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(71)Application Number: KE/P/2010/ 001114   
   
(22) Filing Date: 20/01/2009   
   
(30) Priority data: 08/00308  22/01/2008    FR
   
(86)  PCT data PCT/FR09/000052    20/01/2009 WO  20091112678    17/09/2009

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

(72) Inventors:DUBOIS, Laurent, c/o Sanofi-Aventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France; EVANNO, Yannick, c/o Sanofi-A ventis, DepartementBrevet, 174  avenue de France, F-75013 Paris France; MACHNIK, David, c/o Sanofi-Aventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France and MALANDA, Andre,  c/o Sanofi-Aventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France

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

(54) Title:AZABICYCL!C CARBOXAMIDE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

(57 Abstract: The invention relates to the compounds of general formula (I) in which X1. X:z, X3 and ~ are, independently of one another, a nitrogen atom or a C-R, group; z,, 2 2, z, and ~are, independently of one another, a nitrogen atom or a C-R:z group; Ra and Rb fonn, together with the carbon atoms which bear them, a five-membered ring, this dng comprising a nitrogen atom and carbon atoms, this ring being partially saturated or unsaturated and being optionally substituted with one or more substituents RJ; W is an oxygen or sulphur atom; n is equal to 0, 1, 2 or 3; Y is an optionally substituted aryl or heteroaryl; in the form of a base or of an addition salt with an acid, and also in the fonn of a hydrate or of a solvate. Process for the preparation thereof and therapeutic use.
 
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 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.

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

formula (I) hereinbelow.

Another subject of the invention concerns processes for preparing t~e compounds of

general formula (I).

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 (I):in which:

X, X,, X, and X. represent, independently of each other, a nitrogen atom or a group C-
 
R1;

it being understood that when one from among X1,  X2, ~ and ~represents a nitrogen
atom, the others correspond to a group C-R1;

Z1, Z2,  z, and Z. represent, independently of each other, a nitrogen atom, a carbon

atom or a group C~R2,

at least one from among Z1, Z2, Z3 and .4 corresponding to a nitrogen atom and
one from among Z1, z,, Z., and z.. corresponding to a carbon atom, being bonded to the nitrogen atom of the amide or of the thioamide of formula (I);

Ra and Rb form, togethe( with the carbon atoms that bear them, a 5-membered ring,

this ring comprising a nitrogen atom and carbon atoms, this ring being partially saturated or unsaturated and being optionally substituted with one or more substituents

W represents an oxygen or sulfur atom;

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, a group C1-C6-alkyl, C3-C7-cycloalkyl, C3-C,-cycloalkyi-C1-C3-alkylene, C1-C6-fiuoroalkyl, hydroxyl, C,-C,..alkoxy, C,-C,_cycloalkyloxy, C3-C,-cycloalkyi-C1-C,-alkylene-O-, c,-C,-fluoroalkoxy, cyano, C(O) NR,R,, nitro, NR,R5 ,
C1-C6-thioalkyl,  thiol, •-S(O)-C1-Ca-alkyl,  -S(0)2-C,-C,-alkyl,  SO,NR,R5,   NR6C(O)R7,

NR6S02R6 , C(O)NR,R,, OC(O)NR,R,, -Si-(C,-C,-alkyl),, -SFs, aryi-C1-Cs-alkylene or aryl, heteroaryi-C1-C5-alkylene or heteroaryl; the groups C1-C6-alkyl, C3-C,-cycloalkyl, C3-C7-cycloalkyi-C,-C,-alkylene, C,-C,-fluoroalkyl, C,-C,-alkoxy, C,-C,-cycloalkyloxy and C3-C,_cycloalkyi-C1-C,-alkylene-O- being optionally substituted with a hydroxyl group, C1-C6-alkoxy or NR.Rs. the aryl and heteroaryl groups being optionally substituted with one or more substituents R9, which may be identical to or diFferent from each other;

R1 is chosen from a hydrogen atom, a halogen atom, C1-C6-alkyl, C3-C,-cycloalkyl, C3-C,_cycloalkyi-C,-C3-alkylene, C,-C,-fluoroalkyl, aryloxy-C1-C,-alkyl, heteroaryloxy-C1-C6-alkyl, aryi-C1-C,-alkylenoxy-C1-Ca-alkyl, heteroaryi-C1-C3-alkylenoxy-C1-C,-alkyl,arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, aryi-C1-C3-alkylene-thio-C1-C6-alkyl, heteroaryi-C1-C3-alkylene-thio-C,-C,-alkyl, C1-C6-alkoxy, C3-C,-cycloalkyloxy, C3-C7-cycloalkyi-C1-C3-alkylenoxy, C1-C6-IIuoroalkoxy, cyano, C(O)NR,R5 , nitro, NR,R5 ,

C1-C6-thioalkyl, C,-C,-cycloalkylthio, C,-C7-cyclo•alkyi-C,-C,-alkylene-thio, -S(O)-C1-C6-alkyl, -S(O)-C,-C7 -cycloalkyl, -S(O)-C1-C,-alkylene-C3-C,-cycloalkyl, C1-C6-alkyi-S(O),-,
C -C -fluoroalkyi-S(O),-,    C,-C -cycloalkyi-S(O),-,    C3-C,-cycloalkyi-C -C3-alkylene-
1  6    7    1

S(O),-.  S02NR,R,,  -Si-(C,-C,-alkyl),,  -SF,,  NRaC(O)R,,  NR,SO,Ra,  C(O)NR,R5,

OC(O)NR,R5 , aryl, heteroaryl, aryi-C,-C,-alkylene, heteroaryi-C1-C,-alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio; the heteroaryl or aryl groups being optionally

substituted with one or more substituents R9, which may be identical to or different from

each other;

R2  represents  a  hydrogen  atom,  a  halogen  atom  or  a  group  C1-Ca-alkyl,  C3-Cr
cycloalkyl,    C3-C7-cycloalkyi-C1-C3-alkylene,  C1-C6-fluoroalkyl,  C1-C6-alkoxy,  C3-C7-

cycloalkyloxy, c,-C,-cycloalkyi-C,-C,-alkylene-0-, hydroxyl, thiol or C1-C0-IIuoroalkoxy;

R3  represents, when it is borne by a carbon atom, a hydrogen atom, a hydroxyl group,
thiol,  C,-C,-alkyl,  C,-C,-cycloalkyl,  C,-C,-cycloalkyi-C,-C,-alkylene,  C1-C6-IIuoroalkyl,
C -C -alkoxy, C3-C,-cycloalkyloxy, C,-C -cycloalkyi-C1-C3-alkylenoxy, C -C -alkoxy-C -
1  6    7    1  6    1
C3-alkylene, C,-C,-cycloalkyloxy-C,-C,-alkylene, C3-C,-cycloalkyi-C,-C3-alkylenoxy-C1-C3-alkylene, C(O)NR,Ra. C(O)O-C,-C,-alkyl, CO,H, or an oxo or thio group; the groups C1-C6-alkyl, C3-C,-cycloalkyl, C,-C,-cycloalkyi-C,-C3-alkylene, C1-Ca-fluoroalkyl, C1-C6-alkoxy, C3-C,-cycloalkyloxy, C3-C,-cycloalkyi-C1-C3-alkylenoxy, C1-C6-alkoxy-C1-C3-alkylene, C3-C,-cycloalkyloxy-C1-C3-alkylene and C3-C,-cycloalkyi-C1-C3-alkylenoxy-C1-C3-alkylene possibly being substituted with a hydroxyl group, C1-C6-alkoxy or NR,R5; or

R3 represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1-C6-

alkyl, C3-C,-cycloalkyl, C,-C,-cycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl, aryi-C(O)-, C1-C6-alkyi-C(O)-, C,-C,-cycloalkyi-C(O)-, C3-C7-cycloalkyi-C1-C3-alkylene-C(O)-, C,-C,-fluoroalkyi-C(O)-, aryi-S(O), c,-C,-alkyi-S(O)-, C1-C6-IIuoroalkyi-S(O)-, aryi-S(O),-, C1-C,-alkyi-S(O),-, c,-Cs-fluoroalkyi-S(O),-, c,-C,-cycloalkyi-S(O),-, c,-c,. cycloalkyi-C1-C,-alkylene-S(O),-, c,-C,-alkyi-0-C(O)-, aryi-C,-C,-alkyi-0-C(O)-, C3-C7-cycloalkyi-O-C(O)-, C3-C,-cycloalkyi-C1-C3-alkylene-0-C(O)-, C1-C6-fluoroalkyi-0-C(O)-

• aryi-0-C(O)-, heteroaryi-0-C(O)-, heteroaryl or aryl; the heteroaryl and aryl groups being optionally substituted with one or more substituents R9; the groups C1-C6-alkyl,
 
C3-Crcycloalkyl, C3-Crcycloalkyi-C1-C3-alkylene, C1-C6-fluoroalkyl, possibly being substituted with a hydroxyl group, c,-c,-alkoxy or NR,R5;

R, and Rs 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 R, and R5 together form, with the nitrogen atom that bears them, an azetidine,

pyrrolidine,    piperidine,   azepine,   morpholine,   thiomorpholine,   piperazine   or

homo piperazine; the group NR,R, being optionally substituted with a group C1-C6-alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, aryi-C1-C6 -alkylene, aryl, heteroaryl,

aryi-S(O),-. C -C -alkyi-S(O),-, C,-C,-fluoroalkyl-8(0),, C,-Crcycloalkyl-8(0) C3-Cr 1 6 2-,
cycloalkyi-C1-C3-alkylene-S(O),-, aryi-C(O)-, C1-C6-alkyi-C(O)-, C,-Crcycloalkyi-C(O)-, C3-C7-cycloalkyi-C1-C3-alkylene-C(O)-, C1-C6-fluoroalkyi-C(O)-, hydroxyl, C1-C6-alkyloxy, C3-Crcycloalkyloxy, C,-Crcycloalkyi-C1-C,-alkylenoxy, C,-C,-fiuoroalkyl, aryloxy-C1-C6-alkylene, aryloxy, heteroaryloxy-C,-C,-alkylene or heteroaryloxy;

Rs and R7 represent, independently of each other, a hydrogen atom, a group C1-C6 - alkyl, C3-Crcycloalkyl, C3-Crcycloalkyi-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 C,-C,-alkyl, C,-Crcycloalkyl, C,-Crcycloalkyi-C1-C3-alkylene, C1-C6-fiuoroalkyl, C1-C6-alkoxy, C,-Crcycloalkyloxy, C3-Crcycloalkyi-C1-C3-alkylenoxy, C1-C6-fiuoroalkoxy, nitro or cyano;

or Ra and R7 together form a 4- to 7-membered lactam comprising the nitrogen atom

and the C(O) group that bear them;

Rs represents a group C,-C,-alkyl, C,-C,-cycloalkyl, C,-C,-cycloalkyi-C,-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 c,-C,-alkyl, c,-Crcycloalkyl, C3-C7-cycloalkyi-C1-C,-alkylene, C,-C,-fiuoroalkyl, C,-C,-alkoxy, c,-Crcycloalkyloxy, C3-Crcycloalkyi-C1-C3-alkylenoxy, C,-C,-fiuoroalkoxy, nitro or cyano;

or R6 and Ra together form a 4- to 7-membered sultam comprising the nitrogen atom

and the S(O), group that bear them;

R9 represents a halogen atom or a group C1-C6 -alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C,-C,-fiuoroalkyl, C1-C,-alkoxy, C,-Crcycloalkyloxy, C3-Cr cycloalkyi-C1-C3-alkylenoxy or C1-C6-fiuoroalkoxy; these groups being optionally
 
substituted with a group OH, C1-Ca-a!koxy or N~R5: or alternatively Rg represents a

nitro, cyano or NR.Rs group.

In the compounds of general formula (1):

the sulfur atom(s) may be in oxidized form (S(O) or 8(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.

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 fonmula (I) may exist in the form of bases or of acid-addition salts.

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.

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.

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;

an alkyl: a linear or branched saturated aliphatic group. Examples that may be

mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-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

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

propylene;
 
a cycloalkyl: a salurated or partially unsaturated cyclic alkyl group. Examples that may be mentioned include the groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;

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;

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 hi which the alkyl group is as defined

previo':lsly;

an  aryl:  a  monocyclic  or  bicyclic aromatic  group  containing  between  6  and  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, S and N.

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, 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 ,2-a]pyridazinyl, imidazo[1 ,2-c]pyrimidinyl, imidazo[1 ,2-a]pyrimidinyl, imidazo[1 ,2-a]pyrazinyl, imidazo[4,5-b]pyrazinyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[2,3-a]pyridyl, pyrazolo[2,3-a]pyrimidinyl and pyrazolo[2,3-a]pyrazinyl.

"axe" means "=0";

uthio" means "=S".

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, X, and X.
 
represent, independently of each other, a group C-R,; R, being as defined. in the general formula (\).

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

second subgroup of compounds is constituted by the compounds for which one from

among X, X2,  Xs and X. represents a nitrogen atom, the others among X1,  X2,  Xs and

X, represent, independently of each other, a group C-R1; R1 being as defined in the general formula (1).

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, among X1, X2, Xa and ~. one from among Xa and ~ represents a nitrogen atom, and the others

represent, independently of each other, a group C-R1; R1 being as defined in the general fonmula (1).

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

R1 is chosen from a hydrogen atom, a halogen atom and a group C1-C6-fluoroalkyl or -Si(C1-C6-alkyl),.

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
R1 is chosen from a hydrogen atom, a fluorine atom and a group CF3 or Si(CH3)s.

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

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

Among the compounds of general fonmula (/) that are subjects of the invention, a

seventh subgroup of compounds is constituted by the compounds for which

Y represents an aryl or a heteroaryl optionally substituted with one or more groups chosen from a halogen atom, a group C1-C6-alkyl and C1-C6-fiuoroalkyl.

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

Y represents a phenyl, optionally substituted with one or more groups chosen from a
 
halogen atom and a group C,-C,-alkyl or c,-C,-fluoroalkyl; or alternatively Y represents a pyridyl or a thiazolyl.

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

Y represents a phenyl, optionally substituted with a fluorine atom, a methyl group or CF3; or alternatively Y represents a pyridyl or a thiazolyl.

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
Y represents a phenyl, optionally substituted with a fluorine atom, a methyl group or

CF3 •

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

Among the compounds of general fonmula (I) that are subjects of the invention, a twelfth sub.group of compounds is constituted by the compounds for which
z,, Z2, z, and Z., represent, independently of each other, a nitrogen atom, a carbon atom or a group C-R,,

one from among Z1, Z2, Zs and ~corresponding to a nitrogen atom and possibly being

in oxidized form;

one from among Z1,  Z2, ~and ~. corresponding to a carbon atom, being bonded to

the nitrogen atom of the amide or of the thioamide of formula (I);
and the two others from among z,, z,, Z, and Z., corresponding to a group C-R2;

R2 being as defined in the general formula (1).

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
Z1 ,  Z2,  z, and Z., represent, independently of each other, a nitrogen atom, a carbon

atom or a group C-R2,

one from among Z1, Z2, 4 and ~corresponding to a ~itrogen atom and possibly being

in oxidized fonn;

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

and the two others from among Z1, Z2, 23 and ,4corresponding to a CH group.

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

fourteenth subgroup of compounds is constituted by the compounds for which

Ra and Rb form, together with the carbon atoms that bear them, a 5-membered ring,

this  ring  comprising  a  nitrogen  atom  and  carbon  atoms,  this  ring  being  partially

saturated or unsaturated and being optionally substituted with one or more substituents

R,;

R3 represents, when it is borne by a carbon atom, a hydrogen atom or an oxo group;
~ represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1~C6-

alkyl or C1-C,-alkyi-C(O)-.

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

Ra and Rb fonm, together with the carbon atoms that bear them, a 5-membered ring,

this  ring  comprising  a  nitrogen  atom  and  carbon •atoms,  this  ring  being  partially

saturated or unsaturated and being optionally substituted with one or more substituents

R,;

~ represents, when it is borne by a carbon atom, a hydrogen atom or an oxo group;

~represents, when it is borne by a nitrogen atom, a hydrogen atom, a methyl group or

CH3 -C(O)-.

Among the compounds of general fonmula (I) that are subjects of the invention, a sixteenth subgroup of compounds is constituted by the compounds for which the group
Z    Ra
zf'~
~z  Rb
4

is chosen from the groups
 



10

-Qj -cPH -co HN
-cPH >=PH
N

these groups being optionally substituted with R2 and R, as defined in the general formula (I) hereinabove.

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

group

Z    Ra
zf''i
~z}-._Rb
4

is chosen from the groups
-Qj -cPH -co HN

-cPH >=PH

one from among z, z,, Z. and z. corresponding to a nitrogen atom and possibly being

in oxidized fonn;

these groups being optionally substituted with R2 and R, as defined in the general formula (I);
R2 represents a hydrogen atom;

~represents, when it is borne by a carbon atom, a hydrogen atom or an oxo group;

~represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1-C6-

alkyl or C1-C.-alkyi-C(O)-.
 

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 the group

Z    Ra
z1' '->{\--
_ . y
Zf:::,z    Rb
4

is chosen from the following groups:
-cPHN   -co -cPH

~

N    -    -    /,   N,   
        N       
'cH~ /,     'cH   ~    NCH,   
NJ    N    3       
    -cPV   
--6'0

Among the compounds of general formula (I) that are subjects of the invention, a nineteenth subgroup of compounds is constituted by the compounds for which the group
Z    Ra
zf''(
~z)l-._Rb
4

is chosen from the groups
-cPH

these groups being optionally substituted with R2  and R3  as defined in the general formula (I) hereinabove.

Among the compounds of general formula (I) that are subjects of the invention, a twentieth subgroup of compounds is constituted by the compounds for which the group
Z    Ra
zf''§__
-z;z  Rb
4

is chosen from the groups




one from among Z1, Z:,, Z:, and :Z, corresponding to a nitrogen atom and possibly being

in oxidized form;

these groups being optionally substituted with R, and R, as defined in the general formula(!);
R2 represents a hydrogen atom;

~represents, when it is borne by a carbon atom, a hydrogen atom or an oxo group;

R3  represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1-C6 -

alkyl or C1-C6-alkyi-C(O)-.

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



is chosen from the following groups:
 
-Qj _zyH -cb HN
-cPHN    >Y"
one from among Z1,  Z2, Z3 and~ corresponding to a nitrogen atom and possibly being

in oxidized form;

these groups being optionally substituted with R2  and R, as defined in the general

fonnula (I};

R2 represents a hydrogen atom;

R3 represents, when it is borne by a carbon atom, a hydrogen atom or an axe group;

R3 represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1-C;-

alkyl or C1-C.-alkyi-C(O}-.

Among the compounds of general fonnula (I} that are subjects of the invention, a twenty-fourth subgroup of compounds is defined such that
the compounds for which

X1, X2, X3 and X. represent, independently of each other, a group C-R1;

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

C1-C6-fluoroalkyl, C1-C.-alkoxy, C1-C6-fluoroalkoxy, NR,R5, C1-C6-thioalkyl, phenyl or isoxazolyl; the phenyl group being optionally substituted with one or more substituents
R9, which may be identical to or different from each other;

R, and R5 represent, independently of ~ach other, a hydrogen atom or. a group C1-C6-

alkyl,

W represents an oxygen atom;

n is equal to 0;

Y represents a phenyl optionally substituted with one or more substituents R9,  which

may be identical to or different fronl each other; or Y represents an isoxaz?le;

R9 represents a halogen atom or a group C1-C,-alkyl, C1-C6-alkoxy or cyano;

the group
 Z    Ra
zt'1

~)l--.Rb

4

represents the group D:



in which

L represents a hydrogen atom, a halogen atom or a group CrC4-alkoxy;

the 5-membered ring is partially saturated or unsaturated; J represenls N or C=O; when J represents N, then E and G represent, independently of each other, a group C=O or CH2; when J represenls C=O, one from among E and G represenls a group

C=O  or  CH2,   and  the  other from  among  E  and  G  represents  a  group  N-R'; R'

represents a hydrogen atom or a group C1-C4-alkyl or aryi-C(O)-, the aryl group being optionally substituted with one or more groups C1-C6-alkyl;

are excluded.

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

a hydrogen atom and a halogen atom, more particularly a fluorine atom.

Among the compounds of general formula {I) that are subjects of the invention, a twenty-sixth 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 one or more halogen atoms, more particularly fluorine atoms.

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

Among the compounds of general fonmula {I) that are subjects of the invention, a twenty-eighth subgroup of compounds is constituted by the compounds for which the group

Z    Ra
zf'1

~/---Rb
4

is chosen from the groups
-cPH-co
N
H

these groups being optionatty substituted with R2 and R, as defined in the general formula (I) hereinabove.

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

twenty~ninth subgroup of compounds is constituted by the compounds for which

X1 ,  X2,  X, and X. represent, independently of each other a group C-R1;  and  R1  is

chosen from a hydrogen atom and a halogen atom, more particularly a fluorine atom;

n is equal to 1;

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

halogen atoms, more particularly nuarine atoms;

W represents an oxygen atom;

the group

~~-yRa

~z)l-...Rb
4

is chosen from the groups these groups being optionatty substituted with R2 and R, as defined in the general fonmula (I) hereinabove.

Among the compounds of general fonmula (I) that are subjects of the invention, mention
 
may be made especially of the following compounds: N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-(3-fluorobenzyi)-

1H-indole-2-carboxamide

2    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-(3-fluorobenzyl)-1 H-indole-2-

carboxamide

N-(2,3:dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-(3-fluorobenzyl)-1 H-

indole-2-carboxamide

4    N-(1 H-pyrrolo[3,2-b]pyrid-6-yl)-5-fluoro-1-(3-fluorobenzyl)-1 H-indole-2-

carboxamide

5    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[(3-melhylphenyl)melhyl]-1 H-indole-

2-carboxamide

6    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]-methyl]-1 H-indole-2-carboxamide
7    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]-methyl]-1 H-indole-2-carboxamide
8    N-(1 H-Pyrrolo[2,3-c]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl]methyl]-1 H-indole-2-

carboxamide

9    N-(1 H-Pyrrolo[2,3-b]pylid-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1 H-

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

10    N-(7-0xy-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fiuoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide

11    N-(1-Melhyl-1 H-pyrrolo[2,3-b]pynd-5-yl)-5-lrifluoromethyl-1-[(3-fiuorophenyl)-methyl]-1 H-indole-2-carboxamide
12    N-(1-Melhyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl)melhyl]-1 H-

indole-2-carboxamide

13    N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromelhyl-1-[(3-fiuorophenyl)-methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide

14    N-(1-Methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-fiuorophenyl)-methyi]-1H-indole-2-carboxamide
15    N-(1-Methyl-1 H-pyrrolo[2,3-b]pynd-5-yl)-1-[[(3-trifluoromethyl)phenyl]methyi]-1H-indole-2-carboxamide
16    N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-6-yl)-5-fiuoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide

17    N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fiuoro-1-[[(3-trifiuoromethyl)phenyl]-

methyl]-1 H-indole-2-carboxamide
 
18    N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-methylphenyl)methyl]-1 H-

indole-2-carboxamide

19    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1 H-

indole-2-carboxamide

20    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[(3-methylphenyl)methyl]-1 H-

indole-2-carboxamide

21    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(3-methylphenyl)methyl]-1 H-

indole-2-carboxamide

22    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1 H-

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

23    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(3-methylphenyl)methyl]-1 H-

indole-2-carboxamide

24    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]-methyl]-1 H-indole-2-carboxamide
25    N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]-

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

26    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]-methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide
27    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[[(3-trifluoromethyl)phenyl]methyl]-1 H-

indole-2-carboxamide

28    N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-4-yl)methyl)]-1 H-

indole-2-carboxamide

29    N-(1-Methyl'1H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-3-yl)methyl)]-1 H-

indole-2-carboxamide

30 N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide
31    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1 H-

indole-2-carboxamide

32    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1 H-

indole-2-carboxamide

33    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1 H-

indole-2-carboxamide

34    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1 H-

indole-2-carboxamide

35    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[(thiazol-2-yl)methyl]-1 H-indole-2-
 carboxamide

36    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifiuoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-

indole-2-carboxamide

37    N-(1 H-Pyrro lo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-

indole-2-carboxamide

38    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-

indole-2-carboxamide

39    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-

indole-2-carboxamide

40    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fiuoro-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamipe

41 N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifiuoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-pyrrolo[2,3-b]pyridine -2-carboxamide

42    N-(2-0xo-2,3-dihydro-1H-pyrrolo[2,3-b]pyrid-5-yl)-5-fiuoro-1-[(3-

fiuorophenyl)methyl]~ 1H-indole-2-carboxamide

43    N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyi]-1H-

indole-2-carboxamide

44    N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-1-[{3-fiuorophenyl)methyl]-1 H-

pyrrolo[2,3-c]pyridine-2-carboxamide

45    N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-1-[(3-fiuorophenyl)methyl]-1 H-pyrrolo[2,3-

c}pyridine-2-carboxamide

46    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

ca.rboxamide

47 N-(1-Methyl-1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifiuoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-carboxamide.

In the text hereinbelow, the term "leaving group" means a group that can be readily cleaved from a molecule by breaking a heterolytic band, with lass 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-to\uenesulfate,

trillate, acetate, etc. Examples of leaving groups and references for preparing them are

given in "Advances in Organic Chemist!)l'',J. March, 5th Edition, Wiley Interscience,

2001.
 
In  the  text  hereinbelow,  the  term  "protecting  group"  means  a group  that  can  be

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.

In  accordance  with  the  invention,  the  compounds  of  general  formula  (I)  may  be

prepared according to the process illustrated by the general scheme 1 below:



The compounds of general formula (I} may be obtained by reacting a compound of general formula (11}, in which X, X,, X,, X.. n, Y and W are as defined in the general formula (I) hereinabove and B corresponds to a hydroxyl group, with an amine of general formula (Ill), in which z,, z,, z,, Z.,, Ra and Rb are as defined in the general

formula {I) hereinabove and D corresponds to an amino group, in the presence of a

coupling agent such as a dialkylcarbodiimide, [(benzotriazol-1-yl)oxy][tris(pyrrolidino)]-phosphonium hexafluorophosphate, diethyl cyanophosphonate or any other coupling agent known to those skilled in the art, optionally in the presence of a base such as

triethylamine, in a solvent, for instance dimethylformamide.

The compound of general fonmula (11}, for which B represents a group C1-C6-aikoxyJ, may be converted into a compound of general fonmula (11), in which B represents a

hydroxyl group,  via  the action  of a base such as  sodium  hydroxide  or  potassium

hydroxide dissolved in a solvent such as ethanol. The compound of general formula (11) in which B represents a hydroxyl group may then be converted Into a compound of
general fonn~la (II),  in  which  8  represents  a  chlorine  atom,  via  the  action  of a

chlorinating agent such as thionyl chloride in a solvent such as dichloromethane.
 

The compounds of general formula (I) may be obtained by reacting a compound of general formula (II), in which X, x,, X,, X,, n, Y and W are as defined in the general

formula (I) hereinabove and B corresponds to a chlorine atom, with an amine of general formula (Ill), in which z,, z,, Z,, Z.,, Ra and Rb are as defined in the general

formula (I) hereinabove and D correspond to an amino group, via reaction in solution in

a solvent such as dichloromethane or toluene.

The compounds of general formula (I) may also be obtained by reacting a compound of general formula (II) in which X, x,, X,, X,, n, Y and W are as defined in the general formula (I) hereinabove and B correspond? to a group C,-C,-alkoxyl, with an amide, resulting from (Ill), in which Z1, z,, Za, Z.,, Ra and Rb are as defined in the general

formula {I) hereinabove and D corresponds to an amino group, and an organometallic reagent such as trimethylaluminium. This reaction may be performed in a solvent such as toiuene.

Starting with compounds of general formula (II), in which B represents an NH2  group,

W represents an oxygen atom and X,. X2, Xs, ~. n and Yare as defined in the general

formula (I) hereinabove, the compound of general formula (I) may be obtained by reaction with the compound of general formula (Ill), in which z, Z2, Za. Z.,, Ra and Rb

are as defined in the general formula (I) hereinabove and D corresponds to a leaving group as defined hereinabove, such as a bromine atom or a triflate group, for example
according to a method similar to that described in J.Am.Chem.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 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.

In Scheme 1, the compounds of general formula (I) and the other reagents, when their

mode of preparation is not described, are commercially available, are described in the

literature or are prepared by analogy with processes described in the literature (D. Knittel Synthesis 1985, 2, 186; T.M. Williams J. Med. Chern. 1993, 36 (9), 1291; JP2001-151 771 A2, W02006/024 776, W02006/072 736, W02007/010 144, W02007/010 138 orW02007/088 277, for example).
 
The  compounds  of general  fonmula  (Ill),  when  their  mode  of  preparation  is  not

described, are commercially available, are described in the literature or are prepared

by analogy with processes described in the literature (Tetrahedron Lett.  1987, 1589,

Synthesis 2005, 15,2503, Synthesis 2008, 2, 201, W02006/040 520).

The compounds of general formula (II) or (I), for which one from among X1,  X2,  X, and

~ corresponds to a carbon atom substituted with an alkyl group, may be obtained via a

coupling reaction, catalysed by a metal such as palladium or iron, performed on the

corresponding compounds of general fonmula (II) or (1),  substituted with a halogen

atom, such as chlorine, in the presence, for example, of an alkylmagnesium ~alide or

an alkylzinc halide, according to the methods described in the literature (A. Furstner et al., J. Am. Chern. Soc. 2002, 124(46), 13856; G. Queguiner et al., J. Org. Chern. 1998, 63(9), 2892) for example, or known to those skilled in the art.

The compounds of general fonmula (II) or (1), for which one from among X,, X2,  X, 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 (II) or (1), substituted,

for 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 fonmula (I) or (II), for which one from among X,. X2,  X3 and

X., corresponds to a carbon atom substituted with a group NR.,R5, NRaCOR7 or NRaS02Ra, may be obtained from the corresponding compounds of general formula (I) or (II), substituted, for example, with a bromine atom, via a coupling reaction with,

respectively,  an  amine,  an •amide  or a sulfonamide  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.

The compounds of general fonmula (I) or (II) substituted with a group C(O)NR.,R5 may be obtained from the corresponding compounds of general fonmula (I) or (II) 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) or (II) substituted with a group -S(O)-alkyl or -S(O),-alkyl may be obtained via oxidation of the corresponding compounds of general formula (II) or (1), substituted with a thioalkyl group, ac<;arding to methods

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

The compounds of general formula (II) or (I) substituted with a group NR.,R5, NRaCOR7 or NR,S02Ra may be obtained from the corresponding compounds of general formula (II) or (I), 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.

The compounds of general formula (II) or (I) substituted with a group S02NR.,R5 may be obtained via a method similar to that described in Pharmazie 1990, 45, 346, or

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

The compounds of general formula (I) or (II) in which W represents a sulfur atom may

be obtained, for example, by reacting the corresponding compounds of general formula

(I) or (II), in which W represents an oxygen atom, with a reagent such as Lawesson's

reagent.

The compounds of general formula (I) for which Ra corresponds to a protecting group borne by a nitrogen atom, such as an acetyl, ethoxycarbonyl or tert-butyloxycarbonyl group or a benzyloxycarbonyl group, may be deprotected, according to chemical methods known to those skilled in the art, to give compounds of general formula (I) in which Ra is a hydrogen atom.

The compounds of general formula (I), in which at least one from among z,, z,, z, and z., corresponds to an N-oxide group, may be obtained, for example, by reacting the corresponding compounds of general formula (I) in which at least one from among Z1,
Z2,   4   and  ~ corresponds  to  a  nitrogen  atom,  with  a  reagent  such  as  meta-

chloroperbenzoic acid.

The compounds of general formula (II) of Scheme 1, in which one from among X1,  X2,

X, and X. represents a group C-R1 in which R, corresponds to a group -Si-(C1-C6-alkyl)3 and B represents a group C1-C,-alkoxyl, may be obtained, for example,

2001, 123, 7727 and 2002, 124, 11684), preferably under an inert atmosphere in basic

medium, for example in the presence of potassium triphosphate, in the presence of a

copper salt such as copper iodide, optionally in the presence of an additive such as

N,N'-dimethylcyclohexane-1,2-diamine, the  whole  in  an  organic  solvent  such  as

toluene.

The compounds of general formula (VI) are prepared from aromatic or heteroaromatic

aldehydes substituted with a silyl group of general fonmula (IV), in which X1,  X2, X3 and

X. are as defined in the general fonmula (I) with one of them oorresponding to a silyl group, by reaction with an alkyl•azidoacetate of general fonmula (VII) in which B

represents a group C1-Cs-alko~l, for instance ethyl azidoacetate, in the Presence of a

base such as sodium ethoxide, in a solvent such as ethanol or methanol, to give the

alkyl 2-azidocinnamates of general fonmula M• These products are then converted into

indole or azaindole esters in a refluxing solvent, for example in xylene or toluene, by

adaptation of the protocols described in the literature (Hemetsberger et al., Monatsh. Chern., 1969, 100, 1599 and 1970, 101, 161; P. Roy et al., Synthesis., 2005, 16, 2751-2757; R. Guilard et al., J. Heterocyclic. Chern., 1981, 18, 1365-1377; W. Rees et al., J. Chern. Soc., Perkin Trans. 11984, 2189-2196; P. Molina et al., J. Org. Chern., 2003,
68(2}, 489-499; C. Moody et al., J. Chern.  Soc., Perkin  Trans.  11984, 2189-2196; J.

Sawyer et al., J. Med. Chern., 2005, 48, 893-896; D. Tanner Syn/ett 2006, 18, 3140-3144).

Alternatively, the fonmation of the compounds of general fonmula (VI) may be obtained by decomposition of the alkyl 2-azidocinnamate of general fonmula (V), in the presence
of a rhodium dimer complex, in a solvent such as toluene, at a temperature of between

25'Cand 60'C,according to an adaptation of protocols described in the literature (Tom G. Drivers et al., J. Am. Chern. Soc., 2007, 129, 7500-7501; J. Sawyer et al., J. Med. Chern., 2005, 48, 893-896).

The aromatic or heteroaromatic aldehydes substituted with a silyl group of general fonmula (IV), when they are not commercially available, may be obtained from the

corresponding aromatic or heteroaromatic aldehydes, which are preferably masked in the form of an acetal, for example, substituted with a halogen atom such as a bromine or an iodine, in the position at which the silyl group is to be introduced:
-for example by reaction with a disilane such as hexamethyldisilane, in the presence of
 
a catalytic amount of a metal complex, preferably a palladium complex, for instance

tetrakis(triphenylphosphine)palladium, without solvent or in a solvent, preferably a polar

solvent, for instance hexamethylphosphoramide, in the presence of a base such as potassium carbonate, at a temperature of between zooc and the boiling point of the

solvent  (adaptation  of  the  protocols  described  in  the  literature:  J.  Babin  et  al.,

J. Organometa/1. Chem., 1993, 446 (1-2), 135-138; E. Shirakawa et al., Chern. Cornrnun., 2000, 1895-1896; L. Goossen et al., Synlett, 2000, 1801-1803; H. Matsumoto et al., J. Organorneta/1. Chern.,1975, 85, C1; FR 2 677 358).

-for example by reaction with a disilane such as hexamethyldisilane, in the presence of

a strong base, for instance hexamethylphosphorotriamide (HMPT), at a temperature close to 20'C(adaptation of the protocols described in the literature: A. I. Meyers et al.,
J. Org. Chern., 1977, 42 (15), 2654-2655; K. lshimaru et al., Heterocycles., 2001, 55 (8), 1591-1597).

The aromatic or heteroaromatic aldehydes substituted with a silyl group of general formula (IV), when they are not commercially available, may also be obtained from the
corresponding  dihalo  aromatic  or  heteroaromatic  derivatives,  such  as  a  dibromo

derivative, in the position at which the silyl group is to be introduced, by exchange with

an  organometallic  reagent,  for  instance  n-butyllithium.  The  metallic  aromatic  or

heteroaromatic derivatives thus formed may then react with organohalosilanes or may be converted into formyl 9erivatives by adaptation of the methods described in the literature. The reaction is preferably performed at low temperatures of between -110°C and room temperature, •in a solvent such as ether or THF (adaptation of the protocols
described in the literature: Bao-Hui Ye et al., Tetrahedron., 2003, 59, 3593-3601; P. Pierrat et al., Synlett 2004, 13, 2319-2322; K.T. Warner et al., Heterocycles 2002, 58, 383; D. Deffieux et al., J. Organorneta/1. Chern., 1994, 13 (6), 2415-2422; W02005/0BO 328; S.G. Davies et al., J. Chern. Soc., Perkin Trans. 1 1991, 501; G. Queguiner et al., J. Org. Chern., 1981, 46, 4494-4497; G. Breton et al., Tetrahedron
2000, 56 (10), 1349-1360; S. De Mentis et al., Tetrahedron 2004, 60 (17), 3915-3920;

L. Buchwald et al., J. Am. Chern. Soc., 1998, 120, 4960-4976).

According to another of its aspects, a subject of the invention is also the compounds of

general fonmulae (lia), (lib), (lie), (lid), (lie), (lif), (lig) and (lih), in which Et represents an ethyl group. These compounds are useful as intenmediates for the synthesis of the compounds of formula (1).
 


                    27       
H,\,cH,        "~ J):) -f    H,C\/       
H,C~Si~Et        H,C..,SI~0£1   
I ~            ..,,IJ       
"•~        H,C-f    -d    0        o   
    0    CF~    ~:               
        '"        ""    (11,)   
H,C\ ,CH,    {tl~)        [lib)               
H~C-SI~OE\                -~,c-SI~oet   
    1-\1~0!:\ ~""'-'"       
~0    I-I,C-f   &r~    0    do   
    '" .--(           
            !,).               
    (Ita)        (Ill)            (llg}   
 






~oe•
~-~,:f    0
'""'-d--: (lid)

"~~0"
H,C-f    AN    0
~.d

(II h)
 

The esters (I Ia), (lib), (lie), (lid), (lie), (llf), (llg) and (llh) are prepared according to the

processes described in Examples 9, 10, 14, 16, 21, 38,40 and 41.

The examples that follow describe the preparation of certain compounds in accordance with the invention. These examples are not limiting, and serve merely to illustrate the
present invention. The numbers of the 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 confinm the slructures of the

compounds obtained.

Example 1 (Compound 1)

N-[1-Acetyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl]-5-fluoro-1-[(3-fluorophenyl)-

methyl]-1 H-indol~-2-carboxamide

1.1    5-Fiuoro-1-(3-fluorobenzyl)-1 H-indole-2-carboxylic acid

An aqueous sodium hydroxide solulion, 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-fiuoro-1-(3-fluorobenzyi)-1H-indole-2-carboxylate (W02006/024 776) in 241 ml

of ethanol. The mixture is heated for 2 hours and then concentrated under reduced

pressure. The resulting solid is taken up in 200 ml of water. The solution is washed wilh 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 so•c under reduced pressure, 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    1-Acetyl-5-amino-2.3-dihydro-1 H-pyrrolo[2,3-b]pyridine

A suspension of 0.43 g (2.08 mmol) of 1-acelyl-2,3-dihydro-5-nitro-1H-pyrrolo[2,3-b]pyridine (Tetrahedron LeN. 1987, 1589) and 0.044 g of 10% palladium-on-charcoal in

15 ml  of ethanol  is  stirred  vigorously for 6  hours  at  room  temperature  and  under

5 atmospheres of hydrogen. After this time, the suspension is filtered through Celite

and the filtrate is concentrated under reduced pressure to give 0.24 g of the expected

product in the form of a solid. m.p. = 193 -195°C

1H NMR (DMSO-D6), 5 ppm: 7.5 (s, 1H); 6.93 (s, 1 H); 5 (s, 2H); 3.91 (dxd, 2H); 2.95 (dxd, 2H); 2.49 (s, 3H).

1.3    N-[1-Acetyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl]-5-fluoro-1-(3-fluorobenzyl)-

1H-indole-2-carboxamide (Compound 1)

To a solution, stirred at 20°C, of 0.28 g (0.97 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1 H-indole-2-carboxylic acid prepared in step 1.1, 186 mg (0.97 mmol) of N-(3-dimethylaminopropyi)-N'-ethylcarbodiimide hydrochloride (EDAC) and 131 mg (0.97 mmol) of 1-hydroxybenzotriazole (HOBT) in 15 mL of DMF are added 206 mg (1.17 mmol) of 1-acetyl-5-amino-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, prepared in step

1.2. The reaction mixture is stirred for 14 hours at 20"C and then concentrated under

reduced  pressure.  The  resulting  product  is  taken  up  in  100 mL  of  water.  The

suspension is then extracted with three times 30 mL of ethyl acetate. The combined

organic phases are washed twice with 20 mL of water, dried over sodium sulfate and

then  concentrated  under  reduced  pressure.  The  product  obtained  is  purified  by

chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 290 mg of the expected product are thus isolated.

m.p. = 186-188°C

1H NMR (DMSO-Da), o ppm: 8.4 (s, 1H); 8.07 (s, 1H); 7.6 (m, 1H); 7.56 (m, 1H); 7.43 (s, 1H); 7.33 (m, 1H); 7.19 (m, 1H); 7.08 (m, 1H); 6.90 (m, 2H); 5.9 (s, 2H); 4.05 (dxd, 2H); 3.12 (dxd, 2H); 2.51 (s, 3H).
 Example 2 {Compound 2)

N-[1 H,Pyrrolo[2,3-b]pyrid•5•yl]•5-fluoro-1-{3•fluorobenzyl)•1H•indole-2•

carboxamide.

The process is performed according to a method similar to that described in Example

1.3 starting wilh 0.4 g (1.39 mmol) of 5-fluoro-1-{3-fluorobenzyi)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.22 g {1.67 mmol) of 5-amino-1H-pyrrolo[2,3-b]pyridine

{Synthesis 2005, 15, 2503). 0.44 g of the expected product is lhus isolated in the form of a while solid.
m.p. = 266- 26rc

1H NMR {DMSO-De), B ppm: 11.55 {s, 1H); 10.37 {s, 1H); 8.45 {s, 1H); 8.31 {s, 1H); 7.6 {m, 1H); 7.53 {m, 1H); 7.45 {m, 2H); 7.3 {m, 1H); 7.17 {m, 1H); 7.05 {m, 1H); 6.92 {m, 2H); 6;45 {s, 1 H); 5.9 {s, 2H).

Example 3 (Compound 3)

N-[2,3-Dihydro-1 H-pyrrolo[2,3-b]pyrid•5•yl]-5-fluoro-1-{3-fluorobenzyl)•1H -i ndo le-

2-carboxamide.

0.62 mL {8.96 mmol) of acelyl chloride is added dropwise to a solution, stirred at O'C, of 0.2 g {0.45 mmol) of compound 1, described in slep 1.3, in 4 mL of methanol. The

reactor is then closed and the mixture is stirred for 30 minutes at 20°C and then for 16 hours at 70°C. After this time, the mixture is concentrated under reduced pressure
and then laken up in 100 mL of ethyl acetate and 50 mL of saturated sodium hydrogen

carbonate solution. The organic phase is separated out, washed with saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The resulting product is purified by chromatography on a column of silica,

eluting with a mixture of dichloromethane and methanol. 108 mg of the expected product are thus isolaled.

m.p. = 230- 232'C

1H NMR {DMSO-De), B ppm: 10.19 {s, 1H); 7.98 {s, 1H); 7.6 {s, 1H); 7.55 {m, 2H); 7.34 {m, 2H); 7.19 {m, 1H); 7.09 {m, 1H); 6.9 {m, 2H); 6.22 {s, 1H); 5.9 {s, 2H); 3.5 {dxd, 2H); 3.01 {dxd, 2H).

Example 4 {Compound 4)

N-[1H-Pyrrolo[3,2•b]pyrid•6-yl]•5•fluoro-1•{3•fluorobenzyi)•1H•indole-2-

carboxamide.
 
The process is perfonned according to a method similar to that of Example 1.3 starting

with 0.4 g (1.39 mmol) of 5-fiuoro-1-(3-fiuorobenzyi)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.22 g (1.67 mmol) of 6-amino-1H-pyrrolo[3,2-b]pyridine {Adesis). 0.22 g of the expected product is thus isolated in the form of a white solid. m.p. = 277- 278°C

1H NMR (DMS0-06), 5 ppm: 11.49 (s, 1H); 10.58 {s, 1H); 8.29 (m, 2H); 7.88 (s, 1H); 7.6 {m, 2H); 7.42 {s, 1H); 7.32 {m, 1H); 7.1 (m, 3H); 6.94 {m, 2H); 5.91 (s, 2H).

Example 5 (Compound 36)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yt)-5-trifluoromethyl-1-[(pyrid-4-yt)methyt)]-1 H-indole-

2-carboxamide

5.1    Ethyl 5-trifiuoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-carboxylate

To a solution of 333 mg (1.29 mmol) of ethyl 5-trifluoromethyi-1H-indole-2-carboxylate

in 5 mL of dry toluene, maintained  under an inert atmosphere, are added,  at room

temperature,  283 mg (2.59 mmol) of 4-pyridylmethanol and 0.92 g (3.826 mmol) of

(cyanomethylene)tributylphosphorane (CMBP). The reaction mixture is stirred at 11ooc

for 15 hours and then concentrated  to dryness. The crude reaction  product is then

purified by nash chromatography on a column of silica gel, eluting with a mixture of heptane and ethyl acetate to give 386 mg of the expected ethyl 5-trifiuoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-carboxylate in the form of a white solid.

1H NMR (DMSO Da), 5 (ppm): 8.46 {d, 2H); 8.22 {s, 1H); 7.80 {d, 1H); 7.62 (d, 1H); 7.58 (s, 1H); 6.93 {d, 2H); 5.95 (s, 2H); 4.28 (q, 2H); 1.26 {t, 3H).

LC-MS: 349 [M+Ht

5.2    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifiuoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-

indole-2-carboxamide

To a solution of 150 mg (0.43 mmol) of ethyl 5-trifiuoromethyl-1-[(pyrid-4-yl)methyl)]-1H-indole-2-carboxylate, obtained according to the protocol described in the preceding step, and 69 mg (0.52 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in 1.5 ml of dry toluene,
maintained    under  an  inert  atmosphere,  is  added   dropwise,  at  0°C,  0.32 mL

(0.645 mmol) of a solution of trimethylaluminium (2M/toluene). The reaction mixture is stirred at 110°C for 15 hours and then concentrated under reduced pressure. The crude reaction product is then diluted with 50 ml of normal HCJ solution and 100 ml of

ethyl acetate. The organic phase is separated out, washed with 50 ml of saturated

sodium chloride solution and then dried over sodium sulfate and concentrated under

reduced pressure. The resulting product is purified by chromatography on a column of silica.147 mg of the expected product are thus isolated.

1H NMR (DMSO D6), 8 (ppm): 11.62 (s, 1H); 10.62 (s, 1H); 8.47 (d, 2H); 8.42 (s, 1H), 8.29-8.24 (m, 2H); 7.76 (d, 1H); 7.66 (s, 1H); 7.58 (dd, 1H); 7.46 (t, 1H); 7.03 (d, 2H); 6.45-6.43 (m, 1H); 6.00 (s, 2H).

LC-MS: 436 [M+H]' m.p. = 216 - 217'C

Example 6 •(Compound 5)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[(3-methylphenyl)methyl]-1 H-indole-2-

carboxamide

6.1    Methyl 5-fluoro-1-((3-methylphenyl)methyl]-1 H-indole-2-carboxylate

This  compound  is  prepared,  according  to  a  process  similar  to  that  described  in

Example 5.1, by reacting 475 mg (2.459 mmol) of methyl. 6-fluoro-1H-indole-2-carboxylate with 0.59 ml (4.918 mmol) of 3-methylphenylmethanol in the presence of 0.92 g (3.826 mmol) of (cyanomethylene)tributylphosphorane (CMBP). The resulting crude mixture is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate to give 539 mg of the expected product in the

fonn of a colourless oil.

1H NMR (DMSO D6),  8 (ppm): 7.76 (dd, 1H); 7.46 (dd, 1H); 7.40 (s, 1H); 7.14 (!.1 H);

7.06-6.99 (m, 2H); 6.89 (s, 1H); 6.75 (d, 1H); 5.78 (s, 2H); 3.81 (s, 3H); 2.21(s, 3H). LC-MS: 298 [M+H]'

6.2    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-methylphenyl)methyl]-1 H-indole-

2- carboxamide (Compound 5).

Compound 5 was prepared according to a process similar to that described in step 5.2

by reacting 200 mg (0.673 mmol) of methyl 5-fluoro-1-[(3-methylphenyl)methyi]-1H-indole-2-carboxylate prepared according to the protocol described in step 6.1 with 107 mg (0.807 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.5 ml (1.01 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give 107 mg of the expected product.

1H NMR (DMSO D,), 8 (ppm): 11.61 (s, 1H); 10.45 (s, 1H); 8.44 (d, 1H); 8.32 (d, 1H);
 
7.76 (dd, 1H); 7.47-7.42 (m, 3H); 7.14 (t, 1H); 7.05-6.98 (m, 3H); 6.86 (d, 1H); 6.45 (m, 1 H); 5.82 (s, 2H); 2.20 (s, 3H).
m.p. = 310-311oC

Example 7 (Compound 30)

N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyi]-1H-

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

7.1    Ethyl    5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-
carboxylate   

This compound was prepared according to a process similar to that described in step

5.1. by reacting 390 mg (1.51 mmol) of ethyl 5-trifluoromethyi-1H-pyrrolo[2,3-b]pylidine-2-carboxylate (W02008/1 07 543) with 348 mg (3.02 mmol) of thiazol-2-ylmethanol in the presence of 0.92 g (3.826 mmol) of (cyanomethylene)-tributylphosphorane (CMBP). The reaction mixture is then purified by flash

chromatography on a column of silica gel in a mixture of heptane and ethyl acetate to

give 446 mg of the expected product in the form of an oil.

1H NMR (DMSO Da), o(ppm): 8.84 (s, 1H); 8.69 (s, 1H); 7.67 (d, 1H), 7.60 (d, 1H), 7.54 (s, 1H); 6.22 (s, 2H); 4.32 (q, 2H); 1.28 (t, 3H).
LC-MS: 356 [M+H]'

7.2    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1 H-

pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 30)

Compound 30 was prepared according to a process similar to that described in step

5.1 by reacting 186 mg (0.523 mmol) of ethyl5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate prepared according to the protocol described in step 7.1 with 84 mg (0.628 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.39 ml (0.785 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give 144 mg of expected product.

1H NMR (DMSO D,), o (ppm): 11.70 (s, 1H); 10.76 (s, 1H); 8.81-8.76 (m, 2H); 8.47 (s, 1H); 8.35 (s, 1H); 7.67-7.58 (m, 3H); 7.50-7.49 (m, 1H); 6.49-6.47 (m, 1H); 6.29 (s, 2H). LC-MS: 443 [M+H]'

m.p. = 274- 275°C

Example 8 (Compound 37)
 
N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-

2•carboxamide

8.1    Methyl 6-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-carboxylate

This compound was prepared according to a process similar to that described in step

5.1 by .reacting 500 mg (2.056 mmol) of methyl 6-trifluoromethyi-1H-indole-2-carboxylate with 44g mg (4.11 mmol) of 4-pyridylmethanol in the •presence of o.g2 g (3.826 mmol) of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate to give 407 mg of the expected product in the form of a beige-coloured solid.

1H NMR (DMSO Da), 6 (ppm): 8.46 (d, 2H); 8.og (s, 1H); 7,gg {d, 1H); 7.54 (s, 1H), 7.46 (d, 1 H); 6.go (d, 2H); 6.00 (s, 2H); 3.82 {s, 3H).

LC-MS: 335 [M+H]'

8.2    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-

indole-2-carboxamide (Compound 37).

Compound 37 was prepared according to a process similar to that described in step

5.2 by reacting 150 mg (0.44g mmol) of methyl 6-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1H-indole-2-carboxylate prepared in the preceding step with 72 mg (0.538 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.34 ml (0.674 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give gg mg of expected product.
1H NMR (DMSO 0,), 6 {ppm): 11.71 (s, 1H); 10.72 {s, 1H); 8.77 {d, 2H); 8.45 (d, 1H),

8.30    {d, 1H); 8.12 (s, 1H); 8.06 {d, 1H); 7.76 (s, 1H); 7.52-7.47 {m, 4H); 6.45 (m, 1H);

6.23    (s, 2H).

LC-MS: 436 [M+Hj' m.p. = 311- 313°C

Example 9 (Compound 6)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)•6-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]•

methyi]-1H-indole-2-carboxamide

9.1    Etliyl 2-azido-3-(4-trimethylsilylphenyl)propenoate

1.26    g (54,g6 mmol) of sodium and 30 ml of anhydrous ethanol are introduced into a
 
100 ml round-bottomed flask, equipped with a magnetic stirrer and maintained under a

nitrogen  atmosphere.  The  reaction  mixture  is  stirred  at  room  temperature  until  a

homogeneous solution is obtained. To this solution, cooled to -10°C, is added dropwise

a solution containing 16.83 ml (54.96 mmol) of ethyl azidoacetate (34% in CH2CI 2) and

5 g  (27.48 mmol) of 4-trimethylsilylbenzaldehyde  in  5 ml of ethanol. The  reaction

mixture is then stirred at ooc for 4 hours. The reaction medium is hydrolysed by adding, with vigorous stirring, 100 ml of ammonium chloride solution (30% aqueous). The product is extracted with thr:ee times 50 ml of ethyl acetate. The combined organic phases are washed with twice 20 ml of water, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica gel, eluting with a mixture of heptane and dichloromethane. 4.96 g

of the expected product are isolated in the fonm of a yellow oil.

1H NMR (DMSO D0), 1i (ppm): 7.6 (d, 2H); 7.35 (d, 2H); 6.7 (s, 1H); 4.1 (q, 2H); 1.1 (t, 3H); 0 (s, 9H).

9.2    Ethyl 6-trimethylsilyl-1 H-indole-2-carboxylate

To a solution of 1.0 g (3.14 mmol) of ethyl 2-azido-3-(4-trimethylsilylphenyl)propenoate obtained in the preceding step, in 20 ml of dry toluene, maintained under an inert atmosphere, is added 0.17 g (0.16 mmol) of dirhodium (II) heptafiuorobutyrate dimer
complex. The reaction mixture is then stirred for 12 hours at 70°C. After cooling to

room temperature, the reaction mixture is filtered through silica gel, eluting with ethyl

acetate.  The  filtrate  is  then  concentrated  under reduced  pressure.  The  residue  is

purified by chromatography on a column of silica gel, eluting with a mixture of heptane and dichloromethane. 0.61 g of the expected product is isolated in the form of a beige-

coloured powder.

m.p. = 127-129'C

1H NMR (DMSO D0), 1i (ppm): 11.7 (s, 1H); 7.41 (dd, 1H); 7.39 (d, 1H); 6.97 (dd, 1H); 6.88 (d, 1 H); 4.1 (q, 2H); 1.1 (t, 3H); 0.0 (s, 9H).

9.3    Ethyl    6-trimethylsilyl-1-[[(3-trifiuoromethyl)phenyl]methyl]-1 H-indole-2-

carboxylate (Compound lib)

This compound was prepared according to a process similar to that described in step

5.1 by reacting 500 mg (1.913 mmol) of ethyl 6-trimethylsilyi-1H-indole-2-carboxylate

with 0.52 ml (3.826 mmol) of 3-(trifiuoromethyl)phenylmethanol in the presence of 0.92

g (3.826 mmol) of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction
 
product is then purified by flash chromatography on a column of silica gel in a mixture

of heptane and ethyl acetate to give 720 mg of the expected product.

1H NMR (DMSO 0 6), 5 (ppm): 7.49-7.45 (m, 2H); 7.36-7.33 (m, 2H); 7.25 (t, 1H); 7.12 (s, 1 H); 7.04-7.00 (m, 2H); 5.73 (s, 2H); 4.04 (q, 2H); 1.03 (t, 3H); 0.00 (s, 9H).
LC-MS: 420 [M+H]+

9.4    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]-

methyi]-1H-indole-2- carboxamide (Compound 6).

Compound 6 was prepared according to a process similar to that described in step 5.2

by reacting 200 mg (0.477 mmol) of ethyl 6-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]-methyi]-1H-indole-2-carboxylate prepared according to the protocol described in the preceding step with 76 mg (0.572 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.36 mL (0.716 mmol) of a solution of trimethylaluminium (2M/toluene).
The product is isolated by purification by flash chromatography on a column of silica

gel in a mixture of heptane and ethyl acetate. 163 mg of expected product are obtained.

1H NMR (DMSO D,), 5 (ppm): 11.60 (s, 1H); 10.49 (s, 1H); 8.45 (d, 1H); 8.32 (d, 1 H); 7.74-7.68 (m, 3H); 7.51-7.43 (m, 5H); 7.28 (d, 1H); 7.45-7.44 (m, 1H); 6.01 (s, 2H); 0.25 (s, 9H).

LC-MS: 507 [M+Hj'

m.p. = 251 -  252°C

Example 10 (Compound 7)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)•5-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]-

methyi]-1H-indole-2-carboxamide

1 0.1   1-Bromo-3-trimethylsilylbenzene

To a solution of 10 g (42.39 mmol) of 1,3-dibromobenzene in 80 mL of anhydrous Et20,

cooled to -78°C and maintained under a nitrogen atmosphere, are added dropwise with

stirring, over 30 minutes, 26.49 mL (42.39 mmol) of a solution of BuLi (1.5M/hexane).

After stirring for a further 30 minutes at -78°C, 5.96 mL (46.63 mmol) of TMSCI are

added dropwise to the reaction mixture. Stirring is maintained at this temperature for 90

minutes and the reaction mixture is then hydrolysed by adding 15 mL of water. The product is extracted with ethyl acetate (3 x 50 mL). The combined organic phases are washed with saturated aqueous NaCI solution (2 x 25 mL), dried over Na2S04 , filtered
 
and  evaporated  under reduced  pressure. The crude  reaction  product is  purified by

chromatography on a column of silica gel, eluting with heptane, to give 9.3 g of the expected 1-bromo-3-trimethylsilylbenzene, in the form of a colourless oil.

1H NMR (DMSO D,), B (ppm): 5.75 (s, 1H), 7.46 (m, 1H), 7.4 (m, 1H), 7.22 (t, 1H), 0.2 (s, 9H).

10.2    3-Trimethylsilylbenzaldehyde

To a solution of 5 g (21.89 mmol) of 1-bromo-3-trimethylsilylbenzene prepared according to the protocol described in the preceding step, in 40 mL of anhydrous Et20, cooled to aoc and maintained under a nitrogen atmosphere, are added dropwis.e, with
stirring and over 30 minutes, 16.36 mL (26.18 mmol) of BuLi (1.6M/hexane). Stirring is

continued at ooc for a further 30 minutes, and the mixture is then maintained at room

temperature  for 90  minutes. 2.69 mL (34.91 mmol) of DMF, diluted  with  17 mL of

anhydrous Et20, are then introduced into the reaction mixture. After stirring for 3 hours at room temperature, the reaction mixture is hydrolysed at aoc by successive addition

of 10 mL of concentrated HCI solution and 100 mL of water. The product is extracted

with 3 x 50 mL of CH,CI,. The combined organic phases are washed with 100 mL of ,

water, drted over Na2S04, filtered and evaporated under reduced pressure. The crude

reaction product is purified by flash chromatography on a column of silica gel, eluting with a gradient of from 10 to 20% of CH,CI, in heptane to give 1.82 g of the expected 3-trimethylsilylbenzaldehyde in the form of a yellow oil.

1H NMR (DMSO D,), B (ppm): 10.01 (s, 1H); 8.0 (s, 1H); 7.85 (d, 1H); 7.8 (d, 1H); 7.5 (dd, 1 H) 0.3 (s, 9H)

10.3    Ethyl 2-azido-3-(3-trimethylsilylphenyl)propenoate

To a solution of 2 g (87.5 mmol) of sodium in 30 mL of anhydrous EtOH, maintained

under a nitrogen atmosphere and cooled to -10°C, is added, dropwise, a mixture of

31.4 mL (87.5 mmol) of ethyl azidoacetate (at 34% in CH,CI2) and 3.9 g (21.87 mmol) of 3-trimethylsilylbenzaldehyde prepared according to the procedure described in the preceding step, diluted with 3 mL of EtOH. The reaction mixture is stirred at O'Cfor 4 hours. It is then hydrolysed by adding, with vigorous stirring, 100 mL of aqueous NH4CI solution (30%). The aqueous phase is extracted with 3 x 50 mL of EtOAc. The

combined organic phases are washed with water, dried over Na2S04 ~nd concentrated

under reduced pressure. The crude reaction product is purified by chromatography on

a column of silica gel, eluting with an isocratic mixture of heptane and CH2Ct, (80/20).
 
1. 7  g  of  the  expected  ethyl  2-azido-3-(3-trimethylsilylphenyl)propenoate  are  thus

isolated in the form of a yellow oil.

1H NMR (OMSO 0,), B (ppm): 7.9 (d, 1H); 7.8 (s, 1H); 7.4 (d, 1H); 7.3 (dd, 1H); 6.9 (s, 1H); 4.2 (q, 2H); 1.2 (t, 3H); 0.15 (s, 9H)

MS: [MHt = 289

10.4    Ethyl 5-trimethylsilyi-1H-indole-2-carboxylate

To a solution of 1.7 g (5.90 mmol) of ethyl 2-azido-3-(3-trtmethylsilylphenyl)propenoate prepared according to the procedure described in the preceding step, in 25 mL of dry toluene, maintained under an inert atmosphere, is added 0.62 g (0.59 mmol) of dirhodium (II) heptafluorobutyrate dimer complex. The reaction mixture is stirred for 7 hours at 40°C. A second portion of 0.62 g (0.59 mmol) of dirhodium (II)

heptafluorobutyrate dimer complex is added to the reaction mixture while maintaining

the stirring and heating at 40°C for a further 1 hour. After cooling to room temperature, the reaction mixture is filtered through silica gel, eluting with toluene. The filtrate is then

concentrated under reduced pressure. The greenish solid obtained is triturated several

times in a minimum amount of heptane, until a white powder is obtained. This powder

is dried under reduced pressure to give 0.87 g of the expected ethyl 5-trimethylsilyl-1 H-indole-2-carboxylate in the form of a white powder.

m.p. = 114-115oc

1H NMR (OMSO 0,), B (ppm): 7.7 (s, 1H);7.35 (d, 1H); 7.25 (d, 1H); 7.0 (s, 1H); 4.2 (q, 2H); 1.2 (t, 3H); 0,15 (s, 9H)
LC-MS: [MHr = 260

10.5    Ethyl    5-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]methyl]-1 H-indole-2-

carboxylate (Compound lla)

This compound was prepared according to a process similar to that described in step

5.1 by reacting 0.49 g (1.87 mmol) of ethyl 5-trimethylsilyl-1H-indole-2-carboxylate with 0.51 mL (3.749 mmol) of 3-(trinuoromethyl)phenylmethanol in the presence of 0.9 g (3.749 mmol) of (cyanomethylene)trtbutylphosphorane (CMBP). The crude reaction product is then purified by flash chromatography on a column of silica gel in a mixture of heptane and ethyl acetate to give 730 mg of the expected product:

1H NMR (DMSO D,), B (ppm): 7.90 (s, 1H); 7.62-7.57 (m, 2H); 7.51-7.43 (m, 3H); 7.40 (s, 1H); 7.17 (d, 1H); 5.92 (s, 2H); 4.28 (q, 2H); 1.26 (t, 3H); 0.27 (s, 9H).

LC-MS: 420 ([M+Ht
 
1 0.6    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)•5-trimethylsilyl-1-[[(3•trinuoromethyl)phenyl]-

methyi]-1H-indole-2-carboxamide (Compound 7)

Compound 7 was prepared according to a process similar to that described in step 5.2

by reacting 200 mg (0.477 mmol) of ethyl 5-trimethylsilyl-1•[[(3-trinuoromethyl)phenyl]-methyl]-1 H-indole-2-carboxylate, prepared according to the protocol described in step 10.5, with 76 mg (0.572 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.36 ml (0.716 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give 107 mg of the expected product.

1H NMR (DMSO 0 6), 5 (ppm): 11.51 (s, 1H); 10.38 (s, 1H); 8.34 (d, 1H); 8.21 (d, 1H); 7.80 (s, 1H); 7.51-7._41 (m, 3H); 7.38-7.30 (m, 4H); 7.26-7.23 (m, 1H); 6.36-6.34 (m, 1 H); 5.87 (s, 2H); 0.19 (s, 9H).

LC-MS: 507 ([M+H]' m.p. = 199- 20o•c

Example 11 (Compound 42)

N-(2-0xo-2,3-dihy~ro-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5•fluoro-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide

11.1    5-Fiuoro-1-[(3-nuorophenyl)methyl]-1 H-indole-2-carboxylic acid chloride

This product is prepared by renuxing for 3 hours a solution of 10 g (34.81 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-carboxylic acid, prepared in step 1.1, and 25.4 ml (0.348 mol) of sulfonyl chloride in 174 ml oftoluene. After this time, the

reaction  mixture  is  concentrated  under  reduced  pressure.  The  resulting  mixture  is

taken up twice successively in 100 ml of toluene and then concentrated under reduced

pressu~e. The product is used in the rest of the synthesis without a further purification

step.

11.2 N-(2-0xo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl)-methyl]-1 H-indole-2-carboxamide (Compound 42)

A solution of 1.3 g (4.25 mmol) of 5-fluoro-1-[(3-nu.orophenyl)methyi]-1H-indole-2-carboxylic acid chloride, prepared in the preceding step, 2.1 ml (14.9 mmol) of triethylamine and 1.45 (4.68 mmol) of 5-amino-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine dihydrobromide (US 2005/256 125) in 42.5 ml of dichloromethane is stirred for 24 hours at room temperature. After this time, the mixture is poured into 200 mL of


water. 100 mL of dichloramethane are added and the organic phase is then separated

out, washed with twice 50 ml of water and concentrated under reduced pressure. The

product obtained is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and dichloromethane. The product thus purified is taken up in 100 ml of hot methanol, and the resulting suspension is filtered. The filtrate is concentrated under reduced pressure, thus allowing 0.4 g of the expected product to be isolated.
m.p. = 272- 275'C

1H NMR (DMS0-06), 5 ppm: 10.94 (s, 1H); 10.49 (s, 1H); 8.32 (s, 1H); 7.95 (s, 1H); 7.6 (m, 1H); 7.55 (m, 1H); 7.41 (s, 1H); 7.31 (m, 1H); 7.17 (m, 1H); 7.05 (m, 1H); 6.9 (m, 2H); 5.9 (s, 2H); 3.58 (s, 2H).

Example 12 (Compound 19)

N-(1 H-Pyrrolo[2,3-b]pyrid•5-yl)-5•trifluoromethyl-1-[(3•methylphenyl)methyl]•1H•

indole-2-carboxamide

This  compound  was  prepared  according  to  a  protocol  similar to  that described  in

Example 5.

m.p.: 311-312'C

1H NMR (DMSO 06), S (ppm): 11.6 (s, 1H); 10.6 (s, 1H); 8.5 (s, 1H); 8.35 (s, 1H); 8.2 (s, 1H); 7.8 (d, 1H); 7.55 (m, 2H); 7.5 (m, 1H); 7.15 (t, 1H); 7.0 (m, 2H); 6.9 (d, 1H); 6.5 (d, 1 H); 5.9 (s, 2H); 2.2 (s, 3H).

Example 13 (Compound 20)

N-(1 H-Pyrrolo[2,3-b]pyrid•5-yl)•6•trifluoromethyl-1-[(3•methylphenyl)methyl]•1H•

indole-2-carboxamide

This  compound  was  prepared  according  to  a protocol similar to  that described  in

Example 5.

m.p.: 278-279'C

1H NMR (DMSO 06), S (ppm): 11.7 (s, 1H); 10.6 (s, 1H); 8.5 (s, 1H); 8.4 (s, 1H); 8.05 (s, 1H); 7.95 (d, 1H); 7.50 (m, 2H); 7.45 (d, 1H); 7.15 (t, 1H); 7.05 (d, 1H); 7.0 (s, 1H); 6.9 (d, 1H); 6.5 (s, 1H); 5.95 (s, 2H); 2.2 (s, 3H).

Example 14 (Compound 21)

N-(1H•Pyrrolo[2,3•b]pyrid-5•yl)•5-trimethylsilyl-1•[(3•methylphenyl)methyi]-1H•

indole-2-carboxamide
 16.1    Ethyl    6-trimethylsilyl-1-[(3-methylphenyl)methyl]-1 H-indole-2-carboxylate

(Compound lid)

This compound was prepared according to a process similar to that described in step

5.1 by reacting ethyl6-trimethylsilyi-1H-indole-2-carboxylate prepared according to the process described in step 9.2 with (3-methylphenyl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by fiash chromatography on a column of silica gel to give the expected product.

1H NMR (DMSO D6), B (ppm): 7.71-7.68 (m, 2H); 7.33 (s, 1H); 7.24-7.21 (m, 1 H); 7.14-7.11 (m, 2H); 7.09-7.0 (m; 1H); 6.81-6.79 (m, 1H); 5.85 (s, 2H); 4.30 (q, 2 H); 2.21 (s, 3H); 1.17 (t, 3H), 0.25 (s, 9H).

16.2    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-((3-methylphenyl)methyl]-1 H-

indole-2-carboxamide (Compound 23)

This  compound  was  prepared  according  to  a protocol  similar to  that described  in

Example 5.

m.p.: 202-203°C

'HNMR (DMSO D6 ), B (ppm): 11.6 (s, 1H); 10.45 (s, 1H); 8.5 (s, 1H); 8.35 (s, 1H); 7.7 (m, 2H); 7.5 (d, 1H); 7.35 (m, 1H); 7.25 (d, 1H); 7.15 (t, 1H); 7.1 (s, 1H); 7.0 (d, 1H); 6.95 (d, 1H); 6.45 (s, 1H); 5.9 (s, 2H); 2.2 (s, 3H); 0.25 (s, 9H).

Example 17 (Compound 24)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5•1rifluoromethyl•1•[((3•1rifluoromethyl)phenyl]•

methyl)-1 H-indole-2-carboxamide

This  compound  was  prepared  according  to  a protocol  similar to  that described  in

Example 5.

m.p.: 247-248°C

1H NMR (DMSO D6), B (ppm): 11.65 (s, 1H); 10.7 (s, 1H); 8.5 (s, 1H); 8.35 (s, 1H); 8.25 (s, 1H); 7.9 (d, 1H); 7.7-7.5 (m, 6H); 7.4 (m, 1H); 6.5 (m, 1H); 6.1 (s, 2H).

Example 18 (Compound 25)

N-(1 H-Pyrrolo[2,3-b)pyrid-5•y•l)•6•1rifluoromethyl-1•[[(3-trifluoromethyl)phenyl)•

methyl)-1 H•indole-2-carboxamide

This  compqund  was  prepared  according  to a protocol similar to  that described  in

Example 5.

m.p.: 334-335°C
 
1H NMR (DMSO D,), o (ppm): 11.6 (s,1H); 10.6 (s, 1H); 8.49 (s, 1H); 8.30 (s. 1H); 8.1 (s,1H); 8.0 (d,1H); 7.6-7.4 (m, 6H); 7.35 (m,1H); 6.45 (m,1H); 6.1 (s, 2H).

Example 19 (Compound 26)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]-

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

This  com.pound was  prepared  according  to a protocol  similar to  that described  in

Example 5.

m.p.: 273-274oC

1H NMR (DMSO D,), o (ppm): 11.65 (s, 1H); 10.7 (s, 1H); 8.85 (s, 1H); 8.75 (s, 1H); 8.45 (s,1H); 8.3 (s,1H); 7.65-7.35 (m, 6H); 6.5 (m,1H); 6.1 (s. 2H).

Example 20 (Compound 27)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[[(3-trifluoromethyl)phenyl]methyl]-1 H-

indole~2-carboXamide

This  compound  was  prepared  according  to a protocol similar to  that described  in

Example 5.

m.p.: 288-289°C

1H NMR (DMSO D6), o (ppm): 11.6 (s,1H); 10.45 (s,1H); 8.45 (d,1H); 8.25 (d,1H); 7.8 (m,1H); 7.65-7.45 (m, 6H); 7.35 (m,1H); 7.05 (m,1H); 6.45 (m,1H); 5.95 (s. 2H).

Example 21 (Compound 31)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1 H-indole-

2-carboxamide

21.1    Ethyl    6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1 H-indole-2-carboxylate

(Compound llf)

This compound was prepared according to a process similar to that described in step

5.1 by reacting ethyl6-trimethylsilyi-1H-indole-2-cerboxylate prepared according to the process described in step 9.2 with (thienyl-2-yl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by fiash chromatography on a column of silice gel to give the expected product.

1H NMR (DMSO D6), o (ppm): 7.76 (s, 1H); 7.65-7.61 (m, 2H); 7.52 (d, 1H); 7.28 (s, 1H); 7.22 (s,1H); 6.09 (s, 2H); 4.23 (q, 2H); 1.22 (t, 3H); 0.2 (s, 9H).
 
21.2    N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1 H-indole-

2-carboxamide (Compound 31)

This  compound  was  prepared  according  to  a  protocol  similar to  that  described  in

Example 5.

m.p.: 269-270'C

1H NMR (DMSO 0 6), 8 (ppm): 11.6 (s, 1H); 10.45 (s, 1H); 8.45 (d, 1H); 8.35 (d, 1H); 7.85 (s, 1H); 7.75 (m, 2H); 7.6 (d, 1H); 7.45 (m, 2H); 7.3 (d, 1H); 6.45 (m, 1H); 6.2 (s, 2H); 0.3 (s, 9H).

Example 22 (Compound 41)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl)]•1H-

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

This  compound  was  prepared  according  to  a  protocol  similar to  that described  in

Example 5.

m.p.: 296-298'C

1H NMR (DMSO 0 6), 8 (ppm): 8.8 (d, 2H); 8.6 (d, 2H); 8.4 (s, 1H); 8.30 (s, 1H); 7.75 (s, 1H); 7.5 (m, 1H); 7.35 (d, 2H); 6.45 (m, 1H); 6.1 (s, 2H).

Example 23 (Compound 8)

N-(1H-Pyrrolo[2,3-c]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl]methyi]-1H-indole-2-

carboxamide

This  compound  was  prepared  according  to  a  protocol  similar to  that described  in

ExampleS.

m.p.: 203-204'C

1H NMR (DMSO 0 6), 8 (ppm): 11.5 (s, 1H); 10.59 (s, 1H); 8.57 (s, 1H); 8.25 (s, 1H); 7.52 (m, 4H); 7.31 (m, 1H); 7.15 (m, 1H); 7.03 (m, 1H); 6.92 (m, 2H); 6.5 (m, 1H); 5.92 (s,2H).

Example 24 (Compound 9)

N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyi]-1H-

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

This compound was prepared according to a method similar to that of Example 1.3. m.p.: 319-320'C

•'HNMR (DMSO D,), 8 (ppm): 11.65 (s, 1H); 10.7 (s, 1H); 8.82 (s, 1H); 8.73 (s, 1H); 8.42 (s, 1H); 8.3 (s, 1H); 7.6 (s, 1H); 7.5 (s, 1H); 7.31 (m, 1H); 7.09 (m, 1H); 6.98 (m,
 
2H); 6.49 (m, .1 H); 6.01 (s, 2H).

Example 25 (Compound 10)

N-(7 -Oxy-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole~2~carboxamide

This compound was prepared by stirring for 30 hours at 20°C a mixture of 0.5 g (1.24 mol) of compound 2 (Example 2) in the presence of 0.66 g (2.74 mmol) of meta-

chloroperbenzoic acid in  130 ml of dichloromethane. After this  time,  the  mixture is

poured into 200 mL of water and 200 mL of dichloromethane. The organic phase is

separated out, washed once with  100 mL of saturated sodium hydrogen  carbonate

solution,  twice  with  100 ml  of  water,  dried  over  magnesium  sulfate  and  then

concentrated    under   reduced   pressure.   The   resulting   product   is   purified   by

chromatography on a column of silica, to give 0.13 g of expected product. m.p.: 260-263°C

1H NMR (DMSO D,), B (ppm): 12.41 (s, 1H); 10.6 (s, 1H); 8.59 (s, 1H); 8.03 (s, 1H); 7.6 (m, 2H); 7.42 (m, 2H); 7.31 (m, 1H); 7.19 (m, 1H); 7.05 (m, 1H); 6.93 (m, 2H); 6.59 (s, 1 H); 5.89 (s, 2H).

Example 26 (Compound 12)

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide

26.1    5-Fiuoro-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)methyi]-1H-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

stirred  for  2  hours  at  reflux  and  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 in water. The reaction mixture is stirred for 14 hours at 20°C. After this time, a solid is collected by filtration and triturated in 50 mL of diisopropyl ether. After filtering and drying under reduced pressure, 0.58 g of expected product is collected.

1H NMR (DMSO-D,), B 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).
 
26.2    N-[1-Methylpyrrolo[2,3-b]pyrid-5-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide (Compound 26)

0.4 g (1.4 mmol) of the amide prepared in the preceding step, 0.32 g (1.54 mmol) of 5-bromo-1-methylpyrrolo[2,3-b]pyridine (Heterocycles 2003, 60(4) 865), 0.08 g (0.42 mmol) of copper iodide, 0.39 g (2.79 mmol) of potassium carbonate and 10 ml of

dry  dioxane  are  placed  in  a  pressure  tube  equipped  with  a  magnetic  stirrer.  The

suspension is degassed, 53 mg (0.46 mmol) of trans-cyclohexane-1,2-diamine are then added, and the tube is sealed and heated at 120°C with stirring for .16 hours. After this time, 50 ml of ethyl acetate and 50 ml of water are added to the medium. The aqueous phase is separated out and then extracted with 2x30 ml of ethyl acetate. The

organic phases are combined, washed with 50 ml of water, dried over sodium sulfate and then concentrated under reduced pressure. The resulting product is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and

acetone, and then by recrystallization from isopropyl alcohol. m.p.: 203-204oC
1H NMR (DMSO D6), B (ppm): 10.51 (s, 1H); 8.51 (s, 1H); 8.36 (s, 1H); 7.59 (m, 2H); 7.55 (s,1H); 7.46 (s, 1H); 7.32 (m, 1H); 7.19 (m, 1H); 7.08 (m,1H); 6.93 (m, 2H); 6.49 (s, 1 H); 5.9 (s, 2H); 3.82 (s, 3H).

Example 27 (Compound 11)

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)-

methyi]-1H-indole-2-carboxamide

This compound was prepared according to a method similar to that of Example 26.

m.p.: 249-250°C

1H NMR (DMSO D6), B (ppm): 8.5 (s, 1H); 8.36 (s, 1H); 8.22 (s, 1H); 7.81 (m, 1H); 7.6 (m, 2H); 7.54 (s, 1H); 7.32 (m, 1H); 7.07 (m, 1H); 6.97 (m, 2H); 6.49 (s, 1H); 5.99 (s, 2H); 3.82 (s, 3H).

Example 28 (Compound 13)

N-(1-Methyi•1H-pyrrolo[2,3-b]pyrid•5•yi)-5•1rifluoromethyl•1-[(3-fluorophenyl)•

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

This compound was prepared according to a method similar to that of Example 26. m.p.: 237-238°C

1H NMR (DMSO D,), B (ppm): 10.69 (s, 1H); 8.82 (s, 1H); 8.76 (s, 1H); 8.49 (s, 1H); 8.33 (s, 1H); 7.62 (s, 1H); 7.53 (d, 1H); 7.32 (m,1H); 7.07 (m, 1H); 6.99 (m, 2H); 6.5 (d,
 
1 H); 6.00 (s, 2H); 3.82 (s, 3H).

Example 29 (Compound 14)

N-[1-Methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl]-5-fluoro-1-[(3-fluorophenyl)-

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

29.1    5-Bro'!'o-2,3-dihydro-1-methylpyrrolo[2,3-b]pyridine

To a suspension stirred at o•c, under an inert atmosphere, of 0.48 g (12.06 mmol) of

60% sodium hydride in 5 ml of dimethylformamide is added dropwise a solution of 5-

bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine  in  10 ml  of  dimethylforrnamide.  The

mixture is stirred at ooc for 15 minutes and then at 20°C for 45 minutes. A solution of

0.77 ml (12.06 mmol) of methyl iodide in 5 ml of dimethylforrnamide is then added to this stirred suspension at ooc. The mixture is then stirred for 48 hours. After this time,

50 ml of water and 50 ml of ethyl acetate are added to the mixture. The aqueous

phase is separated out and then extracted with 3X30 ml of ethyl acetate. The organic

phases are combined, washed  with 2x50 ml of water and then concentrated  under

reduced pressure. The resulting product is purified by chromatography on a column of

silica, eluting with a mixture of dichloromethane and methanol. 0.97 g of the expected product is thus isolated.
LC-MS: 213 [M+Ht

1H NMR (DMSO D6), B {ppm): 7.81 {s, 1H); 7.39 (s, 1H); 3.46 {t, 2H); 2.94 (t, 2H); 2.82 {s, 3H).

29.2    N-[1-Methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyrid-5-yl]-5-fluoro-1-[(3-fluorophenyl)-

methyl]-1 H-indole-2-carboxamide (Compound 14)

This compound was prepared according to a method similar to that of Example 26.

m.p.: 189-191•c

1H NMR (DMSO D6), B (ppm): 10.21 (s, 1H); 8.06 (s, 1H); 7.65 {s, 1H); 7.57 (m, 2H); 7.35 (m, 2H); 7.18 {m, 1H); ?:as (m, 1H); 6.91 (m, 2H); 5.9 {s, 2H); 3.42 (t, 2H); 2.95 {t,

2H); 2.85 {s, 3H).

Example 30 (Compound 15)

N-(1-Methyi-1H-pyrrolo[2,3-b]pyrid-5-yl)-1-[[(3-trifluoromethyl)phenyl]methyi]-1H-

indole-2-carboxamide

This compound was prepared according to a method similar to that of Example 26.
 
m.p.: 211-212oC

1H NMR (DMSO D,), B (ppm): 10.49 (s, 1H); 8.51 (s, 1H); 8.35 (s, 1H); 7.79 (d, 1H); 7.54 (m, 6H); 7.39 (m, 1H); 7.31 (m, 1H); 7.19 (m, 1H); 6.47 (s, 1H); 6.0 (s, 2H); 3.84 (s,3H).

Example 31 (Compound 28)

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-4-yl)methyl)]-1 H-indole-

2-carboxamide

This compound was prepared according to a method similar to that of Example 26.

m.p.: 176-17rc

1H NMR (DMSO D,), B (ppm): 10.51 (s, 1H); 8.7-8.4 (broad peak+ s, 3H); 8.35 (s, 1H); 7.59 (m •. 2H); 7.5 (m, 2H); 7.2 (m, 2H); 7.09 (broad peak, 1H); 6.48 (s, 1H); 5.91 (s, 2H); 3.85 (s, 3H).

Example 32 (Compound 29)

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-3-yl)methyl)]-1 H-indole-

2-carboxamide

This compound was prepared according to a method similar to that of Example 26. m.p.: 214-215°C

1H NMR (DMSO D,), B (ppm): 10.52. (s, 1H); 8.51 (s, 1H); 8.46 (s, 2H); 8.37 (s, 1H); 7.69 (m, 1H); 7.55 (m, 4H); 7.34 (m, 1H); 7.19 (m, 1H); 6.49 (s, 1H); 5.95 (s, 2H); 3.82

(s, 3H).

Example 33 (Compound 16)

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

indole-2-carboxamide

33.1    6-Bromo-1-methylpyrrolo[2,3-b]pyridine

This compound was prepared according to a method similar to lhat of Example 29.1 starting with commercial 6-bromo-1 H-pyrrolo[2,3-b]pyridine.

LC-MS: 211 [M+H]'

1H NMR (DMSO Ds), B (ppm): 7.92 (d, 1H); 7.53 (s, 1H); 7.28 (d, 1H); 6.5 (s, 1H); 3.82 (s,3H).

33.2    N-[1-Methylpyrrolo[2,3-b]pyrid-6-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-

indole-2-carboxamide (Compound 16)
 

This compound was prepared according to a method similar to that of Example 26 starting with 6-bromo-1-methylpyrrolo[2,3-b]pyridine prepared in the preceding step. m.p.: 189-191°C

'HNMR (DMSO D,), 5 (ppm): 10.8 (s, 1H); 7.99 (d, 1H); 7.81 (d, 1H); 7.59 (m, 2H); 7.53 (m, 1H); 7.45 (s, 1H); 7.32 (m, 1H); 7.18 (m, 1H); 7.05 (m, 1H); 6.91 (m, 2H); 6.49 (s, 1 H); 5.93 (s, 2H); 3.84 (s, 3H).

Example 34 (Compound 17)

N•(1-Methyi-1H-pyrrolo[2,3-b]pyrid-5-yl)•5-fluoro-1-[[(3-trifluoromethyl)phenyl]•

methyl]•1H•indole-2-carboxamide

This compound was prepared according to a method similar to that of Example 26. m.p.: 181-182°C

1H NMR (DMSO D,), B (ppm): 10.56 (s, 1H); 8.5 (s, 1H); 8.32 (s, 1H); 7.45-7.7 (m, 7H); 7.38 (m, 1H); 7.15 (m, 1H); 6.48 (s, 1H); 6.0 (s, 2H); 3.79 (s, 3H).

Example 35 (Compound 1 B)

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid•5-yl)•5•fluoro•1•[(3•methylphenyl)methyl]•1H-

indole-2-carboxamide

This compound was prepared according to a method similar to that of Example 26.

m.p.: 1B5-186°C

1H NMR (DMSO Da), B (ppm): 10.51 (s, 1H); 8.5 (s, 1H); 8.37 (s, 1H); 7.56 (m, 3H); 7.4

(s, 1H); 7.16 (m, 2H); 7.0 (m, 2H); 6.87 (m, 1H); 6.48 (s, 1H); 5.87 (s, 2H); 3.82 (s, 3H); 2.2 (s, 3H).

Example 36 (Compound 32)

N-(1 H-Pyrrolo[2,3•b]pyrid•5•yl)•5-trifluoromethyl-1•[(thiazol-2-yl)methyl]•1H-

indole-2-carboxamide

Thi~ compound  was  prepared  according  to  a  protocol  similar to  that •described  in

Example 5.

m.p.: 218-219°C

'HNMR (DMSO D6), B (ppm): 11.9 (s, 1H); 10.75 (s, 1H); 8.6 (s, 1H); 8.5 (s, 1H); 8.2 (s, 1H); 7.95 (d, 1H); 7.7 (d, 1H); 7.65 (m, 3H); 7.5 (m, 1H); 6.55 (m, 1H); 6.2 (s, 2H).
 

Example 37 (Compound 33)

N•(1H-Pyrrolo[2,3•b]pyrid-5-yl)•6•!rifluoromethyl•1•[(thiazol•2•yl)methyi]•1H•

indole-2-carboxamide

This  compound  was. prepared  according  to  a protocol  similar to  that described  in

Example 5.

m.p.: 165•166°C

1 H NMR (DMSO D6), B (ppm): 11.8 (s, 1H); 10.7 (s, 1H); 8.6 (s, 1H); 8.45 (s, 1H); 8.2 (s, 1H); 7.95 (d, 1H); 7.75 (d, 1H); 7.6 (m, 2H); 7.5 (m, 2H); 6.55 (m, 1H); 6.3 (s, 2H).

Example 38 (Compound 34)

N-(1 H•Pyrrolo(2,3-b]pyrid•5-yl)•5•trimethylsilyl•1•[(thiazol-2-yl)methyl]•1H•indole•

2-carboxamide

38.1    Ethyl    (5-trimethylsilyl-1•[(thiazol-2-yl)methyi]•1H-indole•2•carboxylate

(Compound lie)

This compound was prepared according to a process similar to that described in step

5.1 by reacting ethyl5•trimethylsilyi-1H-indole-2-carboxylate prepared according to the process described in step 10.4 with (thienyl-2-yl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by flash chromatography on a column of silica gel to give the expected product.

1H NMR (DMSO D,), B (ppm): 7.80 (s, 1H); 7.64 (d, 1H); 7.61 (d, 1H); 7.51 (d, 1H); 7.40 (d, 1 H); 7.30 (s, 1 H); 6.04 (s, 2H) 4.24 (q, 2H); 1.23 (t, 3H); 0.19 (s, 9H).

38.2    N-(1 H-Pyrrolo[2,3•b]pyrid-5-yl)•5•trimethylsilyl1-•[(thiazol-2-yl)methyl]•1H-indole•

2-carboxamide (Compound 34)

This  compound  was  prepared  according  to  a  protocol  similar to  that described  in

ExampleS. m.p.: 213•214oC
1H NMR (DMSO Do), B (ppm): 11.7 (s, 1H); 10.45 (s, 1H); 8.5 (d, 1H); 8.35 (d, 1H); 7.9 (s, 1H); 7.75-7.65 (m, 2H); 7.6 (d, 1H); 7.5•7.4 (m, 3H); 6.5 (m, 1H); 6.2 (s, 2H); 0.3 (s, 9H).

Example 39 (Compound 35)

N•(1H•Pyrrolo[2,3•b]pyrid•5-yl)•6•fluoro•1•[(thiazol•2•yl)methyl]•1H•indole•2•

carboxamide
 



50

This  compound  was  prepared  according  to  a  protocol  similar to  that  described  in

Example 5. m.p.: 255-256°C

1H NMR (DMSO D,), li (ppm): 11.6 (s, 1H); 10.45 (s, 1H); 8.45 (d, 1H); 8.35 (d, 1H); 7.75 (m, 2H); 7.65-7.45 (m, 4H); 7.05 (m, 1H); 6.45 (m, 1H); 6.2 (s, 2H).

Example 40 (Compound 38)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamide

40.1    Ethyl (6-trimethylsilyl-1-[(pyrid-2-yl)methyl]-1 H-indole-2-carboxylate (Compound

II h)

This compound was prepared according to a process similar to that described in step

5.1 by reacting ethyl 6-trimethylsilyl-1 H-indole-2-carboxylate prepared according to the process described in step 9.2 with (pyrid-2-yl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by fiash chromatography on a column of silica gel to give the expected product.
1H NMR (DMSO D,), li (ppm): 8.2 (d, 2H); 7.49 (d, 1H); 7.42 (s, 1H); 7.15 (s, 1H); 7.05 (d, 1H); 6.70 (d, 2H); 5.68 (s, 2H); 4.01 (q, 2H); 1.01 (t, 3H); 0.0 (s, 9H).

40.2 N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-carboxamide (Compound 38)

This  compound  was  prepared  according  to  a  protocol  similar to  that  described  in

Example 5.

m.p.: 235-236°C

1H NMR (DMSO D,), li (ppm): 8.45 (m, 3H); 8.30 (d, 1H); 7.75 (d, 1H); 7.65 (s, 1H); 7.5 (m, 2H); 7.3 (d, 1H); 7.0 (d, 2H); 6.45 (d, 1H); 6.0 (s, 2H); 0.25 (s, 9H).

Example 41 (Compound 39)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2•

carboxamide

41.1    Ethyl (5-trimethylsilyl-1-[(pyrid-4-yl)methyl]-1 H-indole-2-carboxylate (Compound

llg)

This compound was prepared according to a process similar to that described in step
 



51

5.1 by reacting ethyl 5-trimethylsilyi-1H-indole-2-carboxylate prepared acccrding to the process described in step 10.4 with (pyrid-2-yl)methanol in the presence of (cyanomethylene)tributylphosphorane (CMBP). The crude reaction product is then purified by fiash chromatography on a column of silica gel to give the expected product.

1H NMR (OMSO 0,), 8 (ppm): 8.37 (d, 2H), 7.83 (s, 1H), 7.47 (d, 1H), 7.37 (d, 1H), 7.34 (s, 1H), 6.84 (d, 2H), 5.80 (s, 2H), 4.18 (q, 2H), 1.18 (t, 3H), 0.19 (s, 9H).

41.2 N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-carboxamide (Compound 39)

This  compound  was  prepared  according  to  a  protocol  similar  to  that described  in

Example 5. m.p.: 279-281•c

1H NMR (OMSO 0,), 8 (ppm): 8.45 (m, 3H); 8.30 (d, 1H); 7.9 (s, 1H); 7.6-7.35 (m, 4H); 7.0 (d, 2H); 6.45 (m, 1 H); 5.9 (s, 2H); 0.3 (s, 9H).

Example 42 (Compound 40)

N-(1 H-Pyrrolo[2,3•b]pyrid-5-yl)-6-fluoro-1-[(pyrid-4-yl)methyl)]-1H-indole-2-

carboxamide

This  compound  was  prepared  according  to  a  protocol  similar to  that  described  in

Example 5.

m.p.: 284-286•c

1H NMR (OMSO 0,), 8 (ppm): 11.6 (s, 1H); 10.4 (s, 1H); 8.45 (d, 2H); 8.4 (d, 1H); 8.3 (s, 1H); 7.8 (m, 1H); 7.55 (s, 1H); 7.45 (m, 2H); 7.0 (m, 3H); 6.45 (m, 1H); 5.9 (s, 2H).

Example 43 (Compound 43)

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1 H-indole-2-

carboxamide.

This compound was prepared according to a protocol similar to that described in Example 1.3.
m.p.: 286- 287•c

1H NMR (OMSO Os), 8 (ppm): 11.61 (s, 1H); 10.62 (s, 1H); 8.47 (s, 1H); 8.35 (s, 1H); 8.21 (s, 1H); 7.82 (d, 1H); 7.6 (m, 2H); 7.5 (s, 1H); 7.33 (m, 1H); 7.08 (m, 1H); 6.98 (m, 2H); 6.48 (s, 1H); 5.98 (s, 2H).

Example 44 (Compound 44)
 



52

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid•5•yl)-1•[(3-fluorophenyl)methyl]•1H•

pyrrolo[2,3-c]pyridine-2-carboxamide.

This  compound  was  prepared  according  to  a  protocol  similar to  that  described  in

Example 26.

m.p.: 225•22rC

1H NMR (DMSO D6), o (ppm): 10.8 (s, 1 H); 9.08 (s, 1 H); 8.49 (d, 1 H); 8.38 (d, 1 H); 8.27 (d, 1H); 7.72 (d, 1H); 7.55 (d, 1H); 7.47 (s, 1H); 7.32 (m, 1H); 7.02 (m, 3H); 6.45 (m, 1H); 5.95 (s, 2H); 3.82 (s, 3H).

Example 45 (Compound 45)

N-(1 H-pyrrolo[2,3•b]pyrid•5•yl)•1•[(3•fluorophenyl)methyl]•1H-pyrrolo[2,3•

c]pyridine-2-carboxamide

This  compound  was  prepared  according  to  a  protocol  similar to  that  described  in

Example 26.

m.p.: 270-271•c

1H NMR (DMSO D,), o (ppm): 11.62 (s, 1H); 10.68 (s, 1H); 9.04 (s, 1H); 8.49 (d, 1H); 8.38 (d, 1H); 8.28 (d, 1H); 7.73 (d, 1H); 7.4 (m, 3H); 7.05 (m, 3H); 6.49 (s, 1H); 6.01 (s, 2H).

Example 46 (Compound 46)

N-(1 H-Pyrrolo[2,3-b]pyrid•5•yl)•5-fluoro•1•[(pyrid-4•yl)methyl)]•1H•indole-2-

carboxamide

This  compound  was  prepared  according  to  a  protocol  similar  to  that described  in

Example 5.

m.p.: 259-260°C

1H NMR (DMSO D,), o(ppm): 11.6 (s, 1H); 10.5 (s, 1H); 8.48 (m, 3H); 8.3 (s, 1H); 7.55 (m, 2H); 7.48 (m, 2H); 7.18 (m, 1H); 7.02 (m, 2H); 6.45 (s, 1H); 5.95 (s, 2H).

Example 47 (Compound 47)

N-(1•Methyi-1H-Pyrrolo[2,3-b]pyrid•5-yl)•5•trifluoromethyl-1•[(pyrid-4•yl)methyl)]•

1H-indole-2-carboxamide

This compound was prepared according to a protocol similar to that described in Example 5.
m.p.: 213-214•c

1H NMR (DMSO D0),  o (ppm): 10.63 (s, 1H); 8.49 (m, 3H); 8.35 (s, 1H); 8.27 (s, 1H);
 



53

7.78 (d, 1H); 7.7(s, 1H); 7.6 (d, 1H); 7.52 (d, 1H); 7.04 (m, 2H); 6.49 (s, 1H); 6.02 (s, 2H); 3.82 (s, 3H).

Table I that follows illustrales lhe chemical structures and the physical properties of a

number of examples of compounds according to the invention.

In this table:

-    the column "m.p. ('C)"indicates the melting points of the products in degrees Celsius ('C); -all the compounds are in the form of the free base,
-    W represents an oxygen atom;

-    Z2 represents a carbon atom bonded to the nitrogen atom of the amide of formula (I);

-    n is equal to 1;

-    R represents a substituent on the phenyl group;

-    UMe" corresponds to a methyl group.

            v/x,_,        H,    z,J(Ra   
                    N --(  I           
        ~ ~~•    Z~z    Rb   
            "-xrl-Nr-\~    •           
            R~        (I)           
                                       
                            Z    Ra       
No.    X1, X2, X3, X4        R    --f'J(    m.p.('C)   
                            Z,"""z•    Rb       
                                0       
1        CH, C-F, CH, CH        F    -Cb~    186-188   
                                       
                                       
 



54
                    Ra       
                           
    No.    X1, X2, X3, X4    R    i~~r_Rb    m.p.(oC)   
                    •       
    2    CH, C-F, CH, CH    F    ---cPHN    266-267   
    3    CH, C•F, CH, CH    F    -QJ    230-232   
    4    CH, C-F, CH, CH    F    ~N    277 -278   
                       
                           
                    H       
                           
    5    CH, CH, C-F, CH    Me    -cPH    310-311   
                           
    6    CH, CH, C-Si(Me)3 ,    CF3    -cPH    251-252   
        CH               
                       
                           
    7    CH, C-SI(Me),, CH,    CF3    ---cPHN    199-200   
        CH               
                       
                           
    8    CH, C-F, CH, CH    F    ~H    203-204   
                       
    9    CH, C-CF3 , CH, N    F    -cPH    319-320   
 



55

                        Z    Ra           
    No.        X1, X2, X3, X4    R    -t'J(        m.p.(°C)   
                        Zf:::,z    Rb       
                        4               
                                   
    10            CH, C-F, CH, CH    F    ~H        260-263   
                        b-               
                                       
    11            CH, C-CF3 , CH, CH    F                249-250   
                        N        Me       
                        ---cP'       
    12            CH, C-F, CH, CH    F                203-204°C   
                        N        Me       
                                       
                        ---cP'       
            13    CH, C-CF,, CH, N    F                237-238   
                        N        Me       
                        ---cP'       
    14            CH, C-F, CH, CH    F                189-191   
                        N        Me       
                        -cP'           
        15        CH, CH, CH, CH    CF3                211-212   
                        N        Me       
                        ---cP'       
    16            CH, C-F, CH, CH    F        Me    189-191   
                                   
                        >Y'       
    17            CH, C-F, CH, CH    CF3                18.1-182   
                        N        Me       
                                       
                        ---cP'       
 



56

                z(a       
No.    X1, X2, X3, X4    R    ---{'I        m.p.(°C)   
                Z,""'z4    Rb       
18        CH, C-F, CH, CH    Me    -c)),    185-186   
                       
                N    Me       
                       
19        CH, C-CF,, CH, CH    Me    -cPH    311-312   
20        CH, CH, C-CF,, CH    Me    -cPHN    278-279   
21        CH, C-Si(Me),. CH,    Me    -cPH    327-328   
        CH               
                       
                       
22        CH, C-CF3 , CH, N    Me    -cPHN    305-306   
23        CH, CH, C-Si(Me),,    Me    -cPHN    202-203   
        CH               
                       
                       
                       
24        CH, C-CF,, CH, CH    CF,    -cPHN    247-248   
25        CH, CH, C-CF3, CH    CF3    -cPH    334-335   
                           
 



57

            Z    Ra               
No.    X1, X2, X3, X4    R    -f'J(    m.p.("C)   
            Zf:::::-z    Rb               
            4                   
                       
26    CH, C-CF3 , CH, N    CF3    --cPHN    273-274   
27    CH, CH, C-F, CH    CF,    -cPH    288-289       
    CH, C-F, CH, CH    F    -QXO           
42                272-275   
            N                   
                       
43    CH, C-CF3 , CH, CH    F    -cPH    286-287       
44    CH, CH, N, CH    F            225-227       
            N    Me               
            --cP'               
45    CH,CH, N, CH    F    -cPH    270-271  -   
                               

Table 2 that follows illustrates the chemical structures and the physical properties of a

number of compounds according to the invention.

In this table:

-    the column "m.p. ec)" indicates the melting points of the products in degrees Celsius ("C);
-    ell the compounds are in the fonm of the free base,

-    W represents an oxygen atom;
 



58

-    Z2 represents a carbon atom bonded to the nitrogen atom of the amide of formula (I);

-    n is equal to 1.







            Ra               
                           
N'    X1, X2, X3, X4    y    -t~f4-Rb    m.p.('C)   
                           
28    CH, C-F, CH, CH    Pyrid-4-yl                176-177   
            N    Me       
            -cP'               
29    CH, C-F, CH, CH    Pyrid-3-yl                214-215   
            N    Me       
                       
            -cP'               
30    CH, C-CF,, CH, N    Thiazol~2-yl    _zyH    274-275   
                           
31    CH, CH, C-Si(Me),,    Thiazol-2-yl    _zyH    269-270   
                   
    CH               
32    CH, C-CF,, CH, CH    Thiazol-2-yl    -cPH    218-219   
                   
            N               
                           
 



59

                        Z    Ra           
    No    X1, X2, X3, X4    y    -t''(        m.p.(°C)   
                        zt:::,z    Rb           
                        4               
                                       
    33            CH, CH, C-CF,, CH    Thiazol-2-y/    ---cPH    165-166   
                        N               
                                       
    34            CH, C•Si(Me),, CH,    Thiazol-2-yl    -cPH    213-214   
                CH               
                                   
                                   
                                       
                CH, CH, C-F, CH    Thiazol-2-yl    ---cPH           
        35                255-256   
                        N               
                                       
    36            CH, C•CF,, CH, CH    Pyrid-4-yl    ---cPH    216-217   
                        N               
                                   
    37        CH, CH, C-CF,, CH    Pyrid-4-yl    -cPH    311 -313   
    36            CH, CH, C•Si(Me),,    Pyrid-4-yl    -cPH    235-236   
                               
                CH               
                                   
                                   
    39            CH, C-Si(Me),, CH,    Pyrid-4-yl    -cPH    279-261   
                CH               
                                   
                                   
    40            CH, CH, C-F, CH    Pyrid-4-yl    ---cPH    264-266   
                        N               
                                       
 



60

                Ra   
w        X1, X2, X3, X4    y    i~~r_Rb    m.p.('C)
                •   
41        CH, C-CF,, CH, N    Pyrid-4-yl    -cPH    296-298
46        CH, C•F, CH, CH    Pyrid-4-yl    -cPH    259-260
47        CH, C-CF3 ,  CH, CH    Pyrid-4-yl        213-214
                NMe   
                ---cP'   

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:

DRG neurones naturally express the TRPV1 receptor.

The primary cultures of newborn rat DRGs are prepared using 1-day-old rats. Briefiy, after dissection, the ganglions are trypsinized and the cells dissociated by mechanical
trituration. The cells are resuspended  in an  Eagle  basal culture medium containing

10% foetal calf serum, 25 mM KCI, 2 mM glutamine, 100 pg/ml gentamicin and 50 nglml 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 3rC in a humidified atmosphere containing 5% C02  and 95% air.

Cytosine ~-D-arabinoside (1  pM) is added 48 hours after culturing, to prevent the

growth of nonRneuronal cells. The slides are transferred into experimental chambers for

the patch-clamp studies after 7-10 days of culturing.
 



61

- 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 (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

(resistance 5-10 MOhms) are brought to the cell by means of a 30 piezoelectrtc micromanipulator (Burleigh, PC1000). The overall currents (membrane potential set at -60 mV) are recorded with an Axopatch 10 amplifier (Axon Instruments, Foster City, California), connected to a PC running the Pclamp8 software (Axon Instrument). The current plots are recorded on paper and simultaneously digitized (sampling frequency 15 to 25 Hz) and acquired on the hard drive of the PC.

The application of a 300 nM capsaicin solution induces on the ORG cells (voltage set

at -70 mV) an entering cationic current. In order to minimize the desensitization of the

receptors, a minimum interval of 1 minute  between two applications of capsaicin is

observed. After a control period (stabilization of the capsaicin response alone), the test

compounds  are  applied  alone  at a given  concentration  (concentration  of  10  nM  or

1 nM) for a time of 4 to 5 minutes, during which several capsaicin + compound tests

are  performed  (to  obtain  the  maximum  inhibition).  The  results  are  expressed  as  a

percentage of inhibition of the control capsaicin response.

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

capsaicin response (1 J.JM) 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
effective antagonists of receptors of TRPV1  type. Table 3 gives an example of the

percentage of inhibition obtained with the compounds of the invention.



Compound No.    % inhibition in DRG patch
   
2    82% (1 nM)
   
 



62


67.5% (100 nM)


Pain induced by intra plantar administration of capsaicin to mice.

The intraplantar injection of capsaicin to mice rapidly produces short-lived nociceptive

behaviour, which is  reflected by licking,  biting and flexing  of the administered  leg.

These nociceptive responses are probably associated with the activation of the local

TRPV1 receptors by the capsaicin.

Methodology:

(E)-Capsaicin is initially diluted to 3 mglml in DMSO, and then diluted again for its final use to 1.5 Jlg/20 Jll in physiological saline. The administration of solvent has no effect

on the  behaviour of the  mouse. The  capsaicin  is  injected  into the  hind  legs  of the

animal, on the upper face.

The  test  compounds  are  administered  orally  120  minutes  before  the  injection  of

capsaicin. Two hours after administration of the compounds, the mice are placed in a

glass beaker. The nociceptive behaviour of the animals is then assessed immediately

by the experimenter, and the duration of the capsaicin-induced behavioural manifestations is timed over a period of 2 minutes (licking and biting, total or partial
flexure of the injected leg).

For each compound, an inhibition corresponding to the mean of the capsaicin-induced nociceptive responses, in response to a dose of test product (expressed in mg/kg) administered orally to a sample of a given number (n) of mice, is determined.

Table 4 gives an example of a percentage of inhibition obtained with the compounds of

the invention.



% inhibition of the

capsaicin-induced
 



63

            nociceptive responses
           
2    10 mg/kg    10    61%(±6%)
           

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.

The compounds of the invention may be useful for preventing or treating pathologies in

which receptors ofTRPV1 type are involved.

Thus, a subject of the invention is medicaments comprising at least one compound of

formula (I), or a pharmaceutically acceptable salt, or alternatively a hydrate or a solvate

of the said compound.

The~e 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

iatrogenic treatment), (osteo)arthritic pain, rheumatic pain, fibromyalgia,  back pain,

cancer-related  pain,  facial  neuralgia,  headaches,  migraine,  dental  pain,  burns,

sunburn, animal bites or insect bites, post-herpetic neuralgia, muscular pain, trapped

nerves (central and/or peripheral), spinal column and/or brain trauma, ischaemia (of the spinal column and/or the brain), neurodegeneration, haemorrhagic strokes (of the spinal column and/or of the brain) and post-stroke pain.

The compounds of the invention may 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

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 gynaecological disorders, for instance vulvodynia and pain associated with salpingitis
 



64

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

ulcers, functional dyspepsia, colitis, IBS, Grahn'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

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.

The compounds of th~ 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 cancer~.

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

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 th~ oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal route. These compositions may be administered in a
 



65

unit administration form, as a mixture with standard phannaceuticcil excipients. They are intended to be administered to animals and human beings for the prophylaxis or treatment of the disorders or diseases mentioned above.

The appropriate unit forms of administration include oral fonns such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensionS, sublingual,
buccal,  intratracheal,  intraocular  and  intranasal  administration  fonns,  forms  for

administration  by  inhalation,  topical,  transdermal,  subcutaneous,  intramuscular  or

intravenous administration forms, rectal administration forms and implants. For topical

application, the compounds according to the invention may be used in creams, gels, pomades or lotions.

By way of example, a unit form of administration of a compound according to the invention in tablet fonn may comprise the following components:
Compound according to the invention    50.0 mg
Mannitol    223.75 mg
Croscarmellose sodium    6.0mg
Corn starch    15.0mg
Hydroxypropylmethylcellulose    2.25 mg
Magnesium stearate    3.0mg

The said unit fonns are dosed to allow a daily administration of from 0.001 to 30 mg of active principle per kg of body weight, according to ttie galenical form.

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.

The compounds of the invention may also 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 in~olved, as mentioned previously.

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
 





pali8l)t  f>f an  ~ dose  of  a  ~d aooording  to  the  invention,  or  a

~~san, or hydrate or solVate thereGI.
 



67




1. Compound corresponding to formula (I)
H    z1"z~Ra1I'
x('X"'X}iN----'z;;;;z' I   Rb
x;;II--.. ~    N    w    •
x.    \       
    fCH2)n   
y    (I)

in which:

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

R1;

it being understood that when one from among X1, X2. Nand ~represents a nitrogen

atom, the others correspond to a group C-R1;

Z1,  Z2,  Z3  and 4 represent, independently of each other, a nitrogen atom, a carbon

atom or a group C-R2,

at least one from among 211 22, ~and ~corresponding to a nitrogen atom and

one from among Z1, Z2, Z3 and ~. corresponding to a carbon atori1, being bonded to

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

Ra and Rb form, together with the carbon atoms that bear them, a 5-membered ring,

this  ring  comprising  a  nitrogen  atom  and  carbon  atoms,  this  ring  being  partially

saturated or unsaturated and being optionally substituted with one or more substituents

R,;

W represents an oxygen or sulfur atom;

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, a group C1-C6-all<yl, C3-Crcycloalkyl, C3-Crcycloalkyl-
 


68

C1-C3-alkylene, C,-C,-fluoroalkyl, hydroxyl, C1-C6-alkoxy, C3 -Crcycloalkyloxy, C3-Cr cycloalkyi-C1-C6-alkylene-O-, C1-C6-fiuoroalkoxy, cyano, C(O) NR,R5 , nitro, NR,R5 ,
C1-C6-thioalkyl,  thiol,  -S(O)-C1-C6-alkyl,  -S(O),-C1-C6-alkyl,  S02NR,R5,   NR6C(O)R7,
NRaS02Ra, C(O)NR,Rs, OC(O)NR,Ra, -Si-(C1-C6-alkyl),, -SF5 , aryi-C1-C5-alkylene or aryl, heteroaryi-C,-C,-alkylene or heteroaryl; the groups C1-C6-alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C1-C6-fiuoroalkyl, C1-C6-alkoxy, C3-C7-cycloalkyloxy, C3-C7-cycloalkyi-C,-C,-alkylene-O- being optionally substituted with a hydroxyl group,

C -C6-alkoxy or NR,Rs, the aryl and heteroaryl groups being optionally substituted with 1

one or more substituents Rg, which may be identiCal to or different from each other;

R1 is chosen from a hydrogen atom, a halogen atom, C,-C,-alkyl, C3-Crcycloalkyl, C3-C7-cycloalkyi-C,-C,-alkylene, C,-C,-fluoroalkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, aryi-C,-C,-alkylenoxy-C1-C,-alkyl, heteroaryi-C1-C,-alkylenoxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, aryi-C1-C3-alkylene-thio-C1-C6-alkyl, heteroaryi-C1-C3-alkylene-thio-C1-C6-alkyl, C1-C6-alkoxy, C3-Crcycloalkyloxy, C3-Cr cycloalkyi-C1-C3-alkylenoxy, C1-C6-fiuoroalkoxy, cyano, C(O)NR,R5, nitro, NR,R5,
C1-C6-thioalkyl, C,-Crcycloalkylthio, C,-C,-cycloalkyi-C1-C3-alkylene-thio, -S(O)-C1-C6-

alkyl, -S(O)-C -C,-cycloalkyl, -S(O)-C -C -alkylene-C -C    7    -cycloalkyl, C -C    -alkyi-S(O),-,   
3    1    3    3            1    6       
C1-C6-fiuoroalkyi-S(O),-,    C,-Crcycloalkyi-S(O),-,        C,-Crcycloalkyi-C1-C3-alkylene-   
S(O),-,  S02NR,R5 ,   -Si-(C,-C,-alkyl),,  -SF5 ,   NR,C(O)R,,  NRaS02R6,   C(O)NR,R5,
OC(O)NR,R5, aryl, heteroaryl, aryi-C1-C,-alkylene, heteroaryi-C,-C,..alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio; the heteroaryl or aryl groups being optionally

substituted with one or more substituents R9, which may be identical to or different from

each other,

R2 represents a hydrogen atom, a halogen atom or a grqup C1-C6-alkyl, C3-Cr cycloalkyl, C3-C,-cycloalkyi-C,-C3 -alkylene, C1-C,-fiuoroalkyl, C1-C6-alkoxy, C3-Cr cycloalkyloxy, C..-Crcycloalkyi-C1-C.,-alkylene-0-, hydroxyl, thiol or C1-C6-fiuoroalkoxy;

Ra represents, when it is borne by a carbon atom, a hydrogen atom, a hydroxyl group, thiol, C1-C6-alkyl, C3-Crcycloalkyl, C3-Crcycloalkyi-C,-C.,-alkylene, C1-C6-fluoroalkyl, C1-Ca-alkoxy, C,-CrcycloalkyloXy, C,-Crcycloalkyi-C,-C3-alkylenoxy, C1-C6-alkoxy-C1-c,-alkylene, C,-C,-cycloalkyloxy-C,-C,-alkylene, C,-Crcycloalkyi-C1-C3-alkylenoxy-C1-C3-alkylene, C(O)NR,R,, C(O)O-C1-C6-alkyl, C02H, or an oxo or thio group; the groups C1-C,-alkyl, C,-Crcycloalkyl, C,-Crcycloalkyi-C1-C,-alkylene, C1-C,-fiuoroalkyl, C1-C6-
 


69

alkoxy, C3-C,-cycloalkyloxy, Ca-Crcycloalkyi-C1-Ca-alkylenoxy, C1-C6-alkoxy-C1-C3-alkylene, Ca-Crcycloalkyloxy-C,-C,-alkylene, C3-Crcycloalkyi-C1-C3-alkylenoxy-C1-C3-alkylene possibly being subslituted with a hydroxyl group, C1-C6-alkoxy or NR,R5 ;

or

R3 represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1-C6-

alkyl, C3-C7-cycloalkyl, Ca-Crcycloalkyi-C1-C3-alkylene, C1-C6-nuoroalkyl, aryi-C(O)-, C1-C6-alkyi-C(Q)-, C,-C,-cycloalkyi-C(O)-, C3-C,-cycloalkyi-C1-C3-alkylene-C(O)-, C1-C6-fluoroalkyi-C(O)-, aryi-S(O), C1-C6-alkyi-S(O)-, c,-c,-nuoroalkyi-S(O)-, aryi-S(O)z-, C1-C6-alkyi-S(O)z-, C1-C6-fluoroalkyi-S(O),-, C3-C;-cycloalkyi-S(O),-, C3-Cr cycloalkyi-C1-Ca-alkylene-S(O),-, C1-C6-alkyi-O-C(O)-, aryi-C,-C,-alkyi-0-C(O)-, C3-Cr cycloalkyi-0-C(O)-, C,-C,-cycloalkyi-C1-C3-alkylene-0-C(O)-, C1-C6-fluoroalkyi-O-C(O)-'aryi-0-C(O)-, heteroaryi-0-C(O)-, heteroaryl or aryl; the heteroaryl and aryl groups being optionally substituted with one or more substituents R9; the groups C1-C6-alkyl, C3-C7-cycloalkyl, Ca-Crcycloalkyi-C1-C3-alkylene, C,-C,-fluoroalkyl, possibly being substituted with a hydroxyl group, C1-C6-alkoxy or NR,R5;

R, and R5 represent, independently of each other, a hydrogen atom or a group C1-C6-alkyl, C3-C7-cycloalkyl, Ca-Crcycloalkyi-C1-C3-alkylene, aryi-C1-C5-alkylene or aryl, or R, and R5 together form, with the nitrogen atom that bears them, an azetidine,

pyrrolidine,    piperidine,    azepine,    morpholine,   thiomorpholine,    piperazine    or

homopiperazine group; the group NR,R5 being optionally substituted with a group C1-C6-alkyl, C3-C7-cycloalkyl, C3-Crcycloalkyi-C1-C,-alkylene, aryi-C1-C6-alkylene, aryl, heteroaryl, aryi-S(O),-, C,-C,-alkyl-8(0),-, C1-C6-fluoroalkyi-S(O), C3-Crcycloalkyi-S(O)z-, C3-C7-cycloalkyi-C,-C3-alkylene-S(O),-, aryi-C(O)-, C1-C6-alkyi-C(O)-, C3-Cr cycloalkyi-C(O)-, C,-C,...cycloalkyi-C1-C3-alkylene-C(O)-, C1-C6-fluoroalkyi-C(O)-, hydroxyl, C1-C6-alkyloxy, C3-C,.-cycloalkyloxy, Ca-Crcycloalkyi-C1-C3-alkylenoxy, C1-C6-fluoroalkyl, aryloxy-C,-C,-alkylene, aryloxy, heteroaryloxy-C1-C6-alkylene or

heteroaryloxy;

Ra and R7 represent, independently of each other, a hydrogen atom or a group C1-C6-alkyl, Ca-Crcycloalkyl, Ca-C,.-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-C7-cycloalkyi-C1-C3-alkylene, C1-Ca-fluoroalkyl, C,-C,-alkoxy, C3-C,.-cycloalkyloxy, C3-C7-cycloalkyi-C1-C3-alkylenoxy, C1-Cs-fluoroalkoxy, nitro or cyano;
 



70

or Rs and R7 together form a 4- to ?-membered lactam comprising the nitrogen atom

and the C(O) group that bear them;

Ra represents a group C,-C,-alkyl, C,-C,-cycloalkyl, C,-C,-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, a group c,-c,-alkyl, c,-c,-cycloalkyl, c,-c,-cycloalkyi-C,-C,-alkylene, C1-C6-fluoroalkyl, C1-C6-alkoxy, C3-C7-cycloalkyloxy, C3-C,-cycloalkyi-C1-C,-alkylenoxy, c,-C,-fluoroalkoxy, nitro or cyano;

or R6  and Ra together form a 4- to ?-membered sultam comprising the nitrogen atom

and the S(O), group that bear them;

R9 represents a halogen atom, a group C1-C6-alkyl, C3-C7-cycloalkyl, C3-C7-cycloalkyi-C1-C3-alkylene, C1-C6-fiuoroalkyl, C1-C6-alkoxy, C3-C,-cycloalkyloxy, C3-C,-cycloalkyi-C1-C3-alkylenoxy, c,-C,-fiuoroalkoxy; these groups being optionally substituted with a group OH, C1-C,-alkoxy or NRaRs; or alternatively Ro represents a nitro group, cyano or NRaRs;

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

form;

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

solvate.

2. Compound of fonmula (I) according to Claim 1, characterized in that
X1, X2, X3 and X., 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 fonm of hydrate or

solvate.

3. Compound of fonmula (I) according to Claim 1, characterized in that

among X1, X2, X, and X.,, one from among X, and X., represents a nitrogen atom, and the others represent, independently of each other, a group C-R,; R, being as defined in the general fonmula (I) according to Claim 1;

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


71

solvate.

4. Compound of fonnula (I) according to any one of Claims 1 to 3, characterized in that

R1  is  chosen  from  a  hydrogen  atom,  a  halogen  atom,  a  group  C1-C6-fluoroalkyl

or -Si(C1-C6-alkyl),,

irl 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

solvate.

6. Compound of fonnula (I) according to any one of Claims 1 to 5, characterized in that

y represents a phenyl, optionally substituted with one or more groups chosen from a

halogen atom and a group C1-C6-alkyl or C1-C6-fluoroalkyl; or allernalively Y represents a pyridyl or a thiazolyl;

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

solvate.

1. Compound offonnula (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

solvate.

a. Compound offonnula (I) according to any one of Claims 1 to 7, characterized in that the group

Z    Ra
zf'"{

~z)l-..Rb
4

is chosen from the groups
 


72
-Qj -cPH -<b -cPH V" HN
one from among Z1, Z2, Za and~ corresponding to a nitrogen atom and possibly being

in oxidized form;

these groups being optionally substituted with R2  and R, as defined in the general

formula (I) according to Claim 1;

R2 represents a hydrogen atom;

Ra represents, when it is borne by a carbon atom, a hydrogen atom or an oxo group; R3. represents, when it is borne by a nitrogen atom, a hydrogen atom or a group CrCa~
alkyl or c,-C,-alkyi-C(O)-;

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

solvate.

9. Compound of formula (I) according to any one of Claims 1 to 8, characterized in that the group
Z    Ra
zf''§__
~z  Rb
4

is chosen from the groups
-cPH

one from among Z1, Zz, Za and ~corresponding to a nitrogen atom and possibly being

in oxidized form;

these groups being optionally substituted with R2  and R, as defined in the general

formula (I);

R2 represents a hydrogen atom;
 


73

R3 represents, when it is borne by a carbon atom, a hydrogen atom or an oxo group; R3 represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1-C6-
alkyl or C1-C6-alkyi-C(O)-;

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 B. characterized in that
either X1, X2, X3 and X, represent, independently of each other, a group C-R1; or, among X, Xz, XJ and ~. one from among XJ and ~ represents a nitrogen atom, and
the others represent, independently of each other, a group C-R1;

R1  is chosen from a hydrogen atom, a halogen atom and a group C1-C6-f\uoroalkyl

or -Si(C,-C,-alkyl),;

n is equal to 1;

Y represents a phe!lyl, optionally substituted with one or more groups chosen from a

halogen atom, a group c,-c,-alkyl or C1-C6-fluoroalkyl; or alternatively Y represents .a

pyridyl or a thiazolyl;

W represents an oxygen atom;

the group

Z    Ra
zf''§__
- i;    Rb
2 4
is chosen from the groups
-Qj -cPH -<:0 -cPHN fP" HN

one from among Zt. Zz, ~ and .4 corresponding to a nitrogen atom and possibly being in oxidized form;
these groups being optionally substituted with R2  and R, as defined in the general
 


74

formula (I) according to Claim 1;

R2 represents a hydrogen atom;

Ra represents, when it is borne by a carbon atom, a hydrogen atom or an axe group;

~ represents, when it is borne by a nitrogen atom, a hydrogen atom or a group C1-C6-alkyl or C1-C6-alkyi-C(O)-;

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) chosen from:

N-(1-acetyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-(3-fiuorobenzyl)-1 H-

indole-2-carbo~mide;

N-(1H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-(3-fluorobenzyi)-1H-indole-2-carboxamide;

N-(2,3-dihyd ro-1H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-(3-fluorobenzyl)-1 H-indole-2-

carboxamide;

N-(1H-pyrrolo[3,2-b]pyrid-6-yl)-5~fluoro-1-(3-fluorobenzyi)-1H-indole-2-carboxamide;

N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[(3-methylphenyl)methyi]-1H-indole-2-

carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[[(3-trifiuoromethyl)phenyl]methyl]-1 H-indole-2-carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[[(3-trifluoromethyl)phenyl]methyl]-1 H-

indole-2-carboxamide;

N-(1H-Pyrrolo[2,3-c]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl]methyi]-1H-indole-2-

carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifiuoromethyl-1-[(3-fluorophenyl)methyl]-1 H-pyrrolo[2,3-b]pyridine-2-carboxamide;

N-(7 -Oxy-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-2-

carboxamide;

N-(1-Methyi-1H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyi]-

1H-indole-2-carboxamide;

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3,fluorophenyl)methyl]-1 H-indole-

2-carboxamide;

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-fluorophenyl)methyi]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;

N-(1-Methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-fluorophenyl)methyi]-

1H-indole-2-carboxamide;
 


75

N-(1-Methyt-1 H-pyrrolo[2,3-b]pyrid-5-yl)-1-[[(3-trifluoromethyl)phenyl]methyl]-1 H-indole-

2-carboxamide;

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-6-yl)-5-fluoro-1-[(3-fluorophenyl)methyl]-1 H-indole-

2-carboXamide;

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[[(3-trifluoromethyl)phenyl]-

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

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(3-methylphenyl)methyl]-1 H-indole-

2-carboxamide;

N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1 H-indole-

2-carboxamide;

N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[(3-methylphenyl)methyl]-1 H-indole-

2-carboxamide;

N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(3-methylphenyl)methyl]-1 H-indole-2-

carboxamide;

N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-methylphenyl)methyl]-1 H-

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

N-(1 H-pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(3-methylphenyl)methyl]-1 H-indole-2-

carboxamide;

N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]methyl]-

1H-indole-2-carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]methyl]-

1H-indole-2-carboxamide;

N-(1H-pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[[(3-trifluoromethyl)phenyl]methyl]-

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

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[[(3-trifluoromethyl)phenyl]methyl]-1 H-indole-

2-carboxamide;

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamide;

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-3-yl)methyl)]-1 H-indole-2-

carboxamide;

N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyi]-1H-pyrrolo[2,3-

b]pyridine-2-carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(thiazol-2-yl)methyl]-1 H-indole-2-

carboxamide;

N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(thiazol-2-yl)methyi]-1H-indole-2-
 


76

carboxamide;

N-(1 H-Pyrrolo(2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-((thiazol-2-yl)methyl]-1 H-indole-2-

carboxamide;

N-(1H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(thiazol-2-yl)methyi]-1H-indole-2-

carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-fluoro-1-[(thiazol-2-yl)methyl]-1 H-indole-2-carbox-

amide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trifluoromethyl-1-((pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-6-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamide~

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trimethylsilyl-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamide;

N-(1 H-Pyrrolo(2,3-b]pyrid-5-yl)-6-fiuoro-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-carbox-

amide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1 H- pyrrolo[2,3-b]pyridine -2-carboxamide;

N-(2-0xo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-((3-fluorophenyl)methyl]-

1H-indole-2-carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(3-fiuorophenyl)methyl]-1 H-indole-2-

carboxamide;

N-(1-Methyl-1 H-pyrrolo[2,3-b]pyrid-5-yl)-1-[(3-fluorophenyl)methyl]-1 H-pyrrolo[2,3-

c]pyridine-2-carboxamide;

N-(1 H-pyrrolo(2,3-b]pyrid-5-yl)-1-((3-fluorophenyl)methyl]-1 H-pyrrolo[2,3-c]pyridine-2-

carboxamide;

N-(1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-fluoro-1-[(pyrid-4-yl)methyl)]-1 H-indole-2-

carboxamide;

N-(1-Methyl-1 H-Pyrrolo[2,3-b]pyrid-5-yl)-5-trifluoromethyl-1-[(pyrid-4-yl)methyl)]-1 H-

indole•2-carboxamide.

12. Process for preparing a compound of formula (I) according to any one of Claims 1 to 11, characterized in that a compound of general formula (II)
 


77






in which X1, X2, X.,, X.,, n, Y and W are as defined in the general formula {I) according to Claim 1,

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

zfZ"'XRa

o    zhz    Rb
4
(Ill)

in which Z1, Z2, Z,, Z,, Ra and Rb are as defined in the general formula {I) according to Claim 1,

when  B represents  a  hydroxyl  group  and  D represents an  amino  group,  in  the

presence of a coupling agent in a solvent;

when B represents a chlorine atom and D represents an amino group, by reaction

in solution in a solvent;

when  B represents a group C1-C6-alkoxyl and  D represents an amino  group, by

transformation of the compound of formula {Ill) into an amide and then by reacting

the  amide  obtained  with  the  compound  of formula  {II)  in  the  presence  of an

organometallic reagent;

when B represents an NH2 group, W represents an oxygen atom and D corresponds to a leaving group, in the presence of a copper salt in catalytic
amount, a catalytic amount of a copper ligand, and a base, in a solvent.

13. Process for preparing a compound of general formula {II)

x('x~_l

~l,_~N~ (II)
4    \
;cH,)n

y

in which X,, X,, X.,, X.,, n, Y and Ware as defined in the general formula {I) according to Claim 1, one from among X, X,, X., and X., corresponding to a group C-R1 in which R, represents a group -Si-{C,-C,-alkyl)a as defined in the general formula {I) according to
 


78

Claim 1 and B represents a group C1-C,-alkoxyl, characterized in that a compound of general formula (VI)
x('x'y-'\__ _l

x~~N/~
4    H

(VI)

in which X1, X2, X,, X. and W are as defined in the general formula (I) according to Claim 1 and B represents a group C,-C,-alkoxyl
is reacted with a compound of general formula (VIII)

GP\
>CH2)n

Y    (VIII)

in which Y and n are as defined in the general formula (I) according to Claim 1,

- when n is equal to 1, 2 or 3, with a reagent of general formula (VIII) in which LG

represents a leaving group, in the presence of a base in a polar solvent;

-when n is equal to 1, 2 or 3, with a reagent of general formula (VIII) in which LG represents a hydroxyl group, in the presence of a phosphine and diethyl

azodicarboxylate in a solvent; or alternatively in the presence of a phosphine supported

on a resin and diisopropyl azodicarboxylate in solution in a solvent;

-when n is equal to 0, with a reagent of general formula (VIII) in which LG represents a

leaving group, under an inert atmosphere in basic medium, in the presence of a copper

salt in an organic solvent.

14. Compound of general formula (II a), (lib), (lie), (lid), (lie), (liD. (llg) or (llh):

H~c, ,cw,                    H,C\/               
HC..-S!"CC:)-(Et    tt~q_~oa    w,c-SI~OEI    H~1VK0El   
•    I    "        I'\       
    CF,J 0    w,c-r    H    o    ,,,J 0    "ri,~    o   
        CF,   ~ :                   
                    ~    ~.       
        '"'    '~-d    (lib)        ~    Q       
                        (II~)        (lid)       
w,c,,cw,                    w,c, ,cw,               
HC..-SI~OEt    H,1_~0Et    w,c-SI~OEt    HJ~~OEt   
'    I    '\        do       
        do    "•'-r A:;    o        w,c-r    N'    o   
            c~    s            '~d       
        pro)        ~"    (Ill)    [II g)    ~    u       
                                (llh)       

15. Medicament, characterized in that it comprises a compound of formula (I) according

 

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