DERIVATIVES OF 2-PYRIDIN-2-YL-PYRAZOL-3(2H)-ONE, PREPARATION
AND THERAPEUTIC USE THEREOF
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) (HIF1-alpha) 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 HIF1-alpha 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 HIF1-alpha or HIF2-alpha and another transcription factor ARNT
(formerly known as HIF1-alpha). ARNT is constitutively and stably expressed in
cells and the main part of the transcription complex regulation is associated with
the amount of HIF1 -alpha present in the cells, which is thus the limiting factor.
Under normal oxygen conditions, the protein HIF1-alpha is rapidly degraded (half-
life of δ minutes). This degradation follows the hydroxylation of HIF1-alpha or
HIF2-alpha, 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 HIF1-alpha or HIF2-
alpha by the ubiquitin proteasome system. When the cell or tissue are subjected
to high hypoxia/ischaemia, HIF1-alpha or HIF2-alpha 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 HIF1-alpha
and HIF2-alpha, 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
HIF1-alpha and/or HIF2-alpha 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
n is equal to 0, 1, 2, 3 or 4;
m is equal to 0, 1 or 2;
o is equal to 0 or 1;
X represents a group -CH2, -CH(R')-, -N(R')- or a heteroatom chosen from an
oxygen atom and a sulfur atom, it being understood that R' represents a group -
(C1-C5)alkyl, -(C1-C5)alkoxy, -CH2-aryl, -C(O)R5 or -COOR5 with R5 as defined
below;
R1 represents an oxo group, a group -COOR5, a group -W-OH or a group -W-
NR5R6, with W, R5 and R6 as defined below; and
R2 represents a hydrogen atom or a group chosen from (i) groups -(C1-
C5)aikyl, (ii) groups -(C1-C5)alkoxy, (iii) groups -COOR5, (iv) groups -NR5R6, (v)
groups -C(O)-NR5R6, (vi) groups -SO2-NR3R4, (vii) heteroaryl groups optionally
substituted with a group -(C1-C5)alkyl, (viii) groups -W-aryl, (ix) groups -W-
heteroaryl, (x) groups -O-W-aryl, (xi) groups -O-W-heteroaryl and (xii) groups -O-
W-NR5R6, with W, R3, R4, R5 and R6 as defined below;
it being understood that:
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, an aryl group, a heteroaryl group, a group -CH2-
heteroaryl, a group -(C1-C5)alkyl-NR5R6, a group -W-OH or a group
-W-NR5R6; or
(ii) form, together with the nitrogen atom that bears them, a
heterocycloalkyl group optionally substituted with one or more
groups chosen from groups -(C1-C5)alkyl and groups -CH2-aryl;
W is a group -(C1-C5)alkylene, optionally substituted with one or more
hydroxyl groups; and
R5 and R6, which may be identical or different, represent, independently of
each other, a hydrogen atom or a group chosen from groups -(C1-C5)alkyl and
groups -(C3-C6)cycloalkyl.
The compounds of formula (I) may exist in the form of bases or salts, the
compounds of formula (I) having been, in this case, salified with acids or bases,
especially pharmaceutically acceptable acids or bases. They are then referred to
as addition salts, in particular salts of addition to an acid or a base, which form
part of the invention. The 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. Mention may be made of hydrochloride salts, trifluoroacetic acid
salts and sodium salts.
The compounds of formula (I) may also exist in the form of solvates, i.e. in the
form of associations or combinations with one or more solvent molecules. Such
solvents also form part of the invention.
When o is equal to 0, then the ring comprises only hydrogen atoms.
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 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 δ 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 alkyl group: a linear or branched, saturated aliphatic group, which
may contain 1, 2, 3, 4 or δ 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 or tert-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 δ 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-) groups;
- a cycloalkyl group: a cyclic alkyl group which may contain 3, 4, δ or δ carbon atoms, also abbreviated as -(C3-C6)cycloalkyl. Examples that may be
mentioned include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;
- an alkoxv group: a radical -O-alkyl in which the alkyl group is as defined
previously. Examples that may be mentioned include the groups -O-(C1-C5)alkyl
or -(C1-C5)alkoxy, and in particular, as (i) group -O-C1alkyl, the group -Omethyl,
as (ii) group -O-C2alkyl, the group -Oethyl, as (iii) group -O-C3alkyl, the group -
Opropyl or -Oisopropyl, as (iv) group -O-C4alkyl, the group -Obutyl, -Oisobutyl or
-Otert-butyl, as (v) group -O-C5alkyl the group -Opentyl or -Oisopentyl;
- an alkoxy-alkyl 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-O-(C1-
C5)alkyl, with -(C1-C5)alkylene- and -(C1-C5)alkyl as defined above;
- a haloalkvl group: an alkyl group as defined above, substituted with 1, 2,
3, 4 or δ halogen atoms, as defined previously. Examples that will be mentioned
include groups -halo(C1-C5)alkyl, with (C1-C5)alkyl as defined above, and in
particular the trifluoromethyl group (abbreviated as -CF3);

- an aryl group: a cyclic aromatic group containing δ or δ 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 δ carbon
atoms and comprising 1 to 3 heteroatoms, which may be chosen from a nitrogen
atom, an oxygen atom and a sulfur atom, independently of each other, so as to be
identical or different, when there are 2 of them, or independently of each other, so
as to be identical or different, when there are 3 of them. Mention may be made of
pyridyl, pyrrol and furyl groups;

- a heterocvcloalkyl: an optionally bridged cyclic alkyl group, containing 5, δ or 7 carbon atoms and comprising 1, 2 or 3 heteroatoms which may be chosen,
independently of each other, so as to be identical or different, when there are 2 of
them, or independently of each other, so as to be identical or different, when there
are 3 of them, from a nitrogen atom, an oxygen atom and a sulfur atom. Mention
may be made especially of piperidyl, piperazinyl, pyrrolidinyl,
hexamethyleneimino, morpholinyl and 1,1-dioxidotetrahydrothienyl groups;
- the letters α,β,γ and δ around the pyridine of the compounds of formula
(I) serve 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:
n is equal to 0, 1, 2, 3 or 4,
and/or
m is equal to 0, 1 or 2,
and/or
o is equal to 0 or 1,
and/or
X represents a group -CH2-, -CH(R')-, -N(R')- or a heteroatom chosen from an
oxygen atom and a sulfur atom,
and/or
R' represents a group -(C1-C5)alkyl, a group -(C1-C5)alkoxy, a group -CH2-aryl, a
group -C(O)R5 or a group -COOR5;
and/or
R1 represents an oxo group, a group -COOR5, a group -W-OH or a group -W-
NR5R6;
and/or
R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-C5)alkoxy, a
group -COOR5, a group -NR5R6, a group -C(O)-NR5R6 or a group -SO2-NR3R4;
and/or
R3 and R4

(i) represent, independently of each other, a hydrogen atom, a group -(C1-
C5)alkyl, a group -(C3-C6)cycloalkyl, an aryl group, a heteroaryl group, a
group -CH2-heteroaryl or a group -(C1-C5)alkyl-NR5R6; or
(ii) form, together with the nitrogen atom that bears them, a heterocycloalkyl
group optionally substituted with a group -(C1-C5)alkyl or with an aryl group,
and/or
W represents a group -(C1-C5)alkylene, optionally substituted with one or more
hydroxyl groups;
and/or
R5 and R6 represent, independently of each other, a hydrogen atom or a group -
(C1-C5)alkyl.
A first subgroup of compounds of the invention is formed by the compounds of
formula (I) in which n is equal to 0, 1, 2, 3 or 4.
A second subgroup of compounds of the invention is formed by the compounds of
formula (I) in which m is equal to 0, 1 or 2.
A third subgroup of compounds of the invention is formed by the compounds of
formula (I) in which o is equal to 0.
A fourth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R1 represents an oxo group, a group -CH2-aryl, a group -
C(O)R5- or a group -COOR5, the said group R1 possibly being linked to a carbon
atom or a heteroatom. Advantageously, the aryl group represents a phenyl group.
A fifth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R2 represents (i) a hydrogen atom, (ii) a group -(C1-C5)alkyl,
(iii) a group -(C1-C5)alkoxy, (iv) a group -COOR5, (v) a group -NR5R6, (vi) a
group -C(O)-NR5R6, (vii) a heteroaryl substituted with a group -(C1-C5) alkyl, (viii)
a group -O-W-aryl or (ix) a group -O-W-heteroaryl.

A sixth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R2 represents a group -SO2-NR3R4.
A seventh subgroup of compounds of the invention is formed by the compounds
of formula (I) in which R2 is a substituent on the atom in the beta position of
pyridine.
An eighth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R2 is a substituent on the atom in the gamma position of
pyridine.
A ninth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R3 and R4 represent, independently of each other, a
hydrogen atom, a group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, an aryl group,
a heteroaryl group, a group -CH2-heteroaryl or a group -(C1-C5)alkyl-NR5R6.
Advantageously, the aryl group represents a phenyl group and the heteroaryl
group represents a pyridyl group or a furyl group.
A tenth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R3 and R4 form, together with the nitrogen atom that bears
them, a heterocycloalkyl group optionally substituted with one or more group(s) -
(C1-C5)alkyl and/or aryl. Advantageously, the heterocycloalkyl group represents a
piperidyl group, a pyrrolidinyl group or a hexamethyleneimino group and the aryl
group represents a phenyl group.
An eleventh subgroup of compounds of the invention is formed by the compounds
of formula (I) in which R5 represents a group -(C1-C5)alkyl or a group -(C1-
C5)cycloalkyl.
A twelfth subgroup of compounds of the invention is formed by the compounds of
formula (I) in which R6 represents a hydrogen atom or a group (C1-C5)alkyl.

The subgroups defined above, taken separately or in combination, also form part
of the invention.
Among the compounds described in the present invention, mention may also be
made of a subgroup of compounds corresponding to formula (I) in which:
• n is equal to 1, 2, 3 or 4;
• m is equal to 0, 1 or 2;
• o is equal to 0 or 1;
• X represents a -CH2- group, a group -CH(R')-, a group -N(R')- or a
heteroatom chosen from an oxygen atom and a sulfur atom;
• R' represents a group -(C1-C5)alkyl, a group -(C1-C5)alkoxy, a group -
CH2-aryl, a group -C(O)R5 or a group -COOR5;
• R1 represents an oxo group, a group COOR5, a group -W-OH or a group -
W-NR5R6;
• R2 represents a group -SO2-NR3R4;
• R3 and R4 represent, independently of each other, a hydrogen atom, a
group -(C1-C5)alkyl, a group -(C3-C6)cycioalkyl, an aryl group, a heteroaryl
group or a group -CH2-heteroaryl, or R3 and R4 form, together with the
nitrogen atom that bears them, a heterocycloalkyl group; and
• R5 and R6 represent a group -(C1-C5)alkyl.
Among the compounds described in the present invention, mention may be made,
finally, of a subgroup of compounds corresponding to formula (I) in which:
• n is equal to 1, 2, 3 or 4;
• m is equal to 0, 1 or 2;
• o is equal to 0 or 1;
• X represents a group -CH2-, a group -CH(R')-, a group -N(R')- or a
heteroatom chosen from an oxygen atom and a sulfur atom;
• R' represents a group -(C1-C5)alkyl, a group -(C1-C5)alkoxy, a group -
CH2-aryl, a group -C(O)R5 or a group -COOR5;
• R1 represents an oxo group;
• R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-

C5)alkoxy, a group -COOR5, a group -NR5R6 or -C(O)-NR5R6; and
• R5 and R6 represent, independently of each other, a hydrogen atom, a
group -(C1-C5)alkyl or a group -(C1-C5)cycloalkyl.
Among the compounds of formula (I) that are subjects of the invention, mention
may be made especially of the following compounds:
o 2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,2,4,5,6,7-hexahydro-3H-indazol-3-
one;
o 6-methyl-2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,2,4,5,6,7-hexahydro-3H-
indazol-3-one;
o 2-[5-(piperidin-1-ylsulfonyl)pyridin-2-yl]-1,4,5,6,7,8-
hexahydrocyclohepta[c]pyrazol-3(2H)-one;
o N-ethyl-6-(3-oxo-1,3,4,5,6,7-hexahydro-2H-indazol-2-yl)-N-phenylpyridine-3-
sulfonamide;
o 6-(5-benzyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N-
ethyl-N-phenylpyridine-3-sulfonamide;
o (±)2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-1,2,4,5,6,7-
hexahydro-3H-indazol-3-one;
o 2-(4-methoxypyridin-2-yl)-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one;
o 2-(pyridin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3(2H)-one;
o (±)5-benzyl-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-
1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one;
o (±)2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-6-methyl-
1,2,4,5,6,7-hexahydro-3H-indazol-3-one;
o 6-(5-benzyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-
N,N-diethylpyridine-3-sulfonamide;
o N-ethyl-6-(3-oxo-1,3,4,5,6,7,8,9-octahydro-2H-cycloocta[c]pyrazol-2-yl)-N-
phenylpyridine-3-sulfonamide;
o N-ethyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-
phenylpyridine-3-sulfonamide;
o 6-(5-benzyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-
N,N-di(propan-2-yl)pyridine-3-sulfonamide;
o 6-methoxy-2-(pyridin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3(2H)-one;
o 2-(pyridin-2-yl)-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3(2H)-one;
o N-ethyl-6-(3-oxo-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-2(3H)-yl)-N-
phenylpyridine-3-sulfonamide;
o N-ethyl-6-(3-oxo-3l5,6,7-tetrahydrothiopyrano[3,2-c]pyrazol-2(1H)-yl)-N-
phenylpyridine-3-sulfonamide;
o N,N-diethyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-
3-sulfonamide;

o N,N-dimethyl-6-(3-oxo-4,6-dihydro-1H-thieno[3)4-c]pyra2ol-2(3H)-
yl)pyridine-3-sulfonamide;
o 2-[5-(pyrrolidin-1-ylsulfonyl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one;
o N-cyclopropyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
o 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-(propan-2-
yl)pyridine-3-sulfonamide;
o N-tert-butyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-
3-sulfonamide;
o N-(furan-2-ylmethyl)-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
o N-cyclopentyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
o N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-(pyridin-
2-yl)pyridine-3-sulfonamide;
o 2-(pyridin-2-yl)-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one;
o 2-[4-(dimethylamino)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-
3-one;
o 2-{5-[(4-benzylpiperidin-1-yl)sulfonyl]pyridin-2-yl}-1,2,4,6-tetrahydro-3H-
thieno[3,4-c]pyrazol-3-one;
o 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-(pyridin-2-
yl)pyridine-3-sulfonamide;
o N-ethyl-6-(3-oxo-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-2(3H)-yl)-N-
phenylpyridine-3-sulfonamide;
o sodium 2-(4-ethylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate;
o 2-[5-(azepan-1 -ylsulfonyl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one;
o sodium 4-benzyl-2-{5-[ethyi(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-4,5,6,7-
tetrahydro-2H-pyrazolo[4,3-b]pyridin-3-olate;
o N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yI)-N-(pyridin-
2-ylmethyl)pyridine-3-sulfonamide;
o tert-butyl 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-1,2,3,4,6,7-
hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;
o 6-(5-acetyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N-
ethyl-N-phenylpyridine-3-sulfonamide;
o tert-butyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-
carboxylate;
o sodium 2-(4-methylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate;

o sodium 2-{5-[tert-butyl(methyl)sulfamoyl]pyridin-2-yl}-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate;
o sodium 2-{5-[tert-butyl(ethyl)sulfamoyl]pyridin-2-yl}-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate;
o sodium 2-(5-methylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate;
o sodium 2-[5-(tert-butylcarbamoyl)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-
c]pyrazol-3-olate;
o sodium 2-(5-methoxypyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-
olate;
o N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-(pyridin-
4-yl)pyridine-3-sulfonamide;
o sodium 2-{5-[cyclopentyl(ethyl)sulfamoyl]pyridin-2-yl}-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate;
o sodium 2-[4-(pyridin-3-ylmethoxy)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-
c]pyrazol-3-olate;
o methyl 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-1,2,3,4,6,7-
hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;
o cyclopentyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-
3-carboxylate;
o 2-methylpropyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazoI-2(3H)-
y I )py rid i ne-3-carboxyiate;
o 2-[4-(propan-2-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-
one;
o sodium 2-[5-(propan-2-yl)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-c]pyrazoi-3-
olate;
o methyl 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3,4,6-tetrahydro-
1H-thieno[3,4-c]pyrazole-4-carboxylate;
o propan-2-yl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-
3-carboxylate;
o sodium 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-6-methoxy-2,4,5,6-
tetrahydrocyclopenta[c]pyrazol-3-olate;
o N-ethyl-6-(3-oxo-3,4,5,6-tetrahydrocyclopenta[c]pyrazoi-2(1H)-yl)-N-
phenylpyridine-3-sulfonamide;
o sodium 2-[4-(pyridin-3-ylmethoxy)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-
c]pyrazol-3-olate;
o 2,2-dimethylpropyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-carboxylate;
o 2-[5-(5-tert-butyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-
thieno[3,4-c]pyrazol-3-one;
o N-cyclopentyl-N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
o N-cyclopentyl-N-ethyl-6-(3-oxo-3,4,5,6-tetrahydrocyclopenta[c]pyrazol-
2(1H)-yl)pyridine-3-sulfonamide;
o N-cyclopentyl-N-(2,3-dihydroxypropyl)-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-
c]pyrazol-2(3H)-yl)pyridine-3-sulfonamide;

o 2,2-dimethylpropyl 6-[5-(methylsulfonyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-
pyrazolo[4,3-c]pyridin-2-yl]pyridine-3-carboxylate;
o 2-[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-
thieno[3,4-c]pyrazol-3-one.
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", Greene 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 process that follows, illustrated in Scheme 1.

The synthesis of the compounds of general formula (I) is performed starting with
the compounds of formula (II), in which R1, X, n, m and o are as described

previously and z represents an alkyl group, preferentially methyl or ethyl, which is
condensed in a protic solvent of alcohol type, preferably methanol, at a
temperature of between 20 and 60°C, with a compound of formula (III) in which
R2 is as described previously, to give an intermediate of formula (IV) that is in the
form of a compound of formula (IVa) or (IVb), or a mixture of the two, and which is
cyclized in the presence of an organic base, preferably sodium methoxide, in a
protic solvent such as methanol, at a temperature of between 20 and 50°C.
The compounds (I) obtained are optionally converted with the corresponding acid
or base into the salt.
When their preparation method is not described, the compounds of formula (II)
are commercially available or described in the literature, or alternatively may be
prepared according to methods that are known to those skilled in the art.
Schemes 2a, 2b and 2c describe the preparation of the compounds of formula
(III).
The compounds of formula (III) are obtained from the compound of formula (V),
with LG and R2 as defined previously, via addition of hydrazine hydrate,
preferably in a protic solvent such as ethanol, at a temperature of between 60 and
80°C (Scheme 2a).

The compounds of formula (III) may also be obtained in two steps starting with the
compound of formula (V). The hydrazine function is then introduced, via a
coupling reaction between benzophenone hydrazone of formula (VI) and the
compound of formula (V) in the presence of a catalytic amount of palladium, to
give the intermediate of formula (VII), the hydrazine function of which is freed by
acidic treatment, such as hydrochloric acid, preferably at a concentration of
between δ and 12 N, in a binary mixture of immiscible solvents such as toluene
and water at a temperature of 100°C (Scheme 2b).


Alternatively, the compounds of formula (III) may be synthesized from an amino
pyridine of formula (VIII) with R2 as defined previously, via the action of a mixture
of nitric acid and concentrated sulfuric acid at 0°C to obtain the N-nitroamine
intermediate, which is reduced in 10N sodium hydroxide in the presence of zinc
(Scheme 2c).

In the preceding schemes, the starting compounds, intermediates and reagents,
when their preparation method is not described, are commercially available or
described in the literature, or else may be prepared according to methods known
to those skilled in the art.
According to another of its aspects, a subject of the invention is also the
compounds of formulae (IVa) and (IVb). These compounds are useful as
intermediates for synthesizing the compounds of formula (I).
EXAMPLES:
The examples that follow illustrate the preparation of certain compounds in
accordance with the invention. The numbers of the compounds presented as

examples refer to those in the table given later, which illustrates the chemical
structures and physical properties of a few compounds according to the invention.
The abbreviations and semi-structural formulae below are used:
EtOAc Ethyl acetate
AcOH Acetic acid
anh. Anhydrous
TLC Thin-layer chromatography
LC Liquid chromatography
Cs2CO3 Caesium carbonate
DCM Dichloromethane
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
DME 1,2-Dimethoxyethane
EtOH Ethanol
MeOH Methanol
h Hour(s)
HCI Hydrochloric acid
K2CO3 Potassium carbonate
NH4CI Ammonium chloride
NaHCO3 Sodium hydrogen carbonate
Na2SO4 Sodium sulfate
MS Mass spectrometry
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
RT Room temperature
HNO3 Nitric acid
H2SO4 Sulfuric acid
Conc. Concentrated
racBINAP (±)-2,2-Bis(diphenylphosphino)-1,1'binaphthalene
TBTU 2-(1-H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate

DIEA Diisopropylethylamine
NMO 4-Methylmorpholine N-oxide
OSO4 Osmium tetroxide
pTsOH para-Toluenesulfonic acid
Tr Retention time
T Time
T°C 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 δ 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 µM;
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 µM); 220 nm
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 µL
Example 1; 2-pyridin-2-yl-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one
(Compound 1 of Table I)


A mixture of 7 g (64.1 mmol) of 2-hydrazinopyridine and 10.3 g (64.1 mmol) of
methyl 4-oxotetrahydrothiophene-3-carboxylate in 130 mL of MeOH is heated for
12 hours at 80°C. The medium is then concentrated under reduced pressure and
the residue obtained is purified by chromatography on a column of silica gel,
eluting with a DCM/MeOH gradient of from 0 to 10% MeOH. After concentrating
under reduced pressure, 8.7 g (34.5 mmol) of hydrazone intermediate, in the form
of a yellow powder, are isolated and are then added portionwise, at room
temperature, to a solution of 0.8 g (34.5 mmol) of sodium in 46 mL of anhydrous
MeOH. The reaction medium is stirred for 2 hours at room temperature, and the
precipitate formed is then filtered off and washed successively with 10 mL of
MeOH and 20 mL of pentane. The residue obtained is dissolved in 20 mL of water
and 10 mL of acetic acid are added. The precipitate obtained is filtered off,
washed with 10 mL of water, dried under vacuum and recrystallized from EtOH.
4.2 g of 2-pyridin-2-yl-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one are
obtained in the form of a whitish powder.
Yield = 56%
m.p. (°C)=152
M = C10H9N3OS = 219; M+H = 220; Method 2: Tr = 0.81 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.45 (d, 1H); 8.2 (d, 1H); 7.95 (m, 1H); 7.3
(t, 1H);4.0(s,2H);3.8(s,2H).
Example 2: 2-[4-(Dimethylamino)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-
thieno[3,4-c]pyrazol-3-one hydrochloride (Compound 56 of Table II)

2.1. 2-bromo-N,N-dimethylpyridin-4-amine
To a solution of 12.6 mL (125 mmol) of N, N-dimethylethanolamine in 160 mL of
anhydrous hexane are added, under an argon atmosphere, at -5°C, over 2 hours
30 minutes, 100 mL (250 mmol) of 2.5 M n-butyllithium in hexane, and the
reaction medium is then stirred for 30 minutes at 0°C, followed by addition of 7.6 g

(62.5 mmol) of 4-dimethylaminopyridine. After stirring for 1 hour at 0°C, the
reaction medium is cooled to -78°C and 51.8 g (156.2 mmol) of carbon
tetrabromide dissolved in 250 mL of anhydrous hexane are added over 2 hours 30
minutes at -78°C. The temperature is allowed to rise to 0°C and stirring is then
continued for 1 hour 30 minutes.
The medium is then hydrolysed with water (400 mL) and subsequently extracted
with Et20 (400 mL) and DCM (2 x 400 mL). The combined organic phases are
dried over Na2SO4, filtered and concentrated under reduced pressure. 6.4 g of 2-
bromo-N,N-dimethylpyridin-4-amine are obtained in the form of a brown solid,
which is used without further purification in the following step.
Yield = 51%
1H NMR, (CDCI3, 400 MHz, δ (ppm): 7.9 (d, 1H); 6.6 (s, 1H); 6.4 (d, 1H); 2.9 (s,
6H).
2.2. 2-f2-(diphenvlmethylidene)hydrazino1-N,N-dimethylpyridin-4-amine
To a mixture of 3.3 g (16.41 mmol) of 2-bromo-N,N-dimethylpyridin-4-amine in 40
mL of anhydrous toluene, 3.5 g (18.05 mmol) of benzophenone hydrazone, 2.2 g
(23 mmol) of anhydrous sodium tert-butoxide and 100 mg (0.82 mmol) of
benzeneboronic acid in 40 mL of toluene are added, under argon, at room
temperature, after having degassed the reaction medium under argon, 74 mg
(0.33 mmol) of palladium acetate and 205 mg (0.33 mmol) of racBINAP. The
reaction medium is then heated for 4 hours at 80°C. The reaction medium is taken
up in 200 mL of EtOAc, washed successively with water (3 x 30 mL), with
saturated NaHC03 solution (30 mL) and with brine (30 mL) and then dried over
Na2SO4, 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 from 0 to 10% MeOH. After concentrating under reduced pressure, 4.5
g of 2-[2-(diphenylmethylidene)hydrazino]-N,N-dimethylpyridin-4-amine are
obtained in the form of a red solid.
Yield = 87%
2.3. 2-hydrazino-N.N-dimethylpyridin-4-amine

A mixture of 4.5 g (14.22 mmol) of 2-[2-(diphenylmethylidene)hydrazino]-N,N-
dimethylpyridin-4-amine in 300 mL of toluene and 80 mL of aqueous 37%
hydrochloric acid is heated for 4 hours at 110°C. After cooling to room
temperature, the reaction medium is extracted with toluene (3 * 300 mL). The
aqueous phase is diluted with 200 mL of water, neutralized at 0°C by adding 12N
sodium hydroxide solution, and then extracted with DCM (3 * 150 mL). The
organic phases are combined, washed with brine (300 mL) and then dried over
Na2SO4, filtered and concentrated under reduced pressure. 1.87 g of 2-hydrazino-
N,N-dimethylpyridin-4-amine are obtained in the form of a brown solid, which is
used without further purification in the following step.
Yield = 87%
1H NMR (ppm, d6-DMSO, 400 MHz): 7.6 (d, 1H); 6.9 (s, 1H); 6.1 (dd, 1H); 5.9 (d,
1H);4(bs, 2H);2.9(s, 6H).
2.4. 2-r4-(dimethylamino)pyridin-2-vl1-1.2.4.6-tetrahvdro-3H-thienor3,4-
clpyrazol-3-one hydrochloride
According to the process described in Example 1, starting with 1.87 g of 2-
hydrazino-N,N-dimethylpyridin-4-amine and 1.97 g of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 35 mg of 2-[4-(dimethylamino)pyridin-2-yl]-
1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one are obtained. The hydrochloride
is prepared by freeze-drying the 35 mg obtained previously, dissolved in 1 mL of
0.1NHCI.
36 mg of 2-[4-(dimethylamino)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one hydrochloride are thus obtained in the form of a white lyophilizate.
Yield = 1%
m.p. (°C)=182
M = Ci2H14N4OS = 262; M+H = 263; Method 2: Tr = 0.59 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 7.7 (d, 1H); 6.9 (s, 1H); 6.6 (d, 1H); 3.2 (s,
2H); 3.5 (s, 2H); 2.9 (s, 6H).
Example 3; 2-(4-methoxypyridin-2-yl)-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one (Compound 55 of Table II)


3.1. 2-f2-(diphenvlmethylidene)hydrazinol-4-methoxvpyridine
According to the process described in Example 2.2, starting with 0.5 g of 2-chloro-
4-methoxypyridine and 0.75 g of benzophenone hydrazone, 0.76 g of 2-[2-
(diphenylmethylidene)hydrazino]-4-methoxypyridine is obtained in the form of a
yellow solid, which is used without further purification in the following step.
Yield = 73%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.2 (s, 1H); 7.9 (d, 1H); 7.7-7.5 (m, 5H); 7.4-
7.2 (m, 5H); 7.1 (s, 1H); 6.4 (d, 1H); 3.9 (s, 3H).
3.2. 2-hydrazino-4-methoxypyridine
According to the process described in Example 2.3, starting with 0.76 g of 2-[2-
(diphenylmethylidene)hydrazino]-4-methoxypyridine, 0.24 g of 2-
hydrazinomethoxypyridine is obtained in the form of a yellow lyophilizate, which is
used without further purification in the following step.
Yield = 69%
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 9.7 (bs, 1H); 7.7 (d, 1H); 6.5 (d, 1H); 6.4
(s, 1H);4.8(bs, 2H); 3.9 (s, 3H).
3.3. 2-(4-methoxvpyridin-2-vl)-1.2.4,6-tetrahvdro-3H-thienor3.4-c1pyrazol-3-one
According to the process described in Example 1, starting with 243 mg of 2-
hydrazino-4-methoxypyridine and 280 mg of methyl 4-oxotetrahydrothiophene-3-
carboxylate, 82 mg of 2-(4-methoxypyridin-2-yl)-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one are obtained in the form of a white solid.
Yield = 40%
m.p. (°C) = 254
M = CHHHN3O2S = 249; M+H = 250; Method 2: Tr = 0.8 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.1 (d, 1H); 8.05 (d, 1H); 6.05 (d, 1H); 3.8
(s, 3H); 3.7 (s, 2H); 3.6 (s, 2H)

Example 4: N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-
N-pyridin-2-ylpyridine-3-sulfonamide (Compound 21 of Table I)

4.1. 6-chloro-N-methyl-N--2-vlpyridine-3-sulfonamide
To a solution of 1.3 g (11.8 mmol) of N-methylpyridin-2-amine in 25 mL of DCM
are added, at 0°C, 3.3 mL (23.6 mmol) of triethylamine and then, portionwise,
2.5 g (11.8 mmol) of 6-chloropyridine-3-sulfonyl chloride (prepared according to
document WO 98/40332). After stirring for 12 hours at room temperature, the
reaction medium is taken up in 100 mL of DCM, washed successively with 100
mL of water and 30 mL of brine, dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue obtained is purified by chromatography on a
column of silica gel, eluting with a 4/1 cyclohexane/EtOAc mixture. After
concentrating under reduced pressure, 2.8 g of 6-chloro-N-methyl-N-pyridin-2-
ylpyridine-3-sulfonamide are obtained in the form of a brown solid.
Yield = 84%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.5 (s, 1H); 8.25 (d, 1H); 7.8 (dd, 1H); 7.7 (t,
1H); 7.5 (d, 1H); 7.3 (d, 1H); 7.15 (t, 1H); 3.2 (s, 3H).
4.2. 6-hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide
A solution of 1.4 g (4.9 mmol) of 6-chloro-N-methyl-N-pyridin-2-ylpyridine-3-
sulfonamide and 0.96 mL (19.7 mmol) of hydrazine monohydrate in 8 mL of EtOH
is heated for 12 hours at 80°C. The precipitate obtained, after cooling to room
temperature, is filtered off, washed with 10 mL of EtOH and then dried under
vacuum. 0.85 g of 6-hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide is
obtained in the form of pale yellow crystals.
Yield = 62%.

1H NMR, CDCl3, 400 MHz, δ (ppm): 8.35 (s, 2H); 8.7 (m, 2H); 7.5 (d, 1H); 7.15
(dd, 1H); 6.7 (d, 1H); 6.4 (bs, 1H); 3.5-4.0 (bs, 2H); 3.3 (s, 3H).
4.3. N-methyl-6-(3-oxo-4.6-dihvdro-1H-thienof3.4-clpvrazol-2(3H)-vn-N-pyridin-
2-ylpyridine-3-sulfonamide
According to the process described in Example 1, starting with 476 mg of 6-
hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide and 273 mg of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 416 mg of N-methyl-6-(3-oxo-4,6-dihydro-
1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-pyridin-2-ylpyridine-3-sulfonamide are
obtained in the form of a white solid.
Yield = 45%
m.p. (°C) = 226
M = C16H15N503S2 = 389; M+H = 390; Method 2: Tr = 0.98 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.0 (bs, 1H); 8.6 (s, 1H); 8.5 (bs, 1H);
8.4 (d, 1H); 8.2 (dd, 1H); 7.55 (d, 1H); 7.3 (t, 1H); 4.0 (s, 2H); 3.8 (s, 2H); 3.3 (s,
3H).
Example 5: N-ethyl-6-(3-oxo-3,5,6,7-tetrahydrothiopyrano[3,2-c]pyrazol-
2(1H)-yl)-N-phenylpyridine-3-sulfonamide (Compound 24 of Table I)

5.1. Ethyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate
To a solution of δ g (219 mmol) of sodium in 13 mL of anhydrous EtOH and 88 mL
of ether are added dropwise, at 0°C and under argon, 20.5 g (87.5 mmol) of ethyl
4-[(2-ethoxy-2-oxoethyl)sulfanyl]butanoate. After stirring for 18 hours at room
temperature, the reaction mixture is poured into a mixture of AcOH (12 mL)/ice
(70 g). The medium is then concentrated under reduced pressure, and the residue
obtained is taken up in 100 mL of ether, washed with brine (2x50 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The residue obtained
is purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc

gradient of from 0 to 10% EtOAc. 5.64 g of ethyl 3-oxotetrahydro-2H-thiopyrane-2-
carboxylate are obtained in the form of a yellow oil.
Yield = 34%.
1H NMR, CDCI3, 400 MHz, δ (ppm): 12.3 (s, 1H); 4.3 (q, 2H); 2.80 (m, 2H); 2.4 (t,
2H);2.15(m,2H); 1.4 (t, 3H).
5.2. N-ethyl-6-(3-oxo-3,5,6,7-tetrahydrothiopyrano[3,2-c]pyrazol-2(1H)-yl)-N-
phenylpyridine-3-sulfonamide
A mixture of 1 g (5.31 mmol) of ethyl 3-oxotetrahydro-2H-thiopyrane-2-carboxylate
and 1.55 g of 6-hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide in 10 mL
of MeOH is heated for 15 hours at 80°C. After cooling to room temperature, the
precipitate obtained is filtered off and washed with δ mL of MeOH, and then
recrystallized from EtOH. 395 mg of N-ethyl-6-(3-oxo-3,5,6,7-
tetrahydrothiopyrano[3,2-c]pyrazol-2(1H)-yl)-N-phenylpyridine-3-su!fonamide are
obtained in the form of a white powder.
Yield = 16%
m.p. (°C)=198
M = C19H20N4O3S2 = 416; M+H = 417; Method 2: Tr = 1.12 min
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 11.9 (bs, 1H); 8.6 (bs, 1H); 8.5 (s, 1H);
8.1 (d, 1H); 7.4 (m, 3H); 7.1 (d, 2H); 3.6 (q, 2H); 3.0 (t, 2H); 2.6 (t, 2H); 2.0 (q,
2.0); 1.0 (t, 3H).
Example 6: tert-butyl 2-[5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl]-3-oxo-
1,2,3,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Compound
28 of Table I)

6.1. 1-tert-butyl-3-methyl-4-oxopiperidine 1,3-dicarboxylate

To a mixture of 10 g (51.6 mmol) of methyl 4-oxopiperidine-3-carboxylate and 7.3
mL (51.6 mmol) of triethylamine in 100 mL of DCM are added 11.3 g (51.6 mmol)
of di-tert-butyl dicarbonate. After 2 hours at room temperature, the medium is
taken up in 300 mL of DCM, washed with 200 mL of water, dried over Na2SO4 and
then filtered and concentrated under reduced pressure. 13 g of 1-tert-butyl-3-
methyl-4-oxopiperidine 1,3-dicarboxylate are obtained in the form of a white solid,
which is used without further purification in the following step.
6.2. tert-butyl 2-[5-fethyl(phenyl)sulfamoyllpyridin-2-yl]-3-oxo-1.2.3.4,6.7-
hexahydro-5H-pvrazolor4,3-clpyridine-5-carboxvlate
According to the process described in Example 1, starting with 1.7 g of 6-
hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide and 1.5 g of 1-tert-butyl-
3-methyl-4-oxopiperidine 1,3-dicarboxylate, 190 mg of tert-butyl 2-[5-
[ethyl(phenyl)sulfamoyl]pyridin-2-yl]-3-oxo-1,2,3,4,6,7-hexahydro-5H-pyrazolo[4,3-
c]pyridine-5-carboxylate are obtained in the form of a white solid.
Yield = 16%
m.p. (°C) = 192
M = C24H29N505S = 499; M+H = 500; Method 2: Tr = 1.23 min
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.1 (bs, 1H); 8.6 (bs, 1H); 8.5 (s, 1H);
8.1 (dd, 1H); 7.4 (m, 3H); 7.1 (d, 2H); 4.1 (s, 2H); 3.6 (m, 4H); 2.7 (m, 2H); 1.4 (s,
9H); 1.0(t,3H).
Example 7: N-ethyl-6-(3-oxo-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-2(3H)-yl)-
N-phenylpyridine-3-sulfonamide (Compound 25 of Table I)

7.1. propyl 4-oxotetrahydro-2H-pyran-3-carboxvlate

The compound is prepared according to the procedure described in JACS Vol.
119, No. 18, pp. 4285-4291.
7.2. N-ethvl-6-(3-oxo-1.4.6.7-tetrahvdropyranof4,3-c]pyrazol-2(3H)-yl-N-
phenylpyridine-3-sulfonamide
According to the process described in Example 1, starting with 0.47 g of 6-
hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide and 0.3 g of propyl 4-
oxotetrahydro-2H-pyran-3-carboxylate, 370 mg of N-ethyl-6-(3-oxo-1,4,6,7-
tetrahydropyrano[4,3-c]pyrazol-2(3H)-yl)-N-phenylpyridine-3-sulfonamide are
obtained in the form of a white powder.
Yield = 57%
m.p. (°C) = 164
M = C19H20N4O4S = 400; M+H = 401; Method 2: Tr = 1.0 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.0 (bs, 1H); 8.6 (d, 1H); 8.4 (s, 1H); 8.0
(d, 1H); 7.4 (m, 3H); 7.1 (m, 2H); 4.3 (s, 2H); 3.85 (t, 2H); 3.6 (q, 2H); 2.6 (t, 2H);
1.0 (t, 3H).
Example 8: sodium 4-benzyl-2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-
oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-3-olate (Compound 35 of
Table I)
According to the process described in Example 1, starting with 0.8 g of 6-
hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide and 0.76 g of ethyl 1-
benzyl-3,6-dioxopiperidine-2-carboxylate obtained according to Tetrahedron, Vol.

40, No. 13 p. 2505, 220 mg of the expected compound are obtained in the form of
a white solid, which is taken up in δ mL of a water/CH3CN mixture (5/1) and 1 eq.
of 1N NaOH, and then freeze-dried. 225 mg of sodium 4-benzyl-2-{5-
[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-
b]pyridin-3-olate are thus obtained in the form of a white lyophilizate.
Yield = 12%
m.p. (°C) >250
M = C26H25N5O4S = 503; M+H = 504; Method 2: Tr = 1.16 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.7 (d, 1H); 8.4 (s, 1H); 7.8 (d, 1H); 7.5-
7.1 (m, 10H); 4.7 (s, 2H); 4.2 (s, 2H); 3.6 (q, 2H); 3.1 (s, 2H); 1.0 (t, 3H).
Example 9: sodium 2-(4-ethylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-
c]pyrazol-3-olate (Compound 57 of Table II)

9.1. 4-ethyl-2-hydrazinopyridine
To a solution of 5 g (40.9 mmol) of 4-ethylpyridin-2-amine in 10 mL of
concentrated H2SO4 at 0°C are added 8 mL of an H2SO4/HNO3 mixture (1/1) at a
temperature of between 0 and 10°C, and stirring is maintained for 1 hour at 0°C.
The reaction medium is then poured onto 100 g of ice and the white precipitate
obtained is filtered off and washed successively with 10 mL of water, 10 mL of
Et2O and 10 mL of pentane. The solid obtained is taken up in 100 mL of 10N
NaOH at 0°C, 7.76 g (187 mmol) of zinc powder are added and the reaction
medium is then stirred for 3 hours at 0°C. The reaction medium is then filtered
through Celite and the filtrate is extracted with EtOAc (3 * 200 mL). The organic
phases are combined, dried over Na2SO4, filtered and then concentrated under
reduced pressure. 4.3 g of 4-ethyl-2-hydrazinopyridine are obtained in the form of
a red oil, which is used without further purification in the following step.
Yield = 77%
1H NMR, CDCI3, 400 MHz, δ (ppm): 7.9 (d, 1H); 7.2 (bs, 1H); 6.5 (s, 1H); 6.4 (d,
1H);4.1(s,2H);2.5(q,2H);1.1(t, 3H).

9.2. Sodium 2-(4-ethvlpyridin-2-vn-2,6-dihvdro-4H-thienor3,4-clpyrazol-3-olate
According to the process described in Example 8, starting with 0.88 g of 4-ethyl-2-
hydrazinopyridine and 1.0 g of methyl 4-oxotetrahydrothiophene-3-carboxylate,
225 mg of sodium 2-(4-ethylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-
olate are obtained in the form of a white lyophilizate.
Yield = 15%
m.p. (°C) >260°C
M = C12Hi3N3OS = 247; M+H = 248; Method 2: Tr = 1.05 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.2 (s, 1H); 8.1 (d, 1H); 6.7 (d, 1H); 3.7 (s,
2H);3.5(s,2H);2.5(q,2H);1.1(t,3H).
Example 10: sodium 2-{5-[tert-butyl(methyl)sulfamoyl]pyridin-2-yl}-2,6-
dihydro-4H-thieno[3,4-c]pyrazol-3-olate (Compound 36 of Table I)

10.1. N-tert-butyl-6-chloropyridine-3-sulfonamide
According to the process described in Example 4.1, starting with 2 g (9.43 mmol)
of 6-chloropyridine-3-sulfonyl chloride and 0.99 mL (9.43 mmol) of tert-butylamine,
1.91 g of N-tert-butyl-6-chloropyridine-3-sulfonamide are obtained in the form of a
white solid.
Yield = 82%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.8 (d, 1H); 8 (dd, 1H); 7.4 (d, 1H); 4.5 (bs,
1H); 1.2 (s, 9H).
10.2. N-tert-butvl-6-chloro-N-methylpyridine-3-sulfonamide

A mixture of 0.97 g (3.9 mmol) of N-tert-butyl-6-chloropyridine-3-sulfonamide, 2.43
mL (39 mmol) of methyl iodide and 5.4 g (39 mmol) of K2C03 in 40 mL of acetone
is refluxed for 12 hours. The reaction medium is filtered at room temperature, and
the filtrate is concentrated under reduced pressure. The residue obtained is
purified on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 20%
EtOAc, to give 0.66 g of N-tert-butyl-6-chloro-N-methylpyridine-3-sulfonamide in
the form of a yellow solid.
Yield = 65%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.8 (d, 1H); 8 (dd, 1H); 7.4 (d, 1H); 3(s.3H);
1.4 (s, 9H).
10.3. N-tert-butvl-6-hydrazino-N-methylpyridine-3-sulfonamide
According to the process described in Example 4.2, starting with 0.66 g (2.53
mmol) of N-tert-butyl-6-chloro-N-methylpyridine-3-sulfonamide and 0.46 mL of
hydrazine monohydrate, 0.55 g of N-tert-butyl-6-hydrazino-N-methylpyridine-3-
sulfonamide is obtained in the form of a white solid, which is used without further
purification in the following step.
Yield = 84%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.8 (d, 1H); 8 (dd, 1H); 7 (d, 1H); 6.6 (bs, 1H);
4.1 (bs, 2H);3.1 (s, 3H); 1.5 (s, 9H).
10.4. sodium 2-{5-rtert-butvl(methyl)sulfamovnpyridin-2-vl)-2,6-dihydro-4H-
thieno[3,4-c1pyrazol-3-olate
According to the process described in Example 8, starting with 0.55 g of N-tert-
butyl-6-hydrazino-N-methylpyridine-3-sulfonamide and 0.34 g of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 0.34 g of sodium 2-{5-[tert-butyl(methyl)-
sulfamoyl]pyridin-2-yl}-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate is thus
obtained in the form of a white lyophilizate.
Yield = 67%
m.p. (°C)=130
M = C15H2oN403S2 = 368; M+H = 369; Method 2: Tr = 1.09 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.6 (m, 2H); 8.0 (s, 1H); 3.75 (s, 2H); 3.6
(s, 2H);2.9(s, 3H); 1.3 (s, 9H).

Example 11: sodium 2-[5-(tert-butylcarbamoyl)pyridin-2-yl]-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate (Compound 33 of Table I)

11.1. 6-(3-oxo-4.6-dihvdro-1H-thienor3.4-clpvrazol-2(3H)-vl)pyridine-3-carboxvlic
acid
According to the process described in Example 1, starting with 1.75 g of 6-
hydrazinopyridine-3-carboxylic acid and 1.8 g of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 2.5 g of 6-(3-oxo-4,6-dihydro-1 H-
thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-carboxylic acid are obtained in the form of
a yellow solid.
Yield = 94%
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.5 (bs, 1H); 9.0 (s, 1H); 8.4 (d, 1H); 8.3
(bs, 1H);4.1 (s, 2H); 3.8 (s, 2H).
11.2. sodium 2-f5-(tert-butvlcarbamovnpyridin-2-vn-2.6-dihvdro-4H-thienor3,4-
clpyrazol-3-olate
To a mixture of 200 mg (0.84 mmol) of 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-
c]pyrazol-2(3H)-yl)pyridine-3-carboxylic acid, 90 pi (0.84 mmol) of tert-butylamine
and 0.46 mL of DIEA in 3 mL of CH3CN, cooled to 0°C, are added 365 mg of
TBTU. The reaction medium is then allowed to warm slowly to room temperature,
and stirring is continued for 12 hours. The reaction medium is concentrated under
reduced pressure, and the residue obtained is taken up in 20 mL of water and
extracted with DCM (3 x 20 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure, and purified on silica gel, eluting with a DCM/MeOH
gradient of from 0 to 10% MeOH. 66 mg of the expected compound are obtained,
and are taken up in 2 mL of a water/CH3CN mixture (5:1) and 1 eq. of 1N NaOH,

and then freeze-dried. 66 mg of sodium 2-[5-(tert-butylcarbamoyl)pyridin-2-yl]-2,6-
dihydro-4H-thieno[3,4-c]pyrazol-3-olate are thus obtained in the form of a white
lyophilizate.
Yield = 25%
m.p. (°C) >260°C
M = C15Hi7N402S = 317; M+H = 318; Method 2: Tr = 0.94 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.7 (s, 1H); 8.5 (d, 1H); 8.1 (d, 1H); 7.6 (s,
1H); 3.75 (s, 1H); 3.6 (s, 2H); 1.4 (s, 9H).
Example 12: tert-butyl 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-carboxylate (Compound 30 of Table I)

12.1. tert-butyl 6-chloropyridine-3-carboxvlate
To a suspension of 1 g (6.35 mmol) of 6-chloropyridine-3-carboxylic acid in 10 mL
of refluxing toluene are added dropwise 7.6 mL (31.75 mmol) of 1,1 -di-tert-butoxy-
N,N-dimethylmethanamine, and the reaction medium is then refluxed for 30
minutes. After cooling to room temperature, the reaction medium is taken up in
200 mL of EtOAc, washed successively with water (2 * 100 mL), with saturated
NaHC03 solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure. 1.16 g of tert-butyl 6-chloropyridine-3-
carboxylate are obtained in the form of a yellow oil, which is used without further
purification in the following step.
Yield = 86%
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.8 (s, 1H); 8.2 (d, 1H); 7.3 (d, 1H); 1.5 (s,
9H).
12.2. tert-butyl 6-hydrazinopyridine-3-carboxylate

According to the process described in Example 4.2 starting with 1.16 g of tert-
butyl 6-chloropyridine-3-carboxylate and 1 mL of hydrazine hydrate, 900 mg of
tert-butyl 6-hydrazinopyridine-3-carboxylate are obtained in the form of a solid,
which is used without further purification in the following step.
Yield = 79%
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.7 (s, 1H); 8.0 (d, 1H); 6.6 (d, 1H); 6.3
(bs, 1H);3.2(bs, 2H);1.5(s, 9H).
12.3. tert-butvl 6-(3-oxo-4.6-dihvdro-1H-thienor3.4-clDvrazol-2(3H)-vl)pyridine-3-
carboxvlate
According to the process described in Example 1, starting with 0.75 g of tert-butyl
6-hydrazinopyridine-3-carboxylate and 0.58 g of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 0.7 g of tert-butyl 6-(3-oxo-4,6-dihydro-1H-
thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-carboxylate is obtained in the form of a
white solid.
Yield = 61%
m.p. (°C) > 250°C
M = C15H17N303S = 319; M+H = 320; Method 2: Tr = 1.27 min
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.9 (s, 1H); 8.4 (d, 1H); 8.2 (d, 1H); 4.0 (s,
2H); 3.7 (s, 2H), 3.4 (bs, 1H); 1.6 (s, 9H).
Example 13: sodium 2-[5-(propan-2-yl)pyridin-2-yl]-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate (Compound 44 of Table I)

13.1. 5-(prop-1-en-2-yl)pyridin-2-amine
A mixture of 2 g (11.56 mmol) of 5-bromopyridin-2-amine, 2.39 mL (13.87 mmol)
of 4.4.5.5-tetramethyl-2-(prop-1-en-2-yl)-1.3.2-dioxaborolane and 3.83 g (27.74
mmol) of K2C03 in 30 mL of DME and 10 mL of water is stirred for δ minutes

under argon, followed by addition of 1 g (2.1 mmol) of palladium bis(tri-t-
butylphosphine). The reaction medium is heated for 3 hours at 80°C. After cooling
to room temperature, the reaction medium is taken up in 40 mL of water and
extracted with EtOAc (3 * 30 mL). The organic phases are washed with 0.5N HCI
solution (3 * 30 mL). The aqueous phases are neutralized with 1N sodium
hydroxide solution and then extracted with EtOAc (2 * 50 mL). The combined
organic phases are dried over Na2SO4, filtered and concentrated under reduced
pressure. 1.10 g of 5-(prop-1-en-2-yl)pyridin-2-amine are obtained in the form of a
yellow solid, which is used without further purification in the following step.
Yield = 71%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.0 (s, 1H); 7.6 (d, 1H); 6.5 (d, 1H); 5.3 (s,
1H); 5.0 (s, 1H); 4.5 (bs, 2H); 2.1 (s, 3H);
13.2. 5-(propan-2-v0pyridin-2-amine
In a Parr flask, a mixture of 1.1 g (8.2 mmol) of 5-(prop-1-en-2-yl)pyridin-2-amine
in 40 mL of MeOH and 0.11 g of 10% Pd/C is hydrogenated at 7 bar for 24 hours.
The reaction mixture is then filtered through Whatman GF/F paper and
concentrated under reduced pressure. 1.07 g of 5-(propan-2-yl)pyridin-2-amine
are thus obtained in the form of a yellow oil, which is used without further
purification in the following step.
Yield = 96%.
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.0 (s, 1H); 7.4 (dd, 1H); 6.5 (d, 1H); 4.4 (bs,
2H);2.8(m, 1H); 1.2 (s, 6H)
13.3. 2-hvdrazinvl-5-(propan-2-vl)pyridine
According to the process described in Example 9.1, starting with 1.07 g of 5-
(propan-2-yl)pyridin-2-amine, 0.52 g of 2-hydrazinyl-5-(propan-2-yl)pyridine is
obtained in the form of a brown oil.
Yield = 44%
13.4. sodium 245-(propan-2-yl)pyridin-2-vll-2,6HJihydro-4H-thienof3,4-c1pyrazol-
3-olate

According to the process described in Example 8, starting with 520 mg of 2-
hydrazinyl-5-(propan-2-yl)pyridine and 251 mg of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 102 mg of 2-[5-(propan-2-yl)pyridin-2-yl]-
2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate are obtained in the form of a
lyophilizate.
Yield = 11%
m.p. (°C) > 260°C
M = C13Hi5N3OS = 261; M+H = 262; Method 2: Tr = 1.26 min
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.4 (d, 1H); 8.1 (s, 1H); 7.6 (dd, 1H); 3.7
(s, 2H); 3.6 (s, 2H); 2.9 (qt, 1H); 1.2 (s, 6H).
Example 14: sodium 2-[4-(pyridin-3-ylmethoxy)pyridin-2-yl]-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate (Compound 60 of Table II)

14.1. 2-chloro-4-(pyridin-3-vlmethoxy)pyridine
A mixture of 2 g (15.4 mmol) of 2-chloropyridin-4-ol, 3.82 g (15.1 mmol) of 3-
(bromomethyl)pyridine hydrobromide, 3 g (75.6 mmol) of sodium hydroxide and
1.39 g (4.3 mmol) of tetrabutylammonium bromide in 90 mL of toluene is refluxed
for 12 hours. After cooling to room temperature, the reaction medium is taken up
in 300 mL of EtOAc, washed successively with water (2 x 100 mL), with saturated
NaHC03 solution (100 mL) and with brine (100 mL), dried over Na2SO4, filtered,
concentrated under reduced pressure and then purified by chromatography on
silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.5 g of 2-chloro-4-(pyridin-3-
ylmethoxy)pyridine are obtained in the form of a yellow oil.
Yield = 73%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.7 (s, 1H); 8.6 (d, 1H); 8.25 (d, 1H); 7.8 (d,
1H); 7.4 (dd, 1H); 7.0 (s, 1H); 6.8 (d, 1H); 5.1 (s, 2H)

14.2. 2-hvdrazinvl-4-(pyridin-3-vlmethoxv)pyridine
A mixture of 0.5 g (2.27 mmol) of 2-chloro-4-(pyridin-3-ylmethoxy)pyridine and 2
mL (40.5 mmol) of hydrazine hydrate is heated at 80°C for 12 hours. The reaction
medium is then taken up in 30 mL of water and extracted with EtOAc (3 * 30 mL).
The organic phases are combined, washed with brine (20 mL) and then dried over
Na2SO4, filtered, concentrated under reduced pressure and purified on silica gel,
eluting with a 95/5 DCM/MeOH mixture. 197 mg of 2-hydrazinyl-4-(pyridin-3-
ylmethoxy)pyridine are obtained in the form of a yellow oil.
Yield = 37%
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.7 (s, 1H); 8.5 (d, 1H); 7.9 (d, 1H); 7.8 (d,
1H); 7.4 (dd, 1H); 7.3 (s, 1H); 5.2 (s, 2H); 4.1 (s, 2H)
14.3. sodium 2-f4-(pyridin-3-vlmethoxv)pyridin-2-vl1-2,6-dihydro-4H-thienor3,4-
clpvrazol-3-olate
According to the process described in Example 8, starting with 197 mg of 2-
hydrazinyl-4-(pyridin-3-ylmethoxy)pyridine and 146 mg of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 225 mg of sodium 2-(4-ethylpyridin-2-yl)-
2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate are obtained in the form of a white
lyophilizate.
Yield = 48%
m.p. (°C) >260°C
M = C16H14N4O2S = 326; M+H = 327; Method 2: Tr = 0.71 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.8 (s, 1H); 8.6 (d, 1H); 8.2 (s, 1H); 8.1 (d,
1H); 8.0 (d, 1H); 7.5 (t, 1H); 6.5 (d, 1H); 5.2 (s, 2H); 3.75 (s, 2H); 3.5 (s, 2H)
Example 15A: 2-[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]-1,2,4,6-
tetrahydro-3H-thieno[3,4-c]pyrazol-3-one (Compound 50A of Table I)

15A.1. 5-(3-tert-butvl-1,2,4-oxadiazol-5-vl)-2-chloropyridine

To a solution of 3.8 g (21.5 mmol) of 6-chloropyridine-3-carbonyl chloride in 100
mL of toluene, in Dean-stark apparatus, are added portionwise 2.5 g (21.5 mmol)
N-hydroxy-2,2-dimethylpropanimidamide, and the reaction medium is stirred for 2
hours at room temperature and then heated for 2 hours. After cooling to room
temperature, the medium is concentrated under reduced pressure and purified by
chromatography on silica gel, eluting with a cyclohexane/EtOAc gradient of from 0
to 10% EtOAc. 4.1 g of 5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-chloropyridine are
obtained in the form of a white solid.
Yield = 81%
1H NMR, CDCI3, 400 MHz, δ (ppm): 9.2 (s, 1H); 8.4 (dd, 1H); 7.5 (d, 1H); 7.8 (d,
1H); 1.4 (s, 9H)
15A.2. 5-(3-tert-butyl-1.2,4-oxadiazol-5-vl)-2-hvdrazinvlpyridine
According to the process described in Example 4.2 starting with 2 g of 5-(3-tert-
butyl-1,2,4-oxadiazol-5-yl)-2-chloropyridine and 3.9 mL of hydrazine hydrate, 1.9 g
of 5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)-2-hydrazinylpyridine are obtained in the
form of a solid, which is used without further purification in the following step.
Yield = 97%
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 8.7 (s, 1H); 8.1 (d, 1H); 6.9 (d, 1H); 6.5
(bs, 1H);3.5(bs, 2H); 1.3(s, 9H).
15A.3. 2-f5-(3-tert-butvl-1.2.4-oxadiazol-5-vnpyridin-2-vll-1,2.4.6-tetrahvdro-3H-
thienof3,4-c1pyrazol-3-one
According to the process described in Example 1, starting with 0.6 g of 5-(3-tert-
butyl-1,2,4-oxadiazol-5-yl)-2-hydrazinylpyridine and 0.41 g of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 0.32 g of 2-[5-(3-tert-butyl-1,2,4-oxadiazol-
5-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one is obtained in
the form of a white solid.
Yield = 38%
m.p. (°C) =240°C
M = deHuNsOzS = 343; M+H = 344; Method 2: Tr = 1.34 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.3 (bs, 1H); 9.1 (s, 1H); 8.6 (d, 1H); 8.4
(d, 1H); 4.0 (s, 2H); 3.8 (s, 2H); 1;4 (s, 9H).

Example 15B: 2-[5-(5-tert-butyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl]-1,2,4,6-
tetrahydro-3H-thieno[3,4-c]pyrazol-3-one (Compound 50B of Table I)

15B.1 5-(5-tert-butvl-1,2,4-oxadiazol-3-vl)-2-chloropyridine
A mixture of 1.5 g (8.74 mmol) of 6-chloro-N'-hydroxypyridine-3-carboximidamide
and 1.13 mL (9.18 mmol) of trimethylacetyl chloride in 15 mL of toluene is stirred
for 1 hour at room temperature and then refluxed for 4 hours. The medium is
filtered. The insoluble material formed is dissolved in 15 mL of AcOH and then
heated at 60°C for δ hours. After cooling to room temperature, the medium is
concentrated under reduced pressure and then purified by chromatography on
silica gel, eluting with a cyclohexane/EtOAc mixture (9/1). 0.39 g of 5-(5-tert-butyl-
1,2,4-oxadiazol-3-yl)-2-chloropyridine is obtained in the form of a white solid.
Yield = 21%
15.B2 2-r5-(5-tert-butvl-1.2.4-oxadiazDl-3-vnpyridin-2-vn-1.2,4.6-tetrahvdro-3H-
thienof3,4-clpyrazol-3-one (Compound 50 B of Table I)
The compound is obtained, according to Processes 15.A2-15.A3, starting with 5-
(5-tert-butyl-1,2,4-oxadiazol-3-yl)-2-chloropyridine and methyl 4-
oxotetrahydrothiophene-3-carboxylate, in the form of a white solid.
m.p. (°C) =240°C
M = C16H17N5O2S = 343; M+H = 344; Method 2: Tr = 1.39 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.3 (bs, 1H); 9.1 (s, 1H); 8.5 (d, 1H); 8.4
(d, 1H); 4.1 (s, 2H); 3.8 (s, 2H); 1.5 (s, 9H)
Example 16: N-cyclopentyl-N-(2,3-dihydroxypropyl)-6-(3-oxo-4,6-dihydro-1H-
thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-sulfonamide (Compound 53 of Table
I)


16.1. 6-chloro-N-cyclopentvlpyridine-3-sulfonamide
According to Process 4.1, starting with δ g of 6-chloropyridine-3-sulfonyl chloride
and 2 g of cyclopentylamine, 5.1 g 6-chloro-N-cyclopentylpyridine-3-sulfonamide
are obtained in the form of a yellow solid.
Yield = 83%
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.9 (s, 1H); 8.0 (d, 1H); 7.4 (d, 1H); 4.5 (d,
1H);3.6(q, 1H); 1.8-1.2 (m, 8H)
16.2 6-chloro-N-cyclopentyl-N-(prop-2-en-1-yl)pyridine-3-sulfonamide
According to Process 10.2, starting with 1 g of 6-chloro-N-cyclopentylpyridine-3-
sulfonamide and 0.42 mL of allyl bromide, 1.2 g of 6-chloro-N-phenyl-N-(prop-2-
en-1-yl)pyridine-3-sulfonamide are obtained in the form of an orange-coloured oil.
Yield = 94%
1H NMR, CDCk 400 MHz. δ (ppm): 8.9 (s. 1H); 8.0 (d. 1H): 7.4 (d. 1H); 5.7 (dd.
1H); 5.2 (dd. 1H); 5.1 (d. 1H): 4.2 (m. 1H); 3.7 (d. 2H); 1.8-1.2 (m, 8H)
16.3. 6-chloro-N-cyclopentvl-N-(2,3-dihvdroxypropvl)pyridine-3-sulfonamide
To a solution of 1.1 g (3.7 mmol) of 6-ch!oro-N-cyclopentyl-N-(prop-2-en-1-
yl)pyridine-3-sulfonamide in 15 mL of a mixture (1/1) of tBuOH and water are
added, at room temperature, 1.2 g (10.3 mmol) of NMO and 0.52 mL (0.04 mmol)
of 2.5% OSO4 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
Na2SC>4, filtered and concentrated under reduced pressure. 0.92 g of 6-chloro-N-
cyclopentyl-N-(2,3-dihydroxypropyl)pyridine-3-sulfonamide is obtained in the form
of a brown solid, which is used without further purification in the following step.
Yield = 75%.
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.8 (s, 1H); 8.1 (d, 1H); 7.5 (d, 1H); 4.3 (m,
1H); 4.0 (m, 1H); 3.6 (dd, 2H); 3.2 (dd, 2H); 1.8-1.4 (m, 10H)

16.4. 6-chloro-N-cvclopentvl-N-r(2,2-dimethyl-1,3-dioxolan-4-yl)methvnpyridine-3-
sulfonamide
A mixture of 0.83 g (2.48 mmol) of 6-chloro-N-cyclopentyl-N-(2,3-
dihydroxypropyl)pyridine-3-sulfonamide, 0.67 mL (5.45 mmol) of 2,2-
dimethoxypropane and 47 mg of pTsOH in δ 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
Na2SO4, filtered and concentrated under reduced pressure. 0.92 g 6-chloro-N-
cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyridine-3-sulfonamide is
obtained in the form of a brown oil, which is used without further purification in the
following step.
Yield = 98%.
1H NMR, CDCI3, 400 MHz, δ (ppm): 8.8 (s, 1H); 8.0 (d, 1H); 7.3 (d, 1H); 4.3 (m,
1H); 4.0 (m, 2H); 3.7 (m, 1H), 3.3 (dd, 1H); 3.1 (dd, 1H); 1.8-1.3 (m, 8H); 1.3 (s,
3H);1.2(s, 3H)
16.5. N-cvclopentvl-N-r(2,2-dimethyl-1.3-dioxolan-4-vnmethyll-6-
hydrazinvlpyridine-3-sulfonamide
According to Process 4.2, starting with 0.92 g of 6-chloro-N-cyclopentyl-N-[(2,2-
dimethyl-1,3-dioxolan-4-yl)methyl]pyridine-3-sulfonamide and 0.24 mL of
hydrazine hydrate, 0.85 g of N-cyclopentyl-N-[(2,2-dirnethyl-1,3-dioxolan-4-
yl)methyl]-6-hydrazinylpyridine-3-sulfonamide is obtained in the form of a yellow
oil.
Yield = 99%
16.6. N-cvclopentvl-N-r(2.2-dimethyl-1.3-dioxolan-4-yl)methvn-6-(3-oxo-4,6-
dihydro-1H-thienof3,4-clpyrazol-2(3H)-vl)pyridine-3-sulfonamide
According to Process 1, starting with 0.4 g of N-cyclopentyl-N-[(2,2-dimethyl-1,3-
dioxolan-4-yl)methyl]-6-hydrazinylpyridine-3-sulfonamide and 0.173 g of methyl 4-
oxotetrahydrothiophene-3-carboxylate, 470 mg N-cyclopentyl-N-[(2,2-dimethyl-
1,3-dioxolan-4-yl)methyl]-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide are obtained in the form of a brown solid.
Yield = 97%

16.7. N-cvclopentvl-N-(2,3-dihvdroxvDropyl)-6-(3-oxo-4,6-dihvdro-1H-thienor3,4-
clpvrazol-2(3HVvnpyridine-3-sulfonamide
A solution of 470 mg (0.54 mmol) of δ N-cyclopentyl-N-[(2,2-dimethy 1-1,3-
dioxolan-4-yl)methyl]-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide in 1 mL of AcOH is heated at 80°C for 4 hours. The
medium is concentrated under reduced pressure and then purified by reverse-
phase chromatography on a C18 column, eluting with a 10~3N HCI/CH3CN
gradient of from 0 to 100% CH3CN. 48 mg of N-cyclopentyl-N-(2,3-
dihydroxypropyl)-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-
sulfonamide are obtained in the form of a white solid.
Yield = 30%
m.p. (°C)=190
M = C18H24N4O5S2 = 440; M+H = 441; Method 2: Tr = 0.89 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.1 (bs, 1H); 8.7 (s, 1H); 8.3 (bs, 1H);
8.2 (d, 1H); 4.7 (s, 1H); 4.5 (t, 1H); 4.1 (m, 1H); 3.9 (s, 2H); 3.6 (m, 3H); 3.4-3.2
(m, 3H); 2.8 (dd, 1H); 1.7-1.2 (m, 8H)
Example 17: 2,2-dimethylpropyl 6-[5-(methyIsulfonyl)-3-oxo-1,3,4,5,6,7-
hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]pyridine-3-carboxylate (Compound
54 of Table I)

17.1. methyl 1 -(methylsulfonvl)~4-oxopiperidine-3-carboxvlate
To a mixture of 1 g (6.36 mmol) of methyl 4-oxopiperidine-3-carboxylate
hydrochloride and 2.2 mL of Et3N in 12 mL of DCM is added dropwise at room
temperature 0.5 mL of mesyl chloride. The reaction medium is stirred for 1 hour
and then taken up in 50 mL of EtOAc, washed with 20 mL of water and 20 mL of
brine and then dried over Na2SO4, filtered and concentrated under reduced
pressure. 0.35 g of methyl 1-(methylsulfonyl)-4-oxopiperidine-3-carboxylate is
obtained.

Yield = 23%
17.2. 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 at
80°C for δ hours. 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), with saturated NaHC03 solution (2 * 200 mL) and with
brine (100 mL), dried over Na2SO4, then concentrated under reduced pressure
and purified by chromatography on a column of silica gel, eluting with a
cyclohexane/EtOAc gradient of from 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, δ (ppm): 7.5 (m, 5H); 4.2 (m, 5H); 3.0 (dd, 2H; 1.0 (t,
6H)
17.3. 2,2-dimethylpropyl 6-hydrazinylpyridine-3-carboxylate
According to the process described in Example 4.2, 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, δ (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).
17.4. 2,2-dimethylpropyl 6-f5-(methylsulfonyl)-3-oxo-1.3,4.5.6.7-hexahvdro-2H-
pyrazolor4,3-c1pyridin-2-vnpyridine-3-carboxylate
According to Process 1, starting with 0.21 g of methyl 1-(methylsulfonyl)-4-
oxopiperidine-3-carboxylate and 0.2 g of 2,2-dimethylpropyl 6-hydrazinylpyridine-
3-carboxylate, 10 mg of 2,2-dimethylpropyl 6-[5-(methylsulfonyl)-3-oxo-
1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl]pyridine-3-carboxylate are
obtained.

Yield = 3%
m.p. (°C)=230
M = C18H24N4O5S = 408; M+H = 409; Method 2: Tr = 1.11 min.
1H NMR, d6-DMSO, 400 MHz, δ (ppm): 12.2 (bs, 1H); 9.0 (s, 1H); 8.6 (bs, 1H);
8.5 (d, 1H); 4.1 (s, 2H); 4.0 (s, 2H); 3.5 (t, 2H); 3.0 (s, 3H); 2.8 (t, 2H); 1.0 (s, 9H)
The tables that follow 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 R2
is in the beta position. These compounds are referred to hereinbelow as
compounds of formula (I').
Table II illustrates compounds of formula (I) according to the invention in which
R2 is in the gamma position. 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 main part 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 (O2 < 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 δ 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) a 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 * 1(T* M in medium containing 0.1% FCS (10 ul in 990 pi 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"4 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 ul of Deferoxamine
10"3M to column 2, wells A B C D and 100 ul of Deferoxamine 5x10"3 M to
column 2, wells E F G H.
• DL plate distribution in cell plates
3.3 uL 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
(HEKEA_HIF1-alphaPLBL cell plate).
The cells are then placed for δ hours in an incubator at 37°C (ambient O2, 6%
C02).
1.3.4 Measurement of the beta-galactosidase activity.
The kit used is the Prolabel chemiluminescent kit (Ref 93-0001 DiscoverX).
After incubation for δ hours at 37°C, the cells are lysed with addition of 15 pi
of lysis buffer containing the beta-galactosidase substrate (19 volumes of
Path hunter cell assay buffer + δ volumes of Emarald II solution + 1 volume of
Galacton star) directly added to 30 pi 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.


1.4 Various
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 HIF1alpha 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 δ 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 ul 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 ul in 194 ul of MEM). 200 pi of
each compound are deposited in column 12 of a 96-well plate. Dilution ranges
from 3x10^M to 3x10"^ 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 & 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
02l 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. Various
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.


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 of formula (I):

in which
n is equal to 0, 1, 2, 3 or 4;
m is equal to 0, 1 or 2;
o is equal to 0 or 1;
X represents a group -CH2, -CH(R')-, -N(R)- or a heteroatom chosen from
an oxygen atom and a sulfur atom, it being understood that R' represents a
group -(C1-C5)alkyl, -(C1-C5)alkoxy, -CH2-aryl, -C(O)R5 or -COOR5 with R5
as defined below;
R1 represents an oxo group, a group -COOR5, a group -W-OH or a group
-W-NR5R6, with W, R5 and R6 as defined below; and
R2 represents a hydrogen atom or a group chosen from (i) groups -(C1-
C5)alkyl, (ii) groups -(C1-C5)alkoxy, (iii) groups -COOR5, (iv) groups -NR5R6,
(v) groups -C(O)-NR5R6, (vi) groups -SO2-NR3R4, (vii) heteroaryl groups
optionally substituted with a group -(C1-C5)alkyl, (viii) groups -W-aryl, (ix)
groups -W-heteroaryl, (x) groups -O-W-aryl, (xi) groups -O-W-heteroaryl and
(xii) groups -O-W-NR5R6, with W, R3, R4, R5 and R6 as defined below;
it being understood that:
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, an aryl group, a heteroaryl group, a group -CH2-heteroaryl,
a group -(C1-C5)alkyl-NR5R6, a group -W-OH or a group -W-NR5R6; or
(ii) form, together with the nitrogen atom that bears them, a
heterocycloalkyl group optionally substituted with one or more groups
chosen from groups -(C1-C5)alkyl and groups -CH2-aryl;

W is a group -(C1-C5)alkylene, optionally substituted with one or more
hydroxyl groups; and
R5 and R6, which may be identical or different, represent, independently
of each other, a hydrogen atom or a group chosen from groups -(C1-C5)alkyl
and groups -(C3-C6)cycloalkyl;
in the form of the base or of an acid-addition salt.
2. Compound of formula (I) according to Claim 1, characterized in that
• n is equal to 0, 1, 2, 3 or 4;
• m is equal to 0, 1 or 2;
• o is equal to 0 or 1;
• X represents a group -CH2-, -CH(R')-, -N(R')- or a heteroatom chosen
from an oxygen atom and a sulfur atom;
• R' represents a group -(C1-C5)alkyl, a group -(C1-C5)alkoxy, a group -
CH2-aryl, a group -C(O)R5 or a group -COOR5;
• R1 represents an oxo group, a group -COOR5, a group -W-OH or a group
-W-NR5R6;
• R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-
C5)alkoxy, a group -COOR5, a group -NR5R6, a group -C(O)-NR5R6 or a
group -SO2-NR3R4;
• R3 and R4
(i) represent, independently of each other, a hydrogen atom, a
group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, an aryl group,
a heteroaryl group, a group -CH2-heteroaryl or a group -(C1-
C5)alkyl-NR5R6; or
(ii) form, together with the nitrogen atom that bears them, a
heterocycloalkyl group optionally substituted with a group -(C1-
C5)alkyl or with an aryl group;
• W represents a group -(C1-C5)alkylene, optionally substituted with one or
more hydroxyl groups; and/or
• R5 and R6 represent, independently of each other, a hydrogen atom or a

group-(C1-C5)alkyl.
3. Compound of formula (I) according to Claim 1, characterized in that
• n is equal to 0, 1, 2, 3 or 4;
• m is equal to 0, 1 or 2;
• o is equal to 0;
• R1 represents an oxo group, a group -CH2-aryl, a group -C(O)R5- or a
group -COOR5, the said group R1 possibly being linked to a carbon atom or a
heteroatom, the said aryl group advantageously representing a phenyl group;
• R3 and R4
(i) represent, independently of each other, a hydrogen atom, a
group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, an aryl
group, a heteroaryl group, a group -CH2-heteroaryl or a
group -(C1-C5)alkyl-NR5R6, advantageously, the said aryl
group representing a phenyl group and the said heteroaryl
group representing a pyridyl group or a furyl group; or
(ii) form, together with the nitrogen atom that bears them, a
heterocycloalkyl group optionally substituted with one or
more group(s) -(C1-C5)alkyl and/or aryl, advantageously, the
said heterocycloalkyl group representing a piperidyl group or
a hexamethyleneimino group and the said aryl group
representing a phenyl group;
• R5 represents a group -(C1-C5)alkyl or a group -(C1-C5)cycloalkyl;
and/or
• R6 represents a hydrogen atom or a group (C1-C5)alkyl.
4. Compound of formula (I) according to Claim 1, characterized in that
• n is equal to 1, 2, 3 or 4;
• m is equal to 0, 1 or 2;
• o is equal to 0 or 1;
• X represents a group -CH2- a group -CH(R')-, a group -N(R')- or a

heteroatom chosen from an oxygen atom and a sulfur atom;
• R' represents a group -(C1-C5)alkyl, a group -(C1-C5)alkoxy, a group -
CH2-aryl, a group -C(O)R5 or a group -COOR5;
• R1 represents an oxo group, a group COOR5, a group -W-OH or a
group -W-NR5R6;
• R2 represents a group -SO2-NR3R4;
• R3 and R4
(i) represent, independently of each other, a hydrogen atom, a
group -(C1-C5)alkyl, a group -(C3-C6)cycloalkyl, an aryl group,
a heteroaryl group or a group -CH2-heteroaryl, or
(ii) form, together with the nitrogen atom that bears them, a
heterocycloalkyl group; and
• R5 and R6 represent a group -(C1-C5)alkyl.
5. Compound of formula (I) according to Claim 1, characterized in that
• n is equal to 1,2, 3 or 4;
• m is equal to 0, 1 or 2;
• o is equal to 0 or 1;
• X represents a group -CH2-, a group -CH(R')-, a group -N(R')- or a
heteroatom chosen from an oxygen atom and a sulfur atom;
• R' represents a group -(C1-C5)alkyl, a group -(C1-C5)alkoxy, a group -
CH2-aryl, a group -C(O)R5 or a group -COOR5;
• R1 represents an oxo group;
• R2 represents a hydrogen atom, a group -(C1-C5)alkyl, a group -(C1-
C5)alkoxy, a group -COOR5, a group -NR5R6 or -C(O)-NR5R6; and
• R5 and R6 represent, independently of each other, a hydrogen atom, a
group -(C1-C5)alkyl or a group -(C1-C5)cycloalkyl.
6. Compound of formula (I) according to Claim 1, characterized in that R2
represents (i) a hydrogen atom, (ii) a group -(C1-C5)alkyl, (iii) a group -(C1-
C5)alkoxy, (iv) a group -COOR5, (v) a group -NR5R6, (vi) a group -C(O)-

NR5R6, (vii) a heteroaryl substituted with a group -(C1-C5) alkyl, (viii) a group
-O-W-aryl or (ix) a group -O-W-heteroaryl.
7. Compound of formula (I) according to Claim 1, characterized in that R2
represents a group -SO2-NR3R4.
8. Compound of formula (I) according to any one of Claims 1 to 7,
characterized in that R2 is a substituent on the atom in the beta position of
pyridine.
9. Compound of formula (I) according to any one of Claims 1 to 7,
characterized in that R2 is a substituent on the atom in the gamma position of
pyridine.
10. Compound of formula (I) according to any one of the preceding claims,
characterized in that it is:
• 2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,2,4,5,6,7-hexahydro-3H-indazol-
3-one;
• 6-methyl-2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,2,4,5,6,7-hexahydro-
3H-indazol-3-one;
• 2-[5-(piperidin-1 -ylsulfonyl)pyridin-2-yl]-1,4,5,6,7,8-hexahydrocyclo-
hepta[c]pyrazol-3(2H)-one;
• N-ethyl-6-(3-oxo-1,3,4,5,6,7-hexahydro-2H-indazol-2-yl)-N-phenylpyridine-
3-sulfonamide;
• 6-(5-benzyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N-
ethyl-N-phenylpyridine-3-sulfonamide;
• (±)2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-
1,2,4,5,6,7-hexahydro-3H-indazol-3-one;
• 2-(4-methoxypyridin-2-yl)-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-
one;
• 2-(pyridin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3(2H)-one;
• (±)5-benzyl-2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-
1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one;
• (±)2-(5-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]sulfonyl}pyridin-2-yl)-6-methyl-
1,2,4,5,6,7-hexahydro-3H-indazol-3-one;
• 6-(5-benzyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-
N,N-diethylpyridine-3-sulfonamide;

• N-ethyl-6-(3-oxo-1,3,4,5,6,7,8,9-octahydro-2H-cycloocta[c]pyrazol-2-yl)-N-
phenylpyridine-3-sulfonamide;
• N-ethyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-
phenylpyridine-3-sulfonamide;
• 6-(5-benzyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-cJpyridin-2-yl)-
N,N-di(propan-2-yl)pyridine-3-sulfonamide;
• 6-methoxy-2-(pyridin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3(2H)-
one;
• 2-(pyridin-2-yl)-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3(2H)-one;
• N-ethyl-6-(3-oxo-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-2(3H)-yl)-N-
phenylpyridine-3-sulfonamide;
• N-ethyl-6-(3-oxo-3,5,6,7-tetrahydrothiopyrano[3,2-c]pyrazol-2(1H)-yl)-N-
phenylpyridine-3-sulfonamide;
• N,N-diethyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-
3-sulfonamide;
• N,N-dimethyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
• 2-[5-(pyrrolidin-1 -ylsulfonyl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one;
• N-cyclopropyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
• 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-(propan-2-
yl)pyridine-3-sulfonamide;
• N-tert-butyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-
3-sulfonamide;
• N-(furan-2-ylmethyl)-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
• N-cyclopentyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-sulfonamide;
• N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-
(pyridin-2-yl)pyridine-3-sulfonamide;
• 2-(pyridin-2-yl)-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-one;
• 2-[4-(dimethylamino)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one;
• 2-{5-[(4-benzylpiperidin-1 -yl)sulfonyl]pyridin-2-yl}-1,2,4,6-tetrahydro-3H-
thieno[3,4-c]pyrazol-3-one;
• 6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-(pyridin-2-
yl)pyridine-3-sulfonamide;

• N-ethyl-6-(3-oxo-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-2(3H)-yl)-N-
phenylpyridine-3-sulfonamide;
• sodium 2-(4-ethylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-olate;
• Z-[5-(azepan-1-ylsurfonyl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-
c]pyrazol-3-one;
• sodium 4-benzyl-2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-4,5,6,7-
tetrahydro-2H-pyrazolo[4,3-b]pyridin-3-olate;
• N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-
(pyridin-2-ylmethyl)pyridine-3-sulfonamide;
• tert-butyl 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-1,2,3,4,6,7-
hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;
• 6-(5-acetyl-3-oxo-1,3,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)-N-
ethyl-N-phenylpyridine-3-sulfonamide;
• tert-butyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-3-
carboxylate;
• sodium 2-(4-methylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-
olate;
• sodium 2-{5-[tert-butyl(methyl)sulfamoyi]pyridin-2-yl}-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate;
• sodium 2-{5-[tert-butyl(ethyl)sulfamoyl]pyridin-2-yl}-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-olate;
• sodium 2-(5-methylpyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-
olate;
• sodium 2-[5-(tert-butylcarbamoyl)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-
c]pyrazol-3-olate;
• sodium 2-(5-methoxypyridin-2-yl)-2,6-dihydro-4H-thieno[3,4-c]pyrazol-3-
olate;
• N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-2(3H)-yl)-N-
(pyridin-4-yi)pyridine-3-sulfonamide;
• sodium 2-{5-[cyclopentyl(ethyl)sulfamoyl]pyridin-2-yl}-2,6-dihydro-4H-
thieno[3,4-c]pyrazol-3-o!ate;
• sodium 2-[4-(pyridin-3-ylmethoxy)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-
c]pyrazol-3-olate;
• methyl 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-1,2,3,4,6,7-
hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;
• cyclopentyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-yl)pyridine-
3-carboxylate;
• 2-methylpropyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-carboxylate;
• 2-[4-(propan-2-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-thieno[3,4-c]pyrazol-3-
one;

• sodium 2-[5-(propan-2-yl)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-c]pyrazol-
3-olate;
• methyl 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2 -yl}-3-oxo-2,3,4,6-tetrahydro-
1H-thieno[3,4-c]pyrazole-4-carboxylate;
• propan-2-yl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-carboxylate;
• sodium 2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-6-methoxy-2,4,5,6-
tetrahydrocyclopenta[c]pyrazol-3-oiate;
• N-ethyl-6-(3-oxo-3,4,5,6-tetrahydrocyclopenta[c]pyrazol-2(1H)-yl)-N-
phenylpyridine-3-sulfonamide;
• sodium 2-[4-(pyridin-3-ylmethoxy)pyridin-2-yl]-2,6-dihydro-4H-thieno[3,4-
c]pyrazol-3-olate;
• 2,2-dimethylpropyl 6-(3-oxo-4,6-dihydro-1 H-thieno[3,4-c]pyrazol-2(3H)-
yl)pyridine-3-carboxylate;
• 2-[5-(5-tert-butyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-
thieno[3,4-c]pyrazol-3-one;
• N-cyclopentyl-N-methyl-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazol-
2(3H)-yl)pyridine-3-sulfonamide;
• N-cyclopentyl-N-ethyl-6-(3-oxo-3,4,5,6-tetrahydrocyclopenta[c]pyrazol-
2(1H)-yl)pyridine-3-sulfonamide;
• N-cyclopentyl-N-(2,3-dihydroxypropyl)-6-(3-oxo-4,6-dihydro-1H-thieno[3,4-
c]pyrazol-2(3H)-yl)pyridine-3-sulfonamide;
• 2,2-dimethylpropyl 6-[5-(methylsulfonyl)-3-oxo-1,3,4,5,6,7-hexahydro-2H-
pyrazolo[4,3-c]pyridin-2-yl]pyridine-3-carboxylate;
• 2-[5-(3-tert-butyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]-1,2,4,6-tetrahydro-3H-
thieno[3,4-c]pyrazol-3-one.
11. Process for preparing a compound of formula (I) according to any one of
Claims 1 to 10, characterized in that a compound of formula (IV), which is in
the form of a compound of formula (IVa) or (IVb) or both:


in which X, R1, R2, n, m and are as defined in Claim 1, and z represents an
alkyl group,
is reacted with an organic base.
12. Compounds of formulae (IVa) and (IVb)

in which X, R1, R2, n, m and o are as defined in Claim 1, and z represents an
alkyl group.
13. Medicament, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 10, or an addition salt of this compound
with a pharmaceutically acceptable acid of the compound of formula (I).
14. Pharmaceutical composition, characterized in that it comprises a
compound of formula (I) according to any one of Claims 1 to 10, or a

pharmaceutically acceptable salt of this compound, and also at least one
pharmaceutically acceptable excipient.
15. Use of a compound of formula (I) according to any one of Claims 1 to 10,
for the preparation of a medicament for the treatment/prophylaxis of
cardiovascular diseases.
16. Use of a compound of formula (I) according to any one of Claims 1 to 10,
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.
17. Use of a compound of formula (I) according to any one of Claims 1 to 10,
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.
18. Use of a compound of formula (I) according to any one of Claims 1 to 10,
. for the preparation of a medicament for the treatment/prophylaxis of cardiac
or peripheral diseases of ischaemic origin via regenerative medicine using
stem cells.
19. Combination of a compound of formula (I) according to any one of Claims
1 to 10 with one or more active compound(s) that is (are) useful in the
treatment of hypertension, cardiac insufficiency, diabetes and anaemia.

20. Uniform test 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 δ 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.
21. 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 10.

The invention relates to compounds with the formula (I), in a basic state or as an acid addition salt: (I) where n is
equal to 0, 1, 2, 3 or 4; m is equal to 0, 1 or 2; o is equal to 0 or 1; X is a -CH2,-CH(R')-, -NH(R')- group or a heteroatom selected
from among O and S, where R' is a -(C1 -C5)alkyl, -(C1-C5)alcoxy, -CH2-aryl, -C(O)R5 or -COOR5 group; R1 is an oxo,
-COOR5, -W-OH or -W-NR5R6 group; R2 is an H atom or a group selected from among the following groups: (i) -(C1 -C5)alkyl,
(ii) -(C1-C5)alcoxy, (iii) -COOR5, (iv) -NR5R6, (v) -C(O)-NR5R6, (vi) -SO2-N R3R4, (vii) heteroaryl optionally substituted by a
-(Cl-C5)alkyl group, (viii) -W-aryl, (ix) -W-heteroaryl, (x) -O-W-aryl (xi) -O-W-heteroaryl and (xii) -O-W-NR5R6; where R3
and R4, which may be identical or different, (i) independently from one another are an H atom, a -(Cl-C5)alkyl, -(C3-
C6)cycloalkyl, aryL heteroaryl, -CH2-heteroaryl, -(Cl-C5)a]kyl-NR5R6, -W-OH or -W-NR5R6 group; or (ii) together with the
nitrogen atom that carries them, jointly form a heterocycloalkyl group, optionally substituted by one or more groups selected from
among the -(Cl-C5)alkyl and -CH2-aryl groups; W is a -(Cl-C5)alkylene group, optionally substituted by one or more hydroxy
groups; R5 and R6, which may be identical or different, independently from one another are a hydrogen atom or a group selected
among the -(C1-C5)alkyl groups and the -(C3-C6)cycloalkyl groups, as well as to the preparation method and to the therapeutic
uses of said compounds.