EP1487803A1 - Indazoles substitues avec une activite anticancereuse - Google Patents

Indazoles substitues avec une activite anticancereuse

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Publication number
EP1487803A1
EP1487803A1 EP03744395A EP03744395A EP1487803A1 EP 1487803 A1 EP1487803 A1 EP 1487803A1 EP 03744395 A EP03744395 A EP 03744395A EP 03744395 A EP03744395 A EP 03744395A EP 1487803 A1 EP1487803 A1 EP 1487803A1
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EP
European Patent Office
Prior art keywords
indazol
phenyl
benzenesulfonamide
methanesulfonylbenzenesulfonamide
methylsulfonylbenzenesulfonamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03744395A
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German (de)
English (en)
French (fr)
Inventor
Dominique Damour
Jean-Christophe Carry
Patrick Nemecek
Corinne Terrier
Frederico Nardi
Bruno Filoche
Marie-Pierre Cherrier
Daniel Bezard
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Aventis Pharma SA
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Aventis Pharma SA
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Publication of EP1487803A1 publication Critical patent/EP1487803A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/04—Heterocyclic 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

Definitions

  • the present invention relates in particular to new chemical compounds, particularly new substituted indazoles, the compositions containing them, and their use as medicaments.
  • the invention relates to novel specific indazoles exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.
  • Protein kinases are a family of enzymes that catalyze the phosphorylation of hydroxy groups of protein-specific residues such as tyrosine, serine or threonine residues. Such phosphorylations can greatly alter the function of proteins; thus, protein kinases play an important role in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, cell migration, and cell survival. Among the various cellular functions in which the activity of a protein kinase is involved, some processes represent attractive targets for treating cancerous diseases as well as other diseases.
  • compositions having anticancer activity in particular by acting against to kinases.
  • kinases for which modulation of activity are preferred.
  • FAK Fluor Adhesion Kinase
  • integrins a family of heterodimeric receptors for cell adhesion.
  • FAK and integrins are colocalized in perimembrane structures called adhesion plates.
  • Src can then phosphorylate FAK on tyrosine 925, thereby recruiting the Grb2 adapter protein and inducing in certain cells the activation of the ras and MAP kinase pathway involved in the control of cell proliferation [Schlaepfer et al. Nature; 372: 786-791. 1994; Schlaepfer et al. Prog. Biophy. Mol. Biol. 71: 435-478. 1999; Schlaepfer and Hunter, J. Biol. Chem. 272: 13189-13195. 1997].
  • Activation of FAK may also induce the Jun NH2-terminal kinase (JNK) signaling pathway and result in cell progression to the G1 phase of the cell cycle (Oktay et al., J. Cell. Biol. 145: 1461-1469. 1999].
  • JNK Jun NH2-terminal kinase
  • Phosphatidylinositol-3-OH kinase (PI3-kinase) also binds to FAK on tyrosine 397 and this interaction may be required for PI3-kinase activation [Chen and Guan, Proc. Nat. Acad. Sci. USA. 91: 10148-10152. 1994; Ling et al. J. Cell. Biochem. 73: 533-544. 1999].
  • the FAK / Src complex phosphorylates various substrates such as paxillin and p130CAS in fibroblasts [Vuori et al. Mol. Cell. Biol. 16: 2606-2613. 1996].
  • the results of many studies support the hypothesis that FAK inhibitors may be useful in the treatment of cancer.
  • overexpression of p125FAK leads to an acceleration of the G1 to S transition, suggesting that p125FAK promotes cell proliferation [Zhao J.-H et al. J. Cell Biol. 143: 1997-2008. 1998].
  • Indazoles are relatively unrepresented among marketed pharmaceuticals.
  • the 5-substituted indazoles there are essentially sulfonic acids, which are widely used in the field of photosensitization, with a predilection in the field of photography.
  • a sulfonamide is known from JP 62025747, which claims - (1H-indazol-5-yl) -methanesulfonamide as a film preservative and a fogging inhibitor.
  • Therapeutic use is neither described nor contemplated here.
  • the following documents propose the therapeutic use of 5-substituted indazoles:
  • US Patent 5,880,151 claims pentafluorophenylsulfonamide derivatives for treating atherosclerosis.
  • This patent shows an example of indazole substituted in the 5-position by a pentafluorophenylsulfonamide group.
  • the same series of products is claimed in the application WO 98/05315 for use as anti-proliferative agents, and also for treating inflammatory diseases, myocardial infarction, glomerular nephritis, transplant rejections, and infectious diseases. such as HIV infections and malaria.
  • the product 15, whose preparation is described on page 37 is the only indazole in the patent application.
  • the use of these products as kinase inhibitors is not mentioned.
  • these products aim to inhibit tubulin polymerization, which is a function of different mechanisms of cell proliferation inhibition.
  • Patent application WO 00/73264 claims inhibitors of cell proliferation, and in particular inhibitors of tubulin polymerization.
  • This patent application discloses the preparation of numerous products, including a single indazole (page 42, example 34: / V- (1H-indazol-5-yl) -3,4,5-trimethoxybenzenesulfonamide).
  • This product is tested (page 20) at a concentration of 100 ⁇ M against NCI-H460 cells (18.5% growth inhibition) and HCT-15 (47.6% growth inhibition). The activity of this product is very modest compared to that obtained for the other compounds tested.
  • Example 42 has an indazole substituted in the 5-position by a phenylsulfonylamino group.
  • the products described herein are useful for inhibiting JNK protein.
  • Patent application WO 03/004488 published January 16, 2003, discloses 2- (3-benzimidazolyl) indazoles useful as tyrosine and serine / threonine kinase inhibitors. These products are substituted interchangeably on positions 4 to 7 of indazole and / or imidazole.
  • Examples 843 to 854 are indazoles substituted at the 3-position with a benzimidazol-2-yl substituent and at the 5-position with a (alkyl / aryl) -sulfonamido substituent. All these benzimidazoles are substituted in the 6-position by N, N-dialkylamino substituents. No test on FAK is presented. No relationship between the activity of the compounds and their structure is discussed.
  • indazoles substituted in position 5 by a sequence of substituents ZX- as defined below, and optionally substituted in position 3, have a significant kinase inhibitory activity, in particular against FAK.
  • Another merit of the invention is to have found that the substitution of indazole at the 5-position by an appropriate group results in a significant inhibition of the FAK kinase, even when indazole is not substituted on any other position, especially in position 3.
  • Another merit of the invention is to have found that the substitution of the indazole nucleus for a position other than the position 5 resulted in systematically a drop in activity against the kinases tested here:
  • a sequence of substituents ZX- is placed on one of the positions 1, 4, 6 or 7 of the indazole nucleus, this results in a loss of very important activity which then renders the product unsuitable for use as a kinase inhibitor, particularly for FAK.
  • indazole is substituted in the 5-position by a suitable group ZX-as claimed, it is possible to substitute indazole at the 6-position with a small substituent, such as a C1-C3 alkyl group. , although it is not preferred.
  • another of the merits of the invention is to have demonstrated that even when indazole is correctly substituted with an appropriate X group, it is essential that the nitrogen at position 1 of indazole is not substituted in order to to maintain a satisfactory inhibitory activity.
  • c) Z is selected from the group consisting of alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl;
  • alkyl is n-propyl
  • X may advantageously be S (O 2 ) -NH, or S (O 2 ) -O.
  • Z may advantageously be substituted aryl. More preferably, Z may be phenyl substituted with one to three substituents.
  • Z may be phenyl substituted with one or more substituents selected from the group consisting of: 3-fluoro; 3,4-dichloro; 3,4-difluoro; 2-sulfonylmethyl.
  • R 1 may be selected from the group consisting of H, CH 3 , C 2 -C 6 alkyl, Cl, Br, I, CN, C (O) NH (R 2), NHC (O) (R 2), aryl, substituted aryl, alkylene, substituted alkylene.
  • N-Phenyl-5- (2-methylsulfonylphenylsulfonyloxy) -1H-indazole-3-carboxamide N-methyl-5- (2-methylsulfonylphenylsulfonyloxy) -1H-indazole-3-carboxamide 5- (2-methylsulfonylphenylsulfonyloxy) -1H-indazole 3-chloro-1H-indazol-5-yl 3-chloro-1H-indazol-5-yl 3-fluorobenzenesulfonate 3-carboxamide 3-fluoroxenesulfonate 3-hydroxy-1H-indazol-5-yl 3-fluorobenzenesulfonate 3-fluorobenzenesulfonate 3-Iodo-3-phenyl-1H-indazol-5-yl 3-methyl-1H-indazol-5-yl 3-fluorobenzenesulfonate 3-cyano-1H-
  • R1 is selected from the group consisting of H, halogen, alkyl, alkylene, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, cycloalkyl substituted, substituted heterocyclyl, CN, O (R 2), OC (O) (R 2), OC (O) N (R 2) (R 3), OS (O 2 ) (R 2), N (R 2) (R 3),
  • N C (R 2) (R 3), N (R 2) C (O) (R 3), N (R 2) C (O) O (R 3),
  • R2 R3, R4 is independently selected from the group consisting of H, alkyl, aryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted aryl, substituted cycloalkyl, substituted heterocyclyl, alkylene, substituted alkylene; e) X is selected from the group consisting of S (O 2 ) -NH; S (O 2 ) -O; NH-S (O 2 ); 0-S (0 2 ); f) Z is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkenyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted hetero
  • Aryl is 3-fluorophenyl and Subst is selected from methyl, 2,2,2
  • Aryl is selected from 6- (2-dimethylaminomethyl-5-methyl-morpholin-
  • Aryl is 4-fluorophenyl and Subst is phenyl
  • Aryl is 4-trifluoromethyl-phenyl and Subst is N, N-dimethylamino
  • Aryl is thien-2-yl and Subst is 3,5-bis - (trifluoromethyl) -phenyl
  • Aryl is 3,4-methylenedioxy-phenyl and Subst is 1-methyl-ethyl
  • Aryl is 3,5-bis (trifluoromethyl) -phenyl and Subst is 5- ( pyrid-2-yl) -thien-2-yl
  • Aryl is 4-methoxyphenyl and Subst is 4-phenylsulfonyl-thien-2-yl,
  • Subst is selected from 3,4,5-trimethoxyphenyl, 2,3,4,5,6-pentafluorophenyl,
  • a product according to the invention is advantageously a product of formula (I) in which ZX is selected from ZS (O 2 ) -NH and ZS (O 2 ) -O.
  • R is preferably a hydrogen atom.
  • the invention relates to a product of formula (I) wherein Z is substituted aryl, preferably phenyl substituted with one to three substituents.
  • Z is particularly advantageously chosen from 2-methylsulfonylphenyl, 3-fluorophenyl and 3,5-difluorophenyl. This product is particularly useful for inhibiting FAK.
  • R 1 is advantageously selected from the group consisting of NH 2 , NHCOPh, NHCOMe, CONH 2 , CONHPh, phenyl, 3-cyanophenyl, 3-C0 2 MePh, 3- (Me 3 SiC ⁇ C-) Ph, 3-nitrophenyl, 3-aminophenyl, 3-methylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 4-carboxyphenyl, 4-methoxyphenyl, 4-aminophenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, thiophen-2-yl, 5-methoxy-1H-indol-2yl, benzofuran-2-yl, 1H-indol-2-yl, pyrrol-2-yl, 1H-benzimidazol-2-yl, pyrid-4-yl, pyrid-3 yl.
  • This product is particularly useful for inhibiting FAK.
  • the invention relates to a product of formula (I) wherein Z is substituted aryl, preferably phenyl substituted with one to three substituents.
  • Z is particularly advantageously chosen from 2-methylsulfonylphenyl, 3-fluorophenyl, 2-trifluoromethoxyphenyl, thiophenyl
  • R 1 is advantageously selected from the group consisting of 4-carboxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, 5-methoxy-1H-indol-2yl, 1H-indol-2-yl, 1H-benzimidazol-2 -yl, pyrid-4-yl, pyrid-3-yl, benzothiophen-2-yl, stiryl, 4-fluorophenylethylen-2-yl, and 4-chlorophenylethylen-2-yl. This product is particularly useful for inhibiting Aurora2.
  • Products according to the invention may advantageously be chosen from the group consisting of: N- (1H-indazol-5-yl) benzenesulfonamide;
  • a product according to the invention may be in the form: 1) non-chiral, or
  • a product according to the invention may be used for the manufacture of a medicament useful for treating a pathological state, in particular a cancer.
  • the present invention also relates to therapeutic compositions comprising a product according to the invention, in combination with a pharmaceutically acceptable excipient according to the chosen mode of administration.
  • the pharmaceutical composition may be in solid, liquid or liposome form.
  • solid compositions include powders, capsules, tablets.
  • Oral forms may also include solid forms protected from the acidic environment of the stomach.
  • the supports used for the solid forms consist in particular of mineral supports such as phosphates, carbonates or organic supports such as lactose, celluloses, starch or polymers.
  • the liquid forms consist of solutions of suspensions or dispersions. They contain as dispersive carrier either water, or an organic solvent (ethanol, NMP or others) or mixtures of surfactants and solvents or complexing agents and solvents.
  • the liquid forms will preferably be injectable and therefore will have an acceptable formulation for such use.
  • Acceptable injection routes of administration include intravenous, intraperitoneal, intramuscular, and subcutaneous routes, with the intravenous route usually being preferred.
  • the administered dose of the compounds of the invention will be adapted by the practitioner according to the route of administration to the patient and the state of the latter.
  • the compounds of the present invention may be administered alone or in admixture with other anticancer agents.
  • anticancer agents Alkylating agents and in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocine, decarbazine, temozolomide, procarbazine and 'hexamethylmelamine
  • Platinum derivatives such as cisplatin, carboplatin or oxaliplatin
  • antibiotic agents such as bleomycin, mitomycin, dactinomycin • antimicrotubule agents such as vinblastine, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel)
  • Anthracyclines such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone
  • topoisomerase inhibitors such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex
  • Fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine
  • Cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine
  • Adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate
  • antivascular agents such as derivatives of combretastatin or colchicine and their prodrugs. It is also possible to associate the compounds of the present invention with a radiation treatment. These treatments can be administered simultaneously, separately, sequentially. The treatment will be adapted by the practitioner according to the patient to be treated.
  • the products of the invention are useful as inhibitory agents of a kinase catalyzed reaction.
  • FAK is a kinase for which the products of the invention will be particularly useful as inhibitors.
  • the products of the invention may also be useful as inhibitors of Aurora and / or KDR kinases. More generally, the products of the invention may also be useful as inhibitors of Src, Tie2, IGF1R, CDK2 and CDK4 kinases, preferably Src and Tie2.
  • KDR KDR Keratinase insert Domain Receptor
  • VEGF-R2 Vascular Endothelial Growth Factor Receptor 2
  • VEGF-R2 Vascular Endothelial Growth Factor Receptor 2
  • VEGF-R2 Vascular Endothelial Growth Factor Receptor 2
  • VEGF-R2 mutants have been demonstrated in particular using VEGF-R2 mutants (Millauer et al., Cancer Research, 1996, vol 56, p.1615-1620).
  • the VEGF-R2 receptor appears to have no other function in the adult than that related to the angiogenic activity of VEGF. Therefore, a selective inhibitor of VEGF-R2 kinase activity should demonstrate only low toxicity.
  • VEGF expression contributes to tumor cell survival after chemo- and radiotherapies, highlighting the potential synergy of KDR inhibitors with other agents (Lee et al Cancer Research, 2000, vol 60, p.5565-5570).
  • Aurora2 Many proteins involved in chromosome segregation and spindle assembly have been identified in yeast and Drosophila. The disorganization of these proteins leads to non-segregation of chromosomes and monopolar or disorganized spindles. Among these proteins, some kinases, including Aurora and Ipl1, respectively from S. cerevisiae and Drosophila, are needed for chromosome segregation and centrosome separation. A human analogue of yeast Ipl1 has recently been cloned and characterized by different laboratories. This kinase, named aurora2, STK15 or BTAK belongs to the family of serine / threonine kinases. Bischoff et al. have shown that Aurora2 is oncogenic, and is amplified in human colorectal cancers (EMBO J, 1998, 17, 3052-3065). This has also been exemplified in cancers involving epithelial tumors such as breast cancer.
  • Src It has been found that Src kinase, which is involved in many signaling cascades, is often activated or overexpressed in many types of cancer such as colon or breast cancer (Moasser MM et al., Cancer Res, 1999. 59 6245-6152, Wiener et al., Clin Cancer Res, 1999 5: 2164-2170). In addition, Src appears to play a major role in the development of bone metastases by its involvement in the development of bone tissue (Soriano P. et al., Cell 1991, 64: 693-702, Nakagawa et al, J. Cancer). 2000. 88: 384-391).
  • Tie-2 is a member of a family of tyrosine kinase receptors, specific for endothelial cells.
  • Tie2 is the first tyrosine kinase receptor known to have both the agonist (angiopoietin 1 or Ang1) that stimulates receptor autophosphorylation and cell signaling [S.
  • Angiopoietin 1 can synergize with VEGF in the late stages of neoangiogenesis [AsaharaT. Wax. Res (1998) 233-240). The knockout experiments and the transgenic manipulations of Tie2 expression or
  • Ang1 lead to animals with vascularization defects [DJ Dumont et al (1994) Genes Dev. 8, 1897-1909 and C. Suri (1996) Cell 87, 1171-1180]. Angl's binding to its receiver leads to autophosphorylation of the Tie2 kinase domain which is essential for neovascularization as well as for the recruitment and interaction of vessels with pericytes and smooth muscle cells; these phenomena contribute to the maturation and stability of newly formed vessels [PC Maisonpierre et al (1997) Science 277, 55-60]. Lin et al (1997) J. Clin. Invest 100, 8: 2072-2078 and Lin P.
  • Tie2 inhibitors may be used in situations where neovascularization is inappropriate (ie diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, chronic neovascularization due to macular degeneration, rheumatoid arthritis, infantile hemangioma and cancers).
  • neovascularization is inappropriate (ie diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, chronic neovascularization due to macular degeneration, rheumatoid arthritis, infantile hemangioma and cancers).
  • the type 1 receptor for insulin-like growth factor is a transmembrane receptor with tyrosine kinase activity that binds primarily to IGFI but also to IGFII and insulin with a higher low affinity.
  • IGFI binding to its receptor results in oligomerization of the receptor, activation of tyrosine kinase, intermolecular autophosphorylation, and phosphorylation of cellular substrates (major substrates: IRS1 and Shc).
  • IRS1 and Shc major substrates
  • the ligand-activated receptor induces mitogenic activity in normal cells.
  • IGF-I-R plays an important role in so-called abnormal growth.
  • IGF-I-R is often found on expressed in many tumor types (breast, colon, lung, sarcoma %) and its presence is often associated with a more aggressive phenotype.
  • IGF-1R plays an important role in the independent growth of the substrate. IGF-IR has also been shown to be a protector in chemotherapy-induced apoptosis, radiation-, and cytokine-induced apoptosis. In addition, inhibition of endogenous IGF-1R by a dominant negative, triple helix formation or expression of antisense causes suppression of the transforming activity in vitro and decreased tumor growth in the cells. animal models.
  • Cyclin-dependent kinases are a family of protein kinases that are involved predominantly in the control of progression between different phases of the cell cycle.
  • CDK4 associates with cyclin D and phosphorylates the Rb protein, which has the effect of inactivating it, and inducing the dissociation of transcription factors E2F and DP1. These transcription factors then go into the nucleus, where they control the expression of genes required for the G1 / S transition and progression in the S phase.
  • the CDK2-Cyclin E complex is also responsible for the G1 / S transition and more, regulates the duplication of the centrosome.
  • the deregulation of the kinase activity of CDKs in many tumors has stimulated an intensive search for inhibitors for antiproliferative purposes. (see, for example, TRENDS in Pharmacological Sciences Vol.23 No.9 September 2002)
  • halogen refers to an element selected from F, Cl, Br, and I.
  • alkyl refers to a linear or branched, saturated hydrocarbon substituent having from 1 to 12 carbon atoms.
  • the substituents methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3,
  • Examples of alkyl substituents are 3-dimethylbutyl, heptyl, 1-ethylpentyl, octyl, nonyl, decyl, undecyl, and dodecyl.
  • alkylene refers to a linear or branched hydrocarbon substituent having one or more unsaturations, having 2 to 12 carbon atoms.
  • alkynyl refers to a linear or branched hydrocarbon substituent having at least two unsaturations carried by a pair of vicinal carbon atoms having 2 to 12 carbon atoms.
  • Ethynyl substituents; prop-1-ynyl; prop-2-ynyl; and but-1 -ynyl are examples of alkynyl substituents.
  • aryl refers to a mono- or polycyclic aromatic substituent having from 6 to 14 carbon atoms. Phenyl, naphth-1-yl substituents; naphth-2-yl; 1,2,3,4-tetrahydronaphth-5-yl; and 1,2,3,4-tetrahydronaphth-6-yl are examples of aryl substituents.
  • heteroaryl refers to a mono- or polycyclic heteroaromatic substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms.
  • Pyrrol-1-yl substituents; pyrrol-2-yl; pyrrol-3-yl; furyl; thienyl; imidazolyl; oxazolyl; thiazolyl; isoxazolyl; 1,2,4-triazolyl; oxadiazolyl; thiadiazolyl; tetrazolyl; pyridyl; pyrimidyl; 1,3,5-triazinyl; indolyl; benzo [b] furyl; benzo [b] thienyl; indazolyl; benzimidazolyl; azaindolyl; quinolyl; isoquinolyl; and carbazolyl are examples of heteroaryl substituents.
  • heteroatom refers here to at least one divalent atom, different from carbon. NOT; O; S; and are examples of heteroatoms.
  • cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having from 3 to 12 carbon atoms.
  • Cyclopropyl substituents are examples of cycloalkyl substituents.
  • cyclobutyl; cyclopentyl; cyclopentenyl; cyclopentadienyl; cyclohexyl; cyclohexenyl; cycloheptyl; bicyclo [2.2.1] heptyl; cyclooctyl; bicyclo [2.2.2] octyl; adamantyl; and perhydronaphthyl are examples of cycloalkyl substituents.
  • heterocyclyl refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms.
  • the saturated or partially unsaturated cyclic hydrocarbon substituent will be monocyclic and will have 4 or 5 carbon atoms and 1 to 3 heteroatoms.
  • substituted refers to a substituent other than H, for example halogen; alkyl; aryl; heteroaryl, cycloalkyl; heterocyclyl; alkylene; alkynyl; OH ; O-alkyl; O-alkylene; O-aryl; O-heteroaryl; NH 2 ; NH-alkyl; NH-aryl; NH-heteroaryl; SH; S-alkyl; S-aryl; S (O 2 ) H; S (O 2 ) -alkyl; S (O 2 ) -aryl; S0 3 H; S0 3 -alkyl; S0 3 -aryl; CHO; C (0) -alkyl; C (O) - aryl; C (O) OH; C (0) 0-alkyl; C (O) O-aryl; OC (0) alkyl; OC (0) -aryl; C (O) NH 2 ;
  • the present invention also relates to the process for preparing the products of formula (I).
  • the compounds of formula (I) for which X is selected from the group consisting of S ( ⁇ 2 ) -NH and S ( ⁇ 2 ) -O may be prepared by reacting a derivative of formula (II) in which R and R1 have the same meanings as in formula (I) with a sulfonyl chloride ZS (O) CI for which Z has the same meaning as in formula (I) and A represents a hydroxyl (OH) or amino (NH 2) function ): or
  • This reaction is preferably carried out in an inert solvent (tetrahydrofuran, dichloromethane, diethyl ether or dimethylformamide for example) in the presence of an acid acceptor such as an alkylamine (triethylamine, cyclohexylamine for example) or in the presence a base such as pyridine, sodium hydroxide or a hydride (sodium hydride for example) at a temperature between 0 ° C. and the boiling point of the medium or by application or adaptation of the methods described by LZ FLORES-LOPEZ et al., Synth. Comm. 2000, 30 (1), 147, J.
  • an inert solvent tetrahydrofuran, dichloromethane, diethyl ether or dimethylformamide for example
  • an acid acceptor such as an alkylamine (triethylamine, cyclohexylamine for example) or in the presence a base such as pyridine, sodium hydroxide or
  • protective groups of the amine function include tert-butyl carbamate which can be regenerated using iodotrimethylsilane or in acid medium (trifluoroacetic acid, or hydrochloric acid in a solvent such as dioxane for example), acetyl which can be regenerated in an acid medium (hydrochloric acid for example), benzoyl which can be regenerated in an acid medium (hydrochloric acid for example), 2-trimethylsilanyl-ethoxymethyl which can be regenerated in the presence of tetrabutylammonium fluoride or in acidic medium for example (hydrochloric acid for example).
  • Other useful protecting groups are described by TW GREENE et al.
  • This reduction reaction can be carried out according to the usual methods known to those skilled in the art, such as for example using ammonium formate in the presence of palladium on carbon (S. RAM et al., Tetrahedron Lett., 1984, 25, 3415) or with the aid of ferrous sulphate (S. CASTELLANO et al., J.
  • the nitration reaction can be carried out according to the usual methods known to those skilled in the art, such as, for example, using nitric acid or nitrate of an alkali metal (potassium, for example) in the presence of sulfuric acid ( GA OLAH et al., Nitration: Methods and Mechanisms, VCH: NY, 1989) at a temperature between 0 ° C and the boiling temperature of the reaction medium.
  • an alkali metal potassium, for example
  • sulfuric acid GA OLAH et al., Nitration: Methods and Mechanisms, VCH: NY, 1989
  • the compounds of formula (III) for which R and R 1 have the same meanings as in formula (I) may also be prepared by cyclization of compounds of formula (V) in the presence of hydrazine, hydrate or hydrochloride or by application or adaptation methods described for the preparation of products (IV).
  • the cyclization reaction of the compounds (V) is carried out in an inert solvent such as an alcohol (methanol, ethanol for example) at a temperature between 0 ° C. and the boiling temperature of the reaction medium.
  • an inert solvent such as an alcohol (methanol, ethanol for example)
  • the compounds of formula (IV) for which R and R 1 have the same meanings as in formula (I) can be commercial or prepared by application or adaptation of the methods described by AP KRAPCHO et al., Bioorg. Med. Chem. Lett., 2000, 10 (3), 305 and J. Heterocycl. Chem., 1997, 34 (5), 1637, A. VARVARESOU et al., J. Heterocycl. Chem., 1996, 33 (3), 831, F. HALLEY et al., Synth.
  • the compounds of formula (IV) for which R and R 1 have the same meanings as in formula (I) can also be prepared by cyclization of the compounds of formula (VA) in the presence of nitrite R'ONO (sodium nitrite, tert-butyl nitrite, isoamyl nitrite for example) in the presence of acid (acetic acid for example) or anhydride (anhydride acetic acid, for example) at a temperature between 0 ° C. and the boiling temperature of the reaction medium (C. RUECHARDT et al., Synthesis, 1972, 375, Ann Chem, 1980, 6, 908).
  • nitrite R'ONO sodium nitrite, tert-butyl nitrite, isoamyl nitrite for example
  • acid acetic acid for example
  • anhydride anhydride acetic acid, for example
  • the compounds of formula (V) for which R and R 1 have the same meanings as in formula (I) may be commercial or prepared by application or adaptation of the methods described by E. KUMAZAWA et al., Chem. Pharm. Bull., 1997, 45 (9), 1470, F. D. BELLAMY et al., J. Med. Chem., 1991, 34 (5), 1545, J. DEUTSCH et al., Synth. Commun., 1991, 21 (4), 505, A. VARVARESOU et al., J. Heterocycl. Chem., 1996, 33 (3), 831, in WO9322287 and D.M. McKinnon et al., J. Heterocycl. Chem., 1991, 28 (2), 347.
  • the compounds of formula (VB) can be prepared by application or adaptation of the methods described by B. BENNETAU et al., Tetrahedron, 1994, 50, 1179, JJ PARLOW et al., J. Org. Chem., 1997, 62, 5908, SA HERMITAGE et al., Tetrahedron, 2001, 57, 7765, T. KAMETANI et al., J. Chem. Soc. Perkin Trans. 1, 1978 (5), 460 and RE BOLTON et al., J. Chem. Soc. Perkin Trans. 1, 988 (8), 2491.
  • the compounds of formula (I) for which X is selected from the group consisting of NH-S (O 2 ) and O-S (O) may be prepared by reacting a derivative of formula (VI) in which R and R 1 have the same meanings as in formula (I) with a Z-NH 2 amine or a Z-OH alcohol for which Z has the same meaning as in formula (I):
  • the compounds of formula (VI) can be prepared by diazotization followed by a sulfochlorination reaction of the derivatives of formula (MB):
  • the diazotization reaction is carried out for example using sodium nitrite in the presence of acid (hydrochloric acid and acetic acid for example) at a temperature between 0 ° C and the boiling temperature of the reaction medium.
  • the sulfochlorination reaction is effected for example at using sulfur dioxide in the presence of copper salt (such as CuCl or CuCl 2 ).
  • copper salt such as CuCl or CuCl 2 .
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents a group O (R2) can also be prepared by reaction of an alkylating agent R2-Hal with compounds of formula (I) for which R1 represents an OH group.
  • This reaction is generally carried out in the presence of a base (sodium hydride, potassium carbonate for example) in an inert solvent (diethyl ether, dimethylformamide, tetrahydrofuran for example) at a temperature between 0 ° C. and the temperature of 20 ° C. boiling of the reaction medium or by application or adaptation of the methods described by VJ FLORES et al., Liebigs Ann., 1996, 5, 683 and M. YAMAGUCHI et al., Chem. Pharm. Bull., 1995, 43 (2), 332.
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents a group OC (O) (R2) may also be prepared by acylation of the compounds of formula (I) for which R1 represents an OH group.
  • These compounds can be obtained by reacting a (R2) C (O) Cl acid chloride in the presence of a base such as pyridine, triethylamine for example (JK GAWRONSKI et al., J. Am. Chem. Soc. 1987, 109, 6726, JB LAMBERT et al J.
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents a group OC (O) N (R2) (R3) may also be prepared by acylation of the compounds of formula ( I) for which R1 represents an OH group.
  • R2 carbamoyl chloride
  • R 3 NC (O) Cl
  • A. BORIONI Heterocycl Chem, 2000, 37 (4), 799
  • formula (I) for which X and R have the same meanings as in formula (I) and R1 represents an OS (O 2 ) group (R2) may also be prepared by sulphonation of the compounds of formula (I) for which R1 represents an OH group.
  • These compounds can be obtained by reaction of a (R2) S ( ⁇ 2 ) Cl derivative as described for the preparation of the compounds of formula (I) from the compounds of formula (IIC).
  • organometallic a Grignard reagent R2MgX for example, MB SMITH and J. MARCH, Wiley Interscience, Advanced Organic Chemistry, 5th edition, 1217 ALBEROLA, A. et al., Te
  • the hydrolysis of the nitrile function can be carried out in an acidic or basic medium by the methods known to those skilled in the art.
  • this reaction can be carried out in the presence of aqueous sodium hydroxide at a temperature of between 0 ° C. and the boiling point of the medium (PL COMPAGNON et al., Ann Chem (Paris), 1970, 14 (5)). ), 11 and 23).
  • the esterification reaction can be carried out by methods known to those skilled in the art, such as, for example, in the presence of an acid and by reaction with an alcohol (R2) OH (E. HASLAM et al. Tetrahedron, 1980, 36, 2409).
  • the derivatives of formula (ID) can be obtained by reaction (step c) of an amine (R2) (R3) NH in the presence of an activating agent (O- (7-azabenzotriazol-1-yl) hexafluorophosphate) N, N, N ', N'-tetramethyluronium (HATU), or 1-hydroxybenzotriazole hydrate (HOBT) / 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride (EDCI) for example), in the presence of a base (diisopropylethylamine or triethylamine for example) within an inert solvent (dimethylformamide or dimethylformamide / dichloromethane or dimethylformamide / 1-methyl-2-pyrrolidinone mixture for example) at a temperature between 0 ° C.
  • an activating agent O- (7-azabenzotriazol-1-yl) hexafluoro
  • the nitration (step a) can be carried out as described above.
  • the synthesis of the amide intermediate IIIB (step b) can be carried out using NO-dimethyl hydroxylamine, in the presence of an activating agent (1-hydroxybenzotriazole hydrate (HOBT) / hydrochloride of 1 ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDCI) for example), in the presence of a base (triethylamine, for example) in an inert solvent (for example dichloromethane) at a temperature of between 0.degree. ° C and the boiling temperature of the medium, or according to the well-known methods of coupling the peptide chemistry (M.
  • an activating agent (1-hydroxybenzotriazole hydrate (HOBT) / hydrochloride of 1 ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDCI) for example
  • EDCI 1-
  • step c BODANSZKY et al., Principles of Peptide Synthesis, Spinger-Verl, New York, NY, 1984, 9-58) or amide formation.
  • step d The reduction step (step c) and step d can be performed as described above.
  • step e The hydrolysis of the amide function (step e) can be carried out in acidic or basic medium by methods known to those skilled in the art. For example, this reaction can be carried out in the presence of aqueous sodium hydroxide at a temperature between 0 ° C and the boiling point of the medium.
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents a group N (R2) (R3) may also be prepared from compounds of formula (I) for which R1 represents an NH2 group. These compounds can be obtained by alkylation reaction from a derivative (R2) (R3) ⁇ Hal in the presence of a base at a temperature between 0 ° C and the boiling temperature of the medium by application or adaptation methods described by H. KAWAKUBO et al., Chem. Phar. Bull., 1987, 35 (6), 2292.
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents the group N (R2) (R3) in which R2 represents a hydrogen atom and R3 represents a disubstituted alkyl radical may also be prepared from the compounds of formula (I) for which R1 represents an NH 2 group.
  • R2 represents a hydrogen atom
  • R3 represents a disubstituted alkyl radical
  • These compounds can be obtained by reacting an aldehyde or a ketone in the presence of a reducing agent (MB SMITH and J. MARCH, Wiley Interscience, Advanced Organic Chemistry, 5th edition, 1185) at a temperature of between 0 ° C. C and the boiling temperature of the medium.
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents a grouping N (R 2) C (O) (R 3) in which R 2 represents a hydrogen atom may also be prepared by acylation from the compounds of formula (I) for which R 1 represents an NH 2 group, with the aid of an acid chloride (R 3) C (O) Cl in the presence of a base such as pyridine, triethylamine or diisopropylethylamine in an inert solvent (dimethylformamide, tetrahydrofuran, for example) at a temperature of between 0 ° C. and the boiling temperature of the medium
  • a base such as pyridine, triethylamine or diisopropylethylamine in an inert solvent (dimethylformamide, tetrahydrofuran, for example) at a temperature of between 0 ° C. and the boiling temperature of the medium
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents a group N (R2) S (O 2 ) (R3) in which R2 represents a hydrogen atom can also be prepared from the compounds of formula (I) for which R1 represents an NH 2 group. These compounds can be obtained by reaction of a (R 3) S (O 2 ) Cl derivative as described for the preparation of the compounds of formula (I) from the compounds of formula (II).
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 is selected from the group consisting of S (0) (R2), and S (0 2) (R2) may also be prepared by oxidation of the compounds of formula (I) for which R1 represents a group S (R2) at a temperature between 0 ° C. and the boiling point of the medium by application or adaptation of the methods described by (MB SMITH and J MARCH, Wiley Interscience, Advanced Organic Chemistry, 5th Edition, 1541).
  • the compounds of formula (I) for which X and R have the same meanings as in formula (I) and R1 represents a group S (O 2 ) N (R 2) (R 3) may also be prepared from compounds of formula (I) for which R 1 represents the NH 2 group as described for the preparation of the compounds (I) for which X represents an NH-S (02) group from the compounds (IIB).
  • R 1 represents alkyl, alkylene, alkynyl, aryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted cycloalkyl, substituted heterocyclyl, CN, O (R 2), N (R 2) groups ( R3), N (R2) S (0 2) (R 3), N (R2) C (0) (R3) N (R2) C (0) 0 (R3), S (R2), C (0) (R 2), C (O) O (R 2), C (O) N (R 2) (R 3) can also be obtained by reactions involving palladium chemistry: SUZUKI (A.
  • step a) and step b can be carried out as described above.
  • the protection steps (steps c and d) can be carried out using di-tert-butyldicarbonate in the presence of a base such as triethylamine in an inert solvent (dichloromethane for example) at a temperature of between -10 ° C and the temperature medium boiling or or according to well-known methods of protecting the amino function (TW GREENE et al in Protective Groups in Organic Synthesis, Third Edition, 1999, Wiley-Interscience).
  • a base such as triethylamine
  • inert solvent dichloromethane for example
  • the iodination step (step a) can be carried out using iodine in the presence of a base such as potassium hydroxide in an inert solvent (dimethylformamide for example) at a temperature of between 25 ° C. and the boiling temperature of the medium by application or adaptation of the method described by S. RAULT (S. RAULT et al Tetrahedron Lett., 2002, 43, 2695).
  • a base such as potassium hydroxide
  • an inert solvent dimethylformamide for example
  • the protection (step a) can be carried out using 2- (trimethylsilyl) ethoxymethyl chloride in the presence of a base such as sodium hydride in an inert solvent (dimethylformamide for example) at a temperature between -10 ° C. and the boiling temperature of the medium or or according to the well-known methods for protecting the amine function (TW GREENE et al in Protective Groups in Organic Synthesis, third edition, 1999, Wiley-Interscience) .
  • the synthesis of the amide intermediate MIE (step b) can be carried out using N, O-dimethyl-hydroxylamine, in the presence of an activating agent (1-hydroxybenzotriazole hydrate (HOBT) / hydrochloride).
  • step c may be carried out using diisobutylaluminum hydride in an inert solvent such as an ether (tetrahydrofuran, for example) at a temperature of between -10.degree. ° C and the boiling temperature of the medium or according to the well known methods of reducing this function (J. SINGH et al., J. Prakt Chem., 2000, 342 (4), 340).
  • Step d may be carried out using 1,2-diamino-benzene in the presence of sulfur (O) in an inert solvent (dimethylformamide for example) at a temperature of between 0 ° C.
  • step e and the step f can be carried out as described above.
  • the deprotection step (step g) can be carried out in an acidic medium (hydrochloric acid for example) at in an alcohol (for example ethanol) at a temperature between 0 ° C. and the boiling temperature of the medium or according to the well-known deprotection methods of the amino function (TW GREENE et al in Protective Groups in Organic Synthesis) , third edition, 1999, Wiley-Interscience).
  • Step a may be carried out using 1,2-diaminobenzene in the presence of an activating agent (N, N'-diisopropylcarbodiimide for example), in an inert solvent (dimethylformamide for example) at a temperature between 0 ° C and the boiling temperature of the medium, or according to the well-known methods of coupling peptide chemistry (M.
  • the deprotection step b may be carried out for example by means of hydrogen or of a hydrogen donor such as cyclohexene, in the presence of a catalyst (palladium on carbon for example), in a solvent inert form such as an alcohol (methanol for example) at a temperature of between 25 ° C. and the boiling point of the medium, or according to the well-known methods of deprotection of the function Alcohol (TW GREENE et al in Protective Groups in Organic Synthesis, third edition, 1999, Wiley-Interscience).
  • the last step (step c) can be carried out as described above.
  • protective groups of the amine function include tert-butyl carbamate which can be regenerated using iodotrimethylsilane or in an acid medium (trifluoroacetic acid, or hydrochloric acid in a solvent such as dioxane for example), benzyl carbamate which can be regenerated in the presence of hydrogen or in the presence of a mixture of a thiol (benzenethiol for example) and a Lewis acid (boron trifluoride etherate for example), acetyl which can be regenerated in acidic medium (hydrochloric acid for example), benzoyl which can be regenerated in an acidic medium (hydrochloric acid for example), 2- trimethylsilanyl-ethoxymethyl which can be regenerated in the presence of tetrabutylammonium fluoride or in acidic medium for example (hydrochloric acid for example).
  • esters methoxymethyl ester, benzyl ester, methyl ester for example
  • esters methoxymethyl ester, benzyl ester, methyl ester for example
  • protecting groups for the alcohol function mention may be made of esters (benzoylester for example) which can be regenerated in an acid medium or by catalytic hydrogenation, or ethers such as methylether, for example, which can be regenerated in the presence of tribromide. of boron.
  • Other useful protecting groups are described by TW GREENE et al. in Protective Groups in Organic Synthesis, Third Edition, 1999, Wiley-Interscience.
  • the compounds of formula (I) are isolated and can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
  • the enantiomers and diastereoisomers of the compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) comprising a basic residue may optionally be converted into addition salts with a mineral or organic salt by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
  • the compounds of formula (I) comprising an acidic residue may optionally be converted into metal salts or addition salts with nitrogenous bases according to the methods known per se.
  • These salts can be obtained by the action of a metal base (alkaline or alkaline earth for example), ammonia, an amine or an amine salt on a compound of formula (I), in a solvent.
  • the salt formed is separated by the usual methods. These salts are also part of the invention.
  • salts can be prepared by reaction between said product and a mineral or organic acid.
  • Pharmaceutically acceptable salts include chlorides, nitrates, sulphates, hydrogen sulphates, pyrosulphates, bisulphates, sulphites, bisulphites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, acetates, propionates, acrylates, 4-hydroxybutyrates, caprylates, caproates, decanoates, oxalates, malonates, succinates, glutarates, adipates, pimelates, maleates, fumarates, citrates, tartrates, lactates, phenylacetates, mandelates, sebacates, suberates, benzoates, phthalates, methanesulfonates, propanesulfonates, xylenesulfonates, salicylates,
  • compositions may be prepared by reaction between said product and a mineral or organic base.
  • Pharmaceutically acceptable bases include hydroxides of alkali or alkaline earth metal cations such as Li, Na, K, Mg, Ca, basic amine compounds such as ammonia, arginine, histidine, piperidine, morpholine, piperazine, triethylamine.
  • N- (3-chloro-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be obtained as follows: to a solution of 0.22 g of 5-amino-3-chloro-1H-indazole of 15 ml of tetrahydrofuran and 0.37 ml of triethylamine cooled to 0 ° C. is added dropwise a solution of 0.36 g of 2-methylsulfonylbenzenesulfonyl chloride and 3.6 ml of tetrahydrofuran.
  • reaction medium After 30 minutes of reaction at a temperature of 0 ° C and 18 hours at a temperature of 20 ° C, the reaction medium is supplemented with 30 ml of distilled water. The medium is extracted with 30 ml and 15 ml of ethyl acetate. The organic phase is then dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure. The residue thus obtained is purified by chromatography on a silica column with a dichloromethane-methanol mixture (99-1 by volume) as eluent. The solid thus obtained is recrystallized from 45 ml of isopropanol.
  • 5-Amino-3-chloro-1H-indazole can be prepared as described by G. BOYER et al. in J. Chem. Res., Synop., (11), 350 (1990).
  • N- (3-chloro-1H-indazol-5-yl) -3,4-dichlorobenzenesulfonamide can be obtained as follows: to a solution of 0.75 g of 5-amino-3-chloro-1 H- indazole and 14 ml of pyridine cooled to 0 ° C is added dropwise a solution of 1.1 g of 3,4-dichlorobenzenesulfonyl chloride. After reaction for 10 minutes at a temperature in the region of 0 ° C. and 2 hours 30 minutes at a temperature in the region of 20 ° C., 50 ml of distilled water are added to the reaction medium.
  • the medium is extracted with 50 ml and 25 ml of ethyl acetate.
  • the organic phase is then dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • the residue thus obtained is purified by chromatography on a silica column with a dichloromethane-methanol mixture (99-1 by volume) as eluent.
  • the yellow oil thus obtained is purified again by chromatography on a silica column with dichloromethane as eluent.
  • N- (3-chloro-1H-indazol-5-yl) -3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.18 g of 5-amino-3-chloro-1H- indazole, 20 ml of tetrahydrofuran, 0.25 ml of triethylamine and 0.23 g of 3-fluorobenzenesulfonyl chloride. There is thus obtained 0.13 g of N- (3-chloro-1H-indazol-5-yl) -3-fluorobenzenesulfonamide in the form of a yellow meringue decomposing at about 80 ° C.
  • N- (3-cyano-1H-indazol-5-yl) -3-fluorobenzenesulfonamide can be obtained as described in Example 2 from 0.6 g of 5-amino-3-cyano-1H-indazole, 12 ml of pyridine and 0.73 g of 3-fluorobenzenesulfonyl chloride. There is thus obtained 1 g of N- (3-cyano-1H-indazol-5-yl) -3-fluorobenzenesulfonamide in the form of a yellow solid melting at 227 ° C.
  • 5-Amino-3-cyano-1H-indazole can be obtained as follows: to a suspension of 3.1 g of 3-cyano-5-nitro-1H-indazole and 145 ml of ethanol, A suspension of 33 g of ferrous sulfate and 52 ml of distilled water is added portionwise. The reaction medium is stirred at a temperature of 20 ° C for 30 minutes, then 39 ml of 32% ammonia are added dropwise over 10 minutes. The black suspension thus obtained is refluxed for two hours and then brought to a temperature of 20 ° C. The reaction medium is added 300 ml of distilled water and extracted with 300 ml and 150 ml of ethyl acetate.
  • the organic phase is filtered on clarcel, dried over magnesium sulphate and concentrated by evaporation under reduced pressure.
  • the brown solid thus obtained is purified by chromatography on a silica column with a dichloromethane-methanol mixture (99-1 by volume). After drying under reduced pressure, 1.1 g of 5-amino-3-cyano-1H-indazole are obtained in the form of a brown solid melting at 211 ° C.
  • 3-cyano-5-nitro-1H-indazole can be obtained as described by N.V. SAVITSKAYA et al. in J. Gen. Chem. USSR, (31), 3037 (1961).
  • N- (3-cyano-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 0.55 g of 3-cyano-5-amino-1 H- indazole, 10 ml of pyridine and 0.88 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.15 g of N- (3-cyano-1H-indazol-5-yl) -2-methylsulphonylbenzenesulfonamide are thus obtained in the form of a yellow powder melting at 272 ° C.
  • 3-Fluoro-N- (3-phenyl-1H-indazol-5-yl) -benzenesulfonamide can be obtained in the following manner: A solution of 0.4 g of N- (N-tert-butoxycarbonyl) -3- phenyl-1H-indazol-5-yl) -3-fluorobenzenesulfonamide, 3.5 ml of chloroform and 0.127 ml of iodotrimethylsilane is stirred for 18 hours at a temperature in the region of 20 ° C. The reaction mixture is supplemented with 10 ml of 5% ammonia and extracted with 40 ml of dichloromethane.
  • N- (N-tert-butoxycarbonyl-3-phenyl-1H-indazol-5-yl) -3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino -N-tert-butoxycarbonyl-3-phenyl-1H-indazole, 15 ml of tetrahydrofuran, 0.36 ml of triethylamine and 0.27 g of 3-fluorobenzenesulfonyl chloride.
  • 5-amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole can be obtained as follows: to a solution of 0.8 g of N-iron-butoxycarbonyl-5-nitro-3-phenyl- 1 H-indazole and 14 ml of methanol are added 0.12 g of 10% palladium on carbon and 0.68 g of ammonium formate. The suspension is stirred for 18 hours at a temperature close to 20 ° C. The reaction medium is treated with 50 ml of distilled water and extracted with 50 ml and 25 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • N-tert-butoxycarbonyl-5-nitro-3-phenyl-1H-indazole can be obtained as follows: to a solution of 5 g of 5-nitro-3-phenyl-1H-indazole, 100 ml of dichloromethane, 5.9 ml of triethylamine and 0.6 g of 4-dimethylaminopyridine, cooled to a temperature in the region of 0 ° C., are added dropwise 6.8 g of di-tetf-butyldicarbonate in solution in 70 ml. ml of dichloromethane in 30 minutes. Stirring is maintained for 18 hours at a temperature of 20 ° C.
  • the reaction medium is treated with 200 ml of distilled water and extracted with 100 ml of dichloromethane.
  • the organic phases are dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • the residue obtained is purified by chromatography on a silica column with dichloromethane as eluent. 6.9 g of N-tert-butoxycarbonyl-5-nitro-3-phenyl-1H-indazole are thus obtained in the form of a white solid melting at 110 ° C.
  • 2-Methylsulfonyl-N- (3-phenyl-1H-indazol-5-yl) benzenesulfonamide can be prepared as described in Example 1 from 0.5 g of 5-amino-3-phenyl-1 H-indazole, 26 ml of tetrahydrofuran, 0.67 ml of triethylamine and 0.66 g of 2-methylsulfonylbenzenesulfonyl chloride. The residue obtained is purified by chromatography on a silica column with a dichloromethane-methanol mixture (99-1 by volume) as eluent.
  • 5-Amino-3-phenyl-1H-indazole can be obtained as described in Example 4 from 5 g of 5-nitro-3-phenyl-1H-indazole, 75 ml of ethanol, 77.5 g of ferrous sulphate, 65 ml of water and 50 ml of 32% ammonia. 2.1 g of 5-amino-3-phenyl-1H-indazole are thus obtained in the form of a white powder melting at 62 ° C.
  • 3,4-Dichloro-N- (3-phenyl-1H-indazol-5-yl) -benzenesulfonamide can be prepared as described in Example 1 from 1 g of 5-amino-3-phenyl-1H. -indazole, 52 ml of tetrahydrofuran, 1.34 ml of triethylamine and 1.29 g of 3,4-dichlorobenzenesulfonyl chloride. The residue obtained is purified by chromatography on a silica column with a dichloromethane-methanol mixture (99-1 by volume) as eluent.
  • 3-Fluoro-N- (3-methyl-1H-indazol-5-yl) -benzenesulfonamide can be obtained as described in Example 6, starting from 1.35 g of N- (N-tert-butoxycarbonyl) 3-methyl-1H-indazol-5-yl) -3-fluorobenzenesulfonamide, 13.5 ml of chloroform and 0.47 ml of iodotrimethylsilane. 0.6 g of 3-fluoro-N- (3-methyl-1H-indazol-5-yl) -benzenesulfonamide are thus obtained in the form of a white meringue, melting at 120 ° C.
  • N- (N-Fert -butoxycarbonyl-3-methyl-1H-indazol-5-yl) -3-fluorobenzenesulfonamide can be obtained as described in Example 1, starting from 0.9 g of 5-amino -N-Fert -butoxycarbonyl-3-methyl-1H-indazole, 40 ml of tetrahydrofuran, 1 ml of triethylamine and 0.78 g of 3-fluorobenzenesulfonyl chloride.
  • 5-Amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole can be obtained as described in Example 6, starting from 3.4 g of N-tert-butoxycarbonyl-3-methyl-5- 1-nitro-H-indazole, 50 ml of methanol, 0.61 g of 10% palladium on carbon and 3.53 g of ammonium formate. 2.7 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole are thus obtained in the form of a cream solid melting at 185 ° C.
  • N-tert-butoxycarbonyl-3-methyl-5-nitro-1H-indazole can be obtained as described in Example 6, starting from 1.9 g of 3-methyl-5-nitro-1H-indazole. 85 ml of dichloromethane, 3 ml of triethylamine, 0.31 g of 4-dimethylaminopyridine and 3.5 g of di-tert-butyldicarbonate. 3.5 g of N-tert-butoxycarbonyl-3-methyl-5-nitro-1H-indazole are thus obtained in the form of a cream solid melting at 171 ° C.
  • 3-methyl-5-nitro-1H-indazole can be obtained as follows: to a solution of 16.3 g of 2-bromo-5-nitroacetophenone and 400 ml of ethanol are added 13 ml of hydrazine hydrate. The medium is stirred for 8 hours under reflux and then brought to a temperature of 20 ° C. After adding 600 ml of distilled water, the aqueous phase is extracted with 600 ml and 300 ml of ethyl acetate. The organic phases are dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • 2-Methylsulfonyl-N- (3-methyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 6, from 1.45 g of N- (N-butoxycarbonyl) 3-methyl-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide, 12.6 ml of chloroform and 0.44 ml of iodotrimethylsilane. 0.35 g of 2-methylsulfonyl-N- (3-methyl-1H-indazol-5-yl) -benzenesulfonamide are thus obtained in the form of a white solid melting above 260 ° C. (Analysis: C15 H15 N3 O4). S 2% calculated C 49.30, H 4.14, N 11 O 50, O 17.51, S 17.55% found C 48.99, H 4.45, N 11, 67, S: 17,23)
  • N- (N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 1 from 0.9 g of 5-amino N-tert-butoxycarbonyl-3-methyl-1H-indazole, 55 ml of tetrahydrofuran, 1 ml of triethylamine and 1.02 g of 2-methylsulfonylbenzenesulfonyl chloride.
  • N- (3-fluorophenyl) - (1H-indazol-5-yl) -sulfonamide can be obtained as follows: to a solution of 2.57 g of (1H-indazol-5-yl) sulfonyl chloride in 40 ml of pyridine, cooled to a temperature in the region of 0 ° C., 0.98 ml of 3-fluoroaniline are added dropwise. Stirring is maintained for 2 hours at a temperature in the region of 0 ° C. and then at a temperature in the region of 20 ° C. for 18 hours.
  • the medium is concentrated by evaporation under reduced pressure, and the residue obtained is taken up in 50 ml of ethyl acetate and 40 ml of water.
  • the organic phase is washed twice with 20 ml of water, dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • the residue obtained is purified by chromatography on a column of silica in a mixture of ethyl acetate and cyclohexane (1-3 by volume) as eluent. 8 mg of N- (3-fluorophenyl) - (1H-indazol-5-yl) -sulfonamide are thus obtained in the form of an orange solid.
  • the reaction medium is brought to a temperature of 20 ° C and then warmed to a temperature of 30 ° C until the end of the release of sulfur dioxide.
  • the medium is concentrated by evaporation under reduced pressure. There is thus obtained 2.57 g of a solid brick color, used as is in the next step.
  • 3-Fluoro-N- (3-iodo-1H-indazol-5-yl) -benzenesulfonamide can be obtained as described in Example 2 from 230 mg of 5-amino-3-iodo-1H-indazole 5 ml of pyridine and 173 mg of 3-fluorobenzenesulfonyl chloride. There is thus obtained 40 mg of 3-fluoro-N- (3-iodo-1H-indazol-5-yl) benzenesulfonamide as a cream solid, mp 189 ° C.
  • 3-iodo-5-nitro-1H-indazole can be obtained as described by U. WRZECIONO et al. in Pharmazie, 34 (1), 20 (1979).
  • 2-Methylsulfonyl-N- (1H-indazol-5-yl) -benzenesulfonamide can be obtained as described in Example 2 from 1 g of 5-amino-1H-indazole, 20 ml of pyridine and 1 91 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.64 g of 2-methylsulfonyl-N- (1H-indazol-5-yl) -benzenesulfonamide are thus obtained in the form of a white solid melting at 245 ° C. (C14 H13 N3 O4 S2% calculated analysis C: 47.85, H: 3.73, N: 11.96, O: 18.21, S: 18.25% found C: 47.42, H: 3.72, N: 11.64, S: 17.97).
  • 3,4-Dichloro-N- (1H-indazol-5-yl) -benzenesulfonamide can be obtained as described in Example 2 from 1 g of 5-amino-1H-indazole, 20 ml of pyridine. and 1.84 g of 3,4-dichlorobenzenesulfonyl chloride. 0.55 g of 3,4-dichloro-N- (1H-indazol-5-yl) -benzenesulfonamide are thus obtained in the form of a green solid melting at 209 ° C.
  • 3-Fluoro-N- (1H-indazol-5-yl) -benzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-1H-indazole, 20 ml of tetrahydrofuran , 0.83 ml of triethylamine and 0.88 g of
  • 3-Fluoro-N- (3-hydroxy-1H-indazol-5-yl) -benzenesulfonamide can be obtained as described in Example 2 from 51 mg of 5-amino-3-hydroxy-1H-indazole , 1.5 ml of pyridine and 69 mg of 3-fluorobenzenesulfonyl chloride. 6 mg of 3-fluoro-N- (3-hydroxy-1H-indazol-5-yl) -benzenesulfonamide are thus obtained in the form of a white solid.
  • 5-Amino-3-hydroxy-1H-indazole can be prepared as described in Example 4 from 360 mg of 3-hydroxy-5-nitro-1H-indazole, 20 ml of ethanol, 4.25 g of ferrous sulphate, 5 ml of 32% ammonia and 6.7 ml of distilled water. 40 mg of 5-amino-3-hydroxy-1H-indazole are thus obtained in the form of a greenish paste used as it is in the next step.
  • the translucent oil obtained is taken up in 2 ml of diisopropyl ether and concreted by trituration.
  • the solid obtained is separated by filtration, washed with twice 1 ml of diisopropyl ether and dried under reduced pressure.
  • 100 mg of (1H-indazol-5-yl) -3-fluorobenzenesulphonate as a whitish solid melting at 104 ° C. (C13 H9 F N2 O3 S analysis, calculated% C: 53.42, H: 3.10, F: 6.50, N: 9.58, O: 16.42, S: 10.97,% found C : 53.5, H: 2.9, F: 6.2, N: 9.6).
  • (1-Acetyl-1H-indazol-5-yl) -3-fluorobenzenesulphonate can be obtained as follows: to a solution of 132 mg of 1-acetyl-5-hydroxy-1H-indazole in 5 ml of anhydrous tetrahydrofuran and 0.2 ml of triethylamine, cooled to a temperature of about 0 ° C, is poured dropwise a solution of 0.15 g of 3-fluorobenzenesulfonyl chloride in 2 ml of tetrahydrofuran. The reaction medium is stirred for 3 hours at a temperature in the region of 0 ° C.
  • 1-Acetyl-5-hydroxy-1H-indazole can be obtained as follows: a suspension of 467 mg of 1-acetyl-5-benzyloxy-1H-indazole, 525 mg of ammonium formate, 1 g 10% palladium on carbon and 50 ml of acetone is refluxed for 3 hours. After returning to a temperature in the region of 20 ° C., the reaction medium is filtered through a bed of Celite 535. The filtrate is concentrated by evaporation under reduced pressure and the oil obtained is purified by chromatography on a column of silica with a dichloromethane-dichloromethane mixture. methanol (98-2 by volume) as eluent.
  • 1-Acetyl-5-benzyloxy-1H-indazole can be obtained as follows: to a solution of 500 mg of 4-benzyloxy-2-methyl-aniline in 3 ml of toluene is poured 0.8 ml of acetic anhydride and the reaction medium is heated at a temperature of 90 ° C for 1 hour. To this solution at about 90 ° C., 0.55 ml of ter-butylnitrite are poured dropwise. The heating is continued for 1 hour 30 minutes then the reaction medium is cooled to a temperature of 20 ° C and concentrated to dryness under reduced pressure.
  • the dry extract is taken up with 5 ml of chloroform and the The organic phase is washed with 4 ml of a 5% aqueous solution of potassium carbonate, dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • 4-Benzyloxy-2-methylaniline may be prepared as described by T. GRAYBILL et al. in Bioorg. Med. Chem. Lett., 5 (4), 387 (1995).
  • N-phenyl-5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazole-3-carboxamide can be obtained as described in Example 2 from 40 mg of N-phenyl-5-amino-1H-indazole-3- carboxamide, 4 ml of pyridine and 40 mg of 2-methylsulfonylbenzenesulfonyl chloride. 50 mg of N-phenyl-5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazole-3-carboxamide are thus obtained in the form of a pale yellow solid, melting at 258 ° C.
  • N-Phenyl-5-amino-1H-indazole-3-carboxamide can be prepared as follows: to a solution of 0.5 g of 5-amino-1H-indazole-3-carboxylic acid in 24 ml of 1.18 ml of 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, 1.1 ml of diisopropylethylamine and 0.28 ml of dimethylformamide are added. 'aniline. The medium is stirred at a temperature of 20 ° C for 18 hours.
  • reaction medium is added 100 ml of distilled water and extracted with 100 ml and 50 ml of ethyl acetate.
  • the combined organic phases are dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • the residue thus obtained is purified by chromatography on a silica column with a dichloromethane-methanol mixture (99-1 by volume) as eluent. This gives 40 mg of N-phenyl-5-amino-1H-indazole-3-carboxamide as a green solid melting at 242 ° C.
  • 5-Amino-1H-indazole-3-carboxylic acid can be prepared as described by G. BISTOCCHI et al. in Farmaco., 36 (5), 315 (1981).
  • N-methyl-5- (3-fluorobenzenesulfonylamino) -1H-indazole-3-carboxamide can be obtained as described in Example 2 from 40 mg of N-methyl-5-amino-1H-indazole. 3-carboxamide, 1.2 ml of pyridine and 40 mg of 3-fluorobenzenesulfonyl chloride. 20 mg of N-methyl-5- (3-fluoro-benzenesulfonylamino) -1H-indazole-3-carboxamide are thus obtained in the form of an off-white solid, melting above 260 ° C. (C15 H13 N4 03 S analysis).
  • N-Methyl-5-amino-1H-indazole-3-carboxamide can be prepared as in Example 18 from 0.5 g of 5-amino-1H-indazole-3-carboxylic acid, from ml of dimethylformamide, 1.18 g of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, 1.6 ml of diisopropylethylamine and 0, 2 g of methylamine monohydrochloride. 60 mg of N-methyl-5-amino-1H-indazole-3-carboxamide are thus obtained in the form of a brown solid melting at 173 ° C.
  • Example 20 5- (2-Methylsulfonylbenzenesulfonylamino) -1H-indazole-3-carboxamide and sodium 5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazole-3-carboxylate
  • 5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazole-3-carboxamide can be obtained as follows: a solution of 6 ml of 10% sodium hydroxide and 0.23 g of N- (3- cyano-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide is heated for 3 hours at a temperature in the region of 100 ° C. The reaction medium is added ice and acidified to 5 ° C with a 2N hydrochloric acid solution, to a pH of about 3, then extracted with 2 times 50 ml of ethyl acetate.
  • Example 21 5- (3-Fluorobenzenesulfonylamino) -1H-indazole-3-carboxamide and 5- (3-fluorobenzenesulfonylamino) -1H-indazole-3-carboxylic acid
  • 5- (3-fluorobenzenesulfonylamino) -1H-indazole-3-carboxamide can be obtained as in Example 20 from 6 ml of 10% sodium hydroxide and 0.4 g of N- (3 -cyano-1H-indazol-5-yl) -3-fluorobenzenesulfonamide.
  • 0.2 g of 5- (3-fluorobenzenesulfonylamino) -1H-indazole-3-carboxamide are thus obtained in the form of a yellow solid melting at 272 ° C. (Analysis C14 H11 F N4 O3 S, 0.23 H20, 0.48 CH3CO2C2H5% calcd. C: 50.29, H: 3.32, F: 5.68, N: 16.76, O: 14.36, S: 9.59,% found C, 50.42, H: 3.25 , F: 5.57, N: 16.31, S: 9.14).
  • N-phenyl-5- (3-fluorobenzenesulfonylamino) -1H-indazole-3-carboxamide can be obtained as described in Example 18, starting from 0.45 g of 5- (3-fluorobenzenesulfonylamino) -1H acid.
  • N- [5- (3-fluorobenzenesulfonylamino) -1H-indazol-3-yl] -benzamide can be obtained as described in Example 2 from 0.45 g of N- (5-amino-1H- indazol-3-yl) -benzamide, 10 ml of pyridine and 0.35 g of 3-fluorobenzenesulfonyl chloride. 0.6 g of N- [5- (3-fluorobenzenesulfonylamino) -1H-indazol-3-yl] -benzamide are thus obtained in the form of a white solid melting at 225 ° C.
  • N- (5-amino-1H-indazol-3-yl) -benzamide can be obtained as described in Example 4 from 0.6 g of N- (5-nitro-1H-indazol-3- yl) -benzamide, 21 ml of ethanol, 4.2 g of ferrous sulfate, 6.6 ml of water and 5.1 ml 32% ammonia. There is thus obtained 0.4 g of N- (5-amino-1H-indazol-3-yl) -benzamide as a yellow powder melting at 116 ° C.
  • N- (5-nitro-1H-indazol-3-yl) -benzamide can be obtained as follows: to a solution of 0.6 g of 3-amino-5-nitro-1H-indazole and 5 ml of pyridine cooled to 0 ° C is added dropwise 0.39 ml of benzoyl chloride. The medium is brought to a temperature of 20 ° C and stirred for 18 hours. After addition of 20 ml of distilled water, the medium is extracted with 20 ml and 10 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • N- (1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 1 from 0.5 g of 5-amino-1H-indazole, 25 ml of tetrahydrofuran, 1.05 g. ml of triethylamine and 0.73 g of benzenesulfonyl chloride. There is thus obtained 0.6 g of N- (1H-indazol-5-yl) benzenesulphonamide in the form of a cream solid melting at 179 ° C. (C13 H11N2 O2 S% analysis calculated C: 57.13, H: 4.06). , N: 15.37, O: 11, 71, S: 11, 73% found C: 56.90, H: 4.24, N: 14.21, S: 10.67).
  • 3,4-Dichloro-N- (3-methyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 6, from 0.8 g of N- (N-tert-butoxycarbonyl) -3-methyl-1H-indazol-5-yl) -3,4-dichlorobenzenesulfonamide, 7.1 ml of chloroform and 0.25 ml of iodotrimethylsilane.
  • 0.5 g of 3,4-dichloro-N- (3-methyl-1H-indazol-5-yl) benzenesulfonamide are thus obtained in the form of a white solid melting at 184 ° C.
  • N- (N-fetf-butoxycarbonyl-3-methyl-1H-indazol-5-yl) -3,4-dichlorobenzenesulfonamide can be obtained as described in Example 1, from 1 g of 5-amino -N-tert-butoxycarbonyl-3-methyl-1H-indazole, 50 ml of tetrahydrofuran, 1.15 ml of triethylamine and 1.1 g of 3,4-dichlorobenzenesulfonyl chloride.
  • N- (3-amino-1H-indazol-5-yl) -3-fluorobenzenesulfonamide can be obtained as follows: a solution of 0.3 g of N- [5- (3-fluorobenzenesulfonylamino) -1H- indazol-3-yl] -benzamide, 24 ml of ethanol and 1.08 ml of 37% hydrochloric acid is heated at a temperature of 100 ° C for 30 hours. The cooled reaction medium is concentrated under reduced pressure. The residue thus obtained is added with 20 ml of water and aqueous sodium hydroxide to a pH of about 11, and then extracted with three times 25 ml of ethyl acetate.
  • 3-Fluoro-N- (3-methylsulfonylamino-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 2 from 0.1 g of 5-amino-3-methylsulfonylamino-1 H- indazole, 5 ml of pyridine and 83 mg of 3-fluorobenzenesulfonyl chloride. 30 mg of 3-fluoro-N- (3-methylsulfonylamino-1H-indazol-5-yl) benzenesulphonamide are thus obtained in the form of a beige solid melting at 230 ° C.
  • 5-Amino-3-methylsulfonylamino-1H-indazole can be obtained as described in Example 4 from 256 mg of 3-methylsulfonylamino-5-nitro-1H-indazole, 10 ml of ethanol, 2 g of ferrous sulphate, 3.2 ml of water and 2.4 ml of 32% ammonia. 0.1 g of 5-amino-3-methylsulfonylamino-1H-indazole is thus obtained in the form of an oil used as it is in the next step.
  • the 3-methylsulfonylamino-5-nitro-1H-indazole can be obtained as described in Example 2 from 0.7 g of 3-amino-5-nitro-1H-indazole, 23 ml of pyridine and 0.455 g of methylsulfonyl chloride. There is thus obtained 0.85 g of 3-methylsulfonylamino-5-nitro-1H-indazole in the form of an orange powder used as it is in the next step.
  • 3-Amino-5-nitro-1H-indazole can be prepared as described by E. PARNELL in Journal of Chemical Society, 2363 (1959).
  • N- [5- (3-fluorobenzenesulfonylamino) -1H-indazol-3-yl) -acetamide can be obtained as follows: to a solution cooled to 0 ° C of 0.16 g of 3-fluoro-N - (3-Amino-1H-indazol-5-yl) benzenesulfonamide and 3.2 ml of pyridine, 0.037 ml of acetyl chloride are added dropwise. The reaction medium is then kept stirring at a temperature of 25 ° C overnight. After addition of 20 ml of water, the medium is extracted with three times 10 ml of ethyl acetate.
  • N-Cyclohexyl-5- (2-methylsulfonyl-benzenesulfonylamino) -1H-indazole-3-carboxamide can be prepared as described in Example 2 from 0.25 g of 5-amino-N-cyclohexyl-1H- indazole-3-carboxamide, 5 ml of pyridine and 246 mg of 2-methylsulfonylbenzenesulfonyl chloride. 38 mg of N-cyclohexyl-5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazole-3-carboxamide are thus obtained in the form of an off-white solid melting at a temperature above 260 ° C.
  • 5-Amino-N-cyclohexyl-1H-indazole-3-carboxamide can be obtained in the following manner: a suspension of 1. 57 g of N-cyclohexyl-5-nitro-1H-indazole-3-carboxamide, 80 ml of methanol, 1.37 g of ammonium formate and 0.314 g of palladium hydroxide were refluxed for two hours. The reaction medium is then brought to a temperature in the region of 25 ° C. and filtered through Celite® on sintered glass. The solid obtained is washed with methanol and the filtrate is concentrated by evaporation under reduced pressure. The oil thus obtained is taken up in 80 ml of dichloromethane and 80 ml of water.
  • N-cyclohexyl-5-nitro-1H-indazole-3-carboxamide can be obtained in the following manner: a solution of 2.5 g of 5-nitro-1H-indazole-3-carboxylic acid, 150 ml of dichloromethane, 75 ml of dimethylformamide, 0.16 g of 1-hydroxybenzotriazole and 2.75 g of 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride are stirred for 15 minutes at a temperature of 25.degree. ° C. 1.7 ml of cyclohexylamine and 1.7 ml of triethylamine are then added.
  • the reaction medium is stirred for 70 hours and concentrated by evaporation under reduced pressure.
  • the residue thus obtained is taken up in 50 ml of dichloromethane and 50 ml of diisopropyl ether.
  • the paste obtained is taken up in 80 ml of distilled water and the solid formed is filtered on sintered glass, washed with twice 50 ml of water and then dried under reduced pressure.
  • the resulting solid is taken up in 50 ml of ethyl acetate, filtered on sintered glass, washed twice with 25 ml of ethyl acetate and dried at 50 ° C. under reduced pressure.
  • 5-Nitro-1H-indazole-3-carboxylic acid can be prepared as described by G. BISTOCCHI et al. in Farmaco, 36 (5), 315 (1981).
  • N- [3- (4-chlorophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as follows: to a solution of 0.45 g of 5-amino-3- (4-Chlorophenyl) -1H-indazole, 15 ml of tetrahydrofuran and 0.165 ml of pyridine cooled to 0 ° C is added dropwise a solution of 0.515 g of 2-methylsulfonylbenzenesulfonyl chloride in 3 ml of tetrahydrofuran.
  • the reaction medium is supplemented with 50 ml of distilled water.
  • the medium is extracted with 30 ml of ethyl acetate.
  • the organic phase is then washed with 3 times 20 ml of distilled water and the aqueous phase is extracted again with 30 ml of ethyl acetate.
  • the organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness by evaporation under reduced pressure.
  • the residue thus obtained is purified by chromatography on a silica column with a dichloromethane-ethyl acetate mixture (99/1 by volume) as eluent.
  • 5-Amino-3- (4-chlorophenyl) -1H-indazole can be prepared as described in Example 4 from 1 g of 3- (4-chlorophenyl) -5-nitro-1H-indazole, 15 ml of ethanol, 13.5 g of ferrous sulfate, 13 ml of distilled water and 10 ml of 32% ammonia. 0.45 g of 5-amino-3- (4-chlorophenyl) -1H-indazole are thus obtained in the form of a salmon powder melting at 163 ° C.
  • 3- (4-Chlorophenyl) -5-nitro-1H-indazole can be prepared in the following manner: a solution of 5.9 g of 2,4'-dichloro-5-nitrobenzophenone, 4.8 ml d hydrazine hydrate and 140 ml of ethanol is refluxed for 20 hours. The reaction medium is then brought to a temperature of 20 ° C and the precipitate formed is filtered on sintered glass and washed with diisopropyl ether. The powder thus obtained is purified by chromatography on a silica column with dichloromethane as eluent. 3.5 g of 3- (4-chlorophenyl) -5-nitro-1H-indazole are thus obtained in the form of a yellow powder melting at 212 ° C.
  • 2,4'-Dichloro-5-nitrobenzophenone can be obtained as described by F. D. BELLAMY et al. in J. Med. Chem., 1991, 34 (5), 1545.
  • N- [3- (4-methoxyphenyl) -1H-indazol-5-yl] benzenesulfonamide can be prepared as in Example 2 from 3.47 g of 5-amino-3- (4-methoxyphenyl) - 1 H-indazole, 1.29 ml of pyridine and 2.03 ml of benzenesulfonyl chloride. There is thus obtained 1.7 g of N- [3- (4-methoxyphenyl) -1H-indazol-5-yl] benzenesulfonamide in the form of a white solid melting at 172 ° C.
  • 5-Amino-3- (4-methoxyphenyl) -1H-indazole may be prepared as described in WO 0210137.
  • Example 32 N- [3- (4-Methoxyphenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide
  • N- [3- (4-methoxyphenyl) -1H-indazol-5-yl] -2-methylbenzenesulfonamide can be prepared as in Example 2 from 2.3 g of 5-amino-3- (4- methoxyphenyl) -1H-indazole, 0.94 ml of pyridine, 50 ml of tetrahydrofuran and 2.93 g of 2-methylsulfonylbenzenesulfonyl chloride. There is thus obtained 1.
  • N- [3- (4-fluorophenyl) -1H-indazol-5-yl] -2-methylbenzenesulfonamide can be prepared as in Example 2 from 0.7 g of 5-amino-3- (4 fluorophenyl) -1H-indazole, 0.27 ml of pyridine, 18 ml of tetrahydrofuran and 866 mg of 2-methylsulfonylbenzenesulfonyl chloride. 0.54 g of N- [3- (4-fluorophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a pink solid melting at 209 ° C.
  • 5-Amino-3- (4-fluorophenyl) -1H-indazole may be prepared as described in WO 0210137.
  • N- [3- (4-hydroxyphenyl) -1H-indazol-5-yl] benzenesulfonamide can be prepared in the following manner: to a slurry cooled to -60 ° C of 0.8 g of N- [3- ( 4-methoxyphenyl) -1H-indazol-5-yl] benzenesulfonamide, and 150 ml of dichloromethane, 6.56 ml of boron tribromide are added. The reaction medium is then stirred at a temperature of -60 ° C for one hour and then overnight at a temperature of 25 ° C. The solution thus obtained is poured into 300 ml of an aqueous solution of sodium hydrogencarbonate.
  • N- [3- (4-hydroxyphenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be prepared as described in Example 34 from 2 g of N- [3- (4- methoxyphenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide, 1 l of dichloromethane and 21 ml of boron tribromide.
  • N- (3-benzylamino-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be prepared as in Example 2 from 0.12 g of 5-amino-3-benzylamino-1H-indazole, 10 ml of pyridine and 0.13 g of 2-methylsulfonylbenzenesulfonyl chloride.
  • 0.1 g of N- (3-benzylamino-1H-indazol-5-yl) -2-methylsulphonylbenzenesulfonamide are thus obtained in the form of a yellow solid melting at 226 ° C. (C21 H20 N4 O4 S2 analysis, 0.62 CH2Cl2%). calculated C: 55.25, H: 4.42, N: 12.27, O: 14.02; S: 14.05% ⁇ found C: 55.35, H: 4.22, N: 12.12 , S: 14.10).
  • 5-Amino-3-benzylamino-1H-indazole can be obtained as described in Example 4 from 0.6 g of 3-benzylamino-5-nitro-1H-indazole, 22 ml of ethanol, 4.5 g ferrous sulphate, 7 ml water and 5.4 ml 32% ammonia. 0.15 g of 5-amino-3-benzylamino-1H-indazole is thus obtained in the form of a brown powder melting at 196 ° C.
  • 3-Benzylamino-5-nitro-1H-indazole can be obtained as follows: a solution of 0.5 g of 3-amino-5-nitro-1H-indazole, 10 ml of methanol, 0 33 ml of benzaldehyde and 0.24 g of sodium cyanoborohydride are refluxed for 4 hours. The reaction medium cooled to a temperature in the region of 25 ° C. is added with 30 ml of distilled water and then extracted with 3 times 15 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • the residue thus obtained is dissolved in 25 ml of methanol and 0.24 g of sodium cyanoborohydride are added.
  • the pH of this solution is adjusted to about 2 by addition of hydrochloric methanol and stirred for 24 hours at a temperature of 25 ° C.
  • the suspension thus obtained is concentrated by evaporation under reduced pressure and the residue obtained is added with 30 ml of water.
  • This aqueous phase is neutralized with 0.5 ml of ammonia to pH 10 and extracted with 3 times 25 ml of ethyl acetate.
  • the organic phases are combined, dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure.
  • N- (3-methylamino-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be prepared as in Example 2 from 0.21 g of 5-amino-3-methylamino-1H-indazole, 25 ml of pyridine and 0.33 g of 2-methylsulfonylbenzenesulfonyl chloride. 0.3 g of N- (3-methylamino-1H-indazol-5-yl) -2-methylsulphonylbenzenesulfonamide are thus obtained in the form of a cream solid melting at 220 ° C.
  • 5-Amino-3-methylamino-1H-indazole can be obtained as described in Example 4 from 0.5 g of 3-methylamino-5-nitro-1H-indazole, 25 ml of ethanol 5.2 g of ferrous sulphate, 8 ml of water and 6.2 ml of 32% ammonia. 0.1 g of 5-amino-3-methylamino-1H-indazole is thus obtained in the form of a cream powder melting at 215 ° C.
  • 3-Methylamino-5-nitro-1H-indazole can be obtained as follows: To a solution of 5 ml of acetic anhydride cooled at 0 ° C., 2.4 ml of formic acid are added dropwise. . The solution is then brought to 50 ° C. for one hour and then cooled again to -20 ° C. 3.5 g of 3-amino-5-nitro-1H-indazole in solution in 150 ml of tetrahydrofuran are then added and the stirring is maintained at -20 ° C. for one hour. The reaction medium is concentrated by evaporation under reduced pressure and the residue thus obtained is dissolved in 50 ml of tetrahydrofuran.
  • the solution thus obtained is cooled to 0 ° C. and 25 ml of borane-dimethylsulfide complex (2M solution in tetrahydrofuran) are added dropwise.
  • the reaction medium is slowly brought to a temperature of 25 ° C and then refluxed for 3 hours and again brought to a temperature of 0 ° C.
  • 50 ml of 3M hydrochloric methanol are added dropwise and the mixture is refluxed for one hour.
  • the medium is brought to a temperature of 25 ° C and concentrated under reduced pressure by evaporation.
  • N- (3-bromo-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be prepared as in Example 2 from 3.7 g of 5-amino-3-bromo-1H-indazole 75 ml of pyridine and 4.54 g of 2-methylsulfonylbenzenesulfonyl chloride.
  • 5-Amino-3-bromo-1H-indazole can be prepared as described by M. BENCHIDMI et al. in Journal of Heterocyclic Chemistry, 16 (8), 1599 (1979).
  • N- (3-amino-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be obtained as follows: To a solution of 240 mg of 3,5-diamino-1H-indazole, 2 ml of pyridine and 3 ml of tetrahydrofuran cooled to -10 ° C are added in portions 391 mg of 2-methylsulfonylbenzenesulfonyl chloride. The medium is stirred for two hours at a temperature of -10 ° C and then brought to a temperature of 25 ° C.
  • N- (3-amino-1H-indazol-5-yl) -2,6-difluorobenzenesulfonamide can be obtained as described in Example 39 from 1 g of 3,5-diamino-1H-indazole, from 10 ml of pyridine, 10 ml of tetrahydrofuran and 1.4 g of 2,6-difluorobenzenesulfonyl chloride. 179 mg of N- (3-amino-1H-indazol-5-yl) -2,6-difluorobenzenesulfonamide are thus obtained in the form of a gray solid melting at 241 ° C.
  • N- (3-amino-1H-indazol-5-yl) -2,6-dichlorobenzenesulfonamide can be obtained as described in Example 39 from 0.8 g of 3,5-diamino-1H-indazole. 8 ml of pyridine, 8 ml of tetrahydrofuran and 1.29 g of 2,6-dichlorobenzenesulfonyl chloride. There is thus obtained 350 mg of N- (3-amino-1H-indazol-5-yl) -2,6-dichlorobenzenesulfonamide in the form of a pale yellow solid melting at 250 ° C.
  • N- (3-Amino-1H-indazol-5-yl) -3,5-difluorobenzenesulfonamide can be obtained as described in Example 39 from 2.1 g of 3,5-diamino-1H- indazole, 20 ml of pyridine, 20 ml of tetrahydrofuran and 1.47 g of 3,5-difluorobenzenesulfonyl chloride. 0.727 g of N- (3-amino-1H-indazol-5-yl) -3,5-difluorobenzenesulfonamide are thus obtained in the form of a white solid melting at 232 ° C.
  • N- [5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl) -acetamide can be obtained as described in Example 28 from 0.5 g of N- (3-amino-1H-indazol). 5-yl) -2-methylsulfonylbenzenesulfonamide, 3 ml of pyridine and 98 ⁇ l of acetyl chloride. 338 mg of N- [5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl) -acetamide are thus obtained in the form of a white solid which decomposes around 145 ° C.
  • N- [5- (3,5-difluorobenzenesulfonylamino) -1H-indazol-3-yl) acetamide can be obtained as described in Example 28 from 0.1 g of N- (3-amino-1H). -indazol-5-yl) -3,5-difluorobenzenesulfonamide, 9 ml of pyridine and
  • N- [5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl) benzamide can be obtained as described in Example 28 from 0.5 g of N- (3-amino-1H-indazol). 5-yl) -2-methylsulfonylbenzenesulfonamide, 3 ml of pyridine and 0.158 ml of benzoyl chloride. 435 mg of N- [5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl) benzamide are thus obtained in the form of a pink solid decomposing around 200 ° C.
  • N- [5- (3,5-difluorobenzenesulfonylamino) -1H-indazol-3-yl) benzamide can be obtained as described in Example 28 from 0.15 g of N- (3-amino-1H). -indazol-5-yl) -3,5-difluorobenzenesulfonamide, 13.5 ml of pyridine and 0.06 ml of benzoyl chloride. There is thus obtained 30 mg of N- [5- (3,5-difluorobenzenesulfonylamino) -1H-indazol-3-yl) benzamide in the form of a cream solid melting at 246 ° C.
  • N- ⁇ 2- [5- (3-Fluoro-benzenesulfonylamino) -1H-indazol-3-yl] -phenyl ⁇ -acetamide can be prepared as follows: to a suspension, maintained under argon atmosphere, 528 tert-butyl 3-iodo-5- (N-tertbutoxycarbonyl-3-fluoro-benzenesulfonylamino) -indazole-1-carboxylate and 200 mg of 2- (acetylaminophenyl) boronic acid in 15 ml of dimethylformamide are added successively.
  • the feti-butyl 3-iodo-5- (N-tert-butoxycarbonyl-3-fluoro-benzenesulfonylamino) -indazole-1-carboxylate can be obtained in the following manner: to a mixture of 3.9 g of 3-fluoro -N- (3-iodo-1H-indazol-5-yl) benzenesulfonamide in 140 ml of dichloromethane under argon, 2.45 ml of triethylamine and then 269 mg of 4- (dimethylamino) -pyridine are added.
  • the mixture is cooled to a temperature in the region of 0 ° C., then a solution of 4.55 g of di-tert-butyldicarbonate in 20 ml of dichloromethane is added dropwise over 10 minutes.
  • the reaction mixture is stirred at a temperature of 0 ° C for 0.5 hour and then at a temperature of 20 ° C for 5 hours.
  • the organic phase is washed with 2 times 20 ml of distilled water, dried over magnesium sulphate, decolorized with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa ) at a temperature of 40 ° C.
  • N- ⁇ 2- [5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl] phenyl ⁇ acetamide can be obtained as described in Example 47 from 1.35 g of 3-iodine.
  • N- ⁇ 2- [5- (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl] -phenyl ⁇ -acetamide are thus obtained in the form of a white solid melting at 245 ° C. (C22 H20 analysis).
  • N4 O5 S2% calculated C, 54.53, H: 4.16, N: 11.56, O: 16.51, S: 13.24% found C, 54.54, H: 4.15, N: 11, 34, S: 13.14).
  • the tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino) indazole-1-carboxylate can be obtained as follows: to a mixture of 63.6 g of N- (3- 1-iodo-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide in 1.8 l of dichloromethane under argon, 37 ml of triethylamine and then 3.9 g of 4- (dimethylamino) pyridine are added. The mixture is cooled to a temperature in the region of 0 ° C.
  • the residue thus obtained is purified by chromatography on a silica column (particle size 40-63 ⁇ m), eluting with a cyclohexane-ethyl acetate mixture (70-30 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue is taken up in diisopropyl ether, triturated, filtered on sintered glass and then drained and dried under reduced pressure (3 kPa) at a temperature in the region of 40 ° C.
  • N- (3-iodo-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 25.7 g of 5-amino-3-iodo-1H- indazole, 440 ml of pyridine and 25.3 g of 2- (methylsulfonyl) benzenesulfonyl chloride.
  • N- [3- (2-aminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained in the following manner: at reflux of a solution 280 mg of N- [3- (2-nitrophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide, 10 ml of ethanol, 82 ⁇ l of distilled water and 51 ⁇ l of acid 12 N hydrochloric acid, 59 mg of powdered iron are added in small portions and the reaction medium is then refluxed for 3 hours.
  • the suspension After returning to a temperature in the region of 20 ° C., the suspension is filtered and washed with ethanol.
  • the filtrate is diluted with water and brought to the vicinity of pH 10 with a 1N sodium hydroxide solution.
  • the filtrate is extracted with ethyl acetate and the remaining insoluble material is removed by filtration.
  • the organic phase is washed with distilled water, dried with magnesium sulfate, treated with 3S black, filtered and concentrated to dryness under reduced pressure.
  • the meringue thus obtained is triturated with diisopropyl ether, filtered and dried.
  • N- [3- (2-nitrophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from 620 mg of 3-iodo-5- (N-fer).
  • tert-butyl -butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate 202 mg of 2-nitrophenylboronic acid, 2 ml of saturated aqueous sodium hydrogencarbonate solution, 31.7 mg of tetrakis (triphenylphosphine) palladium [ 0] and 20 ml of dimethylformamide.
  • 2-Methylsulfonyl-N- (3-thiophen-2-yl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 47 from 1.5 g of 3-iodo-5- ( N-tert-butoxycarbonyl-2-méthylsulfonylbenzènesulfonylamino) indazol-1- tert-butyl carboxylate, 339 mg of 2-thiophene boronic acid, 50 ml of dimethylformamide, 4.8 ml of saturated aqueous sodium hydrogencarbonate solution and 64 mg of tetrakis (triphenylphosphine) palladium [0] ].
  • 2-Methylsulfonyl-N- (3-thiophen-3-yl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 47 from 1 g of 3-iodo-5- (N-) tert-butyl tert-butoxycarbonyl-2-methylsulfonyl-benzenesulfonylamino) -indazol-1-carboxylate, 376 mg of 3-thiophene boronic acid, 40 ml of dimethylformamide, 3.2 ml of saturated aqueous sodium hydrogen carbonate solution, sodium and 42.7 mg of tetrakis (triphenylphosphine) palladium [0].
  • N- (3-furan-3-yl-1H-indazol-5-yl) -2-methylsulphonylbenzenesulfonamide can be obtained as described in Example 47 from 2 g of 3-iodo-5- (N-) tert-Butyl tert-butoxycarbonyl-2-methylsulfonyl-benzenesulfonylamino) -indazol-1-carboxylate, 660 mg of 3-furanboronic acid, 80 ml of dimethylformamide, 6.4 ml of saturated aqueous sodium hydrogen carbonate solution. sodium and 85.4 mg of tetrakis (triphenylphosphine) palladium [0].
  • N- (3-furan-2-yl-1H-indazol-5-yl) -2-methylsulphonylbenzenesulfonamide can be obtained as described in Example 47 from 1 g of 3-iodo-5- (N-) tert-butyl tert-butoxycarbonyl-2-methylsulfonyl-benzenesulfonylamino) -indazole-1-carboxylate, 330 mg of 2-furanboronic acid, 40 ml of dimethylformamide, 3.2 ml of saturated aqueous sodium hydrogencarbonate solution. sodium and 42.7 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 54 2-methylsulfonyl-N- (3-pyrid m-4-yl-1H-indazol-5-yl) benzene-sulfonamide
  • 2-Methylsulfonyl-N- (3-pyridin-4-yl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 47 from 1 g of 3-iodo-5- (N tert-butyl-tert-butoxycarbonyl-2-methylsulfonyl-benzenesulfonylamino) -indazole-1-carboxylate, 380 mg of 4-pyridylboronic acid, 40 ml of dimethylformamide, 3.2 ml of saturated aqueous solution of hydrogen carbonate of sodium and 42.7 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 55 Methyl 3- [5- (2-methylsulfonylbenzenesulfonamino) -1H-indazol-3-yl] benzoate.
  • the methyl 3- [5- (2-methylsulfonylbenzenesulphonamino) -1H-indazol-3-yl] benzoate can be obtained as described in Example 47 from 1 g of Tert-Butyl 3-iodo-5- (N-tert-butoxycarbonyl-2-methylsulfonyl-benzenesulfonylamino) -indazole-1-carboxylate, 530 mg of 3-methoxycarbonylphenylboronic acid, 30 ml of dimethylformamide, 3.2 ml of saturated aqueous solution of sodium hydrogen carbonate and 42 mg of tetrakis (triphenylphosphine) palladium [0].
  • 3- [5- (2-methylsulfonylbenzenesulfonamino) -1H-indazol-3-yl] benzoic acid can be obtained as follows: to a suspension of 220 mg of 3- [5- (2-methylsulfonylbenzenesulfonamino) -1 Methyl H-indazol-3-yl] benzoate, 2 ml of tetrahydrofuran and 2 ml of methanol are successively added 64.7 mg of lithium hydroxide monohydrate and 2 ml of distilled water, the reaction medium is stirred for 16 hours at room temperature. a temperature of 20 ° C.
  • the medium is then concentrated to dryness under reduced pressure and the evaporation residue is taken up in distilled water and the neutrals are extracted with diethyl ether and then with ethyl acetate.
  • the precipitate formed is isolated by filtration, washed with distilled water and then with diethyl ether, dried under reduced pressure in an oven at room temperature. temperature close to 50 ° C for 2 hours.
  • 153 mg of 3- [5- (2-methylsulfonylbenzenesulphonamino) -1H-indazol-3-yl] benzoic acid are thus obtained in the form of a pinkish white solid melting at a temperature above 260 ° C.
  • Example 58 2-Methylsulfonyl-N- [3- (5-methoxy-1H-indol-2-yl) -1H-indazol-5-yl] benzenesulfonamide.
  • 2-Methylsulfonyl-N- [3- (5-methoxy-1H-indol-2-yl) -1H-indazol-5-yl] benzenesulfonamide can be obtained as described in Example 47 from 1.77 g of tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-2-methylsulfonyl-benzenesulfonylamino) -indazole-1-carboxylate, 1.52 g of 1- (tert-butyl) butoxycarbonyl) -5-methoxy-indole-2-boronic acid, 70 ml of dimethylformamide, 5.65 ml of saturated aqueous sodium hydrogencarbonate solution and 151 mg of tetrakis (triphenylphosphine) palladium [0].
  • 5-Methoxy-1- (tert-butoxycarbonyl) -7-azaindole-2-boronic acid can be obtained as follows: to a solution, maintained under an argon atmosphere and cooled in an ice bath between 0 ° C and 5 ° C, 2 g of 5-methoxy-1-tert-butoxy-7-azaindole in 10 ml of tetrahydrofuran and 2.85 ml of triisopropyl borate, 2.85 ml of a solution of 1.5 M in cyclohexane lithiumdiisopropylamide-tetrahydrofuran complex in 1 hour and maintaining the temperature below 5 ° C. It is maintained at 0 ° C for 30 minutes.
  • reaction mixture is then brought to a pH of between 2 and 3 by adding 1.5 ml of 2M hydrochloric acid.
  • the reaction mixture is then decanted, and the aqueous phase is extracted with 3 times 5 ml of ethyl acetate.
  • the combined organic extracts are dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. • ⁇ "ta"% -
  • 2-Methylsulfonyl-N- (3-pyridin-3-yl-1H-indazol-5-yl) benzenesulfonamide can be prepared as follows: to a suspension, maintained under an argon atmosphere, 1 g of 3- tert-butyl iodo-5- (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate and 200 mg of 3-pyridylboronic acid in 40 ml of dimethylformamide are successively added 3.75 ml of saturated aqueous sodium hydrogen carbonate solution.
  • the tert-butyl 3-iodo-5- (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate can be obtained in the following manner: to a suspension of 38.8 g of N- (3-iodo-1H-indazol) 5-yl) -2-methylsulfonylbenzenesulfonamide in 1.1 l of dichloromethane under argon, 22.6 ml of triethylamine and 2.4 g of 4- (dimethylamino) pyridine are added. The mixture is cooled to a temperature in the region of 0 ° C.
  • the solid is drained, dried and then purified by chromatography on a column of 1.2 kg of silica gel (particle size 40-63 ⁇ m), eluting successively with cyclohexane-ethyl acetate mixtures (80-20; 30, 50-50 by volume) and then with pure ethyl acetate.
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35 ° C.
  • the residue is taken up and triturated in diisopropyl ether, filtered on sintered glass and then drained and dried.
  • Example 60 2-Ethylsulfonyl-N- [3- (1H-pyrrol-2-yl) -1H-indazol-5-yl] benzenesulfonamide.
  • 2-Methylsulfonyl-N- [3- (1H-pyrrol-2-yl) -1H-indazol-5-yl] benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of 3 tert-butyl 5- [2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 365 mg 1- (tert-butyloxycarbonyl) -pyrrole-2-boronic acid, 20 ml dimethylformamide, 87 ml of saturated aqueous solution of sodium hydrogen carbonate and 24.5 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 61 N- [3- (1H-Indol-2-yl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide.
  • N- [3- (1H-Indol-2-yl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of 3-iodine.
  • Example 62 N- [3- (3-Aminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide.
  • N- [3- (3-aminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of 3-iodo-5- Tert-butyl (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 276 mg of 3-aminophenylboronic acid, 20 ml of dimethylformamide, 1.6 ml of saturated aqueous sodium hydrogencarbonate solution and 25 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 63 N- [3- (4-Dimethylaminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide.
  • N- [3- (4-dimethylaminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of 3-iodo-5- ( Tert-butyl 2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 570 mg of 4-dimethylaminophenylboronic acid, 40 ml of dimethylformamide, 3.2 ml of saturated aqueous sodium hydrogen carbonate and 50 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 64 N- (3-Benzo [b] thiophen-3-yl-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide.
  • N- (3-benzo [b] thiophen-3-yl-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of 3 tert-butyl iodo-5- (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 300 mg thionaphthene-3-boronic acid, 20 ml dimethylformamide, 1.9 ml saturated aqueous solution of hydrogen carbonate of sodium and 25 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 65 N- (3-Benzo [b] thiophen-2-yl-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide.
  • N- (3-benzo [b] thiophen-2-yl-1H-indazol-5-yl) -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of 3 tert-butyl iodo-5- (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 300 mg thionaphthene-2-boronic acid, 20 ml dimethylformamide, 1.9 ml saturated aqueous solution of hydrogen carbonate of sodium and 25 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 66 N- [3- (4-Nitrophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide.
  • N- [3- (4-nitrophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 5 g of 3-iodo-5- Tert-butyl (2-methylsulfonylbenzenesulfonylamino) -indazol-1-carboxylate, 2.9 g of 4-nitrophenylboronic acid, 200 ml of dimethylformamide, 19 ml of saturated aqueous sodium hydrogencarbonate solution and 250 mg of tetrakis (triphenylphosphine) palladium [0]. 2.5 g of a yellow powder are thus obtained.
  • 2-Methylsulfonyl-N- (3-quinolin-8-yl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 59 from 2 g of 3-iodo-5- (2 tert-butyl methylsulfonylbenzenesulfonylamino) indazole-1-carboxylate, 1.17 g of 8-quinolinboronic acid, 80 ml of dimethylformamide, 7.5 ml of saturated aqueous sodium hydrogencarbonate solution and 98 mg of tetrakis (triphenylphosphine) palladium [0].
  • Methyl 4- [5- (2-methylsulfonylbenzenesulfonamino) -1H-indazol-3-yl] benzoate can be obtained as described in Example 59 from 1 g of 3-iodo-5- (2-methylsulfonylbenzenesulfonylamino).
  • 4- [5- (2-methylsulfonylbenzenesulfonamino) -1H-indazol-3-yl] benzoic acid can be obtained as described in Example 56 from 166 mg of 4- [5- (2-methylsulfonylbenzenesulfonamino) - 1 H-indazol-3-yl] methyl benzoate, 2 ml of tetrahydrofuran, 2 ml of methanol, 48.7 mg of lithium hydroxide monohydrate and 2 ml of distilled water.
  • Example 70 N- [3- (4-Aminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide
  • N- [3- (3-aminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 49 from 200 mg of N- [3- (3- nitrophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide, 6 ml of ethanol, 73 mg of iron powder, 100 ml of distilled water and 40 ⁇ l of 12 N hydrochloric acid There is thus obtained 70 mg of N- [3- (3-aminophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide as light yellow crystals, m.p.
  • N- [3- (3-cyanophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.75 g of 3-iodo-5- Tert-butyl (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 380 mg of 3-cyanophenylboronic acid, 30 ml of dimethylformamide, 2.85 ml of saturated aqueous sodium hydrogen carbonate solution and 37 mg of tetrakis (triphenylphosphine) palladium [0].
  • Example 72 2-Methylsulfonyl-N- (3-naphthalen-1-yl-1H-indazol-5-yl) benzenesulfonamide.
  • 2-Methylsulfonyl-N- (3-naphthalen-1-yl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of 3-iodo-5- Tert-Butyl (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 298 mg of 1-naphthalenboronic acid, 20 ml of dimethylformamide, 1.9 ml of saturated aqueous sodium hydrogen carbonate solution and 24.5 mg tetrakis (triphenylphosphine) palladium [0].
  • Example 73 2-Methylsulfonyl-N- (3-naphthalen-2-yl-1H-indazol-5-yl) benzenesulfonamide.
  • 2-Methylsulfonyl-N- (3-naphthalen-2-yl-1H-indazol-5-yl) benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of 3-iodo-5- ( Tert-butyl 2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 298 mg of 2-naphthalenboronic acid, 20 ml of dimethylformamide, 1.88 ml of saturated aqueous sodium hydrogen carbonate solution and 24.5 mg Tetrakis (triphenyl phosphine) palladium [0].
  • N- ⁇ 3 - [(E) -2- (4-fluorophenyl) vinyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g. tert-butyl 3-iodo-5- (2-methylsulfonylbenzenesulfonylamino) -indazol-1-carboxylate, 575 mg trans-2- (4-fluorophenyl) vinylboronic acid, 28 ml dimethylformamide, ml of saturated aqueous sodium hydrogencarbonate solution and 41 mg of tetrakis (triphenylphosphine) palladium [0].
  • N- ⁇ 3- [2- (4-fluorophenyl) ethyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide can be obtained as follows: A mixture of 300 mg N- ⁇ 3- [(E) -2- (4-fluorophenyl) vinyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide, 30 mg of 10% palladium on carbon and 8 ml of dimethylformamide are autoclaved. under a pressure of 10 bar of hydrogen and the whole is stirred at a temperature of 20 ° C for 1 hour until complete absorption of hydrogen.
  • Example 76 N- ⁇ 3 - [(E) -2- (4-Chlorophenyl) vinyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide N- ⁇ 3 - [(E) -2- (4-chlorophenyl) vinyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g.
  • Example 77 N - ⁇ 3- [2- (4-Chlorophenyl) ethyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide.
  • N- ⁇ 3- [2- (4-chlorophenyl) ethyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide can be described as in Example 75 from 465 mg of N- ⁇ 3 ⁇ [(E) -2- (4-chlorophenyl) vinyl] -1H-indazol-5-yl ⁇ -2-methylsulfonylbenzenesulfonamide, 47 mg of 10% palladium on carbon and 8 ml of dimethylformamide.
  • 2-Methylsulfonyl-N- [3 - ((E) -styryl) -1H-indazol-5-yl] benzenesulfonamide can be prepared as follows: to a suspension, maintained under an argon atmosphere, 500 mg Tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate and 220 mg of trans-2-phenylvinylboronic acid in 20 ml of dimethylformamide are added successively 1, 6 ml of saturated aqueous solution of sodium hydrogen carbonate and 21.35 mg of tetrakis (triphenylphosphine) palladium [0].
  • the reaction medium is kept at reflux for 5 hours. After returning to a temperature of 20 ° C, the reaction medium is diluted with 20 ml of distilled water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The brown oil thus obtained is purified by chromatography on a silica cartridge (particle size 20-40 ⁇ m) with pure dichloromethane and then with a mixture of dichloromethane-methanol (99% by volume) as eluent.
  • the yellow paste obtained is a second time chromatographed on a silica cartridge (particle size 20-40 microns) with a cyclohexane-ethyl acetate mixture (80-20 and then 70-30 by volume) as eluent.
  • a silica cartridge particle size 20-40 microns
  • a cyclohexane-ethyl acetate mixture 80-20 and then 70-30 by volume
  • 206 mg of 2-methylsulfonyl-N- [3 - ((E) -styryl) -1H-indazol-5-yl] benzenesulfonamide are thus obtained in the form of a white solid melting at 200 ° C.
  • Methyl (E) -3- [5 (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl] -acrylate can be obtained as follows: to a solution of 150 mg of (E) -3- [5] Methyl (2-methylsulfonylbenzenesulfonylamino) -1-tert-butoxycarbonyl-indazol-3-yl] -acrylate in 10 ml of chloroform, maintained under an argon atmosphere, 40 ⁇ l of iodotrimethylsilane are added dropwise and the whole is stirred at a temperature of 20 ° C for 16 hours.
  • Methyl (E) -3- [5 (2-methylsulfonylbenzenesulfonylamino) -1-fert-butoxycarbonylindazol-3-yl] -acrylate can be obtained as follows: to a solution, maintained under an argon atmosphere and at a temperature in the region of 20 ° C, 500 mg of tert-butyl 3-iodo-5- (2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate, 1.2 ml of diisopropylethylamine, 121 mg of lithium chloride 11.6 mg of palladium acetate in 15 ml of anhydrous dimethylformamide is added dropwise to 74 ⁇ L of methyl acrylate, the reaction medium is then heated for 1 hour at 60 ° C.
  • (E) -3- [5 (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl] -acrylic acid can be obtained as follows: to a suspension of 72 mg of (E) -3- [ Methyl 5 (2-methylsulfonylbenzenesulfonylamino) -1H-indazol-3-yl] acrylate, 0.5 ml of tetrahydrofuran and 0.5 ml of methanol are successively added 36 mg of lithium hydroxide monohydrate and I * II '''--
  • N- [3- (1H-benzimidazol-2-yl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be prepared in the following manner: A solution of 175 mg of N- [3] - (1H-benzimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide, 7 ml of ethanol and 42 ml of 2N hydrochloric acid is heated at 50 ° C for 24 hours.
  • the reaction medium After returning to a temperature of 20 ° C, the reaction medium is brought to a pH of 9 with a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.
  • the paste thus isolated is triturated in 5 ml of ethanol and the insoluble material is isolated by filtration, dried and then triturated in 3 ml of acetonitrile, drained and dried.
  • N- [3- (1 H -benzimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 130 mg of 3- (1H-benzimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-ylamine, 5 ml of pyridine and 87 mg of chloride of 2 -méthylsulfonylbenzènesulfonyle.
  • 3- (1H-benzimidazol-2-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl-amine can be obtained as follows: to a solution, refluxed, 350 mg of 3- (1H-benzimidazol-2-yl) -5-nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole, 15 ml of ethanol, 200 ⁇ l of distilled water and of 320 ⁇ l of 12N hydrochloric acid, 485 mg of iron powder are added in small portions and the mixture is kept at reflux for 16 hours.
  • the medium After returning to a temperature of 20 ° C, the medium is diluted with 60 ml of ethanol, stirred and filtered on a bed of Celite ® 535, it is then washed with ethanol.
  • the filtrate is basified to a pH of about 9 with a saturated aqueous solution of sodium hydrogencarbonate.
  • the precipitate thus formed is removed by filtration, washed with ethanol and the filtrate is then concentrated to dryness under reduced pressure.
  • the evaporation residue is dissolved in distilled water and extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.
  • the reaction medium After returning to a temperature of 20 ° C, the reaction medium is concentrated to dryness under reduced pressure and the evaporation residue is taken up in 20 ml of distilled water and 20 ml of ethyl acetate.
  • 5-Nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole-3-carboxaldehyde can be obtained by the following method: to a solution, maintained near 0 ° C and under an argon atmosphere, 760 mg of 3- (N-methoxy-N-methyl) -5-nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazolecarboxamide in 25 ml of anhydrous tetrahydrofuran were poured over 15 minutes. 33 ml of a 20% by weight solution of diisobutylaluminum hydride in toluene. The reaction medium is then stirred at around 0 ° C. for 4 hours.
  • 3- (N-Methoxy-N-methyl) -5-nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazolecarboxamide can be prepared as follows: to a solution of 674 mg of acid 5-nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole-3-carboxylic acid, 170 mg of 1-hydroxybenzotriazole monohydrate, 240 mg of 1-ethyl-3- [3- (dimethylamino) propyl hydrochloride ] Carbodiimide in 20 ml of dichloromethane is successively added 390 mg of N-methoxymethylamine hydrochloride and 0.56 ml of triethylamine.
  • the reaction medium is stirred for 16 hours at a temperature of close to 20 ° C, then washed successively with an aqueous solution of 5% sodium carbonate, twice with 80 ml in total of 1N hydrochloric acid and twice with 80 ml in total of distilled water.
  • the organic phase is dried over calcium chloride, filtered and concentrated to dryness under reduced pressure.
  • 5-Nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole-3-carboxylic acid can be prepared in the following manner: on a suspension, maintained near 0 ° C and under argon atmosphere 690 mg of 80% sodium hydride dispersed in petrolatum oil and 12 ml of anhydrous dimethylformamide are poured into a solution of 2.07 g of 5-nitro-
  • the medium is then cooled to a temperature in the region of -10 ° C. using a refrigerant mixture of ice and sodium chloride and then 2.8 ml of 2- (trimethylsilyl) ethoxymethyl chloride are poured in 10 minutes.
  • the medium is then stirred for 48 hours at a temperature in the region of 20 ° C. before being concentrated to dryness under reduced pressure.
  • the residue is taken up in distilled water and brought to a pH of about 2 with 1N hydrochloric acid, extracted with ethyl acetate.
  • the combined organic extracts are washed with distilled water, then a saturated aqueous solution of sodium hydrogen carbonate and brine solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Example 82 N- [3- (1H-Indol-2-yl) -1H-indazol-5-yl] benzenesulfonamide
  • N- [3- (1H-indol-2-yl) -1H-indazol-5-yl] benzenesulfonamide can be obtained as follows: to a solution of 101.9 mg of 3-iodo-5- ( Tert-butyl N-tert-butoxycarbonylbenzenesulfonylamino) indazole-1-carboxylate in 4.5 ml of dimethylformamide, 158.1 mg of N-tert-butoxycarbonylindole-2-boronic acid and 360 ⁇ l are added.
  • N-tert-butoxycarbonyl-indole-2-boronic acid in dimer form can be prepared according to the procedure described by E. VASQUEZ et al. in Journal of Organic Chemistry, 67, 7551-52 (2002).
  • the tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-benzenesulfonylamino) -indazole-1-carboxylate can be prepared in the following manner: 2 g of 5-amino-3-iodo-1H-indazole are introduced dissolved in 40 ml of dichloromethane, 3.11 ml of pyridine is added and the temperature is then lowered to 0 ° C. 1.08 ml of benzenesulphonyl chloride are then added dropwise. The medium is stirred for 30 minutes at 0 ° C. and then for 16 hours at room temperature.
  • 2-Methylsulfonyl-N- (3-phenylamino-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: the compound is prepared by reaction under microwave radiation on a Personal Chemistry Emrys Optimizer. Four identical reactions are conducted. Each reaction is prepared as follows: 60 mg of tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino) -indazole-1-carboxylate are placed in a SmithProcessVial TM tube of Personal Chemistry of a maximum volume of 5 ml.
  • the catalyst is filtered through Celite ® 535 and the four reaction crude are combined, concentrated to dryness under reduced pressure on a rotary evaporator and purified by preparative LC / MS (conditions A). The fractions containing the protected intermediate compound are combined and concentrated under reduced pressure. The yellow oil obtained is dissolved in 2 ml of dichloromethane and then 500 ⁇ l of trifluoroacetic acid is added. The solution is stirred for 2 hours at room temperature, until the starting material disappears. 10 ml of dichloromethane and 10 ml of a saturated solution of sodium hydrogencarbonate are then added.
  • N- [3- (1H-indol-2-yl) -1H-indazol-5-yl] -2-trifluoromethoxy-benzenesulfonamide can be obtained as follows: to a solution of 150 mg of 3 tert-butyl iodo-5- (N-tert-butoxycarbonyl-2-trifluoromethoxy-benzenesulfonylamino) -indazolecarboxylate in 4.5 ml of dimethylformamide is added 213.3 mg of N-tert-butoxycarbonyl acid.
  • the tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-2-trifluoromethoxy-benzenesulfonylamino) -indazolecarboxylate can be prepared as described in Example 82 from 2 g of 5-amino 3-iodo-1H-indazole and 2.21 g of 3-trifluoromethoxybenzenesulfonyl chloride.
  • the intermediate compound is purified by flash chromatography (eluent dichloromethane-methanol 99-
  • 3-Fluoro-N- [3- (1H-indol-2-yl) -1H-indazol-5-yl] benzenesulfonamide can be prepared in the following manner: at a solution of 150 mg of 3-iodo-5- Tert-butyl (N-tert-butoxycarbonyl-3-fluorobenzenesulfonylamino) -1H-indazolecarboxylate in 5 ml of dimethylformamide, 236 mg of N-tert-butoxycarbonylindole-2-boronic acid in dimer form are added, 70.2 mg of tetrakis (triphenylphosphine) palladium [0] and 290 ⁇ l of a saturated solution of sodium hydrogencarbonate.
  • the medium is heated to around 120 ° C for 15 hours.
  • the catalyst is filtered through Celite ® 535 and then, after evaporation of the solvent the crude is purified by preparative LC / MS (conditions A).
  • the fractions containing the expected product are concentrated then the product obtained is dissolved in 3 ml of dichloromethane and then neutralized with 3 ml of a saturated solution of sodium hydrogencarbonate.
  • the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.
  • Example 86 4-Dimethylamino-2,3,5,6-tetrafluoro-N- [3- (1H-indol-2-yl) -1H-indazol-5-yl] benzenesulfonamide
  • 4-Dimethylamino-2,3,5,6-tetrafluoro-N- [3- (1H-indol-2-yl) -1H-indazol-5-yl] benzenesulfonamide can be prepared as follows: to a solution of 150 mg of tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-2,3,4,5,6-pentafluorobenzenesulfonylamino) indazolecarboxylate in 4.5 ml of dimethylformamide, 211.5 mg of N-tert-butoxycarbonyl-indole-2-boronic acid in the form of a dimer, 62.8 mg of tetrakis (triphenylphosphine) palladium [0] and 240 ⁇ l of a saturated hydrogen carbonate solution are added.
  • the medium is heated to around 120 ° C for 15 hours.
  • the catalyst is filtered through Celite ® 535 and after evaporation of the solvent, the crude is purified by preparative LC / MS (conditions A).
  • the fractions containing the expected product are concentrated then the product obtained is dissolved in 3 ml of dichloromethane and then neutralized with 3 ml of a saturated solution of sodium hydrogencarbonate.
  • the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.
  • Tert-Butyl 3-iodo-5- (N-tert-butoxycarbonyl-2,3,4,5,6-pentafluoro-benzenesulfonylamino) -indazolecarboxylate can be prepared as described in Example 85 using 2 g of 5-amino-3-iodo-1H-indazole and 1.13 ml of pentafluorobenzenesulfonyl chloride. 1.77 g of an orange solid obtained by purification by flash chromatography (eluent dichloromethane-methanol 98-2 by volume) are obtained. This compound is then treated with 1.89 g of di-tert-butyl dicarbonate according to the procedure described in Example 82.
  • ⁇ N- [3- (1H-Indol-2-yl) -1H-indazol-5-yl] ⁇ thiophene-2-sulfonamide can be prepared as follows: to a solution of 155.8 mg of 3 tert-Butyl iodo-5- (N-tert-butoxycarbonyl-2-thiophenesulfonylamino) -indazolecarboxylate in 5 ml of dimethylformamide, 250.3 mg of N-tert-butoxycarbonylindole-2-boronic acid is added. 74.3 mg of tetrakis (triphenylphosphine) palladium [0] and 290 ⁇ l of a saturated solution of sodium hydrogencarbonate.
  • the medium is heated to around 120 ° C for 15 hours.
  • the catalyst is filtered through Celite ® 535 and then, after evaporation of the solvent the crude is purified by preparative LC / MS (conditions A).
  • the fractions containing the expected product are concentrated to dryness under reduced pressure and the product obtained is dissolved in 3 ml of dichloromethane and then neutralized with 3 ml of a saturated solution of sodium hydrogen carbonate.
  • the tert-butyl 3-iodo-5- (N-tert-butoxycarbonyl-2-thiophenesulfonylamino) -indazolecarboxylate can be prepared as described in Example 85 using 2 g of 5-amino-3-iodine. 1H-indazole and 1.61 g of thiophene-2-sulphonyl chloride.
  • the intermediate crude is purified by flash chromatography (dichloromethane-methanol 98-2 by volume) to yield 2.30 g of an orange solid, which is then treated with 3.71 g of di-tert-butyl dicarbonate according to the procedure. .
  • 2-Methylsulfonyl-N- (3-phenylsulfanyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: to a suspension of 0.38 g of 2-methylsulfonyl-N- [3-phenylsulfanyl-1 - (2-Trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] benzenesulfonamide in 11.5 ml of absolute ethanol are added dropwise 3.8 ml of a 5N aqueous hydrochloric acid solution. The reaction mixture is then refluxed for 30 minutes and then cooled to a temperature of 20 ° C.
  • the residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 25 g of silica (particle size 20-40 ⁇ m), eluting successively with pure dichloromethane then with a dichloromethane-methanol mixture (99 / 1 in volumes).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30 ° C.
  • the solid thus obtained is taken up in 2 ml of isopropanol in the presence of 3S black, dissolved hot and the mixture is filtered on paper.
  • 2-methylsulfonyl-N- [3-phenylsulfanyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] benzenesulfonamide can be obtained as follows: to a solution of 0.61 g of 5- amino-3-phenylsulfanyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole in 10 ml of pyridine at a temperature of 0 ° C and under argon is added 0.44 g of 2-methylsulfonylbenzenesulfonyl chloride. The reaction mixture is then stirred for 1 hour at a temperature in the region of 0 ° C.
  • the filtrate is diluted with a mixture of 45 ml of ethyl acetate and 30 ml of water. After decantation, the organic phase is washed with 2 times 30 ml of water. The organic extracts are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25 ° C.
  • the residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 150 g of silica (particle size 20-40 ⁇ m), eluting successively with cyclohexane-ethyl acetate mixtures (90/10). 85/15, 70/30 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20 ° C.
  • 5-amino-3-phenylsulfanyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole can be obtained as follows: a solution of 0.4 g of 5-nitro-3-phenylsulfanyl-1- ( 2-trimethylsilanyl-ethoxymethyl) -1H-indazole in 16 ml of ethyl acetate containing 40 mg of 10% palladium on carbon is hydrogenated under a pressure of 200 kPa at a temperature of 25 ° C for 18 hours. After filtration of the catalyst on Celite® under argon and washing with ethyl acetate, the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature of 25 ° C.
  • the two crude products are combined and purified by chromatography under argon pressure (50 kPa), on a column of 53 g of silica (particle size 40-63 ⁇ m), eluting successively with pure cyclohexane and then with cyclohexane-acetate mixtures. ethyl (97/3, 95/5, 90/10, 80/20 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30 ° C.
  • 5-nitro-3-phenylsulfanyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole can be obtained as follows: to a solution of 0.11 g of palladium acetate, 0.36 g of (R) - (+) - 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl, 0.64 g of sodium tert-butoxide in 40 ml of toluene under argon, 2 g of 3-iodo-5-nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole and then 0.88 g of sodium thiophenate are added.
  • the reaction mixture is heated at a temperature of 80 ° C for 21 hours, then it is cooled to a temperature of 20 ° C. After dilution with 100 ml of ethyl acetate and 80 ml of water and then decantation, the aqueous phase is extracted with 100 ml of ethyl acetate. The organic extracts are combined, washed with 60 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25 ° C. The residue thus obtained is filtered through silica (particle size 15-35 ⁇ m), eluting with pure dichloromethane.
  • the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20 ° C.
  • the residue is purified by chromatography under argon pressure (50 kPa), on a column of 80 g of silica (particle size 40-63 ⁇ m), eluting successively with pure cyclohexane and then with cyclohexane-ethyl acetate mixtures (95/5, 90/10 in volumes).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25 ° C.
  • 3-iodo-5-nitro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole can be obtained in the following manner: 30 g of water at a temperature in the region of 0 ° C. are added 30 g of potassium hydroxide pellets. After complete dissolution, 7 g of 3-iodo-5-nitro-1H-indazole, 50 ml of dichloromethane and 82 mg of tetrabutylammonium bromide are added. The reaction mixture is stirred at a temperature in the region of 0 ° C. and 5 ml of 2- (trimethylsilyl) ethoxymethyl chloride are added over 15 minutes.
  • the reaction mixture is stirred at a temperature of 0 ° C for 1.5 hours, then 150 ml of water are added and the mixture is heated to a temperature of 20 ° C. After decantation, the aqueous phase is extracted with 2 times 70 ml of dichloromethane. The organic extracts are combined, washed twice with 70 ml of water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25 ° C. The residue thus obtained is dissolved in 40 ml of hot diisopropyl ether, filtered hot on paper and then recrystallized.
  • 2-methylsulfonyl-N- (3-phenylethynyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: to a solution of 0.2 g of 5-amino 3-phenylethynyl-1H-indazole in 3.5 ml of pyridine at a temperature in the region of 0 ° C. and under argon is added 0.23 g of 2-methylsulfonylbenzenesulphonyl chloride. The reaction mixture is then stirred for 1.5 hours at 0 ° C. and then for 2 hours at a temperature in the region of 20 ° C., and is then diluted with 10 ml of water.
  • the aqueous phase is washed with 3 times 15 ml of ethyl acetate.
  • the organic extracts are combined, washed with 3 times 5 ml of water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20 ° C.
  • the residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 25 g of silica (particle size 20-40 ⁇ m), eluting with pure dichloromethane, then successively with dichloromethane-methanol mixtures ( 99.5 / 0.5, 99/1 in volumes).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20 ° C.
  • the residue is recrystallized from 5 ml of isopropanol in the presence of 3S black.
  • the crystals are filtered on sintered glass, washed with diisopropyl ether, drained and then dried under reduced pressure (3 kPa) at a temperature in the region of 50 ° C. for 2 hours.
  • 66 mg of 2-methylsulfonyl-N- (3-phenylethynyl-1H-indazol-5-yl) benzenesulfonamide are thus obtained in the form of an off-white powder melting at 198 ° C.
  • 5-amino-3-phenylethynyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole can be obtained as follows: to a solution of 0.84 g of 5-nitro-3-phenylethynyl-1 (2-trimethylsilanyl-ethoxymethyl) -1H-indazole in 15 ml of absolute ethanol at the reflux temperature of the solvent are added 18 ml of water, 0.2 ml of a 12N aqueous hydrochloric acid solution and 0.36 g of iron powder. The reaction mixture is then stirred at reflux of the solvent for 4 hours, then it is cooled to a temperature of 20 ° C.
  • the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature of 35 ° C.
  • the residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a column of 60 g of silica (particle size 40-63 ⁇ m), eluting successively with cyclohexane-ethyl acetate mixtures (95/5). 90/10, 80/20, 70/30, 60/40, 50/50, 30/70 by volume), then by pure ethyl acetate and finally pure ethanol.
  • 5-nitro-3-phenylethynyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole can be obtained as follows: to a solution of 3 g of 3-iodo-5-nitro-1- (2 -trimethylsilanyl-ethoxymethyl) -1H-indazole in 200 ml of acetonitrile under argon, 0.16 g of triphenylphosphine, 0.54 g of tetrakis (triphenylphosphine) palladium (0) and 0.27 g of sodium iodide are added. copper.
  • the residue is purified by chromatography under argon pressure (50 kPa), on a column of 200 g of silica (particle size 40-63 ⁇ m), eluting successively with pure cyclohexane and then with cyclohexane-ethyl acetate mixtures ( 98/2, 97/3, 95/5, 90/10 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. 2.31 g of 5-nitro-3-phenylethynyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole are thus obtained in the form of a brown solid melting at 88 ° C.
  • Example 90 2-Methylsulfonyl-N- (3-phenethyl-1H-indazol-5-yl) benzenesulfonamide
  • 2-Methylsulfonyl-N- (3-phenethyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: to a suspension of 0.56 g of 2-methylsulfonyl-N- [3-phenethyl] 1- (2-Trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] benzenesulfonamide in 17 ml of absolute ethanol are added dropwise 5.6 ml of a 5N aqueous hydrochloric acid solution.
  • reaction mixture is then refluxed for 30 minutes and then cooled to a temperature of 20 ° C. 6.8 ml of 5N aqueous sodium hydroxide solution are then added and stirred. The mixture is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. and the residue is taken up in a mixture of 35 ml of ethyl acetate and 50 ml of water. After decantation, the aqueous phase is extracted with 2 times 30 ml of ethyl acetate.
  • the organic extracts are combined, washed twice with 20 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30 ° C.
  • the residue thus obtained is purified by chromatography under argon pressure (50 kPa) on a column of 75 g of silica (particle size 40-63 ⁇ m), eluting with a dichloromethane-methanol mixture (98/2 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30 ° C.
  • the residue thus obtained is repurified by chromatography under argon pressure (50 kPa), on a silica column (particle size 40-63 microns), eluting with a cyclohexane / ethyl acetate mixture (70/30 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30 ° C.
  • the residue thus obtained is taken up in 15 ml of diisopropyl ether, triturated, filtered and dried.
  • 2-Methylsulfonyl-N- [3-phenethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazol-5-yl] benzenesulfonamide can be obtained as follows: to a solution of 0.83 g of 3-amino-3-phenethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole in 13 ml of pyridine at a temperature in the region of 0 ° C. and under argon is added per portion of 0.6 g of chloride of -méthylsulfonylbenzènesulfonyle.
  • reaction mixture is then stirred for 0.5 hour at a temperature of 0 ° C and then 2 hours at a temperature of 20 ° C, then it is diluted with 13 ml of water. After decantation, the aqueous phase is extracted with 3 times 30 ml of ethyl acetate. The organic extracts are combined, washed twice with 15 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 70 g of silica (particle size 20-40 ⁇ m), eluting successively with pure cyclohexane and then with a cyclohexane-acetate mixture. ethyl (80/20 by volume). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25 ° C.
  • 5-amino-3-phenethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indazole can be obtained as follows: a solution of 0.9 g of 5-amino-3-phenylethynyl-1- ( 2-trimethylsilanyl-ethoxymethyl) -1H-indazole in a mixture of 50 ml of absolute ethanol and 2 ml of water containing 100 mg of 10% palladium on carbon is hydrogenated under a pressure of 1000 kPa at a temperature close to 25 ° C for 21.5 hours.
  • 2-Methylsulfonyl-N- [3- (3-trimethylsilanylethynyl-phenyl) -1H-indazol-5-yl] benzenesulfonamide can be obtained as follows: to a solution of 0.73 g of N- [3- (3-bromophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide in 45 ml of acetonitrile under argon, 0.28 g of trimethylsilylacetylene, 0.06 g of copper iodide, 0 are successively added.
  • the residue is purified by chromatography on a silica column (particle size 40-63 ⁇ m), eluting with pure dichloromethane.
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • N- [3- (3-bromophenyl) -1H-indazol-5-yl] -2-methylsulfonylbenzenesulfonamide can be obtained in the following manner: to a suspension, maintained under argon, of 2.3 g of tert-butyl 3-iodo-5- (2-methylsulphonylbenzenesulfonylamino) indazole-1-carboxylate in 90 ml of dimethylformamide, 1.6 g of (3-bromophenyl) boronic acid are added successively. 7 ml of saturated aqueous solution of sodium hydrogencarbonate and 0.11 g of tetrakis (triphenylphosphine) palladium [0].
  • the reaction mixture is refluxed for 5 hours. After cooling to a temperature of 20 ° C, the reaction medium is hydrolyzed with 200 ml of water and extracted with 200 ml and then 100 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the brown oil thus obtained is purified by chromatography on silica column (particle size 63-200 ⁇ m), eluting with a dichloromethane-methanol mixture (99/1 by volume).
  • 2-Methylsulfonyl-N- (6-methyl-3-phenyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: to a solution of 0.4 g of 5-amino-6 -methyl-3-phenyl-1H-indazole in 35 ml of pyridine at a temperature of 0 ° C and under argon is added 0.45 g of 2-methylsulfonylbenzenesulfonyl chloride. The reaction mixture is then stirred for 10 minutes at a temperature in the region of 0 ° C. and then for 16 hours at a temperature in the region of 20 ° C. and then diluted with 50 ml of water.
  • the aqueous phase is extracted with 50 ml and then 25 ml of ethyl acetate.
  • the organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue thus obtained is purified by chromatography on a silica column (particle size 63-200 ⁇ m), eluting with a dichloromethane-methanol mixture (99/1 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue is taken up and recrystallized from 20 ml of diethyl ether.
  • 5-Amino-6-methyl-3-phenyl-1H-indazole can be obtained as follows: to a solution of 0.53 g of 6-methyl-5-nitro-3-phenyl-1H-indazole in 30 ml of ethanol are added 0.5 ml of water and 0.18 ml of a 12N aqueous hydrochloric acid solution. The reaction mixture is then heated to reflux of the solvent and 0.36 g of iron powder are added in two portions. The reaction mixture is then stirred at reflux of the solvent for 4.5 hours, then it is cooled to a temperature of 20 ° C and treated with 50 ml of ice water. The mixture is then basified with a 32% aqueous solution of ammonium hydroxide to a pH of about 11.
  • the aqueous phase is extracted with once 50 ml and then twice with 25 ml of acetate. ethyl.
  • the organic extracts are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue thus obtained is purified by chromatography on a silica column (particle size 63-200 ⁇ m), eluting with a cyclohexane-ethyl acetate mixture (75/25 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • 6-Methyl-5-nitro-3-phenyl-1H-indazole can be obtained as follows: to a solution of 0.8 g of 6-methyl-3-phenyl-1H-indazole in 8 ml of An aqueous solution of 98% sulfuric acid cooled to a temperature in the region of 0 ° C. is added in the course of 5 minutes to 0.43 g of potassium nitrate. The reaction mixture is stirred at a temperature of 0 ° C for 5 minutes, then it is heated to a temperature of 35-40 ° C for 10 minutes and cooled again to a temperature of 0 ° C and stirred for 1 minute. hour.
  • the mixture is then poured into 50 g of ice, stirred at a temperature in the region of 0 ° C. for 1 hour and then filtered on sintered glass.
  • the solid obtained is washed with 3 times 30 ml of water and filtered and then redissolved in 100 ml of ethyl acetate and the mixture is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature of 40 ° C.
  • the residue thus obtained is purified by chromatography on a silica column (particle size 40-63 ⁇ m), eluting successively with cyclohexane-ethyl acetate mixtures (90/10, 80/20 by volume).
  • 6-Methyl-3-phenyl-1H-indazole can be obtained as described in Example 1, by iodination of 6-methyl-1H-indazole followed by a Suzuki type reaction as described in the example 4.
  • 6-Methyl-1H-indazole can be prepared according to J. Heterocycl. Chem. 1984, 21 (4), 1063.
  • 5-Fluoro-2-methylsulfonyl-N- (3-phenyl-1H-indazol-5-yl) benzenesulfonamide can be prepared as described in Example 2 from 0.52 g of 5-amino-3 1-phenyl-1H-indazole, 5 ml of pyridine and 0.68 g of 5-fluoro-2-methylsulfonylbenzenesulfonyl chloride. The residue obtained is purified by chromatography on a column of 50 g of silica (particle size 40-63 ⁇ m), eluting with pure dichloromethane.
  • the chloride of 5-fluoro-2-methylsulfonylbenzenesulfonyl can be obtained as follows: to a solution of 1 g of 5-fluoro-2-methylsulfonylphenylamine in 3.7 ml of 100% acetic acid are added 2 ml of concentrated aqueous hydrochloric acid solution. The reaction mixture is cooled to a temperature of -5 ° C, then a solution of 0.4 g of sodium nitrate in 0.63 ml of water is added dropwise. The reaction mixture is stirred at a temperature of -10 ° C for 20 minutes, then sulfur dioxide is bubbled for one hour.
  • a solution of 0.53 g of copper (II) chloride in 0.6 ml of water is then added at a temperature in the region of -5 ° C. and, after 2 minutes, 6.9 ml of acetic acid at 100 ° C. %, then the bubbling of sulfur dioxide is resumed. After 40 minutes, the bubbling is stopped and the mixture is allowed to warm to a temperature of 20 ° C and then stirred for 1.5 hours. The reaction mixture is then warmed in a water bath in order to remove the excess of sulfur dioxide, and then it is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • 5-Fluoro-2-methylsulfonylphenylamine can be obtained in the following way: to a solution of 1.2 g of 4-fluoro-1-methylsulfonyl-2-nitrobenzene in 80 ml of ethanol is added 1, 25 ml of water and 0.47 ml of 12N aqueous hydrochloric acid solution. The reaction mixture is then heated to reflux of the solvent and 0.92 g of powdered iron are added portionwise. The reaction mixture is then stirred at reflux of the solvent for 2 hours, then at a temperature of 20 ° C for 16 hours. It is then filtered on sintered glass and the solid is washed with ethanol.
  • the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue is taken up in a mixture of water and ethyl acetate and then basified with an aqueous solution of sodium hydrogen carbonate to a pH of about 10 and decanted.
  • the aqueous phase is extracted with 4 times 50 ml of ethyl acetate.
  • the organic extracts are combined, washed with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • 4-Fluoro-1-methylsulfonyl-2-nitro-benzene can be obtained as follows: to a suspension of 1.5 g of 3-chloro-peroxybenzoic acid in 15 ml of dichloromethane stirred at a temperature in the region of - 5 ° C under argon, 1.3 g of 4-fluoro-1-methylsulfinyl-2-nitrobenzene in 15 ml of dichloromethane are added dropwise. The reaction mixture is then stirred at a temperature in the region of 0 ° C. for 30 minutes and is then allowed to warm to a temperature in the region of 20 ° C. It is then filtered on sintered glass and the solid is washed with dichloromethane.
  • the filtrate is washed with aqueous solution of sodium hydrogencarbonate and then with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue thus obtained is purified by chromatography on a column of 125 g of silica (particle size 40-63 ⁇ m), eluting with pure dichloromethane.
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • 4-Fluoro-1-methylsulfinyl-2-nitro-benzene can be obtained as follows: to a solution of 1.9 g of 4-fluoro-1-methylsulfanyl-2-nitrobenzene in 6 ml of methanol and 30 ml of dichloromethane under argon are added 4.7 g of magnesium monoperoxyphthalate in portions. The reaction mixture is then stirred at a temperature of 20 ° C for 3 hours, then it is filtered on sintered glass and the solid is washed with dichloromethane.
  • the filtrate is washed with an aqueous solution of sodium hydrogencarbonate and then with water, dried over magnesium sulphate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. .
  • the residue thus obtained is purified by chromatography on a column of 125 g of silica (particle size 40-63 ⁇ m), eluting with pure dichloromethane. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • 4-amino-N- (3-phenyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: to a suspension of 0.3 g of N- [4- (3-phenyl) -1 H-indazol-5-ylsulfamoyl) -phenyl] acetamide in 6 ml of 95% ethanol are 1.5 ml of 5N aqueous hydrochloric acid solution was added. The reaction mixture is then refluxed for 30 minutes and then cooled to a temperature of 20 ° C.
  • the solid thus obtained is taken up in 9 ml of ethanol in the presence of 3S black, dissolved hot and the mixture is filtered hot on sintered glass and recrystallized.
  • the crystals are filtered on sintered glass, washed with 0.5 ml of 95% ethanol and then with 2 times 2 ml of diisopropyl ether, drained and then dried under reduced pressure (3 kPa) at a temperature in the region of 50 ° C.
  • 70 mg of 4-amino-N- (3-phenyl-1H-indazol-5-yl) benzenesulfonamide are thus obtained in the form of a light beige powder melting at 249 ° C. (IC mass analysis: m / z 365 (M + H) + ).
  • N- [4- (3-phenyl-1H-indazol-5-ylsulfamoyl) -phenyl] acetamide can be prepared as described in Example 2 from 0.45 g of 5-amino-3-phenyl-1 H-indazole, 42 ml of pyridine and 0.5 g of 4-acetylaminobenzenesulfonyl chloride. The residue obtained is purified by chromatography on a silica column (particle size 63-200 ⁇ m), eluting successively with dichloromethane-methanol mixtures (98.5 / 1.5, 95/5 by volume).
  • N- (3-phenyl-1H-indazol-5-yl) -pyridine-3-sulfonamide can be prepared as described in Example 2 from 0.5 g of 5-amino-3-phenyl-1H. - indazole, 45 ml of pyridine and 0.46 g of pyridine-3-sulphonyl chloride.
  • the residue obtained is purified by chromatography on a silica column (particle size 40-63 ⁇ m), eluting with a dichloromethane-methanol mixture (97.5 / 2.5 by volume).
  • the solid thus obtained is taken up in 20 ml of acetonitrile in the presence of 3S black, dissolved hot and the mixture is filtered while hot on sintered glass and recrystallized.
  • 3-nitro-N- (3-phenyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: to a solution of 0.7 g of 5-amino-3-phenyl-1H- indazole in 15 ml of THF at a temperature of 0 ° C and under argon is added 0.89 g of 3-nitrobenzenesulfonyl chloride. The reaction mixture is cooled to a temperature in the region of 0 ° C. and then a solution of 0.33 ml of pyridine in 4 ml of THF is added over 10 minutes. The reaction mixture is stirred at a temperature of 0 ° C for 0.5 hour and then at a temperature of 20 ° C for 3 hours.
  • 3-amino-N- (3-phenyl-1H-indazol-5-yl) benzenesulfonamide can be obtained as follows: to a solution of 0.28 g of 3-nitro-N- (3-phenyl) 1H-indazol-5-yl) benzenesulfonamide in 15 ml of absolute ethanol and 0.3 ml of water is added 0.06 ml of concentrated aqueous hydrochloric acid solution. The reaction mixture is refluxed and then 0.12 g of powdered iron is added in small portions. The reaction mixture is heated at reflux for 2 hours, then it is cooled to a temperature of 20 ° C.
  • N- (3-phenyl-1H-indazol-5-yl) cyclohexanesulfonamide can be prepared as described in Example 2 from 0.5 g of 5-amino-3-phenyl-1H-indazole, 45 ml. pyridine and 0.43 g of cyclohexylsulfonyl chloride.
  • the residue obtained is purified by chromatography on a silica column (particle size 40-63 ⁇ m), eluting with a dichloromethane-methanol mixture (97.5 / 2.5 by volume).
  • the solid thus obtained is taken up in 40 ml of dichloromethane in the presence of 3S black, dissolved hot and the mixture is filtered while hot on sintered glass and recrystallized.
  • Cyclohexylsulfonyl chloride may be prepared according to EP 0 788 796 A1.
  • N- (3-phenyl-1H-indazol-5-yl) -piperidine-4-sulfonamide can be obtained as follows: to a solution of 0.5 g of 4- (3-phenyl-1H-indazol) 5-ylsulfamoyl) -piperidine-1-benzylcarboxylate in 5 ml of dichloromethane under argon, are added 1.89 g of ethanethiol and then 1.45 g of boron trifluoride etherate dropwise. The reaction mixture is stirred at a temperature of 20 ° C for 16 hours and then concentrated to dryness under reduced pressure (2 kPa) at a temperature of 40 ° C.
  • the residue is taken up in 10 ml of water, basified with 5 ml of a 32% aqueous solution of ammonium hydroxide and then extracted successively with 30 ml and 15 ml of ethyl acetate.
  • the organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue thus obtained is purified by chromatography on a silica column (particle size 40-63 ⁇ m), eluting successively with dichloromethane-methanol mixtures (99/1, 95/5 by volume).
  • the fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 ° C.
  • the residue is taken up in 6 ml of acetonitrile in the presence of 3S black, dissolved hot and the mixture is filtered while hot on sintered glass and recrystallized.
  • the crystals are filtered on sintered glass, washed with twice 0.5 ml then 1 ml of acetonitrile, drained and then dried under reduced pressure (3 kPa) at a temperature of 50 ° C.
  • the benzyl 4- (3-phenyl-1H-indazol-5-ylsulfamoyl) -piperidine-1-carboxylate can be prepared as described in Example 2 from 0.7 g of 5-amino-3-phenylphenylbenzylate. 1 H-indazole, 63 ml of pyridine and 1.2 g of benzyl 4-chlorosulfonyl-piperidine-1-carboxylate. The residue obtained is purified by chromatography on a silica column (particle size 40-63 ⁇ m), eluting with a dichloromethane-methanol mixture (98.5 / 1.5 by volume).
  • Benzyl 4-chlorosulfonyl-piperidine-1-carboxylate can be prepared according to WO 00/46221.
  • the boronic acids described above (295 ⁇ mol) are distributed in 4 filter reactors of a 48-well Bohdan miniblock, and then a solution of 0.1 g of 3-iodo-5- (N-tert-butoxycarbonyl) 2- tert-butyl methylsulfonylbenzenesulfonylamino) indindole-1-carboxylate in 2 ml of dimethylformamide, 0.32 ml of saturated aqueous sodium hydrogencarbonate solution and 4.3 mg of tetrakis (triphenylphosphine) palladium (0). After closing the reactors, the reaction mixtures thus obtained are stirred at a temperature in the region of 105 ° C. for 20 hours.
  • reaction mixtures After cooling to a temperature in the region of 20 ° C., the reaction mixtures are filtered and then diluted with 2 ml of ethyl acetate and 2 ml of water each, stirred and decanted. The organic phases are separated (Myriad Allex automaton) and for each sample thus obtained, a sample of 15 .mu.l is analyzed by LC / MS, then they are concentrated to dryness under reduced pressure (centrifugal evaporator Genevac HT8) at a temperature close to 40. ° C. The residues are dissolved in dimethylsulfoxide so as to have concentrations of 0.1 mg / ⁇ l and the corresponding solutions are purified by LCMS (conditions B).
  • the fractions containing the expected products are concentrated to dryness under reduced pressure (Genevac HT8 centrifugal evaporator) at a temperature in the region of 40 ° C. and the residues are weighed (Mettler Toledo Automated Workstation LA200), dissolved at room temperature. concentration of 10 mM in dimethylsulfoxide (Zinsser) and analyzed by LC / MS.
  • concentration of 10 mM in dimethylsulfoxide (Zinsser) and analyzed by LC / MS.
  • the fractions containing the expected products of satisfactory purity are combined and a sample of 10 .mu.l diluted in 10 .mu.l of dimethylsulfoxide is analyzed by LC / MS.
  • the following compounds were isolated and characterized by their retention time (Tr) and molecular peak in mass spectrometry.
  • 2-Methylsulfonyl-N- (3-o-tolyl-1H-indazol-5-yl) benzenesulfonamide can be prepared as described in Examples 101-104 from 40.1 mg of o-tolylboronic acid. (heating for 4 hours). 9.3 mg of 2-methylsulfonyl-N- (3-o-tolyl-1H-indazol-5-yl) benzenesulfonamide are thus obtained in solution in 10 mM dimethylsulfoxide (C21H19N3O4S2, molecular weight 441.53; LC analysis). / MS: UV purity: 93%, analytical Tr: 3.93 min, theoretical m / z: 441, molecular ion detected: 442).
  • the 54 reagents (lines 1 to 54 of Table 2) are weighed and then diluted in tetrahydrofuran (THF) or N-methylpyrrolidone (NMP) so as to obtain ready-to-use solutions of 0.166 mol / liter .
  • THF tetrahydrofuran
  • NMP N-methylpyrrolidone
  • 4-Trifluoromethoxy-N- (3-phenyl-1H-indazol-5-yl) benzenesulfonamide can be prepared as described in the library of Examples 106-159 from 4-trifluoromethoxyphenylsulfonate chloride and 5-amino 2-phenyl-1H-indazole.
  • a suspension of tetrakis (triphenylphosphine) palladium (0) in dimethylformamide is then distributed (50 .mu.l per well) and the reactors are then closed and heated to a temperature of 105.degree. C. using a suitable heating jacket. (Mettler-Toledo, Viroflay, France). After one night at this temperature, the reaction mixtures are filtered hot in suitable collection racks (Mettler-Toledo, Viroflay, France) equipped with 75x100mm hemolysis tubes and after returning to ambient temperature, each reaction medium is diluted with 2 ml.
  • the organic extracts are transferred (Zinsser Winlissy, Zinsser Analytical, Frankfurt, Germany) into previously tared tubes (AWS LA200, Mettler-Toledo, Viroflay, France); before evaporation, 10 .mu.l of each organic extract are transferred (Zinsser Winlissy, Zinsser Analytical, Frankfurt, Germany) into a microtitre plate and diluted with 40 .mu.l of dimethylsulfoxide, thus constituting 65 raw samples used for LC / MS analysis.
  • each sample is solubilized in 1 ml of dimethylsulfoxide, filtered in a filter plate. The filtrates are then divided into two wells of 500 ⁇ l each and subjected to purification by LC / MS (conditions B).
  • the LC / MS analyzes were performed on a Micromass LCT model connected to an HP 1100.
  • the abundance of the products was measured using an HP G1315A diode array detector over a range of 200-600 nm and a Sedex 65 light scattering detector.
  • Mass spectra mass spectra were acquired over a range of 180 to 800.
  • the data were analyzed using the Micromass MassLynx software.
  • the separation was carried out on a Hypersil BDS C18 column, 3 ⁇ m (50 ⁇ 4.6 mm), eluting with a linear gradient of 5 to 90% acetonitrile containing 0.05% (v / v) of acid.
  • TFA trifluoroacetic acid
  • the products were purified by LC / MS using a Waters FractionsLynx system consisting of a Waters Model 600 gradient pump, a Waters Model 515 regeneration pump, a Waters Reagent Manager dilution pump, a car -injector Waters Model 2700, two Rheodyne Model LabPro valves, a Waters Model 996 diode array detector, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector.
  • the system was controlled by of the Waters FractionLynx software.
  • the separation was carried out alternately on two Waters Symmetry columns (C-is, 5 ⁇ M, 19 ⁇ 50 mm, catalog number 186000210), a column being regenerated with a 95/5 (v / v) water / acetonitrile mixture. containing 0.07% (v / v) trifluoroacetic acid, while the other column was being separated. Elution of the columns was carried out using a linear gradient of 5 to 95% acetonitrile containing 0.07% (v / v) trifluoroacetic acid in water containing 0.07% (v / v) d. trifluoroacetic acid, at a flow rate of 10 ml / min.
  • one thousandth of the effluent is separated by an LC Packing Accurate, diluted with methyl alcohol at a flow rate of 0.5 mL / min and sent to the detectors, at a rate of 75%. to the diode array detector, and the remaining 25% to the mass spectrometer.
  • the remainder of the effluent (999/1000) is sent to the fraction collector where the flow is eliminated until the mass of the expected product is detected by the software FractionLynx.
  • the molecular formulas of the expected products are provided to the FractionLynx software which triggers the product collection when the detected mass signal corresponds to the [M + H] + and / or [M + Na] + ion.
  • the products were purified by preparative chromatography coupled to mass spectral detection on the Waters system driven by the Mass Lynx software for detection (positive electro-spray mode) completed by Fraction Lynx for collection.
  • the purification was carried out on X Terra ® column (graft phase C-is 5 ⁇ m) of 100 mm in length and 30 mm in diameter.
  • the flow rate of the eluent was set at 20 ml / min. Either a 0.05% (v / v) water / acetonitrile / trifluoroacetic acid gradient whose composition varies linearly over time is used as follows: 0 min water: 50% (v / v) acetonitrile: 50% ( v / v)
  • Either an isocratic system consisting of: water 60% (v / v) / acetonitrile: 40% (v / v) / trifluoroacetic acid 0.05% (v / v).
  • step b can be prepared by protecting indazole position 1 (MG) (step b), coupling between the iodinated derivative (II H) and an acid boronic RI-B (OH) 2, (in Examples 227-232: indol-2-boronic acid), then a debenzylation of the coupling product (IIK), its condensation on a sulfonyl chloride Z- S0 2 CI and deprotection of NH in position 1 on indazole to result in the expected product (IL):
  • the inhibitory activity of the compounds on FAK is determined by measuring the inhibition of autophosphorylation of the enzyme using a time resolved fluorescence assay (HTRF).
  • HTRF time resolved fluorescence assay
  • the complete human FAK cDNA whose N-terminus was labeled with histidine, was cloned into a baculovirus expression vector pFastBac HTc.
  • the protein was expressed and purified to about 70% homogeneity.
  • the energy transfer between the excited europium cryptate to the acceptor XL665 is proportional to the degree of autophosphorylation of FAK.
  • the specific long-term signal of XL-665 is measured in a Packard Discovery Plate Counter. All tests are performed in duplicate and the average of the two tests is calculated.
  • Inhibition of autophosphorylation activity of FAK with compounds of the invention is expressed as percent inhibition over a control whose activity is measured in the absence of test compound. For the calculation of% inhibition, the ratio [signal at 665 nm / signal at 620 nm] is considered.
  • KDR The inhibitory effect of the compounds is determined in a substrate phosphorylation assay by the KDR enzyme in vitro by a scintillation technique (96-well plate, NEN).
  • the cytoplasmic domain of the human KDR enzyme was cloned as a GST fusion into the pFastBac baculovirus expression vector.
  • the protein was expressed in SF21 cells and purified to about 60% homogeneity.
  • the reaction is started by adding 20 ⁇ l of solution containing 2 ⁇ g of substrate (SH2-SH3 fragment of PLC ⁇ expressed as GST fusion protein), 2 ⁇ Ci ⁇ 33 P [ATP] and 2 ⁇ M cold ATP. After 1 hour of incubation at 37 ° C., the reaction is stopped by adding 1 volume (100 ⁇ l) of 200 mM EDTA. The incubation buffer is removed, and the wells are washed three times with 300 ⁇ l of PBS. Radioactivity is measured in each well using a Top Count NXT radioactivity counter (Packard). Background noise is determined by measuring radioactivity in four different wells containing radioactive ATP and the substrate alone. A total activity control is measured in four different wells containing all the reagents ( ⁇ 33 P- [ATP], KDR and PLC ⁇ substrate) but in the absence of a compound.
  • substrate SH2-SH3 fragment of PLC ⁇ expressed as GST fusion protein
  • 2 ⁇ Ci ⁇ 33 P [ATP] 2 ⁇ M cold ATP.
  • the inhibition of KDR activity with the compound of the invention is expressed as a percentage inhibition of the control activity determined in the absence of compound.
  • the inhibitory effect of compounds on the Aurora2 kinase is determined by a radioactivity scintillation test using nickel chelate.
  • the C-terminal fragment (Q1687-H2101) of a NuMA (nuclear protein that associates with the M'totic Device) expressed in E. coli, and whose N-terminus has been labeled with histidine was purified by nickel chelate chromatography and used as a substrate in the Aurora2 kinase assay.
  • the NuMA substrate is equilibrated by chromatography on a PD10 Pharmacia column, in a buffer (50 mM Tris-HCl, pH 7.5, 50 mM NaCl, 10 mM MgCl 2 ) added with 10% (v / v) glycerol and 0.05% (w / v) NP40.
  • Aurora2 kinase activity is measured by scintillation with nickel chelate (New England Nuclear, model SMP107). Each well contains 100 ⁇ l of the following solution: 0.02 ⁇ M Aurora2; 0.5 ⁇ M NuMA substrate; 1 ⁇ M of ATP supplemented with 0.5 ⁇ Ci of ATP- [ 33 P].
  • the solutions are incubated for 30 minutes at 37 ° C.
  • the test buffer is then removed and the wells are rinsed twice with 300 .mu.l of kinase buffer. Radioactivity is measured in each well using a Packard Model Top Count NXT.
  • the background noise is deduced from the radioactivity measurement by two-fold measurement in wells containing radioactive ATP alone containing buffered kinase treated in the same manner as the other samples.
  • control activity is performed by measuring in duplicate the radioactivity in the complete test mixture (ATP, Aurora2 and NuMA substrate), in the absence of test compound. Inhibition of Aurora2 activity with a compound of the invention is expressed as percent inhibition of control activity in the absence of test compound. Staurosporine is added to each plate as an inhibition control. 4. Src
  • Inhibition of Src kinase is assessed by measuring the phosphorylation of biotinylated cdc2 substrate (Pierce) detected by fluorescence (DELFIA) using a Europium-labeled anti-phosphotyrosine antibody in 96 well plates.
  • Wallac The c-Src protein used is a recombinant human protein produced in Baculovirus, comprising the SH3, SH2 domains and the catalytic domain.
  • the enzyme, the substrate and the different concentrations of test compounds are placed in the well in 50 mM Tris buffer, 10 mM MgCl 2. The reaction is initiated by the addition of 10 ⁇ M ATP.
  • the background is evaluated in triplicate in wells containing the substrate and the antibody in the absence of enzyme.
  • the activity of the enzyme is measured (in triplicate) in the wells containing all the reagents in the absence of compound.
  • Inhibition of Src activity is expressed as percent inhibition of control activity determined in the absence of compound.
  • the compound PP2 (Calbiochem) is included at different concentrations in each experiment as inhibition control.
  • the human Tie2 coding sequence corresponding to the amino acids of the 776-1124 intracellular domain was generated by PCR using cDNA isolated from human placenta as a template. This sequence was introduced into a baculovirus expression vector pFastBacGT as a GST fusion protein.
  • the inhibitory effect of the molecules is determined in a Tie2 PLC phosphorylation assay in the presence of GST-Tie2 purified to about 80% homogeneity.
  • the substrate is composed of SH2-SH3 fragments of PLC expressed as GST fusion protein.
  • the kinase activity of Tie2 is measured in 20mM MOPS buffer pH 7.2, containing 10mM MgCl 2 , 10mM MnCl 2 , 1mM DTT, 10mM glycerophosphate.
  • a reaction mixture composed of 70 .mu.l of kinase buffer containing 100 ng of GST-Tie2 enzyme per well is deposited.
  • the inhibitory activity of the compounds on IGF1R is determined by measuring the inhibition of autophosphorylation of the enzyme using a time resolved fluorescence assay (HTRF).
  • HTRF time resolved fluorescence assay
  • the human cytoplasmic domain of IGF1 R was cloned in fusion with glutathione S-transferase (GST) in the baculovirus expression vector pFastBac-GST.
  • GST glutathione S-transferase
  • the protein was expressed in SF21 cells and purified to about 80% homogeneity.
  • Kinase activity was determined by incubating the enzyme with different concentrations of test compound in 50 mM Hepes buffer pH 7.5, 5 mM MnCl2, 50 mM NaCl, 3% Glycerol, 0.025% Tween 20, 120 mM ATP .
  • the enzymatic reaction is stopped by the addition of 100mM buffer Hepes buffer pH 7.0, containing 0.4 M KF, 133 mM EDTA, 0.1% BSA containing an anti-GST antibody labeled with XL665 and an anti-phosphotyrosine antibody conjugated to cryptate.
  • europium Eu-K
  • the characteristics of the two fluorophores, XL-665 and Eu-K, are available in G.Mathis et al., Anticancer Research, 1997, 17, pages 3011-3014.
  • the energy transfer between the excited europium cryptate to the acceptor XL665 is proportional at the degree of autophosphorylation of IGF1R.
  • the long-lived specific signal of XL-665 is measured in a Victor plate counter analyzer (Perkin-elmer). Inhibition of the autophosphorylation activity of IGF1 R with compounds of the invention is expressed as percent inhibition compared to a control whose activity is measured in the absence of test compound.
  • Inhibition of the CDK2 / CyclineE kinase is assessed by measuring phosphorylation of the fluorescently detected Rb-biotinylated peptide substrate in Streptavidin-coated 96-well Flashpiates.
  • Substrate preparation Fresh solution at 1 mg / ml in PBS.
  • Inhibition of the CDK4 / CyclineD1 kinase is assessed by measuring the phosphorylation of the Rb-biotinylated peptide substrate, detected by fluorescence, in Streptavidin-lined, 96-well "Flashpiates” scintillation plates.

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EP03744395A 2002-03-11 2003-03-07 Indazoles substitues avec une activite anticancereuse Withdrawn EP1487803A1 (fr)

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US20050059722A1 (en) 2005-03-17
PE20040071A1 (es) 2004-02-13
IL163805A (en) 2009-08-03
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HN2003000094A (es) 2003-12-15
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RU2004130280A (ru) 2005-06-27
JP4643910B2 (ja) 2011-03-02
OA12784A (fr) 2006-07-10
BR0308339A (pt) 2005-02-01
SV2003001493A (es) 2003-07-10
TW200303863A (en) 2003-09-16
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KR20040091128A (ko) 2004-10-27
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US7473701B2 (en) 2009-01-06
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NO20044261L (no) 2004-11-25
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US6858638B2 (en) 2005-02-22
WO2003078402A1 (fr) 2003-09-25
HRP20040825A2 (en) 2005-06-30
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