DERIVATIVES OF 2-PYRIDIN-2-YL-PYRAZOL-3(2H)-ONE. PREPARATION
AND THERAPEUTIC USE THEREOF AS HIF ACTIVATORS
The present invention relates to novel substituted dihydropyrazolone derivatives, to their
preparation and to their therapeutic use as activators of the transcription factor HIF.
Hypoxia-inducible factor (HIF) (HIF1a) is a transcription factor that is constitutively
expressed in all tissues. This protein was discovered in 1994 by Gregg Semenza during
studies on the regulatory sequences of the EPO gene. He identified a sequence located
in the non-coding 3' position in the EPO promoter, which bears the name "hypoxia
response element' (HRE) and which is a site of binding of the protein HIF1a allowing
transcriptional activation of EPO. Thereafter, the HRE sequence was also located on
more than 70 other genes, such as VEGF (vascular endothelial growth factor) or Glutl
(glucose transporter 1). The transcriptional complex HIF-1 is at the minimum a
heterodimer formed from the protein HIF1a or HIF2a and another transcription factor
ARNT (formerly known as HIF1|3). ARNT is constitutively and stably expressed in cells
and the main part of the transcription complex regulation is associated with the amount of
HIF1a present in the cells, which is thus the limiting factor.
Under normal oxygen conditions, the protein HIF1a is rapidly degraded (half-life of
5 minutes). This degradation follows the hydroxylation of HIF1a or HIF2a, respectively, on
prolines 402 and 563 and prolines 405 and 531 for the human forms with HIF prolyl
hydroxylase (HIF-PHDs or EGLNs). This hydroxylation allows binding of the Von Hippell
Lindau protein (pVHL) associated with a ubiquitin ligase, which results in the degradation
of HIF1a or HIF2a by the ubiquitin proteasome system. When the cell or tissue are
subjected to high hypoxia/ischaemia, HIF1a or HIF2a is no longer degraded by the
ubiquitin-proteasome system and can then combine with the other transcription factors of
the HIF complex to transfer into the nucleus and activate their target genes.
Although high hypoxia is the main cause of activation of the proteins HIFta and HIF2a,
other inducers, such as insulin and growth factors, may also play a role in their
stabilization, especially via phosphorylation on their serines 641 and 643.
Phenotypic screening directed towards measuring the stabilization of the protein HIF1a
and/or HIF2a was thus established to identify the compounds of the present invention.
The compounds according to the present invention correspond to formula (I) below:

in which
R represents a group -S02-NR3R4, a hydrogen atom, a halogen atom, a group
-halo(C1-C5)alkyl, a group -C02R5 or a group -S02-R4; R3, R4 and R5 being as defined
below;
R1 represents a heterocycloalkyl group not containing a nitrogen atom, a group
-W-(C3-C6)cycloalkyl, a group -W-aryl, a group -W-heteroaryl, a group -W-
heterocycloalkyl, a group -W-COOR5 or a group -W-CONR5R6,
(i) the said aryl, heteroaryl and heterocycloalkyl groups being optionally
substituted on at least one carbon atom with at least one substituent chosen
from halogen atoms, groups (C1-C5)alkyl, groups -(C1-C5)alkylene-0-(C1-
C5)alkyl, groups -(C1-C5)alkoxy, a hydroxyl function, groups -halo(C1-
C5)alkyl, a cyano function, groups -0(C1-C5)alkylene-0-(C1-C5)alkyl, groups
-0-(C1-C5)alkylene-NR5R6, groups -S02-(C1-C5)alkyl, groups -NR5R6 and
groups -C02R5, and
(ii) it being understood that when it is a heterocycloalkyl group, the said group
comprising at least one nitrogen atom, this atom may optionally bear a
substituent chosen from groups (C1-C5)alkyl,
R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-C5)alkylene-
0-(C1-C5)alkyl, a group -halo(C1-C5)alkyl, a group -W-COOR5, a group -W-C(0)NHR5
or a group -W-C(0)-NR5R6; W, R5 and R6 being as defined below;
it being understood that:
o n represents 0, 1 or 2;
o Wis
(i) a group -(C1-C5)alkylene-, optionally substituted with a group chosen from
groups -(CH2)n-C02R5 and groups -(CH2)n-(CO)NR5R6, with n as defined above
and R5 and R6 as defined below; or
(ii) a group -(C3-C6)cycloalkylene-,
o R3 and R4
(i) which may be identical or different, represent, independently of each other, a
hydrogen atom, a group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, a group -(C1-
C5)alkylene-0-(C1-C5)alkyl, an aryl, a group -CHz-aryl, a heteroaryl, a
heterocycloalkyl, a group -W-OH, a group -W-CHOH-CH2OH, a group -W-C02R5,
a group -W-NR5R6 or a group -W-0-(CH2)n-aryl;
the said groups -(C3-C6)cycloalkyl and heterocycloalkyl being optionally
substituted
o on at least one carbon atom with at least one group chosen from -(C1-
C5)alkyl, a group -(C1-C5)alkoxy, a hydroxyl function, a group -W-
NR5R6 and a group -W-C02R5, in the case of the groups -(C3-
C6)cycloalkyl and heterocycloalkyl and/or
o on at least one heteroatom chosen from nitrogen with at least one
group chosen from -(C1-C5)alkyl in the case of a heterocycloalkyl
group,
with W and n as defined previously and R5 and R6 as defined below and it being
understood that when R3 and R4 are identical, they cannot be a hydrogen atom;
(ii) or alternatively R3 and R4 form, together with the nitrogen atom that bears
them, a heterocycloalkyl group, optionally substituted on at least one carbon atom
and/or, where appropriate, on at least one heteroatom, with at least one
substituent chosen from groups -(C1-C5)alkyl and groups -CH2-aryl;
o R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl,
with the exclusion of the following compounds:
• 4-benzyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(2,4-dichlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(4-methoxybenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(4-bromobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 2-(pyridin-2-yl)-4-[2-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one
• 4-(4-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(1,3-benzodioxol-5-ylmethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(3-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
4-(2-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
4-(4-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
4-(3-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
4-(4-tert-butylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
4-benzyl-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
5-methyl-4-(1-phenylethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
4-benzyl-2-(6-chloropyridin-2-yl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one
4-{1-[4-(diethylamino)phenyl]ethyl}-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-
one.
The compounds of formula (I) may exist in the form of bases or salts, the compounds of
formula (I) having in this case been salified with acids or bases, especially
pharmaceutically acceptable acids or bases. They are then referred to as addition salts,
which form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, but the
salts of other acids that are useful, for example, for purifying or isolating the compounds
of formula (I) also form part of the invention.
The compounds of 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.
The various tautomeric forms of the compounds of formula (I) also form part of the
invention.

Furthermore, a subject of the invention is also a uniform test process for the direct
measurement by beta-galactosidase complementation of the amount of HIF1-alpha
protein in the nucleus of cells, preferably HEK cells, after treating the said cells with one
or more test compounds, which consists in:
(a) inoculating, preferably in 384-well plates, the said cells in a suitable culture
medium, preferably 1% foetal calf serum (abbreviated as FCS);
(b) adding the test compound(s) at a suitable concentration in a suitable solvent to
the cells previously inoculated in the said culture medium; preferably the test
compounds are diluted in 0.1% FCS;
(c) incubating the said cells thus prepared in an indicator at about 37°C,
advantageously for about 6 hours;
(d) lysing the cells with a lysis buffer containing a chemiluminescent substrate for
beta-galactosidase;
(e) incubating in the absence of light, before reading and measuring the
luminescence, which is a function of the beta-galactosidase activity.
The compounds according to the invention underwent a screening test according to the
test as defined above.
In the context of the present invention, and unless otherwise mentioned in the text, the
following definitions apply:
- a halogen atom: a fluorine, chlorine, bromine or iodine atom;
- an alkvl group: a linear or branched, saturated aliphatic group, which may
contain 1, 2, 3, 4 or 5 carbon atoms (abbreviated as -(C1-C5)alkyl). Examples that may
be mentioned include, as (i) group -Clalkyl, the methyl group, as (ii) group -C2alkyl, the
ethyl group, as (iii) group -C3alkyl, the propyl or isopropyl group, as (iv) group -C4alkyl,
the butyl, isobutyl ortert-butyl group, as (v) group -C5alkyl the pentyl or isopentyl group;
- an alkvlene group: a linear or branched, saturated divalent alkyl group as
defined previously, which may contain 1, 2, 3, 4 or 5 carbon atoms (abbreviated as -(C1-
C5)alkylene-). Examples that may be mentioned include methylene (or -CH2-), ethylene
(or-CH2-CH2-) or propylene (-CH2-CH2-CH2- or -C(CH3)2-) groups;
- a cvcloalkvl group: a cyclic alkyl group which may contain 3, 4, 5 or 6 carbon
atoms, also abbreviated as -(C3-C6)cycloalkyl. Examples that may be mentioned include
cyclopropyi, cyclobutyl, cyclopentyl and cyclohexyl groups;
- a cycloalkylene groups: a saturated divalent cycloalkyl group, as defined
previously, which may contain 3, 4, 5 or 6 carbon atoms and which is then abbreviated as
-(C3-C6)cycloalkylene-. Examples that may be mentioned include the radicals
-cyclopropylene-, -cyclobutylene-, -cyclopentylene- and -cyclohexylene-;
- an alkoxy group: a radical -O-alkyl in which the alkyl group is as defined
previously. Examples that may be mentioned include the groups -0-(C1-C5)alkyl or -(C1-
C5)alkoxy, and in particular, as (i) group -0-C1alkyl, the group -Omethyl, as (ii) group -O-
C2alkyl, the group -Oethyl, as (iii) group -0-C3alkyl, the group -Opropyl or -Oisopropyl,
as (iv) group -0-C4alkyl, the group -Obutyl, -Oisobutyl or -Otert-butyl, as (v) group -O-
C5alkyl the group -Opentyl or -Oisopentyl;
- an alkoxy-alkvl group: a radical of formula -alkylene-O-alkyl, in which the alkyl
and alkylene groups, comprising the same number of carbon atoms or not comprising the
same number of carbon atoms, are as defined previously. Examples that may be
mentioned include groups -(C1-C5)alkylene-0-(C1-C5)alkyl, with -(C1-C5)alkylene- and
-(C1-C5)alkyl as defined above;
- an alkoxy-alkoxy group: a radical of formula -O-alkylene-O-alkyl, in which the
alkylene and alkyl groups, comprising the same number of carbons or not comprising the
same number of carbons, are as defined previously;
- a haloalkyl group: an alkyl group as defined above, substituted with 1, 2, 3, 4 or
5 halogen atoms, as defined previously. Examples that will be mentioned include groups
-halo(C1-C5)alkyl, with (C1-C5)alkyi as defined above, for instance the trifluoromethyl
group (abbreviated as -CF3) or the group -CH2-CF3;
- an aryl group: a cyclic aromatic group containing 5 or 6 carbon atoms. An
example of aryl groups that may be mentioned is the phenyl group;
- a heteroaryl group: a cyclic aromatic group containing 2, 3, 4 or 5 carbon atoms
and comprising 1 to 3 heteroatoms, which can be chosen from the nitrogen atom, the
oxygen atom and the sulfur atom, independently of one another, in such a way as to be
identical or different, when there are 2 of them, or independently of one another, in such a
way as to be identical or different, when there are 3 of them. Mention may be made of
pyridyl, pyrrole and furanyl groups;
- a heterocvcloalkvl: an optionally bridged cyclic alkyl group containing 4, 5, 6 or
7 carbon atoms and comprising 1, 2 or 3 heteroatoms chosen from oxygen, nitrogen and
sulfur. Mention may be made especially of piperidyl, piperazinyl, pyrrolidinyl,
hexamethyleneimino, morpholinyl and 1,1-dioxydotetrahydrothienyl groups;
- the letters a, B. v and 5 around the pyridine of the compounds of formula (I)
make it possible to identify the positions of the various carbon atoms.
Among the compounds described in the present invention, mention may be made of a
first group of compounds corresponding to formula (I) in which:
R represents a group -S02-NR3R4, a hydrogen atom, a halogen atom, a group
-halo(C1-C5)alkyl, a group -C02R5 or a group -S02-R4; R3, R4 and R5 being as defined
below;
and/or
R1 represents a heterocycloalkyl group not containing a nitrogen atom, a group
-W-(C3-C6)cycloalkyl, a group -W-aryl, a group -W-heteroaryl, a group -W-
heterocycloalkyl, a group -W-COOR5 or a group -W-CONR5R6,
(i) the said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on
at least one carbon atom with at least one substituent chosen from halogen atoms,
groups (C1-C5)alkyl, groups -(C1-C5)alkylene-0-(C1-C5)alkyl, groups -(C1-
C5)alkoxy, a hydroxyl function, groups -halo(C1-C5)alkyl, a cyano function, groups
-0(C1-C5)alkylene-0-(C1-C5)alkyl, groups -0-(C1-C5)alkylene-NR5R6, groups
-S02-(C1-C5)alkyl, groups -NR5R6 and groups -C02R5, and
(ii) it being understood that when it is a heterocycloalkyl group, the said group
comprising at least one nitrogen atom, this atom may optionally bear a substituent
chosen from groups (C1-C5)alkyl,
and/or
R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-C5)alkylene-
0-(C1-C5)alkyl, a group -halo(C1-C5)alkyl, a group -W-COOR5, a group -W-C(0)NHR5
or a group -W-C(0)-NR5R6; W, R5 and R6 being as defined below;
and/or
n represents 0,1 or 2;
and/or
Wis
(i) a group -(C1-C5)alkylene-, optionally substituted with a group chosen from
groups -(CH2)n-C02R5 and groups -(CH2)n-(CO)NR5R6, with n as defined
above and R5 and R6 as defined below; or
(ii) a group -(C3-C6)cycloalkylene-,
and/or
R3 and R4
(i) which may be identical or different, represent, independently of each other,
a hydrogen atom, a group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, a
group -(C1-C5)alkylene-0-(C1-C5)alkyl, an aryl, a group -CH2-aryl, a
heteroaryl, a heterocycloalkyl, a group -W-OH, a group -W-CHOH-CH2OH,
a group -W-C02R5, a group -W-NR5R6 or a group -W-0-(CH2)n-aryl;
the said groups -(C3-C6)cycloalkyl and heterocycloalkyl being optionally
substituted
o on at least one carbon atom with at least one group chosen from -(C1-
C5)alkyl, a group -(C1-C5)alkoxy, a hydroxyl function, a group -W-
NR5R6 and a group -W-C02R5, in the case of the groups -(C3-
C6)cycloalkyl and heterocycloalkyl and/or
o on at least one heteroatom chosen from nitrogen with at least one
group chosen from -(C1-C5)alkyl, in the case of a heterocycloalkyl
group,
with W and n as defined previously and R5 and R6 as defined below and it being
understood that when R3 and R4 are identical, they cannot be a hydrogen atom;
(ii) or alternatively R3 and R4 form, together with the nitrogen atom that bears
them, a heterocycloalkyl group, optionally substituted on at least one
carbon atom and/or, where appropriate, on at least one heteroatom, with
at least one substituent chosen from groups -(C1-C5)alkyl and groups
-CH2-aryl;
and/or
R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl;
with the exclusion of the compounds already mentioned above per se.
A first subgroup of compounds of the invention is formed by the compounds of formula (I)
in which R represents a group -S02-NR3R4, a group -halo(C1-C5)alkyl, a group -C02R5
or a group -S02-R4 with R3, R4 and R5 as defined above.
A second subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R represents a group -S02-NR3R4 or -C02R5 with R3, R5 and R4 as
defined above.
A third subgroup of compounds of the invention is formed by the compounds of formula
(I) in which R represents a hydrogen atom, a halogen atom, a group -halo(C1-C5)alkyl, a
group -C02R5 or a group -S02-R4 with R4 and R5 as defined above.
A fourth subgroup of compounds of the invention is formed by the compounds of formula
(I) in which R is a substituent of the atom in the p position of pyridine.
A fifth subgroup of compounds of the invention is formed by the compounds of formula (I)
in which R1 represents a heterocycloalkyl group not containing a nitrogen atom, a group
-W-(C3-C6)cycloalkyl, a group -W-aryl, a group -W-heteroaryl, a group -W-
heterocycloalkyl, a group -W-COOR5 or a group -W-CONR5R6,
the said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted
on at least one carbon atom with at least one substituent chosen from halogen atoms,
groups (C1-C5)alkyl, groups -(C1-C5)alkylene-0-(C1-C5)alkyl, groups -(C1-C5)alkoxy, a
hydroxyl function, groups -halo(C1-C5)alkyl, a cyano function, groups -0(C1-C5)alkylene-
0-(C1-C5)alkyl, groups -0-(C1-C5)alkylene-NR5R6, groups -S02-(C1-C5)alkyl, groups
-NR5R6 and groups -C02R5, and
it being understood that when it is a heterocycloalkyl group, the said group
comprising at least one nitrogen atom, this atom may optionally bear a substituent
chosen from groups (C1-C5)alkyl,
in which W is a group (C1-C5)alkylene or a group (C3-C6)cycloalkylene and in
which R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl.
Advantageously, the heterocycloalkyl group represents a piperidyl group, the aryl group
represents a phenyl group and the heteroaryl group represents a pyridyl group.
A sixth subgroup of compounds of the invention is formed by the compounds of formula
(I) in which R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-
C5)alkylene-0-(C1-C5)alkyl, a group -halo(C1-C5)alkyl, a group -W-COOR5, a group -W-
C(0)NHR5 or a group -W-C(0)-NR5R6;
in which W, R5 and R6 are as defined above.
A seventh subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R represents a group -S02-NR3R4, advantageously in the p position
of pyridine, and in which R3 and R4, which may be identical or different, represent,
independently of each other, a hydrogen atom, a group -(C1-C5)alkyl, a group -(C3-
C6)cycloalkyl, a group -(C1-C5)alkylene-0-(C1-C5)alkyl, an aryl, a group -CH2-aryl, a
heteroaryl, a heterocycloalkyl, a group -W-OH, a group -W-CHOH-CH2OH, a group -W-
C02R5, a group -W-NR5R6 or a group -W-0-(CH2)n-aryl;
it being understood that:
when R3 and R4 are identical, they cannot be a hydrogen atom; and that
when R3 and/or R4 are chosen from the said groups -(C3-C6)cycloalkyl and
heterocycloalkyl, these groups may be optionally substituted
o on at least one carbon atom, with at least one group chosen from
-(C1-C5)alkyl, a group -(C1-C5)alkoxy, a hydroxyl function, a group
-W-NR5R6 and a group -W-C02R5, in the case of the groups -(C3-
C6)cycloalkyl and heterocycloalkyl, and/or
o on at least one heteroatom chosen from nitrogen with at least one
group chosen from -(C1-C5)alkyl, in the case of a heterocycloalkyl
group,
in which W, R5 and R6 are as defined above and in which n represents 0, 1 or 2.
Advantageously, the heterocycloalkyl group represents a piperidyl group, the aryl group
represents a phenyl group and the heteroaryl group represents a pyridyl group.
An eighth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R represents a group -S02-NR3R4, advantageously in the p position
of pyridine, and in which R3 and R4 form, together with the nitrogen atom that bears
them, a heterocycloalkyl group, optionally substituted on at least one carbon atom and/or,
where appropriate, on at least one heteroatom, with at least one substituent chosen from
groups -(C1-C5)alkyl and groups -CH2-aryl.
Advantageously, the said heterocycloalkyl group represents a group chosen from
piperidyl, piperazinyl, morpholinyl, pyrrolidinyl and hexamethyleneimino groups, and the
aryl group represents a phenyl group.
A seventh subgroup of compounds of the invention is formed by the compounds of
formula (I) in which the group(s) R, R1 and/or R2 comprise the group(s) R5 and/or R6,
R5 or R6 is a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl,
or
R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl.
Advantageously, R5 and/or R6 are chosen from groups (C1-C5)alkyl.
A tenth subgroup of compounds of the invention is formed by the compounds of formula
(I) in which R represents a group -S02-NR3R4 or a hydrogen atom with R3 and R4 as
-defined above and/or R2 represents a hydrogen atom or a group -(C1-C5)alkyl,
advantageously a methyl and/or R1 represents a group -W-aryl or a group -W-heteroaryl,
advantageously with the said W representing a -CH2-, the said aryl representing a phenyl
and the said heteroaryl representing a pyridyl.
The subgroups defined above, taken separately or in combination, also form part of the
invention.
The compounds below are excluded from the present invention, namely:
> the compounds 4R1-1[2-pyrimidyl]-pyrazolin-5-one for which R1 =

> the compounds 3-methyl-4R1-[2-pyrimidyl]-pyrazoline-5-one below for which R1
represents:

> the compound:

and
> the compound:
Among the compounds of formula (I) that are subjects of the invention, mention may be
made especially of the following compounds:
• 4-(2-chlorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-
3-one;
• Acide 6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]pyridine-3-
carboxylic acid;
• 4-(2-chlorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 4-(2-chlorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1 -yl)sulfonyl]pyhdin-2-yl}-1,2-
dihydro-3H-pyrazol-3-one trifluoroacetate;
• (±)4-(2-chlorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1 -yl]sulfonyl}pyridin-2-yl) -
5-methyl-1,2-dihydro-3H-pyrazol-3-one;
• 6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-diethyl-
pyridine-3-sulfonamide;
• 6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-ethyl-N-phenyl-
pyridine-3-sulfonamide;
• 6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N,N-di(propan-2-
yl)pyridine-3-sulfonamide;
• 4-(2-chlorobenzyl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one;
• N,N-diethyl-6-[4-(2-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-
pyridine-3-sulfonamide;
• 4-(2-fluorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 4-(2-fluorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-
3-one;
• 4-(2-fluorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1 -yl)sulfonyl]pyridin-2-yl}-1,2-
dihydro-3H-pyrazol-3-one trifluoroacetate;
methyl-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-[4-(2-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yI]-N-phenyl-
pyridine-3-sulfonamide;
• 4-(2-fluorobenzyl)-5-methyl-2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one;
• 4-(2,4-dichlorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 4-(2,4-dichlorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one;
• 4-(2,4-dichlorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-
1,2-dihydro-3H-pyrazol-3-one trifluoroacetate;
• 4-(2,4-dichlorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-
5-methyl-1,2-dihydro-3H-pyrazol-3-one;
• 6-[4-(2,4-dichlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-ethyl-N-
phenylpyridine-3-sulfonamide;
• 6-[4-(2,4-dichlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N,N-di(propan-
2-yl)pyridine-3-sulfonamide;
• 4-(2,4-dichlorobenzyl)-5-methyl-2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,2-dihydro-
3H-pyrazol-3-one;
• 4-(2-chloro-6-fluorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one;
• 4-(2-chloro-6-fluorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-
yl}-1,2-dihydro-3H-pyrazol-3-one trifluoroacetate;
• 4-(2-chloro-6-fluorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-
2-yl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one;
• 6-[4-(2-chloro-6-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N,N-
diethylpyridine-3-sulfonamide;
• 6-[4-(2-chloro-6-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-ethyl-N-
phenylpyridine-3-sulfonamide;
• 6-[4-(2-chloro-6-fl uorobenzyl)-3-methyl-5-oxo-2,5-dihyd ro-1 H-pyrazol-1 -yl]-N, N-
di(propan-2-yl)pyridine-3-sulfonamide;
• 4-(2-chloro-6-fluorobenzyl)-5-methyl-2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,2-
di hyd ro-3 H-pyrazol-3-one;
• methyl 6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]pyridine-3-
carboxylate;
4-(4-chlorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-(4-chlorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2-
dihydro-3H-pyrazol-3-one;
4-(4-chlorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-5-
methyl-1,2-dihyd ro-3 H-pyrazol-3-one;
6-[4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-diethyl-
pyridine-3-sulfonamide;
6-[4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenyl-
pyridine-3-sulfonamide;
6-[4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-di(propan-2-
yl)pyridine-3-sulfonamide;
4-(4-chlorobenzyl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one;
6-[4-(2-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-di(propan-2-
yl)pyridine-3-sulfonamide;
4-(1,1-dioxidotetrahydrothiophen-3-yl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-
yl]-1,2-dihydro-3H-pyrazol-3-one;
6-[4-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-
yl]-N-ethyl-N-phenylpyridine-3-sulfonamide;
6-[4-(1,1 -dioxidotetrahydrothiophen-3-yl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -
yl]-N,N-di(propan-2-yl)pyridine-3-sulfonamide;
2-{[5-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]methyl}benzonitrile;
4-{[5-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]methyl}benzonitrile;
N-ethyl-6-{4-[4-(methoxymethyl)benzyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-
N-phenylpyridine-3-sulfonamide;
4-[3-(methoxymethyl)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-{4-[3-(methoxymethyl)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-
N-phenylpyridine-3-sulfonamide;
6-[4-(3-cyanobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyi-N-phenyl-
pyridine-3-sulfonamide;
6-[4-(4-cyanobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenyl-
pyridine-3-suifonamide;
5-methyl-2-(pyridin-2-yl)-4-(pyridin-4-ylmethyl)-1,2-dihydro-3H-pyrazol-3-one;
3-{[5-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]methyl}benzonitrile;
4^enzyl^(§-bF0m0pyfldifi^yl)-§-FT^tl^-4T2^l:iydf©-SH-pyi=azol-3-Qnei---------------
6-[4-(2-cyanobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-
phenylpyridine-3-sulfonamide;
N-ethyl-6-{4-[3-(2-methoxyethoxy)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-
yl}-N-phenylpyridine-3-sulfonamide;
4-(3,5-dimethoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
5-methyl-4-[4-(methylsulfonyl)benzyl]-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-{3-methyl-4-[4-(methylsulfonyl)benzyl]-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-
N-phenylpyridine-3-sulfonamide;
4-[3-(2-methoxyethoxy)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-
one;
4-benzyl-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-2-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
5-methyl-2-(pyridin-2-yl)-4-(pyridin-3-ylmethyl)-1,2-dihydro-3H-pyrazol-3-one;
6-(4-benzyl-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-
sulfonamide;
N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
4-(2,5-dimethoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
6-[4-(2,5-dimethoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-
phenylpyridine-3-sulfonamide;
N-ethyl-e-iS-methyl^-^l-methylpiperidin^-yOmethyll-S-oxo^^-dihydro-IH-pyrazol-
1-yl}-N-phenylpyridine-3-sulfonamide;
N-ethyl-6-{3-methyl-5-oxo-4-[4-(trifluoromethyl)benzyl]-2,5-dihydro-1H-pyrazol-1-yl}-
N-phenylpyridine-3-sulfonamide;
N-ethyl-6-{3-methyl-5-oxo-4-[3-(trifluoromethyl)benzyl]-2,5-dihydro-1H-pyrazol-1-yl}-
N-phenylpyridine-3-sulfonamide;
5-methyl-2-(pyridin-2-yl)-4-[3-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one;
5-methyl-2-(pyridin-2-yl)-4-[4-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one;
• 6-[4-(3,5-dimethoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-ethyl-N-
phenylpyridine-3-sulfonamide;
• 4-(4-hydroxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-[4-(4-hydroxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-
phenylpyridine-3-sulfonamide;
• 6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -
yl)-N-ethyl-N-phenylpyridine-3-sulfonamide;
• 6-{4-[4-(dimethylamino)benzyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl}-N-ethyl-
N-phenylpyridine-3-sulfonamide;
• 5-methyl-2-(pyridin-2-yl)-4-[2-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one;
• 4-[4-(dimethylamino)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-{3-methyl-5-oxo-4-[2-(trifluoromethyl)benzyl]-2,5-dihydro-1 H-pyrazol-1 -yl}-
N-phenylpyridine-3-sulfonamide;
• 6-(4-benzyl-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-(3-methylbutyl)pyridine-3-
sulfonamide;
• 4-[3-(dimethylamino)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 6-{4-[3-(dimethylamino)benzyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl}-N-ethyl-
N-phenylpyridine-3-sulfonamide;
• 4-(4-methoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-[4-(4-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-
phenylpyridine-3-sulfonamide;
• 4-(2-methoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 4-(3-methoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-[4-(3-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
• 6-(4-{3-[2-(dimethylamino)ethoxy]benzyl}-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-
yl)-N-ethyl-N-phenylpyridine-3-sulfonamide;
• N-ethyl-6-[4-(2-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-
phenylpyridine-3-sulfonamide;
• 4-benzyl-5-methyl-2-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-
one;
• N-ethyl-6-[4-(3-hydroxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
-6-(4^ervzyl-3-ethyl^ex0-2T5^ibydr^ --------
sulfonamide;
4-(3-hydroxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-{4-[4-(2-methoxyethoxy)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-
yl}-N-phenylpyridine-3-sulfonamide;
4-benzyl-5-ethyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-benzyl-5-methyl-2-[5-(pyrrolidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-
one;
2-[5-(azepan-1-ylsulfonyl)pyridin-2-yl]-4-benzyl-5-methyl-1,2-dihydro-3H-pyrazol-3-
one;
N,N-diethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
N,N-diethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide hydrochloride;
N,N-dimethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
N,N-dimethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide hydrochloride;
6-(4-benzyl-5-oxo-3-propyl-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-
sulfonamide hydrochloride;
6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-(propan-2-
yl)pyridine-3-sulfonamide hydrochloride;
5-methyl-4-(pyridin-3-ylmethyl)-2-[5-(pyrrolidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-
3H-pyrazol-3-one hydrochloride;
N-tert-butyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-
pyridine-3-sulfonamide hydrochloride;
N-cyclopropyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide hydrochloride;
N-cyclopentyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide hydrochloride;
N-ethyl-6-[3-methyl-5-oxo-4-(2-phenylethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-phenyl-
pyridine-3-sulfonamide;
5-methyl-4-(2-phenylethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-methyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-
(pyridin-2-yl)pyridine-3-sulfonamide hydrochloride;
2-{5-[(4-benzylpiperidin-1-yl)sulfonyl]pyridin-2-yl}-5-methyl-4-(pyridin-3-ylmethyl)-1,2-
dihydro-3H-pyrazol-3-one;
N-ethyl-6-[3-methyl-5-oxo-4-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
N-ethyl-6-{4-[(6-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-
1-yl}-N-phenylpyridine-3-sulfonamide;
6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-(pyridin-2-
yl)pyridine-3-sulfonamide hydrochloride;
N-ethyl-6-[3-methyl-5-oxo-4-(1-phenylcyclopropyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
N-ethyl-6-{4-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-
1 -yl}-N-phenylpyridine-3-sulfonamide hydrochloride;
6-[4-benzyl-3-(methoxymethyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenyl-
pyridine-3-sulfonamide;
6-[4-benzyl-5-oxo-3-(trifluoromethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenyl-
pyridine-3-sulfonamide;
1 -[5-(azepan-1 -ylsulfonyl)pyridin-2-yl]-3-methyl-4-(pyridin-3-ylmethyl)-1 H-pyrazol-5-
olate;
N-ethyl-6-{3-methyl-5-oxo-4-[2-(pyridin-2-yl)ethyl]-2,5-dihydro-1H-pyrazol-1-yl}-N-
phenylpyridine-3-sulfonamide;
N-ethyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-
1-yl}-N-phenylpyridine-3-sulfonamide;
N-(2-methoxyethyl)-N-methyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-
1 H-pyrazol-1 -yl]pyridine-3-sulfonamide;
6-[4-benzyl-3-(2-methylpropyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-
phenylpyridine-3-sulfonamide;
N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-
3-sulfonamide;
6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-phenyl-
pyridine-3-sulfonamide;
N-ethyl-6-[3-methyl-5-oxo-4-(3-phenylpropyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-
phenylpyridine-3-sulfonamide;
sulfonamide;
N-cyclopropyl-N-methyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-
pyrazol-1-yl]pyridine-3-sulfonamide;
N-tert-butyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl}pyridine-3-sulfonamide;
6-{4-[(5-cyanopyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-
ethyl-N-phenylpyridine-3-sulfonamide;
tert-butyl6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
carboxylate;
tert-butyl 6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -
yl]pyridine-3-carboxylate;
N-tert-butyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
N-tert-butyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide hydrochloride;
N-ethyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-phenylpyridine-
3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-tert-butyl-N-methylpyridine-3-
sulfonamide;
N-ethyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-
phenylpyridine-3-sulfonamide;
5-methyl-2-[5-(phenylsulfonyl)pyridin-2-yl]-4-(pyridin-3-ylmethyl)-1,2-dihydro-3H-
pyrazol-3-one;
N-tert-butyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl}-N-rnethylpyridine-3-sulfonamide;
6-{4-[(6-cyanopyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-N-
ethyl-N-phenylpyridine-3-sulfonamide;
(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetic
acid;
2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-N,N-
dimethylacetamide;
methyl (2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-
yl)acetate;
ethyl (4-benzyl-1-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-2,5-dihydro-1H-
pyrazol-3-yl)acetate;
2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-N-
methylacetamide;
N-tert-butyl-6-{4-[(5-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl}-N-methylpyridine-3-sulfonamide;
2-(4-benzyl-1-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-2,5-dihydro-1H-pyrazol-3-
yl)-N,N-dimethylacetamide;
3-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-
propanoic acid;
methyl 3-[(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-methyl-3-oxo-2,3-dihydro-1H-
pyrazol-4-yl)methyl]benzoate;
methyl 3-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-
yl)propanoate;
methyl {2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-
yl}(phenyl)acetate;
methyl 2-[(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-methyl-3-oxo-2,3-dihydro-1H-
pyrazol-4-yl)methyl]benzoate;
N-cyclopentyl-N-ethyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
N-cyclopentyl-N-methyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
2-[(1-{5-[ethyi(phenyl)sulfamoyl]pyridin-2-yl}-3-methyl-5-oxido-1H-pyrazol-4-
yl)methyl]benzoate;
2-[5-(azepan-1-ylsulfonyl)pyridin-2-yl]-4-(pyridin-3-ylmethyl)-1,2-dihydro-3H-pyrazol-
3-one;
N-cycIopentyl-N-methyl-6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
y!]pyridine-3-sulfonamide;
N-cyclopentyl-N-ethyl-6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
methyl 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-
pyrazol-4-yl)-3-phenylpropanoate;
N-(2,2-dimethylpropyl)-N-methyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-
pyrazol-1-yl]pyridine-3-sulfonamide;
yl]pyridine-3-carboxylate;
methyl N-cyclopentyl-N-({6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridin-3-yl}sulfonyl)glycinate;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[2-(benzyloxy)ethyl]-N-
cyclopentylpyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[3-(benzyloxy)propyl]-N-
cyclopentylpyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-(3-hydroxypropyl)-
pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-(2-hydroxyethyl)-
pyridine-3-sulfonamide;
methyl (1 S,2R)-2-[methyl({6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-
yl]pyridin-3-yl}sulfonyl)amino]cyclopentanecarboxylate;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-(2,3-dihydroxy-
propyl)pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-[2-(dimethylamino)-
ethyl]pyridine-3-sulfonamide;
4-benzyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2-dihydro-3H-pyrazol-3-
one;
6-[4-(cyclopentylmethyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenyl-
pyridine-3-sulfonamide;
4-benzyl-2-{5-[(4-methyl-1,4-diazepan-1 -yl)sulfonyl]pyridin-2-yl}-1,2-dihydro-3H-
pyrazol-3-one;
N-(2,2-dimethylpropyl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
N-(2-methylbutan-2-yl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[(1R,3S)-3-(hydroxymethyl)-
cyclopentyl]-N-methylpyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-methyl-N-(1-methylpyrrolidin-3-
yl)pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-(2-methoxy-2-methylpropyl)-
pyridine-3-sulfonamide;
2,2-dimethylpropyl 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)pyridine-3-
carboxylate;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-[(2R)-2,3-
dihydroxypropyl]pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-(2,3-dihydroxypropyl)-N-
phenylpyridine-3-sulfonamide;
N-cyclopentyl-6-{4-[(4-methoxypyridin-3-yl)methyl]-5-oxo-2,5-dihydro-1H-pyrazol-1-
yl}-N-methylpyridine-3-sulfonamide;
N-methyl-N-(2-methylbutan-2-yl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-
pyrazol-1-yI]pyridine-3-sulfonamide;
3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-
yl)-3-phenyl-N-(2,2,2-trifIuoroethyl)propanamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-[3-hydroxy-2-
(hydroxymethyl)propyl]pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-[(2S)-2,3-dihydroxy-
propyl]pyridine-3-sulfonamide;
2,2-dimethylpropyl 6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-carboxylate;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[(1S,2S)-2-hydroxycyclopentyl]-
pyridine-3-sulfonamide;
N-tert-butyl-6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
4-benzyl-2-(5-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}pyridin-2-yl)-1,2-
dihydro-3H-pyrazol-3-one;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-[1 -(dimethylamino)-2-methyl-
propan-2-yl]pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-methyl-N-phenylpyridine-3-
sulfonamide;
methyl 3-{2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-3-
(pyridin-3-yl)propanoate;
ethyl 3-{2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-3-
phenylpropanoate;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-tert-butyl-N-(2,3-dihydroxypropyl)-
pyridine-3-sulfonamide;
-•—6^4-benzyl-5-Qxo4M^bydro^4J^yra^^ _______
sulfonamide;
• N-(2,3-d ihydroxypropyl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-d ihydro-1 H-pyrazol-1 -y I]-
N-phenylpyridine-3-sulfonamide hydrochloride;
• methyl 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1 H-
pyrazol-4-yl)-3-(pyridin-3-yl)propanoate hydrochloride;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-cyclopentyl-N-[3-(dimethylamino)-
propyl]pyridine-3-sulfonamide hydrochloride;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl)-N-cyclopentyl-N-[3-(dimethylamino)-
propyl]pyridine-3-sulfonamide hydrochloride.
In the text hereinbelow, the term "protecting group" (PG) means a group that can, firstly,
protect a reactive function such as an alcohol or an amine during a synthesis. Examples
of protecting groups and of protection and deprotection methods are given in "Protective
Groups in Organic Synthesis", Green et al., 3rd edition (John Wiley & Sons, Inc., New
York).
In the text hereinbelow, the term "leaving group" (LG) means a nucleofugal group that
can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an
electron pair. This group may thus be readily replaced with another nucleophilic group
during a substitution reaction, for example. Such leaving groups are, for example,
halogens or an activated hydroxyl group such as a mesyl, tosyl, triflate, acetyl, etc. group.
Examples of leaving groups and of references for preparing them are given in "Advances
in Organic Chemistry", J. March, 3rd edition, Wiley Interscience, pp. 310-316.
In accordance with the invention, the compounds of general formula (I) may be prepared
according to the processes hereinbelow.
Scheme 1 describes the synthesis of the compounds of formula (I) for which R may be a
group -S02-NR3R4, a hydrogen atom, a halogen atom, a group -halo(C1-C5)alkyl, a
group -C02R5 or a group -S02-R4; R1 may be a heterocycloalkyl group not containing a
nitrogen atom, a group -W-(C3-C6)cycloalkyl, a group -W-aryl, a group -W-heteroaryl, a
group -W-heterocycloalkyl, a group -W-COOR5 or a group -W-CONR5R6, with R3, R4
and R5 as defined above; W may be a group (C1-C5)alkylene, and n may be 0, 1 or 2.
These compounds are referred to hereinbelow as compounds of formula (la).
Scheme 1
(III)
In Scheme 1, compounds of formula (II), for which R1 and R2 are as defined for the
compounds of formula (la) and z represents an alkyl group such as a methyl or ethyl
group, react with the compounds of formula (III) to give the compounds of formula (la),
preferably in a protic solvent such as an ethanol/acetic acid mixture at a temperature of
80°C or in an aprotic solvent such as toluene, at a temperature of between 80 and 110°C,
in the presence of catalytic amounts of an organic acid such as para-toluenesulfonic acid.
Alternatively, they may be obtained sequentially by reaction in a methanol/acetic acid
mixture to obtain the intermediate hydrazone, followed by a cyclization reaction in
methanol in the presence of sodium methoxide, preferably at a temperature of 40°C.
The compounds (I) obtained are optionally converted with an acid or a base into the
corresponding salts thereof.
Scheme 2
The compounds of formula (II) may be obtained according to Scheme 2 via a reaction of
Knoevenagel type between a B-keto ester of formula (IV) R2COCH2C02z and an
aldehyde of formula (V) R1CHQ, for which R1 is as defined previously, and R2 is a group.
(C1-C5)alkyl, -(C1-C5)alkyl-(C1-C5)alkoxy, halo(C1-C5)alkyl, a group -W-COOR5, in
which W is as defined previously; z represents an alkyl group such as a methyl or ethyl
group, in an apolar solvent, preferably n-hexane, in the presence of the salt pyridinium
para-toluenesulfonate in catalytic amount, to give the compound of formula (VI), followed
by a step of hydrogenation in a polar protic solvent, preferably ethanol in the presence of
a catalyst such as palladium-on-charcoal.
Scheme 3

Alternatively, the compounds of formula (II) may be obtained according to Scheme 3
sequentially by deprotonation of the (3-keto ester (IV) of formula R2COCH2C02z with an
organic base of alkoxide type, preferentially sodium methoxide in an alcoholic solvent, or
a mineral base such as potassium hydroxide or a stronger base such as sodium hydride,
followed by the addition of an electrophile of formula (VII) R1-CH2-Lg, in which R1 is as
defined previously and R2 is a group (C1-C5)alkyl, -(C1-C5)alkyl-(C1-C5)alkoxy, halo(C1-
C5)alkyl, a group -W-COOR5, in which W is as defined previously and z is an alkyl group
such as a methyl or ethyl group and Lg is as described previously.
The synthesis of the compounds of formula (II) for which R1 is of the type W-Aryl or W-
Heteroaryl with W representing a branched alkylene group of formula -CH(alkyl)(alkyl) is
described in Scheme 4. These compounds are referred to hereinbelow as compounds of
formula (Ma).
Scheme 4
The compounds of formula (IX) are obtained by condensation of a ketone of formula (VIII)
R7COR8, with R7 and R8 and possibly being, independently or together, a C1 to C4 alkyl
group, with a (3-keto ester of formula (IV) R2-CH2-C02z in which R2 is as defined
previously and z is an alkyl group such as a methyl or ethyl group, in the presence of a
Lewis acid, preferably zinc chloride, in a solvent such as acetic anhydride, at a
temperature of between 40°C and 80°C. The compounds of formula (lla) are then
obtained via 1,4 addition of an organometallic compound of formula (X) Aryl-Metal
("ArM"), preferably an organomagnesium compound of the type Aryl-MgX, with X
representing a halogen atom such as a bromine or chlorine atom, in the presence of a
catalytic amount of copper iodide, with the compound of formula (IX) in an anhydrous
solvent, preferably ethyl ether.
The synthesis of the compounds of formula (II) for which R2 is a hydrogen is described in
Scheme 5. These compounds are referred to hereinbelow as compounds of formula (lib).
Scheme 5
The compounds of formula (lib) are obtained by formylation of the ester (V) of formula
R1-CH2-C02z in which R1 is as defined previously and z is an alkyl group such as a
methyl or ethyl group. The formylation step consists in preferentially reacting methyl or
ethyl formate with the ester (V) in the presence either of sodium metal in an anhydrous
aprotic solvent such as ethyl ether, at a temperature of between 0°C and 30°C, or in the
presence of a Lewis acid such as titanium tetrachloride and an organic base such as
—tobutylamine-----in-----the-----presence-----of—catalytic-----amounts___of___trimethylsilyl
trifluoromethanesulfonate, in an aprotic solvent such as toluene, at a temperature of
between 50°C and 60°C.
When they are not commercially available, the synthesis of the compounds of formula
(III), for which R represents a haloalkyl group or -C02R5 with R5 as described previously,
is described in Scheme 6. These compounds are referred to hereinbelow as compounds
of formula (Ilia).
Scheme 6
The compounds of formula (Ilia) are obtained from compound XI, with Lg and R as
defined previously, by addition of hydrazine hydrate, preferably in a protic solvent such as
EtOH at a temperature of between 60 and 80°C.
The synthesis of the compounds of formula (III), for which R represents a group
-S02NR3R4 and R3 and R4 are as described previously, is described in Scheme 7.
These compounds are referred to hereinbelow as compounds of formula (lllb).
Scheme 7
The compounds of formula (lllb) are obtained from 2-chloro-5-sulfonylpyridine chloride of
formula (XII), by reaction on an amine of formula (XIII) R3NHR4 with R3 and R4 as
defined previously, in the presence of an organic base, preferably triethylamine, in a polar
solvent, preferably dichloromethane. The compound obtained of formula (XIV) is then
treated with hydrazine hydrate in a protic solvent such as ethanol at 70°C, to give the
desired compounds.
The synthesis of the compounds of formula (III) for which R is an alkyl or alkoxy group is
described in Scheme 8. These compounds are referred to hereinbelow as compounds of
formula (lllc). The compounds of formula (lllc) are obtained from the compound of
formula (XV), with Lg and R as defined previously. The hydrazine function is introduced
via a coupling reaction between the benzophenone hydrazone of formula (XVI) and the
compound of formula (XV) in the presence of a catalytic amount of palladium, to give the
intermediate of formula (XVII), the hydrazine function of which is released by acid
treatment, such as hydrochloric acid, in a binary mixture of immiscible solvents such as
toluene and water, at a temperature of 100°C.
Scheme 8
Scheme 9 describes the synthesis of the compounds (I) for which R1 is a group -W-aryl
or -W-heteroaryl, the said groups being substituted with one or more groups -NR5R6 and
in which W is a group (C1-C5)alkylene. These compounds are referred to hereinbelow as
compounds of formula (lb).
Scheme 9
The compound of formula (XIX) is obtained by reacting a p-keto ester compound of
formula (IV) R2COCH2C02z, R2 being a group (C1-C5)alkyl, -(C1-C5)alkyl-(C1-C5)alkoxy
or halo(C1-C5)alkyl and z representing an alkyl group such as a methyl or ethyl group,
and a benzaldehyde compound of formula (XVIII) substituted with one or more nitro
groups. The compound of formula (XX) is then obtained by total hydrogenation in the
presence of a catalyst such as palladium-on-charcoal in a protic solvent such as ethanol,
preferentially followed by a reductive amination, under conditions such as, when R5 and
R6 are a methyl group, formic acid in the presence of a reducing agent such as sodium
triacetoxyborohydride in a protic solvent such as acetic acid. Compound (XX) is then
reacted as described in Scheme 1 with the compound of formula (III) to give the desired
compounds of formula (lb).
Scheme 10 describes the synthesis of the compounds (I) for which R1 is a group -W-aryl,
with W being a group (C1-C5)alkylene; the said aryl group being substituted with one or
more groups -0-(C1-C5)alkyl-0-(C1-C5)alkyl-(C1-C5)alkoxy or -0-(C1-C5)alkyl-NR5R6.
These compounds are referred to hereinbelow as compounds of formula (Ic).
Scheme 10
The compound of formula (XXII) is obtained by reacting a p-keto ester compound of
formula (IV) R2COCH2C02z, with R2 being as described previously and z representing
an alkyl group such as a methyl or ethyl group, and a benzaldehyde compound of formula
(XXI), followed by a step of total hydrogenation in the presence of palladium-on-charcoal,
preferably in a solvent such as ethanol. The compound of formula (XXIV) is then obtained
by alkylation with a compound of formula (XXIII) R9-Lg, with R9 representing a group (C1-
C5)alkylene, -(C1-C5)alkyl-(C1-C5)alkoxy or -(C1-C5)alkyl-NR5R6 and Lg being as
defined previously, in the presence of a base, preferentially a mineral base such as
potassium carbonate, and in a polar solvent such as DMF; it is then reacted as described
in Scheme 1 with the compound of formula (III) to give the desired compounds of formula
(Ic).
In the examples that follow, the starting compounds, the intermediates and the reagents,
when their mode of preparation is not described, are commercially available or are
described in the literature, or else may be prepared according to methods that are known
to those skilled in the art.
The examples that follow illustrate the preparation of certain compounds in accordance
with the invention. The numbers of the compounds given as examples referred to those in
the table given later, which illustrates the chemical structures and physical properties of a
few compounds according to the invention._______
The following abbreviations and formulae are used:
EtOAc Ethyl acetate
DCM Dichloromethane
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
DME 1,2-Dimethoxyethane
EtOH Ethanol
tBuOH tert-Butanol
Et20 Diethyl ether
MeOH Methanol
iPrOH Isopropanol
AcOH Acetic acid
CH3CN Acetonitrile
Et20 Diethyl ether
THF Tetrahydrofuran
h Hour(s)
HCI Hydrochloric acid
H2SO4 Sulfuric acid
K2C03 Potassium carbonate
KOH Potassium hydroxide
NH4CI Ammonium chloride
NaHC03 Sodium hydrogen carbonate
Na2S04 Sodium sulfate
Cs2C03 Caesium carbonate
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
RT Room temperature
ZnCI2 Zinc chloride
PPTS Pyridinium para-toluenesulfonate
anh. Anhydrous
Pd -C Palladium-on-charcoal
Cul Copper iodide
MeCN Acetonitrile
Nal Sodium iodide
DIEA Diisopropylethylamine
TBTU 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate
DCC N,N-Dicyclohexylacarbodiimide
NMM 4-Methylmorpholine
NMO 4-methylmorpholine N-oxide
Os04 Osmium tetroxide
Pd(OAc)2 Palladium acetate
P(OTol)3 Tri(o-tolyl)phosphine
pTsOH para-Toluenesulfonic acid
Tr Retention time
T Time
"PC Temperature in °C
Min Minutes
m.p. Melting point
The proton magnetic resonance (1H NMR) spectra, as described below, are recorded at
400 MHz in DMSO-d6, using the peak of DMSO-d5 as reference. The chemical shifts 5
are expressed in parts per million (ppm). The signals observed are expressed as follows:
s = singlet; bs = broad singlet; d = doublet; dd = doublet of doublets; dt = doublet of
triplets; t = triplet; m = multiplet; H = proton.
The mass spectra are obtained under the following LC/MS coupling conditions:
Method 1: Column: Jsphere 33 x 2 mm; 4 uM;
Eluents: A = H20 + 0.05% TFA; B = CH3CN + 0.05% TFA
TO: 98% A; T1.0 to T5.0 min: 95% B;
Method 2: Column: Acquity BEH C18 (50 x 2.1 mm; 1.7 uM);
Eluents: A = H20 + 0.05% TFA; B = CH3CN + 0.035% TFA.
TO: 98% A; T1.6 to T2.1 min: 100% B; T2.5 to T3 min: 98% A
flow rate 1.0 mL/min; T°C = 40°C, injection 2 uL
Method 3: Column: Kromasil C18 (50 x 2.1 mm; 3.5 urn);
Eluents: A = CH3C02NH4+ 3% CH3CN; B = CH3CN;
TO: 100% A; T5.5 to T7 min: 100% B; T7.1 to T10 min: 100% B; flow rate 0.8 mL/min ; T°
= 40°C - Injection 5 uL
Example 1: N-ethyl-6-[3-methyl-4-(1 -methyl-1 -phenylethyl)-5-oxo-2,5-dihydro-1 H-
pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide (Compound 77 of Table I)

1.1. methyl 2-acetyl-3-methylbut-2-enoate
To a mixture of 9.54 g (70 mmol) of anhydrous ZnCI2, 53.9 mL (500 mmol) of methyl
acetoacetate and 55 mL (750 mmol) of acetone are added 64 mL of acetic anhydride.
The reaction medium is then heated for 3 days at 50°C, and then diluted with 1 L of DCM
and washed with water (3 * 100 mL). The organic phase is dried over Na2S04, filtered
and then concentrated under reduced pressure. The residue obtained is purified by
chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0
to 10% EtOAc. After concentrating under reduced pressure, 51.5 g of methyl 2-acetyl-3-
methylbut-2-enoate are obtained in the form of a colourless oil.
Yield = 70%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 3.79 (s, 3H); 2.29 (s, 3H); 2.12 (s, 3H); 1.97 (s, 3H).
1.2. methyl 2-acetvl-3-methyl-3-phenylbutanoate
To a suspension of 146 mg (0.8 mmol) of anhydrous Cul (I) in 5 mL of anhydrous ether
are added, at 0°C, under a stream of argon, 3.6 mL (10.9 mmol) of a 3M solution of
phenylmagnesium bromide in Et20. After stirring for 30 minutes at 0°C, 1 g (6.4 mmol) of
methyl 2-acetyl-3-methylbut-2-enoate is added in a single portion. The mixture is allowed
to warm to room temperature and stirring is continued for 18 hours. The reaction mixture
is then treated with 100 mL of saturated NH4CI solution, the phases are separated by
settling, and the organic phase is again treated with 100 mL of saturated NH4CI solution.
The aqueous phases are extracted with 4x100 mL of DCM. The organic phases are
combined, dried over anhydrous Na2S04 and concentrated under reduced pressure. After
purification by chromatography on silica gel, eluting with a 95/5 cyclohexane/EtOAc
mixture, 1 g of methyl 2-acetyl-3-methyl-3-phenylbutanoate is obtained in the form of a
colourless oil.
Yield = 67%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.4-7.2 (m, 5H); 3.9 (s, 1H); 3.8 (s, 3H); 1.90 (s, 3H);
1.6 (s, 3H), 1.55 (s,3H).
1.3. N-ethvl-6-[3-methvl-4-(1-methvl-1-phenvlethvn-5-oxo-2,5-dihvdro-1H-pyrazol-1-vn-N-
phenylpyridine-3-sulfonamide
To a solution of 200 mg (0.85 mmol) of methyl 2-acetyl-3-methyl-3-phenylbutanoate in
2 mL of EtOH/AcOH mixture (1:1) are added 249 mg (0.85 mmol) of N-ethyl-6-hydrazino-
N-phenylpyridine-3-sulfonamide and the reaction mixture is then heated for 2 hours at
90°C. After concentrating under reduced pressure, the residue is taken up in 100 mL of
DCM, washed with 2 * 30 mL of saturated NaHC03 solution, dried over Na2S04, filtered,
concentrated under reduced pressure and then purified by chromatography on a column
of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. After
concentrating under reduced pressure, 312 mg of a yellow oil are obtained, and are
solidified in 20 mL of pentane. The solid obtained is filtered off, and then dried under
vacuum. 178 mg of N-ethyl-6-[3-methyl-4-(1-methyl-1-phenylethyl)-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder.
Yield = 44%
m.p. (°C) = 122
M = C26H28N403S = 476; M+H = 477; Method 2: Tr = 1.54 min
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.55 (bs, 1H); 8.45 (s, 1H); 8.1 (d,
1H); 7.5-7.3 (m, 7H); 7.2 (m, 1H); 7.1 (d, 2H); 3.65 (q, 2H); 1.9 (s, 3H); 1.7 (s, 6H); 1.0 (t,
3H).
Example 2: N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-
1-yl]-N-phenylpyridine-3-sulfonamide (Compound 43 of Table I)
2.1. methyl (2E/Z)-3-oxo-2-(pyridin-3-vlmethvlidene)butanoate
A mixture of 10 g (86 mmol) of methyl 3-oxobutanoate, 9.2 g (86 mmol) of pyridine-2-
carboxaldehyde and 70 mg (1.1 mmol) of PPTS in 27 mL of hexane is refluxed for
48 hours in Dean-Stark apparatus. The medium is then concentrated under reduced
pressure, taken up in 50 mL of EtOAc, washed successively with water (2x100 mL) and
brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure.
17,6 g of methyl (2E/Z)-3-oxo-2-(pyridin-3-ylmethylidene)butanoate are obtained in the
form of a yellow oil, which is used without further purification for the following step.
Yield = 99%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.7 (s, 1H); 8.5 (d, 1H); 8.00 (d, 1H); 7.6 (s, 1H); 7.35
(dd, 1H);3.7(s, 3H); 2.3 (s, 3H).
2.2. methyl 3-oxo-2-(pvridin-3-vlmethv0butanoate
In Parr apparatus, a mixture of 14 g (68 mmol) of methyl (2E/Z)-3-oxo-2-(pyridin-3-
ylmethylidene)butanoate in 200 mL of MeOH and 2.2 g of 10% Pd/C is hydrogenated for
48 hours at 7 bar. The reaction mixture is then filtered through Whatman GF/F paper and
concentrated under reduced pressure. 14 g of methyl 3-oxo-2-(pyridin-3-
ylmethyl)butanoate are thus obtained in the form of a dark yellow oil, which is used
without further purification in the following step.
Yield = 99%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.5 (m, 2H); 7.28 (d, 1H); 7.21 (dd, 1H); 3.78 (t, 1H);
3.71 (s, 3H); 3 16 (dd, 2H); 2.23 (s, 3H).
2.3 N-ethvl-6-r3-methvl-5-oxo-4-(pvridin-3-vlmethvl)-2,5-dihvdro-1H-pvrazol-1-vll-N-
phenylpyridine-3-sulfonamide hydrochloride
A solution of 300 mg (1.45 mmol) of methyl 3-oxo-2-(pyridin-3-ylmethyl)butanoate and
423 mg (1.45 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide in 4 mL of
EtOH/AcOH mixture (1/1) is heated for 4 hours at 85°C. After cooling to room
temperature, the precipitate obtained is filtered off and then washed successively with
Et20 (20 mL) and pentane (20 mL). 210 mg of a residue are isolated, and this residue is
taken up in 40 mL of water, 2 mL of acetonitrile and 0.48 mL of 0.2N HCI solution and
then freeze-dried. 220 mg of N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-
1H-pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide hydrochloride are thus obtained in the
form of a white lyophilizate.
Yield = 33%
m.p. (°C) = 128
M = CzjHzsNsOsS = 449; M+H = 450; Method 2: Tr = 0.85 min
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.5 (bs, 1H); 8.90 (s, 1H); 8.8 (d, 1H); 8.6 (d,
1H); 8.5 (d, 1H); 8.4 (s, 1H); 8.2 (dd, 1H); 8.05 (dd, 1H); 7.4 (m, 3H); 7.1 (d, 2H); 3.8 (s,
2H); 3.65 (q, 2H); 2.3 (s, 3H); 1.0 (t, 3H).
Example 3: 6-(4-{3-[2-(dimethylamino)ethoxy]benzyl}-3-methyl-5-oxo-2,5-dihydro-
1 H-pyrazol-1 -yl)-N-ethyl-N-phenylpyridine-3-sulfonamide hydrochloride (Compound
56 of Table I)
3.1. methyl (2E/Z)-2-f(3-hvdroxyphenvl)methvlidene1-3-oxobutanoate
According to the process described in Example 2.1, starting with 5 g of
3-hydroxybenzaldehyde and 4.75 g of methyl 3-oxobutanoate, 2.5 g of methyl (2E/Z)-2-
[(3-hydroxyphenyl)methylidene]-3-oxobutanoate are obtained in the form of a pale yellow
powder.
Yield = 27%
1H NMR (CDCI3, 400 MHz, 5 (ppm): 7.4 (s, 1H); 7.2 (m, 1H); 6.9-6.8 (m, 2H); 5.1 (s, 1H);
3.8 (s, 3H); 2.4 (s, 3H); 2.4 (s, 3H).
3.2. methyl 2-(3-hydroxvbenzv0-3-oxobutanoate
According to the process described in Example 2.2, starting with 2.5 g of methyl (2E/Z)-2-
[(3-hydroxyphenyl)methylidene]-3-oxobutanoate, 2.5 g of methyl 2-(3-hydroxybenzyl)-3-
oxobutanoate are obtained in the form of a translucent wax.
Yield = 99%
1H NMR CDCI3, 400 MHz, 5 (ppm): 7.15 (t, 1H); 6.7-6.85 (m, 3H); 5.6 (s, 1H); 3.7 (s, 3H);
3.15 (d,2H); 2.25 (s,3H).
3.3. methyl 2-(3-r2-(dimethvlamino)ethoxy1benzyl>-3-oxobutanoate
A mixture of 1.5 g (6.75 mmol) of methyl 2-(3-hydroxybenzyl)-3-oxobutanoate, 6.6 g
(20.25 mmol) of anhydrous Cs2C03, 0.1 g (0.67 mmol) of Nal and 1 g (7.1 mmol) of 2-
dimethylaminoethyl chloride hydrochloride in 20 ml_ of anhydrous CH3CN is heated for
4 hours at 90°C, and then stirred overnight at room temperature. The reaction medium is
filtered and then concentrated under reduced pressure. The residue obtained is taken up
in DCM (100 ml_), washed with brine (30 mL), dried over Na2S04, filtered, concentrated
under reduced pressure and then purified by chromatography on a column of silica gel,
eluting with a DCM/MeOH gradient of 0 to 10% MeOH. After concentrating under reduced
pressure, 409 mg of methyl 2-{3-[2-(dimethylamino)ethoxy]benzyl}-3-oxobutanoate are
obtained in the form of a brown wax.
Yield = 19.5%
1H NMR, CDCI3, 400 MHz, 6 (ppm): 7.2 (t, 1H); 6.7-6.8 (m, 3H); 4.1 (t, 2H); 3 8 (t, 1H),
3.7 (s, 3H); 3.15 (d, 2H); 2 8 (t, 2H); 2.4 (s, 6H); 2.3 (s. 3H).
3.4. 6-(443-r2-(dimethvlamino^ethoxv1benzvl>-3-methvl-5-oxo-2.5-dihydro-1H-pvrazol-1-
vl)-N-ethvl-N-phenvlpyridine-3-sulfonamide hydrochloride
According to the process described in Example 2.3, starting with 195 mg of methyl 2-{3-
[2-(dimethylamino)ethoxy]benzyl}-3-oxobutanoate and 194 mg of N-ethyl-6-hydrazino-N-
phenylpyridine-3-sulfonamide, 70 mg of 6-(4-{3-[2-(dimethylamino)ethoxy]benzyl}-3-
methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-sulfonamide
hydrochloride are obtained in the form of a white lyophilizate.
Yield = 20%
m.p. (°C) = 124
M = C28H33N504S = 535, M+H = 536; Method 2: Tr = 0.98 min
1H NMR, d6-DMSO, 400 MHz, 6 (ppm): 12.0 (bs, 1H); 10.0 (bs, 1H); 8.6 (d, 1H); 8.4 (s,
1H); 8.1 (d, 1H); 7.4 (m, 3H); 7.25 (t, 1H); 7.15 (d, 2H); 6.9 (d, 2H); 6.8 (d, 1H); 4.3 (t, 2H);
3.6 (q, 2H); 3.5 (s, 2H); 3.4 (t, 2H); 2.8 (s, 6H); 2.2 (s, 3H); 1.0 (t, 3H).
Example 4: 6-{4-[3-(dimethylamino)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-
1-yl}-N-ethyl-N-phenylpyridine-3-sulfonamide (Compound 53 of Table \)
4.1. methyl (2Z/E)-2-r(4-nitrophenvl)methylidene1-3-oxobutanoate
According to the process described in Example 2.1, starting with 6.18 g of
4-nitrobenzaldehyde and 4.75 g of methyl 3-oxobutanoate, 4.2 g of methyl (2Z/E)-2-[(4-
nitrophenyl)methylidene]-3-oxobutanoate are obtained in the form of an oil.
Yield =41%
1H NMR, CDCI3, 400 MHz, 6 (ppm): 8.4 (s, 1H); 8.3 (d, 1H); 7 8 (d, 1H); 7.6 (m, 2H); 3.9
(s,3H);2.5(s,3H).
4.2. methyl 2-(4-aminobenzyl)-3-oxobutanoate
According to the process described in Example 2.2, starting with 4.2 g of methyl (2Z/E)-2-
[(4-nitrophenyl)methylidene]-3-oxobutanoate, 2g of methyl 2-(4-aminobenzyl)-3-
oxobutanoate are obtained in the form of an oil.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.1 (t, 1H); 6.6-6.5 (m, 3H); 3.9 (t, 1H); 3.8 (s, 3H);
3.7 (bs, 2H); 3.1 (d, 2H); 2.2 (s, 3H).
Yield = 54%
4.3. methyl 2-[4-(dimethylamino)benzvH-3-oxobutanoate
To a mixture of 1.5 g (6.78 mmol) of methyl 2-(4-aminobenzyl)-3-oxobutanoate, 40 ul
(0.04 mmol) of AcOH and 5.1 ml_ (67.8 mmol) of an aqueous 37% solution of
formaldehyde in 13 mL of CH3CN are added portionwise at 0°C 4.3 g (20.34 mmol) of
sodium triacetoxyborohydride. The reaction medium is then allowed to warm slowly to
room temperature, and stirring is continued for 12 hours. The reaction mixture is poured
into 50 mL of saturated NaHC03 solution and 30 g of ice, extracted with EtOAc (2 *
100 mL), dried over Na2S04, filtered and concentrated under reduced pressure, and then
purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc
gradient of 0 to 50% EtOAc. 344 mg of methyl 2-[4-(dimethylamino)benzyl]-3-
oxobutanoate are obtained in the form of a yellow oil.
Yield: 20%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.1 (t, 1H); 6.65 (d, 1H); 6.55 (m, 2H); 3.9 (t, 1H); 3.8
(s, 3H); 3.2 (d, 2H); 3.0 (s, 6H); 2.2 (s, 3H).
4.4. 6-{4-r3-(dimethvlamino)benzvl1-3-methvl-5-oxo-2,5-dihvdro-1H-pvrazol-1-vlVN-ethyl-
N-phenylpyridine-3-sulfonamide
According to the process described in Example 1.3, starting with 172 mg of methyl 2-[4-
(dimethylamino)benzyl]-3-oxobutanoate and 202 mg of N-ethyl-6-hydrazino-N-
phenylpyridine-3-sulfonamide, 138 mg of 6-{4-[3-(dimethylamino)benzyl]-3-methyl-5-oxo-
2,5-dihydro-1H-pyrazol-1-yl}-N-ethyl-N-phenylpyridine-3-sulfonamide are obtained in the
form of a white solid.
Yield = 41%
m.p. (°C) = 122
M = C26H29N503S = 491; M+H = 492; Method 2: Tr = 0.96
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.7 (bs, 1H); 8.45 (s, 1H); 8.1 (d,
1H); 7.4 (m, 3H); 7.2 (d, 2H); 7.1 (t, 1H); 6.7 (s, 1H); 6.5 (d, 2H); 3.7 (q, 2H); 3.5 (s, 2H);
2.9 (s, 6H); 2.15 (s, 3H); 1.0 (t, 3H).
Example 5: N,N-dimethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-
pyrazol-1-yl]pyridine-3-sulfonamide (Compound 66 of Table I)
5.1. 6-chloro-N,N-dimethvlpvridine-3-sulfonamide
To a mixture of 4.7 mL (9.43 mmol) of dimethylamine (2N in THF) and 2.6 mL
(18.86 mmol) of TEA in 20 mL of THF is added dropwise, at 0°C, a solution of 2 g
(9.43 mmol) of 6-chloropyridine-3-sulfonyl chloride (prepared according to patent WO
9840332) in 5 mL of THF. After stirring for 40 minutes at OX, the reaction medium is
taken up in 40 mL of EtOAc, washed with water (2 x 40 mL) and brine (40 mL), dried over
Na2S04, filtered and concentrated under reduced pressure. 1.93 g of 6-chloro-N,N-
dimethylpyridine-3-sulfonamide are obtained in the form of a brown solid, which is used
without further purification in the following step.
Yield = 93%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.8 (s, 1H); 8.0 (d, 1H); 7.4 (d, 1H); 2.7 (s, 6H).
5.2. 6-hvdrazino-N,N-dimethvlpvridine-3-sulfonamide
A mixture of 1.9 g (8.8 mmol) of 6-chloro-N,N-dimethylpyridine-3-sulfonamide and 4.6 mL
(91.5 mmol) of hydrazine monohydrate in 10 mL of EtOH is heated for 2 hours at 80°C.
The precipitate obtained, after cooling to room temperature, is filtered off and then
washed with 10 mL of EtOH and dried under vacuum. 1.62 g of 6-hydrazino-N,N-
dimethylpyridine-3-sulfonamide are obtained in the form of a white powder.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.5 (bs, 1H); 8.3 (s, 1H); 7.7 (d, 1H); 6.85 (d, 1H);
4.4 (s, 2H); 2.6 (s, 6H).
5.3. N,N-dimethvl-6-[3-methvl-5-oxo-4-(pvridin-3-vlmethvl)-2,5-dihydro-1H-pyrazol-1-
vnpvridine-3-sulfonamide
A mixture of 400 mg (1.85 mmol) of 6-hydrazino-N,N-dimethylpyridine-3-sulfonamide and
383 mg (1.85 mmol) of methyl 3-oxo-2-(pyridin-3-ylmethyl)butanoate in 4 mL of
EtOH/AcOH mixture (1:1) is heated for 4 hours at 80°C and then concentrated under
reduced pressure. The residue obtained is taken up in 20 mL of EtOAc, washed
successively with water (2 * 20 mL), saturated NaHC03 solution (20 mL) and brine
(20 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The
residue is then solidified in 20 mL of an Et20/pentane mixture (1/1), filtered and
recrystallized from a cyclohexane/EtOH mixture. 188 mg of N,N-dimethyl-6-[3-methyl-5-
oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]pyridine-3-sulfonamide are
obtained in the form of white crystals.
Yield = 28%
m.p. (°C) = 212
M = C17H19N503S = 373; M+H = 374; Method 2: Tr = 0.58 min
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12 (bs, 1H); 8.7 (s, 1H); 8.65 (d, 1H); 8.5 (s, 1H);
8.4 (d, 1H); 8.35 (d, 1H); 7.7 (d, 1H); 7.3 (dd, 1H); 3.6 (s, 2H); 2.7 (s, 6H); 2.2 (s, 3H).
Example 6: N-ethyl-6-{4-[3-(methoxymethyl)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl}-N-phenylpyridine-3-sulfonamide (Compound 34 of Table I)
6.1. methyl 3-(methoxymethvl)benzoate
To a solution of 15 g (65.5 mmol) of methyl 3-(bromomethyl)benzoate in 20 mL of
anhydrous MeOH is added dropwise, at room temperature, a solution of sodium
methoxide in MeOH, prepared beforehand from 2.25 g (98.2 mmol) of sodium in 65 mL of
MeOH. The reaction medium is then heated for 4 hours at 65°C and then concentrated
under reduced pressure, taken up in 500 mL of DCM, washed with water (100 mL) and
brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure.
7.8 g of methyl 3-(methoxymethyl)benzoate are obtained in the form of an oil, which is
used without further purification in the following step.
Yield = 66%
1H NMR, CDCI3, 400 MHz, 6 (ppm): 8.1 (s, 1H); 8.0 (d, 1H); 7.5 (d, 1H); 7.4 (t, 1H); 4.5 (s,
2H); 4.0 (s, 3H); 3.4 (s, 3H).
6.2. 2 F3-(methoxvmethvl)phenyl1methanol
To a solution of 7.8 g (43.3 mmol) of methyl 3-(methoxymethyl)benzoate in 60 mL of a
THF/dioxane mixture (1/1) is added 0.94 g (43.3 mmol) of lithium borohydride. The
reaction medium is then heated for 3 hours at 80°C and stirred overnight at room
temperature. The reaction medium is taken up in 500 mL of EtOAc, washed with water
(2 x 100 mL), dried over Na2S04, filtered and concentrated under reduced pressure. 5.9 g
of 2 [3-(methoxymethyl)phenyl]rnethanol are obtained in the form of a yellow liquid, which
is used without further purification in the-foliowing step.
Yield = 90%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.4-7.2 (m, 4H); 4.7 (s, 2H); 4.5 (s, 2H); 3.4 (s, 3H);
2.4 (bs, 1H).
6.3. 1-(bromomethvl)-3-(methoxvmethv0 benzene
To a solution of 5.91 g (38 8 mmol) of 2 [3-(methoxymethyl)phenyl]methanol in 75 mL of
Et20 are added dropwise, at 0°C, 9.1 mL (97.1 mmol) of phosphorus tribromide. The
reaction mixture is allowed to warm slowly to room temperature and stirring is continued
for 4 hours. The crude reaction mixture is then poured cautiously into a mixture of 100 g
of ice and 100 mL of MeOH. After evaporating off the MeOH under reduced pressure, the
aqueous phase is extracted with DCM (2 * 200 mL). The organic phases are combined.
dried over Na2S04, filtered and then concentrated under reduced pressure. The residue
obtained is purified by chromatography on a column of silica gel, eluting with a
cyclohexane/EtOAc gradient of 0 to 20% EtOAc.
3.25 g of 1-(bromomethyl)-3-(methoxymethyl)benzene are thus obtained in the form of an
oil.
Yield = 39%
1H NMR CDCI3, 400 MHz, 5 (ppm): 7.4-7.1 (m, 4H); 4 45 (s, 2H); 4.35 (s. 2H): 3.3 (s, 3H)
6.4. methyl 2-f3-(methoxvmethvl)benzvn-3-oxobutanoate
To a solution of 0.34 g (15.1 mmol) of sodium in 8 mL of anhydrous MeOH are added
dropwise, at room temperature and under argon, 1.6 mL (15.1 mmol) of methyl
acetoacetate. After stirring for 30 minutes, 3.25 g (15.11 mmol) of 1-(bromomethyl)-3-
(methoxymethyl)benzene are rapidly added dropwise and the reaction medium is then
heated for 2 hours 30 minutes at 70°C. The reaction medium is then concentrated under
reduced pressure, and the residue obtained is purified by chromatography on a column of
silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 20% EtOAc. 3.2 g of methyl
2-[3-(methoxymethyl)benzyl]-3-oxobutanoate are obtained in the form of an oil.
Yield = 85%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.4-7.1 (m, 4H); 4.45 (s, 2H); 3 8 (t, 1H); 3 7 (t, 3H);
3.4 (t, 3H); 3 2 (d, 2H); 2.2 (s, 3H).
6.5. N-ethvl-644-r3-(methoxvmethvl)benzvll-3-methvl-5-oxo-2,5-dihvdro-1H-pyrazol-1-vl}-
N-phenvlpvridine-3-sulfonamide
According to the process described in Example 1.3, starting with 300 mg of methyl 2-[3-
(methoxymethyl)benzyl]-3-oxobutanoate and 350 mg of N-ethyl-6-hydrazino-N-
phenylpyridine-3-sulfonamide, 341 mg of N-ethyl-6-{4-[3-(methoxymethyl)benzyl]-3-
methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-N-phenylpyridine-3-sulfonamide are obtained
in the form of a white powder.
Yield = 58%
m.p. (°C) = 144
M = C26H28N404S = 492; M+H = 493; Method 2: Tr = 1.29 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.7 (bs, 1H); 8.45 (s, 1H); 8.1 (d,
1H); 7.4 (m, 3H); 7.3-7.1 (m, 6H); 4.35 (s, 2H); 3.6 (q, 2H); 3.5 (s, 2H); 3.3 (s, 3H); 2.15
(s, 3H); 1.0 (t, 3H).
Example 7: N-ethyl-6-[3-methyl-5-oxo-4-(2-phenylethyl)-2,5-dihydro-1 H-pyrazol-1 -
yl]-N-phenylpyridine-3-sulfonamide (Compound 74 of Table I)
7.1. methyl 3-oxo-2-(2-phenvlethvl)butanoate
According to the process described in Example 6.4, starting with 5.16 g of (2-
bromoethyl)benzene and 3.2 g of methyl acetoacetate, 1.9 g of methyl 3-oxo-2-(2-
phenylethyl)butanoate are obtained in the form of a translucent oil.
Yield = 31%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.2-7.35 (m, 5H); 3.75 (s, 3H); 3.5 (t, 1H); 2.5-2.7 (m,
2H); 2.2 (s, 3H); 2.15-2.3 (m, 2H).
7.2. N-ethvl-6-r3-methvl-5-oxo-4-(2-phenvlethvl)-2,5-dihvdro-1H-pyrazol-1-vll-N-
phenvlpyridine-3-sulfonamide
According to the process described in Example 1.3, starting with 264 mg of methyl 3-oxo-
2-(2-phenylethyl)butanoate and 351 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-
sulfonamide, 291 mg of N-ethyl-6-[3-methyl-5-oxo-4-(2-phenylethyl)-2,5-dihydro-1H-
pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder.
Yield = 53%
m.p. (°C) = 158
M = C25H26N403S = 462; M+H = 463; Method 2 = 1.35 min
1H NMR, d6-DMS0, 400 MHz, 5 (ppm): 11.8 (bs, 1H); 8.6 (bs, 1H); 8.45 (s, 1H); 8,1 (d,
1H); 7.4 (m, 3H); 7.3 (m, 2H); 7.2 (d, 3H); 7.1 (d, 2H); 3.6 (q, 2H); 2.8 (t, 2H); 2.5 (t, 2H);
1.9(s. 3H); 1.0(t,3H).
Example 8: 6-(4-benzyl-5-oxo-3-propyl-2,5-dihydro-1H-pyrazoM-yl)-N-ethyl-N-
phenylpyridine-3-sulfonamide (Compound 68 of Table I)
8.1. ethyl 2-benzyl-3-oxohexanoate
According to the process described in Example 6.4, starting with 2.2 g of benzyl bromide
and 4 g of ethyl butyrylacetate, 2.5 g of ethyl 2-benzyl-3-oxohexanoate are obtained in
the form of a translucent oil.
Yield = 40%
1H NMR, CDCI3, 400 MHz, 6 (ppm): 7.15-7.30 (m, 5H); 4.2 (q, 2H); 3.8 (t, 1H); 3.2 (dd,
2H); 2.5-2.3 (m, 2H); 1.55 (m, 2H); 1.2 (t, 3H); 0.86 (t, 3H).
8.2. 6-(4-benzvl-5-oxo-3-propyl-2,5-dihvdro-1H-pyrazol-1-vn-N-ethvl-N-phenvlpvridine-3-
sulfonamide
According to the process described in Example 1.3, starting with 300 mg of ethyl 2-
benzyl-3-oxohexanoate and 353 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-
sulfonamide, 400 mg of 6-(4-benzyl-5-oxo-3-propyl-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-
N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder.
Yield = 69%
m.p. (°C) = 180
M = C26H28N4O3S = 476; M+H = 477; Method 2: Tr = 1.45 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.6 (bs, 1H); 8.45 (s, 1H); 8.1 (d,
1H); 7.45-7.1 (m, 10H); 3.65 (q, 2H); 3.6 (s, 2H); 2.5 (t, 2H); 1.5 (m, 2H); 1.0 (t, 3H); 0.9
(t, 3H).
Example 9: N-ethyl-6-{4-[3-(2-methoxyethoxy)benzyl]-3-methyl-5-oxo-2,5-dihydro-
1H-pyrazol-1-yl}-N-phenylpyrldine-3-sulfonamide (Compound 38 of Table I)
9.1. r3-(2-methoxvethoxy)phenvl1methanol
A mixture of 10 g (80.6 mmol) of 3-(hydroxymethyl)phenol, 78.4 g (241.7 mmol) of
Cs2C03 and 8.4 ml_ (88.6 mmol) of bromoethyl methyl ether in 150 mL of CH3CN is
heated for 12 hours at 110°C. After cooling to room temperature, the medium is filtered,
concentrated under reduced pressure, taken up in 500 mL of DCM, washed with brine
(2 x 100 mL) dried over Na2S04, filtered and then concentrated under reduced pressure.
10.9 g of 3-(2-methoxyethoxy)phenyl]methanol are obtained in the form of a yellow oil.
Yield = 75%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.3 (t, 1H); 6.95 (m, 2H); 6.85 (d, 1H); 4.6 (s, 2H); 4.1
(t, 2H); 3.8 (t, 2H); 3.4 (s, 3H); 2.1 (bs, 1H)
9.2. 1-(bromomethvl)-3-(2-methoxvethoxy)benzene
According to the process described in Example 6.3, starting with 10 g of [3-(2-
methoxyethoxy)phenyl]methanol, 11.8 g of 1-(bromomethyl)-3-(2-methoxyethoxy)-
benzene are obtained in the form of an oil.
Yield = 87%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.3 (m, 1H); 7.0 (m, 2H); 6.9 (d, 1H ); 4.45 (s, 2H);
4.15 (t, 2H); 3.75 (t, 2H); 3.4 (s, 3H)
9.3. methyl 2-f3-(2-methoxvethoxv)benzvn-3-oxobutanoate
According to the process described in Example 6.4, starting with 5.6 g of 1-
(bromomethyl)-3-(2-methoxyethoxy)benzene and 2.52 g of methyl acetoacetate, 3.44 g of
methyl 2-[3-(2-methoxyethoxy)benzyl]-3-oxobutanoate are obtained in the form of a
yellow oil.
1H NMR CDCI3, 400 MHz, 5 (ppm): 7.2 (t, 1H); 6.75 (m, 3H); 4.15 (d, 2H); 3.8 (t, 1H); 3.75
(s, 3H); 3.45 (s, 3H); 3.15 (d, 2H); 2.2 (s, 3H).
9.4. N-ethvl-6-(4-r3-(2-methoxvethoxv)benzvn-3-methvl-5-oxo-2.5-dihvdro-1H-pyrazol-1-
vl)-N-phenylpyridine-3-sulfonamide
According to the process described in Example 1.3, starting with 336 mg of methyl 2-[3-
(2-methoxyethoxy)benzyl]-3-oxobutanoate and 351 mg of N-ethyl-6-hydrazino-N-
phenylpyridine-3-sulfonamide, 441 mg of N-ethyl-6-{4-[3-(2-methoxyethoxy)benzyl]-3-
methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-N-phenylpyridine-3-sulfonamide are obtained
in the form nf a white pnwrier
Yield = 70%
m.p. (°C) = 126
M = C27H3oN405S = 522; M+H = 523; Method 2: Tr = 1.27 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.6 (bs, 1H); 8.45 (s, 1H); 8.1 (d,
1H); 7.4 (m, 3H); 7.3-7.1 (m, 3H); 6.8 (d, 2H); 7.1 (d, 1H); 4.1 (d, 2H); 3.6 (m, 4H); 3.5 (s,
2H); 3.3 (s, 3H); 2.1 (s, 3H); 1.0 (t, 3H).
Example 10: N-ethyl-6-[4-(4-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-
1-yl]-N-phenylpyridine-3-sulfonamide (Compound 54 of Table I)
10.1. methyl 2-(4-methoxvbenzyl)-3-oxobutanoate
A mixture of 1.34 g (8.6 mmol) of 1-(chloromethyl)-4-methoxybenzene, 0.93 mL
(8.6 mmol) of methyl acetoacetate, 0.24 g (0.86 mmol) of tetrabutylammonium chloride
and 6.9 g of a mixture by mass of K2CO3/KOH (4/1) in 5 mL of toluene is heated for
5 minutes at 110°C in a microwave reactor. The reaction medium is taken up in 80 mL of
EtOAc, washed successively with water (2 * 20 mL), saturated NaHC03 solution (20 mL)
and brine (20 mL), dried over Na2S04 and then concentrated under reduced pressure.
The residue obtained is purified by chromatography on a column of silica gel, eluting with
a cyclohexane/EtOAc gradient of 0 to 30% EtOAc.
0.93 g of methyl 2-(4-methoxybenzyl)-3-oxobutanoate is thus obtained in the form of a
yellow oil.
Yield = 48%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.2 (d, 1H); 7.1 (d, 1H); 6.8 (m, 2H); 3.8 (s, 3H); 3.75
(t, 1H); 3.7 (s, 3H); 3.2 (m, 2H); 2.2 (s, 3H).
10.2. N-ethvl-6-f4-(4-methoxvbenzvl)-3-methvl-5-oxo-2.5-dihvdro-1H-pyrazol-1-vn-N-
phenvlpyridine-3-sulfonamide
According to the process described in Example 1.3, starting with 300 mg of methyl 2-(4-
methoxybenzyl)-3-oxobutanoate and 371 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-
sulfonamide, 338 mg of N-ethyl-6-[4-(4-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder.
Yield = 56%
m.p.(°C) = 188
M = CzsHzeN^S = 478; M+H = 479; Method 2: Tr = 1.29 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 11.8 (bs, 1H); 8.6 (bs, 1H); 8.45 (s, 1H); 8.1 (d,
1H); 7.4 (m, 3H); 7.3-7.1 (m, 4H); 6.8 (d, 2H); 3.75 (s, 3H); 3.6 (s, 2H); 3.5 (s, 2H); 2.1 (s,
3H); 1.0 (t, 3H).
Example 11: 6-[4-(2-chloro-6-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-
1-yl]-N-ethyl-N-phenylpyridine-3-sulfonamide (Compound 20 of Table I)
A mixture of 52 mg (0.2 mmol) of methyl 2-(2-chloro-6-fluorobenzyl)-3-oxobutanoate,
73 mg (0.25 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 5 mg of
pTsOH in 2 ml_ of toluene is heated for 12 hours at 110°C and then concentrated under
reduced pressure. The residue is taken up in 2 mL of DMF and filtered, and the filtrate is
chromatographed on an RP18 reverse-phase column, eluting with an H20 (containing 2%
TFA)/CH3CN gradient of 0 to 100% CH3CN.
86 mg of 6-[4-(2-chloro-6-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-
ethyl-N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder;
Yield = 99%
m.p. (°C) = 206
M = ^H^CIFN^sS =501. M+H = 502; Method 1
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 11.9 (bs, 1H); 8.6 (bs, 1H); 8.4 (s, 1H); 8.0 (d,
1H); 7.5-7.3 (m, 5H); 7.2-7.0 (m, 3H); 3.7 (s, 2H); 3.6 (q, 2H); 2.1 (s, 3H); 1.0 (t, 3H).
Example 12: N-ethyl-6-[3-methyl-5-oxo-4-(1 -phenylcyclopropyl)-2,5-dihydro-1 H-
pyrazol-1-yI]-N-phenylpyridine-3-sulfonamide (Compound 80 of Table I)
12.1. methyl 2-acetyl-3-phenvlbut-3-enoate
A suspension of 3.2 g (27.5 mmol) of methyl 3-oxobutanoate, 5.6 g (55.0 mmol) of
phenylacetylene and 700 mg (0.8 mmol) of *[ReBr(CO)3(THF)]2 in 55 mL of anhydrous
toluene is stirred for 18 hours at 50°C. After cooling to room temperature, the medium is
concentrated under reduced pressure. The residue obtained is taken up in 100 mL of
DCM, washed successively with water (100 mL) and brine (100 mL), dried over Na2S04
and then concentrated under reduced pressure and purified by chromatography on a
column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 5 g of methyl 2-acetyl-3-
phenylbut-3-enoate are obtained in the form of a yellow oil.
Yield = 84%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 12.6 (s, 1H); 7.3-7.2 (m, 5H); 5.7 (s, 1H); 5.1 (s, 1H);
3.55 (s,3H); 1.9 (s, 3H).
*:[ReBr(CO)3(THF)]2 is freshly prepared from 2 g (4.9 mmol) of ReBr(CO)5 stirred at reflux
in 60 mL of anhydrous THF for 16 hours. After concentrating under reduced pressure and
recrystallizing from 5 mL of n-hexane/THF (1/1), 700 mg of [ReBr(CO)3(THF)]2 are
obtained in the form of a white powder.
Yield = 35%.
12.2. methyl 3-oxo-2(1-phenvlcvclopropyl)butanoate
To a solution of 1 g (4.6 mmol) of methyl 2-acetyl-3-phenylbut-3-enoate in 16 mL of DCM
are successively added dropwise 20.8 mL (22.9 mmol) of a 1.1 M solution of diethylzinc in
toluene and 3.7 mL (45.8 mmol) of diiodomethane. The reaction medium is refluxed for
18 hours. After cooling to room temperature, the reaction mixture is treated with 100 mL
of water and then extracted with DCM (3 * 100 mL). The organic phases are combined,
washed successively with water (4 * 100 mL) and brine (100 mL), dried over Na2S04,
filtered and then concentrated under reduced pressure. The residue obtained is purified
by chromatography on a column of silica gel, eluting with a 95/5 cyclohexane/EtOAc
mixture. 280 mg of methyl 3-oxo-2(1-phenylcyclopropyl)butanoate are obtained in the
form of a yellow oil.
Yield = 26%.
1H NMR, CDCI3, 400 MHz, 6 (ppm): 7.3-6.9 (m, 5H); 3.7 (s, 1H); 3.6 (s, 3H); 2.0 (s, 3H);
1.4(s,2H); 1.25 (s,2H)
12.3. N-ethvl-6-r3-methvl-5-oxo-4-(1-phenvlcvclopropvn-2.5-dihvdro-1H-pvrazol-1-vn-N-
phenylpyridine-3-sulfonamide
According to the process described in Example 1.3, starting with 280 mg of methyl 3-oxo-
2-(1-phenylcyclopropyl)butanoate and 352 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-
sulfonamide, 110 mg of N-ethyl-6-[3-methyl-5-oxo-4-(1-phenylcyclopropyl)-2,5-dihydro-
1H-pyrazol-1-yl]-N-phenylpyridine-3-sulfonamide are obtained in the form of a white
powder.
m.p. (°C) = 146
M = Cj-eH^OaS = 474, M+H = 475; Method 2: Tr = 1.44 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.6 (bs, 1H); 8.4 (s, 1H); 8.1 (d,
1H); 7.4-7.1 (m, 10H); 3.6 (q, 2H); 2.2 (s, 3H); 1.15 (dd, 4H); 1.0 (t, 3H).
Example 14: N-tert-butyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -
yl]pyridine-3-sulfonamide hydrochloride (Compound 98B of Table I)

14.1. N-tert-butvl-6-chloropyridine-3-sulfonamide
To a mixture of 17.3 ml_ (165 mmol) of tert-butylamine and 69 ml_ (495 mmol) of TEA in
330 mL of DCM are added portionwise, at 0°C, 35 g (165 mmol) of 6-chloropyridine-3-
sulfonyl chloride. After stirring for 2 hours at 0°C, the reaction medium is taken up in
600 mL of DCM, washed with water (1 L), saturated NaHC03 solution (1L) and brine (1L),
dried over Na2S04, filtered and concentrated under reduced pressure. 32.4 g of N-tert-
butyl-6-chloropyridine-3-sulfonamide are obtained in the form of a white solid.
Yield = 79%
1H NMR CDCI3, 400 MHz, 6 (ppm): 8.8 (s, 1H); 8.0 (d, 1H); 7.4 (d, 1H); 4.5 (bs, 1H); 1.2
(s, 9H).
14.2. methyl 2-formvl-3-(pyridin-3-vl)propanoate
To a suspension of 2.1 g (90.8 mmol) of sodium in 55 mL of anhydrous Et20 is added
dropwise, at 0°C under argon, a mixture of 15 g (90.8 mmol) of methyl 3-(pyridin-3-
yl)propanoate and 7.3 ml (57.41 mmol) of ethyl formate. The medium is then stirred for
12 hours at room temperature, taken up in 200 mL of water and extracted with 100 mL of
Et20. The aqueous phase is acidified to pH 5 and then extracted with 2 * 300 mL of
EtOAc. The organic phase is then dried over Na2S04, filtered and concentrated under
reduced pressure. The residue obtained is purified by chromatography on a column of
silica gel, eluting with a DCM/MeOH gradient of 0 to 10% MeOH. 4.8 g of methyl 2-formyl-
3-(pyridin-3-yl)propanoate are obtained in the form of a white solid.
Yield = 28%
1H NMR, d6-DMSO, 400 MHz, 6" (ppm): 11.0 (bs, 1H); 8.45 (s, 1H); 8.4 (d, 1H); 7.7 (d,
1H); 7.5 (d, 1H); 7.2 (dd, 1H); 3.6 (s, 2H); 3.5 (s, 3H)
14.3 N-tert-butvl-6-hvdrazinylpyridine-3-sulfonamide
According to the process described in Example 5.2, starting with 32.4 g of N-tert-butyl-6-
chloropyridine-3-sulfonamide and 12.9 mL of hydrazine monohydrate, 22.6 g of N-tert-
butyl-6-hydrazinylpyridine-3-sulfonamide are obtained in the form of a white solid.
Yield: 71%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.3 (d, 2H); 7.8 (d, 1H); 7.2 (s, 1H); 7.0 (bs, 1H);
4.3 (bs, 2H); 1.2(s,9H).
14.4. N-tert-butvl-6-f5-oxo-4-(pvridin-3-vlmethvl)-2,5-dihvdro-1H-pvrazol-1-vl1pyridine-3-
sulfonamide (Compound 98A of Table I)
According to the process described in Example 1.3, starting with 12 g of N-tert-butyl-6-
hydrazinylpyridine-3-sulfonamide and 9.1 g of methyl 2-formyl-3-(pyridin-3-yl)propanoate,
9.92 g of N-tert-butyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-
3-sulfonamide are obtained in the form of a white solid
1H NMR, d6-DMSO, 400 MHz, 6 (ppm): 8.9 (bs, 1H); 8.5 (bs, 2H); 8.4 (s, 1H); 8.3 (d, 1H);
7.9 (s, 1H); 7.8 (s, 1H); 7.7 (d, 1H); 7.3 (dd, 1H); 3.6 (s, 2H); 1.2 (s, 9H)
Yield = 64%
m.p. (°C) = 160
M = C18H2iN503S=387; M+H = 388; Method 2: Tr = 0.58 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.8 (s, 1H); 8.3 (bs, 3H); 8.4 (s, 1H); 8.3 (d, 1H);
7.9 (s, 1H); 7.7 (d, 1H); 7.4 (t, 1H); 3.6 (s, 2H); 3.4 (bs, 1H); 1.1 (s, 9H)
14.5. N-tert-butvl-6-f5-oxo-4-(pvridin-3-vlmethvl)-2,5-dihvdro-1H-pyrazol-1-vnpvridine-3-
sulfonamide hydrochloride
To 912 mg of N-tert-butyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide in 20 mL of DCM is added 1 eq. of HCI (4N in dioxane) and the
medium is then concentrated under vacuum. 1 g of N-tert-butyl-6-[5-oxo-4-(pyridin-3-
ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-sulfonamide hydrochloride is obtained in
the form of a white powder.
Yield = 100%
m.p. (°C) = 140°C
M = C18H21N503S = 387; M+H = 388; Method 2: Tr = 0.58 min.
1H NMR, d6-DMSO, 400 MHz, 6 (ppm): 12, 0 (bs, 1H); 8.9 (bs, 1H); 8.8 (s, 1H); 8.7 (d,
1H); 8.5 (d, 2H); 8.3 (d, 1H); 8.0 (t, 1H); 7.9 (s, 1H); 7.8 (s, 1H); 3.8 (s, 2H); 1.2 (s, 9H)
Example 15: (2-{5-[ethyi(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-
pyrazol-4-yl)acetic acid (Compound 104 of Table I)

15.1. ethyl 2-formvlbutanedioate
To a suspension of 1.32 g (57.41 mmol) of sodium in 35 mL of anhydrous Et20 is added
dropwise, at 0°C, under argon, a mixture of 10 g (57.41 mmol) of ethyl butanedioate and
4.62 mL (57.41 mmol) of ethyl formate. The medium is then stirred for 12 hours at room
temperature, taken up in 100 mL of water and extracted with 100 mL of Et20. The
aqueous phase is acidified to pH 5 and then extracted with 100 mL of Et20. The organic
phase is then dried over Na2S04, filtered and then concentrated under reduced pressure.
The residue obtained is purified by chromatography on a column of silica gel, eluting with
a 7/3 cyclohexane/EtOAc mixture. 4.3 g of ethyl 2-formylbutanediaote are obtained in the
form of a colourless oil.
Yield: 37%
1H NMR, 1H NMR, CDCI3, 400 MHz, 5 (ppm): 10.0 (s, 1H); 7.1 (d, 1H); 4.4-4.2 (m, 5H);
2.9 (dd, 2H);1.3(m, 6H);
15.2 (2-j5-[ethvl(phenvl)sulfamovnpvridin-2-vl)-3-oxo-2,3-dihvdro-1H-pyrazol-4-vl)acetic
acid
A mixture of 2.17 g (7.42 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide
and 1.5 g (7.42 mmol) of ethyl 2-formylbutanedioate in 15 mL of EtOH is heated for
—5 hours at 80°C. The medium is then concentrated under reduced pressure. The
precipitate obtained is triturated in Et20 and then filtered and dried with a vane pump. The
4.1 g of beige-coloured powder obtained are added to a solution of 212 mg (9.23 mmol)
of sodium dissolved in 17 mL of anhydrous MeOH at room temperature and stirring is
continued for 2 hours. The medium is concentrated under reduced pressure and then
dissolved in 10 mL of water and 4 mL of 1N sodium hydroxide and stirred for 12 hours at
room temperature. The medium is then acidified to pH 5 with 1N HCI and then extracted
with DCM (2 x 100 mL). The combined organic phases are dried over Na2S04, filtered
and then concentrated under reduced pressure. The residue obtained is solidified in
pentane, filtered off and dried under vacuum 2.1 g of (2-{5-
[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1 H-pyrazol-4-yl)acetic acid are
obtained in the form of a white powder.
Yield = 58%
m.p. (°C) = 174°C
M = C18H18N405S = 402; M+H = 403; Method Tr = 1.02 min.
1H NMR, d6-DMSO, 400 MHz, 6 (ppm):12.0 (bs, 2H); 8.6 (bs, 1H); 8.5 (bs, 1H); 8.2 (d,
1H); 7.9 (bs, 1H); 7.4 (m, 3H); 7.2 (d, 2H); 3.7 (q, 2H); 3.4 (s, 2H); 1.0 (t, 3H).
Example 16: methyl (2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-
1 H-pyrazol-4-yl)acetate (compound 107 of Table I)

16.1 methyl (2-(5-fethvl(phenvl)sulfamovllpvridin-2-vl)-3-oxo-2.3-dihvdro-1H-pyrazol-4-
vDacetate
A mixture of 0.5 g (1.24 mmol) of (2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-
dihydro-1H-pyrazol-4-yl)acetic acid and 0.256 g (1.24 mmol) of DCC is stirred for 3 hours
at room temperature. The precipitate formed is filtered off and the filtrate is concentrated
under reduced pressure. The residue obtained is purified by chromatography on a
column of silica gel, eluting with a 9/1 DCM/MeOH mixture. 0.5 g of methyl 2-{5-
[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetate is
obtained in the form of a brown powder.
Yield = 96%
m.p. (°C) = 140°C
M = C9H20N4O5S = 416; M+H = 417; Method 2; Tr = 1.44 min
1H NMR, d6-DMS0, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.6 (s, 1H); 8.4 (s, 1H); 8.2 (d, 1H);
7.9 (s, 1H); 7.4 (m, 3H); 7.2 (d, 2H); 5.6 (d, 0.5H); 3.75 (q, 2H); 3.7 (s, 3H); 3.3 (d, 1.5H);
1.0 (t, 3H)
Example 17: 2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-
pyrazol-4-yl)-N-methylacetamide (compound 108 of Table I)

To a mixture of 0.28 g (0.7 mmol) of (2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-
dihydro-1 H-pyrazol-4-yl)acetic acid, 0.61 mL (3.48 mmol) of DIEA and 0.8 ml_ (1.4 mmol)
of methylamine (2N solution in THF) in 2 mL of DCM is added at 0°C 0.33 g (1.04 mmol)
of TBTU. After stirring for 3 hours at room temperature, the medium is taken up in 500 mL
of DCM, washed successively with 0.1 N HCI (2 x 40 mL), saturated NaHC03 solution
(2 x 40 mL) and brine (30 mL), dried over Na2S04 and then concentrated under reduced
pressure and purified by chromatography on a column of silica gel, eluting with a 95/5
DCM/MeOH mixture. 18 mg of 2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-
dihydro-1 H-pyrazol-4-yl)-N-methylacetamide are obtained in the form of a brown powder.
Yield = 6%
m.p. (°C) = 194°C
M = C19H21N505S = 415; M+H = 416; Method 2 Tr = 0.98
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.6 (bs, 1H); 8.5 (s, 1H); 8.2 (d,
1H); 7.8 (s, 2H); 7.5 (m, 3H); 7.2 (d, 2H); 3.6 (q, 2H); 3.1 (s, 2H); 2.6 (s, 3H); 1.0 (t, 3H)
Example 18: ethyl (4-benzyl-1 -{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-2,5-
dihydro-1H-pyrazol-3-yl)acetate (compound 106 of Table I)
18.1 ethyl 2 -benzvl-3-oxopentanedioate
Under argon, and at room temperature, 1.7 g (74.18 mmol) of sodium are dissolved in
75 mL of anhydrous EtOH. 13.5 mL (74.2 mmol) of diethyl 3-oxopentanedioate and then
8.8 mL (74.2 mmol) of benzyl bromide are then added dropwise, at room temperature.
The medium is then refluxed for 3 hours, concentrated under reduced pressure and
purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc
gradient of 0 to 20% EtOAc. 8.29 g of diethyl 2-benzyl-3-oxopentanedioate are obtained
in the form of a translucent oil.
Yield = 38%
1H NMR, 1H NMR, CDCI3, 400 MHz, 6 (ppm): 7.4-7.2 (m, 5H); 4.2 (m, 4H); 4.1 (t, 1H); 3.2
(d,2H);1.2(m,6H);
18.2. ethyl 4-benzvl-1-{5-rethvl(phenvl)sulfamovnpvridin-2-vlV5-oxo-2,5-dihvdro-1H-
pyrazol-3-yl)acetate
According to the process described in Example 1.3, starting with 5 g (17.1 mmol) of
diethyl 2-benzyl-3-oxopentanedioate and 5 g (17.1 mmol) of N-ethyl-6-hydrazino-N-
phenylpyridine-3-sulfonamide, 3 g of ethyl 4-benzyl-1-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-
yl}-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)acetate are obtained in the form of a white powder.
Yield = 34%
m.p. (°C) = 156
M = C27H28N405S = 520; M+H = 521 Method 2: Tr = 1.52,
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.5 (bs, 2H); 8.15 (d, 1H); 7.4-7.1
(m, 10 H); 4.1 (q, 2H); 3.8-3.6 (m, 6H); 1.2 (t, 3H); 1.0 (t, 3H).
Example 19: 6-{4-[(5-cyanopyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl}-N-ethyl-N-phenylpyridine-3-sulfonamide (compound 97 of Table I)
19.1 (5-bromopyridin-3-vl)methanol
To a solution of 12 g (59.4 mmol) of 5-bromopyridine-3-carboxylic acid in 300 mL of
anhydrous THF, under argon, are added, at -10°C, 6.6 mL of NMM and then 5.7 mL
(59.4 mmol) of ethyl chloroformate. After stirring for 20 minutes at -10°C, 6.8 g
(179.8 mmol) of sodium borohydride are added portionwise. The medium is then cooled
to -70°C and 400 mL of MeOH are added over 1 hour 30 minutes. The temperature is
then allowed to rise to room temperature and stirring is continued for 12 hours. The
medium is then concentrated under reduced pressure and then purified by
chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 8.4 g
of (5-bromopyridin-3-yl)methanol are obtained in the form of a yellow oil.
Yield = 75%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.5 (s, 1H); 8.4 (s, 1H); 7.9 (s, 1H); 4.6 (s, 2H); 2.8
(bs, 1H)
19.2 5-(hvdroxvmethvDpyridine-3-carbonitrile
A mixture of 4.2 g (22.34 mmol) of (5-bromopyridin-3-yl)methanol and 5 g (55.84 mmol) of
copper cyanide in 22 mL of pyridine is heated for 20 hours in a sealed tube at 160°C.
After cooling to room temperature, the medium is taken up in 10 mL of concentrated
aqueous ammonia and 30 mL of saturated NH4CI solution and then stirred for 2 hours.
The medium is then extracted with 200 mL of a DCM/iPrOH mixture (85/15), dried over
Na2S04 and then concentrated under reduced pressure and purified by chromatography
on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.13 g of 5-
(hydroxymethyl)pyridine-3-carbonitrile are obtained in the form of a white solid.
Yield = 51%
1H NMR, CDCI3, 400 MHz, 6 (ppm): 8.9 (d, 2H); 8.0 (s, 1H); 4.9 (s, 2H); 2.3 (bs, 1H)
19.3 5-(chloromethv0pyridine-3-carbonitrile
To 0.2 g (1.49 mmol) of 5-(hydroxymethyl)pyridine-3-carbonitrile in 2 mL of DCM is added
1 mL (4 mmol) of HCI4N in dioxane. The mixture is concentrated under reduced pressure
and then added to 0.65 mL (8.95 mmol) of thionyl chloride followed by heating for 3 hours
at 60°C. After cooling to room temperature, the medium is taken up in 20 mL of toluene,
and the precipitate formed is filtered off and then treated with 30 mL of DCM and 30 mL
of saturated NaHC03 solution. The organic phase is separated out and dried over
Na2S04 and then concentrated under reduced pressure. 161 mg of 5-(chloromethyl)-
pyridine-3-carbonitrile are obtained in the form of an oil.
Yield = 73%
1H NMR, 1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.9 (d, 2H); 8.0 (s, 1H); 3.5 (s, 2H)
19.4. methyl 2-r(5-cvanopyridin-3-v0methvn-3-oxobutanoate
To a suspension of 84 mg (2.11 mmol) of sodium hydride (60% in oil) in 3 mL of
anhydrous DME is added, under argon at 0°C, 0.23 ml (2.11 mmol) of methyl
acetoacetate. The reaction medium is stirred for 30 minutes at 0°C and for 30 minutes at
room temperature, followed by addition of 161 mg (1.06 mmol) of 5-
(chloromethyl)pyridine-3-carbonitrile diluted in 1 mL of DME and 29 mg (0.11 mmol) of
tetrabutylammonium iodide. The medium is then heated at 65°C for 4 hours. After cooling
to room temperature, the medium is taken up in 10 mL of water, neutralized by adding
0.1N HCI, and then extracted with EtOAc (2 x 40 mL), dried over Na2S04, concentrated
under reduced pressure and purified by chromatography on a column of silica gel, eluting
with a cyclohexane/EtOAc mixture (8/2). 140 mg of methyl 2-[(5-cyanopyridin-3-
yl)methyl]-3-oxobutanoate are obtained in the form of a colourless oil.
Yield = 57%
1H NMR, 1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.8 (s, 1H); 8.6 (s, 1H); 7.8 (s, 1H); 3.7 (t,
1H); 3.65 (s, 3H); 3.2 (dd, 2H); 2.2 (s, 3H)
19.5 644-f(5-cvanopvridin-3-vl)methvn-3-methvl-5-oxo-2.5-dihvdro-1H-pvrazol-1-vl)-N-
ethvl-N-phenvlpvridine-3-sulfonamide
According to the process described in Example 1.3, starting with 125 mg (0.43 mmol) of
methyl 2-[(5-cyanopyridin-3-yl)methyl]-3-oxobutanoate and 99 mg (0.43 mmol) of N-ethyl-
6-hydrazino-N-phenylpyridine-3-sulfonamide, 103 mg of 6-{4-[(5-cyanopyridin-3-
yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-ethyl-N-phenylpyridine-3-
sulfonamide are obtained in the form of a yellow powder.
Yield = 51%
m.p. (°C) = 164
M = C^H^NfAS = 474; M+H = 475; Method 2: Tr = 1.24 min.
1H NMR, d6-DMSO, 400 MHz, 6 (ppm): 12.0 (bs, 1H); 8.9 (s, 1H); 8.8 (s, 1H); 8.6 (bs,
1H); 8.4 (s, 1H); 8.2 (s, 1H); 8.15 (d, 1H); 7.4 (m, 3 H); 7.1 (d, 2H); 3.7 (s, 4 H); 2.2 (s,
3H); 1.0 (t, 3H).
Example 20: 5-methyl-2-[5-(phenylsulfonyl)pyridin-2-yl]-4-(pyridin-3-ylmethyl)-1,2-
dihydro-3H-pyrazol-3-one (compound 197 of Table II)
20.1 2-chloro-5-(phenvlsulfanvl)pyridine
A mixture of 3.4 g (14.3 mmol) of 2-chloro-5 iodopyridine, 1.9 g (17.2 mmol) of thiophenol,
0.93 g (17.2 mmol) of sodium methoxide and 0.36 g (5.7 mmol) of copper in 18 mL of
MeOH is heated for 12 hours at 80°C. After cooling to room temperature, the medium is
taken up in 100 mL of 1N NaOH and the MeOH is evaporated off under reduced
pressure. The reaction medium is extracted with EtOAc (2 x 100 mL), the organic phase
is washed with 0.1 N NaOH (2 x 30 mL), and then dried over Na2S04, concentrated under
reduced pressure and purified by chromatography on a column of silica gel, eluting with a
cyclohexane/EtOAc mixture (8/2). 1.90 g of 2-chloro-5-(phenylsulfanyl)pyridine are
obtained in the form of a white powder.
Yield = 60%
1H NMR, CDCI3, 400 MHz, 6 (ppm): 8.5 (d, 1H); 8.3 (s, 1H); 7.9 (s, 1H); 7.5-7.4 (m, 5H)
20.2 2-chloro-5-(phenvlsulfonvQpvridine
To a solution of 1.9 g (8.57 mmol) of 2-chloro-5-(phenylsulfanyl)pyridine in 40 mL of DCM
is added, at room temperature over 15 minutes, a suspension of 4.8 g (21.42 mmol) of 3-
chloroperbenzoic acid at 77% in 20 mL of DCM. After stirring for 1 hour, the precipitate
formed is filtered off, and the filtrate is taken up in 200 mL of DCM, washed successively
with 100 mL of 0.2N sodium hydroxide and then 100 mL of saturated sodium thiosulfate
solution, dried over Na2S04, concentrated under reduced pressure and purified by
chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc mixture
(8/2). 0.67 g of 2-chloro-5-(phenylsulfonyl)pyridine is obtained in the form of a white
powder.
Yield = 31%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.9 (s, 1H); 8.1-7.9 (m, 3H); 7.6-7.4 (m, 3H); 7.3 (m,
1H)
20.3 2-hvdrazinvl-5-(phenvlsulfonyl)pvridine
According to the process described in Example 5.2, starting with 0.67 g (2.64 mmol) of 2-
chloro-5-(phenylsulfonyl)pyridine, 340 mg of 2-hydrazinyl-5-(phenylsulfonyl)pyridine are
obtained in the form of a white powder.
Yield = 51%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 9.0 (s, 1H); 8.6 (d, 1H); 8.5 (s, 1H); 8.4 (m, 2H);
8.0 (d, 1H); 7.8-7.5 (m, 3H); 7.3 (m, 1 H); 3.3 (bs, 1 H);
20.4 5-methvl-2-r5-(phenvlsulfonvl)pvridin-2-vll-4-(pvridin-3-vlmethvl)-1.2-dihvdro-3H-
pyrazol-3-one
According to the process described in Example 1.3, starting with 340 mg (1.36 mmol) of
2-hydrazinyl-5-(phenylsulfonyl)pyridine and 283 mg (1.36 mmol) of methyl 3-oxo-2-
(pyridin-3-ylmethyl)butanoate, 130 mg of 5-methyl-2-[5-(phenylsulfonyl)pyridin-2-yl]-4-
(pyridin-3-ylmethyl)-1,2-dihydro-3H-pyrazol-3-one are obtained in the form of a white
powder.
Yield = 23%
m.p. (°C) = 176
M = C2iH18N403S= 406; M+H = 407; Method 2: Tr = 0.78 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm) 12.0 (bs, 1H); 9.0 (s, 1H); 8.6 (d, 1H); 8.5 (s, 1H);
8.4 (m, 2H); 8.0 (d, 2 H); 7.8-7.6 (m, 4H); 7.3 (m, 1 H); 3.6 (s, 2H); 2.2 (s, 3H)
Example 21: N-ethyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl}-N-phenylpyridine-3-sulfonamide hydrochloride (compound 101 of
Table I)
21.1. methyl (2E)-3-(5-methoxvpvridin-3-yl)prop-2-enoate
To a suspension of 3.12 g (78.1 mmol) of sodium hydride (60% in oil) in 30 mL of
anhydrous THF is added, over 45 minutes, under argon and at 0°C, 16.4 g (78.1 mmol) of
methyl (diethoxyphosphoryl)acetate in 10 mL of THF. Stirring is maintained for
30 minutes at 0°C and 5.1 g (37.2 mmol) of 5-methoxypyridine-3-carbaldehyde in 20 mL
of anhydrous THF are then added dropwise at 0°C. After cooling to room temperature,
the reaction mixture is treated with 150 mL of water and then extracted with EtOAc (3 x
100 mL). The organic phases are combined, washed successively with water (2 *
20 mL), dried over Na2S04, filtered and then concentrated under reduced pressure. The
residue obtained is purified by chromatography on a column of silica gel, eluting with a
cyclohexane/EtOAc gradient of 0 to 40% EtOAc. 1 g of methyl (2E)-3-(5-methoxypyridin-
3-yl)prop-2-enoate is obtained in the form of a white powder.
Yield = 14%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.4 (d, 1H); 7.7 (d, 1H); 7.4 (s, 1H); 6.5 (d, 1 H); 3.9
(s, 3H); 3.8 (s, 3H)
21.2. methyl 3-(5-methoxvpvridin-3-vl)propanoate
In Parr apparatus, a mixture of 1 g (5.33 mmol) of methyl (2E)-3-(5-methoxypyridin-3-
yl)prop-2-enoate in 20 mL of MeOH and 0.1 g of 10% Pd/C is hydrogenated at 7 bar for
5 hours. The reaction mixture is then filtered through Whatman GF/F paper and
concentrated under reduced pressure. 1 g of methyl 3-(5-methoxypyridin-3-yl)propanoate
is thus obtained in the form of a wax, which is used without further purification in the
following step.
Yield = 100%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.3 (s, 1H); 8.2 (s, 1H); 7.1 (s, 1H); 3.85 (s, 3H); 3.6
(s, 3H); 3.0 (t, 2H); 2.7 (t, 3H).
21.3. methyl 2-formvl-3-(5-methoxypvridin-3-vl)propanoate
According to the process described in Example 14.2, starting with 1.04 g (5.33 mmol) of
methyl 3-(5-methoxypyridin-3-yl)propanoate, 600 mg of methyl 2-formyl-3-(5-
methoxypyridin-3-yl)propanoate are obtained in the form of a wax, which is used without
further purification in the following step.
Yield = 51%
21.4. N-ethvl-6-(4-f(5-methoxvpvridin-3-vnmethvn-5-oxo-2,5-dihvdro-1H-pyrazol-1-vl>-N-
phenylpyridine-3-sulfonamide hydrochloride
According to the process described in Example 2.3, starting with 250 mg (1.12 mmol) of
methyl 2-formyl-3-(5-methoxypyridin-3-yl)propanoate and 327 mg (1.12 mmol) of N-ethyl-
6-hydrazino-N-phenylpyridine-3-sulfonamide, 131 mg of N-ethyl-6-{4-[(5-methoxypyridin-
3-yl)methyl]-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-phenylpyridine-3-sulfonamide
hydrochloride are obtained in the form of a lyophilizate.
Yield = 25%
m.p. (°C) = 136
M = C23H23N504S= 465; M+H = 466; Method 2: Tr = 0.97 min,.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 11.0 (bs, 1H); 8.6 (s, 2H); 8.4 (d, 2H); 8.2 (d, 1H);
8.1 (s, 1H); 7.9 (s, 1H); 7.4 (m, 3H); 7.1 (d, 2H); 4.0 (s, 3 H); 3.8 (s, 2H); 3.6 (q, 2H); 1.0
(t, 3H)
Example 22: methyl {2-[5-(tert-butylsulfamoyl)pyrldin-2-yl]-3-oxo-2,3-dihydro-1 H-
pyrazol-4-yl}(phenyl)acetate (compound 113 of Table I)
22.1. ethyl 3-cyano-3-phenvlpropanoate
A mixture of 64 g (257.8 mmol) of diethyl benzylidenepropanedioate and 17 g (261 mmol)
of potassium cyanide in 750 mL of EtOH and 75 mL of water is heated for 18 hours at
60°C. The medium is then concentrated under reduced pressure and taken up in 500 mL
of brine and then extracted with Et20 (2 x 500 mL). The organic phases are dried over
Na2S04, filtered and then concentrated under reduced pressure. 43.5 g of ethyl 3-cyano-
3-phenylpropanoate are obtained in the form of a solid, which is used without further
purification in the following step.
Yield = 83%
22.2. 2-phenvlbutanedioic acid
A mixture of 43.5 g (214 mmol) of ethyl 3-cyano-3-phenylpropanoate and 52.2 g
(930.4 mmol) of potassium hydroxide in 670 mL of EtOH is refluxed for 4 hours. After
cooling to room temperature, the medium is concentrated under vacuum and then treated
with 1L of 1N HCI, and a precipitate then forms, which is filtered off and rinsed with water
(2 x 50 mL). The solid obtained is taken up in a mixture of 200 mL of toluene and 40 mL
of EtOH and concentrated under reduced pressure, and then dried with a vane pump.
37 g of 2-phenylbutanedioic acid are obtained in the form of a solid, which is used without
further purification in the following step.
Yield = 89%
22.3. diethyl 2-phenylbutanedioate
In Dean-Stark apparatus, a mixture of 37 g (190.5 mmol) of 2-phenylbutanedioic acid,
6 mL of cone. H2S04, 80 mL of toluene and 80 mL of EtOH is refluxed for 72 hours. After
cooling to room temperature, the reaction mixture is concentrated under reduced
pressure and then treated with 300 mL of water, and extracted with Et20 (2 x 400 mL).
The organic phases are combined, dried over Na2S04, filtered and then concentrated
under reduced pressure. The residue obtained is purified by chromatography on a
column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 22 g
of diethyl 2-phenylbutanedioate are obtained in the form of an oil.
Yield = 46%.
1H NMR, CDCI3, 400 MHz, 6 (ppm): 7.5 (m, 5H); 4.2 (m, 5H); 3.0 (dd, 2H); 1.0 (t, 6H)
22.4. diethyl 2-fomnyl-3-phenvlbutanedioate
According to the process described in Example 14.2, starting with 7.0 g (28 mmol) of
diethyl 2-phenylbutanedioate, 7.0 g of diethyl 2-formyl-3-phenylbutanedioate are obtained
in the form of an oil.
Yield = 89%
22.5. ethyl (2-r5-(tert-butvlsulfamovnpvridin-2-vn-3-oxo-2.3-dihvdro-1H-pvrazol-4-vl)-
(phenyl)acetate
According to the process described in Example 27.2, starting with 2 g (7.19 mmol) of
diethyl 2-formyl-3-phenylbutanedioate and 1.75 g (7.19 mmol) of N-tert-butyl-6-
hydrazinylpyridine-3-sulfonamide, 3.1 g of methyl {2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-
oxo-2,3-dihydro-1H-pyrazol-4-yl}(phenyl)acetate are obtained in the form of a powder.
Yield = 93%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.6 (s, 1H); 8.6 (d, 1H); 8.0 (d, 1H); 7.7 (s, 2H);
7.3 (m, 5H); 4.6 (s, 1H); 4.1 (q, 2H); 1.0 (m, 12H);
22.6 1-[5-(tert-butvlsulfamovl)pvridin-2-vl1-4-[carboxy(phenyl)methyn-1H-pyrazol-5-olate
A mixture of 2.8 g (5.8 mmol) of ethyl 2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-
dihydro-1H-pyrazol-4-yl}(phenyl)acetate and 5.8 mL (5.8 mmol) of 1N NaOH, in 12 mL of
EtOH is stirred for hours at room temperature. 5.8 mL of 1N HCI are added, and the
medium is extracted with DCM (2 x 100 mL). The organic phases are dried over Na2S04,
filtered and then concentrated under reduced pressure. 2g of 1-[5-(tert-
butylsulfamoyl)pyridin-2-yl]-4-[carboxy(phenyl)methyl]-1 H-pyrazol-5-olate are obtained in
the form of a beige-coloured powder, which is used without further purification in the
following step.
22.7. methyl (2-r5-(tert-butvlsulfamovl)pvridin-2-vn-3-oxo-2.3-dihvdro-1H-pyrazol-4-
vD(phenvl) acetate
To a mixture of 0.3 g (0.66 mmol) of 1-[5-(tert-butylsulfamoyl)pyridin-2-yl]-4-
[carboxy(phenyl)methyl]-1H-pyrazol-5-olate in 3 mL of anhydrous MeOH is added, at 0°C,
0.11 mL (0.73 mmol) of thionyl chloride. After cooling to room temperature, stirring is
continued for 12 hours. The medium is taken up in 40 mL of DCM, washed with 20 mL of
saturated NaHC03 solution, dried over Na2S04 and then concentrated under reduced
pressure. The residue obtained is solidified in a DCM/pentane mixture and then filtered
off and dried under vacuum. 0.67 g of methyl 2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-
2,3-dihydro-1H-pyrazol-4-yl}(phenyl)acetate is obtained in the form of a beige-coloured
powder.
Yield = 73%
m.p. (°C) = 66
M = C21H24N405S = 444; M+H = 445; Method 2: Tr = 1.21 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm):12.3 (bs, 1H); 8.8 (s, 1H); 8.6 (bs, 1H); 8.3 (d,
1H); 7.7 (d, 2H); 7.4 (m, 5H); 4.9 (s, 1H); 3.7 (s, 3 H); 1.0 (t, 9H)
Example 23: methyl N-cyclopentyl-N-({6-[5-oxo-4-(pyrldln-3-ylmethyl)-2>5-dlhydro-
1H-pyrazol-1-yl]pyridin-3-yl}sulfonyl)glycinate hydrochloride (compound 128 of
Table I)

23.1. 6-chloro-N-cvclopentylpyridine-3-sulfonamide
According to the process described in Example 14.1, starting with 5 g (23.6 mmol) of 6-
chloropyridine-3-sulfonyl chloride and 2 g (23.6 mmol) of cyclopentylamine, 5.1 g of 6-
chloro-N-cyclopentylpyridine-3-sulfonamide are obtained in the form of a brown solid.
Yield = 84%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.8 (s, 1H); 8.0 (d, 1H); 7.4 (d, 1H); 4.5 (d, 1H); 3.6
(m, 1H); 1.8 (m, 2H);1.6 (m, 4H); 1.3 (m, 2H)
23.2. methyl N4(6-chloropyridin-3-yl)sulfonvl1-N-cvclopentylglycinate
A mixture of 2 g (7.67 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 0.7 mL
(7.67 mmol) of methyl bromoacetate and 1.2 g (8.4 mmol) of K2C03 in 15 mL of CH3CN is
heated for 12 hours at 80°C. After cooling to room temperature, the medium is filtered
and the filtrate is concentrated. The residue is taken up in 100 mL of DCM, washed
successively with 50 mL of saturated NaHC03 solution and 50 mL of water, and the
organic phase is then dried over Na2S04, concentrated under reduced pressure and
purified by chromatography on a column of silica gel, eluting with an 8/2 heptane/EtOAc
mixture. 2.4 g of methyl N-[(6-chloropyridin-3-yl)sulfonyl]-N-cyclopentylglycinate are
obtained in the form of an oil.
Yield = 93%
1H NMR, CDCI3, 400 MHz, 5 (ppm) 9.0 (s, 1H); 8.3 (d, 1H); 7.4 (d, 1H); 4.1 (s, 2H); 4.05
(m, 1H); 3.8 (s, 3H); 1.9 (m, 2H); 1.6 (m, 4H); 1.3 (m, 2H)
23.3. methyl N-cvclopentvl-N-r(6-hvdrazinvlpyridin-3-vl)sulfonvnglvcinate
According to the process described in Example 5.2, starting with 2.4 g (7.2 mmol) of
methyl N-[(6-chloropyridin-3-yl)sulfonyl]-N-cyclopentylglycinate, 2g of methyl N-
cyclopentyl-N-[(6-hydrazinylpyridin-3-yl)sulfonyl]glycinate are obtained in the form of a
yellow solid.
Yield = 85%
1H NMR, CDCI3, 400 MHz, 5 (ppm) 8.6 (s, 1H); 8.0 (d, 1H); 6.8 (d, 1H); 6.6 (bs, 1H); 4.05
(m, 1H); 4.0 (s, 2H); 3.6 (s, 3H); 1.8 (m, 2H); 1.6 (m, 4H); 1.2 (m, 2H)
23.4. methyl N-cvclopentvl-N-((6-f5-oxo-4-(pyridin-3-vlmethvl)-2,5-dihvdro-1H-
pyrazol-1 -vnpvridin-3-vl)sulfonyl)glvcinate hydrochloride
According to the process described in Example 2.3, starting with 200 mg (0.61 mmol) of
methyl N-cyclopentyl-N-[(6-hydrazinylpyridin-3-yl)sulfonyl]glycinate and 117 mg
(0.61 mmol) of methyl 3-oxo-2-(pyridin-3-ylmethyl)butanoate, 130 mg of methyl N-
cyclopentyl-N-({6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridin-3-
yl}sulfonyl)glycinate hydrochloride are obtained in the form of a white lyophilizate.
Yield = 34%
m.p. (°C) = 100
M = C22H25N505S= 471; M+H = 472; Method 2: Tr = 0.87 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm) 8.7 (d, 2H); 8.6 (d, 1H); 8.4 (d, 2H); 8.3 (d, 1H);
7.8 (m, 1H); 7.7 (s, 1 H); 5.0-4.0 (bs, 2H); 3.9 (m, 1 H); 3.8 (s, 2H); 3.6 (s, 2H); 3.4 (s,
3H); 1.4-1.0 (m,8H).
Example 24: 2,2-dimethylpropyl 6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-
pyrazol-1-yl]pyridine-3-carboxylate (compound 198 of Table II)

24.1. 2,2-dimethylpropyl 6-chloropyridine-3-carboxvlate
To a solution of 10 g (56.8 mmol) of 6-chloropyridine-3-carbonyl chloride in 100 ml_ of
anhydrous toluene are added under argon, at room temperature, 15 g (170.4 mmol) of
2,2-dimethylpropanol. The reaction medium is then heated for 6 hours at 80°C. After
cooling to room temperature, the medium is concentrated and the residue obtained is
taken up in 800 mL of EtOAc, washed successively with water (2 x 200 ml_), saturated
NaHC03 solution (2 x 200 mL) and brine (100 mL), dried over Na2S04, and then
concentrated under reduced pressure and purified by chromatography on a column of
silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 5% EtOAc. 11.9 g of 2,2-
dimethylpropyl 6-chloropyridine-3-carboxylate are obtained in the form of a white powder.
Yield = 92%.
1H NMR, CDCI3, 400 MHz, 6 (ppm): 7.5 (m, 5H); 4.2 (m, 5H); 3.0 (dd, 2H); 1.0 (t, 6H)
24.2. 2,2-dimethylpropvl6-hvdrazinvlpvridine-3-carboxylate
According to the process described in Example 5.2, starting with 11.9 g (52.26 mmol) of
2,2-dimethylpropyl 6-chloropyridine-3-carboxylate, 4.3 g of 2,2-dimethylpropyl 6-
hydrazinylpyridine-3-carboxylate are obtained in the form of a white powder.
Yield = 37%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.7 (s, 1H); 8.15 (d, 1H); 6.9 (d, 1H); 4.0 (s, 2H);
3.5 (bs, 1H); 1.0 (s, 9H).
24.3. 2,2-dimethvlpropyl 6-r5-oxo-4-(pvridin-3-vlmethvl)-2,5-dihvdro-1 H-pyrazol-1 -
vnpyridine-3-carboxylate
According to the process described in Example 1.3, starting with 0.3 g (1.34 mmol) of 2,2-
dimethylpropyl 6-hydrazinylpyridine-3-carboxylate and 0.26 g (1.34 mmol) of methyl 3-
oxo-2-(pyridin-3-ylmethyl)butanoate, 185 mg of 2,2-dimethylpropyl 6-[5-oxo-4-(pyridin-3-
ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]pyridine-3-carboxylate are obtained in the form of a
white solid.
Yield = 38%
m.p. (°C) = 160
M = C20H22N4O3 = 366; M+H = 367; Method 2: Tr = 1.01 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.9 (s, 1H); 8.8 (s, 1H); 8.7 (d, 1H);
8.5 (d, 1H); 8.4 (d, 1H); 8.3 (d, 1H); 8.0 (t, 1H) 7.9 (s, 1H); 3.9 (s, 2H); 3.8 (s, 2 H); 1.0 (s,
9H);
Example 25: methyl 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-
dihydro-1H-pyrazol-4-yl)-3-phenylpropanoate (compound 121 of Table I)
25.1. diethyl 3-phenvlpentanedioate
A mixture of 6 g (28.8 mmol) of 3-phenylpentanedioic acid and 7.9 mL (109.5 mol) of
thionyl chloride is heated at 80°C for 1 hour. The medium is then concentrated and the
solid obtained is added portionwise to 8 mL of EtOH at 0°C. The medium is then heated
at 80°C for 30 minutes. After cooling to room temperature, the medium is concentrated
and the residue obtained is taken up in 400 mL of DCM, washed successively with
saturated NaHC03 solution (2 x 100 mL) and brine (100 mL), dried over Na2S04 and then
concentrated under reduced pressure. 6.97 g of diethyl 3-phenylpentanedioate are
obtained in the form of a powder, which is used without further purification in the following
step.
Yield = 91.5%.
25.2. diethyl 2-formvl-3-phenylpentanedioate
According to the process described in Example 14.2, starting with 3 g (11.35 mmol) of
diethyl 3-phenylpentanedioate, 0.23 g of diethyl 2-formyl-3-phenylpentanedioate is
obtained in the form of a yellow oil.
Yield = 7%
1H NMR, d6-DMSO, 400 MHz, 6 (ppm) 10.9 (s, 1H); 7.7 (d, 1H); 7.3-7.1 (m, 5H); 4.5 (t,
1H); 4.0 (q, 4H); 3.0 (m, 2H); 1;0 (m, 6H)
25.3. 3-(2-(5-rcvclopentvl(methvl)sulfamovllPvridin-2-vl)-3-oxo-2,3-dihvdro-1H-pyrazol-4-
yl)-3-phenylpropanoate
According to processes 22.5 and 22.6, starting with 0.23 g (0.79 mmol) of diethyl 2-
formyl-3-phenylpentanedioate and 0.21 g (0.79 mmol) of N-cyclopentyl-6-hydrazinyl-N-
methylpyridine-3-sulfonamide, 0.38 g of 3-(1-{5-[cyclopentyl(methyl)sulfamoyl] pyridin-2-
yl}-5-oxido-1H-pyrazol-4-yl)-3-phenylpropanoate is obtained in the form of a powder.
Yield = 89%
25.4. methyl 3-(2-{5-fcvclopentvl(methvl)sulfamoynpyridin-2-vl)-3-oxo-2,3-dihydro-1H-
pyrazol-4-vl)-3-phenylpropanoate
According to the process described in Example 22.7, starting with 0.38 g (0.78 mmol) of
3-(2-{5-[cyclopentyl(methyl)sulfamo
phenylpropanoate, 0.34 g of methyl 3-(1-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-5-
oxido-1H-pyrazol-4-yl)-3-phenylpropanoate is obtained.
m.p. (°C) = 80
M = C24H28N405S = 484; M+H = 485; Method 3: Tr = 4.4 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.9 (s, 1H); 8.7 (bs, 1H); 8.5 (d, 1H); 7.9 (s, 1H);
7.4 (d, 1H); 7.3 (t, 3H); 7.2 (t, 2H); 4.4 (t, 1H); 4.3 (t, 1H); 3.6 (s, 3 H); 3.2 (dd, 1H); 3.1
(dd, 1H); 2.7 (s, 3H); 1.8-1.4 (m, 8H)
Example 26: 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-[3-
(dimethylamino)propyl]pyridine-3-sulfonamide hydrochloride (compound 123 of
26.1. N-r3-(benzvloxv)propvn-6-chloro-N-cvclopentvlpyridine-3-sulfonamide
A mixture of 1 g (3.84 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 1.32 g
(9.59 mmol) of K2C03 and 0.88 mL (4.99 mmol) of [(3-bromopropoxy)methyl]benzene in
8 mL of anhydrous DMF is heated for 12 hours at 40°C. After cooling to room
temperature, the medium is taken up in 300 mL of EtOAc, washed successively with
water (2 x 100 mL), saturated NaHC03 solution (100 mL) and brine (100 mL), dried over
Na2S04 and then concentrated under reduced pressure and purified by chromatography
on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc.
1.65 g of N-[3-(benzyloxy)propyl]-6-chloro-N-cyclopentylpyridine-3-sulfonamide are thus
obtained in the form of an oil.
Yield = 99%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.85 (s, 1H); 8.1 (d, 1H); 7.5 (d, 1H); 7.4-7.3 (m, 5H);
4.5 (s, 2H); 4.2 (m, 1H); 3.6 (t, 2H); 3.2 (dd, 2H); 2.1 (m, 2H); 1.6-1.3 (m, 8H)
26.2. N-f3-(benzvloxv)propvll-N-cvclopentvl-6-hvdrazinvlpyridine-3-sulfonamide
According to the process described in Example 5.2, starting with 1.55 g (3.79 mmol) of N-
[3-(benzyloxy)propyl]-6-chloro-N-cyclopentylpyridine-3-sulfonamide, 1.5 g of N-[3-(benzyl-
oxy)propyl]-N-cyclopentyl-6-hydrazinylpyridine-3-sulfonamide are obtained in the form of
a yellow solid.
Yield = 90%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.6 (s, 1H); 8.4 (bs, 1H); 7.95 (d, 1H); 7.85 (d, 1H);
7.5-7.3 (m, 5H); 6.9 (d, 1H); 6.6 (bs, 1H); 4.5 (s, 2H); 4.2 (m, 1H); 3.6 (t, 2H); 3.2 (dd, 2H);
2.1 (m, 2H); 1.6-1.3 (m,8H)
26.3. 6-(4-benzvl-5-oxo-2.5-dihvdro-1H-pvrazol-1-vn-N-r3-(benzvloxv)propvn-N-
cvclopentylpyridine-3-sulfonamide
According to the process described in Example 1.3, starting with 0.19 g of methyl 2-
benzyl-3-oxopropanoate and 0.4 g of N-[3-(benzyloxy)propyl]-N-cyclopentyl-6-
hydrazinylpyridine-3-sulfonamide, 0.29 g of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-
yl)-N-[3-(benzyloxy)propyl]-N-cyclopentylpyridine-3-sulfonamide is obtained in the form of
a beige-coloured solid.
Yield = 55%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 8.8 (s, 1H); 8.6 (bs, 1H); 8.4 (d,
1H); 7.7 (s, 1H); 7.4-7.1 (m, 10H); 4.5 (s, 2H); 4.2 (m, 1H); 3.6 (s, 2H); 3.5 (t, 2H); 3.2 (t,
2H); 2.0 (m, 2H); 1.6-1.2 (6H).
26.4. 6-(4-benzvl-5-oxo-2.5-dihvdro-1H-pyrazol-1-vl)-N-cvclopentvl-N-(3-
hydroxvpropvl)pvridine-3-sulfonamide
To a solution of 150 mg (0.27 mmol) of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-
[3-(benzyloxy)propyl]-N-cyclopentylpyridine-3-sulfonamide in 2 mL of DCM is added
dropwise, at -78°C under argon, 0.82 mL (0.82 mmol) of boron tribromide (1M in DCM).
Stirring is continued for 1 hour at -78°C, and 2 mL of MeOH are then added at 0°C. The
medium is taken up in 40 mL of of DCM, washed successively with saturated NaHC03
solution (30 mL) and brine (30 mL), dried over Na2S04 and then concentrated under
reduced pressure and purified by chromatography on a column of silica gel, eluting with a
9/1 DCM/MeOH mixture. 106 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-
cyclopentyl-N-(3-hydroxypropyl)pyridine-3-sulfonamide are thus obtained in the form of a
powder.
Yield = 85%
1H NMR,_d_6-DMS0, ^100 MHz, 5 (ppm): 8.8 (s, 1H); 8.6 (bs, 1H); 8.4 (d, 1H); 11 (s, 1H);
7.4 (m, 5H); 7.3 (m, 1H); 4.5 (t, 1H); 4.2 (m, 1H); 3.6 (s, 2H); 3.5 (q, 2H); 3.2 (t, 2H); 1.8
(m, 2H); 1.5-1.2 (6H).
26.5. 6-(4-benzvl-5-oxo-2,5-dihvdro-1H-Pvrazol-1-vl)-N-cvclopentvl-N-r3-(dimethyl-
amino)propvnpvridine-3-sulfonamide hydrochloride
To a solution of 82 mg (0.18 mmol) of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-
cyclopentyl-N-(3-hydroxypropyl)pyridine-3-sulfonamide and 50 uL (0.36 mmol) of Et3N in
0.5 ml_ of anhydrous DCM are added, under argon at 0°C, 27 ul_ (0.36 mmol) of mesyl
chloride; the temperature is allowed to return gradually to room temperature, and stirring
is continued for 1 hour. The medium is taken up in 20 mL of of DCM, washed
successively with water (2x10 mL) and brine (20 mL), dried over Na2S04 and then
concentrated under reduced pressure. In a sealed tube, the residue obtained (110 mg of
yellow oil) is taken up in 2 mL of DCM and then treated for 1 minute with a stream of
dimethylamine which is bubbled through the solution. The medium is then, followed by
heating for 11 hours at 60°C. After cooling to room temperature, the medium is
concentrated and the residue obtained is triturated in an Et20/CH3CN mixture. The
precipitate formed filtered off, rinsed with pentane, dried under reduced pressure and
then freeze-dried after addition of 1 eq. of 1N HCI. 57 mg of 6-(4-benzyl-5-oxo-2,5-
dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-[3-(dimethylamino)propyl]pyridine-3-sulfon-
amide hydrochloride are thus obtained in the form of a lyophilizate.
Yield = 88%
m.p. (°C) = 230
M = C25H33N503S= 483; M+H = 484; Method 2: Tr =1.1 min
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12.0 (bs, 1H); 10.8 (bs, 1H); 8.9 (s, 1H); 8.8 (s,
1H); 8.5 (d, 1H); 7.8 (s, 1H); 7.4 (m, 5H); 7.3 (m, 1H); 4.5 (m, 1H); 4.2 (m, 1H); 3.6 (s,
2H); 3.3 (t, 2H); 3.2 (q, 2H); 2.7 t(s, 6H); 2.0 (m, 2H); 1.6-1.3 (6H).
Example 27: 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-ethyl-N-phenyI-
pyridine-3-sulfonamide (Compound 93 of Table I)
27.1. methyl 2-benzvl-3-oxopropanoate
To a mixture of 3 g (18.3 mmol) of methyl 3-phenylpropanoate and 3.57 mL (54.8 mmol)
of methyl formate in 36 mL of toluene, under argon, are added dropwise successively
54.8 mL (54.8 mmol) of a 1 M solution of TiCI4 in toluene, 0.17 mL (0.91 mmol) of
trimethylsilyl trifluoromethanesulfonate and 19.6 mL (82.2 mmol) of tributylamine. The
medium is then heated for 2 hours 30 minutes at 60°C and stirred for 12 hours at room
temperature.
The reaction medium is hydrolysed with 200 mL of water and extracted with 200 mL of
Et20. The organic phase is dried over Na2S04, filtered and concentrated under reduced
pressure. 3.12 g of methyl 2-benzyl-3-oxopropanoate are obtained in the form of an oil,
which is used without further purification in the following step.
Yield = 87%
27.2. 6-(4-benzvl-5-oxo-2,5-dihvdro-1H-pvrazol-1-vl)-N-ethyl-N-phenvlpyridine-3-
sulfonamide
A mixture of 0.38 g (1.3 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide
and 0.25 g (1.3 mmol) of methyl 2-benzyl-3-oxopropanoate in 2 mL of an AcOH/MeOH
mixture (1/1) is heated for 4 hours at 80°C. The medium is then concentrated under
reduced pressure, and the residue obtained is solidified in an Et20/pentane mixture (1/1),
and then filtered off and dried under reduced pressure. At room temperature, the 440 mg
of solid obtained are then added portionwise to a solution of 22 mg (0.96 mmol) of
sodium in 1 mL of MeOH, and stirring is then continued for 3 hours at room temperature.
The reaction mixture is then concentrated under reduced pressure, taken up in 10 mL of
water and then acidified to pH 3-4 by adding AcOH. The precipitate obtained is then
filtered off, washed with pentane and then recrystallized from EtOH and dried. 245 mg of
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenyIpyridine-3-sulfonamide
are thus obtained in the form of a white powder.
Yield = 59%
m.p. (°C) = 180
M = CgoHg^OjS = 434; M+H = 435; Method 2: Tr = 1.35 min._____________________
1H NMR, d6-DMSO, 400 MHz, 6 (ppm): 12 (bs, 1H); 8.6 (bs, 1H); 8.5 (s, 1H); 8.1 (d, 1H)
7.7 (s, 1H); 7.5-7.1 (m, 10H); 3.7 (q, 2H); 3.6 (s, 2H); 1.0 (t, 3H).
Example 28: 6-(4-benzyl-5-oxo-3-trifluoromethyl-2,5-dihydro-1 H-pyrazol-1 -yl)-N-
ethyl-N-phenylpyridine-3-sulfonamide (Compound 83 of Table I)
28.1. methyl 2-benzvl-4,4,4-trifluoro-3,3-dihvdroxvbutanoate
To a solution of 675 mg (29.4 mmol) of sodium in 15 mL of anhydrous MeOH, under
argon, are added dropwise 3.73 mL (29.4 mmol) of methyl 3,3,3-trifluoropropanoate. After
stirring for 30 minutes at room temperature, 3.5 mL of benzyl bromide are added and the
medium is heated for 12 hours at 70°C. The reaction mixture is then concentrated under
reduced pressure. The residue obtained is taken up in 100 mL of EtOAc, washed with
50 mL of brine, dried over Na2S04, filtered and concentrated under reduced pressure.
After purification by chromatography on a column of silica gel, eluting with a
cyclohexane/EtOAc mixture (85/15), 3.4 g of methyl 2-benzyl-4,4,4-trifluoro-3,3-
dihydroxybutanoate are obtained in the form of an oil, which is used without further
purification in the following step.
Yield = 37%.
28.2. 6-(4-benzvl-5-oxo-3-trifluoromethvl-2,5-dihvdro-1H-pyrazol-1-vn-N-ethvl-N-
phenylpyridine-3-sulfonamide
A mixture of 1 g (3.59 mmol) of methyl 2-benzyl-4,4,4-trifluoro-3,3-dihydroxybutanoate,
1.05 g (3.59 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 1 g of 4A
molecular sieves in 8 mL of MeOH is heated for 12 hours at 90°C. At room temperature,
the reaction medium is taken up in 30 mL of toluene, and refluxed for 12 hours in Dean-
Stark apparatus. The reaction medium is then filtered and concentrated under reduced
pressure, and the residue obtained is then taken up in 50 mL of DCM, washed with 1N
HCI solution (2 * 50 mL), dried over Na2S04, filtered and concentrated under reduced
pressure. The solid thus obtained is recrystallized from EtOH. 224 mg of 6-(4-benzyl-5-
oxo-3-trifluoromethyl-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-
sulfonamide are obtained in the form of white crystals.
Yield = 12%
m.p. (°C) = 186
M = C24H21F3N403S = 502; M+H = 503; Method 3: Tr = 4.4 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12 (bs, 1H); 8.7 (s, 1H); 8.25 (d, 1H); 8.0 (d, 1H);
7.5-7.1 (m, 10H); 3.9 (s, 2H); 3.7 (q, 2H); 1.0 (t, 3H).
Example 29: 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-[(1 R,3S)-3-(hydroxy-
methyl)cyclopentyl]-N-methylpyridine-3-sulfonamide (Compound 138 of Table I)

29.1. tert-butyl [(1 R,3S)-3-(hvdroxvmethyl)cvclopentvncarbamate
To a solution of 2 g (8.7 mmol) of (1S,3R)-3-[(tert-butoxycarbonyl)amino]cyclo-
pentanecarboxylic acid and 1.33 ml_ (9.6 mmol) of Et3N in 20 mL of anhydrous THF are
added dropwise, at -20°C, 1.2 mL (9.2 mmol) of isobutyl chloroformate. The medium is
stirred for 45 minutes at -20°C and the insoluble material formed is then filtered off. A
solution of 1 g (26.2 mmol) of sodium borohydride in a THF/H20 mixture (16 mL/4 mL) is
added dropwise to the filtrate at -10°C and stirring is then continued, while allowing the
temperature to return to room temperature. 100 mL of 0.1 N HCI are then added slowly
and the reaction medium is then extracted with 2 * 200 mL of EtOAc, dried over Na2S04,
filtered and concentrated under reduced pressure. After purification by chromatography
on a column of silica gel, eluting with a DCM/MeOH mixture (95/5), 1.4 g of tert-butyl
[(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate are obtained in the form of an oil.
Yield = 77%.
1H NMR, CDCI3, 400 MHz, 6 (ppm): 4.5 (bs, 1H); 3.9 (m, 1H); 3.5 (d, 2H); 2.1 (m, 2H);
1.8-1.7 (m, 3H); 1.5 (s, 2H); 1.4 (s, 9H); 1.0 (m, 1H)
29.2. tert-butvl (f 1 R,3S)-3-r(benzvloxv)methyllcvclopentvl)carbamate
To a solution of 1.4 g (6.7 mmol) of tert-butyl [(1 R,3S)-3-(hydroxymethyl)-
cyclopentyl]carbamate in 20 mL of anhydrous THF are added portionwise under argon, at
room temperature, 0.27 g (6.7 mmol) of sodium hydride at 60% in oil. After stirring for 45
minutes, the medium is cooled to 0°C and 0.8 mL (6.7 mmol) of benzyl bromide is added.
After stirring for 1 hour at room temperature, the medium is hydrolysed with 30 mL of
water and extracted with 2 * 100 mL of EtOAc, dried over Na2S04, concentrated under
reduced pressure and then purified by chromatography on a column of silica gel, eluting
with a 99/1 DCM/MeOH mixture. 1.53 g of tert-butyl {(1R,3S)-3-
[(benzyloxy)methyl]cyclopentyl}carbamate are obtained in the form of an oil.
Yield = 75%
29.3. (1 R,3S)-3-r(benzvloxv)methvncvclopentanamine hydrochloride
To a solution of 1.52 g (5 mmol) of tert-butyl {(1R,3S)-3-[(benzyloxy)methyl]-
cyclopentyljcarbamate in 20 mL of DCM are added, at 0°C, 5 mL (20 mmol) of a 4N
solution of HCI in dioxane. The medium is then stirred for 12 hours at room temperature,
and then concentrated under reduced pressure. The residue obtained is solidified in
20 mL of Et20, filtered and dried under vacuum. 1 g of (1R,3S)-3-[(benzyloxy)-
methyl]cyclopentanamine hydrochloride is obtained in the form of a powder.
Yield = 83%
29.4. N-{(1R,3S)-3-r(benzvloxv)methvncvclopentvl}-6-chloropyridine-3-sulfonamide
According to the process of 14.1, starting with 1 g of (1R,3S)-3-[(benzyloxy)methyl]-
cyclopentanamine hydrochloride and 1 g of 6-chloropyridine-3-sulfonyl chloride, 1.2 g of
N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}-6-chloropyridine-3-sulfonamide are
obtained in the form of a pink powder.
Yield = 83%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.6 (s, 1H); 7.8 (dd, 1H); 7.4-7.3 (m, 5H); 7.2 (s, 1H);
5.8 (d, 1H); 4.5 (dd, 2H); 3.7 (m, 1H); 3.3 (m, 2H); 2.2 (m, 1H); 1.9 (m, 1H); 1.6-1.5 (m,
4H); 1.2 (dd, 1H)
29.5. N-((1R,3S)-3-r(benzvloxv)methvncvclopentvl>-6-chloro-N-methvlpyridine-3-
sulfonamide
According to process 23.2, starting with 0.66 g of 4 N-{(1R,3S)-3-
[(benzyloxy)methyl]cyclopentyl}-6-chloropyridine-3-sulfonamide and 0.22 mL of methyl
iodide, 0.58 g of N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}-6-chloro-N-methylpyridine-
3-sulfonamide is obtained in the form of an oil.
Yield = 86%
29.6. N-((1R.3S)-3-r(benzvloxv)methvl1cvclopentvl)-6-hvdrazinvl-N-methvlpyridine-3-
sulfonamide
According to process 5.2, starting with 0.58 g of N-{(1R,3S)-3-[(benzyloxy)methyl]-
cyclopentyl}-6-chloro-N-methylpyridine-3-sulfonamide and 0.15 ml_ of hydrazine hydrate,
0.49 g of N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}-6-hydrazinyl-N-methylpyridine-3-
sulfonamide is obtained.
Yield = 86%
29.7. 6-(4-benzvl-5-oxo-2,5-dihvdro-1H-pvrazol-1-vn-N-((1R,3S)-3-f(benzvloxv)methvn
cyclopentvl)pyridine-3-sulfonamide
According to the process described in Example 1.3, starting with 0.495 g of N-{(1R,3S)-3-
[(benzyloxy)methyl]cyclopentyl}-6-hydrazinyl-N-methylpyridine-3-sulfonamide and 0.244 g
of methyl 2-benzyl-3-oxopropanoate, 301 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-
pyrazol-1-yl)-N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}pyridine-3-sulfonamide are
obtained in the form of a powder.
Yield = 44%
29.8. 6-(4-benzvl-5-oxo-2.5-dihvdro-1H-pyrazol-1-vn-N-f(1R.3S)-3-(hvdroxvmethvn
cvclopentvn-N-methvlpyridine-3-sulfonamide
To a solution of 0.3 g (0.57 mmol) of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-
{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}pyridine-3-sulfonamide in 2 mL of DCM cooled
to -78°C are added 1.7 mL of boron tribromide. The temperature is then allowed to rise to
0°C and stirring is continued for 1 hour at 0°C. 10 mL of MeOH are then added at -10°C
and the medium is concentrated under reduced pressure. The medium is taken up in
100 mL of DCM, washed successively with saturated NaHC03 solution (2 x 20 mL) and
brine (20 mL), dried over Na2S04, concentrated under reduced pressure and then purified
by chromatography on a column of silica gel, eluting with a 90/10 DCM/MeOH mixture.
126 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[(1R,3S)-3-(hydroxymethyl)-
cyclopentyl]-N-methylpyridine-3-sulfonamide are obtained in the form of a powder.
Yield = 50%
a20D=:-12°(c = 0.1;MeOH)
m.p. (°C) = 108
M = C22H26N404S = 442; M+H = 443; Method 2: Tr = 1.09 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.8 (s, 1H); 8.7 (bs, 1H); 8.4 (d, 1H); 7.8 (bs, 1H);
7.4-7.3 (m, 5H); 7.1 (m, 1H); 4.5 (bs, 1H); 4.4 (m, 1H); 3.6 (bs, 2H); 3.4 (m, 2H); 2.8 (s,
3H); 1.9 (m, 1H); 1.6-1.1 (m, 6H)
Example 30: 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-cyclopentyl-N-[3-
hyrirnyy-2-(hyrimyympthyl)propyl]pyridine-3-SMlfonamide (Compound 147 of Table I)

30.1. (2l2-dimethyl-1,3-dioxan-5-vl) methyl 4-methvlbenzenesulfonate
To a solution of 1.5 g (10.26 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methanol and
1.71 mL of Et3N in 15 mL of DCM, cooled to 0°C, are added 2.15 g (11.3 mmol) of tosyl
chloride. The medium is allowed to warm to room temperature, and stirring is continued
for 1 hour. The medium is taken up in 100 mL of of DCM, washed successively with 0.1N
HCI (2 x 20 mL) and brine (20 mL), dried over Na2S04, concentrated under reduced
pressure and then purified by chromatography on a column of silica gel, eluting with a
99/1 DCM/MeOH mixture. 3g of (2,2-dimethyl-1,3-dioxan-5-yl) methyl 4-methylbenzene-
sulfonate are obtained in the form of a colourless oil.
Yield = 97%
1H NMR, CDCI3, 400 MHz, 6 (ppm): 7.8 (d, 2H); 7.3 (d, 2H); 4.1 (d, 2H); 3.9 (dd, 2H); 3.6
(dd, 2H); 2.4 (s, 3H); 1.9 (m, 1H); 1.4 (s, 3H); 1.2 (s, 3H)
30.2. N-f(2,2-dimethyl-1,3-dioxan-5-vnmethvncyclopentanamine
A mixture of 1.5 g (5 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl) methyl 4-
methylbenzenesulfonate and 10 mL (101 mmol) of cyclopentylamine is heated for
12 hours at 80°C. The medium is concentrated under reduced pressure and then taken
up in 200 mL of Et20, washed with water (2 x 50 mL) and then dried over Na2S04 and
concentrated under reduced pressure. 1 g of N-[(2,2-dimethyl-1,3-dioxan-5-
yl)methyl]cyclopentanamine is obtained in the form of an oil, which is used without further
purification in the following step.
Yield = 100%
30.3 N-cyclopentvl-N-^^-dimethvl-I.S-dioxan-S-vDmethvn-e-hvdrazinvlpyridine-S-
sulfonamide
The compound is prepared according to processes 14.1 and 14.3, starting with N-[(2,2-
dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine, 6-chloropyridine-3-sulfonyl chloride
and hydrazine hydrate.
Yield: 70%
1H NMR, d6-DMS0, 400 MHz, 6 (ppm): 8.5 (s, 1H); 8.25 (s, 1H); 8.0 (s, 1H); 7.8 (d, 1H);
7.7 (s, 1H); 7.2 (d, 1H); 6.8 (d, 1H); 4.4 (s, 1H); 4.2 (m, 1H); 3.9 (dd, 2H); 3.6 (dd, 2H); 3.0
(dd, 2H); 2.0 (m, 1H); 1.9 (d, 2H); 1.6-1.4 (m, 4H); 1.3 (s, 3H); 1.2 (s, 3H)
30.4. 6-(4-benzvl-5-oxo-2,5-dihvdro-1H-pvrazol-1-vn-N-cvclopentvl-N-[3-hvdroxy-2-
(hvdroxymethvl)propvnpvridine-3-sulfonamide
According to the process described in Example 11, starting with 0.485 g of N-cyclopentyl-
N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-6-hydrazinylpyridine-3-sulfonamide and 0.242 g
of methyl 2-benzyl-3-oxopropanoate, 79 mg of 6-(4-benzyI-5-oxo-2,5-dihydro-1H-pyrazol-
1-yl)-N-cyclopentyl-N-[3-hydroxy-2-(hydroxymethyl)propyl]pyridine-3-sulfonamide are
obtained in the form of a powder.
Yield = 14%
m.p. (°C) >260
M = C24H3oN405S = 486; M+H = 487; Method 2: Tr = 2.09 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12 (bs, 1H); 8.8 (s, 1H); 8.6 (t, 2H); 8.25 (d, 1H);
7.7 (s, 1H); 7.4-7.2 (m, 5H); 4.3 (q, 2H); 3.9 (m, 2H); 3.0 (m, 1H); 2.8 (m, 1H); 2.7 (s, 3H);
1.6-1.3 (m, 8H)
Example 31: 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazoM-yl)-N-cyclopentyl-N-[(2R)-
2,3-dihydroxypropyl]pyridine-3-sulfonamide (Compound 142 of Table I)

According to the processes described in Example 30, the compound is obtained from
[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol, cyclopentylamine, 6-chloropyridine-3-
sulfonyl chloride and methyl 2-benzyl-3-oxopropanoate.
m.p. (°C) = 184
a2°D=:-24°(c = 0.1;DMSO)
M = C23H28N405S = 472; M+H = 473; Method 2: Tr = 1.39 min.
1H NMR, d6-DMSO, 400 MHz, 6 (ppm): 12 (bs, 1H); 8.8 (s, 1H); 8.6 (bs, 1H); 8.4 (d, 1H);
7.8 (s, 1H); 7.3-7.1 (m, 5H); 4.8 (s, 1H); 4.6 (s, 1H); 4.2 (m, 1H); 3.8 (s, 1H); 3.6 (s, 2H);
3.3 (m, 2H); 2.9 (m, 1H); 1.6-1.3 (m, 9H)
Example 32: 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-nyra7ol-1-yl)-N-r.yclopentyl-N-[(2S)-
2,3-dihydroxypropyl]pyridine-3-sulfonamide (Compound 148 of Table I)

According to the processes described in Example 30, the compound is obtained
from [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol, cyclopentylamine, 6-chloropyridine-3-
sulfonyl chloride and methyl 2-benzyl-3-oxopropanoate.
m.p.(°C) = 184
a2"°D=: -+33° (c = 0.15; DMSO)
M = C23H28N405S = 472; M+H = 473; Method 2: Tr = 1.39 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12 (bs, 1H); 8.8 (s, 1H); 8.6 (bs, 1H); 8.4 (d, 1H);
7.8 (s, 1H); 7.3-7.1 (m, 5H); 4.8 (s, 1H); 4.6 (s, 1H); 4.2 (m, 1H); 3.8 (s, 1H); 3.6 (s, 2H);
3.3 (m, 2H); 2.9 (m, 1H); 1.6-1.3 (m, 9H)
Example 33: 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-(2,3-dihydroxy-
propyI)-N-phenylpyridine-3-sulfonamide (Compound 143 of Table I)

32.1. 6-chloro-N-phenvlpyridine-3-sulfonamide
According to process 14.1, starting with 1 g of 6-chloropyridine-3-sulfonyl chloride and
0.86 mL of aniline, 1.15 g of 6-chloro-N-phenylpyridine-3-sulfonamide are obtained in the
form of a yellow solid.
Yield = 91%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 10.5 (bs, 1H); 8.7 (s, 1H); 8.1 (dd, 1H); 7.75 (dd,
1H);7.3(m, 2H); 7.2 (m, 3H)
32.2. 6-chloro-N-phenvl-N-(prop-2-en-1-vl)pvridine-3-sulfonamide
According to process 23.2, starting with 1.15 g of 6-chloro-N-phenylpyridine-3-
sulfonamide and 0.37 mL of allyl bromide, 1.29 g of 6-chloro-N-phenyl-N-(prop-2-en-1-
yl)pyridine-3-sulfonamide are obtained in the form of a yellow solid.
Yield = 97%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.6 (s, 1H); 8.0 (dd, 1H); 7.9 (dd, 1H); 7.4 (m,
3H); 7.2 (m, 2H); 5.7 (m, 1H); 5.2 (dd, 1H); 5.1 (dd, 1H); 4.3 (d, 2H)
32.3. 6-chloro-N-(2,3-dihvdroxypropvn-N-phenvlpvridine-3-sulfonamide
To a solution of 1.3 g (4.2 mmol) of 6-chloro-N-phenyl-N-(prop-2-en-1-yl)pyridine-3-
sulfonamide in 17 mL of a mixture (1/1) of tBuOH and water are added, at room
temperature, 1.37 g (11.7 mmol) of NMO and 0.52 mL (0.04 mmol) of 2.5% Os04 in
tBuOH. Stirring is continued for 12 hours. The medium is then diluted with 200 mL of
water and extracted with Et20 (2 * 100 mL), dried over Na2S04, filtered and concentrated
under reduced pressure. 1.14 g of 6-chloro-N-(2,3-dihydroxypropyl)-N-phenylpyridine-3-
sulfonamide are obtained in the form of an oil, which is used without further purification in
the following step.
Yield = 80%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.5 (s, 1H); 7.8 (d, 1H); 7.4-7.3 (m, 4H); 7.1 (d, 2H);
3.7-3.5 (m, 3H); 2.5 (bs, 1H); 2.0 (bs, 1H); (m, 2H)
32.4. 6-chloro-N-f(2.2-dimethvl-1.3-dioxolan-4-vl)methvn-N-phenvlpyridine-3-
sulfonamide
A mixture of 0.67 g (1.96 mmol) of 6-chloro-N-(2,3-dihydroxypropyl)-N-phenylpyridine-3-
sulfonamide, 0.53 mL (4.3 mmol) of 2,2-dimethoxypropane and 37 mg of pTsOH in 4 mL
of DMF is stirred for 3 hours at room temperature. The medium is taken up in 100 mL of
EtOAc, washed with 50 mL of saturated NaHC03 solution and 50 mL of water and then
dried over Na2S04, filtered and concentrated under reduced pressure. 0.54 g 6-chloro-N-
[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-N-phenylpyridine-3-sulfonamide is obtained in the
form of a brown solid, which is used without further purification in the following step.
Yield = 73%.
1H NMR, CDCI3, 400 MHz, 5 (ppm): 8.5 (s, 1H); 7.7 (d, 1H); 7.4 (d, 1H); 7.3 (m, 3H); 7.0
(d, 2H); 4.1 (m, 1H); 3.9 (m, 1H), 3.8 (dd, 2H); 3.5 (m, 1H); 1.3 (s, 3H); 1.2 (s, 3H)
32.5. N-r(2,2-dimethvl-1.3-dioxolan-4-vl)methvn-6-hvdrazinvl-N-phenylpyridine-3-
sulfonamide
According to process 5.2, starting with 0.54 g of 6-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-
yl)methyl]-N-phenylpyridine-3-sulfonamide and 30 uL of hydrazine hydrate, 0.53 g of N-
[(2,2^dimethyl'1,3^dioxolan-4-yl)methyl]-6-hydrazinyl-N-phenylpyridine-3-si.ilfonarriide—is.
obtained in the form of a white solid.
Yield = 99%
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 8.6 (s, 1H); 8.1 (s, 1H); 7.5 (d, 1H); 7.4 (m, 3H);
7.2 (d, 2H); 6.8 (bs, 1H); 1.3 (s, 3H); 1.2 (s, 3H)
32.6 6-(4-benzvl-5-oxo-2.5-dihvdro-1H-pvrazol-1-vn-N-(2.3-dihvdroxvpropvn-N-phenvl-
pyridine-3-sulfonamide
According to process 1.3, starting with 0.2 g (0.53 mmol) of N-[(2,2-dimethyl-1,3-dioxolan-
4-yl)methyl]-6-hydrazinyl-N-phenylpyridine-3-sulfonamide and 0.1 g of methyl 2-benzyl-3-
oxopropanoate, 127 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-(2,3-
dihydroxypropyl)-N-phenylpyridine-3-sulfonamide are obtained in the form of a white
solid.
Yield = 50%
m.p. (°C) = 174
M = C24H24N405S = 480; M+H = 481; Method 2: Tr = 1.39 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12 (bs, 1H); 8.5 (bs, 1H); 8.4 (s, 1H); 8.1 (d, 2H);
7.8 (s, 1H); 7.4-7.2 (m, 7H); 7.2-7.1 (m, 3H); 4.7 (d, 1H); 4.5 (t, 1H); 3.6 (dd, 2H); 3.4 (m,
4H)
Example 33: 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-
1H-pyrazol-4-yl)-3-phenyl-N-(2,2,2-trifluoroethyl)propanamide (Compound 146 of
Table I)
33.1 3-(2-f5-fcvclopentvl(methvl)sulfamovllpyridin-2-vl)-3-oxo-2,3-dihvdro-1H-pvrazol-4-
vl)-3-phenyl-N-(2,2,2-trifluoroethvl)propanamide
To a solution of 200 mg (0.43 mmol) of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl] pyridin-2-
yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenylpropanoate, 0.3 ml_ (1.7 mmol) of DIEA
and 30 uL (0.43 mmol) of 2,2,2-trifluoroethylamine in 1 mL of DCM are added, at 0°C,
207 mg (0.64 mmol) of TBTU. The medium is stirred for 12 hours at room temperature. A
further 0.3 mL of 2,2,2-trifluoroethylamine is then added and the medium is heated at
40°C for 6 hours. The medium is taken up in 20 mL of of DCM, washed successively with
water (2x10 mL) and brine (20 mL), dried over Na2S04 and concentrated under reduced
pressure, and then purified by chromatography on a column of silica gel, eluting with a
cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 32 mg of 3-(2-{5-[cyclopentyl(methyl)-
sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenyl-N-(2,2,2-trifluoro-
ethyl)propanamide are thus obtained in the form of a powder.
Yield = 14%
m.p. (°C) = 80
M = CzsHssFaNsCUS = 551; M+H = 552; Method 2: Tr = 1.21min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12 (bs, 1H); 8.8 (s, 1H); 8.6 (t, 2H); 8.25 (d, 1H);
7.7 (s, 1H); 7.4-7.2 (m, 5H); 4.3 (q, 2H); 3.9 (m, 2H); 3.0 (m, 1H); 2.8 (m, 1H); 2.7 (s, 3H);
1.6-1.3 (m, 8H)
Example 34: 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-cyclopentyl-N-[3-
hydroxy-2-(hydroxymethyl)propyl]pyridine-3-sulfonamide (Compound 147 of Table I)

34.1. (2,2-dimethvl-1,3-dioxan-5-vl) methyl 4-methvlbenzenesulfonate
To a solution of 1.5 g (10.26 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methanol and
1.71 mL of Et3N in 15 mL of DCM, cooled to 0°C, are added 2.15 g (11.3 mmol) of tosyl
chloride. The medium is allowed to warm to room temperature, and stirring is continued
for 1 hour. The medium is taken up in 100 mL of of DCM, washed successively with
0.11N HCI (2 x 20 mL) and brine (20 mL), dried over Na2S04, concentrated under
reduced pressure and then purified by chromatography on a column of silica gel, eluting
with a 99/1 DCM/MeOH mixture. 3g of (2,2-dimethyl-1,3-dioxan-5-yl) methyl 4-
methylbenzenesulfonate are obtained in the form of a colourless oil.
Yield = 97%
1H NMR, CDCI3, 400 MHz, 5 (ppm): 7.8 (d, 2H); 7.3 (d, 2H); 4.1 (d, 2H); 3.9 (dd, 2H); 3.6
(dd, 2H); 2.4 (s, 3H); 1.9 (m, 1H); 1.4 (s, 3H); 1.2 (s, 3H)
34?____N-f (?, ?-dimethvl-1,3-dioxan-5-yl)methvncyclopentanam ine_________________
A mixture of 1.5 g (5 mmol) of (2,2-dimehyl-1,3-dioxan-5-yl) methyl 4-methylbenzene-
sulfonate and 10 mL (101 mmol) of cyclopentylamine is heated for 12 hours at 80°C. The
medium is concentrated under reduced pressure and then taken up in 200 mL of Et20,
washed with water (2 x 50 mL), dried over Na2S04 and concentrated under reduced
pressure. 1 g of N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine is obtained in
the form of an oil, which is used in the following step without further purification.
Yield = 100%
34.3. N-cvclopentvl-N-r(2.2-dimethvl-1.3-dioxan-5-v0methvll-6-hvdrazinvlpyridine-3-
sulfonamide
The compound is prepared according to processes 14.1 and 5.2, starting with N-[(2,2-
dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine, 6-chloropyridine-3-sulfonyl chloride
and hydrazine hydrate.
Yield: 70%
1H NMR, d6-DMSO, 400 MHz, 6 (ppm): 8.5 (s, 1H); 8.25 (s, 1H); 8.0 (s, 1H); 7.8 (d, 1H);
7.7 (s, 1H); 7.2 (d, 1H); 6.8 (d, 1H); 4.4 (s, 1H); 4.2 (m, 1H); 3.9 (dd, 2H); 3.6 (dd, 2H); 3.0
(dd, 2H); 2.0 (m, 1H); 1.9 (d, 2H); 1.6-1.4 (m, 4H); 1.3 (s, 3H); 1.2 (s, 3H)
34.4. 6-(4-benzvl-5-oxo-2.5-dihvdro-1H-pvrazol-1-vl)-N-cvclopentvl-N-f3-hydroxv-2-
(hvdroxvmethvQpropvllpvridine-3-sulfonamide
According to the process described in Example 11, starting with 0.485 g of N-cyclopentyl-
N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-6-hydrazinylpyridine-3-sulfonamide and 0.242 g
of methyl 2-benzyl-3-oxopropanoate, 79 mg of 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-
1-yl)-N-cyclopentyl-N-[3-hydroxy-2-(hydroxymethyl)propyl]pyridine-3-sulfonamide are
obtained in the form of a powder.
Yield = 14%
m.p. (°C) >260
M = C24H3oN405S = 486; M+H = 487; Method 2: Tr = 2.09 min.
1H NMR, d6-DMSO, 400 MHz, 5 (ppm): 12 (bs, 1H); 8.8 (s, 1H); 8.6 (t, 2H); 8.25 (d, 1H);
7.7 (s, 1H); 7.4-7.2 (m, 5H); 4.3 (q, 2H); 3.9 (m, 2H); 3.0 (m, 1H); 2.8 (m, 1H); 2.7 (s, 3H);
1.6-1.3 (m, 8H)
Example 35: methyl 3-{2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1 H-
pyrazol-4-yl}-3-(pyridin-3-yl)propanoate (Compound 154 of Table I)
35.1. diethyl (2Z)-3-(pyridin-3-vl)pent-2-enedioate
To a solution of 15 mL (85.6 mmol) of diethyl (2E)-pent-2-enedioate in 5 ml_ of anhydrous
DMF are added, under a stream of argon, 0.62 g (2.8 mmol) of Pd(OAc)2, 1.7g
(5.56 mmol) of P(OTol)3 and 5.5 mL (39.7 mmol) of Et3N, the medium is then heated to
40°C and 4 mL (39.75 mmol) of 3-bromopyridine are added. The medium is then heated
for 24 hours at 90°C, and then taken up in 100 mL of EtOAc, washed with 100 mL of
water, dried over Na2S04, concentrated under reduced pressure and purified by
chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0
to 10% EtOAc. 9.12 g of diethyl (2Z)-3-(pyridin-3-yl)pent-2-enedioate are obtained in the
form of a yellow wax.
Yield = 87%
1H NMR, CDCI3, 400 MHz, 6 (ppm) 8.8 (s, 1H); 8.6 (d, 1H); 7.8 (dd, 1H); 7.4 (dd, 1H); 6.3
(s, 1H); 4.2 (q, 2H); 4.15 (s, 2H); 4.1 (q, 2H); 1.3 (t, 3H); 1.2 (t, 3H)
35.2. diethyl 2-formyl-3-(pvridin-3-yl)pentanedioate
The compound is prepared according to processes 21.2 and 14.2, starting with diethyl
(2Z)-3-(pyridin-3-yl)pent-2-enedioate.
Yield: 18%
35.3. methyl 3-(2-r5-(tert-butvlsulfamovl)pvridin-2-vn-3-oxo-2,3-dihvdro-1H-pyrazol-
4-vl)-3-(pvridin-3-yl)propanoate
According to processes 22.5 to 22.7, starting with 88 mg of diethyl 2-formyl-3-(pyridin-3-
yl)pentanedioate and 74 mg of N-tert-butyl-6-hydrazinylpyridine-3-sulfonamide, followed
by free-drying of the compound obtained in the presence of 1 eq. of 0.1 N HCI, 17 mg of
methyl 3-{2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-3-
(pyridin-3-yl)propanoate hydrochloride are obtained in the form of a green lyophilizate.
Yield = 17%
m.p. (°C) = 146
M = C21H25N505S = 459; M+H = 460; Method 2: Tr = 1.19 min.
1H NMR, d6-DMS0, 400 MHz, 5 (ppm): 12.5 (bs, 1H); 8.8 (s, 1H); 8.7 (bs, 1H); 8.6 (d,
1H); 8.4 (bs, 1H); 8.3 (d, 1H); 8.2 (d, 1H); 7.9 (s, 1H); 7.8 (t, 1H); 7.6 (s, 1H); 4.3 (t, 1H);
3.5 (s, 3H);3.2(m, 2H);1.0(s, 9H)
Tables I and II below illustrate the chemical structures and the physical properties of a
few examples of compounds according to the invention.
Table I illustrates compounds of formula (I) according to the invention in which R
represents -S02-NR3R4. These compounds are referred to hereinbelow as compounds
of formula (I').
Table II illustrates compounds of formula (I) according to the invention in which R is as
defined in the said table. These compounds are referred to hereinbelow as compounds of
formula (I").
Tables I and II below illustrate the chemical structures and the physical properties of a
few examples of compounds according to the invention.
In these tables:
- in the "salt" column, "-" represents a compound in free base form, whereas
"CF3COOH", "HCI" and "Na" represent, respectively, a compound in the form of the
trifluoroacetic acid salt, in the form of the hydrochloride salt and in the form of the
sodium salt;
- in the other columns,"-" means that the substituent under consideration is not present
on the molecule;
- Me, Et, n-Pr, i-Pr, n-Bu and i-Bu represent, respectively, the methyl, ethyl, n-propyl,
isopropyl, n-butyl and isobutyl groups;
- Ph and Bn represent, respectively, the phenyl and benzyl groups;
- the "m.p." column indicates the melting point, in °C, of the compound under
consideration;
- the peak MH+ identified by mass spectrometry, and the high-performance liquid
chromatography analytical methods used and detailed previously, are indicated,
respectively, in the "LC/MS" column and the "Method" column.
The compounds according to the invention underwent pharmacological trials in order
to determine their properties, with, in particular:
- an in vitro test of direct measurement of stabilization of the protein HIF1-alpha, a
transcription factor constitutively expressed in cells but degraded under normal
oxygen conditions by the ubiquitin/proteasome system;
- a functional test for measuring in He3pB cells the secretion of VEGF and EPO,
which are two markers of activation of HIF1-alpha in hepatocytes.
These two tests are described below.
1. Measurement of the stabilization of HIF1-alpha in HEKEA cells
1.1 Object
HIF is a transcription factor involved in the adaptation of cells to hypoxia. This
transcription factor is at the minimum a heterodimer formed from two proteins, ARNT
and HIF1-alpha. ARNT is constitutively and stably expressed in cells and the bulk of
the transcription complex regulation is performed via stabilization of the protein HIF1-
alpha. In point of fact, this protein, under normal oxygen conditions (20%,
approximately equivalent to the value of ambient oxygen), is hydroxylated
specifically on two prolines (proline 402 and 564 for the human protein) via HIF
prolyl-hydroxylases, resulting in the binding of the von Hippell Lindau (VHL) protein.
This binding of VHL to HIF1-alpha then causes the degradation of HIF1-alpha via the
ubiquitin/proteasome system. Under hypoxia (02 < 5% in the cell tests), the HIF
prolyl-hydroxylases are inhibited, which is reflected by an increase in the amount of
HIF1-alpha protein in the cells. This protein can then combine with ARNT to transfer
into the nucleus and activate its target genes.
Since the genes activated by HIF are involved in the adaptive response of cells to
hypoxia and of tissues to ischaemia, the object is to identify and characterize
compounds that stabilize HIF1-alpha in cells in order to amplify or mimic its
beneficial effect.
Many tests exist describing the indirect measurement of the activity of HIF via
reporter gene systems (HRE-luciferase) or via the measurement of HIF-induced
proteins (for example VEGF or EPO). Furthermore, the only tests that allow direct
measurement of the amount of HIF1-alpha protein in cells are tests using antibodies,
for instance Western blotting comprising phases of cell extraction (total lysates or
nuclear extracts) that are consuming in terms of cells and time, thus limiting the
compound screening capacity. The object was thus to develop a sensitive screening
test, adaptable to 384-well plates, for directly measuring the amount of HIF1-alpha
protein in the nucleus of cells. This test was established in HEK cells (human
epithelial cells derived from a renal adenocarcinoma).
1.2 Test principle
The test is a cell test based on the principle of enzyme complementation, the
enzyme used herein being beta-galactosidase. HEKEA cells are HEK cells stably
expressing, and restricted in their nucleus, mutant beta-galactosidase (omega
fragment, also known as EA) (line sold by DiscoverX). This construct makes it
possible to obtain beta-galactosidase activity only when the protein comprising the
Prolabel complementation fragment has migrated into the nucleus.
The protein of interest comprising the Prolabel fragment is in this case an HIF1-alpha
or HIF1-alpha mutated at the two prolines 402 and 564 replaced with alanines, is C-
terminal fused via molecular biology (DiscoverX vector sold by Clontech) with the
small complementation peptide fragment (Prolabel or ED, about 4 kDa). The vector
coding for the chimeric protein HIF1-alpha_Prolabel is then transfected into HEKEA
cells to obtain stable clones (HEKEA_HIF1-alphaPLBL).
The amount of C-terminal Prolabel-'labelled" HIF1-alpha protein obtained after
treating the cells to hypoxia or compounds that are potentially HIF activators is
measured by adding to the cells a lysis buffer containing a chemiluminescent
substrate for beta-galactosidase.
The measurement of the beta-galactosidase activity will be proportional to the
amount of Prolabel and thus of HIF1 -alpha that has migrated into the nucleus of the
cells.
Experiments were performed internally in parallel to confirm that the Prolabel
fragment alone was not stable in the cells and thus did not allow any activity to be
measured.
1.3 Protocol
1.3.1 Experiment plan
1) Inoculation of the cells on DO
2) Adherence for 24 hours under normoxia
3) Preparation and addition of the products (Biomek 2000 and FX) on D+1
4) Incubation under normoxia for 6 hours
5) Reading of the plates (by luminescence)
1.3.2 Inoculation of the cells
The cells are inoculated with Multidrop in white, opaque-bottomed 384-well plates
(Greiner ref 3704), in 30 ul of culture medium (1% FCS) at 10 000 cells/well (cell
plate).
1.3.3 Treatment
• Preparation of the dilution plate (DL plate)
The test products are prepared at 3 * 10~2 M in 100% DMSO and then diluted to 3 *
10"4 M in medium containing 0.1% FCS (10 ul in 990 ul of MEM). They are then
deposited by hand into column 12 of a round-bottomed 96-well plate (200 pi of each
compound) known as the dilution plate (dl). The complete DL plate of 3 x 10^ M to
10"9 M is then prepared with Biomek 2000 (programme: range of 10 points in series).
For the references and controls, 100 pi of DMEM containing 0.1% FCS are added to
column 1, 100 pi of Deferoxamine 10"3M to column 2, wells A B C D and 100 pi of
Deferoxamine 5x103 M to column 2, wells E F G H.
• DL plate distribution in cell plates
3.3 pL are taken from the DL plate by pipetting with a Biomek FX 96 and placed in
horizontal duplicate (columns 1 to 24) in each 384-well cell plate (HEKEAJHIF1-
alphaPLBL cell plate).
The cells are then placed for 6 hours in an incubator at 37°C (ambient 02, 6% C02).
1.3.4 Measurement of the beta-palactosidase activity.
The kit used is the Prolabel chemiluminescent kit (Ref 93-0001 DiscoverX).
After incubation for 6 hours at 37°C, the cells are lysed with addition of 15 ul of lysis
buffer containing the beta-galactosidase substrate (19 volumes of Path hunter cell
assay buffer + 5 volumes of Emarald II solution + 1 volume of Galacton star) directly
added to 30 ul of medium in the plate. The plates are incubated for 60 minutes in the
absence of light, before reading the luminescence with a Top Count machine. The
EC50 values for the compounds are then calculated with appropriate fitting software
and given in Table III below.
The activating activity of a compound towards HIF is given by the molar
concentration that produces 50% of the maximum response of this same compound.
TABLE III
1.4 Annex
1.4.1. Maintenance of the HEKEA HIF1-alpha PLBL cells.
The cells are cultured in whole medium (cf. below) in a Flask T225 at 37°C in a C02
incubator.
1.4.2. Culture medium for the HEKEA HIF1 alpha PLBL cells
DMEM 500 mL
+ FCS 10% (GIBCO 10500-056) 50 mL
+ Glutamine (2 mM final) 5 mL
+ Penicilllin + streptomycin (200 mg/ mL) 5 mL
+ Hygromycin B (100 ug/ mL) 1.1 mL
+ Geneticin (400 ug/mL final) 4.4 mL
2. Measurement of the secretion of VEGF and EPO by Hep3B hepatocytes
2.1.Object
HIF is a transcription factor involved in the adaptation of cells to hypoxia. Since the
genes activated by HIF are involved in the adaptive response of cells to hypoxia and
of tissues to ischaemia, the object is to identify and characterize compounds that
stabilize HIF1-alpha in cells in order to amplify or mimic its beneficial effect. HIF1-
alpha was identified following the analysis of the EPO gene promoter, which makes
this protein one of the first markers of HIF1-alpha activation. Moreover, VEGF is also
identified in the literature as one of the main markers of HIF activation. It is for this
reason that measurement of these two proteins was selected for characterizing
compounds that are HIF activators in Hep3B cells.
The object was thus to develop a sensitive screening test, adaptable to 96-well
plates, for directly measuring the amount of VEGF and EPO in the supernatant of the
Hep3B cells (cells derived from a human hepatocarcinoma) in response to the
potential HIF activators.
2.2. Test principle
The test is an ELISA test for measuring VEGF and EPO in the supernatant of Hep3B
cells treated under hypoxia or with deferoxamine as controls or with the potential HIF
activators. The test was adapted to a 96-well plate, allowing greater compound
screening capacity.
2.3. Protocol
2.3.1 Experiment plan
1) Inoculation of the cells on DO
2) Adherence for 6 hours under normoxia
3) Preparation and addition of the products (Biomek 2000 and FX)
4) Incubation under normoxia for 18 hours
5) EPO and VEGF assay in the supernatant on D+1
2.3.2 Inoculation of the cells
The cells are subcultured into 100 pi of culture medium (10% FCS) in black, opaque-
bottomed 96-well plates (reference Costar 3916) at 30 000 cells/well, with Multidrop.
2.3.3 Treatment of the cells
• Preparation of the dilution plate (DL plate)
The test products are prepared at 10"2 M in 100% DMSO and then diluted to 3 x
10 4M in medium containing 0.1% FCS (6 pi in 194 pi of MEM). 200 pi of each
compound are deposited in column 12 of a 96-well plate. Dilution ranges from
3x1 O^M to 3x10"8M are prepared with Biomek 2000 (programme: range of 9 points in
series).100 pi of MEM 0.1% FCS and Deferoxamine 5x10"3M are added as controls
to column 3 and, respectively, to wells A,B,C,D and wells E,F,G,H
• DL plate distribution in cell plates
The medium of the cells inoculated the day before into 96-well plates is changed for
90 pi of medium containing 0.1% FCS and 10 pi are distributed with FX 96 from the
96-well DL plates to the cell plates.
The cell plates thus treated are placed for 18 hours in an incubator at 37°C (ambient
02, 6% C02).
2.3.4 EPO and VEGF assay
The supernatants (80 pi) of the Hep3B cells in the 96-well plates treated with the
potential HIF activators are recovered with a multichannel pipette for simultaneous
assay of the VEGF and the EPO by ELISA according to the supplier's instructions
(Kit EPO Mesoscale (ref K15122B-2)). The EC50 values for EPO and VEGF of the
compounds are then calculated with appropriate fitting software and reported in
Table IV below.
2.4. Annex
Culture medium for the Hep3B cells:
MEM + Earles (GIBCO 310095) 500 mL
+ 10% FCS (GIBCO 10500-056) 50 mL
+ Glutamine 2 mM final 5 mL
+ 1% non-essential amino acids 5 mL
3. Results
The activating activity of a compound with respect to HIF is given by the
concentration that produces 50% of the maximum response of this same compound
in Table IV below.
TABLE IV
The compounds according to the invention may thus be used for the preparation of
medicaments, in particular medicaments that are activators of the HIF transcription
factor.
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 of the compound of formula (I).
The invention also relates to a pharmaceutical composition comprising a compound
of formula (I) according to the present invention, or a pharmaceutically acceptable
salt of this compound, and also at least one pharmaceutically acceptable excipient.
These medicaments find their therapeutic use especially in treatment/prophylaxis, in
particular of cardiovascular diseases, ischaemia of the lower limbs, cardiac
insufficiency, coronary diseases of ischaemic origin, for instance angina pectoris or
myocardial infarction, arteriosclerosis, strokes of ischaemic origin, pulmonary
hypertension and any pathology caused by partial or total vascular occlusion in man
and animals.
These medicaments also find their therapeutic use in the treatment/prophylaxis of
glaucoma, renal diseases or in cerebral diseases of neurodegenerative origin or
otherwise, and anaemia, or a medicament for promoting cicatrization or agents for
shortening the post-operative convalescence period or a medicament for treating
general fatigue conditions, or a medicament used for the purpose of obtaining blood
in the context of autotransfusions necessary following major surgical interventions
such as cranial or chest surgery, or cardiac, carotid or aortic operations.
These compounds find their therapeutic use especially in the treatment/prophylaxis
of anaemia.
These compounds may also be used in man and animals for the purpose of
obtaining blood in the context of autotransfusions necessary following major surgical
interventions such as cranial or chest surgery or cardiac, carotid or aortic operations.
These compounds are potentially usable in man and animals as agents for
promoting cicatrization or agents for shortening the post-operative convalescence
period.
These compounds are potentially usable in man and animals in the treatment of
general fatigue conditions ranging up to cachexia appearing in particular in the
elderly.
These compounds are potentially usable in man and animals in the treatment of
glaucoma, renal diseases or cerebral diseases of neurodegenerative origin or
otherwise.
Finally, the compounds described in the invention are potentially usable in man and
animals for treating cardiac or peripheral diseases of ischaemic origin via
regenerative medicine in autologous and heterologous approaches using non-
embryonic stem cells or myoblastic cells for therapeutic purposes, whether as
treatment of these cells before administration or as treatment simultaneously with the
local administration of these cells.
Moreover, the compounds described in the invention may be used, alone or, if
necessary, in combination with one or more other active compounds that are useful
in the treatment of hypertension, cardiac insufficiency, diabetes and anaemia.
For example, mention may be made of the combination of a compound according to
the invention with one or more compounds chosen from converting enzyme
inhibitors, angiotensin II receptor antagonists, beta-blockers, mineralocorticoid
receptor antagonists, diuretics, calcium antagonists, statins and digitalin derivatives.
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 administration, from the usual excipients known to those skilled in
the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active principle of formula (I) above, or the
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 disorders or diseases.
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, nasal and 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
Sodium croscarmellose 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 do not depart from the scope of the invention. According to the usual
practice, the dosage that is appropriate to 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
patient, of an effective dose of a compound according to the invention, or a
pharmaceutically acceptable salt thereof.
CLAIMS
1. Compound corresponding to formula (I) below:

in which
R represents a group -S02-NR3R4, a hydrogen atom, a halogen atom, a group
-halo(C1-C5)alkyl, a group -C02R5 or a group -S02-R4; R3, R4 and R5 being as defined
below;
R1 represents a heterocycloalkyl group not containing a nitrogen atom, a group
-W-(C3-C6)cycloalkyl, a group -W-aryl, a group -W-heteroaryl, a group -W-
heterocycloalkyl, a group -W-COOR5 or a group -W-CONR5R6,
(iii) the said aryl, heteroaryl and heterocycloalkyl groups being optionally
substituted on at least one carbon atom with at least one substituent chosen
from halogen atoms, groups (C1-C5)alkyl, groups -(C1-C5)alkylene-0-(C1-
C5)alkyl, groups -(C1-C5)alkoxy, a hydroxy! function, groups -halo(C1-
C5)alkyl, a cyano function, groups -0(C1-C5)alkylene-0-(C1-C5)alkyl, groups
-0-(C1-C5)alkylene-NR5R6 groups -S02-(C1-C5)alkyl, groups -NR5R6 and
groups -C02R5, and
(iv) it being understood that when it is a heterocycloalkyl group, the said group
comprising at least one nitrogen atom, this atom may optionally bear a
substituent chosen from groups (C1-C5)alkyl,
R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-C5)alkylene-
0-(C1-C5)alkyl, a group -halo(C1-C5)alkyl, a group -W-COOR5, a group -W-C(0)NHR5
or a group -W-C(0)-NR5R6; W, R5 and R6 being as defined below;
it being understood that:
o n represents 0, 1 or 2;
o Wis
(iii) a group -(C1-C5)alkylene-, optionally substituted with a group chosen from
groups -(CH2)n-C02R5 and groups -(CH2)n-(CO)NR5R6, with n as defined above
and R5 and R6 as defined below; or
(iv) a group -(C3-C6)cycloalkylene-,
o R3 and R4
(iii) which may be identical or different, represent, independently of each other, a
hydrogen atom, a group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, a group -(C1-
C5)alkylene-0-(C1-C5)alkyl, an aryl, a group -CH2-aryl, a heteroaryl, a
heterocycloalkyl, a group -W-OH, a group -W-CHOH-CH2OH, a group -W-C02R5,
a group -W-NR5R6 or a group -W-0-(CH2)n-aryl;
the said groups -(C3-C6)cycloalkyl and heterocycloalkyl being optionally
substituted
o on at least one carbon atom with at least one group chosen from -(C1-
C5)alkyl, a group -(C1-C5)alkoxy, a hydroxyl function, a group -W-
NR5R6 and a group -W-C02R5, in the case of the groups -(C3-
C6)cycloalkyl and heterocycloalkyl and/or
o on at least one heteroatom chosen from nitrogen with at least one
group chosen from -(C1-C5)alkyl in the case of a heterocycloalkyl
group,
with W and n as defined previously and R5 and R6 as defined below and it being
understood that when R3 and R4 are identical, they cannot be a hydrogen atom;
(iv) or alternatively R3 and R4 form, together with the nitrogen atom that bears
them, a heterocycloalkyl group, optionally substituted on at least one carbon atom
and/or, where appropriate, on at least one heteroatom, with at least one
substituent chosen from groups -(C1-C5)alkyl and groups -CH2-aryl;
o R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl,
in the form of the base or an acid-addition salt,
with the exclusion of the following compounds:
• 4-benzyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(2,4-dichlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(4-methoxybenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(4-bromobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 2-(pyridin-2-yl)-4-[2-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one
• 4-(4-chlorobenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(1,3-benzodioxol-5-ylmethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(3-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
_•. _Jh(2=ctiloxQbenz.yl)-ii-(pyndin-iJ=yL)- i^a iftyd co-abUpyrazoU3rO ne__
• 4-(4-methylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-(3-chlorobenzyl)-2-(pyridin-2-yi)-1,2-dihydro-3H-pyrazol-3-one
• 4-(4-tert-butylbenzyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-benzyl-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 5-methyl-4-(1-phenylethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one
• 4-benzyl-2-(6-chloropyridin-2-yl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one
• 4-{1-[4-(diethylamino)phenyl]ethyl}-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one.
2. Compound corresponding to formula (I) according to Claim 1, characterized in that:
R represents a group -S02-NR3R4, a hydrogen atom, a halogen atom, a group
-halo(C1-C5)alkyl, a group -C02R5 or a group -S02-R4; R3, R4 and R5 being as defined
below;
and/or
R1 represents a heterocycloalkyl group not containing a nitrogen atom, a group
-W-(C3-C6)cycloalkyl, a group -W-aryl, a group -W-heteroaryl, a group -W-
heterocycloalkyl, a group -W-COOR5 or a group -W-CONR5R6,
(ii) the said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on
at least one carbon atom with at least one substituent chosen from halogen atoms,
groups (C1-C5)alkyl, groups -(C1-C5)alkylene-0-(C1-C5)alkyl, groups -(C1-
C5)alkoxy, a hydroxy! function, groups -halo(C1-C5)alkyl, a cyano function, groups
-0(C1-C5)alkylene-0-(C1-C5)alkyl, groups -0-(C1-C5)alkylene-NR5R6, groups
-S02-(C1-C5)alkyl, groups -NR5R6 and groups -C02R5, and
(ii) it being understood that when it is a heterocycloalkyl group, the said group
comprising at least one nitrogen atom, this atom may optionally bear a substituent
chosen from groups (C1-C5)alkyl,
and/or
R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-C5)alkylene-
0-(C1-C5)alkyl, a group -halo(C1-C5)alkyl, a group -W-COOR5, a group -W-C(0)NHR5
or a group -W-C(0)-NR5R6; W, R5 and R6 being as defined below;
and/or
n represents 0, 1 or 2;
and/or
Wis
(iii) a group -(C1-C5)alkylene-, optionally substituted with a group chosen from
groups -(CH2)n-C02R5 and groups -(CH2)n-(CO)NR5R6, with n as defined
above and R5 and R6 as defined below; or
(iv) a group -(C3-C6)cycloalkylene-,
and/or
R3 and R4
(iii) which may be identical or different, represent, independently of each other,
a hydrogen atom, a group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, a
group -(C1-C5)alkylene-0-(C1-C5)alkyl, an aryl, a group -CH2-aryl, a
heteroaryl, a heterocycloalkyl, a group -W-OH, a group -W-CHOH-CH2OH,
a group -W-C02R5, a group -W-NR5R6 or a group -W-0-(CH2)n-aryl;
the said groups -(C3-C6)cycloalkyl and heterocycloalkyl being optionally
substituted
o on at least one carbon atom with at least one group chosen from -(C1-
C5)alkyl, a group -(C1-C5)alkoxy, a hydroxyl function, a group -W-
NR5R6 and a group -W-C02R5, in the case of the groups -(C3-
C6)cycloalkyl and heterocycloalkyl and/or
o on at least one heteroatom chosen from nitrogen with at least one
group chosen from -(C1-C5)alkyl, in the case of a heterocycloalkyl
group,
with W and n as defined previously and R5 and R6 as defined below and it being
understood that when R3 and R4 are identical, they cannot be a hydrogen atom;
(iv) or alternatively R3 and R4 form, together with the nitrogen atom that bears
them, a heterocycloalkyl group, optionally substituted on at least one
carbon atom and/or, where appropriate, on at least one heteroatom, with
at least one substituent chosen from groups -(C1-C5)alkyl and groups
-CH2-aryl;
and/or
R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl.
3. Compound of formula (I) according to either of Claims 1 and 2, characterized in that R
represents a group -S02-NR3R4, a group -halo(C1-C5)alkyl, a group -C02R5 or a group
-S02-R4 with R3, R4 and R5 as defined in Claim 1.
4. Compound of formula (I) according to any one of Claims 1 to 3, characterized in that R
represents a group -S02-NR3R4 or -C02R5 with R3 and R4 as defined in Claim 1.
5. Compound of formula (I) according to any one of Claims 1 to 3, characterized in that R
represents a hydrogen atom, a halogen atom, a group -halo(C1-C5)alkyl, a group -C02R5
or a group -S02-R4 with R4 and R5 as defined in Claim 1.
6. Compound of formula (I) according to any one of Claims 1 to 5, characterized in that R
is a substituent of the atom in the |3 position of pyridine.
7. Compound of formula (I) according to any one of Claims 1 to 6, characterized in that
R1 represents a heterocycloalkyl group not containing a nitrogen atom, a group -W-(C3-
C6)cycloalkyl, a group -W-aryl, a group -W-heteroaryl, a group -W-heterocycloalkyl, a
group -W-COOR5 or a group -W-CONR5R6,
the said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted
on at least one carbon atom with at least one substituent chosen from halogen atoms,
groups (C1-C5)alkyl, groups -(C1-C5)alkylene-0-(C1-C5)alkyl, groups -(C1-C5)alkoxy, a
hydroxyl function, groups -halo(C1-C5)alkyl, a cyano function, groups -0(C1-C5)alkylene-
0-(C1-C5)alkyl, groups -0-(C1-C5)alkylene-NR5R6, groups -S02-(C1-C5)alkyl, groups
-NR5R6 and groups -C02R5, and
it being understood that when it is a heterocycloalkyl group, the said group
comprising at least one nitrogen atom, this atom may optionally bear a substituent
chosen from groups (C1-C5)alkyl,
in which W is a group (C1-C5)alkylene or a group (C3-C6)cycloalkylene and in
which R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl.
8. Compound of formula (I) according to Claim 7, characterized in that the said
heterocycloalkyl group represents a piperidyl group, the said aryl group represents a
phenyl group and the said heteroaryl group represents a pyridyl group.
9. Compound of formula (I) according to any one of Claims 1 to 8, characterized in that
R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-C5)alkylene-0-(C1-
C5)alkyl, a group -halo(C1-C5)alkyl, a group -W-COOR5, a group -W-C(0)NHR5 or a
group -W-C(0)-NR5R6 in which W, R5 and R6 are as defined in Claim 1.
10. Compound of formula (I) according to any one of Claims 1 to 4 and 6 to 8,
characterized in that R represents a group -S02-NR3R4, advantageously in the B position
of pyridine, and in which R3 and R4, which may be identical or different, represent,
independently of each other, a hydrogen atom, a group -(C1-C5)alkyl, a group -(C3-
C6)cycloalkyl, a group -(C1-C5)alkylene-0-(C1-C5)alkyl, an aryl, a group -CH2-aryl, a
heteroaryl, a heterocycloalkyl, a group -W-OH, a group -W-CHOH-CH2OH, a group -W-
C02R5, a group -W-NR5R6 or a group -W-0-(CH2)n-aryl;
it being understood that:
when R3 and R4 are identical, they cannot be a hydrogen atom; and that
when R3 and/or R4 are chosen from the said groups -(C3-C6)cycloalkyl and
heterocycloalkyl, these groups may be optionally substituted
o on at least one carbon atom, with at least one group chosen from
-(C1-C5)alkyl, a group -(C1-C5)alkoxy, a hydroxyl function, a group
-W-NR5R6 and a group -W-C02R5, in the case of the groups -(C3-
C6)cycloalkyl and heterocycloalkyl, and/or
o on at least one heteroatom chosen from nitrogen with at least one
group chosen from -(C1-C5)alkyl, in the case of a heterocycloalkyl
group,
in which W, R5 and R6 are as defined according to Claim 1 and in which n represents 0,
1 or 2.
11. Compound of formula (I) according to Claim 10, characterized in that the said
heterocycloalkyl group represents a piperidyl group, the said aryl group represents a
phenyl group and the said heteroaryl group represents a pyridyl group.
12. Compound of formula (I) according to any one of Claims 1 to 4 and 6 to 8,
characterized in that R represents a group -S02-NR3R4, advantageously in the p position
of pyridine, and in which R3 and R4 form, together with the nitrogen atom that bears
them, a heterocycloalkyl group, optionally substituted on at least one carbon atom and/or,
where appropriate, on at least one heteroatom, with at least one substituent chosen from
groups -(C1-C5)alky! and groups -CH2-aryl.
13. Compound of formula (I) according to Claim 12, characterized in that the said
heterocycloalkyl group represents a group chosen from piperidyl, piperazinyl,
morpholinyl, pyrrolidinyl and hexamethyleneimino groups, and the said aryl group
represents a phenyl group.
14. Compound of formula (I) according to any one of Claims 1 to 13, characterized in that
the group(s) R, R1 and/or R2 comprise the group(s) R5 and/or R6,
R5 or R6 is a hydrogen atom, a group -(P.l-P.fijalkyl nr a group -(C1.C5)haloalkyl,
R5 and R6, which may be identical or different, represent, independently of each
other, a hydrogen atom, a group -(C1-C5)alkyl or a group -(C1-C5)haloalkyl.
15. Compound of formula (I) according to Claim 14, characterized in that R5 and/or R6
are chosen from groups (C1-C5)alkyl.
16. Compound of formula (I) according to any one of Claims 1 to 14, characterized in that
R represents a group -S02-NR3R4 or a hydrogen atom with R3 and R4 as defined in
Claim 1 and/or R2 represents a hydrogen atom or a group -(C1-C5)alkyl, advantageously
a methyl, and/or R1 represents a group -W-aryl or a group -W-heteroaryl, advantageously
with the said W representing a -CH2-, the said aryl representing a phenyl and the said
heteroaryl representing a pyridine.
7. Compound of formula (I) according to any one of Claims 1 to 16, characterized in that
4-(2-chlorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-one;
6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]pyridine-3-carboxylic acid;
4-(2-chlorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-(2-chlorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2-dihydro-
3H-pyrazol-3-onetrifluoroacetate;
(±)4-(2-chlorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-5-methyl-
1,2-dihydro-3H-pyrazol-3-one;
6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-diethylpyridine-3-
sulfonamide;
6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N,N-di(propan-2-yl)-
pyridine-3-sulfonamide;
4-(2-chlorobenzyl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-
one;
N,N-diethyl-6-[4-(2-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
4-(2-fluorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-(2-fluorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-one;
4-(2-fluorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2-dihydro-3H-
pyrazol-3-one trifluoroacetate;
2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-4-(2-fluorobenzyl)-5-methyl-1,2-
dihydro-3H-pyrazol-3-one;
N-ethyl-6-[4-(2-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N-phenylpyridine-3-
sulfonamide;
4-(2-fluorobenzyI)-5-methyl-2-[5-(piperidin-1-yisulfonyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-
one;
4-(2,4-dichlorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-(2,4-dichlorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-
one;
4-(2,4-dichlorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)suIfonyl]pyridin-2-yl}-1,2-
dihydro-3H-pyrazol-3-onetrifluoroacetate;
4-(2,4-dichlorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-5-methyl-
1,2-dihydro-3H-pyrazol-3-one;
6-[4-(2,4-dichlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl
-N-phenylpyridine-3-sulfonamide;
6-[4-(2,4-dichlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-di(propan-2-
yl)pyridine-3-sulfonamide;
4-(2,4-dichlorobenzyl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one;
4-(2-chloro-6-fluorobenzyl)-5-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-
3-one;
4-(2-chloro-6-fluorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2-
dihydro-3H-pyrazol-3-onetrifluoroacetate;
4-(2-chloro-6-fluorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyi}pyridin-2-yl)-5-
methyl-1,2-dihydro-3H-pyrazol-3-one;
6-[4-(2-chloro-6-fiuorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-diethyl-
pyridine-3-sulfonamide;
6-[4-(2-chloro-6-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-
phenylpyridine-3-sulfonamide;
6-[4-(2-chloro-6-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-di(propan-2-
yl)pyridine-3-sulfonamide;
4-(2-chloro-6-fluorobenzyl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one;
methyl 6-[4-(2-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
carboxylate;
4-(4-chlorobenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-(4-chlorobenzyl)-5-methyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2-dihydro-
3H-pyrazol-3-one;
4-(4-chlorobenzyl)-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-5-methyl-1,2-
dihydro-3H-pyrazol-3-one;
6-[4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-diethylpyridine-3-
sulfonamide;
6-[4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
6-[4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-di(propan-2-
yl)pyridine-3-sulfonamide;
4-(4-chlorobenzyl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-
one;
6-[4-(2-fluorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-di(propan-2-yl)pyridine-
3-sulfonamide;
4-(1,1-dioxidotetrahydrothiophen-3-yl)-5-methyl-2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,2-
dihydro-3H-pyrazol-3-one;
6-[4-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-
N-phenylpyridine-3-sulfonamide;
6-[4-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N,N-
di(propan-2-yl)pyridine-3-sulfonamide;
2-{[5-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]methyl}benzonitrile;
4-{[5-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]methyl}benzonitrile;
m___N-ethyl-6-{4-[4-(methoxymethyl)benzyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl}- N-----------
^henylpyrldine^slirfonamicle;
• 4-[3-(methoxymethyl)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-{4-[3-(methoxymethyl)benzyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)~N-
phenylpyridine-3-sulfonamide;
• 6-[4-(3-cyanobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
• 6-[4-(4-cyanobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
• 5-methyl-2-(pyridin-2-yl)-4-(pyridin-4-ylmethyl)-1,2-dihydro-3H-pyrazol-3-one;
• 3-{[5-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]methyl}benzonitrile;
• 4-benzyl-2-(5-bromopyridin-2-yl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one;
• 6-[4-(2-cyanobenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
• N-ethyl-6-{4-[3-(2-methoxyethoxy)benzyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl}-N-
phenylpyridine-3-sulfonamide;
• 4-(3,5-dimethoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 5-methyl-4-[4-(methylsulfonyl)benzyl]-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-{3-methyl-4-[4-(methylsulfonyl)benzyl]-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl}-N-
phenylpyridine-3-sulfonamide;
• 4-[3-(2-methoxyethoxy)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 4-benzyl-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]-N-phenyl-
pyridine-3-sulfonamide;
• N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-2-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]-N-phenyl-
pyridine-3-sulfonamide;
• 5-methyl-2-(pyridin-2-yl)-4-(pyridin-3-ylmethyl)-1,2-dihydro-3H-pyrazol-3-one;
• 6-(4-benzyl-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-ethyl-N-phenylpyridine-3-
sulfonamide;
• N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]-N-phenyl-
pyridine-3-sulfonamide;
• 4-(2,5-dimethoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
• 6-[4-(2,5-dimethoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N-ethyl-N-phenyl-
pyridine-3-sulfonamide;
• N-ethyl-6-{3-methyl-4-[(1-methylpiperidin-4-yl)methyl]-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-
phenylpyridine-3-sulfonamide;
• N-ethyl-6-{3-methyl-5-oxo-4-[4-(trifluoromethyl)benzyl]-2,5-dihydro-1 H-pyrazol-1 -yl}-N-
phenylpyridine-3-sulfonamide;
• N-ethyl-6-{3-methyl-5-oxo-4-[3-(trifluoromethyl)benzyl]-2,5-dihydro-1 H-pyrazol-1 -yl}-N-
phenylpyridine-3-sulfonamide;
• 5-methyl-2-(pyridin-2-yl)-4-[3-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one;
• 5-methyl-2-(pyridin-2-yl)-4-[4-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one;
• 6-[4-(3,5-dimethoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N-ethyl-N-phenyl-
pyridine-3-sulfonamide;
• 4-(4-hydroxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-[4-(4-hydroxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-phenylpyridine-
3-sulfonamide;
6-(4-{4-[2-(dimethylamino)ethoxy]benzyl}-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-
ethyl-N-phenyipyridine-3-sulfonamide;
6-{4-[4-(dimethylamino)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-ethyl-N-
phenylpyridine-3-sulfonamide;
5-methyl-2-(pyridin-2-yl)-4-[2-(trifluoromethyl)benzyl]-1,2-dihydro-3H-pyrazol-3-one;
4-[4-(dimethylamino)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-{3-methyl-5-oxo-4-[2-(trifluoromethyl)benzyl]-2,5-dihydro-1H-pyrazol-1-yl}-N-
phenylpyridine-3-sulfonamide;
6-(4-benzyl-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-(3-methylbutyl)pyridine-3-
sulfonamide;
4-[3-(dimethylamino)benzyl]-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
6-{4-[3-(dimethylamino)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-ethyl-N-
phenylpyridine-3-sulfonamide;
4-(4-methoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-[4-(4-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-phenyl-
pyridine-3-sulfonamide;
4-(2-methoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-(3-methoxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-[4-(3-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-phenyl-
pyridine-3-sulfonamide;
6-(4-{3-[2-(dimethylamino)ethoxy]benzyl}-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-
ethyl-N-phenylpyridine-3-sulfonamide;
N-ethyl-6-[4-(2-methoxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-phenyl-
pyridine-3-sulfonamide;
4-benzyl-5-methyl-2-[5-(morpholin-4-ylsuIfonyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-[4-(3-hydroxybenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-phenylpyridine-
3-sulfonamide;
6-(4-benzyl-3-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-
sulfonamide;
4-(3-hydroxybenzyl)-5-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-ethyl-6-{4-[4-(2-methoxyethoxy)benzyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-
phenylpyridine-3-sulfonamide;
4-benzyl-5-ethyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
4-benzyl-5-methyl-2-[5-(pyrrolidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazol-3-one;
2-[5-(azepan-1-ylsulfonyl)pyridin-2-yl]-4-benzyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one;
N,N-diethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
N,N-diethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide hydrochloride;
N,N-dimethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
N,N-dimethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide hydrochloride;
6-(4-benzyl-5-oxo-3-propyl-2,5-dihydro-1H-pyrazol-1-yl)-N-ethyl-N-phenylpyridine-3-
sulfonamide hydrochloride;
6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-(propan 2-yQpyridine-
^sulfonamiclehydrocfrloricte;
5-methyl-4-(pyridin-3-ylmethyl)-2-[5-(pyrrolidin-1-ylsulfonyl)pyridin-2-yl]-1,2-dihydro-3H-
pyrazol-3-one hydrochloride;
N-tert-butyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide hydrochloride;
N-cyclopropyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide hydrochloride;
N-cyclopentyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide hydrochloride;
N-ethyl-6-[3-methyl-5-oxo-4-(2-phenylethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-phenylpyridine-3-
sulfonamide;
5-methyl-4-(2-phenylethyl)-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one;
N-methyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-(pyridin-2-
yl)pyridine-3-sulfonamide hydrochloride;
2-{5-[(4-benzylpiperidin-1-yl)sulfonyl]pyridin-2-yl}-5-methyl-4-(pyridin-3-ylmethyl)-1,2-dihydro-
3H-pyrazol-3-one;
N-ethyl-6-[3-methyl-5-oxo-4-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrazol-1-yl]-N-phenyl-
pyridine-3-sulfonamide;
N-ethyl-6-{4-[(6-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-
phenylpyridine-3-sulfonamide;
6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-(pyridin-2-yl)pyridine-
3-sulfonamide hydrochloride;
N-ethyl-6-[3-methyl-5-oxo-4-(1 -phenylcyclopropyl)-2,5-dihydro-1 H-pyrazol-1 -yl]-N-phenyl-
pyridine-3-sulfonamide;
N-ethyl-6-{4-[(3-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-
phenylpyridine-3-sulfonamide hydrochloride;
6-[4-benzyl-3-(methoxymethyl)-5-oxo-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-
3-sulfonamide;
6-[4-benzyl-5-oxo-3-(trifluoromethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
1-[5-(azepan-1-ylsulfonyl)pyridin-2-yl]-3-methyl-4-(pyridin-3-ylmethyl)-1H-pyrazol-5-olate;
N-ethyl-6-{3-methyl-5-oxo-4-[2-(pyridin-2-yl)ethyl]-2,5-dihydro-1H-pyrazol-1-yl}-N-phenyl-
pyridine-3-sulfonamide;
N-ethyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yr}-N-
phenylpyridine-3-sulfonamide;
N-(2-methoxyethyl)-N-methyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-
1-yl]pyridine-3-sulfonamide;
6-[4-benzyl-3-(2-methylpropyl)-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
N-ethyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyI)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]-N-phenylpyridine-3-
sulfonamide;
N-ethyl-6-[3-methyl-5-oxo-4-(3-phenylpropyl)-2,5-dihydro-1 H-pyrazol-1 -yl]-N-phenylpyridine-3-
sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazoI-1-yl)-N-ethyl-N-phenylpyridine-3-sulfonamide;
N-cyclopropyl-N-methyl-6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-
yl]pyridine-3-sulfonamide;
N-tert-butyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-
yl}pyridine-3-sulfonamide;
6-{4-[(5-cyanopyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl}-N-ethyl-N-
phenylpyridine-3-sulfonamide;
tert-butyl 6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]pyridine-3-carboxylate;
tert-butyl 6-[3-methyl-5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]pyridine-3-
carboxylate;
N-tert-butyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-yl]pyridine-3-
sulfonamide;
N-tert-butyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-yl]pyridine-3-sulfonamide
hydrochloride;
N-ethyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-yl]-N-phenylpyridine-3-
sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl)-N-tert-butyl-N-methylpyridine-3-sulfonamide;
N-ethyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-N-phenyl-
pyridine-3-sulfonamide;
5-methyl-2-[5-(phenylsulfonyl)pyridin-2-yl]-4-(pyridin-3-ylmethyl)-1,2-dihydro-3H-pyrazol-3-
one;
N-tert-butyl-6-{4-[(5-methoxypyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-
N-methylpyridine-3-sulfonamide;
6-{4-[(6-cyanopyridin-3-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-N-ethyl-N-
phenylpyridine-3-sulfonamide;
(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)aceticacid;
2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-N,N-dimethyl-
acetamide;
methyl (2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetate;
ethyl (4-benzyl-1-{5-[ethyI(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-2,5-dihydro-1H-pyrazol-3-
yl)acetate;
2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-N-methyl-
acetamide;
N-tert-butyl-6-{4-[(5-methoxypyridin-2-yl)methyl]-3-methyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl}-
N-methylpyridine-3-sulfonamide;
2-(4-benzyl-1-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-N,N-
dimethylacetamide;
3-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)propanoicacid;
methyl 3-[(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-
yl)methyl]benzoate;
methyl 3-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-
propanoate;
methyl {2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}(phenyl)-
acetate;
methyl 2-[(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-
yl)methyl]benzoate;
N-cyclopentyl-N-ethyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
N-cyclopentyl-N-methyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
2-[(1-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-methyl-5-oxido-1H-pyrazol-4-yl)methyl]-
benzoate;
2-[5-(azepan-1-ylsulfonyl)pyridin-2-yl]-4-(pyridin-3-ylmethyl)-1,2-dihydro-3H-pyrazol-3-one;
N-cyclopentyl-N-methyl-6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
N-cyclopentyl-N-ethyl-6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
methyl 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-
3-phenylpropanoate;
N-(2,2-dimethylpropyl)-N-methyl-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
2,2-dimethylprnpylfi-[fi-nYn^-(pyriHin-3-ylmfithyl)-?,.ci-Hihyrirn-1H-pyra2ol-1-yl]pyridine-3--------
xarboxylate,
methyl N-cyclopentyl-N-({6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]pyridin-3-
yl}sulfonyl)glycinate;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-[2-(benzyloxy)ethyl]-N-cyclopentylpyridine-
3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-[3-(benzyloxy)propyl]-N-cyclopentylpyridine-
3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-(3-hydroxypropyl)pyridine-3-
sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl)-N-cyclopentyl-N-(2-hydroxyethyl)pyridine-3-
sulfonamide;
methyl (1 S,2R)-2-[methyl({6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-yl]pyridin-
3-yl}sulfonyl)amino]cyclopentanecarboxylate;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-(2,3-dihydroxypropyl)pyridine-
3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl)-N-cyclopentyl-N-[2-(dimethylamino)ethyl]-
pyridine-3-sulfonamide;
4-benzyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1,2-dihydro-3H-pyrazol-3-one;
6-[4-(cyclopentylmethyl)-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl]-N-ethyl-N-phenylpyridine-3-
sulfonamide;
4-benzyl-2-{5-[(4-methyl-1,4-diazepan-1 -yl)sulfonyl]pyridin-2-yl}-1,2-dihydro-3H-pyrazol-3-
one;
N-(2,2-dimethylpropyl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
N-(2-methylbutan-2-yl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-yl]pyridine-3-
sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-[(1 R,3S)-3-(hydroxymethyl)yclopentyl]-N-
methylpyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl)-N-methyl-N-(1-methylpyrrolidin-3-yl)pyridine-3-
sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-(2-methoxy-2-methylpropyl)pyridine-3-
sulfonamide;
2,2-dimethylpropyl 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)pyridine-3-carboxylate;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl)-N-cyclopentyl-N-[(2R)-2,3-dihydroxypropyl]-
pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl)-N-(2,3-dihydroxypropyl)-N-phenylpyridine-3-
sulfonamide;
N-cyclopentyl-6-{4-[(4-methoxypyridin-3-yl)methyl]-5-oxo-2,5-dihydro-1 H-pyrazol-1-yl}-N-
methylpyridine-3-sulfonamide;
N-methyl-N-(2-methylbutan-2-yl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1H-pyrazol-1-
yl]pyridine-3-sulfonamide;
3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-
phenyl-N-(2,2,2-trifluoroethyl)propanamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-cyclopentyl-N-[3-hydroxy-2-
(hydroxymethyl)propyl]pyridine-3-sulfonamide;
6-(4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-N-cyclopentyl-N-[(2S)-2,3-dihydroxypropyl]-
pyridine-3-sulfonamide;
2,2-dimethylpropyl 6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1 H-pyrazol-1 -yl]pyridine-3-
carboxylate;
6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-[(1 S,2S)-2-hydroxycyclopentyl]pyridine-3-
sulfonamide;
N-tert-butyl-6-[5-oxo-4-(pyridin-4-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-yl]pyridine-3-
sulfonamide;
4-benzyl-2-(5-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}pyridin-2-yl)-1,2-dihydro-3H-
pyrazol-3-one;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-[1 -(dimethylamino)-2-methylpropan-2-
yl]py ridi ne-3-su Ifonam ide;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-methyl-N-phenylpyridine-3-sulfonamide;
• methyl 3-{2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-3-(pyridin-
3-yl)propanoate;
• ethyl 3-{2-[5-(tert-butylsulfamoyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1 H-pyrazol-4-yl}-3-phenyl-
propanoate;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-tert-butyl-N-(2,3-dihydroxypropyl)pyridine-3-
sulfonamide;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-(2-hydroxyethyl)pyridine-3-sulfonamide;
• N-(2,3-dihydroxypropyl)-6-[5-oxo-4-(pyridin-3-ylmethyl)-2,5-dihydro-1 H-pyrazol-1-yl]-N-phenyl-
pyridine-3-sulfonamide hydrochloride;
• methyl 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1 H-pyrazol-4-yl)-
3-(pyridin-3-yl)propanoate hydrochloride;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-cyclopentyl-N-[3-(dimethylamino)propyl]-
pyridine-3-sulfonamide hydrochloride;
• 6-(4-benzyl-5-oxo-2,5-dihydro-1 H-pyrazol-1 -yl)-N-cyclopentyl-N-[3-(dimethylamino)propyl]-
pyridine-3-sulfonamide hydrochloride.
18. Process for preparing a compound of formula (I) according to any one of Claims 1 to
17, characterized in that a compound of formula (II)

(II)
in which R1 and R2 are as defined in Claim 1 and z represents an alkyl group,
is reacted with a compound of formula (III)
(III)
in which R is as defined in Claim 1.
19. Medicament, characterized in that it comprises a compound of formula (I) according
to any one of Claims 1 to 17, or an addition salt of this compound with a pharmaceutically
acceptable acid of the compound of formula (I).
20- PharmarPi itjnaj rnrnpnsitinn, r.harartpri7Pri in that it comprises a compound of
formula (I) according to any one of Claims 1 to 17, or a pharmaceutical^ acceptable salt
of this compound, and also at least one pharmaceutical^ acceptable excipient.
21. Use of a compound of formula (I) according to any one of Claims 1 to 17, for the
preparation of a medicament for the treatment/prophylaxis of cardiovascular diseases.
22. Use of a compound of formula (I) according to any one of Claims 1 to 17, for the
preparation of a medicament for the treatment/prophylaxis of ischaemia of the lower
limbs, cardiac insufficiency, coronary diseases of ischaemic origin, for instance angina
pectoris or myocardial infarction, arteriosclerosis, strokes of ischaemic origin, pulmonary
hypertension and any pathology caused by partial or total vascular occlusion.
23. Use of a compound of formula (I) according to any one of Claims 1 to 17, for the
preparation of a medicament for the treatment/prophylaxis of glaucoma, renal diseases or
cerebral diseases of neurodegenerative origin or otherwise, anaemia, or a medicament
for promoting cicatrization, or agents for shortening the post-operative convalescence
period, or a medicament for treating general fatigue conditions, or alternatively a
medicament used for the purpose of obtaining blood in the context of autotransfusions
necessary following major surgical interventions such as cranial or chest surgery, or
heart, carotid or aortic operations.
24. Use of a compound of formula (I) according to any one of Claims 1 to 17, for the
preparation of a medicament for the treatment/prophylaxis of cardiac or peripheral
diseases of ischaemic origin via regenerative medicine using stem cells.
25. Combination of a compound of formula (I) according to any one of Claims 1 to 17 with
one or more active compound(s) that is (are) useful in the treatment of hypertension,
cardiac insufficiency, diabetes and anaemia.
26. Uniform test process for the direct measurement by beta-galactosidase
complementation of the amount of HIF1-alpha protein in the nuclei of cells, preferably
HEK cells, after treating the said cells with one or more of the test compounds, which
consists in:
(a) inoculating the said cells in a suitable culture medium;
(b) adding the test compound(s) at a suitable concentration in a suitable solvent to the
cells previously inoculated in the said culture medium;
(c) incubating the said cells thus prepared in an incubator at about 37°C,
advantageously for about 6 hours;
(d) lysing the cells with a lysis buffer containing a chemiluminescent substrate for
beta-galactosidase;
(e) incubating in the absence of light before reading and measuring the
luminescence, which is a function of the beta-galactosidase activity.
27. Test according to the preceding claim, characterized in that the test compound(s) is
(are) chosen from the compounds according to any one of Claims 1 to 17.

The invention relates to compounds according to the formula (I): R is a -S02-NR3R4 group, a hydrogen atom, a
halogen atom, a -halogeno(C 1 -C5)alkyl group, a -CO2R5 group or a -SO2-R4 group; Rl is a heterocycloalkyl group containing no
nitrogen atoms, a -W-(C3-C6)cycloalkyl group, a -W-aryl group, a -W-heteroaryl group, a -W-heterocycloalkyl group, a -W-
COOR5 group, a -W-CONR5R6 group; R2 is a hydrogen atom, a -(Cl-C5)alkyl group, a -(C1-C5)alkylene-O-(Cl-C5)alkyl group,
a -halogeno(Cl-C5)alkyl group, a -W-COOR5 group, a -W-C(O)NHR5 group or a -W-C(0)-NR5R6 group; n is 0, 1 or 2; W is a -
(C1-C5)alkylene- group- or a -(C3-C6)cycloalkylene- group; R3 and R4, identical or different, are, independently from one
another, a hydrogen atom, a -(Cl-C5)alkyl group, a -(C3-C6)cycloalkyl group, a -(Cl-C5)alkylene-O-(Cl-C5)alkyl group, an aryl,
a -CH2-aryl group, a heteroaryl, a heterocycloalkyl, a -W-OH group, a -W-CHOH-CH2OH group, a -W-CO2R5 group, a -W-
NR5R6 group or a -W-O-(CH2)n-aryl group; or else R3 and R4 jointly form a heterocycloalkyl group with the nitrogen atom that
supports them; R5 and R6, identical or different, are, independently from one another, a hydrogen atom, a -(Cl-C5)alkyl group or
a (Cl-C5)halogenoalkyl group, as well as to a method for preparing same and to the therapeutic applications thereof.