FR2949466A1 - New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators useful to treat e.g. lower limb ischemia, angina pectoris, myocardial infarction, atherosclerosis, pulmonary hypertension, glaucoma and kidney diseases - Google Patents

New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators useful to treat e.g. lower limb ischemia, angina pectoris, myocardial infarction, atherosclerosis, pulmonary hypertension, glaucoma and kidney diseases Download PDF

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FR2949466A1
FR2949466A1 FR0904092A FR0904092A FR2949466A1 FR 2949466 A1 FR2949466 A1 FR 2949466A1 FR 0904092 A FR0904092 A FR 0904092A FR 0904092 A FR0904092 A FR 0904092A FR 2949466 A1 FR2949466 A1 FR 2949466A1
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c1
group
alkyl
1h
c5
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Jean Michel Altenburger
Valerie Fossey
Stephane Illiano
Geraldine Manette
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Sanofi-Aventis France
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The invention relates to compounds of formula (1): R represents a -SO -NR3R4 group or a group R 'chosen from a hydrogen or halogen atom or a halo (C1-C5) alkyl group; CO R5, -SO-R4, (C1-C5) alkoxy, -O- (C1-C5) alkyl-heteroaryl, or O- (C1-C5) alkyl-NR5R6; R1 represents a (C3-C6) cycloalkyl group, a heterocycloalkyl group containing no nitrogen atom or a -W- (C3-C6) cycloalkyl, -W-aryl, -W-heteroaryl, -W-heterocycloalkyl group , -W-COOR5, -W-CONR5R6, said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted; where W is (C1-C5) alkylene, (C3-C6) cycloalkylene, or -C (O) -NH-; n represents 0, 1 or 2; R2 represents a hydrogen atom, a (C1-C5) alkyl, - (C1-C5) alkyl- (C1-C5) alkoxy, halogen (C1-C5) alkyl group, a -W-COOR5 group, -W- NCOR5 or -WC (O) -NR5R6, wherein W is as previously defined; R3 and R4 represent, independently of one another, a hydrogen atom, a (C1-C5) alkyl, (C3-C6) cycloalkyl, - (C1-C5) alkyl- (C1-C5) alkoxy, aryl group; , -CH -aryl, heteroaryl, heterocycloalkyl, -W-OH, -W-CHOH-CH OH, -W-CO R5, W-NR5R6, W-OH- (CH) n-aryl where W is as previously defined wherein said (C3-C6) cycloalkyl and heterocycloalkyl groups are optionally substituted, or R3 and R4 together with the nitrogen atom carrying them, form a heterocycloalkyl group optionally substituted on a carbon atom or a heteroatom by one or more substituents selected from (C1-C5) alkyl, -CH-aryl; R5 and R6 represent, independently of one another, a hydrogen atom or a (C1-C5) alkyl group. Preparation process and therapeutic application

Description

2-PYRIDIN-2-YL-PYRAZOL-3 (2H) -ONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION AS HIF ACTIVATORS

The present invention relates to novel substituted dihydropyrazolone derivatives, their preparation and their therapeutic application as activators of the transcription factor HIF. Hypoxia-Inducing Factor (HIF) (HIF1a) is a constitutively expressed transcription factor in all tissues. This protein was discovered in 1994 by Gregg Semenza during the study of regulatory sequences of the EPO gene. He identified a sequence located in the 3 'non-coding position in the EPO promoter, which is called the hypoxia response element (HRE) and which is a binding site of the HIF1a protein allowing the transcriptional activation of the Po. Subsequently, the HRE sequence was also localized on more than 70 other genes, such as VEGF (vascular endothelial growth factor) or GIut1 (glucose transporter 1). The HIF-1 transcriptional complex is at least one heterodimer consisting of the HIF1a or HIF2a protein and another transcription factor (formerly named HIF1 (3).) ARNT is constitutively and stably expressed in cells and the essential The regulation of the transcriptional complex is related to the amount of HIF1a present in the cells and is therefore the limiting factor.

Under normal oxygen conditions the HIF1a protein is rapidly degraded (half-life of 5 minutes). This degradation is due to the hydroxylation of HIF1a or HlF2a respectively on Prolines 402 and 563 and Prolines 405 and 531 on human forms by HIF Prolyl Hydroxylase (HIF_PHDs or EGLNs). This hydroxylation allows the binding of the Von Hippell Lindau protein (pVHL) associated with a ubiquitin ligase, which will cause the degradation of HIF1a or HIF2a by the ubiquitin proteasome system. When the cell or tissue is subjected to hypoxia / ischemia, HIF1a or HIF2a are no longer degraded by the ubiquitinproteasome system and can then associate with other transcription factors of the HIF complex to switch into the nucleus and activate their target genes .

Although hypoxia is the main cause of the activation of HIF1-a and HIF2a proteins by other inducers, such as insulin, growth factors can also play a role in their stabilization, notably via its serine phosphorylation. 641 and 643.

A phenotypic screening aimed at measuring the stabilization of the HIF1a and / or HIF2a protein has therefore been established to identify the compounds of the present invention. The compounds according to the present invention correspond to the formula (I): in which R represents a group -SO2-NR3R4 or a group R 'chosen from a hydrogen or halogen atom or a halogen (C1-C5) alkyl group, -CO2R5, -SO2-R4, (C1-05) alkoxy, -O- (C1-05) alkyl-heteroaryl, or O- (CI-05) alkyl-NR5R6;

R1 represents a (C3-C6) cycloalkyl group, a heterocycloalkyl group containing no nitrogen atom or a group -W- (C3-C6) cycloalkyl, -W-aryl, ûW-heteroaryl, û W-heterocycloalkyl, -W -COOR5, -W-CONR5R6, said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom optionally by one or more substituents selected from one or more halogen atoms, a group (CI- 05) alkyl, û (C 1 -C 5) alkyl- (C 1 -C 5) alkoxy, (C 1 -C 5) alkoxy, hydroxy, halo (C 1 -C 5) alkyl, cyano group, (CIC 5) alkoxy- (CI) -05) alkoxy, -O- (Cl-05) alkyl-NR5R6, SO2, -SO2- (C1-05) alkyl, -NR5R6, - CO2R5; wherein W is a (C1-C5) alkylene group, a (C3-C6) cycloalkylene group, or a -C (O) -NH- group; when W is an alkylene group (CI-05), W may be substituted by a group Z where Z is a group (CH2) n-OH, (CH2) n-CO2R5, - (CH2) n -CO2NR5R6, - (CH2 n-CO2NH-heteroaryl, - (CH2) n-NR5R6, - (CH2) n-NCOR5 or - (CH2) nO (CH2) -aryl; N is 0, 1 or 2;

R2 represents a hydrogen atom, a (C1-05) alkyl group, - (C1-05) alkyl- (C1-05) alkoxy, halogen (C1-05) alkyl, a -W-COOR5 group, -W- NCOR5 or ûW-C (O) -30 NR5R6, wherein W is as previously defined; R3 and R4 are, independently of one another, a hydrogen atom, a (C1-C5) alkyl group, C3-C6) cycloalkyl, - (C1-05) alkyl- (C1-05) alkoxy, aryl, -CH2-aryl, heteroaryl, heterocycloalkyl, -W-OH, -W-CHOH-CH2OH, -W-CO2R5, W -NR5R6, WOH- (CH2) n-aryl where W is as previously defined, said (C3-C6) cycloalkyl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom by one or more groups (C1-05 ) alkyl, (C 1 -C 5) alkoxy, hydroxy, -W-NR 5 R 6, -W-CO 2 R 5 where W is as previously defined, or R 3 and R 4 together with the nitrogen atom carrying them form an optionally heterocycloalkyl group; substituted on a carbon atom or a heteroatom by one or more substituents isis from a group (C1-05) alkyl, -CH2-aryl;

R5 and R6 represent, independently of one another, a hydrogen atom or a (C1-5) alkyl group.

The compounds of formula (I) may exist in the form of bases or salified by acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I), also form part of the invention.

The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

The different tautomeric forms of the compounds of formula (I) are also part of the invention.

In the context of the present invention, and unless otherwise indicated in the text, is meant by: a halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a saturated, linear or branched aliphatic group containing from 1 to 5 carbon atoms. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and the like; an alkylene group: an alkyl group as defined above, divalent saturated, linear or branched, which may contain from 1 to 5 carbon atoms. By way of example, mention may be made of methylene, ethylene and propylene radicals; a cycloalkyl group: a cyclic alkyl group comprising from 3 to 6 carbon atoms. By way of examples, mention may be made of cyclopropyl, cyclobutyl and cyclopentyl groups, and the like; a cycloalkylene group: a cycloalkyl group as defined above, divalent saturated, linear or branched, which may contain from 3 to 6 carbon atoms. By way of example, mention may be made of cyclopropylene radicals; an alkoxy group: an -O-alkyl radical in which the alkyl group is as previously defined; an alkoxy-alkyl group: a radical of formula alkyl-O-alkyl, in which the alkyl groups, which are identical or different, are as defined previously; an alkoxy-alkoxy group: a radical of formula -O-alkyl-O-alkyl, in which the alkyl groups, which are identical or different, are as defined previously; a haloalkyl group: an alkyl group as defined above substituted with 1 to 5 halogen atoms, as defined above. For example, trifluoromethyl group; an aryl group: a cyclic aromatic group comprising between 5 and 6 carbon atoms. As examples of aryl groups, mention may be made of the phenyl group; a heteroaryl group: a cyclic aromatic group comprising between 5 and 6 carbon atoms and comprising between 1 and 2 heteroatoms, such as nitrogen, oxygen or sulfur. As examples of heteroaryl groups, mention may be made of pyridyl groups, etc .; a heterocycloalkyl: an optionally bridged cyclic alkyl group comprising between 5 and 7 carbon atoms and comprising between 1 and 3 heteroatoms, such as oxygen, nitrogen or sulfur. Mention may especially be made of piperidinyl, piperazinyl, pyrrolidinyl, hexamethyleneimino, morpholinyl, 1,1-dioxydotetrahydrothienyl, and the like; the letters a, 3, y and S around the pyridine of the compounds of formula (I) make it possible to identify the positions of the various carbon atoms.

Among the compounds described in the present invention, there may be mentioned a first group of compounds corresponding to formula (I) in which: R represents an SO 2 -NR 3 R 4 group or an R 'group chosen from a hydrogen or halogen atom or a halo (C1-C5) alkyl group, -CO2R5, a group -SO2-R4, a (C1-05) alkoxy group, -O- (C1-05) alkyl-heteroaryl, or O- (CI-05) alkyl -NR5R6 and / or R1 represents a (C3-C6) cycloalkyl group, a heterocycloalkyl group containing no nitrogen atom or a W- (C3-C6) cycloalkyl, WW-aryl, ûW-heteroaryl, û W group; heterocycloalkyl, -W-COOR5, -W-CONR5R6, said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom optionally with one or more substituents selected from one or more halogen atoms, a (C1-05) alkyl, (C1-C5) alkyl- (C1-C5) alkoxy, (C1-C5) alkoxy, hydroxy, halogen (C1-C5) alkyl, a cyano group, a group (C1- 05) alco xy- (C1-05) alkoxy, -O- (C1-05) alkyl-NR5R6, -SO2, -SO2- (C1-05) alkyl, -NR5R6, - CO2R5, where W is a group (C1-05) alkylene, a (C 3 -C 6) cycloalkylene group, or a C (O) -NH- group; when W is a (C 1 -C 5) alkylene group, W may be substituted with a group Z where Z is a group (CH 2) n-OH, (CH 2) n -CO 2 R 5, - (CH 2) n -CO 2 N NR 5 R 6, - (CH 2 n-CO2NH-heteroaryl, - (CH2) n-NR5R6, - (CH2) n-NCOR5 or - (CH2) nO (CH2) -aryl; and / or n represents 0, 1 or 2; and / or R 2 represents a hydrogen atom, a (C 1 -C 5) alkyl, - (C 1 -C 5) alkyl- (C 1 -C 5) alkoxy, halogen (C 1 -C 5) alkyl, a -W-COOR 5 group, Wherein W is as previously defined; and / or R3 and R4 represent, independently of one another, a hydrogen atom, a (C1-C5) alkyl, (C3-C6) cycloalkyl, - (C1-C5) alkyl- (C1-C5) group; alkoxy, aryl, -CH2-aryl, heteroaryl, heterocycloalkyl, -W-OH, -W-CHOH-CH2OH, -W-CO2R5, W-NR5R6, WOH- (CH2) n-aryl where W is as previously defined, said (C3-C6) cycloalkyl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom by one or more (C1-05) alkyl, (C1-5) alkoxy, hydroxy, -W-NR5R6, -W groups; -CO2R5 where W is as previously defined, or R3 and R4 together with the nitrogen atom carrying them a heterocycloalkyl group optionally substituted on a carbon atom or a heteroatom by one or more substituents selected from a group ( C1-C5) alkyl, -CH2-aryl; and / or R5 and R6 represent, independently of one another, a hydrogen atom or a (C1-C5) alkyl group.

A first subgroup of compounds of the invention is composed of the compounds of formula (I) wherein R is -SO2-NR3R4 with R3 and R4 as defined above.

A second subgroup of compounds of the invention consists of the compounds of formula (I) in which R represents a group R 'chosen from a hydrogen or halogen atom or a halo group (C1-05) alkyl, -CO2R5, a group -SO2-R4, a (C1-05) alkoxy, -O- (C1-05) alkyl-heteroaryl, or O- (C1-05) alkyl-NR5R6.

A third subgroup of compounds of the invention consists of the compounds of formula (I) wherein R is a substituent of the atom located in position 3 of pyridine A fourth subgroup of The invention consists of the compounds of formula (I) in which R1 represents a (C3-C6) cycloalkyl group, a heterocycloalkyl group containing no nitrogen atom or a group ùW- (C3-C6) cycloalkyl, ùW aryl, -W-COOR5, -W- CONR5R6, wherein said aryl, heteroaryl and heterocycloalkyl groups are optionally substituted on a carbon atom or a heteroatom optionally by one or more one or more halogen atoms, a (C 1 -C 5) alkyl, - (C 1 -C 5) alkyl- (C 1 -C 5) alkoxy, (C 1 -C 5) alkoxy, hydroxy, halogen (C 1 -C 5) alkyl group, cyano group, - (C1-C5) alkoxy- (C1-C5) alkoxy, -O- (C1-C5) alkyl-NR5R6, -SO2, -SO2- (C1-05) alkyl, -NR5R6, - CO2R5 where W is a (C1-C5) alkylene group, a (C3-C6) cycloalkylene group, or a -C (O) -NH- group. Advantageously, the heterocycloalkyl group represents a piperidinyl group, the aryl group represents a phenyl group and the heteroaryl group represents a pyridine group.

A fifth subgroup of compounds of the invention consists of the compounds of formula (I) in which R 2 represents a hydrogen atom, a (C 1 -C 5) alkyl group, - (C 1 -C 5) alkyl- (CI) -05) alkoxy, halo (C1-C5) alkyl, -W-COOR5, -OH, -W-NR5R6, -W-NCOR5 or -W-C (O) -NR5R6, wherein W is such that previously defined.

A sixth subgroup of compounds of the invention consists of the compounds of formula (I) in which R 3 and R 4 represent, independently of one another, a hydrogen atom, a (C 1 -C 5) alkyl group, (C3-C6) cycloalkyl, - (CI-05) alkyl- (C1-05) alkoxy, aryl, -CH2-aryl, heteroaryl, heterocycloalkyl, -W-OH, -W-CHOH-CH2OH, -W-CO2R5, Wherein W is as previously defined, said (C3-C6) cycloalkyl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom by one or more groups ( C1-05) alkyl, (C1-5) alkoxy, hydroxy, -W-NR5R6, -W-OO2R5 where W is as previously defined. Advantageously, the aryl group represents a phenyl group, the heteroaryl group represents a pyridinyl group.

A seventh subgroup of compounds of the invention consists of the compounds of formula (I) in which R3 and R4 together with the nitrogen atom carrying them form a heterocycloalkyl group optionally substituted on a carbon atom or a heteroatom with one or more substituents selected from a group (CI-05) alkyl, - CH2-aryl Advantageously, the heterocycloalkyl group represents a group selected from a piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, hexamethyleneimino group, and the aryl group represents a group phenyl.

An eighth subgroup of compounds of the invention consists of the compounds of formula (I) wherein R5, R6 are independently of each other a (C1-05) alkyl group.

The subgroups defined above taken separately or in combination are also part of the invention.

There may also be mentioned the subgroup of compounds of formula (I) according to the invention in which R represents a group SO2-NR3R4; R 1 represents a heterocycloalkyl group containing no nitrogen atom or a -W-aryl, -W-heteroaryl, ûW-heterocycloalkyl group, said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom if appropriate by one or more substituents selected from one or more halogen atoms, a (C 1 -C 5) alkyl, C (C 1 -C 5) alkyl- (C 1 -C 5) alkoxy, (C 1 -C 5) alkoxy, hydroxy, halogen ( C1-C5) alkyl, cyano group, - (C1-C5) alkoxy- (C1-C5) alkoxy group, -O- (Cl-05) alkyl-NR5R6, -SO2- (Cl-05) alkyl, - NR5R6, where W is a (C1-C5) alkylene group, a (C3-C6) cycloalkylene group, or a -C (O) -NH- group; when W is a (C 1 -C 5) alkylene group, W may be substituted with a group Z where Z is a group (CH 2) n-OH, (CH 2) n -CO 2 R 5, - (CH 2) n -CO 2 N NR 5 R 6, - (CH 2 n-CO2NH-heteroaryl, - (CH2) n-NR5R6, - (CH2) n-NCOR5 or - (CH2) nO (CH2) -aryl; R2 represents a hydrogen atom, a (C1-05) alkyl, - (C1-05) alkyl- (C1-05) alkoxy, halogen (CI-05) alkyl, -WÛCOOR5, -WC (O) -NR5R6 group; or -W-C (O) -NR5R6; R3 and R4 independently of one another represent a hydrogen atom or a (C1-05) alkyl group, a - (C1-05) alkyl- (CI-05) alkoxy group, a (C3-C6) group ) cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -W-OH, -WCHOH-CH2OH, -W-CO2R5, W-NR5R6, wherein W-OH- (CH2) n-aryl, where W is as previously defined ; or R3 and R4 form together with the nitrogen atom carrying them a heterocycloalkyl group optionally substituted with a (C1-C5) alkyl or -CH2-aryl group; R5, R6 represent independently of each other a hydrogen atom or a group (C1-05) alkyl.

In what follows, the term protecting group (Pg) a group that allows, on the one hand, to protect a reactive function such as an alcohol or an amine during a synthesis. Examples of protecting groups as well as methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., 3rd Edition (John Wiley & Sons, Inc., New York).

By leaving group (Lg) is meant, in the following, a nucleofugal group that can be easily cleaved from a molecule by breaking a heterolytic bond, with the departure of an electronic pair. This group can thus be easily replaced by a nucleophilic group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups and references for their preparation are given in Advances in Organic Chemistry, J. March, 3rd Edition, Wiley Interscience, p. 310-316.

According to the invention, the compounds of general formula (I) can be prepared according to the following methods.

Scheme 1 describes the synthesis of the compounds of formula (I) for which R represents an -SO2-NR3R4 group or a group R 'chosen from a hydrogen or halogen atom or a halogen (C1-C5) alkyl group; CO2R5, -SO2-R4, (C1-5) alkoxy, -O- (C1-05) alkyl-heteroaryl, or O- (CI-05) alkyl-NR5R6; R 1 represents a cycloalkyl group, a heterocyclic group containing no nitrogen atom or a W-aryl group, ùW-heteroaryl, -W-CO 2 R 5, said groups being optionally substituted by one or more halogen atoms, an alkyl group , Ⓒ, alkoxy, hydroxy, haloalkyl, cyano, -CO2R5, where W is (C1-5) alkylene, W may be substituted by Z, where Z is (CH2) n-OH, (CH2) n-CO2R5, - (CH2) n -CO2NR5R6, - (CH2) n CO2NH-heteroaryl, - (CH2) n -NR5R6, (CH2) n-NCOR5; n may be 0, 1 or 2. These compounds are hereinafter referred to as compounds of formula (Ia). Embedded image In Scheme 1, compounds of formula (II) for which R 1 and R 2 are as defined for R 1 and R 2 are as defined for the compounds of formula (Ia) and z represents an alkyl group such as a methyl or ethyl group, react with the compounds of formula (III) to give compounds of formula (Ia) preferably in a protic solvent such as ethanol mixture acetic acid at a temperature of 80 ° C or in an aprotic solvent such as toluene, at a temperature between 80 and 110 ° C, in the presence of catalytic amounts of organic acid such as paratoluene sulfonic acid. Alternatively, they can be obtained sequentially by reaction in a methanol-acetic acid mixture to obtain the intermediate hydrazone followed by a cyclization reaction in methanol in the presence of sodium methoxide, preferably at a temperature of 40 ° C.

The compounds (I) obtained are optionally converted with the corresponding acid or base into their salt. Scheme 2 Oz O O + R 1 'CHO 2 hexane pTsOH. The compounds of formula (II) can be obtained according to Scheme 2 by a Knovenagel-type reaction between a betacetoester of formula (IV) R2000H2CO2z and an aldehyde of formula ## STR2 ## (V) R 1 CHO, for which R 1 is defined as above, and R 2 is a group (C 1 -C 5) alkyl, - (C 1 -C 5) alkyl- (C 1 -C 5) alkoxy, halogen (C 1 -C 5) alkyl, a group -W-COOR5, wherein W is as previously defined, z represents an alkyl group such as a methyl or ethyl group, in an apolar solvent, preferably n-hexane, in the presence of pyridinium paratoluensulfonate salt; catalytic amount to yield the compound of formula (VI), followed by a hydrogenation step in a polar protic solvent, preferably ethanol in the presence of a catalyst such as Palladium on Coal.

Scheme 3 R1 R2 z + R1 Lg R2 0, z O O (VII) 0 0 (IV) (II)

Alternatively, the compounds of formula (II) can be obtained according to scheme 3 sequentially by deprotonation of betacetoester of formula (IV) R2000H2CO2z with an organic alkoxide base, preferably sodium methoxide in an alcoholic solvent, or an inorganic base. such as potassium hydroxide or a strong base such as sodium hydride, followed by the addition of an electrophile of formula (VII) R1-CH2-Lg, where R1 is as defined above and R2 is

A group (C1-05) alkyl, - (C1-05) alkyl- (C1-5) alkoxy, halogen (C1-05) alkyl, a group -W-COOR5, wherein W is as previously defined and z is an alkyl group such as a methyl or ethyl group and Lg is as previously described. The synthesis of the compounds of formula (II) wherein R1 is of the type W-Aryl or W-heteroaryl with W representing a branched alkylene group of the formula CH (alkyl) (alkyl) is described in Scheme 4. These compounds are referred to hereinafter compounds of formula (IIa).

Embedded image The compounds of formula (IX) are obtained by condensation of a ketone of formula (VIII) R7COR8, with R7 and R8 being able to be independently or together a C1 alkyl group. at C4, on a betacetoester of formula (IV) R2-CH2-OO2z where R2 is defined as

As before and z is an alkyl group such as a methyl or ethyl group, in the presence of a Lewis acid, preferably zinc chloride in a solvent such as acetic anhydride at a temperature between 40 ° C and 40 ° C. 80 ° C. The compounds of formula (IIa) are then obtained by the addition of 1,4 an organometallic compound of formula (X) Aryl-Metal (ArM), preferably an organomagnesium compound of type

Aryl-MgX, with X representing a halogen atom such as a bromine or chlorine atom, in the presence of a catalytic amount of copper iodide on the compound of formula (IX) in an anhydrous solvent, preferably ethyl ether. The synthesis of the compounds of formula (II) for which R 2 is hydrogen is described in Scheme 5. These compounds are hereinafter referred to as compounds of formula (IIb). Embedded image The compounds of formula (II) IIb) are obtained by formylation of the ester (V) of formula R1-CH2-OO2z where R1 is defined as above and z is an alkyl group such as a methyl or ethyl group. The formylation step consists in preferentially reacting the methyl or ethyl formate on the ester (V) in the presence of either metallic sodium in an anhydrous solvent such as ethyl ether, at a temperature of between 0 ° C. C and 30 ° C, in the presence of a Lewis acid such as titanium tetrachloride, an organic base such as tributylamine in the presence of catalytic amounts of trimethylsilyltrifluoromethanesulfonate in an aprotic solvent such as toluene at a temperature between 50 ° C and 60 ° C. When they are not commercial, the synthesis of the compounds of formula (III) for which R represents a haloalkyl group or -CO 2 R 5 with R 5 as described above is described in scheme 6. These compounds are hereinafter called compounds of formula (IIIa).

Embedded image The compounds of formula (IIIa) are obtained from compound XI, with Lg and R as defined above, by addition of hydrazine hydrate, preferably in a mixture. protic solvent such as EtOH at a temperature between 60 and 80 ° C.

The synthesis of the compounds of formula (III) for which R represents a group - SO2NR3R4 and R3 and R4 are as previously described is described in scheme 7. These compounds are hereinafter referred to as compounds of formula (IIIb). Scheme 7 R3,, SO2, R4 (XIV) NH2-NH2. The compounds of formula (IIIb) are obtained from 2-chloro-5-sulphonylpyridine chloride of formula (XII), by reaction with an amine of (IIb) formula (X111) R3NHR4 with R3 and R4 as defined above, in the presence of an organic base, preferably triethylamine, in a polar solvent, preferably dichloromethane.

The resulting compound of formula (XIV) is then treated with hydrazine hydrate in a protic solvent such as ethanol at 70 ° C to yield the desired compounds. The synthesis of the compounds of formula (III) for which R represents R 'which is an alkyl or alkoxy group is described in scheme 8.

These compounds are hereinafter called compounds of formula (IIIc). The compounds of formula (IIIc) are obtained from the compound of formula (XV), with Lg and R as defined above. The hydrazine function is introduced by a coupling reaction between the benzophenone hydrazone of formula (XVI) and the compound of formula (XV) in the presence of a catalytic amount of palladium to yield the intermediate of formula (XVII), the Hydrazine function is released by acid treatment such as hydrochloric acid, in a binary mixture of immiscible solvents such as toluene and water at a temperature of 100 ° C. Scheme 8 R "Pd" XVII 'NH2 XVI XV HN'NH2 Scheme 9 describes the synthesis of the compounds (I) for which RI is a group ùW-aryl, ùW-heteroaryl, said groups being substituted with one or more groups - NR5R6 and wherein W is a (Cl-05) alkylene group. These compounds are hereinafter referred to as compounds of formula (Ib). ## STR3 ## ## STR1 ## ## STR2 ## ## STR2 ## The compound of formula (XIX) is obtained by reaction of a betacetoester compound of formula (IV) R2000H2CO2z, R2 being (C1-05) alkyl, - (C1-05) alkyl- (C1-C5) alkoxy, halogen (C1-05) alkyl and z representing an alkyl group such as a methyl or ethyl group, and a benzaldehyde compound of formula (XVIII) substituted with one or more nitro groups. The compound of formula (XX) is then obtained by total hydrogenation in the presence of a catalyst such as palladium on carbon in a protic solvent such as ethanol, preferably followed by a reductive amination, under conditions such that when R5 and R6 is a methyl group, formic acid in the presence of a reducing agent such as sodium triacetoxyborohydride in a solvent such as acetic acid. Compound (XX) is then reacted as described in Scheme 1 with the compound of formula (III) to yield the desired compounds of formula (Ib). 5

Scheme 10 describes the synthesis of compounds (I) wherein R1 is a--aryl group, with W is a (CI-O 5) alkylene group; said aryl group being substituted with one or more groups, O- (C 1 -C 5) alkyl-O- (C 1 -C 5) alkyl- (C 1 -C 5) alkoxy, -O- (C 1 -C 5) alkyl-NR 5 R 6. These compounds are hereinafter called compounds of formula (Ic).

Scheme 10 R2 CHO1 pTsOHPy, hexane OO A; Embedded image The compound of formula (XXII) is obtained by reacting a beta-beta-ester compound. of formula (IV) R2000H2CO2z with R2 is as previously described and z represents an alkyl group such as a methyl or ethyl group and a benzaldehyde compound of formula (XXI), followed by a total hydrogenation step of presence of palladium on carbon, preferably in a solvent such as ethanol. The compound of formula (XXIV) is then obtained by alkylation with a compound of formula (XXIII) R9-Lg, with R9 representing a (C1-05) alkylene group, - (C1-05) alkyl- (C1-05 ) alkoxy, - (C1-05) alkyl-NR5R6 and Lg as defined above, in the presence of a preferentially inorganic base such as potassium carbonate and in a polar solvent such as DMF; then it is reacted as described in Scheme 1 with the compound of formula (III) to yield the desired compounds of formula (Ic). Scheme 11 describes the synthesis of the compounds of formula (I) wherein R 1 is -CONH-R 10, where R is aryl or heteroaryl optionally substituted by one or more halogen atoms, alkyl, -alkoxy, a -O-alkyl-alkoxy group. These compounds are hereinafter referred to as compounds of formula (Id).

Embedded image The compounds of formula (Id) are obtained by addition to the compound of formula (XXV) with R 3 and R 4. independently of one another a hydrogen atom, a (C 1 -C 5) alkyl, (C 3 -C 6) cycloalkyl, - (C 1 -C 5) alkyl- (C 1 -C 5) alkoxy, aryl, -CH 2 group aryl, heteroaryl and R2 being a (C1-C5) alkyl, - (C1-C5) alkyl- (C1-C5) alkoxy, halogen (C1-C5) alkyl, of an isocyanate of formula (XXVI) R10NCO, with R10 as previously defined in a polar solvent, preferably DMSO in the presence of an organic base such as triethylamine at room temperature.

In the following schemes, starting compounds, intermediates and reagents, when their mode of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods known from the art. the skilled person.

The invention, according to another of its aspects, also relates to the compounds of formula (XXV). These compounds are useful as synthesis intermediates for the compounds of formula (I). The following examples illustrate the preparation of certain compounds according to the invention. The numbers of the compounds exemplified refer to those of the table given below which illustrates the chemical structures and the physical properties of some compounds according to the invention.

The following abbreviations and formulas are used: AcOEt Ethyl acetate DCM Dichloromethane DMF Dimethylformamide DMSO Dimethyl sulfoxide DME 1,2 dimethoxyethane EtOH Ethanol Et2O diethyl ether MeOH Methanol iPrOH Isopropanol AcOH Acetic acid CH3CN Acetonitrile Et2O Diethyl ether THF Tetrahydrofuran h s) 20 HCl Hydrochloric acid H2SO4 Sulfuric acid K2CO3 Potassium carbonate KOH Potassium hydroxide NH4Cl Ammonium chloride NaHCO3 Sodium hydrogencarbonate Na2SO4 Sodium sulphate Cs2CO3 Cesium carbonate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TA Room temperature ZnCl2 Zinc chloride PPTS Pyridinium paratoluenesulfonic acid anh. anhydrous 35 Pd -1 Palladium on carbon Cu 1 Copper iodide MeCN Acetonitrile Nal Sodium iodide DIEA Diisopropylethylamine TBTU O- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate DCC N, N-Dicyclohexylacarbodiimide NMM N-methyl

Proton magnetic resonance (1 H NMR) spectra, as described below, are recorded at 400MHz in DMSO-d6, using the peak of DMSO-d5 as a reference. The chemical shifts 8 are expressed in parts per million (ppm). The signals observed are expressed as follows: s = singlet; sl = broad singlet; d = doublet; dd = doublet of doublet; dt = doublet of triplet; t = triplet; m = massive; H = proton The mass spectra are obtained under the following LC / MS coupling conditions: Method 1: Column Jsphere33 * 2 mm; 4pM; eluents: A = H2O + 0.05% TFA; B = CH3CN +0.05% TFA; TO: 98% A; T1.0 to T5.0min: 95% B;

Method 2: Column: Acquity BEH C18 (50 * 2.1 mm, 1.7 NM); eluents: A = H2O 20 + 0.05% TFA; B = CH3CN + 0.035TFA; TO: 98% A; T1.6 to T2.1min: 100% B; T2.5 at T3min: 98% A, Flow rate 1.0mL / min-T ° C = 40 ° C, 2pL injection Method 3: Kromasil C18 column (50 * 2.1mm, 3.5pm); eluents: CH3CO2NH4 + 3% CH3CN; B = CH3CN; TO: 100% A; T5.5 to T7min: 100% B, T7.1 to Tl Omin: 100% B; Flow 0.8mL / min -T ° = 40 ° C - Injection 5pL 25 The retention time is recorded by Tr.

Example 1: N-ethyl-6- (3-methyl-4- (1-methyl-1-phenylethyl) -5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine 3-sulfonamide (Compound No. 77 of Table I) 1.1 Methyl 2-acetyl-3-methylbut-2-enoate To a mixture of 9.54 g (70 mmol) of ZnCl 2 anh, 53.9 mL (500 mmol) of methylacetoacetate, and 55 ml (750 mmol) of acetone, 64 ml of acetic anhydride are added, the reaction medium is then heated for 3 days at 50 ° C., then diluted with 1 L of DCM and washed. with water (3 × 100 mL) The organic phase is dried over Na 2 SO 4, filtered and then concentrated under reduced pressure The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 10% of AcOEt After concentration under reduced pressure, 51.5 g of methyl 2-acetyl-3-methylbut-2-enoate are obtained in the form of a colorless oil.

Yield = 70% 1H NMR, CDCl 3, 400MHz, b (ppm): 3.79 (s, 3H); 2.29 (s, 3H); 2.12 (s, 3H); 1.97 (s, 3H).

1.2. Methyl 2-acetyl-3-methyl-3-phenylbutanoate to a suspension of 146 mg (0.8 mmol) of Ass (I) anh. in 5 mL of ether is added, at 0 ° C, under argon flow, 3.6 mL (10.9 mmol) of a 3M solution in Et2O phenylmagnesium bromide. After stirring for 1 h at 0 ° C., 1 g (6.4 mmol) of methyl 2-acetyl-3-methylbut-2-enoate is added all at once at 0 ° C. It is allowed to return to RT and stirring is continued 18h. The reaction mixture is then treated with 100 ml of saturated NH 4 Cl solution, decanted, and the organic phase is again treated with 100 ml of a saturated solution of NH 4 Cl. The aqueous phases are extracted with 4X100 mL of DCM. The organic phases are combined, dried over Na2SO4 anh. and concentrated under reduced pressure. After purification on silica gel, eluting with a mixture of cyclohexane / AcOEt 95: 5, 1 g of methyl 2-acetyl-3-methyl-3-phenylbutanoate is obtained in the form of a colorless oil.

Yield = 67%. 1H NMR, CDCl3, 400MHz, b (ppm): 7.4-7.2 (m, 5H); 3.9 (s, 1H); 3.8 (s, 3H); 1.90 (s, 3H); 1.6 (s, 3H), 1.55 (s, 3H).

1.3. N-ethyl-6- (3-methyl-4- (1-methyl-1-phenylethyl) -5-oxo-2,5-dihydro-1H-pyrazol-1-yl-N-phenylpyridine-3-sulfonamide solution of 200 mg (0.85 mmol) of methyl 2-acetyl-3-methyl-3-phenylbutanoate in 2 mL of an EtOH / AcOH mixture (1: 1), 249 mg (0.85 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and the reaction mixture is then heated for 2 hours at 90 ° C. After concentration under reduced pressure, the residue is taken up in 100 ml of DCM, washed with 2 × 30 ml of saturated NaHCO 3 solution, dried over Na 2 SO 4, filtered, concentrated under reduced pressure and then purified by chromatography on a gel column. silica eluting with a cyclohexane / AcOEt gradient from 0 to 20% AcOEt. After concentration under reduced pressure, 312 mg of a yellow oil are obtained which is concretized in 20 ml of pentane. The solid obtained is filtered and then dried under vacuum. 178 mg of N-ethyl-6- [3-methyl-4- (1-methyl-1-phenylethyl) -5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -N- are obtained. phenylpyridine-3-sulfonamide in the form of a white powder. Yield = 44% F (° C) = 122 M = C 26 H 28 N 4 O 3 S = 476; M + H = 477; Method 2: Tr = 1.54 min 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.55 (sl, 1H); 8.45 (s, 1H); 8.1 (d, 1H); 7.5-7.3 (m, 7H); 7.2 (m, 1H); 7.1 (d, 2H); 3.65 (q, 2H); 1.9 (s, 3H); 1.7 (s, 6H); 1.0 (t, 3H).

Example 2: N-ethyl-6- [3-methyl-5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3 sulfonamide (Compound No. 43 of Table I) 2.1. (2E / Z) -3-oxo-2- (pyridin-3-ylmethylidene) methyl butanoate A mixture of 10 g (86 mmol) of methyl 3-oxobutanoate 9.2 g (86 mmol) of pyridine-2 -carboxaldehyde and 70 mg (1.1 mmol) of PPTS in 27 mL of hexane is refluxed in a Dean & Stark assembly for 48 h. The medium is then concentrated under reduced pressure, taken up in 50 ml of AcOEt, washed successively with water (2 × 100 ml), brine (100 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. 17.6 g of methyl 12E / Z) -3-oxo-2- (pyridin-3-ylmethylidene) butanoate are obtained in the form of a yellow oil which is used as it is in the next step. Yield = 99%. 1H NMR, CDCl3, 400MHz, b (ppm): 8.7 (s, 1H); 8.5 (d, 1H); 8.00 (d, 1H); 7.6 (s, 1H); 7.35 (dd, 1H); 3.7 (s, 3H); 2.3 (s, 3H). 2.2. Methyl 3-oxo-2- (pyridin-3-ylmethyl) butanoate In a Parr apparatus, a mixture of 14 g (68 mmol) of (2E / Z) -3-oxo-2- (pyridin-3-ylmethylidene) ) Methyl butanoate in 200 mL of MeOH and 2.2 g of 10% Pd / C is hydrogenated at 7 bar for 48 h. The reaction mixture is then filtered on Whatman GF / F paper and concentrated under reduced pressure. 14 g of methyl 3-oxo-2- (pyridin-3-ylmethyl) butanoate are thus obtained in the form of a dark yellow oil which is used as it is in the next step.

Yield = 99%. 1H NMR, CDCl3, 400MHz, b (ppm): 8.5 (m, 2H); 7.28 (dl H); 7.21 (ddI H); 3.78 (t, 1H); 3.71 (s, 3H); 3.16 (dd, 2H); 2.23 (s, 3H).

2.3 N-Ethyl-6- [3-methyl-5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-yl-N-phenylpyridine-3-sulfonamide hydrochloride A solution of 300 mg (1.45 mmol) of methyl 3-oxo-2- (pyridin-3-ylmethyl) butanoate and 423 mg (1.45 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine 3-sulfonamide in 4 mL of EtOH / AcOH (1: 1) is heated for 4 h at 85 ° C. After returning to RT, the precipitate obtained is filtered and then washed successively with Et2O (20 mL) and pentane (20 mL). 210 mg of a residue are isolated, which is taken up in 40 ml of water, 2 ml of acetonitrile and 0.48 ml of a 0.2N HCl solution and then lyophilized. Thus 220 mg of hydrochloride are obtained N-ethyl-6- [3-methyl-5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide under form of a white lyophilisate.

Yield = 33% F (° C) = 128 M = C23H23N5O3S = 449; M + H = 450; Method 2: Tr = 0.85min 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.5 (sl, 1H); 8.90 (s, 1H); 8.8 (d, 1H); 8.6 (d, 1H); 8.5 (d, 1H); 8.4 (s, 1H); 8.2 (dd, 1H); 8.05 (dd, 1H); 7.4 (m, 3H); 7.1 (d, 2H); 3.8 (s, 2H); 3.65 (q, 2H); 2.3 (s, 3H); 1.0 (t, 3H).

Example 3: 6- (4- {3- [2- (Dimethylamino) ethoxy] benzyl} -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-hydrochloride ethyl-N-phenylpyridine-3-sulfonamide (Compound No. 56 of Table I) 3.1. Methyl (2E / Z) -2 - [(3-hydroxyphenyl) methylidene-3-oxobutanoate According to the process described in Example 2.1, from 5 g of 3-hydroxybenzaldehyde and 4,75 g of 3-oxobutanoate are obtained. methyl, 2.5 g of methyl (2E / Z) -2 - [(3-hydroxyphenyl) methylidene] -3-oxobutanoate as a light yellow powder.

Yield = 27% 1H NMR (CDCl3, 400MHz, δ (ppm): 7.4 (s, 1H), 7.2 (m, 1H), 6.9-6.8 (m, 2H); 5.1 (s, 1H), 3.8 (s, 3H), 2.4 (s, 3H), 2.4 (s, 3H).

3.2 Methyl 2- (3-hydroxybenzyl) -3-oxobutanoate According to the method described in Example 2.2, from 2.5 g of methyl (2E / Z) -2 - [(3-hydroxyphenyl) methylidene) is obtained. ] -3-oxobutanoate, 2.5 g. methyl 2- (3-hydroxybenzyl) -3-oxobutanoate in the form of a translucent wax. Yield = 99% 1 H NMR CDCl3, 400 MHz, δ (ppm): 7.15 (t, 1H); 6.7-6.85 (m, 3H); 5.6 (s, 1H); 3.7 (s, 3H); 3.15 (d, 2H); 2.25 (s, 3H).

3.3. Methyl 2- (3- [2- (dimethylamino) ethoxylbenzyl) -3-oxobutanoate A mixture of 1.5 g (6.75 mmol) of methyl 2- (3-hydroxybenzyl) -3-oxobutanoate, 6.6 g (20.25 mmol) of Cs2CO3 anh, 0.1 g (0.67 mmol) of NaI and 1 g (7.1 mmol) of 2-dimethylaminoethyl chloride hydrochloride in 20 mL of CH3CN anh. heated for 4 h at 90 ° C., then stirred overnight at RT The reaction medium is then filtered and then concentrated under reduced pressure The residue obtained is taken up in DCM (100 mL), washed with brine (30 mL) ), dried over Na2SO4, filtered, concentrated under reduced pressure and then purified by chromatography on a silica gel column eluting with a DCM / MeOH gradient of 0 to 10% MeOH.After concentration under reduced pressure, 409 mg is obtained. of methyl 2- {3- [2- (dimethylamino) ethoxy] benzyl} -3-oxobutanoate as a brown wax, Yield = 19.5% 1H NMR, CDCl3, 400MHz, δ (ppm): 7, 2 (t, 1H), 6.7-6.8 (m, 3H), 4.1 (t, 2H), 3.8 (t , 1H), 3.7 (s, 3H), 3.15 (d, 2H); 2.8 (t, 2H); 2.4 (s, 6H); 2.3 (s, 3H).

3.4. 6- (443- [2- (Dimethylamino) ethoxylbenzyl) -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3- hydrochloride According to the process described in Example 2.3, from 195 mg of methyl 2-35 {3- [2- (dimethylamino) ethoxy] benzyl} -3-oxobutanoate and 194 mg of N-ethyl- 6-hydrazino-N-phenylpyridine-3-sulfonamide, 70 mg of 6- (4- {3- [2- (dimethylamino) ethoxy] benzyl} -3-methyl-5-oxo-2,5-dihydro-hydrochloride 1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide as a white lyophilizate. Yield = 20% F (° C) = 124M = C28H33N5O4S = 535; M + H = 536; Method 2: Tr = 0.98 min 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 10.0 (sl, 1H); 8.6 (d, 1H); 8.4 (s, 1H); 8.1 (d, 1H); 7.4 (m, 3H); 7.25 (t, 1H); 7.15 (d, 2H); 6.9 (d, 2H); 6.8 (d, 1H); 4.3 (t, 2H); 3.6 (q, 2H); 3.5 (s, 2H); 3.4 (t, 2H); 2.8 (s, 6H); 2.2 (s, 3H); 1.0 (t, 3H).

Example 4: 6- {4- [3- (Dimethylamino) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-ethyl-N-phenylpyridine-3 -sulfonamide (Compound No. 53 of Table I) 1 4.1. Methyl (2Z / E) -2 - [(4-nitrophenyl) methyliden-3-oxobutanoate According to the method described in Example 2.1, from 6.18 g of 4 nitrobenzaldehyde and 4.75 g of Methyl 3-oxobutanoate, 4.2 g of methyl (2Z / E) -2 - [(4-nitrophenyl) methylidene] -3-oxobutanoate as an oil. Yield = 41% 1HCDCl3 NMR, 400MHz, b (ppm): 8.4 (s, 1H); 8.3 (d, 1H); 7.8 (d, 1H); 7.6 (m, 2H); 3.9 (s, 3H); 2.5 (s, 3H). 4.2. Methyl 2- (4-aminobenzyl) -3-oxobutanoate According to the process described in Example 2.2, 4.2 g of methyl (2ZIE) -2 - [(4-nitrophenyl) methylidene] -3 are obtained. oxobutanoate, 2 g of methyl 2- (4-aminobenzyl) -3-oxobutanoate in the form of an oil. 1H NMR, CDCl3, 400MHz, b (ppm): 7.1 (t, 1H); 6.6-6.5 (m, 3H); 3.9 (t, 1H); 3.8 (s, 3H); 3.7 (sl, 2H); 3.1 (d, 2H); 2.2 (s, 3H). Yield = 54%

4.3. Methyl 2- [4- (dimethylamino) benzyl] -3-oxobutanoate To a mixture of 1.5 g (6.78 mmol) of methyl 2- (4-aminobenzyl) -3-oxobutanoate, 40 ul (0.04 mmol) of AcOH and 5.1 ml (67.8 mmol) of a 37% aqueous formaldehyde solution in 13 mL of CH 3 CN were added at 0 ° C in small portions, 4.3 g H 2 O ( 20.34 mmol) of sodium triacetoxyborohydride. The reaction medium is then allowed to gradually return to RT and stirring is continued for 12 hours. The reaction mixture is poured into 50 ml of a saturated solution of NaHCO 3 and 30 g of ice, extracted with AcOEt (2 × 100 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure and then purified by chromatography on a gel column. silica eluting with a cyclohexane / AcOEt gradient from 0 to 50% AcOEt. Afterwards 344 mg of methyl 2- [4- (dimethylamino) benzyl] -3-oxobutanoate are obtained in the form of a yellow oil. Yield: 20% 1H NMR, CDCl3, 400MHz, b (ppm): 7.1 (t, 1H); 6.65 (d, 1H); 6.55 (m, 2H); 3.9 (t, 1H); 3.8 (s, 3H); 3.2 (d, 2H); 3.0 (s, 6H); 2.2 (s, 3H).

4.4. 6- {4- [3- (dimethylamino) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-ethyl-N-phenylpyridine-3-sulfonamide According to the process described in Example 2.3, 172 mg of methyl 2- [4- (dimethylamino) benzyl] -3-oxobutanoate and 202 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3 are obtained from 172 mg. sulfonamide, 138 mg of 6- {4- [3- (dimethylamino) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-ethyl-N-phenylpyridine- 3-sulfonamide as a white solid. Yield = 41% F (° C) = 122 M = C 26 H 29 N 5 O 3 S = 491; M + H = 492; Method 2: Tr = 0.96 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.7 (sl, 1H); 8.45 (s, 1H); 8.1 (d, 1H); 7.4 (m, 3H); 7.2 (d, 2H); 7.1 (t, 1H); 6.7 (s, 1H); 6.5 (d, 2H); 3.7 (q, 2H); 3.5 (s, 2H); 2.9 (s, 6H); 2.15 (s, 3H); 1.0 (t, 3H).

Example 5: N, N-dimethyl-6- [3-methyl-5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-yl] pyridine-3-sulfonamide (Compound No. 66 of Table I) 5.1. 6-chloro-N, N-dimethylpyridine-3-sulfonamide To a mixture of 4.7 mL (9.43 mmol) of dimethylamine (2N in THF) and 2.6 mL (18.86 mmol) of TEA in 20 ml of THF is added, at 0 ° C., dropwise a solution of 2 g (9.43 mmol) of 6-chloropyridine-3-sulphonyl chloride (prepared according to document WO9840332) in 5 ml of THF. . After 40 minutes of stirring at 0 ° C., the reaction medium is taken up in 40 ml of AcOEt, washed with water (2 × 40 ml) and brine (40 ml), dried over Na 2 SO 4, filtered and dried. concentrated under reduced pressure. 1.93 g of 6-chloro-N, N-dimethylpyridine-3-sulfonamide are obtained in the form of a brown solid which is used as it is in the next step. Yield = 93% 1 H NMR CDCl3, 400MHz, b (ppm): 8.8 (s, 1H); 8.0 (d, 1H); 7.4 (d, 1H) 2.7 (s, 6H).

5.2. 6-Hydrazino-N, N-dimethylpyridine-3-sulfonamide A mixture of 1.9 g (8.8 mmol) of 6-chloro-N, N-dimethylpyridine-3-sulfonamide and 4.6 ml (91.5 mmol) of hydrazine monohydrate in 10 mL of EtOH is heated for 2 h at 80 ° C. The precipitate obtained, after returning to RT, is filtered and then washed with 10 mL of EtOH and dried under vacuum. 1.62 g of 6-hydrazino-N, N-dimethylpyridine-3-sulfonamide is obtained in the form of a white powder.

1H NMR, d6-DMSO, 400MHz, b (ppm): 8.5 (sl, 1H); 8.3 (s, 1H); 7.7 (d, 1H); 6.85 (d, 1H); 4.4 (s, 2H); 2.6 (s, 6H).

5.3. N, N-dimethyl-6- [3-methyl-5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-ylpyridine-3-sulfonamide A mixture of 400 mg ( 1.85 mmol) of 6-hydrazino-N, N-dimethylpyridine-3-sulfonamide and 383 mg (1.85 mmol) of methyl 3-oxo-2- (pyridin-3-ylmethyl) butanoate in 4 mL of EtOH / AcOH (1: 1) was heated for 4 h at 80 ° C and then concentrated under reduced pressure. The residue obtained is taken up in 20 ml of AcOEt, washed successively with water (2 × 20 ml), a saturated solution of NaHCO 3 (20 ml), brine (20 ml), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue is then concreted in 20 ml of Et2O / pentane (1: 1), filtered and recrystallized from a cyclohexane / EtOH mixture. 188 mg of N, N-dimethyl-6- [3-methyl-5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-yl] pyridine-3 are obtained sulphonamide in the form of a white crystals.

Yield = 28% F (° C) = 212 M = C 17 H 19 N 5 O 3 S = 373; M + H = 374; Method 2: Tr = 0.58 min 1H NMR, d6-DMSO, 400MHz, 6 (ppm): 12 (sl, 1H); 8.7 (s, 1H); 8.65 (d, 1H); 8.5 (s, 1H); 8.4 (d, 1H); 8.35 (d, 1H); 7.7 (d, 1H); 7.3 (dd, 1H); 3.6 (s, 2H); 2.7 (s, 6H); 2.2 (s, 3H). Example 6: N-ethyl-6- {4- [3- (methoxymethyl) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol 1-yl} -N-phenylpyridine-3-sulfonamide (Compound No. 34 of Table I) 6.1. Methyl 3- (methoxymethyl) benzoate To a solution of 15 g (65.5 mmol) of methyl 3- (bromomethyl) benzoate in 20 ml of MeOH anh., A solution of methoxide is added dropwise to RT. of sodium in MeOH, prepared from 2.25 g (98.2 mmol) of sodium in 65 mL of MeOH. The reaction medium is then heated for 4 h at 65 ° C. and then concentrated under reduced pressure, taken up in 500 ml of DCM, washed with water (100 ml) and brine (100 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. 7.8 g of methyl 3- (methoxymethyl) benzoate are obtained in the form of an oil which is used as it is in the next step. Yield = 66% 1H NMR, CDCl3, 400MHz, b (ppm): 8.1 (s, 1H); 8.0 (d, 1H); 7.5 (d, 1H); 7.4 (t, 1H); 4.5 (s, 2H); 4.0 (s, 3H); 3.4 (s, 3H).

6.2. 2 (3- (methoxymethyl) phenylmethanol To a solution of 7.8 g (43.3 mmol) of methyl 3- (methoxymethyl) benzoate in 60 mL of THF / dioxane (1: 1) is added 0, 94 g (43.3 mmol) of lithium borohydride The reaction medium is then heated for 3 h at 80 ° C. and then stirred overnight at RT The reaction medium is taken up in 500 ml of AcOEt, washed with water ( 2X100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, 5.9 g of 2 [3- (methoxymethyl) phenyl] methanol are obtained in the form of a yellow liquid which is used as it is in the next step. Yield = 90% 1H NMR, CDCl3, 400MHz, 15 (ppm): 7.4-7.2 (m, 4H), 4.7 (s, 2H), 4.5 (s, 2H); 4 (s, 3H); 2.4 (sl, 1H). 6.3.1- (bromomethyl) -3- (methoxymethyl) benzene To a solution of 5.91 g (38.8 mmol) of (Methoxymethyl) phenyl] methanol in 75 ml of Et2O, 9.1 ml (97.1 mmol) of phosphorus tribromide are added dropwise at 0 ° C. The reaction mixture is allowed to rise slowly. at RT and stirring is maintained for 4 h. The reaction crude is then poured carefully onto a mixture of 100 g of ice and 100 ml of MeOH. After evaporation of the MeOH under reduced pressure, the aqueous phase is extracted with DCM (2 × 200 mL). The organic phases are combined, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 20% AcOEt. 3.25 g del- (bromomethyl) -3- (methoxymethyl) benzene are thus obtained in the form of an oil. Yield = 39% 1H NMR CDCl3, 400MHz, b (ppm): 7.4-7.1 (m, 4H); 4.45 (s, 2H); 4.35 (s, 2H); 3.3 (s, 3H).

6.4. Methyl 2- (3-methoxymethyl) benzyl-3-oxobutanoate To a solution of 0.34 g (15.1 mmol) of sodium in 8 mL of MeOH anh., Under argon, is added dropwise at RT, 6 mL (15.1 mmol) of methylacetoacetate.

After% h stirring, 3.25 g (15.11 mmol) of 1- (bromomethyl) -3- (methoxymethyl) benzene are added by dropwise dropwise and the reaction medium is heated for 2 h 30 at 70 ° C. The reaction medium is then concentrated under reduced pressure, the residue obtained is purified by column chromatography on silica gel eluting with a cyclohexane / AcOEt gradient from 0 to 20% AcOEt. 3.2 g of methyl 2- [3- (methoxymethyl) benzyl] -3-oxobutanoate are obtained in the form of an oil. Yield = 85% 1H NMR, CDCl 3, 400MHz, b (ppm): 7.4-7.1 (m, 4H); 4.45 (s, 2H); 3.8 (t, 1H); 3.7 (t, 3H); 3.4 (t, 3H); 3.2 (d, 2H); 2.2 (s, 3H). 6.5. N-ethyl-6- {4- [3- (methoxymethyl) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-phenylpyridine-3-sulfonamide According to the process described in Example 2.3, from 300 mg of methyl 2- [3- (methoxymethyl) benzyl] -3-oxobutanoate and 350 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide are obtained 341 mg of N-ethyl-6- {4- [3- (methoxymethyl) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-phenylpyridine- 3-sulphonamide in the form of a white powder. Yield = 58% F (° C) = 144 M = C 26 H 28 N 4 O 4 S = 492; M + H = 493; Method 2: Tr = 1.29 min.

1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.7 (sl, 1H); 8.45 (s, 1H); 8.1 (d, 1H); 7.4 (m, 3H); 7.3-7.1 (m, 6H); 4.35 (s, 2H); 3.6 (q, 2H); 3.5 (s, 2H); 3.3 (s, 3H); 2.15 (s, 3H); 1.0 (t, 3H).

Example 7: N-ethyl-6- [3-methyl-5-oxo-4- (2-phenylethyl) -2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide (Compound No. 74 of Table I) 7.1. Methyl 3-oxo-2- (2-phenylethyl) butanoate According to the process described in Example 6.4, 5.16 g of (2-bromoethyl) benzene and 3.2 g of methylacetoacetate are obtained, 1.9 g of methyl 3-oxo-2- (2-phenylethyl) butanoate in the form of a translucent oil. Yield = 31%.

1H NMR, CDCl3, 400MHz, b (ppm): 7.2-7.35 (m, 5H); 3.75 (s, 3H); 3.5 (t, 1H); 2.5-2.7 (m, 2H); 2.2 (s, 3H); 2.15-2.3 (m, 2H).

7.2.N-Ethyl-6- [3-methyl-5-oxo-4- (2-phenylethyl) -2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide According to the process described in Example 2.3, from 264 mg of methyl 3-oxo-2- (2-phenylethyl) butanoate and 351 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide are obtained. 291 mg of N-ethyl-6- [3-methyl-5-oxo-4- (2-phenylethyl) -2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide in the form of a white powder.

Yield = 53% F (° C) = 158 M = C25H26N4O3S = 462; M + H = 463; Method 2 = 1.35 min. 1H NMR, d6-DMSO, 400MHz, b (ppm): 11.8 (sl, 1H); 8.6 (sl, 1H); 8.45 (s, 1H); 8.1 (d, 1H); 7.4 (m, 3H); 7.3 (m, 2H); 7.2 (d, 3H); 7.1 (d, 2H); 3.6 (q, 2H); 2.8 (t, 2H); 2.5 (t, 2H); 1.9 (s, 3H); 1.0 (t, 3H).

Example 8 6- (4-Benzyl-5-oxo-3-propyl-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide (Compound No. 68 of Table I) 8.1. Ethyl 2-benzyl-3-oxohexanoate According to the process described in Example 6.4, from 2.2 g of benzyl bromide and 4 g of ethyl butyryl acetate, 2.5 g of 2-benzylpropionate are obtained. Ethyl 3-oxohexanoate as a translucent oil.

Yield = 40% 1H NMR, CDCl3, 400MHz, b (ppm): 7.15-7.30 (m, 5H); 4.2 (q, 2H); 3.8 (t, 1H); 3.2 (dd, 2H); 2.5-2.3 (m, 2H); 1.55 (m, 2H); 1.2 (t, 3H); 0.86 (t, 3H). 8.2. 6- (4-Benzyl-5-oxo-3-propyl-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide According to the method described in the example 2.3, from 300 mg of ethyl 2-benzyl-3-oxohexanoate and 353 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide, 400 mg of 6- (4- benzyl-5-oxo-3-propyl-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide as a white powder.

Yield = 69%

F (° C) = 180 M = C 26 H 28 N 4 O 3 S = 476; M + H = 477; Method 2: Tr = 1.45 min. 1H NMR, d 6 -DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.6 (sl, 1H); 8.45 (s, 1H); 8.1 (d, 1H); 7.45-7.1 (m, IOH); 3.65 (q, 2H); 3.6 (s, 2H); 2.5 (t, 2H); 1.5 (m, 2H); 1.0 (t, 3H); 0.9 (t, 3H).

Example 9: N-ethyl-6- {4- [3- (2-methoxyethoxy) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-phenylpyridine 3-sulfonamide (Compound No. 38 of Table I)

H O I I SUI 9.1. 3- (2-Methoxyethoxy) phenylmethanol A mixture of 10 g (80.6 mmol) of 3- (hydroxymethyl) phenol, 78.4 g (241.7 mmol) of Cs2CO3 and 8.4 mL (88.6 g) were added. mmol) of bromoethylmethyl ether in 150 ml of CH 3 CN is heated at 110 ° C. for 12 hours. After returning to RT, the medium is filtered, concentrated under reduced pressure, taken up in 500 ml of DCM, washed with brine (2 × 100 ml) dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. 10.9 g of 3- (2-methoxyethoxy) phenyl] methanol are obtained in the form of a yellow oil. Yield = 75% 1H NMR, CDCl3, 400MHz, b (ppm): 7.3 (t, 1H); 6.95 (m, 2H); 6.85 (d, 1H); 4.6 (s, 2H); 4.1 (t, 2H); 3.8 (t, 2H); 3.4 (s, 3H); 2.1 (sil H)

9.2. 1- (bromomethyl) -3- (2-methoxyethoxy) benzene According to the method described in Example 6.3, 10.8 g of [3- (2-methoxyethoxy) phenyl] methanol are obtained. 1- (bromomethyl) -3- (2-methoxyethoxy) benzene, as an oil. Yield = 87% 1H NMR, CDCl3, 400MHz, b (ppm): 7.3 (m, 1H); 7.0 (m, 2H); 6.9 (d, 1H); 4.45 (s, 2H); 4.15 (t, 2H); 3.75 (t, 2H); 3.4 (s, 3H)

9.3. Methyl 2- [3- (2-methoxyethoxy) benzyl] -3-oxobutanoate According to the process described in Example 6.4, 5.6 g of 1- (bromomethyl) -3- (2-methoxyethoxy) benzene are obtained. and 2.52 g of methylacetoacetate, 3.44 g of methyl 2- [3- (2-methoxyethoxy) benzyl] -3-oxobutanoate, as a yellow oil. 1H NMR CDCl3, 400MHz, b (ppm): 7.2 (t, 1H); 6.75 (m, 3H); 4.15 (d, 2H); 3.8 (t, 1H); 3.75 (s, 3H); 3.45 (s, 3H); 3.15 (d, 2H); 2.2 (s, 3H).

9.4. N-ethyl-6-M- [3- (2-methoxyethoxy) benzyl-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-phenylpyridine-3-sulfonamide According to the method described in Example 2.3, from 336 mg of methyl 2- [3- (2-methoxyethoxy) benzyl] -3-oxobutanoate and 351 mg of N-ethyl-6-hydrazino-N are obtained. phenylpyridi-3-sulfonamide, 441 mg of N-ethyl-6- {4- [3- (2-methoxyethoxy) benzyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol 1-yl} -N-phenylpyridine-3-sulfonamide as a white powder. Yield = 70% F (° C) = 126M = C27H30N4O5S = 522; M + H = 523; Method 2: Tr = 1.27 min. 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.6 (sl, 1H); 8.45 (s, 1H); 8.1 (d, 1H); 7.4 (m, 3H); 7.3-7.1 (m, 3H); 6.8 (d, 2H); 7.1 (d, 1H); 4.1 (d, 2H); 3.6 (m, 4H); 3.5 (s, 2H); 3.3 (s, 3H); 2.1 (s, 3H); 1.0 (t, 3H).

Example 10: N-ethyl-6- [4- (4-methoxybenzyl) -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide ( Compound No. 54 of Table I) 10.1. Methyl 2- (4-methoxybenzyl) -3-oxobutanoate A mixture of 1.34 g (8.6 mmol) of 1- (chloromethyl) -4-methoxybenzene, 0.93 ml (8.6 mmol) of methylacetoacetate, 0.24 g (0.86 mmol) of tetrabutylammonium chloride and 6.9 g of a mass mixture of K 2 CO 3 / KOH (4: 1) in 5 ml of toluene are heated for 5 minutes at 110 ° C. in a microwave. The reaction medium is taken up in 80 ml of AcOEt, washed successively with water (2 × 20 ml), a saturated solution of NaHCO 3 (20 ml) of the brine (20 ml), dried over Na 2 SO 4 and then concentrated under reduced pressure. . The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 30% AcOEt.

0.93 g of methyl 2- (4-methoxybenzyl) -3-oxobutanoate are thus obtained in the form of a yellow oil. Yield = 48% 1H NMR, CDCl3, 400MHz, b (ppm): 7.2 (d, 1H); 7.1 (d, 1H); 6.8 (m, 2H); 3.8 (s, 3H); 3.75 (t, 1H); 3.7 (s, 3H); 3.2 (m, 2H); 2.2 (s, 3H). 10.2. N-ethyl-6- [4- (4-methoxybenzyl) -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl-N-phenylpyridine-3-sulfonamide According to the method described in Example 2.3 gives, from 300 mg of methyl 2- (4-methoxybenzyl) -3-oxobutanoate and 371 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide, 338 mg of N-ethyl-6- [4- (4-methoxybenzyl) -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide as a White powder. Yield = 56% F (° C) = 188 M = C25H26N4O4S = 478; M + H = 479; Method 2: Tr = 1.29 min. 1H NMR, d6-DMSO, 400MHz, b (ppm): 11.8 (sI, 1H); 8.6 (sI, 1H); 8.45 (s, 1H); 8.1 (d, 1H); 7.4 (m, 3H); 7.3-7.1 (m, 4H); 6.8 (d, 2H); 3.75 (s, 3H); 3.6 (s, 2H); 3.5 (s, 2H); 2.1 (s, 3H); 1.0 (t, 3H).

Example 11: 6- [4- (2-Chloro-6-fluorobenzyl) -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -N-ethyl-N-phenylpyridine 3-sulfonamide (Compound No. 20 of Table I) A mixture of 52 mg (0.2 mmol) of methyl 2- (2-chloro-6-fluorobenzyl) -3-oxobutanoate, 73 mg (0.25 g) mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 5 mg of pTsOH in 2 mL of toluene is heated for 12 h at 110 ° C and then concentrated under reduced pressure. The residue is taken up in 2 mL of DMF, filtered and the filtrate is chromatographed on RP18 reverse phase by eluting with a gradient H2O (2% TFA) / CH3CN from 0 to 100% CH3CN.

86 mg of 6- [4- (2-chloro-6-fluorobenzyl) -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -N-ethyl-N-phenylpyridine are obtained. 3-sulphonamide in the form of a white powder; Yield = 99% F (° C) = 206 M = C24H22ClFN4O3S = 501. Mid-H = 502; Method 1 1H NMR, d6-DMSO, 400MHz, δ (ppm): 11.9 (sil H); 8.6 (sl, 1H); 8.4 (s, 1H); 8.0 (d, 1H); 7.5-7.3 (m, 5H); 7.2-7.0 (m, 3H); 3.7 (s, 2H); 3.6 (q, 2H); 2.1 (s, 3H), 1.0 (t, 3H).

Example 12: N-ethyl-6- [3-methyl-5-oxo-4- (1-phenylcyclopropyl) -2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide ( Compound No. 80 of Table I) 12.1. Methyl 2-acetyl-3-phenylbut-3-enoate A suspension of 3.2 g (27.5 mmol) of methyl 3-oxobutanoate, 5.6 g (55.0 mmol) of phenylacetylene and 700 mg (0.8 mmol) of * [ReBr (CO) 3 (THF)] 2 in 55 mL of toluene anh. is stirred 18 h at 50 ° C. After returning to RT, the medium is concentrated under reduced pressure. The residue obtained is taken up in 100 ml of DCM, washed successively with water (100 ml) and brine (100 ml), dried over Na 2 SO 4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel. eluent with a 99: 1 DCM / MeOH mixture. 5 g of methyl 2-acetyl-3-phenylbut-3-enoate are obtained in the form of a yellow oil.

Yield = 84% 1H NMR, CDCl3, 400MHz, b (ppm): 12.6 (s, 1H); 7.3-7.2 (m, 5H); 5.7 (s, 1H); 5.1 (s, 1H); 3.55 (s, 3H); 1.9 (s, 3H).

*: [ReBr (CO) 3 (THF)] 2 is freshly prepared from 2 g (4.9 mmol) of ReBr (CO) 5 under reflux in 60 mL of THF for 16 h. After concentration under reduced pressure and recrystallization from 5 ml of n-hexane / THF (1: 1), 700 mg of [ReBr (CO) 3 (THF)] 2 are obtained in the form of a white powder. Yield = 35%. 12.2. Methyl 3-oxo-2 (1-phenylcyclopropyl) butanoate To a solution of 1 g (4.6 mmol) of methyl 2-acetyl-3-phenylbut-3-enoate in 16 mL of DCM is added successively, dropwise. 20.8 mL (22.9 mmol) of a 1.1M solution of diethylzinc in toluene and 3.7 mL (45.8 mmol) of diiodomethane were added dropwise. The reaction medium is heated for 18 hours under reflux. After returning to RT, the reaction mixture is treated with 100 mL of water and then extracted with DCM (3X100 mL). The organic phases are combined, washed successively with water (4 × 100 mL), brine (100 mL), dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a 95: 5 cyclohexane / ACOEt mixture. 280 mg of methyl 3-oxo-2 (1-phenylcyclopropyl) butanoate are obtained in the form of a yellow oil. Yield = 26%. 1H NMR, CDCl3, 400MHz, b (ppm): 7.3-6.9 (m, 5H); 3.7 (s, 1H); 3.6 (s, 3H); 2.0 (s, 3H); 1.4 (s, 2H); 1.25 (s, 2H) 12.3. N-ethyl-6- [3-methyl-5-oxo-4- (1-phenylcyclopropyl) -2,5-dihydro-1H-pyrazol-1-yl-N-phenylpyridine-3-sulfonamide According to the process described in US Pat. Example 2.3 gives, from 280 mg of methyl 3-oxo-2 (1-phenylcyclopropyl) butanoate and 352 mg of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide, 110 mg of N-ethyl-6- [3-methyl-5-oxo-4- (1-phenylcyclopropyl) -2,5-dihydro-1H-pyrazol-1-yl] -N-phenylpyridine-3-sulfonamide in the form of a powder white. 36 F (° C) = 146 M = C 26 H 26 N 4 O 3 S = 474, M + H = 475; Method 2: Tr = 1.44 min. 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.6 (sl, 1H); 8.4 (s, 1H); 8.1 (d, 1H); 7.4-7.1 (m, 10H); 3.6 (q, 2H); 2.2 (s, 3H); 1.15 (dd, 4H); 1.0 (t, 3H). Example 13: 2- (5 - ([Ethyl (phenyl) amino] sulfonyl) pyridin-2-yl) -5-methyl-3-oxo-N-phenyl-2,3-dihydro-1H-pyrazole-4- Carboxamide (Compound No. 84 of Table I) 13.1 N-ethyl-6- (3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-phenylpyridine-3-sulfonamide A A mixture of 5 g (17.1 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 1.98 g (17.1 mmol) of methylacetoacetate in 30 ml of AcOH is heated for 12 hours. at 80 ° C. The medium is then concentrated to 2/3 The precipitate thus formed is filtered off, washed with 20 ml of EtOH and then dried under vacuum to give 4.87 g of N-ethyl-6- (3- Methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-phenylpyridine-3-sulfonamide as a solid, used as is in the following step Yield = 80% 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.3 (s, 1H), 8.6 (ss, 1H), 8.4 (s, 1H), 8.1 (d, 1H), 7.4 (m, 3H), 7.1 (d, 2H), 5.2 (s, 1H), 3.6 (q, 2H), 2.2 (s, 3H), 1.15; , 0 (t, 3H).

13.2. 2- (5-ethyl (phenyl) aminolsulfonyl) pyridin-2-yl) -5-methyl-3-oxo-N-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide To a mixture 0.4 g (1.12 mmol) of N-ethyl-6- (3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-phenylpyridine-3-sulfonamide and 0.15 mL (1.12 mmol) of TEA in 1 mL of DMSO is added 0.12 mL (1.12 mmol) of phenylisocyanate. After stirring for 1 h at RT, 6 ml of 2.5N HCl are added and the stirring is continued for 1 hour. The precipitate formed is filtered off, washed with water (2 × 20 mL), taken up in DCM and dried over Na 2 SO 4. The residue obtained is recrystallized from EtOH. 375 mg of 2- (5- {{ethyl (phenyl) amino] sulfonyl} pyridin-2-yl) -5-methyl-3-oxo-N-phenyl-2,3-dihydro-1H-pyrazole are obtained. -4-carboxamide as a white powder. Yield = 70% F (° C) = 218 ° C M = C24H23N5O4S = 477; M + H = 478; Method 2: Tr = 1.29min. 1H NMR, d 6 -DMSO, 400MHz, b (ppm): 14.0 (sl, 1H); 10.5 (s, 1H); 8.7 (d, 1H); 8.5 (s, 1H); 8.2 (d, 1H); 7.6 (d, 2H); 7.5-7.4 (m, 5H); 7.2 (d, 2H); 7.1 (t, 1H); 3.7 (q, 2H); 2.7 (s, 3H); 1.0 (t, 3H).

Example 14: (2- {5- [Ethyl (phenyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) acetic acid (Compound 104 of Table I 14.1 Ethyl 2-formylbutanedioate To a suspension of 1.32 g (57.41 mmol) of sodium in 35 ml of Et2O, a mixture of 10 g (57.degree. 41 mmol) of ethyl butanedioate and 4.62 mL (57.41 mmol) of ethyl formate. The medium is then stirred 12 h at RT, taken up in 100 mL of water and extracted with 100 mL of Et2O. The aqueous phase is acidified to pH = 5 and then extracted with 100 mL of Et2O. The organic phase is then dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography on silica gel, eluting with a cyclohexane / ACOEt mixture 7: 3. 4.3 g of ethyl 2-formylbutanediaote are obtained in the form of a colorless oil.

Yield: 37% 1H NMR, 1H NMR, CDCl3, 400MHz, b (ppm): 10.0 (s, 1H); 7.1 (d, 1H); 4.4-4.2 (m, 5H); 2.9 (dd, 2H); 1.3 (m, 6H);

14.2 (245-Fethyl (phenyl) sulfamoylpyridin-2-yl) -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) acetic acid A mixture of 2.17 g (7.42 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 1.5 g (7.42 mmol) of ethyl 2-formylbutanedioate in 15 mL of EtOH is heated for 5 h at 80 ° C. The medium is then concentrated under reduced pressure. The precipitate obtained is triturated in Et2O, then filtered and dried at the pump. The 4.1 g of beige powder obtained are added to a solution of 212 mg (9.23 mmol) of sodium dissolved in 17 ml of MeOH anh. at T.A. and stirring continued for 2 h. The medium is concentrated under reduced pressure, then solubilized in 10 ml of water and 4 ml of 1N sodium hydroxide and then stirred for 12 hours at RT. The medium is then acidified to pH = 5 by addition of 1N HCl, extracted with DCM (2x100mL). The organic phase is dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. The residue obtained is triturated in pentane, the insoluble matter is filtered and dried at the pump. 2.1 g of (2- {5- [ethyl (phenyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) acetic acid are obtained in the form of a white powder. Yield = 58% F (° C) = 174 ° C M = C18H18N4O5S = 402; M + H = 403; Method Tr = 1.02 min. 1H NMR, d 6 -DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.6 (sl, 1H); 8.5 (sl, 1H); 8.2 (d, 1H); 7.9 (si, 1H); 7.4 (m, 3H); 7.2 (d, 2H); 3.7 (q, 2H); 3.4 (s, 2H); 1.0 (t, 3H).

Example 15: Methyl (2- (5- [ethyl (phenyl) sulfamoyl] pyridin-2-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) acetate (Compound 107 of Table I) 15.1 (Methyl 2- (5-methylphenyl) sulfamoylpyridin-2-yl) -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) acetate A mixture of 0.5 g (1.24 mmol) ) (2- {5- [ethyl (phenyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) acetic acid and 0.256 g ( 1.24 mmol) of DCC is stirred for 3 hours at RT .The precipitate formed is filtered off and the filtrate is concentrated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel, eluting with a 9/1 DCM / MeOH mixture. 0.5 g of methyl 2- {5- [ethyl (phenyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) acetate are obtained in the form of a brown powder. Yield = 96% F (° C) = 140 ° C M = C19H20ON4O5S = 416; M + H = 417; Method 2; Tr = 1.44.201H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.6 (s, 1H); 8.4 (s, 1H); 8.2 (d, 1H); 7.9 (s, 1H); 7.4 (m, 3H); 7.2 (d, 2H); 5.6 (d, 0.5H); 3.75 (q, 2H); 3.7 (s, 3H); 3.3 (d, 1.5H); 1.0 (t, 3H) Example 16: 2- (2- {5- [Ethyl (phenyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4- yl) -N-methylacetamide (compound 108 of Table I) To a mixture of 0.28 g (0.7 mmol) of (2- {5- [ethyl (phenyl) sulfamoyl] pyridin-2-yl} -3-oxoacetate 2,3-dihydro-1H-pyrazol-4-yl) acetic acid, 0.61 mL (3.48 mmol) of DIEA, and 0.8 mL (1.4 mmol) of methylamine (2N in solution in THF) in 2 mL of DCM, 0.33 g (1.04 mmol) of TBTU is added at 0 ° C. After stirring for 3 hours at RT, the medium is taken up in 500 ml of DCM, washed successively with 0.1N HCl (2 × 40 ml), a saturated solution of NaHCO 3 ( 2 * 40mL) and brine (30 mL), dried over Na 2 SO 4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 95: 5 DCM / MeOH mixture. 18 mg of 2- ( 2- {5- [Ethyl (phenyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) -N-methylacetamide as a brown powder. Yield = 6% F (° C) = 194 ° C M = C 19 H 21 N 5 O 5 S = 415; M + H = 416; Method 2 Tr = .0.98 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.6 (sl, 1H); 8.5 (s, 1H); 8.2 (d, 1H); 7.8 (s, 1H); 7.5 (m, 3H), 7.2 (d, 2H); 3.6 (q, 2H); 3.1 (s, 2H); 2.6 (s, 3H); 1.0 (t, 3H) Example 17: (4-Benzyl-1- {5- [ethyl (phenyl) sulfamoyl] pyridin-2-yl} -5-oxo-2,5-dihydro-1H-pyrazol 3-yl) ethyl acetate (compound 106 of Table I) 17.1 2-diethyl benzyl-3-oxopentanedioate

Under argon, 1.7 g (74.18 mmol) of sodium are dissolved in 75 mL of EtOH anh. 13.5 ml (74.2 mmol) of diethyl 3-oxopentanedioate and then 8.8 ml (74.2 mmol) of benzyl bromide are then added dropwise and with AT. The medium is then refluxed for 3 hours, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient of 0 to 20% AcOEt. 8.29 g of diethyl 2-benzyl-3-oxopentanedioate, in the form of a translucent oil, are obtained.

Yield = 38% 1H NMR, 1H NMR, CDCl3, 400MHz, b (ppm): 7.4-7.2 (m, 5H); 4.2 (m, 4H); 4.1 (t, 1H); 3.2 (d, 2H); 1.2 (m, 6H);

17.2. Ethyl 4-benzyl-1- {5-ethyl (phenyl) sulfamoylpyridin-2-yl} -5-oxo-2,5-dihydro-1H-pyrazol-3-VI) acetate According to the process described in US Pat. Example 2.3, from 5 g (17.1 mmol) of diethyl 2-benzyl-3-oxopentanedioate and 5 g (17.1 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide are obtained, 3 g of ethyl 4-benzyl-1- {5- [ethyl (phenyl) sulfamoyl] pyridin-2-yl} -5-oxo-2,5-dihydro-1H-pyrazol-3-yl) acetate under form of a white powder. Yield = 34% F (° C) = 156 M = C 27 H 28 N 4 O 5 S = 520; M + H = 521 Method 2: Tr = 1.52, 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.0 (sl, 1H); 8.5 (sl, 2H); 8.15 (d, 1H); 7.4-7.1 (m, 10H); 4.1 (q, 2H); 3.8-3.6 (m, 6H); 1.2 (t, 3H); 1.0 (t, 3H).

Example 18: 6- {4 - [(5-Cyanopyridin-3-yl) methyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-ethyl-N Phenylpyridine-3-sulfonamide (compound 97 of Table I) 18.1 (5-bromopyridin-3-yl) methanol To a solution of 12 g (59.4 mmol) of 5-bromopyridine-3-carboxylic acid in 300 ml of THF anh. . under argon are added at -10 ° C, 6.6 ml of NMM and then 5.7 ml (59.430 mmol) of ethyl chloroformate. After stirring for 20 minutes at -10 ° C., 6.8 g (179.8 mmol) of sodium borohydride are added in small portions. The medium is then cooled to -70 ° C. and 400 ml of MeOH are added over 1 hour 30 minutes. The temperature is then allowed to rise to RT and stirring is maintained for 12 hours. The medium is then concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 98: 2 DCM / MeOH mixture. 8.4 g of (5-bromopyridin-3-yl) methanol are obtained in the form of a yellow oil. Yield = 75% 1H NMR, 1H NMR, CDCl3, 400MHz, δ (ppm): 8.5 (s, 1H), 8.4 (s, 1H); 7.9 (1H, $); 4.6 (s, 2H); 2.8 (sl, 1H)

18.2 5- (hydroxymethyl) pyridine-3-carbonitrile A mixture of 4.2 g (22.34 mmol) of (5-bromopyridin-3-yl) methanol, 5 g (55.84 mmol) of copper cyanide in 22 mL of pyridine is heated 20 h in a tube sealed at 160 ° C. After returning to RT, the medium is taken up in 10 ml of concentrated ammonia and 30 ml of a saturated solution of NH 4 Cl and then stirred for 2 h. The miileu is then extracted with 200 ml of a DCM / iPrOH mixture (85:15), dried over Na 2 SO 4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 98: 2 DCM / MeOH mixture. . 2.13 g of 5- (hydroxymethyl) pyridine-3-carbonitrile are obtained in the form of a white solid. Yield = 51% 1H NMR, 1H NMR, CDCl3, 400MHz, δ (ppm): 8.9 (d, 2H), 8.0 (s, 1H); 4.9 (s, 2H); 2.3 (sl, 1H) 18.3 5- (Chloromethyl) pyridine-3-carbonitrile 0.2 g (1.49 mmol) of 5- (hydroxymethyl) pyridine-3-carbonitrile in 2 ml of DCM is added 1 ml (4 mmol ) of 4N HCl in dioxane. The mixture is concentrated under reduced pressure and then added to 0.65 ml (8.95 mmol) of thionyl chloride and heated for 3 h at 60 ° C. After returning to T.A., the medium is taken up in 20 ml of toluene, the precipitate formed is filtered and then taken up in 30 ml of DCM and 30 ml of a saturated solution of NaHCO 3. The organic phase is dried over Na 2 SO 4 and then concentrated under reduced pressure. 161 mg of 5- (chloromethyl) pyridine-3-carbonitrile in the form of an oil are obtained. Yield = 73% 1 H NMR, 1 H NMR, CDCl 3, 400 MHz, δ ( ppm): 8.9 (d, 2H); 8.0 (s, 1H); 3.5 (s, 2H) 18.4 Methyl 2-f (5-cyanopyridin-3-yl) methyl-3-oxobutanoate at a suspension of 84 mg (2.11 mmol) of sodium hydride (60% in oil) in 3 ml of DME anh., 0.23 ml (2.11 mmol) of methylacetoacetate are added under argon at 0 ° C. The reaction medium is stirred for 1/2 h at 0 ° C. and 1/2 h at RT, then 161 mg (1.06 mmol) of 5- (chloromethyl) pyridine-3-carbonitrile diluted in 1 ml of DME and 29 mg (0.11 mmol) are added. ) of tetrabutylammonium iodide. The medium is then heated at 65 ° C. for 4 hours. After returning to RT, the medium is taken up in 10 mL of water, neutralized by addition of 0.1N HCl, then extracted with AcOEt (2 × 40 mL), then dried over concentrated Na 2 SO 4 under reduced pressure and purified by column chromatography. silica gel eluting with cyclohexane / AcOEt (8: 2). 140 mg of methyl 2 - [(5-cyanopyridin-3-yl) methyl] -3-oxobutanoate are obtained in the form of a colorless oil. Yield = 57% 1H NMR, 1H NMR, CDCl3, 400MHz, δ (ppm): 8.8 (s, 1H), 8.6 (s, 1H); 7.8 (s, 1H); 3.7 (t, 1H); 3.65 (s, 3H); 3.2 (d * d, 2H); 2,2 (s, 3H) 18.5 6- {4- (5-cyanopyridin-3-yl) methyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} N-ethyl-N-phenylpyridine-3-sulphonamide According to the process described in Example 2.3, starting from 125 mg (0.43 mmol) of 2 - [(5-cyanopyridin-3-yl) methyl] - Methyl 3-oxobutanoate and 99 mg (0.43 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide, 103 mg of 6- {4 - [(5-cyanopyridin-3-yl) methyl] -3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-ethyl-N-phenylpyridine-3-sulfonamide as a yellow powder. Yield = 51% F (° C) = 164 M = C24H22N6O3S = 474; M + H = 475; Method 2: Tr = 1.24min. 1H NMR, d6-DMSO, 400MHz, δ (ppm): 12.0 (sl, 1H); 8.9 (s, 1H); 8.8 (s, 1H); 8.6 (sl, 1H); 8.4 (s, 1H); 8.2 (s, 1H); 8.15 (d, 1H); 7.4 (m, 3H); 7.1 (d, 2H); 3.7 (s, 4H); 2.2 (s, 3H); 1.0 (t, 3H).

Example 19: 5-methyl-2- [5- (phenylsulfonyl) pyridin-2-yl] -4- (pyridin-3-ylmethyl) -1,2-dihydro-3H-pyrazol-3-one (Compound 165 of Table II) 19.1 2-Chloro-5- (phenylsulfanyl) pyridine A mixture of 3.4 g (14.3 mmol) of 2-chloro-5-iodopyridine, 1.9 g (17.2 mmol) of thiophenol, 0.93 g (17.2 mmol) of Sodium methoxide and 0.36 g (5.7 mmol) of copper in 18 mL of MeOH is heated for 12 h at 80 ° C. After returning to T.A., the medium is taken up in 100 ml of 1N NaOH and the MeOH is evaporated off under reduced pressure. The reaction medium is extracted with AcOEt (2 × 100 mL), the organic phase is washed with 0.1N NaOH (2 × 30 mL), then dried over Na 2 SO 4, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt mixture (8: 2). 1.90 g of 2-chloro-5- (phenylsulfanyl) pyridine are obtained in the form of a white powder. Yield = 60% 1H NMR, 1H NMR, CDCl3, 400MHz, δ (ppm): 8.5 (d, 1H), 8.3 (s, 1H); 7.9 (1H, $); 7.5-7.4 (m, 5H) 19.2 2-Chloro-5- (phenylsulfonyl) pyridine To a solution of 1.9 g (8.57 mmol) of 2-chloro-5- (phenylsulfanyl) pyridine in 40 mL of DCM is added at RT. 1 / 4h a suspension of 4.8 g (21.42 mmol) of 3-chloro-perbenzoic acid 77% in 20 ml of DCM. After stirring for 1 hour, the precipitate formed is filtered, the filtrate is taken up in 200 ml of DCM, washed successively with 100 ml of 0.2N sodium hydroxide and then 100 ml of a saturated solution of sodium thiosulfate, dried over Na 2 SO 4, concentrated under reduced pressure and purified by silica gel column chromatography eluting with cyclohexane / AcOEt (8: 2). 0.67 g of 2-chloro-5- (phenylsulfonyl) pyridine is obtained in the form of a white powder. Yield = 31% 1 H NMR, 1 H NMR, CDCl 3, 400MHz, b (ppm): 8.9 (s, 1H), 8.1-7.9 (m, 3H); 7.6-7.4 (3H, m); 7.3 (m, 1H)

19.3 2-Hydrazinyl-5- (phenylsulfonyl) pyridine According to the method described in Example 5.2, from 0.67 g (2.64 mmol) of 2-chloro-5- (phenylsulfonyl) pyridine, 340 mg of 2- hydrazinyl-5- (phenylsulfonyl) pyridine as a white powder. Yield = 51% 1H NMR, d6-DMSO, 400MHz, b (ppm): 9.0 (s, 1H); 8.6 (d, 1H); 8.5 (s, 1H); 8.4 (m, 2H); 8.0 (d, 1H); 7.8-7.5 (m, 3H); 7.3 (m, 1H); 3.3 (sl, 1H); 19.4 5-methyl-2- [5- (phenylsulfonyl) pyridin-2-yl] -4- (pyridin-3-ylmethyl) -1,2-dihydro-3H-pyrazol. According to the method described in Example 2.3, from 340 mg (1.36 mmol) of 2-hydrazinyl-5- (phenylsulfonyl) pyridine and 283 mg (1.36 mmol) of 3-oxo-2 are obtained. methyl (pyridin-3-ylmethyl) butanoate, 130 mg of 5-methyl-2- [5- (phenylsulfonyl) pyridin-2-yl] -4- (pyridin-3-ylmethyl) -1,2-dihydro- 3H-pyrazol-3-one in the form of a white powder. Yield = 23% F (° C) = 176 M = C21H18N4O4 = 406; M + H = 407; Method 2: Tr = 0.78 min ,. 1H NMR, d6-DMSO, 400MHz, b (ppm) 12.0 (sl, 1H); 9.0 (s, 1H); 8.6 (d, 1H); 8.5 (s, 1H); 8.4 (m, 2H); 8.0 (d, 2H); 7.8-7.6 (m, 4H); 7.3 (m, 1H); 3.6 (s, 2H); 2.2 (s, 3H);

Example 20: N-ethyl-6- {4 - [(5-methoxypyridin-3-yl) methyl] -5-oxo-2,5-dihydro-1H-pyrazol-1-yl} -N-phenylpyridine hydrochloride 3-sulfonamide (Compound 101 of Table I) Methyl 20.1 (2E) -3- (5-methoxypyridin-3-yl) prop-2-enoate To a suspension of 3.12 g (78.1 mmol) of sodium hydride (60 % in the oil) in 30 mL THF anh. 45.4 g (78.1 mmol) of methyl (diethoxyphosphoryl) acetate in 10 ml of THF are added over 45 minutes under argon at 0 ° C. Stirring is maintained for 1 / 2h at 0 ° C. and then 5.1 g (37.2 mmol) of 5-methoxypyridine-3-carbaldehyde in 20 ml of THF anh. are added dropwise at 0 ° C. After returning to RT, the reaction mixture is treated with 150 mL of water and then extracted with AcOEt (3 × 100 mL). The organic phases are combined, washed successively with water (2 × 20 mL), dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 40% AcOEt. 1 g of methyl 1 (2E) -3- (5-methoxypyridin-3-yl) prop-2-enoate in the form of a white powder is obtained. Yield = 14%. o ~ S-N 1 H NMR, CDCl3, 400MHz, b (ppm): 8.4 (d, 1H); 7.7 (d, 1H); 7.4 (s, 1H); 6.5 (d, 1H); 3.9 (s, 3H); 3.8 (s, 3H)

20.2 Methyl 3- (5-methoxypyridin-3-yl) propanoate In a Parr apparatus, a mixture of 1 g (5.33 mmol) of (2E) -3- (5-methoxypyridin-3-yl) prop-2- methyl enoate in 20 mL of MeOH and 0.1 g of 10% Pd / C is hydrogenated at 7 bar for 5 hours. The reaction mixture is then filtered on Whatman GF / F paper and concentrated under reduced pressure. There is thus obtained 1 g of methyl 3- (5-methoxypyridin-3-yl) propanoate in the form of wax used as is in the next step. Yield = 100% 1H NMR, CDCl3, 400MHz, b (ppm): 8.3 (s, 1H); 8.2 (s, 1H); 7.1 (s, 1H); 3.85 (s, 3H); 3.6 (s, 3H); 3.0 (t, 2H); 2.7 (t, 3H). 20.3 Methyl 2-formyl-3- (5-methoxypyridin-3-yl) propanoate According to the method described in Example 14.1, from 1.04 g (5.33 mmol) 3- (5-methoxypyridin-3) is obtained. methyl-methyl propanoate, 600 mg of methyl 2-formyl-3- (5-methoxypyridin-3-yl) propanoate in the form of a wax used as it is in the next step.

Yield = 51%

20.4 N-Ethyl-6-Mf (5-methoxypyridin-3-yl) methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-phenylpyridine-3-sulfonamide hydrochloride According to described in Example 2.3, from 250 mg (1.12 mmol) of methyl 2-formyl-3- (5-methoxypyridin-3-yl) propanoate and 327 mg (1.12 mmol) of N 6-ethyl-hydrazino-N-phenylpyridine-3-sulfonamide, 131 mg of N-ethyl-6- {4 - [(5-methoxypyridin-3-yl) methyl] -5-oxo-2,5-dihydro hydrochloride -1H-pyrazol-1-yl} -N-phenylpyridine-3-sulfonamide as a lyophilizate. Yield = 25% F (° C) = 136 M = C23H23N5O4S = 465; M + H = 466; Method 2: Tr = 0.97 min ,. 1H NMR, d6-DMSO, 400MHz, b (ppm): 8.6 (s, 2H); 8.4 (d, 2H); 8.2 (d, 1H); 8.1 (s, 1H); 7.9 (s, 1H); 7.4 (m, 3H); 7.1 (d, 2H); 4.0 (s, 3H); 3.8 (s, 2H); 3.6 (q, 2H); 1.0 (t, 3H) Example 21: {2- [5- (tert-Butylsulfamoyl) pyridin-2-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} ( phenyl) methyl acetate (compound 113 of Table I) 21.1 Ethyl 3-cyano-3-phenylpropanoate A mixture of 64 g (257.8 mmol) of diethyl benzylidenepropanedioate, 17 g (261 mmol) of potassium cyanide in 750 mL of EtOH and 75 mL of water is heated for 18h at 60 ° C. The medium is then concentrated under reduced pressure and taken up in 500 ml of brine and then extracted with Et2O (2 * 500 ml). The organic phases are dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. 43.5 g of ethyl 3-cyano-3-phenylpropanoate in the form of a solid are obtained and used as such in the next step. Yield = 83% 21.2 2-Phenylbutanedioic acid A mixture of 43.5 g (214 mmol) of ethyl 3-cyano-3-phenylpropanoate, 52.2 g (930.4 mmol) of potassium hydroxide in 670 ml of EtOH is heated at reflux for 4h. After returning to T.A., the medium is concentrated under vacuum and then treated with 1 L of 1N HCl, a precipitate is then formed which is filtered off and rinsed with water (2 × 50 ml). The solid obtained is taken up in a mixture of 200 mL of toluene and 40 mL of EtOH and concentrated under reduced pressure and then dried at the pump. 37 g of 2-phenylbutanedioic acid in the form of a solid are obtained and used as such in the next step. Yield = 89% 21.3 Diethyl 2-phenylbutanedioate In a Dean-Stark apparatus, a mixture of 37 g (190.5 mmol) of 2-phenylbutanedioic acid of 6 mL of conc. H 2 SO 4, 80 mL of toluene and 80 mL of EtOH is refluxed for 72 hours. After returning to RT, the reaction mixture is concentrated under reduced pressure and then treated with 300 mL of water, and then extracted with Et2O (2 × 400 mL). The organic phases are combined, dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel eluting with a cyclohexane / AcOEt gradient from 0 to 10% AcOEt, 22 g of diethyl 2-phenylbutanedioate in the form of an oil are obtained.

Yield = 46%. 1H NMR, CDCl3, 400MHz, b (ppm): 7.5 (m, 5H); 4.2 (m, 5H); 3.0 (dd, 2H, 1.0 (t, 6H)

21.4 diethyl 2-formyl-3-phenylbutanedioate According to the procedure described in Example 14.1, 7.0 g (28 mmol) of diethyl 2-phenylbutanedioate, 7.0 g of 2-formyl-3-phenylbutanedioate were obtained. diethyl in the form of an oil. Yield = 89% 21.5 {2- [5- (tert-Butylsulfamoyl) pyridin-2-yl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl} (phenyl) ethyl acetate According to method described in Example 26.2, from 2 g (7.19 mmol) of diethyl 2-formyl-3-phenylbutanedioate and 1.75 g (7.19 mmol) of N-tert-butyl-6-hydrazinylpyridine-3 are obtained sulphonamide, 3.1 g of methyl {2- [5- (tert-butylsulfamoyl) pyridin-2-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} (phenyl) acetate in the form of of a powder are obtained. Yield = 93% 1H NMR, d6-DMSO, 400MHz, b (ppm): 8.6 (s, 1H); 8.6 (d, 1H); 8.0 (d, 1H); 7.7 (s, 2H); 7.3 (m, 5H); 4.6 (s, 1H); 4.1 (q, 2H); 1.0 (m, 12H); 21.6 1- [5- (tert-Butylsulfamoyl) pyridin-2-yl] -4- [carboxy (phenyl) methyll-1H-pyrazol-5-olate A mixture of 2.8 g (5.8 mmol of 2- [5- Ethyl (tert-butylsulfamoyl) pyridin-2-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} (phenyl) acetate, 5.8 mL (5.8 mmol) 1N NaOH 12 ml of EtOH is stirred for 5 h at RT, 5.8 ml of 1 N HCl are added and the medium is extracted with DCM (2 × 100 ml) The organic phases are dried over Na 2 SO 4, filtered and then concentrated under reduced pressure. 2 g of - [5- (tert-butylsulfamoyl) pyridin-2-yl] -4- [carboxy (phenyl) methyl] -1H-pyrazol-5-olate in the form of a beige powder are obtained and used as such in the next step 21.7 {2- [5- (tert -butylsulfamoyl) pyridin-2-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} (phenyl) methyl acetate mixture of 0.3 g (0.66 mmol) of 1- [5- (tert-butylsulfamoyl) pyridin-2-yl] -4- [carboxy (phenyl) methyl] -1H-pyrazol-5-olate in 3 mL of MeOH anh. is added at 0 ° C., 0.11 mL (0.73 mmol) of thionyl chloride. For T.A, stirring is maintained for 12 hours. The medium is taken up in 40 ml of DCM, washed with 20 ml of saturated NaHCO 3 solution, dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue obtained is triturated in a DCM / pentane mixture and then filtered and dried under vacuum. 0.67 g of methyl 2- [5- (tert-butylsulfamoyl) pyridin-2-yl] -3-oxo-2,3-dihydro-1H-pyrazol-4-yl} (phenyl) acetate are obtained in the form of a beige powder. Yield = 73% mp (° C) = 66 M = C21H24N4O5S = 444; M + H = 445; Method 2: Tr = 1.21 min ,. 1H NMR, d6-DMSO, 400MHz, b (ppm): 12.3 (sI, 1H); 8.8 (s, 1H); 8.6 (sl, 1H); 8.3 (d, 1H); 7.7 (d, 2H); 7.4 (m, 5H); 4.9 (s, 1H); 3.7 (s, 3H); 1.0 (t, 9H) Example 22: N-Cyclopentyl-N - ({6- [5-oxo-4- (pyridin-3-ylmethyl) -2-hydrochloride, Methyl 5-dihydro-1H-pyrazol-1-yl] pyridin-3-yl} sulfonyl) glycinate (Compound 128 of Table I) 22.1 6-Chloro-N-cyclopentylpyridine-3-sulfonamide According to the method described in the example 5.1, from 5 g (23.6 mmol) of 6-chloropyridine sulfonyl chloride and 2 g (23.6 mmol) of cyclopentylamine, 5.1 g of 6-chloro-N-cyclopentylpyridine-3-sulfonamide in the form of a brown solid.

Yield = 84% 1H NMR, CDCl3, 400MHz, b (ppm): 8.8 (s, 1H); 8.0 (d, 1H); 7.4 (d, 1H); 4.5 (d, 1H); 3.6 (m, 1H); 1.8 (m, 2H), 1.6 (m, 4H); 1.3 (m, 2H)

22.2 Methyl N - [(6-chloropyridin-3-yl) sulfonyll-N-cyclopentylglycinate A mixture of 2 g (7.67 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 0.7 ml (7.67 mmol) of bromoacetate of methyl and 1.2 g (8.4 mmol) of K 2 CO 3 in 15 mL of CH 3 CN is heated for 12 h at 80 ° C. After returning to T.A., the medium is filtered and the filtrate is concentrated. The residue is taken up in 100 ml of DCM, washed successively with 50 ml of a saturated solution of NaHCO 3, 50 ml of water, then the organic phase is dried over Na 2 SO 4, concentrated under reduced pressure and purified by chromatography on a gel column. silica eluting with heptane / AcOEt 8: 2. 2.4 g of methyl N - [(6-chloropyridin-3-yl) sulfonyl] -N-cyclopentylglycinate in the form of an oil are obtained. Yield = 93% 1H NMR, CDCl3, 400MHz, b (ppm) 9.0 (s, 1H); 8.3 (d, 1H); 7.4 (d, 1H); 4.1 (s, 2H); 4., 05 (m, 1H); 3.8 (s, 3H); 1.9 (m, 2H), 1.6 (m, 4H); 1.3 (m, 2H) 22.3 N-Cyclopentyl-Nf (6-hydrazinylpyridin-3-yl) methyl sulfonyl glycinate According to the process described in Example 5.2, from 2.4 g (7.2 mmol) of N- Methyl (6-chloropyridin-3-yl) sulfonyl] -N-cyclopentylglycinate 2 g of methyl N-cyclopentyl-N - [(6-hydrazinylpyridin-3-yl) sulfonyl] glycinate as a yellow solid. Yield = 85% 1H NMR, CDCl3, 400MHz, b (ppm) 8.6 (s, 1H); 8.0 (d, 1H); 6.8 (d, 1H); 6.6 (sl, 1H); 4., 05 (m, 1H); 4.0 (s, 2H); 3.6 (s, 3H); 1.8 (m, 2H), 1.6 (m, 4H); 1.2 (m, 2H)

22.4 N-Cyclopentyl-N - ((6-f5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-ylpyridin-3-yl} sulfonyl) glycinate hydrochloride According to the method described in Example 2.3, from 200 mg (0.61 mmol) of methyl N-cyclopentyl-N - [(6-hydrazinylpyridin-3-yl) sulfonyl] glycinate and 117 mg ( 0.61 mmol) of methyl 3-oxo-2- (pyridin-3-ylmethyl) butanoate, 130 mg of N-cyclopentyl-N - ((6- [5-oxo-4- (pyridin-3-ylmethyl) -2- Methyl 5-dihydro-1H-pyrazol-1-yl] pyridin-3-yl} sulfonyl) glycinate as a white lyophilizate.

Yield = 34% F (° C) = 100 M = C22H25N5O5S = 471; M + H = 472; Method 2: Tr = 0.87 min. 1H NMR, d6-DMSO, 400MHz, b (ppm) 8.7 (d, 2H); 8.6 (d, 1H); 8.4 (d, 2H); 8.3 (d, 1H); 7.8 (m, 1H); 7.7 (s, 1H); 5.0-4.0 (sl, 2H); 3.9 (m, 1H); 3.8 (s, 2H); 3.6 (s, 2H); 3.4 (s, 3H); 1.4-1.0 (m, 8H).

Example 23: 2,2-Dimethylpropyl 6- [5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-yl] pyridine-3-carboxylate (Compound 166 Table II) 23.1 6-Chloropyridine-3-carboxylic acid 2,2-dimethylpropyl ester To a solution of 10 g (56.8 mmol) of 6-chloropyridine-3-carbonyl chloride in 100 mL of toluene anh. 15 g (170.4 mmol) of 2,2-30 dimethylpropanol are added under argon to T.A. The reaction medium is then heated for 6 hours at 80 ° C. After returning to RT, the medium is concentrated and the residue obtained is taken up in 800 ml of AcOEt, washed successively with water (2 × 200 ml), a saturated solution of NaHCO 3 (2 × 200 ml) and 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 / AcOEt gradient from 0 to 5% AcOEt. 11.9 g of 2,2-dimethylpropyl 6-chloropyridine-3-carboxylate in the form of a white powder are obtained. Yield = 92%. 1H NMR, CDCl3, 400MHz, b (ppm): 7.5 (m, 5H); 4.2 (m, 5H); 2,2-dimethylpropyl 2,2,2,6-hydrazinylpyridine-3-carboxylate, 3.0 (dd, 2H, 1.0 (t, 6H) According to the method described in Example 5.2, from 11.9 g (52.26 mmol) 2,2-dimethylpropyl 6-chloropyridine-3-carboxylate, 4.3 g 2,2-dimethylpropyl 6-hydrazinyipyridine-3-carboxylate as a white powder, Yield = 37% NMR H, d6-DMSO, 400MHz, δ (ppm): 8.7 (s, 1H), 8.15 (d, 1H), 6.9 (d, 1H), 4.0 (s, 2H); 3.5 (si, 1H); 1.0 (s, 9H).

2,2-Dimethylpropylated 23,3 6- [5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-ylpyridine-3-carboxylate According to the method described in the example 2.3, from 0.3 g (1.34 mmol) of 2,2-dimethylpropyl 6-hydrazinylpyridine-3-carboxylate and 0.26 g (1.34 mmol) of 3-oxo-2- (pyridin-3-ylmethyl) are obtained methyl butanoate, 185 mg of 6- [5-oxo-4- (pyridin-3-ylmethyl) -2,5-dihydro-1H-pyrazol-1-yl] pyridine-3-carboxylate dimethylpropyl in the form of a white solid. Yield = 38% F (° C) = 160 M = C20H22N4O3 = 366; M + H = 367; Method 2: Tr = 1.01 min. 1H NMR, d6-DMSO, 400MHz, b (ppm) 12.0 (sl, 1H); 9.0 (s, 1H); 8.6 (s, 1H); 8.5 (s, 1H); 8.4 (d, 1H); 7.8 (s, 1H); 7.7 (d, 1H); 7.3 (m, 1H); 4.1 (s, 2H); 3.6 (s, 2H); 1.0 (s, 9H); EXAMPLE 24 3- (2- {5- [Cyclopentyl (methyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) -3-phenylpropanoate methyl (compound 121 of Table I) 24.1 diethyl 3-phenylpentanedioate A mixture of 6 g (28.8 mmol) of 3-phenylpentanedioic acid and 7.9 ml (109.5 mol) of thionyl chloride is heated at 80 ° C. for 1 h. The medium is then concentrated and the resulting solid is added in small portions to 8 mL of EtOH at 0 ° C. The medium is then heated at 80 ° C for 1/2 h. After returning to T.A., the medium is concentrated and the residue obtained is taken up in 400 ml of DCM, washed successively with a saturated solution of NaHCO 3 (2x100 ml) and brine (100 ml), dried over Na 2 SO 4 and then concentrated under reduced pressure. 6.97 g of diethyl 3-phenylpentanedioate in the form of a powder are obtained and used as such in the next step. Yield = 91.5%.

24.2 Diethyl 2-formyl-3-phenylpentanedioate According to the process described in Example 14.1, from 3 g (11.35 mmol) of diethyl 3-phenylpentanedioate, 0.23 g of 2-formyl-3-phenylpentanedioate are obtained. Diethyl as a yellow oil. Yield = 7% 1H NMR, d6-DMSO, 400MHz, b (ppm) 10.9 (s, 1H); 7.7 (d, 1H); 7.3-7.1 (m, 5H); 4.5 (t, 1H); 4., 0 (q, 4H); 3.0 (m, 2H); 1; 0 (m, 6H)

24.3 3- (2- [5- (Cyclopentyl (methyl) sulfamoylpyridin-2-yl) -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) -3-phenylpropanoate According to the method described in US Pat. Example 26.2 gives 0.23 g (0.79 mmol) of diethyl 2-formyl-3-phenylpentanedioate and 0.21 g (0.79 mmol) of N-cyclopentyl-6-hydrazinyl-N-methylpyridine-3-sulfonamide, 0.38. 3- (1- {5- [Cyclopentyl (methyl) sulfamoyl] pyridin-2-yl} -5-oxido-1H-pyrazol-4-yl) -3-phenylpropanoate in the form of a powder. = 89% 24.4 3- (2- {5- [Cyclopentyl (methyl) sulfamoyl] pyridin-2-yl} -3-oxo-2,3-dihydro-1H-pyrazol-4-yl) -3-phenylpropanoate According to the method described in Example 21.7, from 0.38 g (0.78 mmol) of 3- (2- {5- [cyclopentyl (methyl) sulfamoyl] pyridin-2-yl} -3-oxo-2 is obtained. 3-dihydro-1H-pyrazol-4-yl) -3-phenylpropanoate, 0.34 g of 3- (1- {5- [cyclopentyl (methyl) sulfamoyl] pyridin-2-yl} -5-oxido-1H Methyl pyrazol-4-yl) -3-phenylpropanoate F (° C) = 80 M = C24H28N4O5S = 484 M + H = 485; ode 3: Tr = 4.4 min.1H NMR, d6-DMSO, 400MHz, b (ppm): 8.7 (s, 1H); 8.5 (sl, 1H); 8.2 (d, 1H); 7.7 (s, 1H); 7.3 (d, 2H); 7.2 (m, 2H); 7.1 (t, 1H); 4.3 (t, 1H); 4.2 (t, 1H); 3.6 (s, 3H); 3.1 (d * d * d, 2H); 2.7 (s, 3H); 1.8-1.4 (m, 8H)

Example 25: 6- (4-Benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-cyclopentyl-N- [3- (dimethylamino) propyl] pyridine-3-sulfonamide hydrochloride (Compound 123 of Table I) 25.1 N- [3- (Benzyloxy) propyll-6-chloro-N-cyclopentylpyridine-3-sulfonamide A mixture of 1 g (3.84 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide , 1.32 g (9.59 mmol) of K2CO3 and 0.88 mL (4.99 mmol) of [(3-bromopropoxy) methyl] benzene in 8 mL of DMF anh. is heated for 12 hours at 40 ° C. After returning to T.A., the medium is taken up in 300 ml of AcOEt, washed successively with water (2 × 100 ml); a saturated solution of NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4 and then concentrated under reduced pressure is purified by chromatography on a column of silica gel, eluting with a cyclohexane / AcOEt gradient from 0 to 10% AcOEt . 1.65 g of N- [3- (benzyloxy) propyl] -6-chloro-N-cyclopentylpyridine-3-sulfonamide in the form of an oil are obtained. Yield = 99%. 1H NMR, CDCl3, 400MHz, δ (ppm): 8.85 (s, 1H); 8.1 (d, 1H); 7.5 (d, 1H); 7.4-7.3 (m, 5H); 4.5 (s, 2H); 4.2 (m, 1H); 3.6 (t, 2H); 3.2 (d * d, 2H); 2.1 (m, 2H); 1.6-1.3 (m, 8H)

25.2 N- [3- (benzyloxy) propyll-N-cyclopentyl-6-hydroxyrazinylpyridine-3-sulfonamide According to the procedure described in Example 5.2, from 1.55 g (3.79 mmol) of N- [3- (benzyloxy) propyl] -6-chloro-N-cyclopentylpyridine-3-sulfonamide, 1.5 g of N- [3- (benzyloxy) propyl] -N-cyclopentyl-6-hydrazinylpyridine-3-sulfonamide as a yellow solid . Yield = 90% 1H NMR, CDCl3, 400MHz, b (ppm): 8.6 (s, 1H); 8.4 (si, 1H); 7.95 (d, 1H); 7.85 (d, 1H); 7.5-7.3 (m, 5H); 6.9 (d, 1H); 6.6 (si, 1H); 4.5 (s, 2H); 4.2 (m, 1H); 3.6 (t, 2H); 3.2 (dd, 2H), 2.1 (m, 2H); 1.6-1.3 (m, 8H)

25.3 6- (4-Benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- [3- (benzyloxy) propyl) -N-cycopentylpyridine-3-sulfonamide According to the method described in US Pat. Example 2.3 gives, from 0.19 g of methyl 2-benzyl-3-oxopropanoate and 0.4 g of N- [3- (benzyloxy) propyl] -N-cyclopentyl-6-hydrazinylpyridine-3-sulfonamide. 0.29 g of 6- (4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- [3- (benzyloxy) propyl] -N-cyclopentylpyridine-3-sulfonamide in the form of a beige solid. Yield = 55% 1H NMR, d6-DMSO, 400MHz, δ (ppm): 12.0 (sl, 1H); 8.8 (s, 1H); 8.6 (sl, 1H); 8.4 (d, 1H); 7.7 (s, 1H); 7.4-7.1 (m, 100H); 4.5 (s, 2H); 4.2 (m, 1H), 3.6 (s, 2H); 3.5 (t, 2H); 3.2 (t, 2H); 2.0 (m, 2H); 1.6-1.2 (6H). 25.4 6- (4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-cyclopentyl-N- (3-hydroxypropyl) pyridine-3-sulfonamide To a solution of 150 mg (0.27 mmol of 6- (4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N- [3- (benzyloxy) propyl] -N-cyclopentylpyridine-3-sulfonamide in 2 mL DCM, 0.82 mL (0.82 mmol) of boron tribromide (1M in DCM) are added dropwise at -78 ° C. under argon, stirring is maintained for 1 hour at -78 ° C. and then 2 mL. of MeOH are added at 0 ° C. The medium is taken up in 40 ml of DCM, washed successively with a saturated solution of NaHCO 3 (30 ml) and brine (30 ml), dried over Na 2 SO 4 and then concentrated under reduced pressure and purified. by chromatography on a silica gel column eluting with a 9: 1 DCM / MeOH mixture 106 mg of 6- (4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) N-cyclopentyl-N- (3-hydroxypropyl) pyridine-3-sulfonamide in powder form are obtained Yield = 85% 1H NMR, d6-DMSO, 400MHz, b (ppm): 8.8 (s, 1H) 8.6 (sl, 1H); 4 (d, 1H) 7.7 (s, 1H); 7.4 (m, 5H); 7.3 (m, 1H); 4.5 (t, 1H); 4.2 (m, 1H), 3.6 (s, 2H); 3.5 (q, 2H); 3.2 (t, 2H); 1.8 (m, 2H); 1.5-1.2 (6H).

25.4 6- (4-Benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-cyclopentyl-N-[3- (dimethylamino) propyl] pyridine-3-sulfonamide hydrochloride solution of 82 mg (0.18 mmol) of 6- (4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-cyclopentyl-N- (3-hydroxypropyl) pyridine-3- sulfonamide, 50 μL (0.36 mmol) of NEt3 in 0.5 mL of DCM anh. 27 μL (0.36 mmol) of mesyl chloride are added under argon at 0 ° C; the temperature is gradually allowed to rise to T.A and stirring is continued for 1 hour. The medium is taken up in 20 ml of DCM, washed successively with water (2 × 10 ml) and brine (20 ml), dried over Na 2 SO 4 and then concentrated under reduced pressure. The 110 mg of yellow oil obtained are diluted in 2 ml of DCM. Dimethylamine is bubbled into the solution for 1 min. The medium is then sealed and heated for 11 h at 60 ° C. After returning to T.A, the medium is concentrated, the residue obtained is triturated in an Et2O / CH3CN mixture. The precipitate formed is filtered off, rinsed with pump-dried pentane and then lyophilized after the addition of 1 N HCl. 57 mg of 6- (4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-cyclopentyl-N- [3- (dimethylamino) propyl] pyridine-3-sulfonamide hydrochloride in the form of lyophilizate are obtained. Yield = 88% F (° C) = 230 M = C25H33N5O3S = 483; M + H = 484; Method 2: Tr = 1.1 min 1H NMR, d6-DMSO, 400MHz, δ (ppm): 12.0 (sl, 1H); 10.8 (sl, 1H); 8.9 (s, 1H); 8.8 (s, 1H); 8.5 (d, 1H); 7.8 (s, 1H); 7.4 (m, 5H); 7.3 (m, 1H); 4.5 (m, 1H); 4.2 (m, 1H); 3.6 (s, 2H); 3.3 (t, 2H); 3.2 (q, 2H); 2.7 t (s, 6H); 2.0 (m, 2H); 1.6-1.3 (6H). Example 26: 6- (4-Benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide (Compound No. 93 of Table I ) 26.1. Methyl 2-benzyl-3-oxopropanoate To a mixture of 3 g (18.3 mmol) of methyl 3-phenylpropanoate and 3.57 ml (54.8 mmol) of methyl formate in 36 ml of toluene, under 54.8 ml (54.8 mmol) of a 1 M solution of TiCl 4 in toluene, 0.17 ml (0.91 mmol) of trimethylsilyltrifluoromethanesulfonate and 19.6 ml (82.degree. 2 mmol) of tributylamine. The medium is then heated for 2 hours at 60 ° C. and then stirred for 12 hours at RT. The reaction medium is hydrolysed with 200 ml of water and extracted with 200 ml of Et2O. The organic phase is dried over Na 2 SO 4, filtered and concentrated under reduced pressure. 3.12 g of methyl 2-benzyl-3-oxopropanoate are obtained in the form of an oil which is used as it is in the next step.

Yield = 87%

26.2. 6- (4-Benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide A mixture of 0.38 g (1.3 mmol) ) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide and 0.25 g (1.3 mmol) of methyl 2-benzyl-3-oxopropanoate in 2 mL of an AcOH / MeOH mixture ( 1: 1) is heated for 4h at 80 ° C. The medium is then concentrated under reduced pressure, the residue obtained is triturated in an Et2O / pentane mixture (1: 1), then filtered and dried under vacuum. At RT, the resulting 440 mg solid is then added in small portions to a solution of 22 mg (0.96 mmol) of sodium in 1 mL of MeOH. The medium is stirred for 3 hours at RT. The reaction mixture is then concentrated under reduced pressure, taken up in 10 ml of water and then acidified to pH 3-4 by addition of AcOH. The precipitate obtained is then filtered, washed with pentane and then recrystallized in EtOH and dried. 245 mg of 6- (4-benzyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide are obtained in the form of a white powder.

Yield = 59% F (° C) = 180 M = C 23 H 22 N 4 O 3 S = 434; M + H = 435; Method 2: Tr = 1.35 min. 1H NMR, d 6 -DMSO, 400MHz, b (ppm): 12 (sl, 1H); 8.6 (sl, 1H); 8.5 (s, 1H); 8.1 (d, 1H) 7.7 (s, 1H); 7.5-7.1 (m, 10H); 3.7 (q, 2H); 3.6 (s, 2H); 1.0 (t, 3H). Example 27: 6- (4-Benzyl-5-oxo-3-trifluoromethyl-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide (Compound No. 83 of Table I) 27.1. Methyl 2-benzyl-4,4,4-trifluoro-3,3-dihydroxybutanoate To a solution of 675 mg (29.4 mmol) of sodium in 15 mL of MeOH anh under argon is added dropwise. 3.73 mL (29.4 mmol) of methyl 3,3,3-trifluoropropanoate After stirring for 30 minutes at RT, 3.5 mL of benzyl bromide is added and the medium is heated for 12 hours at 70 ° C. C. The reaction mixture is then concentrated under reduced pressure, the residue obtained is taken up in 100 ml of AcOEt, washed with 50 ml of brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. After purification by column chromatography on silica gel eluting with a cyclohexane / ACOEt (85:15) mixture, methyl 3,4 g 2-benzyl-4,4,4-trifluoro-3,3-dihydroxybutanoate under form of oil used as it is in the next step. Yield = 37%. 27.2. 6- (4-Benzyl-5-oxo-3-trifluoromethyl-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide A mixture of 1 g (3.59 g) mmol) of methyl 2-benzyl-4,4,4-trifluoro-3,3-dihydroxybutanoate, 1.05 g (3.59 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3 sulfonamide and 1 g of 4A sieve in 8 mL of MeOH is heated for 12 h at 90 ° C. At RT, the reaction medium is taken up in 30 ml of toluene, heated for 12 hours in a Dean & Stark assembly under reflux. The reaction medium is then filtered, concentrated under reduced pressure and the residue obtained is taken up in 50 ml of DCM, washed with 1N HCl solution (2 × 50 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. . The solid thus obtained is recrystallized from EtOH. 224 mg of 6- (4-benzyl-5-oxo-3-5-trifluoromethyl-2,5-dihydro-1H-pyrazol-1-yl) -N-ethyl-N-phenylpyridine-3-sulfonamide are obtained in the form of white crystals. Yield = 12% F (° C) = 186 M = C24H21F3N4O3S = 502; M + H = 503; Method 3: Tr = 4.4min. 1H NMR, d6-DMSO, 400MHz, b (ppm): 12 (sl, 1H); 8.7 (s, 1H); 8.25 (d, 1H); 8.0 (d, 1H); 7.5-7.1 (m, 100H); 3.9 (s, 2H); 3.7 (q, 2H); 1.0 (t, 3H).

The following tables illustrate the chemical structures and the physical properties of some examples of compounds according to the invention.

Table I illustrates compounds of formula (I) according to the invention in which R represents -SO2-NR3R4, these compounds are hereinafter called compounds of formula (I ').

Table II illustrates compounds of formula (I) according to the invention in which R represents R ', these compounds are hereinafter called compounds of formula (I ").

In these tables: Me, Et, n-Pr, i-Pr, n-Bu and i-Bu respectively represent methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl groups, and Ph and Bn respectively represent phenyl and benzyl groups. the column PF indicates the melting point, in ° C, of the compound, and - in the LC / MS column, are indicated successively, the analytical method of high performance liquid chromatography used in detail above and the peak MH + identified by mass spectrometry. Method 1: Column Jsphere33X2 4u, H20 + 0.05% TFA / CH3CN +0.05% TFA ES + Method 2: Acquity column BEH C18 50X2; 220nm UPLC / TOF gradient 3 min H2O / CH3CN / 0.05% TFA TABLE I COMPOUNDS O R3

R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 R4 ci Me And - 260 484 1 No. RI R2 R3 R4 Sel PF L Method MH + S 5 ci Ô Me iPr iPr - 212 464 1 6 ci Ô Me ùN / - 190 448 1 7 F Me And Et - 158 420 1 8 F MeCF3COZH 210 447 1 9 F Me ~ - 230 460 1 \ 10 F Me And - 215 468 1 No. R1 R2 R3 R4 Sel PF L Method MH + S 11 F Me / - 198 432 1 ùN 12 Cl Ô Me ùN / ## STR3 ## ## STR1 ## ## STR2 ## ## STR2 ## S 16 Cl Ô Me ~ ù% - 212 481 1 ci 17 ci Ô F Me ù / / \ Nù CF3CO2H 172 481 1 18 ci MeùN - 240 494 1 19 ci Ô F Me And Et - 170 454 1 20 ci Ô F Me And - 206 502 1 21 ci F Me iPr iPr - 80 482 1 No. R1 R2 R3 R4 Sel PF L Method MH + S 22 1 Me / - 60 466 1 ci Ô F ùN 23 cl Me / \ N CF3CO2H 158 463 1 / - 24 Me Me and Et - 196 436 1 26 cl Me Et - 202 484 1 No. RI R2 R3 R4 Sel PF L MH MS method 27 and Me iPr iPr - 220 464 1 28 CI Me- 228 448 1 29 F Me iPr iPr - 82 448 1 30 0 '\\ Me ù N / - 250 442 1 0 31 0 / SO Me And - 264 478 1 N ° RI R2 R3 R4 Salt PF LMH MS method 32 0- \ Me iPr iPr - 200 458 1 33 o Me And - 177 494 2 34 -o Me And - 144 494 2 NC Me And - 198 475 2 No. R1 R2 R3 R4 Sel PF L method MH + S 36 CN Me And - 218 475 2 37 NC Me And - 112 475 2 38 0 Me And - 126 523 2 -o 39 I Me And - 224 527 2 SO2Me I Me And HCl 192 451 2 NNo R1 R2 R3 R4 Sel PF L method MH + S 41 N Me And - 150 451 2 42 Me And - 212 449 2 43, N Me And HCl 128 451 2 44 Me And - 140 509 2 CF, Me And - 222 518 2 N ° RI R2 R3 R4 Sel PF L method MH + S 46 CF Me And - 178 518 2 3 47 0 Me And - 162 509 2 48 OH Me And - 208 465 2 49 Me And - 178 536 2 N 1 N ° R 1 R 2 R 3 R 4 Sel PF L Method MH + S Me Et - 182 492 2 51 CF3 Me Et .. 172 480 2 52 Me H -CH 2 -HCl 100 416 2 CH (CH 3 CH) 22 - 53 N ~ Me And - 122 491 2 54 o ~ Me And - 188 479 2 Me And - 146 479 2 No. RI R2 R3 R4 Sel PF L method MH + S 56 I Me And HCI 124 537 2 57 o ~ Me And - 108 479 2 58 Me ùNO / - 196 416 59 00H Me And - 202 466 2 And And - 194 464 2 No. RI R2 R3 R4 Sel PF L Method MH + S 61 lI Me And - 176 523 2 62 Me 111 HCI 195 400 2 63 MeHCI 182 428 2 64, N Me And And - 166 403 2 N Me And And HCl 154 403 2 No. RI R2 R3 R4 Sel PF LMH + S Method 66 N Me - Me - 212 375 2 67 Mei Me HCI 170 375 2 68 Pr And - 180 477 2 69 To Me H iPr HCI 228 389 2 NI / N Me ùN ~ HCI 180 401 2 71 N Me H t-Bu HCI 230 403 2 N ° R1 R2 R3 R4 Salt PF LMH MS method 72 I, N Me H> HCl 206 387 2 73 N Me H / - / - db HCl 242 415 2 74 Me And - 158 463 2 Me Me Where HCI 106 438 2 76 Me ~ ùN HCI 160 505 2 77 Me And - 122 477 2 No. RI R2 R3 R4 Salt PF L method MH + S 78 N Me And - 174 480 2 79 Me H HCI 174 424 2 Me And - 146 475 2 81 N Me And - 130 480 2 82 OMe And - 158 479 2 83 -CF3 And - 186 503 3 N ° RI R2 R3 R4 Sel PF LC-MS method MH + 84 HN Me And - 218 478 2 J Me And - 188 464 2 No. 86 N OMe Me And - 138 480 2 87 Name% Me Me - (CH2) 2-OMe - 136 418 2 88 i-Bu And - 138 491 2 N ° RI R2 R3 R4 Salt PF L method MH + S 89 Me H And HCI 196 374 2 Name / Me H HCl 154 422 2 92 Me And - 158 477 2 93 H And - 180 435 2 94 Me And HCI 150 470 2 N ° RI R2 R3 R4 Salt PF LMH + S method 995 N / Me Me HCI 138 400 2 96 N / o Me H tBu HCI 150 432 2 97 N Me And 164 475 2 98 Name / HH tBu HCI 140 388 2 99 N ~ / H And HCl 142 436 2 No. R1 R2 R3 R4 Salt PF L method MH + S 100 H Me tBu 186 401 2 101 N iw OH And HCl 136 466 2/102 NO Me Me tBu 84 446 2 103 III Me And 120 475 2 N 104 0 OH H And 174 403 2 N ° RI R2 R3 R4 Salt PF L method MH + S 105 ONH And 168 430 2 106 0o And 156 521 2 107 OH And 140 417 2 108 ON H And 194 416 2 1 109 ON And 163 520 2 1 110 OH H And 214 417 2 No. R1 R2 R3 R4 Salt PF LMH + S Method 111 Me And 172 507 2 112 OH And 128 431 2 113 HH tBu 66 445 2 114 OOH Me / -rjb 80 485 3 N ° RI R2 R3 R4 Salt PF LMH + S method 115 Nom / H And HCI 110 428 2 116 o Me And 146 507 2 117 I / H Me HCI 124 414 2 N 118 o Me And 2 Na> 260 491 2 119 NH and / - / - b HCI 115 428 2 No. R1 R2 R3 R4 Sel PF L Method MH + S 120 iw H Me HCl 130 414 2 121 OOH Me / - / - / b 80 485 2 122 H Me -CH2-tBu 175 416 2 123 H - (CH 2) 3 - HCl 230 484 2 N (Me) 2 124 H - (CH 2) 2 - O 2 N O R 1 R 2 R 3 R 4 Salt PF L method MH + S 125 H - (CH 2) 3- 138 457 2 OH 126 H CH2-Ph - (CH2) 3-0 - / - / - / b 116 547 2 127 H CH2-Ph - (CH2) 2-0 - / - r- / b 100 533 2 128 Name / ## STR2 ## ## STR1 ## ## STR2 ## ## STR2 ## ## STR2 ## 368 1 130 c Me -C (O) OH HCl 246 381 2 132, CI Me H - 300 1 133 F Me H .. 284 1 No. RI R2 R 'Sel PF LMH + S method 134 Me -CF3 - 352 1 ## STR2 ## ## STR1 ## ## STR1 ## ## STR2 ## 1 No. R1 R2 R 'Salt PF ~ MH + S method 140 CN Me H - 157 291 2 141 CN Me H - 154 291 2 142' w Me H - 55 493 2 ÔCH2-0me 143 'w Me H - 162 267 2 N 144 N 'w Me H HCI 208 267 2 145 CN Me H - 90 291 2 No. R1 R2 R' Salt PF LMH + S method 146 Me -Br - 164 345 2,147 MeO 2 Me - Me --Br - 164 344 2 1490 Me H - 68 340 2 O - CHZ CHZ OMe 150 Me H - 110 266 2 151 N H - 80 267 2 No. R1 R2 R 'Sel PF LC-MS method MH + 152 MeO OMe Me H - 62 326 2 153 nni Me H - 78 334 2 CF3 154 CF3 Me H - 94 334 2 155 OH Me H - 212 465 2 156 CF3 Me H - 106 334 2 No. R1 R2 R 'Sel PF LMH MS method 157 NMe 2 Me H - 110 309 2 158 NMe 2 Me H HCl 132 309 2 159 OMe Me H - 96 296 2 160 OMe Me H - 254 296 2 161 OMe Me H - 120 296 2 No. RI R2 R 'Sel PF LC-MS method MH + 162 OH Me H - 150 281 2 163 And H - 76 280 2 164, w Me H - 128 280 2 165 \ N Me o = s 1 = o 176 407 2 166 0 H -0O2-CH2-tBu 160 367 2 No. R1 R2 R 'Sel PF L method MH + S 167 N. / Me COO t-Bu HCI 156 367 The compounds according to the invention have been the subject of pharmacological tests with a view to determining their properties, with in particular: an in vitro test for the direct measurement of the stabilization of the HIF1a protein, a transcription factor expressed in such a way as to constitutive in the cell but degraded under normal oxygen conditions by the ubiquitin / proteasome system.

A functional test for the measurement in He3pB cells of the secretion of VEGF and EPO which are two markers of the activation of HIF1a in hepatocytes.

These two tests are described below: 1. Measurement of HIF1a Stabilization in HEKEA 1.1 Cells Objective HIF is a transcription factor involved in the adaptation of cells to hypoxia. This transcription factor is at least one heterodimer consisting of 2 proteins, ARNT and HlFla. TNA is constitutively expressed by cells and most of the regulation of the complex is via stabilization of the HIF1a protein. Indeed, this protein, under normal oxygen conditions (20% approximately equivalent to the value of the ambient oxygen), is hydroxylated specifically on 2 prolines (proline 402 and 564 for the human protein) by HIF prolyl hydroxylases leading to binding of von Hippel Lindau protein (VHL). This binding of VHL on HIF1a then causes the degradation of HIF1a by the ubiquitin / proteasome system. In hypoxia (02 <5% in cell tests) the HIF prolyl hydroxylases are inhibited which results in an increase in the amount of the HIF1a protein in the cells. The latter can then associate with ARNT to switch into the nucleus and activate its target genes. Since HIF-activated genes are involved in the adaptive response of cells to hypoxia and tissues to ischemia, the goal is to identify and characterize compounds that stabilize HIF1a in cells to amplify or mimic its beneficial activity. There are numerous tests describing the indirect measurement of HIF activity via reporter gene systems (HRE_luciferase) or via measurement of HIF-induced proteins (eg VEGF or EPO). In addition, the only tests that make it possible to directly measure the amount of the HIF1a protein in the cells are tests using antibodies such as the Western Blot comprising cell extraction phases (total lysates or nuclear extracts) that are consuming in terms of cells. of time thus limiting the screening capacity of compounds. The objective was to develop a sensitive screening test adapted to 384-well plates to directly measure the amount of HIF1a protein in cells. This test was established in HEK cells (epithelial human cells derived from renal adenocarcinoma).

1.2 Principle of the Test

The test is a cell test based on the principle of enzyme complementation, the enzyme used here being beta galactosidase. HEKEA cells are HEK cells stably expressing in their nucleus mutant beta galactosidase (omega fragment also called EA) (line sold by DiscoverX). This construction makes it possible to have 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 HIF1a or HIF1a mutated on the 2 prolines 402 and 564 replaced by Alanines, is fused on the C-terminal side by molecular biology (DiscoverX vector sold by Clontech) with the small peptide fragment of complementation ( Prolabel or ED, about 4 kDa). The vector subsequently coding for the HIF1a_Prolabel chimeric protein is then transfected into HEKEA cells to obtain stable clones (HEKEA HIF1aPLBL). The amount of Prolabel tagged HIF1a tagged at the C-terminal position obtained after treatment of the cells with hypoxia or Potentially activating compounds of HIF is measured by adding to the cells a lysis buffer containing a chemiluminescent substrate of beta galactosidase.

The measurement of the beta-galactosidase activity will be proportional to the amount of Prolabel therefore of HIF1a having migrated into the nucleus of the cells. Experiments were performed internally in parallel to validate that the Prolabel fragment alone was not stable in the cells and thus did not allow the measurement of an activity. 1.3 Protocol

1.3.1 Plan of the experiment35 1) Inoculation of the cells to J 0 2) Adherence 24 hours in normoxia 3) Preparation and addition of the products (Biomek 2000 and FX) D + 1 4) Incubation in Normoxie during 6h 5) Reading of the plates (luminescence)

1.3.2 Seeding of the cells The cells are seeded with Multidrop in plates 384 white wells with opaque bottom (Greiner ref 3704), in 30 μl of culture medium (1% FCS) at 10,000 cells / well (cell plate).

1.3.3 Treatment Preparation of the dilution plate (DL plate) The products to be tested are prepared at 3 × 10 -2 M in 100% DMSO and then diluted to 3 × 10 -4M in the medium at% FCS (10 μl in 990 μl MEM). They are then manually deposited in the column 12 of a round-bottomed 96-well plate (200 μl of each compound) called the dilution plate (d1). The complete plate of 3 × 10 -4 M to 10 -9 M is then produced by the Biomek 2000 (program: Series 10 points in series). For references and controls, 100 μl of DMEM 0.1% FCS are added in column 1, 100 μl of Deferoxamine 10 -3 M in column 2, well ABCD and 100 μl of Deferoxamine 5 × 10 -3 M column 2, EFG well H. Distribution DL plate in 3.3 μL cells are taken from the DL plate by pipetting with Biomek FX 96 to be deposited in horizontal duplicate (column 1 to 24) in each cell plate 384 wells (cell plate HEKEA_HIFIaPLBL) The cells are then deposited for 6 hours in a incubator at 37 ° C (ambient 02, 6% CO2).

1.3.4 Measurement of beta qalactosidase activity.

The kit used is the PROLABEL Chemiluminescent Kit (Ref 93-0001 DiscoverX) After the 6h incubation at 37 ° C the cells are lysed with addition of del5pl of lysis buffer containing the beta galactosidase substrate (19 volumes of Path Hunter cell assay buffer + 5 volumes of Emarald II solution +1 volume of Galacton star) directly added to the 30 μl of medium in the plate. The plates are incubated for 60 minutes in the dark, before reading the luminescence at the Top Count. The EC50's of the compounds are then calculated with appropriate fitting software.

The activating activity of a compound with respect to HIF is given by the concentration which produces 50% of the maximum response of this same compound. No. compound HEK (M) 14 3,8E-06 31 3,0E-06 37 3,2E-06 38 4,7E-06 39 1,8E-06 42 4,8E-06 43 3,1E-06 44 3.1E-06 46 9.6E-06 47 1.1E-06 48 4.3E-06 51 4.4E-06 53 2.6E-06 54 6.4E-06 56 2.1E-06 58 5 7E-06 59 1.7E-06 62 1.6E-05 63 9.2E-06 64 4.3E-06 68 1.5E-06 70 3.5E-06 71 5.0E-06 72 7.5E- 06 74 3.7E-06 76 2.0E-06 77 4.8E-06 80 3.3E-06 81 7.5E-06 82 1.5E-06 83 3.3E-06 84 9.9E-06 85 1.8E-06 87 9.8E-06 88 8.8E-07 92 8.6E-07 93 3.5E-075 1.5 Annex

Maintenance of HEKEA HIF1 aPLBL cells.

The cells are cultured in complete medium (see below) in Flask T225 at 37 ° C. in a CO2 incubator.

HEKEA HIF1 cell culture medium aPLBL DMEM 500 mL + SVF10% (GIBCO 10500-056) 50 mL + Glutamine (2mM final) 5 mL + Penicillline + streptomycin (200mg / mL) 5 mL + Hygromycin B (100pg / mL) 1.1 mL + Geneticine (400 μg / mL final) 4.4 mL 2. Measurement of VEGF and EPO secretion by hepatocytes Hep3B 2.1 Purpose 20 HIF is a transcription factor involved in the adaptation of cells to hypoxia Activated genes by HIF being involved in the adaptive response of cells to hypoxia and tissue to ischemia, the goal is to identify and characterize compounds that stabilize HIFIa in cells to amplify or mimic its activity. beneficial. HIF1a was identified following analysis of the EPO gene promoter, making this protein one of the primary markers of HIF1a activation. On the other hand, VEGF is also identified in the literature as one of the leading markers of HIF activation. This is the reason why the measurement of these two proteins was chosen to characterize the HIF activator compounds in Hep3Bs. The objective was therefore to develop an adaptable sensitive screening test in 96-well plates making it possible to directly measure the amount of VEGF and EPO in the Hep3B supernatant. (Cells derived from human hepato-carcinoma) in response to the potential activators of HIF. 35 .2 Principle of the Test

The test is an ELISA test for the measurement of VEGF and EPO in the supernatant of Hep3B cells treated with hypoxia or deferoxamine in controls or potentiating potentials of HIF. The test was adapted in 96 wells allowing a greater capacity of screening of the compounds.

2.3 Protocol 2.3.1 Plan of the experiment

1) Inoculation of the cells to J 0 2) Adhesion 6 hours in normoxia 3) Preparation and addition of the products (Biomek 2000 and FX) 4) Incubation in normoxia for 18h 5) EPO and VEGF assay in the supernatant at D + 1

2.3.2 Seeding of the cells The cells are subcultured in 100 μl of culture medium (10% FCS) in 96-well black plates with an opaque bottom (Costar reference 3916) at 30,000 cells / well, with multidrop.

2.3.3 Treatment of the cells Preparation of the dilution plate (DL plate) The products to be tested are prepared at 10-2 M in 100% DMSO and then diluted to 310-4M in the medium at 0.1% FCS (6 μl in 194 μl). SAME). 200 μl of each compound is deposited in column 12 of a 96-well dilution plate. The dilution ranges from 3x10-4M to 3x10-8M are carried out by Biomek 2000 (program: Series 9 points in series) .100 μl of MEM 0.1% SVF and 5 × 10 -3 M Deferoxamine are added as controls in column 3 respectively well A , B, C, D and wells E, F, G, H. DL Plate Distribution in Cell Plates The medium of the cells seeded the day before into 96-well plates is changed to 90 μl of medium 0.1% FCS and 10 μl are distributed with FX 96 from the DL 96 plates to the cell plates. The cell plates thus treated are deposited for 18 hours in an incubator at 37 ° C (ambient 02, 6% CO2).

2.3.4 EPO and VEGF assay The supernatants (80 μl) of the Hep3Bs in 96-well plates treated with the HIF activating potentials are collected by multichannel pipette for simultaneous VEGF and EPO assay in ELISA according to the supplier's instructions ( Mesoscale EPO Kit (ref K15122B-2)) The EC50's of the compounds are then calculated with appropriate fitting software. 2.4 Appendix

Hep3B cell culture medium: MEM + Earles (GIBCO 310095) 500mL + 10% FCS (GIBCO 10500-056) 50mL + Glutamine 2mM final 5mL + Non-essential amino acids 1% 5mL 3. Results

The activating activity of a compound with respect to HIF is given by the concentration which produces 50% of the maximum response of this same compound.

The activating activity of a compound with respect to HIF is given by the concentration which produces 50% of the maximum response of this same compound.

Compound number EPO (M) VEGF (M) 14 3.0E-07 - 20 1 E-06 1.1E-06 31 2.1E-06 - 34 9 E-07 - 37 1.0E-06 - 38 1, 0E-06 - 39 2.0E-06 - 42 1.1E-06 1.3E-06 43 1.5E-06 1.7E-06 44 1.9E-06 2.1E-06 46 7.0E-07 1.2E-06 47 2.0E-06 2.8E-06 48 1.1E-06 1.9E-06 51 3.0E-07 4.0E-07 53 9.0E-07 3.2E-06 54 4.5E-07 3.0E-07 56 2E-06 2.5E-06 58 3.2E-06 3.6E-06 59 8.1E-07 6.8E-07 62 9.0E-07 1.0E -06 64 1.4E-06 2.4E-06 68 4.0E-07 5.0E-07 70 2.7E-06 2.9E-06 71 1.6E-06 1.6E-06 72 1.0E -06 1.7E-06 74 3E-07 76 2.0E-07 2.0E-07 77 1.4E-06 1.3E-06 80 4.0E-07 9.0E-07 81 1.2E-06 1.9E-06 82 1E-06 1.2E-06 83 1.4E-06 1.3E-06 84 2.9E-06 3.3E-06 85 2.5E-06 2.5E-06 88 3, The compounds according to the invention can therefore be used for the preparation of medicaments, in particular medicinal products. activators of the transcription factor HIF.

Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid of the compound of formula (I).

These drugs find their therapeutic use, especially in the treatment / prophylaxis in particular of cardiovascular diseases, ischemia of the lower limbs, heart failure, coronary heart disease of ischemic origin such as angina pectoris or infarction myocardial infarction, arteriosclerosis, ischemic strokes, pulmonary hypertension and all pathologies caused by partial or complete vascular occlusion in humans and animals.

These compounds find use in therapy, especially in the treatment / prophylaxis of anemia.

These compounds are also useful in humans and animals for the purpose of obtaining blood in the context of autotransfusions required as a result of major surgical procedures such as cranial or thoracic surgery or as cardiac or surgical operations. carotid or aortic level These compounds are potentially usable in humans and animals as healing agents or agents to shorten the period of postoperative reconvalescence.

These compounds are potentially usable in humans and animals in the treatment of general fatigue states up to cachexia occurring especially in older subjects.

These compounds are potentially usable in humans and animals in the treatment of glaucones, renal diseases or brain diseases of neurodegenerative origin or not.

Finally, the compounds described in the invention are potentially usable in humans and animals for the treatment of cardiac or peripheral diseases of ischemic origin via regenerative medicine in autologous and heterologous approaches using non-embryonic stem cells or cells. myoblasts for therapeutic purposes whether in treatment of these cells before administration or in simultaneous treatment with the local administration of these cells.

On the other hand, the compounds described in the invention can be used alone or if necessary in combination with one or more other active compound (s) useful in the treatment of hypertension, heart failure, diabetes and anemia. For example, mention may be made of the combination of a compound according to the invention with one or more compounds chosen from inhibitors of the conversion enzyme, angiotensin II receptor antagonists, beta blockers, antagonists of the 5 receptor for mineralocorticoids, diuretics, calcium antagonists, statins and derivatives of digitalis.

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 thereof, as well as at least one pharmaceutically acceptable excipient. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or its salt may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, Intranasal, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions. By way of example, a unit dosage form of a compound according to the invention in tablet form may comprise the following components:

Compound of the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg 101 Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.

Claims (12)

  1. REVENDICATIONS1. A compound of formula (I): wherein R is -SO2-NR3R4 or R 'selected from hydrogen or halogen or halogen (C1-05) alkyl, -CO2R5, a group SO2-R4, (C1-05) alkoxy, -O- (C1-05) alkyl-heteroaryl, or O- (C1-05) alkyl-NR5R6; R1 represents a (C3-C6) cycloalkyl group, a heterocycloalkyl group containing no nitrogen atom or a group -W- (C3-C6) cycloalkyl, ùW-aryl, ùW-heteroaryl, ù W-heterocycloalkyl, -W -COOR5, -W-CONR5R6, said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom optionally by one or more substituents selected from one or more halogen atoms, a group (C1- 05) alkyl, ù (C1-C5) alkyl- (C1-C5) alkoxy, (C1-C5) alkoxy, hydroxy, halogen (C1-C5) alkyl, cyano group, (C1-C5) alkoxy group, (C1-C5) alkoxy, -O- (C1-C5) alkyl-NR5R6, -SO2, -SO2- (C1-05) alkyl, -NR5R6, - CO2R5; wherein W is a (C1-C5) alkylene group, a (C3-C6) cycloalkylene group, or a C (O) -NH- group; when W is a (C 1 -C 5) alkylene group, W may be substituted with a group Z where Z is a group (CH 2) n-OH, (CH 2) n -CO 2 R 5, - (CH 2) n -CO 2 N NR 5 R 6, - (CH 2 n-CO2NH-heteroaryl, - (CH2) n-NR5R6, - (CH2) n-NCOR5 or - (CH2) nO (CH2) -aryl; N is 0, 1 or 2; R2 represents a hydrogen atom, a (C1-05) alkyl group, - (C1-05) alkyl- (C1-05) alkoxy, halogen (C1-05) alkyl, a -W-COOR5 group, -W- Wherein W is as previously defined; R3 and R4 independently of one another are hydrogen, (C1-C5) alkyl, (C3-C6) cycloalkyl, - (C1-C5) alkyl- (C1-C5) alkoxy, aryl, -CH2-aryl, heteroaryl, heterocycloalkyl, -W-OH, -W-CHOH-CH2OH, -W-CO2R5, W-NR5R6, WOH- (CH2) n-aryl where W is as previously defined, said groups (C3-C6) cycloalkyl and heterocycloalkyl being optionally substituted on a carbon atom or a heteroatom by one or more (C1-05) alkyl groups, (C1-C2949466 C5) alkoxy, hydroxy, -W-NR5R6, -W -CO2R5 where W is as previously defined, or R3 and R4 together with the nitrogen atom carrying them a heterocycloalkyl group optionally substituted on a carbon atom or a heteroatom by one or more substituents selected from a group ( C1-C5) alkyl, -CH2-aryl; R5 and R6 represent, independently of one another, a hydrogen atom or a (C1-5) alkyl group, in the form of a base or an addition salt with an acid.
  2. 2. Compound of formula (I) according to claim 1, characterized in that R represents a group SO2-NR3R4 or a group R 'chosen from a hydrogen or halogen atom or a halo (C1-05) alkyl group , -CO2R5, a group -SO2-R4, a group (C1-05) alkoxy, -O- (C1-05) alkyl-heteroaryl, or O- (C1-05) alkyl-NR5R6 and / or R1 represents a group ( C3-C6) cycloalkyl, heterocycloalkyl group not containing a nitrogen atom or a group -W- (C3-C6) cycloalkyl, ùW-aryl, ùW-heteroaryl, ù W-heterocycloalkyl, -W-COOR5, -W -CONR5R6, said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom optionally with one or more substituents selected from one or more halogen atoms, a (C1-05) alkyl, C1-05) alkyl- (C1-05) alkoxy, (C1-05) alkoxy, hydroxy, halo (C1-05) alkyl, cyano group, (C1-C5) alkoxy- (C1-05) alkoxy group , -O- (Cl-05) alkyl-NR5R6, -SO2, -SO2- (C1-05) alkyl, -NR5 R6, - CO2R5, where W is a (C1-05) alkylene group, a (C3-C6) cycloalkylene group, or a C (O) -NH- group; when W is a (C 1 -C 5) alkylene group, W may be substituted with a group Z where Z is a group (CH 2) n-OH, (CH 2) n -CO 2 R 5, - (CH 2) n -CO 2 N NR 5 R 6, - (CH 2 n- CO2NH-heteroaryl, - (CH2) n-NR5R6, - (CH2) n-NCOR5 or - (CH2) nO (CH2) -aryl; and / or n represents 0, 1 or 2; and / or R2 represents a hydrogen atom, a (C1-05) alkyl, - (C1-05) alkyl- (C1-C5) alkoxy, halogen (C1-05) alkyl group, a -W-COOR5 group, Wherein W is as previously defined; and / or R3 and R4 represent, independently of one another, a hydrogen atom, a (C1-C5) alkyl, (C3-C6) cycloalkyl, - (C1-C5) alkyl- (C1-C5) group; alkoxy, aryl, -CH2-aryl, heteroaryl, heterocycloalkyl, -W-OH, -W-CHOH-CH2OH, -W-CO2R5, W-NR5R6, W-OH- (CH2) n-aryl where W is as previously defined, said (C3-4 C6) cycloalkyl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom by one or more (C1-05) alkyl, (C1-5) alkoxy, hydroxy, -W-NR5R6 groups Where W is as previously defined, or R3 and R4 form together with the nitrogen atom which carries them a heterocycloalkyl group optionally substituted on a carbon atom or a heteroatom by one or more substituents chosen from a group (C1-05) alkyl, -CH2-aryl; and / or R5 and R6 represent, independently of one another, a hydrogen atom or a (C1-C5) alkyl group, in the form of a base or an addition salt with an acid.
  3. 3. Compound of formula (I) according to claim 1, characterized in that R represents a group ùSO2-NR3R4; R1 represents a heterocycloalkyl group containing no nitrogen atom or a W-aryl, -W-heteroaryl, -W-heterocycloalkyl group, said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted on a carbon atom or a heteroatom if appropriate by one or more substituents selected from one or more halogen atoms, a group (CI-05) alkyl, ù (CI-O 5) alkyl- (C 1 -C 5) alkoxy, (C 1 -C 5) alkoxy, hydroxy, halo ( C 1 -C 5) alkyl, cyano group, (C 1 -C 5) alkoxy- (C 1 -C 5) alkoxy group, -O- (C 1 -C 5) alkyl-NR 5 R 6, -SO 2 - (C 1 -C 5) alkyl, - NR 5 R 6, wherein W is a (C 1 -C 5) alkylene group, a (C 3 -C 6) cycloalkylene group, or a C (O) -NH- group; when W is a (C 1 -C 5) alkylene group, W may be substituted with a group Z where Z is a group (CH 2) n-OH, (CH 2) n -CO 2 R 5, - (CH 2) n -CO 2 N NR 5 R 6, - (CH 2 n-CO2NH-heteroaryl, - (CH2) n-NR5R6, - (CH2) n-NCOR5 or - (CH2) nO (CH2) -aryl; R2 represents a hydrogen atom, a (C1-05) alkyl, - (C1-05) alkyl- (C1-C5) alkoxy, halogen (C1-05) alkyl, -WuCOOR5, -WC (O) -NR5R6 group; or ùW-C (O) -NR5R6; R3 and R4 independently of one another represent a hydrogen atom or a (C1-05) alkyl group, a - (C1-05) alkyl- (C1-05) alkoxy group, a (C3-C6) group ) cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -W-OH, -WCHOH-CH2OH, -W-CO2R5, W-NR5R6, wherein W-OH- (CH2) n-aryl, where W is as previously defined ; or R3 and R4 form together with the nitrogen atom carrying them a heterocycloalkyl group optionally substituted with a (C1-C5) alkyl or -CH2-aryl group; R5, R6 independently of one another represent a hydrogen atom or a (CI-O 5) alkyl group, in the form of a base or an addition salt with an acid. r 2949466 105
  4. 4. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, characterized in that a compound of formula (II) R1 OzOO (II) in which R1 is reacted is reacted. R 2 are as defined in claim 1 and z represents an alkyl group, with a compound of formula (III) wherein R is as defined in claim 1.
  5. 5. A compound of formula (XXV) wherein R3 and R4 represent, independently of one another, a hydrogen atom, a group ) alkyl, (C3-C6) cycloalkyl, - (C1-05) alkyl- (C1-5) alkoxy, aryl, -CH2-aryl, heteroaryl and R2 being a (C1-05) alkyl group, - (C1-05 ) alkyl- (C1-C5) alkoxy or halogen (C1-05) alkyl. R2 2949466
  6. 6. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or an addition salt of this compound to a pharmaceutically acceptable acid of the compound of formula (I) . 5
  7. 7. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 10
  8. 8. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment / prophylaxis of cardiovascular diseases.
  9. 9. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment / prophylaxis of ischemia of the lower limbs, heart failure, coronary diseases of ischemic origin such as angina pectoris or myocardial infarction, arteriosclerosis, ischemic strokes, pulmonary hypertension and all pathologies caused by partial or complete vascular occlusion. 20
  10. 10. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment / prophylaxis of glaucoma, renal diseases or brain diseases of neurodegenerative origin or not, anemia or drug to promote healing or agents or to shorten the period of postoperative reconvalescence or a drug for the treatment of general fatigue states or a drug used in the The goal is to obtain blood for autotransfusion as a result of major surgeries such as cranial or thoracic surgery or cardiac, carotid or aortic operations.
  11. 11. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment / prophylaxis of cardiac or peripheral diseases of ischemic origin via a regenerative medicine using stem cells. 2949466 107
  12. 12. Association of a compound of formula (I) according to any one of claims 1 to 3 with one or more other active compound (s) useful in the treatment of hypertension, heart failure, diabetes and anemia.
FR0904092A 2009-08-28 2009-08-28 New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators useful to treat e.g. lower limb ischemia, angina pectoris, myocardial infarction, atherosclerosis, pulmonary hypertension, glaucoma and kidney diseases Withdrawn FR2949466A1 (en)

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FR0904092A FR2949466A1 (en) 2009-08-28 2009-08-28 New 2-pyridin-2-yl-pyrazol-3(2H)-one compounds are hypoxia inducible factor activators useful to treat e.g. lower limb ischemia, angina pectoris, myocardial infarction, atherosclerosis, pulmonary hypertension, glaucoma and kidney diseases
JP2011542886A JP5734870B2 (en) 2008-12-29 2009-12-24 2-pyridin-2-yl - pyrazol -3 (2h) - derivatives on, therapeutic use as their preparation and hif activator
BRPI0924060A BRPI0924060A8 (en) 2008-12-29 2009-12-24 derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one, their preparation and their application in therapy with HIF activators
EA201170899A EA019591B1 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
PE2011001292A PE04162012A1 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one as HIF activators and preparation thereof
CN 200980157590 CN102333769B (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
PT09805789T PT2382205E (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
DK09805789T DK2382205T3 (en) 2008-12-29 2009-12-24 2-pyridin-2-yl-pyrazol-3 (2H) -one derivatives, their preparation and therapeutic use thereof as HIF activators
NZ59375109A NZ593751A (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
EP20090805789 EP2382205B1 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
CA 2748411 CA2748411A1 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
AU2009334569A AU2009334569B2 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2H)-one, preparation and therapeutic use thereof as HIF activators
MX2011007054A MX2011007054A (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators.
SG2011047503A SG172803A1 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
PCT/FR2009/052691 WO2010076524A2 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
ES09805789.6T ES2481042T3 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one, their preparation and therapeutic use as activators of HIF
SI200930983T SI2382205T1 (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
KR1020117017676A KR20110099786A (en) 2008-12-29 2009-12-24 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
ARP090105126 AR074915A1 (en) 2008-12-29 2009-12-28 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one, pharmaceutical compositions comprising them and use thereof for the treatment of disorders of the cardiovascular system, glaucoma and other pathologies.
TW098145336A TWI482763B (en) 2008-12-29 2009-12-28 2-pyridin-2-yl-pyrazol-3(2h)-one derivatives, preparation and therapeutic use thereof as hif activators
PA8856201A PA8856201A1 (en) 2008-12-29 2009-12-29 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one, their preparation and their use in therapy as HIF activators "
UY32369A UY32369A (en) 2008-12-29 2009-12-29 Derivatives of 2-pyridin-2-yl-pyrazol-3- (2H) -one, their preparation and their therapeutic application as activators hif
TN2011000267A TN2011000267A1 (en) 2008-12-29 2011-05-24 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one, their preparation and their application in therapeutics as activators hif
CL2011001496A CL2011001496A1 (en) 2008-12-29 2011-06-17 Compounds derived from 2-pyridin-2-yl-pyrazol-3 (2H) -one, HIF activators; pharmaceutical composition that comprises; preparation process thereof; and their use in the treatment of peripheral diseases Ischemic heart, among others.
ECSP11011155 ECSP11011155A (en) 2008-12-29 2011-06-22 Substituted 2-pyridine-2-yl-pyrazol-3 (2H) -one, their preparation and their use in therapy HIF activators
CR20110361A CR20110361A (en) 2008-12-29 2011-06-23 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one, their preparation and their therapeutic application as activators hif
IL213789A IL213789A (en) 2008-12-29 2011-06-27 2-pyridin-2-yl-pyrazol-3(2h)-one compound, process for preparing the compound, medicament, pharmaceutical composition, use of a compound in the preparation of a medicament and combinations therewith
ZA2011/04783A ZA201104783B (en) 2008-12-29 2011-06-28 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one,preparation and therapeutic use thereof as hif activators
CO11081326A CO6400141A2 (en) 2008-12-29 2011-06-29 Derivatives 2-pyridin - 2-yl-pyrazol-3 (2H) -one, their preparation and their therapeutic application com activators hif
US13/172,305 US8541455B2 (en) 2008-12-29 2011-06-29 Derivatives of 2-pyridin-2-yl-pyrazol-3(2H)-one, preparation and therapeutic use thereof as HIF activators
MA34027A MA32976B1 (en) 2008-12-29 2011-07-14 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -one, their preparation and their application in therapeutics as activators hif
HRP20140680AT HRP20140680T1 (en) 2008-12-29 2014-07-15 Derivatives of 2-pyridin-2-yl-pyrazol-3(2h)-one, preparation and therapeutic use thereof as hif activators
SM201400097T SMT201400097B (en) 2008-12-29 2014-07-22 Derivatives 2-pyridin-2-yl-pyrazol-3 (2H) -one, loropreparazione and their application in the field tico therapeutically as activators of hif
CY20141100553T CY1115368T1 (en) 2008-12-29 2014-07-23 Derivatives of 2-pyridin-2-yl-pyrazol-3 (2H) -onis, to their preparation and their application in therapeutics as a ACTUATORS of iif

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