DIPHENYL-PYRAZOLOPYRIDINE DERIVATIVES, PREPARATION
THEREOF, AND USE THEREOF AS NUCLEAR RECEPTOR NOT MODULATORS
The present invention relates to diphenylpyrazolopyridine derivatives, to their
preparation and to their therapeutic use in the treatment or prevention of diseases involving
the Nurr-1 nuclear receptors, also known as NR4A2, NOT, TINUR, RNR-1 and HZF3.
One subject of the present invention is the compounds of formula (I):

in which:
R represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
X represents one or more substituents chosen from a hydrogen or halogen atom and a group
(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)aIkoxy, halo(C1-C6)alkoxy, cyano, hydroxyl or
hydroxy(C1-C6)alkyl;
Y represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
Rl represents a group NR2R3 or OR4;
R2 and R3 represent, independently of each other, a hydrogen atom or a group (C1 -C6)alkyl,
hydroxy(C1-C6)alkylor oxo(C1-C6)alkyl, or alternatively R2 and R3 form, with the
nitrogen atom that bears them, a heterocycle optionally substituted with a group
(C1-C6)alkyl, hydroxyl or oxo,
R4 represents a group (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl, in the form
of base or of acid-addition salt.
The compounds of formula (I) may comprise one or more asymmetric carbon atoms.
They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and
diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the
invention.
The compounds of formula (I) may exist in the form of bases or of acid-addition
salts. Such addition salts form part of the invention.
These salts 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, namely 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 group (Cx-Ct): a group comprising between x and t carbon atoms;
a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
an alkyl group: a linear, branched or cyclic, saturated aliphatic group, optionally
substituted with a linear, branched or cyclic, saturated alkyl group. Examples that may
be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, cyclo-
propylmethyl, etc. groups;
an alkoxy group: a radical -O-alkyl in which the alkyl group is as defined previously;
a haloalkyl group: an alkyl group substituted with one or more identical or different
halogen atoms. Examples that may be mentioned include the groups CF3, CH2CF3, CHF2
and CC13;
a hydroxyalkyl group: an alkyl group substituted with a hydroxyl group; examples that
may be mentioned include CH2OH, CH2CH2OH, etc.;
an oxoalkyl group: an alkyl group substituted with an oxo group (C=O); examples that
may be mentioned include CH3CO, CH3COCH2, etc.;
a haloalkoxy group: a radical -O-alkyl in which the alkyl group is as defined previously
and substituted with one or more identical or different halogen atoms. Examples that
may be mentioned include the groups OCF3, OCHF2 and OCCl3;
an aryl group: a monocyclic or bicyclic aromatic group comprising from 6 to 10 atoms.
Examples of aryl groups that may be mentioned include phenyl and naphthyl;
a heterocyclic group: a saturated, nitrogenous, optionally bridged cyclic group,
comprising between 5 and 9 carbon atoms, at least one nitrogen atom and optionally
comprising between 1 and 3 additional heteroatoms, such as oxygen, nitrogen or sulfur.
Mention may be made especially of piperidyl, piperazinyl, pyrrolidinyl, morpholinyl,
etc. groups.
Among the compounds of formula (I) that are subjects of the invention, a first group
of compounds is formed by the compounds for which:
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a halogen atom and a group
(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
Rl represents a group OR4,
R4 represents a methyl group, in the form of base or of acid-addition salt.
Among the compounds of formula (I) that are subjects of the invention, a second
group of compounds is formed by the compounds for which:
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl,
trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
Y represents a hydrogen, chlorine or fluorine atom or a methyl group,
Rl represents a group OR4,
R4 represents a methyl group, in the form of base or of acid-addition salt.
Among the compounds of formula (I) that are subjects of the invention, a third
group of compounds is formed by the compounds for which:
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a halogen atom and a group
(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
Rl represents a group NR2R3,
R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl,
isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that
bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl
group, in the form of base or of acid-addition salt.
Among the compounds of formula (I) that are subjects of the invention, a fourth
group of compounds is formed by the compounds for which:
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl,
trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
Y represents a hydrogen or chlorine atom or a methyl group,
Rl represents a group NR2R3,
R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl,
isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that
bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl
group, in the form of base or of acid-addition salt.
The combinations of groups one to four as defined above also form part of the invention.
Among the compounds of formula (I) that are subjects of the invention, mention
may be made especially of the following compounds:
• Methyl 3-[2-(4-chlorophenyl)pyrazolo[l,5-a]pyridin-5-yl]benzoate
• 3-[2-(4-Chlorophenyl)pyrazolo[ 1,5-a]pyridm-5-yl]benzarnide
• 3-[2-(4-Chlorophenyl)pyrazolo[ 1 ,5-a]pyridin-5-yl]-N,N-dhneihylbenzaimde
• 3 -[2 -(4-Chlorophenyl)pyrazolo [ 1,5 -a]pyridin-5 -yl] -N-methylbenzamide
• Methyl 3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridm-5-yl]benzoate
• 3-[2-(4-Fluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]-N-methylbenzamide
• 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N'-isopropylben2anude
• 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridm-5-yl]-N,N-dimethylbenzmide
• {3-[2-(4-Fluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]phenyl}morpholin-4-yl-
methanone
• 3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-2,N-dimethylbenzamide
• 2-CWoro-5-[2-(4-fluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]-N-methylbenzamide
• 4-CMoro-3-[2-(4-fluorophenyl)pyra2olo[l,5-a]pyridin-5-yl3-N-methylbenzamide
• 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-4,N -dimethylbenzamide
• 2-Fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yI]-N'-methylbenzamide
• N-Cyclopropyl-3-[2-(4-fluorophenyl)pyra2olo[1,5-a]pyridin-5-yl]benzamide
• {3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]phenyl}pyrrolidin-l-
ylmethanone
• 3-[2-(2,6-Difluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl-methylbenzamide
• 3-[2-(2-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-inethylbenzamide
• N-Methyl-3-[2-(4-trifluoromethylphenyl)pyrazolo[l,5-a]pyridin-5-yl]benzamide
• 4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• 2-[2-(4-Fluorophenyl)pyra2olo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• {3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]phenyl}-(3-hydroxypyrrolidin-
l-yl)methanone
• 3-[2-(2,4-Difluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]-N-methylbenzamide
• N-Methyl-3-[2-(4-trifluoromethoxyphenyl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
• 3-[2-(3,4-Difluorophenyl)pyra2olo[1,5-a]pyridin-5-yl]-N-methylbenzainide
• 3-[2-(3,5-Difluorophenyl)pyrazolo[l;5-a]pyridin-5-yl]-N:-methylbenzamide
• 3-[2-(3-Fluoropheoyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• N-Methyl-3-(2-p-tolylpyrazolo[1,5-a]pyridin-5-yl)ben2amide
• 3-[2-(4-Methoxyphenyl)pyrazolo[l,5-a]pyridin-5-yl]-N-methylbenzamide
• 3-[2-(3,4-Dimethylphenyl)pyrazolo[l,5-a]pyridm-5-yl]-N-methylbenzamide
• 3-[2-(4-Cyanophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• 3-[2-(2,3-Difluorophenyl)pyrazolo[ 1,5-a]pyridm-5-yl]-N-memylbenzamide
• N-Methyl-3-o-tolylpyrazolo[l,5-a]pyridin-5-yl)benzamide
• 3-[3-Cldoro-2-(4-fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-N-methylbenzamide
In accordance with the invention, the compounds of general formula (I) may be
prepared according to the process described in Scheme 1.
According to Scheme 1, the compounds of general formula (la), in which Rl
represents OR4, R4 represents an alkyl group ALK, R represents a hydrogen atom, and X
and Y are as defined previously, may be prepared via a coupling reaction, catalysed with a
metal such as palladium, between a compound of general formula (II) in which R represents
a hydrogen atom, X is as defined previously and Hal represents a halogen atom, and a
derivative of general formula (HI) in which Y and ALK are as defined previously, and 2
represents a boron derivative.
According to Scheme 1, the compounds of general formula (lb), in which Rl
represents OR4, R represents a hydrogen atom and X and Y are as defined previously and
R4 represents a hydrogen atom, may be prepared via a hydrolysis reaction of the compounds
of general formula (la) with a base such as sodium hydroxide in an aqueous-alcoholic
medium.
According to Scheme 1 route A, the compounds of general formula (Ic) in which Rl
represents NR2R3, R represents a hydrogen atom and X, Y, R2 and R3 are as defined
previously may be prepared via a coupling reaction, catalysed with a metal such as
palladium, between a compound of general formula (II) in which R represents a hydrogen
atom, X is as defined previously and Hal represents a halogen atom, and a derivative of
general formula (TV) in which Y, R2 and R3 are as defined previously and Z represents a
boron derivative.
According to Scheme 1 route B, the compounds of general formula (Ic), in which Rl
represents NR2R3, R represents a hydrogen atom and X, Y, R2 and R3 are as defined
previously, may be prepared via a reaction between a compound of general formula (la), in
which Rl represents OR4, R4 represents an alkyl group ALK, R represents a hydrogen atom
and X and Y are as defined previously, and an amine of general formula (V) in which R2
and R3 are as defined previously, in the presence of trimemylalurninium in solution or else
complexed with a tertiary amine such as DABCO according to the method described by
D. Glynn, D. Bernier and S. Woodward in Tetrahedron Letters, 2008, 49, 5687-5688.
According to Scheme 1 route C the compounds of general formula (Ic), in which
Rl represents NR2R3, R represents a hydrogen atom and X, Y, R2 and R3 are as defined
previously, may be prepared via a reaction between a compound of general formula (lb), in
which Rl represents OR4, R represents a hydrogen atom, X and Y are as defined previously
and R4 represents a hydrogen atom, and an amine of general formula (V) in which R2 and
R3 are as defined previously, in the presence of an acid activator such as isobutyl
chloroformate.
According to Scheme 1 route D, the compounds of general formula (Ic), in which
Rl represents NR2R3, R represents a hydrogen atom and X, Y, R2 and R3 are as defined
previously, may be prepared via a coupling reaction, catalysed with a metal such as
palladium, between a compound of general formula (VI) in which R represents a hydrogen
atom, X is as defined previously and Z represents a boron derivative, and a derivative of
general formula (VH) in which Y, R2 and R3 are as defined previously and Hal represents a
halogen atom.
The compounds of general formula. (Ic) in which R2 and R3 each represent a
hydrogen atom may also be prepared according to the process described in Scheme 2.
Scheme 2
In Scheme 2, the compounds of general formula (Ic), in which Rl represents NH2, R
represents a hydrogen atom and X and Y are as defined previously, may be obtained via
hydrolysis of the nitriles of general formula (DC), for example using hydrogen peroxide in
the presence of base. The compounds of general formula (DC) may be obtained via a
coupling reaction, catalysed with a metal such as palladium, between a compound of general
formula (IT) in which R represents a hydrogen atom, X is as defined previously and Hal
represents a halogen atom, and a derivative of general formula (VHI) in which Y is as
defined previously, CN represents a cyano group and Z represents a boron derivative.
In accordance with the invention, the compounds of general formula (I) may be
prepared according to the process described in Scheme 3.

According to Scheme 3, the compounds of general formula (Id), in which X, Y and
Rl are as defined previously and R represents a halogen atom Hal, may be prepared via
electrophilic halogenation of compound (la) or (Ic), for example via chlorination, using an
agent such as N-chlorosuccinimide.
In accordance with the invention, the compounds of general formula (H) and (VI)
may be prepared according to the process described in Scheme 4.
In Scheme 4 route A, the compounds of general formula (II), in which X is as
defined previously, R represents a hydrogen atom and Hal represents a halogen atom, may
be prepared via the action of O-(mesitylenesmfonyl)hydroxylamine (MSH) on a compound
of general formula (XIII) in which X and Hal are as defined previously, for example
according to the method described by Y. Tamura, J.-H. Kim, Y. Miki, H. Hayashi, M. Ikeda,
in J. Net Chem., 1975,12,481.
In Scheme 4 route B, the compounds of general formula (II), in which X is as
defined previously, R represents a hydrogen atom and Hal represents a halogen atom, may
also be prepared via conversion of the compounds of general formula (XIII) into compounds
of general formula (XIV) in which X and Hal are as defined previously, via the action of an
acid anhydride such as trifluoroacetic anhydride in the presence of a base such as
triethylamine, followed by cyclization to compounds of general formula (II) in the presence
of a catalyst such as ferrous chloride, for example according to the method described by
K.S. Gudmundsson in Bioorg. Med. Chem., 2005,13, 5346.
Compounds (XIII) may be obtained from compounds (XII) via the action of
hydroxylamine. Compounds (XII) may be obtained from the picolines of general
formula (X) and from the esters of general formula (XI) in which X is as defined previously
and ALK represents an alkyl group, in the presence of a strong base, for example according
to the method described by K.S. Gudmundsson in Bioorg. Med. Chem., 2005,13, 5346.
Finally, compounds (VI) in which Z represents a boron derivative may be prepared
according to Scheme 3 via a coupling reaction, for example of bis(pinacolato)diboron, on
compounds (II), catalysed with a metal such as palladium according to the method described
by E.F. DiMauro and R.Vitullo in J.Org. Chem., 2006, 77(10), 3959.
In Schemes 1, 2, 3 and 4, the starting compounds and the reagents, when their
preparation method is not described, are commercially available or described in the
literature, or alternatively may be prepared according to methods that are described therein
or that are known to those skilled in the art.
According to another of its aspects, a subject of the invention is also the compound
of formula (VI-1). This compound is useful as an intermediate in the synthesis of the
compounds of formula (I).

The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, and serve merely to
illustrate the present invention. The numbers of the compounds given as examples refer to
those given in the table hereinbelow, which illustrates the chemical structures and physical
properties of a number of compounds according to the invention.
Example 1: Methyl 3-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzoate
(compound 1 of the table)
1.1 2-(4-Bromopyridin-2-yl)-l-(4-chlorophenyl)ethanone
Under a stream of nitrogen, 5g (29.07 mmol) of 4-bromo-2-methylpyridine and 11.27g
(61.04 mmol) of ethyl 4-chlorobenzoate are placed in a round-bottomed flask and dissolved
in 50 mL of anhydrous tetrahydrofuran. The solution is cooled to 5°C and 70 mL (70 mmol)
of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise.
After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5°C, and
100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl
acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is
extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried
over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, which is then
concentrated under reduced pressure. The powder obtained is used as solid deposit for a
chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1).
8.4 g (93%) of compound are obtained in the form of a yellow powder.
LC-MS:M+H = 310
1H NMR (DMSO) d (ppm): 4.6 (s, 2H); 6.4 (s, 1H); 7.4 (s, 1H); from 7.5 to 7.6 (m, 6H); 7.7
(s, 1H); 7.9 (d, 2H); 8.1 (d, 2H); 8.3 (d, 1H); 8.4 (d, 1H); 15.0 (s, 1H) (ketone/enol mixture:
40/60).
1.2 2-(4-Bromopyridm-2-yI)-l-(4-chlorophenyl)ethanoneoxune
8.4 g (27.05 mmol) of 2-(4-bromopyridin-2-yl)-l-(4-chlorophenyl)ethanone are placed in
150 mL of ethanol in a round-bottomed flask. 22 mL (272.56 mmol) of pyridine and 7.5 g
(107.93 mmol) of hydroxylamine monohydrochloride are added. The mixture is then stirred
for 5 hours at room temperature, and the reaction medium is then concentrated under
reduced pressure until a pasty yellow solid is obtained, which is taken up in 400 mL of ethyl
acetate and 400 mL of water. The organic phase is separated out and the aqueous phase is
extracted three times with 200 mL of ethyl acetate. The organic phases are then combined,
dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure:
8.1 g (91.9%) of compound are obtained in the form of a blue powder.
LC-MS:M+H = 325
1H NMR (DMSO) d (ppm): 4.3 (s, 2H); 7.45 (m, 2H); 7.50 (d, 1H); 7.55 (s, 1H); 7.75 (m,
2H); 8.35 (d, 1H); 11.65 (s, 1H).
13. 5-Bromo-2-(4-chlorophenyI)pyrazolo[1,5-a]pyridine
12.9 g (45.21 mmol) of ethyl 0-(2-mesitylenesulfonyl)acetohydroxarnate are placed in
30 mL of 1,4-dioxane in a round-bottomed flask. The solution is cooled to 0°C and 13.5 mL
(156.60 mmol) of perchloric acid (70% in water) are added. 10 mL of 1,4-dioxane are then
added and the medium is stirred vigorously for 2 hours 30 minutes at 0°C. The medium is
then poured into 350 mL of ice-cold water. The medium is left at about 0°C for 10 minutes,
and the white solid formed is then recovered by filtration on a sinter funnel (do not dry
completely, since the product is potentially explosive in dry form). The pasty white solid
obtained is washed with 350 mL of ice-cold water and then taken up in 250 mL of 1,2-
dichloroethane and 150 mL of brine cooled to about 5°C. The organic phase is recovered
and filtered through a hydrophobic cartridge. The filtrate is recovered and is added dropwise
to a solution, cooled to about 0°C, of 8.1 g (24.88 mmol) of 2-(4-bromopyridin-2-yl)-l-(4-
chlorophenyl)ethanone oxime (compound obtained in step 1.2) in 150 mL of 1,2-
dichloroethane.
After addition, the mixture is allowed to warm to room temperature and is stirred for
3 hours. 250 mL of dichloromethane, 200 mL of water and 100 mL of aqueous NaOH
solution (IN) are then successively added to the medium. The resulting mixture is stirred
and the phases are then allowed to separate by settling. The organic phase is separated out
and the aqueous phase is extracted with twice 200 mL of dichloromethane. The organic
phases are then combined, filtered on a hydrophobic cartridge (Radleys® 70mL
liquid/liquid extraction column) and then mixed with 15 g of silica. The filtrate is then
concentrated under reduced pressure. A brown powder is obtained, which is used as solid
deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and
dichloromethane (1/1). 5.8 g (75%) of compound are obtained in the form of a slightly
yellow fleecy solid.
LC-MS:M+H = 307.
1H NMR (DMSO) d (ppm): 7.0 (d, 1H); 7.1 (s, 1H); 7.6 (d, 2H); 8.0 (s, 1H); 8.1 (d, 2H); 8.7
(d, 1H).
1.4 Methyl 3-[2-(4-chlororophenyl)pyra2olo[l,5-a]pyridin-5-yl]benzoate
0.235 g (0.76 mmol) of 5-bromo-2-(4-chlorophenyl)pyra2olo[l,5-a]pyridine obtained in step
1.3, 0.165 g (0.92 mmol) of 3-methoxycarbonylphenylboronic acid, 0.750 g (2.30 mmol) of
caesium carbonate and 0.065 g (0.08 mmol) of [l,l'-bis(diphenylphosphino)-
ferrocene]dichloropalladium (H) are placed in a round-bottomed flask in the presence of
5 mL of a THF-water mixture (9/1). The medium is then maintained at 70°C for 1 hour
30 minutes, and is then cooled to room temperature and diluted with 30 mL of
dichloromethane and 30 mL of water. The two-phase medium is filtered on a hydrophobic
cartridge (Radleys® 70 mL liquid/liquid extraction column) and the filtrate is then
concentrated under reduced pressure: the residue obtained is chromatographed on silica gel,
eluting with a mixture of cyclohexane and ethyl acetate (8/2). 0.200 g (72%) of expected
compound is obtained in the form of a beige powder.
Melting point (°C): 180-182
LC-MS:M+H = 363
'H NMR (DMSO) d (ppm): 3.95 (s, 3H); 7.20 (s, 1H); 7.35 (d, 1H); 7.60 (d, 2H); 7.70 (t,
1H); from 8.00 to 8.20 (m, 5H); 8.35 (s, 1H); 8.85 (d, 1H).
Example 2: 3-[2-(4-Chlorophenyl)pyrazolo[1,5-a]pyridiu-5-yl]benzamide (compound 2
of the table)
2.1 3-[2-(4-ChlorophenyI)pyrazolo[l,5-a]pyridin-5-yl]benzonitrile
0.850 g (2.76 mmol) of 5-bromo-2-(4-chlorophenyl)pyrazolo[l,5-a]pyridine obtained
according to the protocol of step 1.3 is placed in a round-bottomed flask with 0.490 g
(3.33 mmol) of 3-cyanophenylboronic acid, 2.70 g (8.29 mmol) of caesium carbonate and
0.225 g (0.26 mmol) of [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (H) in the
presence of 20 mL of a THF-water mixture (9/1). The medium is then maintained at 75°C
for 3 hours, followed by addition of a further 0.245 g (1.66 mmol) of 3-cyanophenylboronic
acid, 1.35 g (4.14 mmol) of caesium carbonate and 0.115 g (0.14 mmol) of [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium (H) and the medium is stirred at 75°C
for 1 hour 30 minutes. The medium is then diluted with 100 mL of ethyl acetate and 100 mL
of water. The organic phase is then recovered and the aqueous phase is extracted twice with
100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate
and filtered. The filtrate is then concentrated under reduced pressure and the residue
obtained is dissolved in tetrahydrofuran and concentrated under reduced pressure, after by
addition of 10 g of silica. The residue is chromatographed on silica gel, eluting with a
mixture of cyclohexane and ethyl acetate (8/2). 0.185 g (20.2%) of expected compound is
obtained in the form of a white powder.
LC-MS:M+H = 330
'H NMR (DMSO) d (ppm): 7.19 (s, 1H); 7.37 (dd, 1H); 7.56 (m, 2H); 7.74 (t, 1H); 7.90 (m,
1H); 8.06 (m, 2H); from 8.15 to 8.24 (m, 2H); 8.35 (m, 1H); 8.82 (d, 1H).
2.2 3-[2-(4-Chlorophenyl)pyrazoIo[l,5-a]pyridin-5-yl]benzamide
0.150 g (0.45 ramol) of [2-(4-chlorophenyl)pyrazolo[ 1,5-«]pyridin-5-yl]benzonitrile
obtained in step 2.1 is placed in a round-bottomed flask with 5 mL of anhydrous dimethyl
sulfoxide. The medium is then cooled to about 10°C and 0.100 mL (1.17 mmol) of aqueous
hydrogen peroxide solution (35% in water) and 0.035 g (0.25 mmol) of potassium carbonate
are added. The medium is gradually warmed to room temperature and stirred for 1 hour. The
medium is then cooled to about 5°C and 0.500 mL (5.85 mmol) of hydrogen peroxide and
0.250 g (1.78 mmol) of potassium carbonate are added. The medium is then stirred for
1 hour 30 minutes at room temperature, followed by dilution in 50 mL of water. The
medium is filtered through a sinter funnel, and a powder is recovered, which is
chromatographed (by solid deposition) on silica gel, eluting with a mixture of dichloro-
methane and methanol (9/1). 0.090 g (56.8%) of expected compound is obtained in the form
of a white powder.
Melting point (°C): 283-285
LC-MS:M+H = 348
'H NMR (DMSO) d (ppm): 7.17 (s, 1H); 7.36 (dd, 1H); 7.47 (s, 1H); 7.56 (m, 2H); 7.61 (t,
1H); 7.94 (m, 1H); 8.00 (m, 1H); 8.07 (m, 2H); 8.11 (m, 1H); 8.15 (s, 1H); 8.32 (m, 1H);
8.82 (d, 1H).
Example 3: 3-[2-(4-Chlorophenyl)pyrazolo[l,5-a]pyridin-5-yI]-iVyV-dimethyl-
benzamide (compound 3 of the table)
Under a stream of nitrogen, 0.900 mL (1.80 mmol) of a dimethylamine solution (2M in
tetrahydrofuran) and 8 mL of toluene are placed in a round-bottomed flask. The medium is
then cooled to about 0°C and 0.900 mL (1.80 mmol) of a trimethylaluminium solution (2M
in toluene) is then added dropwise. After the addition, the medium is stirred at about 0°C for
25 minutes, followed by addition of 0.200 g (0.55 mmol) of methyl 3-[2-(4-chlororophenyi)-
pyrazolo[l,5-a]pyridin-5-yl]benzoate obtained in step 2.1. The medium is then maintained at
90°C for 3 hours, followed by cooling to about 0°C. The medium is then hydrolysed by
dropwise addition of 10 mL of hydrochloric acid solution (IN). After the addition, the
medium is wanned to room temperature and then diluted with 60 mL of dichloromethane
and 60 mL of water. The pH of the aqueous phase is brought to about 11 with sodium
hydroxide solution (IN) and the two-phase medium obtained is then filtered on a sinter
funnel packed with Celite. The filtrate is recovered and passed through a hydrophobic
cartridge (Radleys® 70 mL liquid/liquid extraction column). The filtrate is recovered and
concentrated under reduced pressure after addition of 1.2 g of silica. The residue obtained is
chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate
(3/7).
0.121 g(58.4%) of expected compound is obtained in the form of a white, powder.
Melting point (°C): 175-177
LC-MS:M+H = 376
!H NMR (DMSO) d (ppm): 3.02 (d, 6H); 7.15 (s, 1H); 7.35 (dd, 1H); 7.46 (m, 1H); from
7.50 to 7.67 (m, 3H); 7.85 (m, 1H); 7.91 (m, 1H); from 8.00 to 8.15 (m, 3H); 8.80 (d, 1H).
Example 4: 3-[2-(4-CUorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-iV-methylbeiizamide
(compound 4 of the table)
The process is performed according to the procedure described in Example 3, starting with
0.200 g (0.55 mmol) of methyl 3-[2-(4-chlororophenyl)pyrazolo[l,5-a]pyridin-5-yl]benzoate
obtained in step 3.1, 0.900 mL (1.80 mmol) of a methylamine solution (2M in tetrahydro-
furan) and 0.900 mL (1.80 mmol) of a txmiethylalurninium solution (2M in toluene) in 8 mL
of toluene. After chromatography on silica gel, eluting with a mixture of cyclohexane and
ethyl acetate (1/1), 0.151 g (75.6%) of expected compound is obtained in the form of a white
powder.
Melting point (°C): 234-236
LC-MS:M+H = 362
'H NMR (DMSO) 6 (ppm): 2.85 (d, 3H); 7.18 (s, 1H); 7.35 (m, 1H); from 7.51 to 7.68 (m,
3H); 7.90 (m, 1H); 8.00 (m, 1H); from 8.02 to 8.12 (m, 3H); 8.28 (m, 1H); 8.62 (m, 1H);
8.82 (d, 1H).
Example 5: Methyl 3-[2-(4-fluorophenyl)pyrazoIo[l,5-a]pyridin-5-yl]benzoate
(compound 5 of the table)
5.1 2-(4-bromopyridin-2-yl)-l-(4-fluorophenyl)ethanone
Under a stream of nitrogen, 5.0 g (29.07 mmol) of 4-bromo-2-picoline and 10.2 g
(60.95 mmol) of ethyl 4-fluorobenzoate are placed in a round-bottomed flask and dissolved
in 50 mL of anhydrous tetrahydrofuran. The mixture is cooled to 0°C and 70 mL (70 mmol)
of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise.
After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5°C, and
100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl
acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is
extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried
over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, and the resulting
mixture is stirred and then concentrated under reduced pressure. The powder obtained is
used as a solid deposit for a chromatography on silica gel, eluting with a mixture of
cyclohexane and ethyl acetate (9/1). 7.5 g (88%) of compound are obtained in the form of a
yellow powder.
LC-MS; M+H = 294 (ketone/enol ratio: 43/57)
*H NMR (DMSO) d (ppm): 4.56 (s, 2H); 6.34 (s, 1H); from 7.23 to 7.40 (m, 5H); 7.53 (d,
1H); 7.56 (m, 1H); 7.70 (d, 1H); from 7.81 to 7.92 (m, 2H); from 8.04 to 8.16 (m, 2H); 8.29
(d, 1H); 8.37 (d, 1H); 15.0 (s, 1H).
5.2 2-(4-bromopyridin-2-yl)-l-(4-fluorophenyl)ethanoneoxime
7.5 g (24.26 mmol) of 2-(4-bromopyridin-2-yl)-l-(4-fluorophenyl)ethanone are placed in a
round-bottomed flask containing 100 mL of absolute ethanol. 20 mL (247.78 mmol) of
pyridine and 7.08 g (101.88 mmol) of hydroxylamine monohydrochloride are added, and the
medium is then stirred for 3 hours at room temperature. The ethanol is then evaporated off
under vacuum and the residue obtained is taken up in 250 mL of water and 250 mL of ethyl
acetate. The organic phase is separated out and the aqueous phase is then extracted 5 times
with 150 mL of ethyl acetate. The organic phases are then combined, dried over sodium
sulfate and concentrated under vacuum. 7.82 g of compound are obtained.
LC-MS: M+H = 309
'HNMR (DMSO-de, 6 in ppm): 4.26 (s, 2H); 7.19 (t, 2H); 7.50 (m, 2H); 7.75 (m, 2H); 8.33
(d, 1H); 11.50 (s, 1H) (production of the oxime (E)).
53 5-bromo-2-(4-fluoropheiiyl)pyrazoIo[l,5-a] pyridine
7.82 g (25.50 mmol) of 2-(4-bromopyridin-2-yl)-l-(4-fluorophenyl)ethanone oxime are
placed in a round-bottomed flask and dissolved in 400 mL of 1,2-dichloroethane. An O-
(mesitylenesulfonyl)hydroxylamine solution (0.27 M in 1,2-dichloroethane - compound
obtained according to the protocol described in step 1.3) is added dropwise to the medium
cooled to about 0°C. After the addition, the medium is stirred at room temperature for 1 hour
30 minutes. The medium is then diluted with 200 mL of water and 200 mL of sodium
hydroxide solution (IN). The two-phase medium is stirred and the phases are then separated
by settling. The organic phase is separated out and the aqueous phase is then extracted
4 times with 200 mL of dichloromethane. The organic phases are then combined, dried over
sodium sulfate and filtered. 15 g of silica are then added to the filtrate, and the resulting
mixture is then concentrated under reduced pressure. The powder obtained is used as solid
deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and
dichloromethane (1/1). 5.06 g (68%) of compound are obtained in the form of a fleecy white
powder.
LC-MS:M+H^291
XH NMR (DMSO-d6, 8 in ppm): from 7.00 to 7.10 (m, 2H); 7.45 (m, 2H); 8.05 (m, 3H); 8.70
(d, 1H).
5.4 methyl 3-[2-(4-fliiorophenyl)pyrazolo[l,5-a]pyridin-5-yI]beiizoate
Under a stream of nitrogen, 0.400 g (1.37 mmol) of 5-bromo-2-(4-
fluorophenyl)pyrazolo[l,5-a]pyridine obtained in step 5.3, 0.300 g (1.67 mmol) of 3-
methoxycarbonylphenylboronic acid and 1.330 g (4.08 mmol) of caesium carbonate are
placed in 5 mL of a 9/1 mixture of tetrahydrofuran and water. 0.11 g (0.13 mmol) of [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium (H) is added and the medium is heated
at 70°C for 4 hours. The medium is then cooled to room temperature and diluted with 40 mL
of dichloromethane and 40 mL of water. The medium is then filtered on a hydrophobic
cartridge (Radleys® 70 mL liquid/liquid extraction column) and the organic phase is
recovered and concentrated under reduced pressure after addition of 2 g of silica. The
residue is purified by chromatography on silica gel, eluting with a mixture of cyclohexane
and ethyl acetate (9/1). 0.340 g(71%) of expected product is obtained in the form of a white
powder.
Melting point (°C): 162-164
LC-MS:M+H = 347
*H NMR (DMSO) d (ppm): 3.95 (s, 3H); 7.15 (s, 1H); from 7.30 to 7.38 (m, 3H); 7.70 (t,
1H); from 8.00 to 8.15 (m, 5H); 8.35 (m, 1H); 8.80 (d, 1H).
Example 6 3-[2-(4-Fluorophenyl)pyrazolo[l,5-alpyridin-5-yl]-iV-methyIbenzamide
(compound 6 of the table)
The process is performed according to the procedure described in Example 3, starting with
0.200 g (0.58 mmol) of methyl 3-[2-(4-fluorophenyl)pyra2olo[l,5-a]pyridin-5-yl]benzoate
obtained in step 7.4, 1.00 mL (2.00 mmol) of a methylamine solution (2M in tetrahydro-
furan) and 1.00 mL (2.00 mmol) of a trimethylaluminium solution (2M in toluene) in 8 mL
of toluene. After chromatography on silica gel, eluting with a mixture of cyclohexane and
ethyl acetate (1/1), 0.235 g (67.7%) of expected compound is recovered in the form of a
white powder.
Melting point (°C): 214-216
LC-MS:M+H = 346
*H NMR (DMSO) d (ppm): 2.85 (d, 3H); 7.15 (s, 1H); from 7.26 to 7.46 (m, 3H); 7.62 (m,
1H); 7.90 (m, 1H); 8.00 (m, 1H); from 8.05 to 8.21 (m, 3H); 8.29 (m, 1H); 8.60 (m, 1H);
8.82 (d, 1H).
Example 7: 3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-2^V-dimethyIbenzamide
(compound 10 of the table)
7.1 2-(4-Fluorophenyl)-5-(4,4,5,5-tetramethyl-|13,2]dioxaborolan-2-yl)pyrazolo[l,5-
«]pyridine (compound VI-1)
1.00 g (3.43 mmol) of 5-bromo-2-(4-fluorophenyl)pyrazolo[l,5-a]pyridine obtained as in
step 7.3 is placed in contact with 1.05 g (4.13 mmol) of bis(pinacolato)diboron, 1.00 g
(10.19 mmol) of potassium acetate and 0.280 g (0.34 mmol) of [l,l'-bis(diphenyl-
phosphino)ferrocene]dichloropalladium (II) in 14 mL of dioxane.
The medium obtained is irradiated by microwave at 140°C for 20 minutes and then diluted
with 100 mL of dichloromethane and 100 mL of water. The two-phase medium is then
filtered through a hydrophobic cartridge (Radleys® 70 mL liquid/liquid extraction column).
The organic phase is recovered and concentrated under reduced pressure, after adding 4 g of
silica. The residue obtained is chromatographed on silica gel, eluting with a mixture of
cyclohexane and ethyl acetate (9/1).
0.992 g (85.4%) of expected compound is obtained in the form of a pink powder.
LC-MS: M+H = 338 (degradation on the column to boronic acid M+H = 257)
1H NMR (DMSO) d (ppm): 1.35 (s, 12H); 7.00 (m, 1H); 7.19 (s, 1H); 7.34 (t, 2H); 8.05 (m,
3H); 8.69 (d, 1H).
7.2 3-Bromo-2,N-dimethyl benzamide
0.500 g (2.33 mmol) of 3-bromo-2-methylbenzoic acid is placed in a round-bottomed flask
in the presence of 1.51 mL (10.83 mmol) of triethylamine, 0.408 g (3.02 mmol) of N-
hydroxybenzotriazole monohydrate, 0.579 g (3.02 mmol) of l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide monohydrochloride and 5 mL of dichloromethane. The medium is stirred
at room temperature for 1 hour, followed by addition of 1.51 mL (3.02 mmol) of a
methylamine solution (2M in tetrahydrofuran). The medium is stirred overnight at room
temperature, followed by addition of a further 0.5 mL (1 mmol) of methylamine solution,
and the mixture is stirred overnight. The medium is then concentrated under reduced
pressure, and 5mL of dichloromethane and 0.390 mL (2.99 mmol) of isobutyl
chlorofonnate are added. The medium is again stirred overnight, followed by dilution with
7 mL of dichloromethane and 7 mL of water. The medium is then filtered on a hydrophobic
cartridge (Radleys® 70 mL liquid/liquid extraction column). The organic phase is recovered
and concentrated under reduced pressure.
0.298 g (56.2%) of expected compound is obtained in the form of a white powder.
LC-MS: M+H = 228
*H NMR (DMSO) 6 (ppm): 2.31 (s, 3H); 2.80 (d, 3H); from 7.05 to 7.35 (m, 2H); 7.68 (m,
1H); 8.32 (bs, 1H).
13 3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-4-N-dimethylbenzamide
0.150 g (0.44 mmol) of 2-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-
yl)pyrazolo[l,5-a]pyridine obtained in step 7.1 and 0.144 g (0.63 mmol) of 3-bromo-2-iV-
dimethylbenzamide obtained in step 10.2 are placed in contact with 0.434 g (1.33 mmol) of
caesium carbonate and 0.036 g (0.044 mmol) of [l,l'-bis(diphenylphosphino)-
ferrocene]dichloropalladiurn (II) in 5 mL of a 9/1 mixture of tetrahydrofuran and water. The
medium is stirred at 60°C overnight. The medium is then diluted with 50 mL of
dichloromethane and 50 mL of water. The two-phase medium is then filtered on a
hydrophobic cartridge (Radleys® 70 mL liquid/liquid extraction column). The organic phase
is recovered and concentrated under reduced pressure, after adding 1.5 g of silica. The
residue obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane
and ethyl acetate (1/1).
0.103 g (65%) of expected compound is obtained in the form of a white powder.
Melting point (°C): 240-242
LC-MS:M+H = 360
lK NMR (DMSO) 6 (ppm): 2.37 (s, 3H); 2.80 (d, 3H); 6.86 (d, 1H); 7.10 (s, 1H); from 7.33
to 7.44 (m, 5H); 7.63 (s, 1H); 8.10 (m, 2H); 8.28 (s, 1H); 8.76 (d, 1H).
Example 8: A-Cvclopropvl-3-I2-(4-fluorophenvl)pvrazolo[1.5-glPVridin-5-vll-
benzamide (compound 15 of the table)
0.0382 g (0.67 mmol) of cyclopropylamine is diluted with 10 mL of anhydrous tetrahydro-
furan. 0.0859 g (0.33 mmol) of DABAL (double adduct of trimethylaluminium with 1,4-
diazabicyclo[2.2.2]octane) is then gradually added, and the medium is then stirred for
1 hour. 0.145 g (0.42 mmol) of methyl 3-[2-(4-fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-
benzoate obtained according to protocol 5.4 is then added, and the reaction medium is then
irradiated in a microwave oven for twice 30 minutes at 130°C. The medium is then
hydrolysed at about 5°C using 5 mL of water and 5 mL of aqueous hydrochloric acid
solution (IN). After the hydrolysis, the medium is diluted with 50 mL of water and 50 mL of
dichloromethane, and then filtered through a hydrophobic cartridge (Radleys® 70 mL
liquid/liquid extraction column). The organic phase is recovered and concentrated under
reduced pressure, after adding 1.5 g of silica. The residue obtained is chromatographed on
silica gel, eluting with a mixture of cyclohexane and ethyl acetate (6/4).
0.112 g (72.3%) of expected compound is obtained in the form of a white powder.
Melting point (°C): 179-181
LC-MS:M+H = 372
*H NMR (DMSO) d (ppm): from 0.60 to 0.80 (m, 4H); 3.92 (m, 1H); 7.15 (s, 1H); from 7.30
to 7.39 (m, 3H); 7.61 (t, 1H); 7.88 (d, 1H); 7.98 (d, 1H); 8.10 (m, 3H); 8.22 (s, 1H); 8.57 (m,
lH);8.81(d, 1H).
Example 9: {3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]phenyl}-(3-hydroxy-
pyrrolidin-l-yl)methanone (compound 22 of the table)
0.100 g (0.30 mmol) of 3-[2-(4-fluorophenyl)pyrazolo[l,5-a]pyridm-5-yl]beiizoic acid
prepared as in Example 8 is placed in a round-bottomed flask in the presence of 0.170 mL
(1.20 mmol) of triethylamine and 20 mL of dichloromethane. 0.051 uL (0.39 mmol) of
isobutyl chloroformate is then added and the medium is stirred at room temperature for
2 hours. 0.0341 g (0.39 mmol) of 3-hydroxypyrrolidine is added to the medium, which is
stirred for a further 2 hours at room temperature. The medium is then diluted with 50 mL of
water and 50 mL of dichloromethane. The two-phase medium is then filtered through a
hydrophobic cartridge (Radleys® 70 mL liquid/liquid extraction column). The organic phase
is recovered and concentrated under reduced pressure after adding 1 g of silica. The residue
obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl
acetate (6/4).
0.063 g (50%) of expected compound is obtained in the form of a pale yellow wax.
Melting point (°C): 173-175
LC-MS: M+H = 402
*H NMR (DMSO) 6 (ppm): from 1.65 to 2.05 (m, 2H); from 3.40 to 3.70 (m, 4H); 4.32 (d,
lh); 5.00 (d, 1H); 7.11 (s, 1H); 7.32 (m, 3H); 7.60 (m, 2H); 7.93 (d, 2H); 8.08 (m, 3H); 8.77
(d, 1H).
Example 10: iV-Methyl-3-(2-p-tolylpyrazoIo[l,5-«]pyridm-5-yl)benzamide (compound
328 of the table)
10.1 2-(4-Bromopyridin-2-yl)-l-p-tolylethanone
Under a stream of nitrogen, 1 g (5.81 mmol) of 4-bromo-2-methylpyridine and 1.75 g
(11.60 mmol) of methyl 4-methylbenzoate are placed in a round-bottomed flask and
dissolved in 30 mL of anhydrous tetrahydrofuran. The solution is cooled to 5°C and 14 mL
(14 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added
dropwise. After addition, the mixture is stirred at room temperature for 2 hours 30 minutes
and then cooled to 5°C, followed by gradual addition of 20 mL of water. The medium is
then diluted with 200 mL of ethyl acetate and 200 mL of water. The organic phase is
separated out, dried over sodium sulfate and filtered. 5 g of silica are then added to the
filtrate, which is then concentrated under reduced pressure. The powder obtained is used as
a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and
ethyl acetate (95/5) to give 1.03 g (61 %) of compound in the form of a yellow powder.
LC~MS:M+H = 290
10.2 4-Bromo-2-(3-p-tolyl-2H-azirin-2-yl)pyridine
1.03 g of 2-(4-bromopyridin-2-yl)-l-p-tolylethanone obtained in step 13.1 are placed in a
round-bottomed flask with 0.99 g (14.2 mmol) of hydroxylamine monohydrochloride, 3 mL
(37 mmol) of pyridine and 100 mL of ethanol. The reaction medium is stirred overnight and
then concentrated under reduced pressure. The residue obtained is then taken up in 200 mL
of ethyl acetate and 200 mL of water. The organic phase is recovered, dried over sodium
sulfate and then concentrated under reduced pressure. 1.10 g of compound are recovered and
dissolved in a round-bottomed flask containing 0.660 mL (4.74 mmol) of triethylarnine and
30 mL of dichloromethane. The reaction medium is then cooled to about 5°C and 0.200 mL
(1.42 mmol) of trifluoroacetic anhydride is added dropwise. The medium is then stirred at
room temperature for 3 hours, followed by hydrolysis with 100 mL of water. The medium is
then stirred for 10 minutes, followed by filtration through a hydrophobic cartridge
(Radleys® 70 mL liquid/liquid extraction column). 1.2 g of silica are then added to the
filtrate, followed by concentrating under reduced pressure. The powder obtained is used as a
solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and
ethyl acetate (95/5). 0.746 g (77%) of expected compound is recovered in the form of a
white powder.
'H NMR (DMSO) d (ppm): 2.42 (d, 3H); 3.45 (s, 1H); from 7.42 to 7.58 (m, 4H); 7.78 (m,
2H); 8.30 (d, 1H).
10.3 5-Bromo-2-p-toIyl-pyrazolo[l,5-a]pyridine
0.746 g of 4-bromo-2-(3-p-tolyl-2H-azirin-2-yl)pyridine obtained in step 13.2 is dissolved in
the presence of 6.6 mg (0.052 mmol) of iron (II) chloride in 30 mL of 1,2-dimethoxyethane.
The medium is then refluxed for 6 hours. A further 10 mg (0.078 mmol) of iron (II) chloride
are then added and the mixture is refluxed again with stirring for 3 hours. The medium is
then diluted with 50 mL of ethyl acetate and 50 mL of water. The organic phase is then
recovered, dried over sodium sulfate and filtered. 2 g of silica are then added to the filtrate,
followed by concentrating under reduced pressure. The powder obtained is used as a solid
deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl
acetate (85/15). 0.534 g (71%) of expected compound is recovered in the form of a yellow
powder.
LC-MS: M+H = 287
2H NMR (DMSO) d (ppm): 2.48 (m, 3H); 7.00 (m, 2H); 7.32 (m, 2H); 7.88 (m, 2H); 8.00
(m, 1H); 8.68 (d, 1H).
10.4 Ar-methyl-3-(4,4,5,5-tetramethyI-[13,2]dioxaborolan-2-yl)benzamide
2.50 g (11.68mmol) of 3-bromo-iV-methylbenzamide, 3.56 g (14.01 mmol) of
bis(pinacolato)diboron, 3.43 g (35.04 mmol) of potassium acetate and 0.953 g (1.17 mmol)
of [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (H) are placed in contact with
20 mL of dioxane and then irradiated by microwave at 130°C for 45 minutes. The medium is
then diluted with 150 mL of ethyl acetate and 100 mL of water. The organic phase is
recovered and the aqueous phase is extracted with twice 100 mL of ethyl acetate. The
organic phases are then combined, dried over sodium sulfate and then concentrated under
reduced pressue, after adding 10 g of silica. The residue obtained is chromatographed on
silica gel, eluting with a mixture of cyclohexane and ethyl acetate (8/2).
1.39 g of expected compound are obtained in the form of a pink powder (presence of
pinacol).
'H NMR (DMSO) d (ppm): 1.30 (s, 12H); 2.78 (d, 3H); 7.48 (t, 1H); 7.80 (m, 1H); 7.95 (m,
1H); 8.12 (m, 1H); 8.50 (m, 1H).
10.5 7V-Methyl-3-(2-p-toIylpyrazoIo[l^-fl]pyridin-5-yl)benzamide
0.150 g (0.52 mmol) of 5-bromo-2-p4olylpyrazolo[l,5-a]pyridine obtained in step 13.3,
0.136 g (0.52 mmol) of A^"-methyl-3-(4,4,5,5-tetramethyl-[l;3,2]dioxaborolan-2-yl)benzamide
obtained in step 13.4, 0.510 g (1.57 mmol) of caesium carbonate and 0.043 g (0.05 mmol) of
[l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (H) are placed in 5 mL of a 9/1
mixture of tetrahydrofuran and water. The medium is stirred at 65°C for 4 hours. The
medium is then diluted with 50 mL of dichloromethane and 50 mL of water. The two-phase
medium is then filtered through a hydrophobic cartridge (Radleys® 70 mL liquid-liquid
extraction column). The organic phase is recovered and concentrated under reduced
pressure, after adding 1.5 g of silica. The residue obtained is chromatographed on silica gel,
eluting with a mixture of cyclohexane and ethyl acetate (1/1).
0.138 g (77.7%) of expected compound is obtained in the form of a beige powder.
Melting point (°C): 204-206
LC-MS:M+H = 342
!H NMR (DMSO) d (ppm): 2.38 (s, 3H); 2.85 (d, 3H); 7.10 (s, 1H); 7.31 (m, 3H); 7.62 (t,
1H); 7.90 (m, 3H); 7.98 (d, 1H); 8.08 (s, 1H); 8.29 (s, 1H); 8.61 (d, 1H); 8.81 (d, 1H).
Example 11: 3-[3-Chloro-2-(4-fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-Ar-methyl-
benzamide (compound 34 of the table)
0.100 g (0.29 mtnol) of 3-[2-(4-fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-A^-methyl-
benzamide obtained according to protocol 6 is placed in a round-bottomed flask in the
presence of 3 mL of dichloromethane. 0.060 g (0.45 mmol) of A^-chlorosuccinimide is
added, and the medium is then stirred at room temperature overnight. The reaction medium
is then diluted with 50 mL of dichloromethane and 50 mL of water. The two-phase medium
is then filtered through a hydrophobic cartridge (Radleys® 70 mL liquid/liquid extraction
column). The organic phase is recovered and concentrated under reduced pressure, after
adding 1.2 g of silica. The residue obtained is chromatographed on silica gel, eluting with a
mixture of cyclohexane and ethyl acetate (6/4).
0.0592 g (53.8%) of expected compound is obtained in the form of a white powder.
Melting point (°C): 221-223
LC-MS:M+H = 380
*H NMR (DMSO) d (ppm): 2.88 (d, 3H); 7.42 (m, 2H); 7.47 (dd, 1H); 7.64 (t, 1H); 7.93 (m,
1H); 8.01 (m, 1H); 8.05 (m, 1H); 8.10 (m, 2H); 8.31 (m, 1H); 8.63 (m, 1H); 8.88 (d, 1H).
The tables that follow illustrate the chemical structures of general formula (I)
(Table 1) and the physicochemical characteristics (Table 2) of a number of examples of
compounds according to the invention.
In these tables:
the column "m.p." indicates the melting points of the products in degrees Celsius (°C);
Me and Et represent, respectively, a methyl group and an ethyl group;
* indicates the bonding atom(s).
The compounds according to the invention underwent pharmacological tests for detemiining
their modulatory effect on NOT.
Evaluation of the in vitro activity on N2A cells
The activity of the compounds according to the invention was evaluated on a cell line (N2A)
endogenously expressing the murine Nurrl receptor and stably transfected with the NOT
binding response element (NBRE) coupled to the luciferase reporter gene. The tests were
performed according to the procedure described hereinbelow.
The cell line Neuro-2A is obtained from a standard commercial source (ATCC). The clone
Neuro-2A was obtained from a spontaneous tumour originating from a strain of albino mice
A by R.J Klebe et al. This line Neuro-2A is then stably transfected with 8NBRE-luciferase.
The N2A-8NBRE cells are cultured to the point of confluence in 75 cm2 culture flasks
containing DMEM supplemented with 10% foetal calf serum, 4.5 g/L of glucose and 0.4
mg/ml of geneticin. After culturing for one week, the cells are recovered with 0.25% trypsin
for 30 seconds and then resuspended in DMEM without phenol red, containing 4,5 g/L of
glucose and 10% Hyclone defatted serum, and placed in white, transparent-base 96-well
plates. The cells are deposited at a rate of 60 000 per well in 75 µL for 24 hours before
adding the products. The products are applied in 25 µL and incubated for a further 24 hours.
On the day of measurement, an equivalent volume (100 uL) of Steadylite is added to each
well, and the wells are then left for 30 minutes to obtain complete lysis of the cells and
maximum production of the signal. The plates are then measured in a microplate
luminescence counter, after having been sealed with an adhesive film. The products are
prepared in the form of a 10"2 M stock solution, and then diluted in 100% of DMSO. Each
concentration of product is prediluted in culture medium before incubation with the cells
thus containing 0.625% final of DMSO.
The best compounds have an EC50 value of between 0.1 nM and 10 uM.
For example, compounds 2, 4, 10, 14, 16 and 26 have shown an EC50 value of 45; 2; 6.6;
125; 326 and 1.3 nM, respectively.
It is thus seen that the compounds according to the invention have a modulatory effect on
NOT.
The compounds according to the invention may thus be used for the preparation of
medicaments for their therapeutic application in the treatment or prevention of diseases
involving the NOT receptors.
Thus, according to another of its aspects, a subject of the invention is medicaments that
comprise a compound of formula (I) or an addition salt thereof with a pharmaceutically
acceptable acid.
These medicaments find their therapeutic use especially in the treatment and prevention of
neurodegenerative diseases, for instance Parkinson's disease, Alzheimer's disease,
tauopathies (e.g. progressive supranuclear palsy, frontotemporal dementia, corticobasal
degeneration, Pick's disease); cerebral trauma, for instance ischaemia and cranial trauma
and epilepsy; psychiatric diseases, for instance schizophrenia, depression, substance
dependency, and attention-deficit hyperactivity disorder; inflammatory diseases of the
central nervous system, for instance multiple sclerosis, encephalitis, myelitis and
encephalomyelitis and other inflammatory diseases, for instance vascular pathologies,
atherosclerosis, joint inflammations, arthrosis, rheumatoid arthritis; osteoarthritis, Crohn's
disease, ulcerative colitis; allergic inflammatory diseases such as asthma, autoimmune
diseases, for instance type 1 diabetes, lupus, scleroderma, Guillain-Barre syndrome,
Addison's disease and other immune-mediated diseases; osteoporosis; cancers.
These compounds may also be used as a treatment combined with grafts and/or
transplantations of stem cells.
According to another of its aspects, the present invention relates to pharmaceutical
compositions comprising, as active principle, 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 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 admmistration, from the usual excipients known to those skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active principle of formula (I) above, or the salt
thereof, may be administered in unit administration form, as a mixture with standard
pharmaceutical excipients, to man and animals for the prophylaxis or treatment of the above
complaints or diseases.
The appropriate unit forms of administration include oral forms such as tablets, soft or hard
gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal,
intratracheal, intraocular, intranasal or inhalation administration forms, 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, ointments or lotions.
By way of example, a unit administration form of a compound according to the invention in
tablet form may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Croscarmellose sodium 6.0 mg
Cornstarch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
There may be particular cases in which higher or lower dosages are appropriate; such
dosages are not outside the context 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 and the weight and response of the said patient.
According to another of its aspects, the present invention also relates to a method for
treating the pathologies indicated above, which comprises the administration, to a patient, of
an effective dose of a compound according to the invention, or a pharmaceutically
acceptable salt thereof.
Claims
1. Compounds of formula (I):

in which:
R represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
X represents one or more substituents chosen from a hydrogen or halogen atom and a group
(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, cyano, hydroxyl or
hydroxy(C1-C6)alkyl;
Y represents a hydrogen or halogen atom or a group (C1-C6)alkyl;
Rl represents a group NR2R3 or OR4;
R2 and R3 represent, independently of each other, a hydrogen atom or a group (C1-C6)alkyl,
hydroxy(C1-C6)alkylor oxo(C1-C6)alkyl, or alternatively R2 and R3 form, with the
nitrogen atom that bears them, a heterocycle optionally substituted with a group
(C1-C6)alkyl, hydroxyl or oxo,
R4 represents a group (C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl, in the form
of base or of acid-addition salt.
2. Compounds of formula (I) according to Claim 1, characterized in that
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a halogen atom and a group
(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
Rl represents a group OR4,
R4 represents a methyl group, in the form of base or of acid-addition salt.
3. Compounds of formula (I) according to Claim 1, characterized in that
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl,
trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
Y represents a hydrogen, chlorine or fluorine atom or a methyl group,
Rl represents a group OR4,
R4 represents a methyl group, in the form of base or of acid-addition salt.
4. Compounds of formula (I) according to Claim 1, characterized in that
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a halogen atom and a group
(C1-C6)alkyi, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy or cyano,
Y represents a hydrogen atom, a halogen atom or a group (C1-C6)alkyl;
Rl represents a group NR2R3,
R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl,
isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that
bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl
group, in the form of base or of acid-addition salt.
5. Compounds of formula (I) according to Claim 1, characterized in that
R represents a hydrogen or chlorine atom,
X represents one or more substituents chosen from a chlorine or fluorine atom and a methyl,
trifluoromethyl, methoxy, trifluoromethoxy or cyano group,
Y represents a hydrogen or chlorine atom or a methyl group,
Rl represents a group NR2R3,
R2 and R3 represent, independently of each other, a hydrogen atom or a methyl, ethyl,
isopropyl or cyclopropyl group, or alternatively R2 and R3 form, with the nitrogen atom that
bears them, a morpholinyl or pyrrolidinyl group optionally substituted with a hydroxyl
group, in the form of base or of acid-addition salt.
6. Compounds:
• Methyl 3-[2-(4-chlorophenyl)pyrazolo[l,5-a]pyridin-5-yl]benzoate
• 3-[2-(4-Chlorophenyl)pyrazolo[ 1,5-a]pyridm-5-yl]benzarnide
• 3-[2-(4-Chlorophenyl)pyrazolo[ 1 ,5-a]pyridin-5-yl]-N,N-dhneihylbenzaimde

• 3 -[2 -(4-Chlorophenyl)pyrazolo [ 1,5 -a]pyridin-5 -yl] -N-methylbenzamide
• Methyl 3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridm-5-yl]benzoate
• 3-[2-(4-Fluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]-N-methylbenzamide
• 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N'-isopropylben2anude
• 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridm-5-yl]-N,N-dimethylbenzmide
• {3-[2-(4-Fluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]phenyl}morpholin-4-yl-
methanone
• 3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-2,N-dimethylbenzamide
• 2-CWoro-5-[2-(4-fluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]-N-methylbenzamide
• 4-CMoro-3-[2-(4-fluorophenyl)pyra2olo[l,5-a]pyridin-5-yl3-N-methylbenzamide
• 3-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-4,N -dimethylbenzamide
• 2-Fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yI]-N'-methylbenzamide
• N-Cyclopropyl-3-[2-(4-fluorophenyl)pyra2olo[1,5-a]pyridin-5-yl]benzamide
• {3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]phenyl}pyrrolidin-l-
ylmethanone
• 3-[2-(2,6-Difluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl-methylbenzamide
• 3-[2-(2-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-inethylbenzamide
• N-Methyl-3-[2-(4-trifluoromethylphenyl)pyrazolo[l,5-a]pyridin-5-yl]benzamide
• 4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• 2-[2-(4-Fluorophenyl)pyra2olo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• {3-[2-(4-Fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]phenyl}-(3-hydroxypyrrolidin-
l-yl)methanone
• 3-[2-(2,4-Difluorophenyl)pyrazolo[ 1,5-a]pyridin-5-yl]-N-methylbenzamide
• N-Methyl-3-[2-(4-trifluoromethoxyphenyl)pyrazolo[1,5-a]pyridin-5-yl]benzamide
• 3-[2-(3,4-Difluorophenyl)pyra2olo[1,5-a]pyridin-5-yl]-N-methylbenzainide
• 3-[2-(3,5-Difluorophenyl)pyrazolo[l;5-a]pyridin-5-yl]-N:-methylbenzamide
• 3-[2-(3-Fluoropheoyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• N-Methyl-3-(2-p-tolylpyrazolo[1,5-a]pyridin-5-yl)ben2amide
• 3-[2-(4-Methoxyphenyl)pyrazolo[l,5-a]pyridin-5-yl]-N-methylbenzamide
• 3-[2-(3,4-Dimethylphenyl)pyrazolo[l,5-a]pyridm-5-yl]-N-methylbenzamide
• 3-[2-(4-Cyanophenyl)pyrazolo[1,5-a]pyridin-5-yl]-N-methylbenzamide
• 3-[2-(2,3-Difluorophenyl)pyrazolo[ 1,5-a]pyridm-5-yl]-N-memylbenzamide
• N-Methyl-3-o-tolylpyrazolo[l,5-a]pyridin-5-yl)benzamide
• 3-[3-Cldoro-2-(4-fluorophenyl)pyrazolo[l,5-a]pyridin-5-yl]-N-methylbenzamide
7. Medicament, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 6, or an addition salt of this compound with a
pharmaceutically acceptable acid.
8. Pharmaceutical composition, characterized in that it comprises a compound of
formula (I) according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt of
this compound, and also at least one pharmaceutically acceptable excipient.
9. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the
preparation of a medicament for treating and preventing neurodegenerative diseases.
10. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the
preparation of a medicament for treating and preventing cerebral trauma and epilepsy.
11. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the
preparation of a medicament for treating and preventing psychiatric diseases.
12. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the
preparation of a medicament for treating and preventing inflammatory diseases.
13. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the
preparation of a medicament for treating and preventing osteoporosis and cancers.
14. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the
preparation of a medicament for treating and preventing Parkinson's disease, Alzheimer's
disease, tauopathies and multiple sclerosis.
15. Use of a compound of formula (I) according to any one of Claims 1 to 6, for the
preparation of a medicament for treating and preventing schizophrenia, depression,
substance dependency and attention-deficit hyperactivity disorder.
16. Intermediate compound of formula (VI-1)

17. Use of the compound according to Claim 16 for the synthesis of products of
general formula (I) according to Claim 1.

ABSTRACT

The invention relates to a formula (I), in which R is a hydrogen or halogen atom or a
(C1-C6) alkyl group; X is one or more substituents selected from a hydrogen or halogen
atom, a (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, cyano,
hydroxy, or hydroxy(C1-C6)alkyl group; Y is a hydrogen or halogen atom or a (C1-C6)alkyl
group; R1 is an NR2R3 or OR4 group; R2 and R3 independently are a hydrogen atom, a
(C1-C6)alkyl, hydroxy(C1-C6)alkyl or oxo(C1-C6)alkyl group or R2 and R3, together with
the nitrogen atom supporting the same, form a heterocycle optionally substituted by a (C1-C6)alkyl, hydroxy or oxo group; and R4 is a (C1-C6)alkyl, hydroxy(C1-C6)alkyl, or
oxo(C1-C6)alkyl group, in the base or acid addition salt state. Said formula can be used
therapeutically for treating or preventing diseases linked to the nuclear receptors Nurr-1,
also known as NR4A2, NOT, TINUR, RNR-1, and HZF3.