Indian Patents
Title of Invention

2-ARYL-6-PHENYLIMIDAZO[1,2-alpha ]PYRIDINE DERIVATIVES
Abstract The invention relates to the derivatives of general formula (1) in which: R1 is: a phenyl group or a naphthyl group, it being possible for these two groups to be optionally substituted; R2 and R3 are, independently of one another, a hydrogen atom, a (C1- C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, which is optionally substituted; an optionally substituted aryl group; R4 is: a hydrogen atom, a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, which is optionally substituted; an aryl group optionally substituted with one or more substituents in the form of a base or of an addition salt with an acid.
Full Text 2-ARYL-6-PHENYLIMIDAZ0[l,2-α]PYRIDINE DERIVATIVES, PREPARATION
THEREOF AND THERAPEUTIC USE THEREOF
The present invention relates to 2-aryl-6-phenylimidazo[1,2-α]pyridine derivatives, to the
preparation thereof and to the therapeutic use thereof in the treatment or the prevention of
diseases involving Nurr-1 nuclear receptors, also known as NR4A2, NOT, TINUR, RNR-1 and
HZF3.
A subject of the present invention is the compounds corresponding to formula (I):
in which:
R, is:
a phenyl group or a naphthyl group, it being possible for these two groups to be
optionally substituted with one or more atoms or groups selected, independently
of one another, from the following atoms or groups: halogen, (C1-C6)alkyI, (C3-C7)
cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)alkoxy,
(C3-C7)cycloalkoxy, (C3-C7)cycloalkyl(C1-C3)alkyleneoxy, halo(C1-C6)alkoxy,
(C1-C6)thioalkyl, -S(O)(C1-C6)alkyl, -S(O)2(C1-C6-alkyl), hydroxyl, cyano, nitro,
hydroxy(C1-C6)alkylene, NRaRb(C1-C6)alkylene, (C1-C6)alkoxy(C1-C6)
alkyleneoxy, NRaRb, CONRaRb, SO2NRaRb, NRcCORd, OC(O)NRaRb, NRcC
(O)ORe, NRcSO2Re, aryI(C1-C6)alkylene, aryl or heteroaryl, the aryl or the
heteroaryl being optionally substituted with one or more substituents selected
from a halogen, or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)
alkylene, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl,
nitro or cyano group;
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(G-C6)aIkoxy, NRaRb, hydroxyl, nitro or cyano
group;
R4 is:

a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents chosen
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-CsJalkoxy, (C3-C7)cycloalkoxy, (C3-C7)cycloalkyl(C1-C3)-
alkyleneoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro, cyano, (C1-C6)alkyl(CO)-,
CONRaRb, NRcCORd, OC(O)NRaRb, NRcC(O)ORe or aryl group, the aryl being
optionally substituted with one or more substituents selected from a halogen or a (C1-C6)
alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)
alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano group;
Ra and Rb are, independently of one another,
a hydrogen atom or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
aryl(C1-C6)alkylene or aryl group;
or Ra and Rb form, together with the nitrogen atom which bears them, an azetidine, pyrrolidine,
piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this
group being optionally substituted with a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloaIkyl
(C1-C6)alkylene, aryl or aryl(C1-C6)alkylene group;
Re and Rd are, independently of one another,
a hydrogen atom or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
aryl(C1-C6)alkylene and aryl group;
or Re and Rd together form a (C2-C5)alkylene group;
Re is
a (C1-C6)alkyl, (C3-C7)cycloalkyI, (C3-C7)cycloalkyl(C1-C3)alkylene, aryl(C1-C6)alkylene
and aryl group;
or Re and Re together form a (C2-C5)alkylene group;
Rfis
a halogen atom or a (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C3-C7)
cycloalkyl(C1-C6)alkyleneoxy, hydroxyl, cyano, NRaRb, C(O)NRaRb, NRcCORd, OC(O)
NRaRb, NRcCOORe, SO2NRaRb, NRcSO2Re, aryl(C1-C6)alkylene or aryl group, the aryl
being optionally substituted with one or more substituents selected from a halogen or a
(C1-C6)a!kyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)
alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano group;
in the form of a base or of an addition salt with an acid.
The compounds of formula (I) can contain one or more asymmetrical carbon atoms. They
can therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and

diastereoisomers, and also mixtures thereof, including racemic mixtures, are part of the invention.
In the various groups as defined below, the groups Ra, Rb, Re, Rd, Re and Rf have the
same definitions as those mentioned above.
Among the compounds of formula (I) which are subjects of the invention, a first group of
compounds in the form of a base or of an addition salt with an acid comprises compounds for
which:
R1 is a naphthyl group or a phenyl group which can be optionally substituted with one or more
atoms or groups selected, independently of one another, from the following atoms or groups:
halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkylene, (C1-C6)alkoxy, (C3-C7)
cycloalkyl(C1-C6)aIkoxy, hydroxy, cyano, nitro, NRaRb, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy or aryl, the aryl being optionally substituted with
one or more substituents selected from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)
cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxy!,
nitro or cyano group.
Among the compounds of formula (I) which are subjects of the invention, a second group
of compounds in the form of a base or of an addition salt with an acid comprises compounds for
which:
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group optionally
substituted with an Rf group;
R4 is:
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group optionally
substituted with an Rf group,
an aryl group optionally substituted with one or more substituents selected from a halogen
or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)
alkoxy, (C3-C7)cycloalkoxy, (C3-C7)cycloalkyl(C1-C3)alkyleneoxy, halo(C1-C6)alkoxy, NRaRb,
hydroxy 1, nitro, cyano, (C1-C6)alkyl(CO)-, NRcCORd or aryl group, the aryl being optionally
substituted with one or more substituents selected from a halogen or a (C1-C6)alkyl, (C3-C7)
cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, haIo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy,
NRaRb, hydroxyl, nitro or cyano group.
Among the compounds of formula (I) which are subjects of the invention, a third group
of compounds in the form of a base or of an addition salt with an acid comprises compounds for
which:

the substituent is in the meta-position on the phenyl.
Among the compounds of formula (I) which are subjects of the invention, a fourth group
of compounds in the form of a base or of an addition salt with an acid comprises compounds for
which:
R4 is a hydrogen atom and
R2, R3 are, independently of one another, a hydrogen atom or a (C1-C6)alkyl, (C3-C7)cycloalkyl or
(C3-C7)cycloalkyl(C1-C3)alkylene group optionally substituted with an Rf group.
Among the compounds of formula (I) which are subjects of the invention, a fifth group of
compounds in the form of a base or of an addition salt with an acid comprises compounds for
which:
Ri is a naphthyl group or a phenyl group which can be optionally substituted with one or more
atoms or groups selected, independently of one another, from the following atoms or groups:
halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkylene, (C1-C6)alkoxy, (C3-C7)
cycloalkyl(C1-C6)alkoxy, hydroxy 1, cyano, nitro, NRaRb, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)aIkyI, halo(C1-C6)alkoxy or aryl, the aryl being optionally substituted with
one or more substituents selected from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)
cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl,
nitro or cyano group;
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C1-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano
group;
R4 is:
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group,
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, nitro, cyano, (C1-C6)alkyl(CO)- orNRcCORd group.
Among the compounds of formula (I) which are subjects of the invention, a sixth group of
compounds in the form of a base or addition salt with an acid comprises compounds for which:

R1 is a naphthyl group or a phenyl group which can be optionally substituted with one or more
atoms or groups selected, independently of one another, from the following atoms or groups:
halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkylene, (C1-C6)alkoxy, (C3-C7)
cycloalkyl(C1-C6)alkoxy, hydroxyl, cyano, nitro, NRaRb, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)alkyl or halo(C1-C6)alkoxy,
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano
group;
R, is:
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group,
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, nitro, cyano, (C1-C5)alkyl(CO)- or NRcCORd group.
The combinations of the groups one to six as defined above are also part of the invention.
The compounds of formula (I) can exist in the form of bases or of addition salts with
acids. Such addition salts are part of the invention.
These salts can be prepared with pharmaceutical^ acceptable acids, but the salts of other acids
useful, for example, for the purification or the isolation of the compounds of formula (I) are also
part of the invention.
The compounds of formula (I) can also exist in the form of hydrates or of solvates, i.e. in the form
of associations or combinations with one or more molecules of water or with a solvent. Such
hydrates and solvates are also part of the invention.
In the context of the present invention:
the term "a halogen atom" is intended to mean: a fluorine, a chlorine, a bromine or an
iodine;
- the term "a (C1-C6)alkyl group" is intended to mean: a linear or branched, saturated
aliphatic group containing from 1 to 6 carbons. By way of examples, mention may be
made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc.,
groups;

- the term "a (C3-C7)cycloaIkyl group" is intended to mean: a cyclic carbon-based group
containing from 3 to 7 carbons. By way of examples, mention may be made of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., groups;
- the term "an alkylene" is intended to mean: a linear or branched, saturated divalent
alkyl group; for example, a (C1-C6)alkylene group is a linear or branched, divalent
carbon-based chain containing from 1 to 6 carbon atoms, more particularly a
methylene, ethylene, 1-methylethylene or propylene;
- the term "a (C1-C5)alkoxy group" is intended to mean: an -O-alkyl radical where the
alkyl group is as defined above;
the term "(C3-C7)cycloalkoxy group" is intended to mean: an -O-cycloalkyl radical
where the cycloalkyl group is as defined above;
the term "a halo(C1-C6)alkyl group" is intended to mean: a linear, branched or cyclic,
saturated aliphatic group containing from 1 to 6 carbon atoms which is substituted
with one or more identical or different halogen atoms. By way of examples, mention
may be made of CF3, CH2CF3, CHF2 or CC1? groups;
the term "a halo(C1-C6)alkoxy group" is intended to mean: an -O-alkyl radical where
the alkyl group is as defined above and which is substituted with one or more identical
or different halogen atoms. By way of examples, mention may be made of OCF3,
OCHF2 or OCCl3 groups;
- the term "a thioalkyl group" is intended to mean: an S-alkyl radical where the alkyl
group is as defined above;
- the sulphur and nitrogen atoms can be in the oxidized state (N-oxide, sulphoxide.
sulphone);
- the term "an aryP is intended to mean: a cyclic aromatic group comprising between 6
and 10 carbon atoms. By way of examples of aryl groups, mention may be made of
phenyl or naphthyl groups;
- the term "a heteroaryl" is intended to mean: an aromatic cyclic group having from 5 to
10 ring members containing from 1 to 4 heteroatoms selected from O, S or N. By way
of nonlimiting example, mention may be made of imidazolyl, thiazolyl, oxazolyl,
furanyl, thiophenyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl,
indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl
or quinoxalinyl groups.
Among the compounds of formula (1) which are subjects of the invention, mention may be
made of the following compounds:
[4-(2-phenylimidazo[ 1,2-α]pyridin-6-yl)phenyl]methanol



{3-[2-(3-fluoro-4-methylphenyI)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
2-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}propan-2-ol
{2-[2-(4-chloropheny I)imidazo[ 1,2-α]pyridin-6-y l]phenyl} methanol
{2-[2-(4-chlorophenyl)imidazo[ 1,2-α]pyridin-6-yl]phenyl}methanol hydrochloride (1:1)
racemic l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
{3-[2-(2,4-dichlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(2,4-difluorophenyI)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(3,4-difluorophenyl)imldazo[l,2-α]pyridin-6-yl]phenyl} methanol
{3-[2-(3,4-difluorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol hydrochloride (1:1)
{3-[2-(2-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(4-trifluoromethylphenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(4-(difluoromethyl)phenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanoI
racemic l-{2-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
2-(4-chlorophenyl)-6-(2-methoxymethylphenyl)imidazo[l,2-α]pyridine
2-(4-chlorophenyl)-6-(2-methoxymethylphenyl)irn idazo[ 1,2-α]pyridine hydrochloride (1:1)
2-(4-chlorophenyl)-6-(4-methoxymethyIphenyl)imidazo[l,2-α]pyridine
racemic l-{3-[2-(4-chIorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}propan-l-ol
racemic 1 - {3-[2-(4-chlorophenyl)imidazo[ 1,2-α]pyridin-6-yl]phenyl}pentan-1 -ol
racemic l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}heptan-l-ol
racemic l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}-3-methylbutan-l-ol
racemic {3-[2-(4-chlorophenyl)imidazo[l,2-o]pyridin-6-yl]phenyl}cyclopentylmethanol
racemic {3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}phenylmethanol
dextrorotatory enantiomer of l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
levorotatory enantiomer of l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
2-(4-chlorophenyl)-6-(3-methoxymethyIphenyl)imidazo[l,2-α]pyridine
racemic l-{4-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
racemic l-{3-[2-(2,4-difluorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
racemic 1 -{3-[2-(4-fluorophenyl)imidazo[l ,2-α]pyridin-6-yl]phenyl}ethanol
racemic l-{3-[2-(3,4-difluorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
racemic l-{3-[2-(2-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
racemic l-{3-[2-(3-fluorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanoI
racemic l-{3-[2-(3-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
4-[6-(3-hydroxymethylphenyl)imidazo[l,2-α]pyridin-2-yl]phenol.
In accordance with the invention, the compounds of general formula (I) can be prepared
according to the process described in scheme 1.


Scheme 1
The compounds of the invention can be prepared according to scheme 1 by means of a coupling
reaction, catalysed by a metal such as palladium, between a 2-arylimidazopyridine of general
formula (II), in which Rl is defined as above and Hal is a halogen atom, and a derivative of
general formula (III) in which X is a derivative of boron or of tin and R5 is the group so
as to obtain the compounds of general formula (I).
The compounds of the invention can also be prepared according to scheme 1 by means of a
coupling reaction, catalysed by a metal such as palladium, between a 2-arylimidazopyridine of
general formula (II), in which Rl is as defined above and Hal is a halogen atom, and a derivative
of general formula (III) in which X is a derivative of boron or of tin and R5 is a carbonylated
derivative R2COR3, in which R2 and R3 are defined as above, so as to obtain the compounds of
general formula (IV), for example according to the method described by A. Gueiffier in Helv.
Chim. Acta 2001, 84, 3 610-3 615.
Next, the compounds of general formula (IV) can be converted to compounds of general
formula (I) through the action of an organometallic derivative such as an organomagnesium
compound, or by reduction of the carbonyl group by means of a metal hydride, for example
sodium borohydride or one of its derivatives, or any other method known to those skilled in the
art.
The products of formula (I) can be subjected, if desired and if necessary, to any reactions
known to those skilled in the art, in any order, in order to be converted to other products of
formula (I).
By way of examples of reactions, mention may be made of: acid-function esterification or

amidation reactions, carbamoylation reactions, ester-function hydrolysis reactions, reactions to
convert a hydroxyl function to an alkoxy function, coupling reactions catalysed by a transition
metal, reactions for protecting reactive functions, reactions for eliminating protective groups that
may bear the protected reactive functions, salification reactions with an inorganic or organic acid
or with a base in order to obtain the corresponding salt, reactions for resolving racemic forms into
enantiomers, said products of formula (I) thus obtained being, where appropriate, in any of the
possible racemic, enantiomer and diastereoisomer isomeric forms.
In scheme 1, the starting compounds and the reactants, when the method for preparing
them is not described, are commercially available or described in the literature, or else can be
prepared according to methods which are described therein or which are known to those skilled in
the art.
The following examples describe the preparation of certain compounds in accordance
with the invention. These examples are not limiting and merely illustrate the present invention.
The numbers of the compounds exemplified refer to those given in the tables hereinafter, which
illustrate the chemical structures and the physical characteristics of some compounds according to
the invention.
The naming of the compounds was established based on the Autonom software.
Example 1: [4-(2-Phenylimidazo[l,2-α]pyridin-6-yl)phenyl] methanol (compound 1 of the
table)
1.1 6-Bromo-2-phenylimidazo[l,2-α]pyridine
1.99 g of 2-bromo-l-phenylethanone, 1.73 g of 2-amino-5-bromopyridine and 1 g of sodium
hydrogen carbonate in a mixture of 20 ml of ethanol and 5 ml of water are placed in a round-
bottomed flask. The mixture is heated at 80°C for 4 h and left to cool and 40 ml of water are
added. The mixture is stirred for 15 min and the precipitate is then recovered by filtration; it is
washed with water and then with diisopropyl ether and dried in a desiccator. 1.8 g of compound
are obtained. Mp = 192 - 194°C.

1.2 [4-(2-Phenylimidazo[ 1,2-α] pyridin-6-yl)phenyl] methanol
150 mg of 6-bromo-2-phenylimidazo[l,2-α]pyridine, 125 mg of 4-(hydroxymethyl)phenylboronic
acid, 19 mg of tetrakis(triphenylphosphine)palladium and 2 ml of acetonitrile are placed in a
microwave tube. Under a stream of nitrogen, 2 ml of nitrogen-degassed toluene and then 2 ml of a
2M solution of sodium carbonate are added thereto. The tube is placed in a microwave device and
irradiated at 150°C for 15 min. The organic phase is recovered, dried and then concentrated under
reduced pressure. The residue is taken up with diisopropyl ether and the precipitate is recovered
by filtration, washed and dried. It is purified by recrystallization from n-butanol. 52 mg of
compound are obtained. Mp = 238 - 240°C. 1H NMR (DMSO-d6, δ in ppm): 4.54 (d, J = 5.5 Hz,
2H); 5.2 (t, J = 5.6 Hz, 1H); from 7.24 to 7.73 (m, 9H); 7.96 (m, 2H); 8.36 (s, 1H); 8.84 (t, J = 1.3
Hz, 1H). M+H = 301.
Example 2: [3-(2-(Naphthalen-2-yl)imidazo[ 1,2-α]pyridin-6-yl)phenyl] methanol
(compound 9 of the table)
2.1 6-Bromo-2-(naphthalen-2-yl)imidazo[l,2-α]pyridine
By carrying out the process as in Example 1, and starting from 0.5 g of 2-bromo-l-(naphthalen-
2-yl)ethanone, 0.72 g of 2-amino-5-bromopyridine and 0.29 g of sodium hydrogen carbonate,
0.83 g of 6-bromo-2-(naphthalen-2-yl)imidazo[l,2-α]pyridine is obtained. Mp = 226 - 228°C.
2.2 [3-(2-(Naphthalen-2-yl)imidazo[l,2-α]pyridin-6-yl)phenyl]methanol
Under a stream of nitrogen, 500 mg of 6-bromo-2-(naphthalen-2-yl)imidazo[l,2-α]pyridine,
235 mg of 3-(hydroxymethyl)phenylboronic acid and 90 mg of tetrakis(triphenylphosphine)-
palladium are placed in a microwave tube containing 5 ml of toluene degassed beforehand under a
stream of nitrogen, 5 ml of acetonitrile and 6 ml of a 0.5M solution of sodium carbonate. The tube
is placed in a microwave apparatus and irradiated at 150°C for 15 min. The organic phase is
separated and dried and the filtrate is concentrated under reduced pressure. The residue obtained
is taken up with 5 ml of dichloromethane. A precipitate forms and is recovered by filtration,
washed with dichloromethane and then with diisopropyl ether and dried under reduced pressure.
The experiment is repeated several times (6) and the solids are combined. 2.2 g of compound are
obtained and are recrystallized from a 1/1 n-propanoI/water mixture. The precipitate is filter-dried,
washed with diisopropyl ether and dried under reduced pressure. 1.96 g of compound are
obtained. Mp = 161 - 163°C. 1H NMR (DMSO-d6, δ in ppm): 4.58 (d, J = 5.5 Hz, 2H); 5.24 (t, J
= 5.7 Hz, 1H); from 7.29 to 7.73 (m, 8H); from 7.86 to 8.13 (m, 4H); 8.52 (m, 2H); 8.84 (m, 1H).
M+H = 351.
Example 3: [3-(2-/7-Tolylimidazo[l,2-α]pyridin-6-yl)phenyl]methanol (compound 10 of the
table)

3.1 6-Bromo-2-P-tolylimidazo[l ,2-α] pyridine
By carrying out the process as in Example 1, starting from 150 mg of 2-bromo-l-p-tolylethanone,
185 mg of 2-amino-5-bromopyridine and 87 mg of sodium hydrogen carbonate, 200 mg of
6-bromo-2-p-tolylimidazo[l,2-α]pyridine are obtained. The compound is purified by silica gel
chromatography, elution being carried out with a 98/2 dichloromethane/methanol mixture. 60 mg
of compound are obtained. Mp = 226 - 228°C.
3.2 [3-(2-p-Tolylimidazo[l,2-α]pyridin-6-yl)phenyl]methanol
Under a stream of nitrogen, 200 mg of 6-bromo-2-p-tolylimidazo[l,2-α]pyridine, 160 mg of
3-(hydroxymethyl)phenylboronic acid and 24 mg of tetrakis(triphenylphosphine)palladium are
placed in a microwave tube containing 2 ml of toluene degassed beforehand under a stream of
nitrogen, 2 ml of acetonitrile and 2 ml of a 2M solution of sodium carbonate. The tube is placed in
a microwave apparatus and irradiated at 150°C for 15 min. The organic phase is separated and
dried and the filtrate is concentrated under reduced pressure. The residue obtained is taken up
with 6 ml of dichloromethane. The precipitate is recovered by filtration, washed with
dichloromethane and dried in a desiccator under reduced pressure. 100 mg of compound are
obtained. Mp= 171 - 173°C. 1H NMR (DMSO-d6, δ in ppm): 2.32 (s, 3H); 4.57 (d, J = 5.6 Hz,
2H); 5.23 (t, J = 5.7 Hz, 1H); from 7.19 to 7.67 (m, 8H); 7.84 (d, J = 8 Hz, 2H); 8.32 (s, 1H); 8.82
(m, 1H).M+H = 315.
Example 4: 6-[3-(2-Methoxyethoxymethyl)phenyl]-2-(naphthalen-2-yl)imidazo[ 1,2-α]
pyridine (compound 17 of the table)
100 mg of [3-(2-naphthalen-2-ylimidazo[l,2-α]pyridin-6-yl)phenyl]methanol (Example 2) and
120 mg of 2-bromoethanol methyl ether are dissolved in 5 ml of a 1/1 methanol/
dimethylformamide mixture, in a pressure tube, and 1 g of potassium fluoride on alumina is added
thereto. The tube is closed and heated for 16 h at 80°C. After cooling, the mineral is removed by
filtration and washed with dichloromethane. The filtrate is concentrated under reduced pressure
and purified by silica gel chromatography, elution being carried out with a 99/1
dichloromethane/methanol mixture. An oil which crystallizes from 5 ml of diisopropyl ether is
obtained. The precipitate is recovered by filtration, washed with diisopropyl ether and dried under
reduced pressure. 44 mg of compound are obtained. Mp = 80 - 82°C. 1H NMR (DMSO-d6, δ in
ppm): 3.25 (m, 3H) 3.55 (m, 4H); 4.57 (s, 2H); from 7.27 to 7.80 (m, 8H); from 7.82 to 8.16 (m,
4H); 8.52 (m, 2H); 8.89 (m, 1H). M+H = 409.
Example 5: {3-[2-(4-Chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
(compound 25 of the table)
5.1 6-Bromo-2-(4-chlorophenyl)imidazo [ 1,2-α] pyridine

By carrying out the process as in Example 1, starting from 675 mg of 2-bromo-l-(4-chlorophenyl)
ethanone, 500 mg of 2-amino-5-bromopyridine and 290 mg of sodium hydrogen carbonate,
680 mg of 6-bromo-2-(4-chlorophenyl)imidazo[l,2-α]pyridine are obtained. The compound is
purified by silica gel chromatography, elution being carried out with a 98/2
dichloromethane/methanol mixture. 60 mg of compound are obtained. Mp = 210 - 211°C.
5.2 {3-[2-(4-Chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyi}methanol
Under a stream of nitrogen, 210 mg of 6-bromo-2-(4-chlorophenyl)imidazo[ 1,2-α]pyridine,
155 mg of 3-(hydroxymethyl)phenylboronic acid and 24 mg of tetrakis(triphenylphosphine)-
palladium are placed in a microwave tube containing 3 ml of toluene degassed beforehand under a
stream of nitrogen, 3 ml of acetonitrile and 3 ml of a 2M solution of sodium carbonate. The tube
is placed in a microwave apparatus and irradiated at 150°C for 15min. The organic phase is
separated and dried and the filtrate is concentrated under reduced pressure. The residue obtained
is taken up with dichloromethane. The precipitate is recovered by filtration, washed with
dichloromethane and dried in a desiccator under reduced pressure. 175 mg of compound are
obtained. Mp = 181 - 182°C. 1H NMR (DMSO-d6, 6 in ppm): 4.57 (d, J = 5.5 Hz, 2H); 5.23 (t, J
= 5.6 Hz, 1H); from 7.28 to 7.71 (m, 8H); 7.97 (m, J = 8.5 Hz, 2H); 8.41 (s, 1H); 8.84 (m, 1H).
M+H = 335.
Example 6: {3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yI]phenyl} methanol
hydrochloride (1:1) (compound 26 of the table)
2.37 g of {3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol are suspended in
80 ml of dichloromethane; 4.26 ml of a 5N solution of hydrochloric acid in 2-propanol are added
thereto, dropwise and with stirring, and the mixture is stirred at ambient temperature for 2 hours.
The reaction mixture is then concentrated under reduced pressure. The residue solid is taken up
with diisopropyl ether and the precipitate is recovered by filtration, washed with dichloromethane
and then ethyl acetate and filter-dried. The solid is dissolved at ambient temperature with the
minimum amount of methanol and then reprecipitated using diisopropyl ether. The precipitate is
recovered by filtration and dried in an oven under reduced pressure at 60°C. 2.23 g of pale yellow
solid are obtained. Mp = 244 - 246°C. 1H NMR (DMSO-d6, δ in ppm): 4.59 (s, 2H); from 7.36 to
7.55 (m, 2H); from 7.58 to 7.74 (m, 4H); 7.96 (d, J = 9.4 Hz, 1H); 8.05 (m, J = 8.7 Hz, 2H); 8.14
(dd, J = 9.3 Hz and 1.7 Hz, lH);8.70(s, lH);9.15(m, 1H). M+H = 335.
Example 7: 6-[3-(4-Chlorophenoxymethyl)phenyl]-2-p-tolylimidazo[l,2-α]pyridine
(compound 31 of the table)
200 mg of [3-(2-p-tolylimidazo[l,2-α]pyridin-6-yl)phenyl]methanol (Example 3) are dissolved in
20 ml of dry tetrahydrofuran, 123 mg of p-chlorophenol, 193 mg of tributylphosphine and 210 mg

of l,l'-azodicarbonyldipiperidine are added thereto and the mixture is left to stir at ambient
temperature for 16 h. The solvent is evaporated off under reduced pressure. The residue is taken
up with 10 ml of ethyl acetate, the precipitate is removed, the filtrate is concentrated and the
residue is purified by chromatography. The solid obtained is taken up with petroleum ether and
the precipitate is recovered by filtration and dried under reduced pressure. 52 mg of compound are
obtained. Mp = 182 - 184°C. 1HNMR (DMSO-d6, δ in ppm): 2.32 (s, 3H); 5.17 (s, 2H); 7.06 (d,
J = 7 Hz, 2H); 7.23 (d, J = 7.2 Hz, 2H); 7.32 (d, J = 7.3 Hz, 2H); from 7.40 to 7.80 (m, 6H); 7.84
(m, J = 7.8 Hz, 2H); 8.32 (s, 1H); 8.86 (m, 1H). M+H = 425.
Example 8: 2-{3-[2-(4-Chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}propan-2-ol
(compound 39 of the table)
8.1 1 - {3-[2-(4-Chloropheny I)imidazo [ 1,2-α] py ridin-6-y 1] phenyl} ethanone
300 mg of 6-bromo-2-(4-chlorophenyI)imidazo[l,2-α]pyridine (prepared as described in 5.1),
240 mg of 3-acetylboronic acid and 34 mg of tetrakis(triphenylphosphine)palladium are mixed in
a microwave tube containing 4.5 ml of acetonitrile, 4.5 ml of toluene and 4.5 ml of a 2M solution
of sodium hydrogen carbonate. The tube is placed in a microwave apparatus and irradiated at 150°
C for 15 min. The organic phase is separated, dried and concentrated under reduced pressure. A
solid residue is obtained which is triturated in a mixture of 3 ml of dichloromethane and 3 ml of
diisopropyl ether for 30 min. The precipitate is recovered by filtration, washed with diisopropyl
ether and dried in a desiccator under reduced pressure. 209 mg of compound are obtained.
Mp=173-175°C.
8.2 2-{3-[2-(4-Chlorophenyl)imidazo[1^2-α]pyridin-6-yl]phenyl}propan-2-ol
Under a stream of nitrogen, 150 mg of the compound obtained in stage 8.1 are placed in a round-
bottomed flask and dissolved in a mixture of 20 ml of dry diethyl ether and 10 ml of dry
tetrahydrofuran. The mixture is cooled in an ice bath and 1.3 ml of a 1M solution of methyl
magnesium bromide in dibutyl ether are added dropwise. The mixture is left to stir in the ice bath
for one hour, and then 5 ml of a saturated aqueous solution of ammonium chloride are added. The
organic phase is separated, dried over sodium sulphate and concentrated under reduced pressure.
The residue is purified by silica gel chromatography, elution being carried out with a 99/1
dichloromethane/methanol mixture. The solid obtained is triturated in diisopropyl ether and
recovered by filtration and then dried in a dessicator under reduced pressure. 65 mg of compound
are obtained. Mp = 166 - 168°C. 1H NMR (DMSO-d6, δ in ppm): 1.47 (s, 6H); 5.06 (s, 1H); from
7.33 to 7.69 (m, 7H); 7.78 (m, 1H); 7.97 (m, J = 8.5 Hz, 2H); 8.42 (s, 1H); 8.83 (m, 1H). M+H =
363.
Example 9: {2-[2-(4-Chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol (compound

40 of the table)
Under a stream of nitrogen, 200 mg of 6-bromo-2-(4-chlorophenyl)imidazo[l,2-α]pyridine
(prepared as described in 5.1), 148 mg of 2-(hydroxymethyl)phenyl boronic acid and 22.5 mg of
tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing a mixture of
3 ml of acetonitrile, 3 ml of toluene and 3 ml of a 2M solution of sodium hydrogen carbonate. The
tube is placed in a microwave apparatus and irradiated at 150°C for 15 min. The organic phase is
separated, dried and concentrated under reduced pressure. The residue is purified by silica gel
chromatography, elution being carried out with a 98/2 dichloromethane/methanol mixture. The
solid obtained is triturated in diisopropyl ether and recovered by filtration and then dried in a
dessicator under reduced pressure. 127 mg of compound are obtained. Mp= 164 - 166°C. 1H
NMR (DMSO-d6, δ in ppm): 4.44 (d, J = 5.6 Hz, 2H); 5.19 (t, J = 5.4 Hz, 1H); from 7.25 to 7.64
(m, 8H); 7.98 (m, J = 8.3 Hz, 2H); 8.41 (s, IH); 8.54 (m, 1H). M+H = 335.
Example 10: {2-[2-(4-ChIorophenyI)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
hydrochloride (1:1) (compound 41 of the table)
40 mg of {2-[2-(4-Chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol are suspended in
1.5 ml of ethanol; 1.79 ml of a 0.1N solution of hydrochloric acid in 2-propanol are added thereto,
dropwise and with stirring, and the mixture is stirred at ambient temperature for 30 minutes. The
reaction mixture is then concentrated under reduced pressure. The residue solid is taken up with
ethanol and the precipitate is recovered by filtration, washed with ethanol and then with diethyl
ether and filter-dried. The product is dried in an oven under reduced pressure at 60°C. 17 mg of
white solid are obtained. Mp = 238 - 239°C. 1H NMR (DMSO-d6, δ in ppm): 4.50 (s, 2H); from
7.36 to 7,54 (m, 3H); from 7.60 to 7.70 (m, 3H); 7.77 (m, IH); 7.86 (d, J = 7.7 Hz, 1H); 8.14 (d, J
= 9.2 Hz, 2H); 8.73 (s, IH); 8.86 (s, IH). M+H = 335.
Example 11: Racemic l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
(compound 42 of the table)
164mg of sodium borohydride are added portionwise to 150mg of l-{3-[2-(4-ch!orophenyl)
imidazo[l,2-α]pyridin-6-yl]phenyl}ethanone (compound obtained in 8.1) dissolved in 20 ml of
methanol. The mixture is then stirred at ambient temperature for one hour and the solvent is then
evaporated off under reduced pressure. The residue is taken up in between water and
dichloromethane, the organic phase is separated by settling out and dried over sodium sulphate
and the solvent is then evaporated off under reduced pressure. The residue is triturated in
diisopropyl ether and recovered by filtration and then dried in a dessicator under reduced pressure.
124 mg of compound are obtained. Mp = 174 - 176°C. 1H NMR (DMSO-d6, δ in ppm): 1.37 (d, J
= 6.5 Hz, 3H); 4.79 (m, IH); 5.19 (d, J = 4.2 Hz, IH); from 7.31 to 7.69 (m, 8H) ; 7.97 (m, J = 8.6
Hz, 2H); 8.41 (s, IH); 8.84 (m, IH). M+H = 349.

Example 12: Dextrorotatory enantiomer of l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-
yl]phenyl}ethanol (compound 60 of the table)
263 mg of racemic l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
(compound no. 42, Example 11) are loaded onto a ChiralPAK AD DAICEL 20um 50 x 250 mm
column. Elution is carried out with an 80/20 mixture of n-heptane and 2-propanol. After
crystallization from diisopropyl ether, 115mg of compound which is the least retained are
obtained. Mp = 168 - 170°C. []D = +14.3° (c = 0.4; MeOH). 1H NMR (DMSO-d6, δ in ppm):
1.36 (d, J = 6.2 Hz, 3H); 4.79 (m, 1H); 5.20 (d, J = 4.3 Hz, 1H); from 7.31 to 7.69 (m, 8H) ; 7.97
(m, J = 8.6 Hz, 2H); 8.41 (s, 1H); 8.84 (m, 1H). M+H = 349.
Example 13: Levorotatory enantiomer of l-{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-
yl]phenyl}ethanol (compound 61 of the table)
By carrying out the process as described in Example 12, and using 263 mg of racemic l-{3-[2-(4-
chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol, 112 mg of compound which is the most
retained are obtained. Mp = 168 - 170°C. []D = -13.6° (c = 0.41; MeOH). 1HNMR (DMSO-d6, δ in ppm): 1.37 (d, J = 6.6 Hz, 3H); 4.79 (m, 1H); 5.19 (d, J = 4.3 Hz, 1H); from 7.31 to 7.69 (m,
8H); 7.97 (m, J = 8.7 Hz, 2H); 8.41 (s, 1H); 8.84 (m, 1H). M+H = 349.
REPRESENTATIVE EXAMPLES
In this table:
the "o/m/p" column gives the position of substitution of the group on the phenyl
ring, "ortho/meta/para"; Ph signifies phenyl; C5H9 signifies cyclopentyl; C4H8N signifies
pyrrolidin-1-yl;
The "Mp" column gives the melting points of the products in degrees Celsius (°C) or, when
the products have been isolated in the form of an amorphous solid or of an oil, they are
characterized by their mass [M+H];
in the "salt/base" column, "-" represents a compound in the form of a free base, whereas
"HC1" represents a compound in hydrochloride form and the ratio between parentheses is the
(acid:base) ratio.








The compounds according to the invention were the subject of pharmacological assays for
determining their modulatory effect on Nurr-1/NOT.
Evaluation of the in vitro activity on N2A cells
Assays consisted in measuring the in vitro activity of the compounds of the invention on a cell
line (N2A) endogenously expressing the mouse Nurrl receptor and stably transfected with the
NOT binding response element (NBRE) coupled to the luciferase reporter gene. The EC50 values
are between 0.01 and 1000 nM. The assays were carried out according to the procedure described
below.
The Neuro-2A cell line comes from a standard commercial source (ATCC). The Neuro-2A clone
was obtained from a spontaneous tumour originating from an A albino mouse strain, by R.J Klebe
et col. This Neuro-2A line is subsequently stably transfected with 8NBRE-luciferase. The
N2A-8NBRE cells are cultured until confluence in 75 cm2 culture flasks containing DMEM
supplemented with 10% of foetal calf serum, 4.5 g/1 of glucose and 0.4 mg/ml of geneticin. After
a week of culture, the cells are recovered with 0.25% trypsin for 30 seconds and then resuspended
in DMEM without phenol red, containing 4.5 g/1 of glucose and 10% of Hyclone delipidized
serum, and deposited into transparent-bottom 96-well white plates. The cells are deposited at a
rate of 60 000 per well in 75 ul for 24 hours before the addition of the products. The products are
applied in 25 ul and incubated for a further 24 hours. On the day of the measurement, an
equivalent volume (100 ul) of Steadylite are added to each well and then left for a period of 30
minutes in order to obtain complete cell lysis and maximum signal production. The plates are
subsequently measured in a luminescence counter for microplates after having been sealed with an
adhesive film. The products are prepared in the form of a stock solution at 102M and then diluted
in 100% of DMSO. Each product concentration is prediluted in culture medium before incubation
with the cells, thus containing 0.625% final concentration of DMSO.
For example, compounds No. 17, 31, 39 and 40 of the table showed an EC50 value of 3.6 nM,
14 nM, 0.7 nM and 0.7 nM, respectively.
Evaluation of the binding to the human NOT receptor
The direct binding between compounds of the invention and the human NOT receptor was
evaluated using SPR (surface plasmon resonance) technology. In this assay, the protein is
immobilized covalently to the matrix and the molecule to be studied is injected into the chamber
containing the sensor chip (biosensor or reactive surface). The signal is directly proportional to
the amount of product bound to the protein. The binding assays were carried out in a BIACORE
S51 instrument (Biacore Inc., Piscataway N.J.). The GST-NOT (NOT-FL) whole protein was
provided by Invitrogen (PV3265).
The NOT ligand-binding domain (His-Thr-NOT 329-598) was expressed and purified as
described in Nature 423, 555-560. The two proteins, diluted to a concentration of 20 ug/ml in an

acetate buffer, pH 5.0, containing 5 mM of DTT, were immobilized on a carboxymethyl 5'
dextran surface (CM5 sensor chip, Biacore Inc.) by amine coupling according to the protocol
recommended by Biacore, elution being carried with an HBS-N buffer (10 mM HEPES, 0.15 M
NaCl, 3 mM EDTA, pH 7.4). Approximately 10000-15000 resonance units (RU) of the proteins
are captured on the surface of the CM5 sensor chip. The stock solutions of the compounds to be
studied, at 1.5 mM in DMSO, are serially diluted in elution buffer (50 mM HEPES pH 8; 150 mM
NaCl; 10 mM MgCl2; 2% DMSO, 1 mM DTT) to concentrations ranging from 3.75 to 0.1 uM.
Each product concentration is injected at 4°C for 1 minute at 30 ul/min. The dissociation was
recorded for 5 minutes without any other procedure for regenerating the surface. The signals
obtained are corrected by testing each product concentration on an unmodified dextran surface
(blank). The signal due to the migration buffer is deducted from the total signal ("double
referencing") as is the effect of the DMSO. The signal analysis is carried out using the Biacore
S51 analytical software (version 1.2.1). The compounds are subsequently classified according to
their maximum binding level and to kinetic parameters for binding to the immobilized protein.
By way of example, compound No. 9 has a high affinity and compound No. 10 has a medium
affinity.
It therefore appears that the compounds according to the invention have a NOT-modulating effect.
The compounds according to the invention can therefore be used for the preparation of
medicaments for their therapeutic use in the treatment or prevention of diseases involving NOT
receptors.
Thus, according to another of its aspects, a subject of the invention is medicaments which
comprise a compound of formula (I), or an addition salt of the latter with a pharmaceutically
acceptable acid.
These medicaments find their use in therapeutics, in particular in the treatment and prevention of
neurodegenerative diseases, such as, for example, Parkinson's Disease, Alzheimer's Disease,
tauopathies (for example, progressive supranuclear palsy, frontotemporal dementia, corticobasal
degeneration, Pick's Disease), multiple sclerosis; cerebral traumas such as ischemia and cranial
traumas and epilepsy; psychiatric diseases such as schizophrenia, depression, substance
dependency, attention deficit hyperactivity disorders; inflammatory diseases such as vascular
pathologies, atherosclerosis, joint inflammations, arthrosis, rheumatoid arthritis, osteoarthritis,
allergic inflammatory diseases such as asthma, and finally, the treatment of osteoporosis or
cancers.
These compounds could also be used as a treatment associated with stem cell transplants
and/or grafts.
According to another of its aspects, the present invention relates to pharmaceutical compositions
comprising, as active ingredient, a 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 of said compound, and also at least one pharmaceutically
acceptable excipient.
Said excipients are selected according to the pharmaceutical form and the method of
administration desired, from the usual excipients which are known to those skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or
rectal administration, the active ingredient of formula (I) above, or its salt, can be administered in
unit administration form, as a mixture with conventional pharmaceutical excipients, to animals or
to human beings for the prophylaxis or the treatment of the disorders or the diseases above.
The appropriate unit administration forms include oral forms such as tablets, soft or hard
gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal,
intratracheal, intraocular and intranasal administration forms, forms for administration by
inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms,
rectal administration forms, and implants. For topical application, the compounds according to the
invention can be used in creams, gels, ointments or lotions.
By way of example, a unit administration form of a compound according to the invention
in tablet form can comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscarmellose 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
There may be specific cases where higher or lower dosages are appropriate; such dosages
do not depart from the scope of the invention. According to customary practice, the dosage
appropriate for each patient is determined by the physician according to the method of
administration and the weight and the response of said patient.
According to another of its aspects, the present invention also relates to a method for
treating the pathologies indicated above, which comprises the administration, to a patient, of an
effective dose of a compound according to the invention, or one of its pharmaceutically acceptable
salts.

CLAIMS
1. Compound corresponding to formula (I):

in which:
R1 is:
a phenyl group or a naphthyl group, it being possible for these two groups to be
optionally substituted with one or more atoms or groups selected, independently
of one another, from the following atoms or groups: halogen, (C1-C6)alkyl, (C3-C7)
cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)alkoxy,
(C3-C7)cycloalkoxy, (C3-C7)cycloalkyl(C1-C3)alkyleneoxy, halo(C1-C6)alkoxy,
(C1-C6)thioalkyl, -S(O)(C1-C6)alkyl, -S(O)2(C1-C6-alkyl), hydroxyl, cyano, nitro,
hydroxy(C1-C6)alkylene, NRaRb(C1-C6)alkylene, (C1-C6)alkoxy(C1-C6)
alkyleneoxy, NRaRb, CONRaRb, SO2NRaRb, NRcCORd, OC(O)NRaRb, NRcC
(O)ORe, NRcSO2Re, aryl(C1-C6)alkylene, aryl or heteroaryl, the aryl or the
heteroaryl being optionally substituted with one or more substituents selected
from a halogen, or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)
alkylene, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl,
nitro or cyano group;
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C]-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano
group;
R4 is:
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents chosen

from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C3-C7)cycloalkyl(C1-C3)-
alkyleneoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro, cyano, (C1-C6)alkyl(CO)-,
CONRaRb, NRcCORd, OC(O)NRaRb, NRcC(O)ORe or aryl group, the aryl being
optionally substituted with one or more substituents selected from a halogen or a (C1-C6)
alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C5)alkyl, (C1-C6)
alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano group;
Ra and Rb are, independently of one another,
a hydrogen atom or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
aryl(C1-C6)alkylene or aryl group;
or Ra and Rb form, together with the nitrogen atom which bears them, an azetidine, pyrrolidine,
piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this
group being optionally substituted with a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl
(C1-C6)alkylene, aryl or aryl(C1-C6)alkylene group;
Re and Rd are, independently of one another,
a hydrogen atom or a (C1-C,,)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
aryl(C1-C6)alkylene and aryl group;
or Re and Rd together form a (C2-C5)alkylene group;
Re is
a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, aryl(C1-C6)alkylene
and aryl group;
or Re and Re together form a (C2-C5)alkylene group;
Rfis
a halogen atom or a (C1-C6)alkoxy, halo(C1-C5)alkoxy, (C3-C7)cycloalkoxy, (C3-C7)
cycloalkyl(C1-C6)alkyleneoxy, hydroxyl, cyano, NRaRb, C(O)NRaRb, NRcCORd, OC(O)
NRaRb, NRcCOORe, SO2NRaRb, NRcSO2Re, aryl(C1-C6)alkylene or aryl group, the aryl
being optionally substituted with one or more substituents selected from a halogen or a
(C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)
alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano group;
in the form of a base or of an addition salt with an acid.
2. Compound of formula (I) according to Claim 1, characterized in that:
R1 is a naphthyl group or a phenyl group which may be optionally substituted with one or more
atoms or groups selected, independently of one another, from the following atoms or groups:
halogen, (C1-C5)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkylene, (C1-C6)alkoxy, (C3-C7)
cycloalkyl(C1-C6)alkoxy, hydroxyl, cyano, nitro, NRaRb, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)alkyl, halo(C1-C6)alkoxy or aryl, the aryl being optionally substituted with

one or more substituents selected from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)
cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl,
nitro or cyano group;
in the form of a base or of an addition salt with an acid.
3. Compound of formula (I) according to Claim 1 or 2, characterized in that:
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group optionally
substituted with an Rf group;
R4 is:
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group optionally
substituted with an Rf group,
an aryl group optionally substituted with one or more substituents selected from a halogen
or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl,
(C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C3-C7)cycloalkyl(C1-C3)alkyleneoxy, halo(C1-C6)
alkoxy, NRaRb, hydroxyl, nitro, cyano, (C1-C6)alkyl(CO)-, NRcCORd or aryl group, the
aryl being optionally substituted with one or more substituents selected from a halogen or
a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene, halo(C1-C6)alkyl,
(C1-C6)alkoxy, halo(C1-C5)alkoxy, NRaRb, hydroxyl, nitro or cyano group;
in the form of a base or of an addition salt with an acid.
4. Compound of formula (I) according to any one of Claims 1 to 3, characterized in that:
R3 R2
the substituent R4 ° is in the meta-position on the phenyl; in the form of a base or of an
addition salt with an acid.
5. Compound of formula (I) according to Claim 1 or 3, characterized in that
Rt is a hydrogen atom and
R2 and R3 are, independently of one another, a hydrogen atom or a (C1-C6)alkyl, (C3-C7)cycloalkyl
or (C3-C7)cycloalkyl(C|-C3)alkylene group optionally substituted with an Rf group;
in the form of a base or of an addition salt with an acid.
6. Compound of formula (1) according to Claim 1, characterized in that Ri is a naphthyl group or a
phenyl group which can be optionally substituted with one or more atoms or groups selected,
independently of one another, from the following atoms or groups: halogen, (C1-C6)alkyl, (C3-C7)
cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkylene, (C1-C6)alkoxy, (C3-C7)cycloalkyl(C1-C6)alkoxy,
hydroxyl, cyano, nitro, NRaRb, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkyl,
halo(C1-C6)alkoxy or aryl, the aryl being optionally substituted with one or more substituents

selected from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycIoalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano group, in
the form of a base or of an addition salt with an acid;
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycIoalkyl or (C3-C7)cycloalkyl(C1-C3)alkyIene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyI, (C3-C7)cycloaIkyI(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano
group;
R4 is:
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyI(C1-C3)alkylene group, this group
being optionally substituted with an Rf group,
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, nitro, cyano, (C1-C6)alkyl(CO)- orNRcCORd group;
in the form of a base or of an addition salt with an acid.
7. Compound of formula (I) according to Claim 1, characterized in that
Ri is a naphthyl group or a phenyl group which can be optionally substituted with one or more
atoms or groups selected, independently of one another, from the following atoms or groups:
halogen, (C1-C5)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkylene, (C1-C6)alkoxy, (C3-C7)
cycloalkyl(C1-C6)alkoxy, hydroxyl, cyano, nitro, NRaRb, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)alkyl or halo(C1-C6)aIkoxy,
R2 and R3 are, independently of one another,
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group
being optionally substituted with an Rf group;
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)alkyl, (C1-C6)aIkoxy, halo(C1-C6)alkoxy, NRaRb, hydroxyl, nitro or cyano
group;
R4 is:
a hydrogen atom,
a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, this group

being optionally substituted with an Rf group,
an aryl group, the aryl being optionally substituted with one or more substituents selected
from a halogen or a (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C3)alkylene,
halo(C1-C6)aIkyl, nitro, cyano, (C1-C6)alkyl(CO)- or NRcCORd group;
in the form of a base or of an addition salt with an acid.
8. Compounds
[4-(2-phenylimidazo[l,2-α]pyridin-6-yl)phenyl]methanol
[3-(2-phenylimidazo[ 1,2-α]pyridin-6-yl)phenyl]methanol
{4-[2-(4-pyrrolidin-l-ylphenyl)imidazo[l,2-α]pyridin-6-yl]phenyl} methanol
[4-(2-biphenyl-4-ylimidazo[ 1,2-α]pyridin-6-yl)phenyl]methanol
3-[6-(4-hydroxymethylphenyI)imidazo[l,2-o]pyridin-2-yl]benzonitrile
3 - [6-(3 -hydroxymethylpheny l)im idazo[ 1,2-α] pyridin-2-yl]benzon itri le
3-{6-[3-(2-methoxyethoxymethyl)phenyl]imidazo[l,2-]pyridin-2-yl}benzonitrile
4-[6-(3-hydroxymethylphenyl)imidazo[l,2-]pyridin-2-yl]benzonitrile
[3-[2-(naphthalen-2-yl)imidazo[l,2-α]pyridin-6-yl]phenyl]methanol
[3-(2-/7-tolylimidazo[ 1,2-α]pyridin-6-yl)phenyl]methanol
{3-[2-(4-pyrrolidin-l-ylphenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(3-trifluoromethoxyphenyl)imidazo[l,2-]pyridin-6-yl]phenyl}methanol
{3-[2-(4-nitrophenyl)imidazo[l,2-]pyridin-6-yl]phenyl}methanol
{4-[2-(4-diethylaminophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl} methanol
[3-(2-naphthalen-1 -ylimidazo[ 1,2-α]pyridin-6-yI)phenyl]methanol
{3-[2-(2,4-dimethyIphenyl)imidazo[l,2-]pyridin-6-yl]phenyl}methanol
6-[3-(2-methoxyethoxymethyl)phenyl]-2-naphthalen-2-ylimidazo[l,2-α]pyridine
{3-[2-(4-methoxyphenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(3-methoxyphenyl)imidazo[l,2-o]pyridin-6-yl]phenyl}methanol
{3-[2-(2-methoxyphenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(2,4-dimethoxyphenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(4-fluorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(3,5-difluorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(3-fluoro-5-trifluoromethylphenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(4-chlorophenyl)imidazo[l,2-]pyridin-6-yl]phenyl}methanol
{3-[2-(4-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol hydrochloride (1:1)
{ 3 - [2-(3 -ch lorophenyl )imidazo[ 1,2-α] pyridin-6-yl] phenyl} methanol
{3-[2-(4-chloro-3-methylphenyl)imidazo[l,2-]pyridin-6-yl]phenyl}methanol
{3-[2-(3,4-dichlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol
{3-[2-(3-fluorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}methanol



racemic l-{3-[2-(2-chIorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
racemic l-{3-[2-(3-fluorophenyl)imidazo[1,2-α]pyridin-6-yl]phenyl}ethanol
racemic l-{3-[2-(3-chlorophenyl)imidazo[l,2-α]pyridin-6-yl]phenyl}ethanol
4-[6-(3-hydroxymethylphenyI)imidazotl,2-α]pyridin-2-yl]phenol
in the form of a base or of an addition salt.
9. Medicament, characterized in that it comprises a compound of formula (I) according to any one
of Claims 1 to 8, or an addition salt of this compound with a pharmaceutically acceptable acid.
10. Pharmaceutical composition, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 8, or a pharmaceutically acceptable salt of this compound,
and also at least one pharmaceutically acceptable excipient.
11. Use of a compound of formula (I) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in the treatment or prevention of neurodegenerative diseases.
12. Use of a compound of formula (I) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in the treatment or prevention of cerebral traumas and epilepsy.
13. Use of a compound of formula (I) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in the treatment or prevention of psychiatric diseases.
14. Use of a compound of formula (I) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in the treatment or prevention of inflammatory diseases.
15. Use of a compound of formula (I) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in the treatment or prevention of osteoporosis and cancers.
16. Use of a compound of formula (I) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in treatment combined with stem cell transplants and/or grafts.
17. Use of a compound of formula (1) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in the treatment or prevention of Parkinson's Disease, Alzheimer's Disease,
tauopathies and multiple sclerosis.
18. Use of a compound of formula (I) according to any one of Claims 1 to 8, for the preparation of
a medicament for use in the treatment or prevention of schizophrenia, depression, substance
dependency and attention deficit hyperactivity disorders.
19. Process for obtaining the compounds of formula (I) according to Claim 1, characterized in that
they are obtained by means of a coupling reaction, catalysed by a metal, between a
2-arylimidazopyridine of general formula (II), in which Hal is a halogen atom, and a derivative of
general formula (III), in which X is a derivative of boron or of tin, and R5 is the group.

The invention relates to the derivatives of general formula (1) in which: R1 is: a phenyl group or a naphthyl group, it
being possible for these two groups to be optionally substituted; R2 and R3 are, independently of one another, a hydrogen atom, a (C1-
C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, which is optionally substituted; an optionally substituted
aryl group; R4 is: a hydrogen atom, a (C1-C6)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C3)alkylene group, which is optionally
substituted; an aryl group optionally substituted with one or more substituents in the form of a base or of an addition salt with an acid.

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Patent Number 270341
Indian Patent Application Number 802/KOLNP/2009
PG Journal Number 51/2015
Publication Date 18-Dec-2015
Grant Date 14-Dec-2015
Date of Filing 02-Mar-2009
Name of Patentee SANOFI-AVENTIS
Applicant Address 174, AVENUE DE FRANCE, F-75013 PARIS
Inventors:
# Inventor's Name Inventor's Address
1 ALMARIO GARCIA, ANTONIO C/O SANOFI-AVENTIS, DÉPARTEMENT BREVETS, 174 AVENUE DE FRANCE, F-75013 PARIS
2 OLIVIER, ANNE C/O SANOFI-AVENTIS, DÉPARTEMENT BREVETS, 174 AVENUE DE FRANCE, F-75013 PARIS
3 LARDENOIS, PATRICK C/O SANOFI-AVENTIS, DÉPARTEMENT BREVETS, 174 AVENUE DE FRANCE, F-75013 PARIS
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/FR2007/001517
PCT International Filing date 2007-09-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0608350 2006-09-22 France