mmol) of 2-acetamido-5-aminopyridine and 20 mg of dimethylaminopyridine (DMAP) are then added to the reaction mixture. After stirring for 24 hours at 2o•c, the reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 200 mL of saturated aqueous NaHC03 solution and 200 mL of ethyl acetate. The phases are separated by settling and the aqueous phase

10    is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. A solid is collected, and is purified by chromatography on a column of silica, eluting with a mixture of
dichloromethane and methanol. 2.6 g of the expected product are thus obtained.

1H NMR (DMS0-06 ),  o ppm: 10.6 (s, 1H); 10.5 (s, 1H); 8.7 (s, 1H); 8.1 (s, 2H); 7.6 (m,

15    2H); 7.45 (s, 1H); 7.35 (m, 1H); 7.2 (m, 1H); 7.1 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 2.1 (s, 3H).
LC-MS: 421 ([M+H]+, Rt= 1.10 min.).

4.2    N-[6-Aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carbox-

20    amide

To a suspension of 0.6 g (1.43 mmol) of N-[6-(acetylamino)pyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide, prepared according to the protocol described in step 4.1, in 9 mL of anhydrous methanol, stirred at o•c under an inert atmosphere, are added dropwise 2.03 mL (28.54 mmol) of acetyl chloride. The reaction

25    mixture is stirred at o•c for 30 minutes and then gradually brought to 1o•c and stirred for 48 hours. The reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 200 mL of saturated aqueous NaHC03 solution and 200 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over

30    sodium sulfate and then concentrated under reduced pressure. 0.46 g of the expected product is thus obtained.
1H NMR (DMS0-06), o ppm: 8.2 (s, 1H); 7.7 (m, 1H); 7.6 (m, 2H); 7.35 (m, 2H); 7.2 (m, 1H); 7.1 (m, 1H); 6.9 (m, 2H); 6.5 (d, 1H); 5.9 (s, 2H); 5.8 (s, 2H).
 

35    4.3    N-(3-Methyl-2-phenylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)-
 



27


methyi]-1H-indole-2-carboxamide (compound 4)

0.05 g (0.13 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide prepared according to the protocol described in step 4.2, 0.056 g (0.26 mmol) of 2-bromo-1-phenylpropan-1-one and 4 mL of acetonitrile are introduced

5    into a 10 mL screw-topped tube equipped with a magnetic bar. The top is then screwed on and the tube is heated at 80°C with stirring for 24 hours. After this time and cooling to room temperature, the precipitate obtained is filtered off and rinsed successively with 2 mL of acetonitrile and 2 mL of isopropyl ether. The solid obtained is dried under reduced pressure. 0.024 g of the expected product is thus obtained.

10    m.p.: 258- 259°C

1H NMR (DMS0-06), li ppm: 10.65 (s, 1H); 9.0 (s, 1H); 7.85 (d, 2H); 7.6 (m, 3H); 7.5 (m, 4H); 7.35 (m, 2H); 7.2 (m, 1H); 7.1 (m, 1 H); 6.9 (m, 2H); 5.9 (s, 2H); 2.65 (s, 3H).

Example 5 (Compound 5)

15    N-(2-Ethylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide
Compound 5 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step

20    4.2, with 0.08 g (0.53 mmol) of 1-bromobutan-2-one in 4 mL of acetonitrile. 0.112 g of the expected product is thus obtained.
m.p. = 278 - 279oC

1H NMR (DMSO De), li (ppm): 9.65 (s, 1H); 8.25 (s, 1H); 8.05 (d, 1H); 7.95 (d, 1H); 7.65 (m, 2H); 7.55 (s, 1H); 7.35 (m, 1 H); 7.25 (m, 1H); 7.1 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H);

25    2.9 (q, 2H); 1.3 (t, 3H).

LC-MS: 431 ([M+H]+, Rt = 1.09 min.).

Example 6 (Compound 6)

N-[2-(Thien-2-yl)imidazo[1 ,2-a]pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-

30    2-carboxamide

Compound 6 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step
 

4.2, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 35 0.126 g of the expected product is thus obtained in the form of a white solid.
 



28


m.p. = 316- 318oC

1H NMR (DMSO 0 6), 8 (ppm): 10.8 (s, 1H); 9.5 (s, 1H); 8.6 (s, 1H); 7.8 (s, 2H); 7.7 (d, 1H); 7.6 (m, 3H); 7.55 (s, 1H); 7.35 (m, 1H); 7.2 (m, 2H); 7.1 (m, 1H); 6.95 (m, 2H); 5.9 (s, 2H).

5    LC-MS: 485 ([M+H]+, Rt = 1.16 min.).

Example 7 (Compound 7)

N-(2-terl-Butylimidazo[1 ,2-a] pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-

carboxamide

1 0 Compound 7 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.096 g (0.53 mmol) of 1-bromo-3,3-dimethylbutan-2-one in 4 mL of acetonitrile. 0.119 g of the expected product is thus obtained in the form of a white

15    solid.

m.p. = 190-192°C

1H NMR (DMSO D6), 8 (ppm): 10.9 (s, 1H); 9.6 (s, 1H); 8.3 (s, 1H); 8.0 (m, 2H); 7.65 (m, 2H); 7.55 (s, 1H); 7.35 (m, 1H); 7.25 (m, 1 H); 7.1 (m, 1H); 6.95 (m, 2H); 5.9 (s, 2H); 1.4 (s, 9H).

20    LC-MS: 459 ((M+H]+, Rt = 1.17 min.).

Example 8 {Compound 8)

N-(2-Methoxymethylimidazo(1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide
25

8.1    Ethyl 7-bromoimidazo(1 ,2-a]pyridine-2-carboxylate (Compound lllc)

0.6    g (3.47 mmol) of 2-amino-4-bromopyridine, 1.55 g (7.15 mmol) of ethyl bromopyruvate and 4 mL of acetonitrile are placed in a 20 mL screw-topped tube equipped with a magnetic bar. The top is then screwed on and the tube is stirred at

30    room temperature for 1 hour, and then heated at 150°C with stirring for 30 minutes. After this time and cooling to room temperature, the precipitate obtained is filtered off,

rinsed with acetonitrile and dried. The filtrate is concentrated to dryness and then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. The solid obtained after evaporating off the solvent is

35    dried under reduced pressure. 530 mg of the expected product are obtained in total.
 



29


1H NMR (OMS0-06), o ppm: 8.65 (s, 1H); 8.6 (d, 1H); 8.05 (s, 1H); 7.3 (m, 1H); 4.3 (q, 2H); 1.3 (t, 3H).

8.2    (7-Bromoimidazo[1 ,2-a]pyrid-2yl)methanol (Compound llld)

5    To a suspension of 0.25 g (0.93 mmol) of ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate, prepared according to the protocol described in step 8.1, in 4 mL of anhydrous dichloromethane, stirred at -19°C under an inert atmosphere, are added dropwise 2.09 mL (2.09 mmol) of a molar solution of OIBAL-H in toluene. The reaction mixture is stirred at -19°C for 3 hours and then hydrolysed at -40°C by successive

1 0 addition of 0.1 mL of methanol, 0.1 mL of water and 10 mL of 5N HCI. The reaction mixture is then basified with aqueous sodium hydroxide solution (24%) and then extracted with three times 100 mL of dichloromethane. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel,

15    eluting with a mixture of dichloromethane and methanol. 110 mg of the expected product are thus obtained.

1H NMR (OMS0-06). o ppm: 8.0 (d, 1H); 7.8 (s, 1H); 7.6 (s, 1H); 6.9 (m, 1H); 4.9 (s,

2H).

20    8.3 7-Bromo-2-chloromethylimidazo[1 ,2-a]pyridine (Compound (I lie)

To a solution of 110 mg (0.48 mmol) of (7-bromoimidazo[1 ,2-a]pyrid-2yl)methanol, prepared according to the protocol described in step 8.2, in 8 mL of anhydrous

dichloromethane, stirred at room temperature under an inert atmosphere, is added

0.03 mL  (0.53  mmol)  of thionyl  chloride.  The  reaction  mixture  is  stirred  at room

25    temperature for 4 hours, hydrolysed at ooc by successive addition of 3 mL of cold water and 5 mL of saturated aqueous NaHC03 solution and then extracted with three times 10 mL of dichloromethane. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. 80 mg of the expected product are obtained.

30    1 H NMR (COCh), o ppm: 7.9 (d, 1H); 7.7 (s, 1H); 7.6 (s, 1 H); 6.85 (m, 1 H); 4. 7 (s, 2H).

8.4    7-Bromo-2-methoxymethylimidazo[1 ,2-a]pyridine (Compound (lllf)
 

To a solution of 81 mg (0.33 mmol) of 7-bromo-2-chloromethylimidazo[1 ,2-a]pyridine, prepared  according to the  protocol  described  in  step  8.3,  in  3 mL of anhydrous 35    methanol, stirred at ro~m temperature under an inert atmosphere, are added 35 mg
 



30


(0.99 mmol) of sodium methoxide. The reaction mixture is stirred at 100°C for 4 hours. After this time, the reaction medium, cooled to room temperature, is concentrated under reduced pressure, diluted with 10 mL of chloroform and then washed with 10 mL of saturated aqueous NaCI solution. The crude reaction product obtained after

5    evaporating off the solvent under reduced pressure is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 27 mg of the expected product are thus obtained.

1H NMR (CDC!g), 8 ppm: 7.9 (d, 1H); 7.75 (s, 1H); 7.5 (s, 1H); 6.85 (m, 1H); 4.6 (s, 2H); 3.4 (s, 3H).

10

8. 5 N-(2-Methoxymethylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide (compound 8)

20 mg (0.09 mmol) of copper iodide, 40 mg (0.14 mmol) of 5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide, prepared according to the protocol described in step

15    1.2, 27 mg (0.11 mmol) of 7-bromo-2-methoxymethylimidazo[1 ,2-a]pyridine, prepared according to the protocol described in step 8.3, 50 mg (0.36 mmol) of potassium

carbonate and 3 mL of anhydrous dioxane are placed in a 10 mL pressure tube specific for microwave reactors. The suspension is degassed for a few minutes, and 0.01 mL (0.04 mmol) of trans-1 ,2-cyclohexanediamine is then added. The tube is then sealed

10    and heated in the microwave reactor at 150°C for two 1-hour cycles. After this time, the suspension cooled to room temperature is poured into 20 mL of water and then extracted with 2x3Q mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction
product is then purified by chromatography on a column of silica gel, eluting with a

25    mixture of dichloromethane and methanol. 45 mg of the expected product are thus obtained.

m.p.: 215- 216°C

1H NMR (DMS0-06), 8 ppm: 10.7 (s, 1H); 8.5 (d, 1H); 8.0 (s, 1H); 7.8 (s, 1H); 7.6 (m, 2H); 7.5 (s, 1H); 7.3 (m, 1H); 7.2 (m, 2H); 7.05 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 4.5 (s,
30    2H); 3.3 (s, 3H).

LC-MS: 445 ([M-H]-, Rt =4.3 min.).

Example 9 (Compound 9)

N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

35    indole-2-carboxamide
 



31




9.1    N-[2-(Ethyloxycarbonyl)imidazo[1,2-a]pyrid-7 -yl]-5-fluoro-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide

The compound is prepared according to a process similar to that described in step 4.3,

5    by reacting 0.2 g (0.53 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.21 g (1.06 mmol) of ethyl 3-bromo-2-oxopropionate in 8 mL of acetonitrile. 70 mg of the expected product are thus obtained.

LC-MS: 475 ([M+H]+, Rt = 1.09 min.).

10 1H NMR (DMSO D6 ), 8 (ppm): 10.75 (s, 1H); 8.5 (m, 2H); 7.9 (s, 1H); 7.65 (m, 2H); 7.5 (s, 1H); 7.35 (m, 2H); 7.2 (m, 1H); 7.1 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 4.3 (q, 2H); 1.3 (t, 3H).


9. 2    N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7 -yl]-5-fluoro-1-[(3-fluorophenyl)-

15    methyl]-1 H-indole-2-carboxamide (compound 9)

Compound 9 was prepared according to a process similar to that described in step 8.2, by reacting 0.465 g (0.98 mmol) of N-[2-(ethyloxycarbonyl)imidazo[1,2-a]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide, prepared according to the protocol described in step 9.1, with 2.21 mL (2.21 mmol) of a molar solution of DIBAL-

20    H in toluene, in 4 mL of dichloromethane. 80 mg of the expected product are obtained. m.p. = 244- 245°C
1H NMR (DMSO D6 ), 8 (ppm): 10.6 (s, 1H); 8.48 (d, 1H); 8.0 (s, 1H); 7.7 (s, 1H); 7.6 (m, 2H); 7.5 (s, 1H); 7.35 (m, 1H); 7.2 (m, 2H); 7.05 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 5.1 (t, 1H); 4.6 (d, 2H).

25    LC-MS: 433 ([M+H]+, Rt = 1.06 min.).

Example 10 (Compound 10)

N-(2-Methyl-3-phenylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

30

10.1 N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carbox-amide

0.2 g (1.05 mmol) of copper iodide, 0.6 g (2.10 mmol) of 5-fluoro-1-[(3-fluorophenyl)-methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 35    1.2, 0.4 g (2.31 mmol) of 2-amino-4-bromopyridine, 1.16 g (8.40 mmol) of potassium
 



32


carbonate and 15 ml of anhydrous dioxane are placed in a 10 ml pressure tube specific for microwave reactors. The suspension is degassed for a few minutes and 0.14 ml (1.15 mmol) of trans-1,2-cyclohexanediamine is then added. The tube is then sealed and heated in the microwave reactor at 170°C for two 1-hour cycles. After this

5    time, the suspension cooled to room temperature is poured into 50 ml of water and then extracted with 2x75 ml of dichlororomethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting

with a mixture of dichloromethane and methanol. 0.425 g of the expected product is

10    thus obtained in the form of a beige-coloured solid. m.p.: 217- 218°C

1H NMR (OMS0-06 ), o ppm: 10.4 (s, 1H); 7.8 (d, 1H); 7.6 (m, 2H); 7.45 (s, 1H); 7.35 (m, 1H); 7.2 (m, 1H); 7.1 (m, 2H); 6.9 (m, 2H); 6.8 (d, 1H); 5.9 (m, 4H).

LC-MS: 379 ([M+H]+, Rt = 1.03 min.).

15

10.2 N-(2-Methyl-3-phenylimidazo[1 ,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide (compound 10)

0.1    g  (0.26  mmol)  of  N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide,  prepared  according  to the  protocol  described  in  step  10.1,

20    0.11 g (0.53 mmol) of 2-bromo-1-phenylpropan-1-one and 4 ml of acetonitrile are placed in a 10 ml pressure tube specific for microwave reactors. The tube is then sealed and heated in the microwave reactor at 150°C for two 1-hour cycles. After this

time, the reaction mixture is concentrated under reduced pressure. The crude reaction

product is then purified by chromatography on a column of silica gel, eluting with a

25    mixture of dichloromethane and methanol. 0.03 g of the expected product is thus obtained in the form of a beige-coloured solid.

m.p.: 305- 307"C

1H NMR (OMS0-06 ), o ppm: 10.7 (s, 1H); 8.35 (d, 1H); 8.1 (s, 1H); 7.85 (d, 2H); 7.6 (m, 2H); 7.5 (m, 3H); 7.35 (m, 3H); 7.2 (m, 1H); 7.1 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 2.7 (s,
30    3H).

LC-MS: 493 ([M+H]+, Rt = 1.17 min.).

Example 11 (Compound 11)

N-[2-(Thien-2-yl)imidazo[1 ,2-a]pyrid-7 -yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-
 



33


2-carboxamide

Compound 11 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol} of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyi]-1H-indole-2-carboxamide, prepared according to the protocol described

5    in step 10.1, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 0.026 g of the expected product is thus obtained in the form of a beige-

coloured solid.

m.p.: 259- 260°C

1H NMR (DMS0-06},  8 ppm: 10.7 (s, 1H); 8.5 (d, 1H); 8.2 (s, 1H); 8.0 (s, 1H); 7.6 (m,

10    2H); 7.5 (m, 3H); 7.3 (m, 2H); 7.2 (m, 1 H); 7.15 (m, 1H); 7.05 (m, 1H); 6.95 (m, 2H); 5.9

(s, 2H).

LC-MS: 485 ([M+H]+, Rt = 1.13 min).

Example 12 (Compound 12)

15    N-(2-Ethylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl-1 H-indole-2-carboxamide

Compound 12 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl}methyl]-1 H-indole-2-carboxamide, prepared according to the protocol described

20    in step 10.1, with 0.08 g (0.53 mmol) of 1-bromobutan-2-one in 4 mL of acetonitrile. 66 mg of the expected product are thus obtained.

m.p.: 158 -159oC

1H NMR (DMSO 0 6}, 8 (ppm): 11.2 (s, 1H); 8.65 (d, 1H); 8.4 (s, 1H); 7.9 (s, 1 H); 7.55 (m, 4H); 7.35 (m, 1H); 7.2 (m, 1H); 7.05 (m, 1H); 6.9 (d, 1 H); 6.8 (d, 1H); 5.9 (s, 2H);

25    2.8 (q, 2H); 1.25 (t, 3H).

LC-MS: 431 ([M+H]+, Rt = 1.08 min.).

Example 13 (Compound 13)

N-(2-tert-Butylimidazo[1 ,2-a]pyrid-7 -yl}-5-fluoro-1-[(3-fluorophenyl)methyl-1 H-indole-2-

30    carboxamide

Compound 13 was prepared according to a process similar to that described in step 10.2, by reacting 0.1 g (0.26 mmol} of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-
 

phenyl)methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.096 g (0.53 mmol) of 1-bromo-3,3-dimethylbutan-2-one in 4 mL of

35    acetonitrile. 0.116 g of the expected product is thus obtained.
 


m.p.: 327- 328°C

1 H NMR (DMSO 0 6 ), 8 (ppm): 11.2 (s, 1H); 8.7 (d, 1H); 8.45 (s, 1H); 8.0 (s, 1 H); 7.7 (m, 4H); 7.35 (m, 1H); 7.25 (m, 1 H); 7.1 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 1.4 (s, 9H). LC-MS: 459 ([M+H]+, Rt = 1.14 min.).

5

Example 14 (Compound 14)

N-(2 ,3-Dimethylimidazo[1 ,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-

1H-indole-2-carboxamide

10    14.1 Methyl 2,3-dimethylimidazo[1 ,2-a]pyrid-7-carboxylate (Compound (lllb)

To a suspension of 5 g (32.86 mmol) of methyl 2-aminopyridine-4-carboxylate and 5.52 g (65. 72 mmol) of sodium hydrogen carbonate in 250 ml of ethanol are added

12.4 g (82.15 mmol) of 3-bromo-2-butanone. The reaction mixture is stirred at reflux for 2 hours. A further 12.4 g (82.15 mmol) of 3-bromo-2-butanone are then added to the

15    reaction mixture and refluxing is continued with stirring for 15 hours.

After cooling to room temperature, the solvent is evaporated off. The residue is diluted with 50 mL of water and then basified by adding saturated NaHC03 to pH 8-9. The precipitate formed is filtered off, rinsed several times with water and then dried.

4 g of the expected product are obtained in the form of a beige-coloured solid.

20    NMR (DMS0-06 ) 8 ppm: 8.3 (d, 1H); 8.05 (s, 1H); 7.3 (dd, 1H); 3.9(s, 3H); 2.5 (s, 3H); 2.35 (s, 3H).

14.2    2,3-Dimethylimidazo[1 ,2-a]pyrid-7 -carboxylic acid

To a solution of 1.85 g (9.06 mmol) of methyl 2,3-dimethylimidazo[1 ,2-a]pyridine-7-

25    carboxylate, obtained according to the protocol described in step 14.1, in 50 mL of methanol is added a solution of 0.77 g (13.59 mmol) of potassium hydroxide in 1.5 ml

of water. The reaction mixture is maintained at 50°C for 18 hours. After cooling to room temperature, the solution is cooled to ooc and the pH of the reaction medium is

adjusted to pH 5 by dropwise addition of 6N HCI. The precipitate formed is filtered off

30    and rinsed with water and then with ether to give the expected acid quantitatively. LC-MS: 191 ([M+H]+, Rt = 0.44 min.).
 

14.3    tert-Butyl N-(2,3-dimethylimidazo[1 ,2-a]pyrid-7 -yl]carbamate

To a suspension of 1.7 g (8.94 mmol) of 2,3-dimethylimidazo[1,2-a]pyrid-7-carboxylic 35 acid, obtained according to the protocol described in step 14.2, in 29 ml of tert-butanol
 



35


are added 3.19 g (11.62 mmol) of diphenylphosphorylazide and 3.11 mL (22.34 mmol) of triethylamine. After heating for 4 hours at 90°C and for 12 hours at 40°C, the reaction medium is concentrated to dryness and then diluted with 20 ml of water. The precipitate obtained is filtered off, rinsed several times with water and then dried.

5    Purification by flash chromatography on silica gel, eluting with a gradient of from 1 to 5% of methanol in dichloromethane, gives 1.15 g of the expected product in the form of
a yellow solid.

NMR (DMS0-06 )  o ppm: 7.8 (d, 1H); 7.5-7.2 (m, 2H); 2.4 (2s, 6H); 1.6 (s, 9H).

1 0    14.4   2,3-Dimethylimidazo[1 ,2-a]pyrid-7 -ylamine hydrochloride

To a solution of 1.15 g (4.40 mmol) of tert-butyl 2,3-dimethylimidazo[1,2-a]pyrid-7-yl)carbamate, obtained according to the protocol described in step 14.3, in 15 ml of dioxane are added 15.4 ml (61.61 mmol) of a 4N solution of HCI in dioxane. The reaction mixture is maintained at 55°C for 4 hours. After cooling to room temperature,
15    the reaction mixture is diluted with diethyl ether, with stirring. The precipitate formed is filtered off, rinsed with ether and then dried under reduced pressure. 0.9 g of the

expected 2,3-dimethylimidazo[1 ,2-a]pyrid-7-ylamine hydrochloride is obtained.

NMR (DMSO-Da) o ppm: 13.2 (s, 1H); 8.2 (d, 1H); 6.8 (d, 1H); 6.55 (s, 1 H); 2.3 (s, 3H); 2.25 (s, 3H).
20

14.5 N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-7 -yl)-5-trifluoromethyl-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide (compound 14)

To a solution, stirred at 20°C under an inert atmosphere, of 1 g (2.96 mmol) of 5-

trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxylic    acid    (WO

25    2006/072 736) in 70 mL of DMF are added 0.74 g (3.56 mmol) of dicyclohexylcarbodiimide (DCC) and 0.48 g (3.56 mmol) of 1-hydroxybenzotriazole hydrate (HOBT). The reaction mixture is stirred at room temperature for 30 minutes. 0.7 g (4.45 mmol) of 2,3-dimethylimidazo[1 ,2-a]pyrid-7-ylamine, obtained according to

the protocol described in step 14.4, and 100 mg of dimethylaminopyridine (DMAP) are

30    then added to the reaction mixture. After stirring for 12 hours at 50°C, the reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 50 mL of water and 50 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic

phases are dried over sodium sulfate and then concentrated under reduced pressure.

35    The product is isolated after successive purifications by chromatography on a column
 



36


of silica, eluting with a mixture of dichloromethane and methanol. 50 mg of the expected product are thus obtained.
m.p. ::: 280- 281 oc

1H NMR (DMS0-06 ),  1i ppm: 10.75 (s, 1H); 8.25 (s, 1H); 8.15 (d, 1H); 7.95 (s, 1H); 7.8

5    (d, 1 H); 7.6 (m, 2H); 7.3 (m, 2H); 7.1 (m, 1 H); 6.9 (m, 2H); 5.95 (s, 2H); 2.4 (s, 3H); 2.3 (s, 3H).
LC-MS: 481 ([M+H]+, Rt::: 1.18 min.).

Example 15 (Compound 15)

10    N-(2-Ethylimidazo[1,2-a]pyrid-7 -yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide

15.1   5-Trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-

carboxamide

15    To a suspension, stirred at 20°C, of 1.5 g (4.43 mmol) of 5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxylic acid 0/IJO 2008/093 024) in 40 mL of dry toluene are added 3.2 mL (44.34 mmol) of thionyl chloride. The reaction mixture is stirred at reflux for 2 hours and then concentrated under reduced pressure. The resulting product is taken up in 20 mL of dichloromethane and this solution is

20    poured dropwise into a solution of 5.81 mL (44.34 mmol) of 30% aqueous ammonia. The reaction mixture is stirred for 14 hours at 20°C. After this time, a solid is collected by filtration, and is triturated in 50 mL of diisopropyl ether. After filtering off and drying under reduced pressure, 1.5 g of the expected product are collected.

m.p.: 203- 204°C

25 1H NMR (DMSO-Da), li ppm: 8.78 (d, 1H); 8.65 (d, 1 H); 8.29 (broad peak, 1H); 7.62 (broad peak, 1H); 7.4 (s, 1H); 7.32 (m, 1H); 7.05 (m, 1H); 6.92 (m, 2H); 6.0 (s, 2H). LC-MS: 338 ([M+H]+, Rt::: 1.20 min.).

15.2    N-[2-Aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-pyrrolo-

30    [2,3-b]pyridine-2-carboxamide

0.056 g (0.30 mmol) of copper iodide, 0.2 g (0.59 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyi]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.1, 0.11 g (0.65 mmol) of 2-amino-4-bromopyridine,

0.33    g (2.37 mmol) of potassium carbonate and 5 mL of anhydrous dioxane are placed

35    in a 10 mL pressure tube specific for microwave reactors. The suspension is degassed
 



37


for a few minutes and 0.04 ml (0.33 mmol) of trans-1 ,2-cyclohexanediamine is then added. The tube is then sealed and heated in the microwave reactor at 170°C for 45 minutes. After this time, the suspension cooled to room temperature is poured into 30 ml of water and then extracted with 2x40 ml of dichlororomethane. The combined

5    organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.22 g of the expected product is thus obtained in the form of a white solid.

m.p.: 197 -198oC

10 1H NMR (DMSO-Ds). 8 ppm: 10.6 (s, 1H); 8.85 (s, 1H); 8.75 (s, 1H); 7.85 (d, 1H); 7.65 (s, 1 H); 7.35 (m, 1 H); 7.1 (m, 2H); 6.9 (m, 2H); 6.8 (m, 1H); 5.95 (s, 2H); 5.85 (s, 2H). LC-MS: 430 ([M+H]+, Rt = 1.08 min.).


15.3    N-(2-Ethylimidazo[1 ,2-a]pyrid-7 -yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-

15    1H-pyrrolo[2,3-b]pyridine-2-carboxamide (compound 15)

0.125 g (0.29 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)-methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, 0.088 g (0.58 mmol) of 1-bromobutan-2-one and 4 ml of acetonitrile are placed in a 10 ml pressure tube specific for microwave reactors. The

20    tube is then sealed and heated in the microwave reactor at 150oc for two 1-hour cycles. After this time, the reaction mixture is concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.076 g of the expected product is thus obtained in the form of a yellow solid.

25    m.p.: 264- 265°C

1H NMR (DMS0-06), 8 ppm: 10.8 (s, 1 H); 8.85 (s, 1H); 8.8 (s, 1H); 8.45 (d, 1 H); 7.95 (s, 1 H); 7.65 (m, 2H); 7.35 (m, 1 H); 7, 2 (d, 1H); 7.1 (m, 1H); 6.95 (m, 2H); 6.0 (s, 2H);
2.7 (q, 2H); 1.3 (t, 3H).

LC-MS: 482 ([M+H]+, Rt =4.75 min.).

30

Example 16 (Compound 16)

N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-7 -yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-

1H-pyrrolo[2,3-b]pyridine-2-carboxamide
 



38


Compound 16 was prepared according to a process similar to that described in step 15.3, by reacting 0.12 g (0.28 mmol) of N-[2-aminopyrid-4-yij-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.084 g (0.56 mmol) of 3-bromobutan-2-one in

5    5 mL of acetonitrile. 45 mg of the expected product are obtained. m.p. = 287- 288°C
1H NMR (OMS0-06 ), 8 ppm: 10.8 (s, 1 H); 8.85 (s, 1H); 8.8 (s, 1H); 8.2 (d, 1H); 8.0 (s, 1 H); 7.65 (m, 1H); 7.35 (m, 1H); 7, 28 (m, 1 H); 7.1 (m, 1 H); 6.95 (m, 2H); 6.0 (s, 2H); 2.4 (s, 3H); 2.3 (s. 3H).

10   LC-MS: 482 ([M+H]+, Rt = 1.13 min.).

Example 17 (Compound 17)

N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide

15

17.1    5-Trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

To a suspension, stirred at 20°C, of 8 g (23.72 mmol) of 5-trifluoromethyl-1-(3-fluorobenzyi)-1H-indole-2-carboxylic acid (WO 2006/072 736), in 150 mL of dry toluene are added 17.3 mL (237.2 mmol) of thionyl chloride. The reaction mixture is stirred for

20    2 hours at reflux and then concentrated under reduced pressure. The resulting product is taken up in 25 mL of dichloromethane, and this solution is poured dropwise into 9.32 mL of 30% aqueous ammonia solution. The reaction mixture is stirred for 14 hours at 20°C. After this time, a solid is collected by filtration, and is triturated in 50 mL of pentane. After filtering off and drying under reduced pressure, 5.87 g of the expected
25    product are collected.

1H NMR (OMS0-06 ), 8 ppm: 8.28 (broad peak, 1H); 8.13 (s, 1H); 7.77 (d, 1H); 7.6 (m, 2H); 7.41 (s, 1H); 7.32 (m, 1H); 7.05 (m, 1H); 6.9 (m, 2H); 6 (s, 2H).

17.2    N-[2-Aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-indole-2-

30    carboxamide

0.056 g (0.30 mmol) of copper iodide, 0.2 g (0.59 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyi]-1H-indole-2-carboxamide, prepared according to the protocol
 

described  in  step  17.1,  0.12  g  (0.71  mmol)  of  2-amino-4-bromopyridine,  0.33  g (2.38 mmol) of potassium carbonate and 4 mL of anhydrous dioxane are placed in a 35    10 mL pressure tube speCific for microwave reactors. The suspension is degassed for
 



39


a few minutes and 0.04 ml (0.3 mmol) of trans-1,2-cyclohexanediamine is then added. The tube is then sealed and heated in the microwave reactor at 170°C for 45 minutes. After this time, the suspension cooled to room temperature is poured into 30 ml of water and then extracted with 2x40 ml of dichlororomethane. The combined organic

5    phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.186 g of the expected product is thus obtained.

m.p.: 225- 226°C

10    1H NMR (DMS0-06 ), 3 ppm: 10.6 (s, 1H); 8.25 (s, 1H); 7.8 (m, 2H); 7.6 (m, 2H); 7.35 (m, 1H); 7.1 (m, 2H); 6.9 (m, 2H); 6.8 (d, 1H); 5.9 (s, 2H); 5.85 (s, 2H).
LC-MS: 429 ([M+H]+, Rt = 4.55 min.).

17.3    N-[2-(Ethyloxycarbonyl)imidazo[1 ,2-a]pyrid-7 -yl]-5-trifluoromethyl-1-[(3-fluoro-

15    phenyl)methyl]-1 H-indole-2-carboxamide

The compound is prepared according to a process similar to that described in step 15.3, by reacting 0.23 g (0.54 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide, prepared according to the protocol

described in step 17.2, with 0.21 g (1.07 mmol) of ethyl 3-bromo-2-oxopropionate in

20    4 ml of acetonitrile. 192 mg of the expected product are obtained. m.p. = 282- 283oC

1H NMR (DMSO 0 6), 3 (ppm): 10.9 (s, 1H); 8.55 (d, 1 H); 8.45 (s, 1H); 8.25 (s, 1 H); 8.1 (s, 1 H); 7.85 (d, 1H); 7.65 (s, 1H); 7.6 (d, 1H); 7.35 (m, 2H); 7.1 (m, 1H); 6.95 (d, 2H); 6.0 (s, 2H); 4.3 (q, 2H); 1.3 (t, 3H).

25    LC-MS: 525 ([M+H]+, Rt = 4.83 min.).

17.4   N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7 -yl]-5-trifluoromethyl-1-[(3-fluoro-

phenyl)methyl]-1 H-indole-2-carboxamide (compound 17 )

To 0.47 ml (0.47 mmol) of a molar solution of LiAIH4 diluted in 1 ml of anhydrous THF,

30    cooled to -5°C, is added dropwise by syringe a suspension of 190 mg (0.36 mmol) of N-[2-( ethyloxycarbonyl)imidazo[1,2-a]pyrid-7 -yl]-5-trifluoromethyl-1-[(3-fluorophenyl)-methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 17.3, in 4 ml of anhydrous THF. After stirring for 3 hours at room temperature, the

reaction medium is poured slowly into a mixture (v/v) of water and concentrated sodium

35    hydroxide, and is then extracted with 3x 100 ml of dichloromethane. The combined
 



40


organic phases are dried over magnesium sulfate and then concentrated under reduced pressure. The crude reaction product obtained is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 30 mg of the expected product are thus obtained.

5    m.p. = 254- 255°C

1H NMR (DMS0-06), c5 ppm: 10.8 (s, 1H); 8.49 (d, 1H); 8.25 (s, 1H); 8.0 (s, 1H); 7.8 (d, 1H); 7.7 (s, 2H); 7.6 (m, 2H); 7.3 (m, 1H); 7.2 (m, 1H); 7.05 (m, 1H); 6.95 (d, 2H); 5.95 (s, 2H); 5.1 (m, 1H); 4.55 (d, 2H).

LC-MS: 483 ([M+H]+, Rt = 1.29 min.).

10

Example 18 (Compound 18)

N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7 -yl]-5-trifluoromethyl-1-[ (3-fluorophenyl)-

methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 18)

15

18. 1 N-[2-(Ethyloxycarbonyl)imidazo[1 ,2-a]pyrid-7 -yl]-5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide

The compound is prepared according to a process similar to that described in step 15.3, by reacting 0.197 g (0.46 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-

20    fluorophenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.179 g (0.92 mmol) of ethyl 3-bromo-2-oxopropionate in 5 mL of acetonitrile. 130 mg of the expected product are obtained.

1H NMR (DMS0-06), c5 ppm: 10.9 (s, 1H); 8.9 (s, 1H); 8.8 (s, 1H); 8.5 (m, 2H); 8.1 (s, 1H); 7.7 (s, 1H); 7.35 (m, 2H); 7.1 (m, 1H); 6.95 (m, 2H); 6.0 (s, 2H); 4.3 (q, 2H); 1.3 (t,

25    3H).

18.2    N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 18)

Compound 18 was prepared according to a process similar to that described in step

30    17.4, by reacting 0.13 g (0.25 mmol) of N-[2-(ethyloxycarbonyl)imidazo[1 ,2-a]pyrid-7-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carbox-amide, prepared according to the protocol described in step 18.1, with 0.32 mL of a molar solution of LiAIH4 in 4 mL of tetrahydrofuran. 22 mg of the expected product are

obtained.

35    m.p. = 238 - 240°C
 



41


1H NMR (DMSO-D6), o ppm: 10.8 (s, 1H); 8.85 (s, 1H); 8.8 (s, 1H); 8.45 (d, 1H); 8.0 (s, 1 H); 7.7 (s, 1 H); 7.65 (s, 1H); 7.35 (m, 1H); 7.2 (m, 1H); 7.05 (m, 1H); 6.95 (m, 2H); 6.0 (s, 2H); 5.15 (t, 1 H); 4.55 (d. 2H).

LC-MS: 484 ([M+H]+, Rt = 1.13 min.).

5

Example 19 (Compound 19)

N-(2-Methylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

Compound 19 was prepared according to a process similar to that described in step 1 0    10.2,  by  reacting  0.12  g  (0.32  mmol)  of  N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluoro-phenyl)methyl]-1 H-indole-2-carboxamide, prepared according to the protocol described in step 10. 1, with 0.059 g (0.63 mmol) of 1-chloropropan-2-one in 4 mL of acetonitrile.

50 mg of the expected product are thus obtained. m.p.: 267- 268"C
15    1H NMR (DMSO D6), o (ppm): 10.6 (s, 1H); 8.4 (d, 1 H); 7.95 (s, 1H); 7.6 (m, 3H); 7.45 (s, 1H); 7.35 (m, 1H); 7.2 (m, 2H); 7.05 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 2.3 (s, 3H). LC-MS: 417 ([M+H]+, Rt = 1.2 min.).

Example 20 (Compound 20)

20    N-(2-Methylpyrazolo[1,5-a]pyrimidin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

80 mg (0.42 mmol) of copper iodide, 0.4 g (1.40 mmol) of 5-fluoro-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide, obtained according to the protocol described in step

25    1.2, 0.32 g (1.54 mmol) of6-bromo-2-methylpyrazolo[1,5-a]pyrimidine 0NO 2006/128 693), 0.38 g (2.79 mmol) of potassium carbonate and 10 mL of dioxane are mixed together in a pressure tube, under an inert atmosphere at 20"C. The suspension is degassed for a few minutes, 0.053 g (0.46 mmol) of trans-1,2-cyclohexanediamine is added and the tube is closed. The reaction mixture is stirred for 15 hours at 110"C. After this time, the

30    suspension cooled to room temperature is poured into 50 mL of water and 50 mL of ethyl acetate. The aqueous phase is extracted with 2x30 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under
 

reduced pressure. The resulting product is triturated in a boiling mixture of 5 mL of dichloromethane and 20 mL of isopropyl ether, and then filtered while hot. The solid 35    obtained is purified by chromatography on a column of silica, eluting with a mixture of
 




42


n-heptane and ethyl acetate. After drying, 0.23 g of the expected product is collected in the form of a white solid.

m.p.: 267- 268°C

1H NMR (DMS0-06),  8 ppm: 10.8 (s, 1H); 9.4 (s, 1H); 8.7 (s, 1H); 7.65 (m, 2H); 7.5 (s,

5    1H); 7.35 (m, 1H); 7.2 (m, 1H); 7.05 (m, 1H); 6.95 (m, 2H);6.55 (s, 1 H); 5.9 (s, 2H); 2.4

(s, 3H).

LC-MS: 418 ([M+H]+, Rt = 1.26 min.).

Example 21 (Compound 21)

1 0    N-[2-(Ethyloxycarbonyl)imidazo[1 ,2-b]pyridazin-6-yl]-5-fluoro-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide

21.1    Ethyl 6-bromoimidazo[1 ,2-b]pyridazine-2-carboxylate

To a solution  of 2.0  g  (11.49  mmol) of 3-amino-5-bromopyridazine  in  200  mL of

15    absolute ethanol are added slowly 2.73 g (1.77 mmol) of ethyl 3-bromo-2-oxopropionate. The reaction mixture is refluxed for 18 hours.

After this time, the reaction mixture is cooled to room temperature and the precipitate fonmed is filtered off, rinsed with a minimum amount of ethanol and then oven-dried under reduced pressure. 1.33 g of the expected product are obtained.

20 1H NMR (DMSO-De), 8 ppm: 8.9 (s, 1H); 8.2 (d, 1H); 7.55 (d, 1H); 4.3 (q, 2H); 1.3 (t, 3H).

LC-MS: 270 ([M+H]+, Rt =0.88 min.).

21.2    N-[2-(Ethyloxycarbonyl)imidazo[1 ,2-b]pyridazin-6-yl]-5-fluoro-1-[(3-fluoro-

25    phenyl)methyl]-1 H-indole-2-carboxamide (compound 21)

Compound 21 was prepared according to a process similar to that described in Example 20, by reacting 0.4 g (1.40 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 1.2, with

0.41    g (1.54 mmol) of ethyl 6-bromoimidazo[1 ,2-b]pyridazine-2-carboxylate, prepared

30    according to the protocol described in step 21.1, in the presence of 80 mg (0.42 mmol) of copper iodide, 0.38 g (2.79 mmol) of potassium carbonate and 53 mg (0.46 mmol) of

trans-1 ,2-cyclohexanediamine in 10 mL of dioxane. 20 mg of the expected product are

thus obtained.

m.p.: 267- 268°C

35    1H NMR (DMS0-06 ),  8 ppm: 11.6 (s, 1H); 8.7 (s, 1H); 8.2 (d, 1H); 7.9 (d, 1H); 7.65 (m,
 

3H); 7.35 (m, 1H); 7.25 (m, 1H); 7.05 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 4.35 (q, 2H); 1.3

(t, 3H).

LC-MS: 476 ([M+H]+, Rt = 1.26 min.).

5    Example 22 (Compound 22)

N-[2-(Ethyloxycarbonyl)imidazo[1 ,2-a]pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

Compound 22 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-

10    methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.105 g (0.53 mmol) of ethyl 3-bromo-2-oxopropionate in 4 ml of acetonitrile. 0.05 g of the expected product is obtained in the form of a white solid.

m.p. = 242- 245°C

1H NMR (DMSO 0 6 ),  8 (ppm): 10.8 (s, 1H); 10.55 (s, 1H); 8.8 (s, 1H); 7.8 (m, 2H); 7.65

15    (m, 2H); 7.55 (s, 1H); 7.35 (m, 1H); 7.2 (m, 1H); 7.05 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 4.4 (q, 2H); 1.35 (t, 3H).
LC-MS: 475 ([M+H]+, Rt = 1.15 min.).

Example 23 (Compound 23)

20    N-(2-Methylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide

0.085 g (0.22 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, and 0.043 g (0.45 mmol) of 1-chloropropan-2-one in 6 ml of acetonitrile are placed in a

25    10 ml pressure tube specific for microwave reactors. The tube is then sealed and heated in the microwave reactor at 150°C for two 1-hour cycles. After this time, the reaction mixture is concentrated to dryness. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.058 g of the expected product is thus obtained in the form of a white

30    solid.

m.p.: 200- 203°C

1H NMR (DMS0-06 ), 8 ppm: 10.5 (s, 1H); 9.2 (s, 1H); 7.8 (s, 1H); 7.6 (m, 2H); 7.45 (m, 2H); 7.35 (m, 2H); 7.2 (m, 1H); 7.1 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 2.3 (s, 3H). LC-MS: 417 ([M+H]+, Rt = 1.05 min.).
 

Example 24 (Compound 24)

N-([1,2,4]Triazolo[ 1,5-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide
Compound  24  was  prepared  according  to a process  similar to  that  described  in

5    Example 20, by reacting 0.5 g (1.75 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyi]-1H-indole-2-carboxamide, prepared according to the protocol described in step 1.2, with 0.35 g (1.75 mmol) of 6-bromo[1,2,4]triazolo[1,5-a]pyridine, in the presence of 99 mg (0.52 mmol) of copper iodide, 0.48 g (3.49 mmol) of potassium carbonate and 66 mg

(0.58 mmol) of trans-1,2-cyclohexanediamine in 15 mL of dioxane. 393 mg of the 1 0 expected product are thus obtained.

m.p.: 227- 229•c

1H NMR (DMSO-De), o ppm: 10.8 (s, 1H); 9.55 (s, 1 H); 8.5 (s, 1 H); 7.9 (s, 2H); 7.60 (m, 2H); 7.5 (s, 1H); 7.35 (m, 1H); 7.20 (m, 1H); 7.05 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H) LC-MS: 404 ([M+H]+, Rt = 1.16 min.).

15

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 compounds of general formula (I) are defined with n equal to 1 and W = 0;

20    the "m.p. (°C}" column indicates the melting points of the products in degrees Celsius (•C);

the compounds are in the form of the free base.


No.            x,, x2. ~. >4    y    A    m.p. (°C)   
                                       
1                CH, C-F, CH, CH    3-fluorophenyl    2,3-dimethylimidazo[1,2-a]-        251    -253   
                        pyrid-7-yl           
                                   
2                CH, C-F, CH, CH    3-fluorophenyl    2,3-dimethylimidazo[1,2-a]-        220    -242   
                        pyrid-6-yl           
                                   


No.        x1o x2. Xa. ~    y        A    m.p. (oC)   
                           
                                       
3            CH, C-F, CH, CH    3-fluorophenyl    2-hydroxymethylimidazo-    247-249   
                    [1 ,2-a]pyrid-6-yl       
                           
                           
4            CH, C-F, CH, CH    3-fluorophenyl    3-methyl-2-phenylimidazo-    258-259   
                    [1 ,2-ajpyrid-6-yl       
                           
                           
5            CH, C-F, CH, CH    3-fluorophenyl    2-ethylimidazo[1 ,2-a]pyrid-    278-279   
                        6-yl       
                               
6            CH, C-F, CH, CH    3-fluorophenyl    2-thien-2-ylimidazo[1 ,2-a]-        316-318   
                    pyrid-6-yl       
                           
7            CH, C-F, CH, CH    3-fluorophenyl    2-tert-butylimidazo[1 ,2-a]-        190-192   
                    pyrid-6-yl       
                           
8            CH, C-F, CH, CH    3-fluorophenyl    2-(methyloxymethyl)-    215-216   
                    imidazo-    [1 ,2-a]pyrid-7-yl       
                               
9            CH, C-F, CH, CH    3-fluorophenyl    2-(hydroxymethyl)imidazo-        244-245   
                    [1 ,2-a]pyrid-7-yl       
                           
10            CH, C-F, CH, CH    3-fluorophenyl    2-methyl-3-phenylimidazo-        305-307   
                    [1 ,2-a]pyrid-7-yl       
                           
11            CH, C-F, CH, CH    3-fluorophenyl    2-thien-2-ylimidazo[1 ,2-a]-        259-260   
                    pyrid-7-yl       
                           
                           
12            CH, C-F, CH, CH    3-fluorophenyl    2-ethylimidazo[1 ,2-a]pyrid-        158-159   
                        7-yl       
                               
13            CH, C-F, CH, CH    3-fluorophenyl    2-tert-butylimidazo[1 ,2-a]-        327-328   
                    pyrid-7-yl       
                           
14            CH, C-CF3, CH, CH    3-fluorophenyl    2,3-dimethylimidazo[1 ,2-a]-        280-281   
                    pyrid-7-yl       
                           
15            CH, C-CF3, CH, N    3-fluorophenyl    2-ethylimidazo[1 ,2-a]pyrid-    264-265   
                        7-yl       
                               
16            CH, C-CF3, CH, N    3-fluorophenyl    2,3-dimethylimidazo[1 ,2-a]-        287-288   
                    pyrid-7-yl       
                           
17            CH, C-CF3 ,  CH, CH    3-fluorophenyl    2-(hydroxymethyl)imidazo-        254-255   
                    [1 ,2-a]pyrid-7-yl       
                           
18            CH, C-CF3, CH, N    3-fluorophenyl    2-(hydroxymethyl)imidazo-        238-240   
                    f1 ,2-a]pyrid-7-yl       
                           
19            CH, C-F, CH, CH    3-fluorophenyl    2-methylimidazo[1 ,2-a]-        267-268   
                    pyrid-7-yl       
                           
20            CH, C-F, CH, CH    3-fluorophenyl    2-methylpyrazolo[1 ,5-a]-    267-268   
                           
                    pyrimidin-6-yl       
                           
21            CH, C-F, CH, CH    3-fluorophenyl    2-ethyloxycarbonylimid-    267-268   
                    azo[1 ,2-b]pyridazin-6-yl       
                           
22            CH, C-F, CH, CH    3-fluorophenyl    2-(ethyloxycarbonyl)imid-        242-245   
                    azof1,2-a]pyrid-6-yl       
                           
23            CH, C-F, CH, CH    3-fluorophenyl    2-methylimidazo[1 ,2-a]-        200-203   
                    pyrid-6-yl       
                           
24            CH, C-F, CH, CH    3-fluorophenyl    [1 ,2,4]triazolo[1 ,5-a]pyrid-    227-229   
                        6-yl       
                               

The  compounds  according  to  the  invention  underwent  in   vitro  and  in   vivo

pharmacological  tests  that  demonstrated  their  value  as  therapeutically  active

substances. These compounds have antagonist or agonist activity towards the TRPV1

(or VR1) receptors.

Test of inhibition of the current induced with capsaicin on rat DRGs - Primary culture of rat dorsal root ganglion (DRG) cells:

5    DRG neurones 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 1 0    10% foetal  calf serum,  25  mM  KCI,  2 mM  glutamine,  100 pg/ml  gentamicin  and 50 ng/ml  of  NGF,  and  then  deposited  on  glass  slides  coated  with  laminin (0.25x106 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 pM) is added 48 hours after culturing, to prevent the

15    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 pi) containing the cell preparation are placed on

the platform of an inverted microscope (Olympus IMT2) equipped with Hoffman optics

20    (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 pm), 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

25    (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

30    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 obt-ain the maximum inhibition). The results are expressed as a
5    percentage of inhibition of the control capsaicin response.

In the case of the VR1  antagonist compounds, the percentages of inhibition of the

capsaicin response (1 pM) are between 20% and 100% for the most active compounds

of the invention tested at concentrations of from 0.1 to 100 nM. They are therefore

10    effective antagonists of receptors of TRPV1 type. Table 2 gives a few examples of the percentage of inhibition obtained with the compounds of the invention.


Compound No.    % inhibition in DRG patch
   
1    81.5% (1 nM)
   
20    80% (100 nM)
   
15

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 receptors of TRPV1 type are involved.

20    The compounds of the invention may be useful for preventing or treating pathologies in which receptors of TRPV1 type are involved.

Thus, a subject of the invention is medicaments comprising at least one compound of formula (1), or a pharmaceutically acceptable salt, or alternatively a hydrate or a solvate
25    of the said compound.

These medicaments find  their 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

30    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.

5

The compounds of the invention may also be used for preventing and/or treating metabolic disorders such as diabetes.

The compounds of the invention may be used for preventing and/or treating urological 1 0    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  useful  for  preventing  and/or  treating

15    gynaecological disorders, for instance vulvodynia and pain associated with salpingitis or with dysmenorrhoea.

These  products  may  also  be  used  for preventing  and/or treating  gastrointestinal

disorders  such  as  gastro-oesophageal  reflux  disorder,  stomach  ulcers,  duodenal

20    ulcers, functional dyspepsia, colitis, IBS, Crohn'sdisease, 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,  chronic obstructive

25    pulmonary disease (COPD), bronchoconstriction and inflammatory disorders of the respiratory system.

These products may also be used for preventing and/or treating psoriasis, pruritus, dermal, ocular or mucous irritation, herpes and zona.

30

The compounds of the invention may also be used for treating depression.

The compounds of the invention may also be used for treating central nervous system diseases such as multiple sclerosis.

The compounds of the invention may also be used for treating cancers.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the

5    invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, a hydrate or a solvate of the said compound and also at least one pharmaceutically acceptable excipient.

10    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.

The pharmaceutical compositions of the present invention may be administered via the

oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal,

15    intranasal, transdermal or rectal route. These compositions may be administered in a unit administration form, as a mixture with standard pharmaceutical excipients. They are intended to be administered to animals and human beings for the prophylaxis or treatment of the disorders or diseases mentioned above.

20    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

25    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 following components:
30    Compound according to the invention    50.0 mg
    Mannitol    223.75 mg
    Croscarmellose sodium    6.0 mg
    Corn starch    15.0 mg
    Hydroxypropylmethylcellulose    2.25 mg
35    Magnesium stearate    3.0mg


The said unit forms are dosed to allow a daily administration of from 0.001 to 30 mg of

active principle per kg of body weight, according to the galenical form.

5    There may be particular cases in which higher 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.

1 0    According to another of its aspects, the present invention also relates to a method for

treating  the  pathologies indicated above,  which  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.
CLAIMS


1. Compound corresponding to the general formula (I)


in which:

X1, X2, X3 and~ represent, independently of each other, a nitrogen atom or a group C-R1;

10    it being understood that when one from among1, X2, X3 and ~ represents a nitrogen atom, the others correspond to a group C-R1;

W represents an oxygen or sulfur atom;

15    n is equal to 0, 1, 2 or 3;

Y represents an aryl or a heteroaryl optionally substituted with one or more groups chosen from a halogen atom and a group C1-Ce-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C1-Ce-fluoroalkyl, hydroxyl, C1-C6-alkoxy, C3-Cr

20    cycloalkyloxy,  C3-C7-cycloalkyi-C1-Ce-alkylene-O-,  CrCe-fluoroalkoxy,  cyano,  C(O)

N~~. nitro,  N~~. C1-Ce-thioalkyl,  thiol,  -S(O)-C1-Ce-alkyl,  -S(0)2-C1-C6-alkyl,

S02N~~. NRsC(O)Rs, NReS02R7, C(O)N~~. OC(O)NR3~, -Si-(C1-C6-alkyl)3, -SF5 , aryi-C1-C5-alkylene or aryl, heteroaryi-C1-C5-alkylene or heteroaryl; the groups C1-C6-alkyl, C3-Crcycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl, CrC6-alkoxy,

25    C3-C7-cycloalkyloxy and C3-C7-cycloalkyi-C1-C6-alkylene-O- possibly being substituted with a hydroxyl, C1-Ce-alkoxy or N~~ group; the aryl and heteroaryl groups being optionally substituted with one or more substituents Re. which may be identical to or different from each other;
 

30    A represents a bicyclic heteroaryl of formula:
 

in which
Z1, Z2 ,  Z3 and ~ represent, independently of each other, a carbon atom, a nitrogen

5    atom or a group C-Rz.;

Z5 , Z6 and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b; Z6 represents a carbon atom;

three, at most, from among Z1, Zz, Za, Z4, Zs, Zs and Z1 represent a nitrogen atom;
one from among z, Zz, Za and ~. corresponding to a carbon atom, being bonded to

10    the nitrogen atom of the amide or thibamide of formula (I);

R1 is chosen from a hydrogen atom, a halogen atom, C1-Cs-alkyl, C3-Crcycloalkyl, C3-C1 cycloalkyi-C1-Ca-alkylene, C1-Cs-fluoroalkyl, aryloxy-C,-Cs-alkyl, heteroaryloxy-C1-C6-alkyl, aryi-C1-Ca-alkylenoxy-C1-Cs-alkyl, heteroaryi-C1-C3-alkylenoxy-C1-C6-alkyl,

15    arylthio-C1-Ca-alkyl, heteroarylthio-C1-Cs-alkyl, aryi-C,-C,-alkylenethio-C1-C6 -alkyl, heteroaryi-C1-C,-alkylenethio-C1-Cs-alkyl, C1-Cs-alkoxy, C,-C7-cycloalkyloxy, C3-C7-cycloalkyi-C,-C3-alkylenoxy, C1-Cs-fluoroalkoxy, cyano, C(O)NRa~. nitro, NR3~,
C1-C6-thioalkyl,  Ca-C7-cycloalkylthio, C,-C,cycloalkyi-C1-Ca-alkylenethio, -S(O)-C1-C6-
alkyl, -S(O)-Ca-Crcycloalkyl, -S(O)-C1-Ca-alkylene-Ca-C1 cycloalkyl, C1-Ca-alkyi-S(O)z-,

20    C,-C6-fluoroalkyi-S(O)z-, Ca-C,cycloalkyi-S(O)z-, Ca-C7-cycloalkyi-C1-C3-alkylene-S(O)z-, S02NRa~. (C1-Cs-alkyl)a-Si-, -SFs, NRsC(O)Ra. NRsS02R7, C(O)NRa~.

OC(O)NR3~. aryl, heteroaryl, aryi-C1-Cs-alkylene, heteroaryi-C1-Cs-alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio; the heteroaryl or aryl groups being optionally substituted with one or more substituents Ra. which may be identical to or different from

25    each other;

R2a represents a hydrogen atom, a halogen atom or a group C1-C6-alkyl, C3-C1 cycloalkyl, C3-C1 cycloalkyi-C1-Ca-alkylene, C1-Cs-tluoroalkyl, C1-C6-alkoxy, C3-Cr cycloalkyloxy, C3-C1 cycloalkyi-C1-C3-alkylene-O-, hydroxyl, thiol or C1-C6-fluoroalkoxy;

30
Rzb represents a hydrogen atom, a halogen atom or a group C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyi-C,-C3-alkylene, C,-C6-fluoroalkyl, C1-C6-alkoxy, hydroxyl, thiol, oxo, thio, Ca-Crcycloalkyloxy, C1-Cs-fluoroalkoxy, C3-C7-cycloalkyi-C1-C3-
 



53


alkylenoxy, C1-Ce-alkoxy-C1-C3-alkylene, C3-Crcycloalkyloxy-C1-C3-alkylene, C3-Cr cycloalkyi-C1-C3-alkylenoxy-C1-C3-alkylene, C1-Ca-alkyi-C(O)-O-C1-C3-alkylene, C1-C6-alkyi-C(O)-O-, C3-Crcycloalkyi-C(O)-O-C1-C3-alkylene, CTCrcycloalkyi-C(0)-0-, C1-C6-fluoroalkyi-C(O)-O-C1-CTalkylene, C1-Ca-fluoroalkyi-C(O)-O-, C(O)NR3~, C(0)0-
5    C1-C6-alkyl, cyano, CHO, COzH, -C(O)-C1-Ca-alkyl, -C(O)-C3-Crcycloalkyl,  phenyl or

thienyl; the groups C1-Ca-alkyl, C3-Crcycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl, CrCa-alkoxy, C3-Cr-cycloalkyloxy, C1-Ca-fluoroalkoxy, CTC7-cycloalkyi-C1-C3-alkylenoxy, C1-Ca-alkoxy-C1-C3-alkylene, C3-Cr-cycloalkyloxy-C1-C3-alkylene and C3-Cr-cycloalkyi-C1-C3-alkylenoxy-C1-C3-alkylene possibly being

10    substituted with a hydroxyl, C1-Ca-alkoxy or NR3~ group;

R3  and ~ represent, independently of each other, a hydrogen atom or a group C1-C6-
alkyl, C3-Crcycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, aryi-C1-C5-alkylene or aryl, or

R3   and  ~ together form,  with  the  nitrogen  atom  that  bears  them,  an  azetidine,

15    pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group; the group NR3~ being optionally substituted with a group

C1~C6-alkyl, C3-C7-cycloalkyl, C3-Cr-cycloalkyi-C1-C3-alkylene, aryi-C1-C6-alkylene, aryl, heteroaryl, aryi-S(O)z-, C1-Ca-alkyi-S(O)z-, C1-Ca-fluoroalkyi-S(O)z, C3-C7-cycloalkyi-S(O)z-, C3-C7-cycloalkyi-C1-C3-alkylene-S(O)z-, aryi-C(O)-, C1-C6-alkyi-C(O)-, C3-Cr-
20    cycloalkyi-C(O)-, C3-Cr-cycloalkyi-C1-C3-alkylene-C(O)-, C1-C6-fluoroalkyi-C(O)-,

hydroxyl, C1-Ca-alkyloxy, C3-Cr-cycloalkyloxy, C3-Crcycloalkyi-CrC3-alkylenoxy, C1-C6-fluoroalkyl, aryloxy-CrCa-alkylene, aryloxy, heteroaryloxy-C1-C6-alkylene or heteroaryloxy;

25    R5 and R6 represent, independently of each other, a hydrogen atom or a group CrC6-alkyl, C3-C7-cycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, aryi-C1-Ca-alkylene or aryl; the

aryl group being optionally substituted with one or more substituents chosen from a halogen atom and a group C1-Ca-alkyl, C3-Crcycloalkyl, C3-Cr-cycloalkyi-C1-C3-
alkylene, C1-C6-fluoroalkyl, CrCa-alkoxy,  C3-C7-cycloalkyloxy, C3-C7-cycloalkyi-C1-C3-
30    alkylenoxy, C1-C6-fluoroalkoxy, nitro or cyano;

or R5 and Ra together form a 4- to ?-membered lactam comprising the nitrogen atom and the C(O) group that bear them;
 

R7  represents a group C1-Ca-alkyl,  C3-C7-cycloalkyl,  C3-Cr-cycloalkyi-C,-C3-alkylene,
35    aryi-C1-C6-alkylene or aryl; the aryl group being optionally substituted with one or more
 



54


substituents chosen from a halogen atom and a group C1-C6-alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C,-C6-fluoroalkyl, C,-C6-alkoxy, C3-C7-cycloalkyloxy, C3-C7-cycloalkyi-C,-C3-alkylenoxy, C,-C6-fluoroalkoxy, nitro or cyano;

or R5  and R1 together form a 4- to 7 -membered sultam comprising the nitrogen atom

5    and the S(O)z group that bear them;

~    represents a halogen atom or a group C,-C6-alkyl, C3-C1-cycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C,-C6-fluoroalkyl, C,-C6-alkoxy, C3-C7-cycloalkyloxy, C3-C7-
cycloalkyi-C1-C3-alkylenoxy, C,-C6-fluoroalkoxy, nitro, cyano, N~~. -C(O)-C1-C6-alkyl
10    or -C(O)-C3-C7-cycloalkyl; the groups C,-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl, C,-C6-alkoxy, C3-C1-cycloalkyloxy and C3-C7-cycloalkyi-C1-C3-alkylenoxy possibly being substituted with a group OH, C1-C6-alkoxy or NR3~;

the sulfur atom(s) of the compound of general formula (I) possibly being in oxidized

15    form;

the nitrogen atom(s) of the compound of general formula (I) possibly being in oxidized form;
in the form of the base or of an acid-addition salt, and also in the form of hydrate or solvate.
20

2. Compound of formula (I) according to Claim 1, characterized in that X1, X2 , X3 and~ represent, independently of each other, a group C-R1; R1 being as defined in the general formula (I) according to Claim 1;

in the form of the base or of an acid-addition salt, and also in the form of hydrate or 25 solvate.

3. Compound of formula (I) according to Claim 1, characterized in that X1, X2 and X3 represent a group C-R1; ~represents a nitrogen atom; R1 being as defined in the general formula (I) according to Claim 1;

30    in the form of the base or of an acid-addition salt, and also in the form of hydrate or solvate.

4. Compound of formula (I) according to any one of Claims 1 to 3, characterized in that R1 is chosen from a hydrogen atom, a halogen atom and a group C1-C6-fluoroalkyl;

35    in the form of the base or of an acid-addition salt, and also in the form of hydrate or solvate.
 


5. Compound of formula (I} according to any one of Claims 1 to 4, characterized in that n is equal to 1;

in the form of the base or of an acid-addition salt, and also in the form of hydrate or 5 solvate.

6. Compound of formula (I) according to any one of Claims 1 to 5, characterized in that Y represents an aryl optionally substituted with one or more halogen atoms;
in the form of the base or of an acid-addition salt, and also in the form of hydrate or

10    solvate.

7. Compound of formula (I) according to any one of Claims 1 to 6, characterized in that W represents an oxygen atom;

in the form of the base or of an acid-addition salt, and also in the form of hydrate or

15    solvate.

8. Compound of formula (I) according to any one of Claims 1 to 7, characterized in that A represents a bicyclic heteroaryl of formula:




20

in which
Z1, Z2, Z3 and 4 represent, independently of each other, a carbon atom or a nitrogen atom;
Z5, Zs and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b;

25    Z8 represents a carbon atom;
two, at most, from among Z1, Z2, Z3, 4, Z5, Z6 and Z1 represent a nitrogen atom;

one from among Z1. Z2, Z3 and 4, corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I);
R2b represents a hydrogen atom or a group C1-Ca-alkyl, C(O)O-C1-Ca-alkyl, phenyl or
30    thienyl; the groups C1-Ca-alkyl possibly being substituted with a hydroxyl or C1-C6-alkoxy group;

in the form of the base or of an acid-addition salt, and also in the form of hydrate or solvate.
 

35    9. Compound of formula (I) according to any one of Claims 1 to 8, characterized in that
 




56


A represents the group


V-tR,,

R2b

R2b represents a hydrogen atom or a group C,-Cs-alkyl, C(O)O-C1-Cs-alkyl, phenyl or thienyl; the groups C1-Ce-alkyl possibly being substituted with a hydroxyl or C1-C6-

5    alkoxy group;

in the form of the base or of an acid-addition salt, and also in the form of hydrate or solvate.

10. Compound of formula {I) according to any one of Claims 1 to 9, characterized in

11    that

A represents the group


R2b represents a hydrogen atom or a group C1-C6-alkyl, phenyl or thienyl; the groups C1-C6-alkyl possibly being substituted with a hydroxyl or C1-C6-alkoxy group;

15    in the form of the base or of an acid-addition salt, and also in the form of hydrate or solvate.

11. Compound of formula (I) according to any one of Claims 1 to 8, characterized in

that

20    X1o X2 , X3 and N represent, independently of each other, a group C-R1 ; or alternatively X1, X2 and X3 represent a group C-R1; N represents a nitrogen atom;

R1 is chosen from a hydrogen atom, a halogen atom or a group C1-C6-fluoroalkyl; n is equal to 1;
 


Y represents an aryl optionally substituted with one or more halogen atoms; W represents an oxygen atom;

A represents a bicyclic heteroaryl of formula:


in which
Z1,  Z2,  Z3 and ~ represent, independently of each other, a carbon atom or a nitrogen

atom;

Z5 ,  Zs and Z7 represent, independently of each other, a nitrogen atom or a group C-R2b;

1 0    Z8  represents a carbon atom;

two, at most, from among Z1. Zz, ~. ~. Zs. Zs and Z1 represent a nitrogen atom;

one from among Z1. Zz, Z3 and ~. corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or thioamide of formula (I);
R2b represents a hydrogen atom or a group C1-C6-alkyl, C(O)O-C1-C6-alkyl, phenyl or

15    thienyl; the groups CrCs-alkyl possibly being substituted with a hydroxyl or C1-C6-alkoxy group;

in the form of the base or of an acid-addition salt, and also in the form of hydrate or solvate.

20    12. Compound of formula (I) according to Claim 1, chosen from: N-(2,3-Dimethylimidazo[1,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide;
N-(2, 3-Dimethylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-

2-carboxamide;

25    N-[2-(Hyd roxymethyl)imidazo[1,2-a]pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide;

N-(3-Methyl-2-phenylimidazo[1,2-a] pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide; N-(2-Ethylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl-1 H-indole-2-

30    carboxamide;

N-[2-(Thien-2-yl)imidazo[1,2-a] pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide; N-(2-tert-Butylimidazo[1,2-a]pyrid-6-yl)-5-fluoro-1-[ (3-fluorophenyl)methyl]-1 H-indole-2-

carboxamide;

35    N-(2-Methoxymethylimidazo[1 ,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-
 

indole-2-carboxamide;

N-[2-(Hyd roxymethyl)imidazo[1 ,2-a] pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide;

N-(2-Methyl-3-phenylimidazo[1 ,2-a] pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

5    indole-2-carboxamide;

N-[2-(Thien-2-yl)imidazo[1 ,2-a]pyrid-7-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide;
N-(2-Ethylimidazo[1 ,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl-1 H-indole-2-

carboxamide;

1 0    N-(2-terl-Butylimidazo[1 ,2-a]pyrid-7 -yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-

carboxamide;

N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-

1H-indole-2-carboxamide;

N-(2-Ethylimidazo[1 ,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl) methyl]-1 H-

15    pyrrolo[2,3-b]pyridine-2-carboxamide;

N-(2,3-Dimethylimidazo[1 ,2-a]pyrid-7-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7 -yl]-5-trifluoromethyl-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide;

20    N-[2-(Hydroxymethyl)imidazo[1 ,2-a]pyrid-7 -yl]-5-trifluoromethyl-1-[(3-fluorophenyl)-methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide;

N-(2-Methylimidazo[1 ,2-a]pyrid-7-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide;
N-(2-Methylpyrazolo[1 ,5-a] pyrimidin-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-

25    2-carboxamide;

N-[2-(Ethyloxycarbonyl)imidazo[1 ,2-b]pyridazin-6-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide;

N-[(2-(Ethyloxycarbonyl)imidazo[1 ,2-a] pyrid-6-yl)-5-fluoro-1-[ (3-fluorophenyl)methyl]-

1H-indole-2-carboxamide;

30    N-(2-Methylimidazo[1 ,2-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide;
N-([1 ,2,4]Triazolo[1 ,5-a]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxamide.

35    13. Process for preparing a compound of formula (I) according to any one of Claims 1 to 12, characterized in that a compound of general formula (II)
 
in which X1 , X2, X3 , ~. n, Y and Ware as defined in the general formula (I) according to Claim 1,

is reacted with a compound of general formula (Ill),

z/z1,z--Z7       
2    1    8    •z   
o--T--               
zK    ,.....N--z'    s   
5    z4        s    (Ill)   
                   

in which Z1 , Z2 , Zs. 4. Zs, Ze. Z7 and Za are as defined in the general formula (I) according to Claim 1:

-when B represents an NHz group and D represents a leaving group,

either in the presence of a copper salt in catalytic amount, a copper ligand in catalytic

11    amount and a base, in a solvent; or in the presence of a catalytic amount of a palladium derivative, a catalytic amount of a palladium ligand and a base, in a refluxing

solvent;

-when B represents a hydroxyl group and D represents an NH2 group, in the presence

of a coupling agent in a solvent;

15    -when B is a chlorine atom and D represents an NH2  group, in a solvent.


14. Process for preparing a compound of formula (I) according to any one of Claims 1 to 12, in which W represents an oxygen atom and A represents a group:


20    characterized in that a compound of general formula (V)


in which X1, Xz, Xa. Xa. n and Y are as defined in the general formula (I) according to Claim 1 and PG represents a hydrogen atom,

is reacted with a compound of general formula (IV),

0H X  {IV)

Rzb    Rzb

in which X represents a leaving group and R2b is as defined in the general formula (I) according to Claim 1.

15. Compound of formula (lila), (lllb), (lllc), (llld), (Ill e) or (II If):

8,'0~    H,co2c'O:~=t       
""-    N    ""-    N  0       
(lila}    =t    (lllb}           
Br~N    OH        Br'()}-;0-   
~~-)~r        (1111}   
(I lid}        (llle}       
                   
 

16. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 12, or an addition salt of this compound with a

20    pharmaceutically acceptable acid, or alternatively a hydrate or a solvate of the compound of formula (1).

17. Pharmaceutical composition,  characterized  in that it comprises  a compound  of

formula (I) according to any one of Claims 1 to 12, or a pharmaceutically acceptable

25    salt, a hydrate or a solvate of this compound, and also at least one pharmaceutically acceptable excipient.

18. Use of a compound of formula (I) according to any one of Claims 1 to 12, for the
 

preparation of a medicament for preventing or treating pathologies in which receptors of TRPV1 type are involved.

19. Use of a compound of formula (I) according to any one of Claims 1 to 12, for the

5    preparation of a medicament for preventing or treating pain, inflammation, metabolic disorders, urological disorders, gynaecological disorders, gastrointestinal disorders, respiratory disorders, psoriasis, pruritus, dermal, ocular or mucous irritations, herpes, zona, multiple sclerosis, depression and cancers.

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