FR2888579A1 - New pyrazole substituted pyridine compounds are kinase inhibitors, useful as an inhibiting agent for kinase-catalyzed reaction and for the manufacture of a drug to treat cancer - Google Patents

Abstract

Pyrazole substituted pyridine compound (I) is new. Pyrazole substituted pyridine compound of formula (I) is new. A, Ar1 : aryl, heteroaryl, heterocyclyl or cycloalkyl (all optionally substituted); L : a bond, CO, NH, CO-NH, NH-CO, NH-SO, NH-SO 2, SO 2NH, NH-CH 2, CH 2-NH, CH 2-CO-NH, NH-CO-CH 2, NH-CH 2-CO, CO-CH 2-NH, NH-CO-NH, NH-CS-NH, NH-CO-O or O-CO-NH; one of X, Y1, Z : either N or NO and 2 others of Z, Y and X are C(R5) or C(R6); R5, R6 : H, halo, R2, CN, O(R2), OC(O)(R2), OC(O)N(R2)(R3), OS(O 2)(R2), N(R2)(R3), N=C(R2)(R3), N(R2)C(O)(R3), N(R2)C(O)O(R3), N(R4)C(O)N(R2)(R3), N(R4)C(S)N(R2)(R3), N(R2)S(O 2)(R3), C(O)(R2), C(O)O(R2), C(O)NR(R2)(R3), C(=N (R3))(R2), C(=N (OR3))(R2), S(R2), S(O)(R2), S(O 2)(R2), S(O 2)O(R2) or S(O 2)N(R2)(R3); and R2-R4 : alkyl, alkylene, alkynyl, (hetero)aryl, cycloalkyl, heterocyclyl (all optionally substituted) or H (where R2 and R3 can form a cycle of 4-8 atom containing 1-3 heteroatoms of O, N and S). Independent claims are included for intermediate compounds of general formulae (III) and (IV). G : halo; X3 : Ar1-L-A (where L is NH 2 or NO 2); and X 1, X 2CN, Cl, NH-NH 2, N(tert.butyl oxy carbonyl)-NH(tert.butyl oxy carbonyl) or N(tert.butyl oxy carbonyl)-N(tert.butyl oxy carbonyl) 2. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Kinase inhibitors. The ability of (I) to inhibit focal adhesion kinase was tested invitro. The results showed that (I) had median inhibitory concentration of 73 nM.

Description

SUBSTITUTED PYRAZOLO PYRIDINES, COMPOSITIONS CONTAINING SAME, PROCESS FOR PREPARING

MANUFACTURE AND USE

  The present invention relates in particular to new chemical compounds, particularly new substituted pyrazolo pyridines, the compositions containing them, and their use as medicaments.

  More particularly, and according to a first aspect, the invention relates to new specific pyrazolo pyridines exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.

  To date, most commercial compounds used in chemotherapy pose significant problems of side effects and tolerance by patients. These effects could be limited insofar as the drugs used act selectively on cancer cells, excluding healthy cells. One of the solutions to limit the undesirable effects of chemotherapy may therefore consist of the use of drugs acting on metabolic pathways or constitutive elements of these pathways, mainly expressed in cancer cells, and which would be little or no expression in healthy cells.

  Protein kinases are an enzyme family that catalyze the phosphorylation of hydroxyl 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.

  Thus, one of the objects of the present invention is to provide compositions having an anticancer activity, acting in particular vis-à-vis kinases. Of the kinases for which modulation of activity is desired, FAK, KDR and Tie2 are preferred.

  These products correspond to the following formula (I): Formula (I) in which: 1) A and Ar are independently selected from the group consisting of: aryl, heteroaryl, substituted aryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, heterocyclyl substituted; 2) L is selected from the group consisting of: bond, CO, NH, CO-NH, NH-CO, NH-SO, NH-SO2, SO2NH, NH-CH2, CH2-NH, CH2-CO-NH, NH CO-CH 2, NH-CH 2 -CO, CO-CH 2 -NH, NH-CONH, NH-CS-NH, NH-CO-O, O-CO-NH; 3) One of X, Y and Z is selected from N and NO, and two others of Z, Y and X are C (R5) and C (R6); 4) R5 and R6 are independently selected from the group consisting of: H, halogen, R2, CN, O (R2), OC (O) (R2), OC (O) N (R2) (R3), OS (O2) ) (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), N ( R4) C (O) N (R2) (R3), N (R4) C (S) N (R2) (R3), N (R2) S (O2) (R3), C (O) (R2), C (O) O (R 2), C (O) N (R 2) (R 3), C (= N (R 3)) (R 2), C (= N (OR 3)) (R 2), S (R 2), S (O) (R 2), S (O 2) (R 2), S (O 2) O (R 2), S (O 2) N (R 2) (R 3); wherein each R2, R3, R4 is independently selected from the group consisting of H, alkyl, alkylene, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl, alkylene, substituted alkylene, substituted alkynyl; wherein R2 and R3 may be linked together to form a 4- to 8-membered ring containing from 1 to 3 heteroatoms selected from O, N and S In the products of formula (I), Ar-LA is advantageously: XT-X2 Wherein each X1, X2, X3 and X4 is independently selected from N and C-R11, with R11 having the same definition as R5 defined above. Ar-L-A is advantageously: wherein X 2 is selected from N, C-CH 3, CF and CH.

  R11 substituents selected from the group consisting of H, F, Cl, methyl, NH2, OCF3, and CONH2 are preferred.

  Preferred R5 and R6 substituents are independently selected from H, halogen, OMe and methyl.

  R5 and R6 are preferably selected from H and F. R5 and R6 are preferably H. Preferred L-A substituents are preferably selected from NH-CO-15 NH-A and NH-SO2-A.

  A particularly effective L-A combination is obtained when L-A is NHCONH-A.

  Products according to the invention preferably have a substituent A which is selected from the group consisting of phenyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl. benzoxazolyl and benzothiazolyl; optionally substituted.

  More preferably, A is selected from phenyl, pyrazolyl and isoxazolyl; optionally substituted.

  Substituent A is very advantageously substituted by a first substituent selected from the group consisting of (C 1 -C 6) alkyl, (C 1 -C 6) halogenated alkyl, (C 2 -C 6) alkylene, (C 2 -C 6) alkynyl, aryl, halogen, heteroaryl, O- (C1-C6) alkyl, O-Aryl, O-heteroaryl, S- (C1-C6) alkyl, Sail, S-heteroaryl each being optionally substituted by one or more substituents selected from (C1-C3) alkyl, halogen, O- (C1-C3) alkyl.

  Substituent A is preferably substituted with a second substituent selected from the group consisting of F, Cl, Br, I, OH, SH, SO3M, COOM, CN, NO2, CON (R8) (R9), N (R8) CO ( R9), (C1-C3) alkyl-OH, (C1-C3) alkyl-N (R8) (R9), (C1-C3) alkyl- (R10), (C1-C3) alkyl-COOH, N (R8) ) (R9); wherein R8 and R9 are independently selected from H, (C1-C3) alkyl, (C1-C3) alkylOH, (C1-C3) alkylNH2, (C1-C3) alkylOOOM, (C1-C3) alkylSO3M; wherein when R8 and R9 are simultaneously different from H, they may be linked to form a 5- to 7-membered ring containing from 0 to 3 heteroatoms selected from O, N and S; wherein M is H or an alkali metal cation selected from Li, Na and K; and wherein R10 is H or an optionally substituted non-aromatic heterocycle having 2 to 7 carbon atoms and 1 to 3 heteroatoms selected from N, O and S. Particularly preferred substituents A are selected from phenyl and isoxazolyl; said substituents A may be substituted with halogen, (C1-C4) alkyl, (C1-C3) halogenated alkyl, O- (C1-C4) alkyl, S- (C1-C4) alkyl, O- (C1-C4) alkyl halogenated, and S- (C1-C4) halogenated alkyl. When A is disubstituted, the two substituents of A can form a 5- to 7-membered ring containing from 0 to 3 heteroatoms. According to a preferred embodiment, A is advantageously 2-fluoro-5-trifluoromethyl-phenyl or 2-methoxy-5-trifluoromethyl-phenyl.

  Products in accordance with the invention may be chosen from: 1 - [4- (3Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl) phenyl) -urea; 1- [5- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea; 1- [4- (3Amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea; 1- [5- (3-Amino-1H-pyrazolo [4,3-c] pyridin-4yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea; 1- [4- (3Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -phenyl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea; 1- [5- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4yl) -pyridin-2-yl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea; and 1- [4- (3Amino-1H-pyrazolo [3,4-c] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea.

  A product according to the invention may be in the form: non-chiral, or racemic, or enriched in a stereoisomer, or enriched in an enantiomer; may be optionally salified, optionally hydrated, and possibly solvated.

  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.

  According to a second aspect, the invention relates to a medicament, comprising a product of formula (I) according to its first aspect, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the product of formula (I).

  According to a third aspect, the invention relates to a pharmaceutical composition comprising a product according to its first or second aspect, in combination with a pharmaceutically acceptable excipient.

  According to a fourth aspect, the invention relates to the use of a product according to one of the other aspects of the invention as an inhibitor of a kinase catalyzed reaction. Among the kinases, FAK, KDR and Tie2 are preferred.

  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.

  Among the 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, the intravenous route being usually 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. Among the possible combinations, mention may be made of: the alkylating agents and in particular cyclophosphamide, meiphalan, 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, in particular, bleomycin, mitomycin, dactinomycin, antimicrotubule agents such as vinblastine, vincristine, vindesine, vinorelbine, taxoids (paclitaxel and docetaxel) anthracyclines such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone, group I and II 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 methotrexate and folinic acid various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin as well as estrogenic hormones, androgenic agents 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, KDR and Tie2 are kinases for which the products of the invention will be particularly useful as inhibitors.

  The reasons for which these kinases are chosen are given below:

FAK

  FAK is a cytoplasmic tyrosine kinase that plays an important role in the transduction of the signal transmitted by integrins, a family of heterodimeric receptors for cell adhesion. FAK and integrins are colocalized in perimembrane structures called adhesion plates. It has been shown in many cell types that the activation of FAK and its phosphorylation on tyrosine residues and in particular its autophosphorylation on tyrosine 397 were dependent on the binding of integrins to their extracellular ligands and therefore induced during the cell adhesion [Kornberg L, et al. J. Biol. Chem. 267 (33): 23439-442. (1992)]. Autophosphorylation on tyrosine 397 of FAK represents a binding site for another tyrosine kinase, Src, via its SH2 domain [Schaller et al. Mol. Cell. Biol. 14: 1680-1688. 1994; Xing et al. Mol. Cell. Biol. 5: 413-421. 1994]. 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 and a /. 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 NH NH 2 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]. 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: 26062613. 1996].

  The results of many studies support the hypothesis that FAK inhibitors may be useful in the treatment of cancer. Studies have suggested that FAK may play an important role in cell proliferation and / or survival in vitro. For example, in CHO cells, some authors have demonstrated that 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]. Other authors have shown that tumor cells treated with FAK antisense oligonucleotides lose their adhesion and enter into apoptosis (Xu et al, Coli Growth Differ.4: 413-418, 1996). FAK has also been shown to promote cell migration in vitro. Thus, fibroblasts deficient for FAK expression (knockout mice for FAK) show rounded morphology, cell migration deficiencies in response to chemotactic signals, and these defects are suppressed by re-expression of FAK [DJ. Sieg et al., J. Cell Science. 112: 2677-91. 1999]. Overexpression of the C-terminal domain of FAK (FRNK) blocks the stretching of adherent cells and reduces cell migration in vitro [Richardson A. and Parsons J.T. Nature. 380: 538-540. 1996]. Overexpression of FAK in CHO, COS cells or in human astrocytoma cells promotes cell migration. The involvement of FAK in promoting proliferation and migration of cells in many cell types in vitro suggests the potential role of FAK in neoplastic processes. A recent study has effectively demonstrated the increase in tumor cell proliferation in vivo after induction of FAK expression in human astrocytoma cells [Cary L.A. et al. J. Cell Sci. 109: 1787-1794. 1996; Wang D et al. J. Cell Sci. 113: 42214230. 2000]. In addition, immunohistochemical studies of human biopsies demonstrated that FAK was overexpressed in prostate, breast, thyroid, colon, melanoma, brain and lung cancers, with the level of FAK expression being directly correlated with tumors with the most aggressive phenotype [Weiner TM, et al. Lancet. 342 (8878): 1024-1025. 1993; Owens et al. Cancer Research. 55: 27522755. 1995; Maung K. et al. Oncogene. 18: 6824-6828. 1999; Wang D et al. J. Cell Sci. 113: 4221-4230. 2000].

KDR

  KDR (Kinase insert Domain Receptor) also called VEGF-R2 (Vascular Endothelial Growth Factor Receptor 2), is expressed only in endothelial cells. This receptor binds to the angiogenic growth factor VEGF, and thus mediates a transduction signal via activation of its intracellular kinase domain. Direct inhibition of VEGF-R2 kinase activity reduces the angiogenesis phenomenon in the presence of exogenous VEGF (Vascular Endothelial Growth Factor) (Strawn et al., Cancer Research, 1996, vol 56, pp. 3540-3545). This process has 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 VEGFR2 kinase activity should demonstrate only low toxicity.

  In addition to this pivotal role in the dynamic angiogenic process, recent results suggest that 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). Tie2

  Tie-2 (TEK) 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. Davis et al (1996) Cell 87, 1161-1169] and the antagonist (angiopoietin 2 or Ang2) [P.C. Maisonpierre et al. (1997) Science 277, 55-60]. Angiopoietin 1 can synergize with VEGF in the late stages of neoangiogenesis [AsaharaT. Circ. Res. (1998) 233-240]. Knockout experiments and transgenic manipulations of Tie2 or Ang1 expression lead to animals with vascularization defects [D.J. Dumont et al (1994) Genes Dev. 8, 1897-1909 and C. Suri (1996) Cell 87, 1171-1180]. Angl binding to its receptor leads to autophosphorylation of the Tie2 kinase domain which is essential for neovascularization as well as for recruitment and interaction of vessels with pericytes and smooth muscle cells; these phenomena contribute to the maturation and stability of newly formed vessels [P.C. Maisonpierre et al (1997) Science 277, 55-60]. Lin et al (1997) J. Clin. Invest. 100, 8: 2072-2078 and Lin P. (1998) PNAS 95, 8829-8834, showed inhibition of tumor growth and vascularization, as well as decreased lung metastasis, during adenoviral infections or of Tie-2 extracellular domain (Tek) injections in models of breast tumor and melanoma xenographs.

  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).

  Definitions The term halogen refers to an element selected from F, Cl, Br, and I. The term alkyl refers to a saturated hydrocarbon substituent, linear or branched, having 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, 3,3-dimethylbutyl, heptyl, 1-ethylpentyl, octyl, nonyl, decyl, undecyl, and dodecyl are examples of alkyl substituents.

  The term alkylene refers to a linear or branched hydrocarbon substituent having one or more unsaturations having from 2 to 12 carbon atoms. The substituents ethylenyl, 1-methylethylenyl, prop-1-enyl, prop-2-enyl, Z-1-methylprop-1-enyl, E-1-methylprop-1-enyl, 2-1,2-dimethylprop-1-enyl, E-1,2-dimethylprop-1-enyl, but-1,3-dienyl, 1-methylidenylprop-2-enyl, Z-2-methylbut-1,3-dienyl, E-2-methylbut-1,3-dienyl, 2- Examples of alkylene substituents are methyl-1-methylidenylprop-2-enyl, undec-1-enyl and undec-10-enyl.

  The term alkynyl refers to a linear or branched hydrocarbon substituent having at least two unsaturations carried by a pair of vicinal carbon atoms having from 2 to 12 carbon atoms. Ethynyl substituents; prop-1-ynyl; prop-2-ynyl; and but-1-ynyl are examples of alkynyl substituents.

  The term aryl refers to a mono- or polycyclic aromatic substituent having from 6 to 14 carbon atoms. Phenyl, naphth-1-yl substituents; naphth-2-yl; anthracene-9-yl; 1,2,3,4-tetrahydronaphth-5-yl; and 1,2,3,4-tetrahydronaphth-6-yl are examples of aryl substituents.

  The term heteroaryl refers to a mono- or polycyclic heteroaromatic substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms. Pyrrol-1-yl substituents; pyrrol2-yl; pyrrol3-yl; furyl; thienyl; imidazolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; 1,2,4-triazolyl; oxadiazolyl; thiadiazolyl; tetrazolyl; pyridyl; pyrimidyl; pyrazinyl; 1,3,5-triazinyl; indolyl; benzo [b] furyl; benzo [b] thienyl; indazolyl; benzimidazolyl; azaindolyl; quinolyl; isoquinolyl; carbazolyl; and acridyl are examples of heteroaryl substituents.

  The term heteroatom refers here to at least one divalent atom different from carbon. NOT; O; S; and are examples of heteroatoms.

  The term cycloalkyl refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having from 3 to 12 carbon atoms. Cyclopropyl 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.

  The term heterocyclyl refers to a saturated or partially unsaturated cyclic hydrocarbon substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms. Preferably, the saturated or partially unsaturated cyclic hydrocarbon substituent will be monocyclic and will have 4 or 5 carbon atoms and 1 to 3 heteroatoms.

  The term "substituted" refers to one or more substituents other than H, for example halogen; alkyl; aryl; heteroaryl, cycloalkyl; heterocyclyl; alkylene; alkynyl; OH; 0-alkyl; 0-alkylene; 0-aryl; 0-heteroaryl; NH2; NH-alkyl; NH-aryl; NH-heteroaryl; Nalkyl-alkyl '; SH; S-alkyl; S-aryl; S (O2) H; S (O2) alkyl; S (O2) aryl; 3 H; SO3-alkyl; S03-aryl; CHO; C (0) -alkyl; C (0) -aryl; C (0) OH; C (0) 0alkyle; C (0) 0-aryl; OC (0) alkyl; OC (0) -aryl; C (0) NH2; C (0) NH-alkyl; C (0) NH-aryl; NHCHO; NHC (0) -alkyl; NHC (0) -aryl; NH-cycloalkyl; NHheterocyclyl, CONH-Heterocyclyl, CO-Heteroaryl, CO-Heterocyclyl NHCOHeteroaryl, NHCO-Heterocyclyl, NHCONH-alkyl.

  The present invention also relates to the process for preparing the products of formula (I).

  The products according to the invention can be prepared from conventional methods of organic chemistry. Scheme 1 below is illustrative of the method used for the preparation of Example 1 for pyrazolo [3,4-b] pyridines. As such, it can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds.

Figure 1: LDA I2 / LDA TsCN

CN

H + Boc ÎÉ Boc ÎBoc Boc Boc

CN

CN

CN

R

  Figure 2 below is illustrative of the method used for the preparation of the examples for pyrazolo [4,3-c] pyridines. As such, it can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds. Figure 2: H2N NH2 PBr3 or POBr3

H NH2

Suzuki

HN CF3

  Diagram 3: Process for the preparation of pyrazolo [3,4-c] pyridines (non-limiting): It is understood by those skilled in the art that, for the implementation of the methods according to the invention described above, it may be necessary to introduce protective groups of amino, carboxyl and alcohol functions in order to avoid side reactions. These groups are those that allow to be eliminated without touching the rest of the molecule. Examples of protecting groups of the amino function include tert-butyl carbamate which can be regenerated with trifluoroacetic acid or iodotrimethylsilane, acetyl which can be regenerated in an acid medium (hydrochloric acid for example) . As protecting groups of the carboxyl function, mention may be made of esters (methoxymethyl ester, benzyl ester for example). As 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. Other useful protecting groups are described by T. W. 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 to addition salts with a mineral or organic acid, by the action of such an acid in a solvent, for example an organic solvent such as an alcohol or 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. When a product according to the invention has at least one basic function

  Free, pharmaceutically acceptable 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, p-toluenesulfonate, propanesulfonates, xylenesulfonates, salicylates, cinnamates, glutamates, aspartates , glucuronates, galacturonates.

  When a product according to the invention has at least one free acid function, pharmaceutically acceptable salts 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.

  The invention is also described by the following examples, given by way of illustration of the invention.

  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. Separation was carried out on a Hypersil BDS C18 column, 3 μm (50 x 4.6 mm), eluting with a linear gradient of 5 to 90% acetonitrile containing 0.05% (v / v) trifluoroacetic acid ( TFA) in water containing 0.05% (v / v) TFA in 3.5 min at a flow rate of 1 mL / min. The total analysis time, including the rebalancing period of the column, is 7 minutes. The MS spectra were made in electrospray (ES +) on a Platform II (Micromass). The main ions observed are described.

  The melting points were measured in capillary, on a Mettler FP62 apparatus, range 30 C to 300 C, mounted 2 C per minute.

  LC / MS Purification: Products can be 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 dilution pump Manager, Waters model 2700 auto-injector, two Rheodyne Model LabPro valves, a Model 996 Waters diode array detector, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector The system was controlled by the Waters FractionLynx software. The separation was carried out alternately on two Waters Symmetry columns (C18, 5pM, 19x50 mm, catalog number 186000210), a column being regenerated with a water / acetonitrile mixture 95/5 (v / v) containing 0.07%. (v / v) trifluoroacetic acid, while the other column was being separated. Elution of the columns was performed using a linear gradient of 5-95% 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. At the outlet of the separation column, 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 FractionLynx software. 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. In some cases, depending on the analytical LC / MS results, when an intense ion corresponding to [M + 2H] ++ has been detected, the value corresponding to half of the calculated molecular weight (MW / 2) is also provided to the FractionLynx software. Under these conditions, the collection is also triggered when the mass signal of the ion [M + 2H] + + and / or [M + Na + H] ++ are detected. The products were collected in tared glass tubes. After collection, the solvents were evaporated in a Savant AES 2000 or Genevac HT8 centrifugal evaporator and the masses of products were determined by weighing the tubes after evaporation of the solvents.

Example 1

  1- [4- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-25-trifluoromethyl-phenyl) -urea 2-fluoro 3-iodo-pyridine To a solution of 0, 103mol of LDA in 200mL of THF at -75 ° C. are added 10 g of 2-fluoropyridine in 50 ml of THF. The yellow solution is stirred for 3 hours at -75 ° C., then 26.2 g of iodine are added in 80 ml of THF. The reaction mixture is stirred for 1.5 hours at -75 ° C. and then 50 ml of water are added at this temperature. The temperature is allowed to rise, then at 100.degree. C. 100 ml of additional water are added. The suspension is discolored by addition of sodium thiosulfate. The mixture is extracted with diethyl ether. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The oily residue is purified on Si60 silica (40-63pm) (cyclohexane / diethyl ether, 95: 5). The product obtained is taken up in diethyl ether and a beige insoluble is removed by spinning. After drying under vacuum, 10.21 g of white powder of 2-fluoro-3-iodopyridine are obtained.

  MS (ES +) spectrum: m / z = 224 [MH +] 2-Fluoro-4-iodo-nicotinonitrile To a solution of 21.5 mmol of LDA in 20 ml of THF at -75 ° C., 4.8 g of 2-fluoromers are added. 3-iodopyridine in 20 mL of THF. The yellow solution is stirred for 1 h 10 at -75 ° C. and then at this temperature are added 3.9 g of para-toluenesulfonyl cyanide in 20 ml of THF. The reaction mixture is stirred for 2 hours at -75 ° C., then 20 ml of water are added at this temperature. The temperature is allowed to rise, then at 0 C 40mL of additional water is added. The mixture is extracted with diethyl ether. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The brown resin obtained is purified on Si60 silica (40-63pm) (cyclohexane / diethyl ether, 8: 2). A fraction of 667 mg of a yellow powder of 2-fluoro-4-iodo-nicotinonitrile and a second fraction of 2.1 g of a pale yellow powder of 2-fluoro-3iodoisonicotinonitrile are obtained.

  MS (ES +) spectrum: m / z = 249 [MH +] 2-Hydrazino-4-iodo-nicotinonitrile To a solution of 1.2 g of 2-fluoro-4-iodo-nicotinonitrile in 20 mL of 20 C MeOH are added. , 4mL of hydrazine hydrate. The yellow suspension is stirred for 20 min at 20 ° C. and then filtered. The precipitate is washed with methanol to give 947 mg of white powder of 2Hydrazino-4-iodo-n icotinonitrile after drying under vacuum.

  MS (ES +) spectrum: m / z = 261 [MH +] (3-Cyano-4-iodo-pyridin-2-yl) -hydrazine di-tert-butyl dicarboxylate and N, N ', N' - (3- Tri-tert-butyl cyano-4-iodo-pyridin-2-yl) hydrazine tricarboxylate To a mixture of 234 mg of 2-hydrazino-4-iodo-nicotinonitrile, 27.5 mg of N, N-dimethylaminopyridine and 0.316 ml of triethylamine in 11 ml of dichloromethane at 4 ° C. are added 492 mg of di-terbutyl dicarbonate in 5 ml of dichloromethane. The reaction is stirred for 30 min at 4 ° C., then the temperature is allowed to rise to 20 ° C. and stirred for 5 hours. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The oily yellow residue is purified on a Biotage KPSil column of 60Â SiO2 32-63pm pre-filled (eluent: dichloromethane / methanol, 99.5: 0.5 then 99: 1) giving 2 major fractions, a first fraction of 110 mg of a yellow powder of tri-tert-butyl N, N ', N' - (3-cyano-4-iodo-pyridin-2-yl) -hydrazinetricarboxylate (MS spectrum (ES +): m / z = 561 [MH +]) ) and a second fraction of 202 mg of a pale yellow oil containing di-tert-butyl (3-cyano-4-iodo-pyridin-2-yl) -hydrazine dicarboxylate. This yellow oil is re-purified on a Biotage KP-Sil column of 60Â SiO2 32-63pm pre-filled (eluent: cyclohexane / ethyl acetate, 95: 5 then 9: 1) giving 114 mg of a beige powder of Di-tert-butyl 4-iodo-pyridin-2-yl) hydrazine dicarboxylate, MS (ES +) spectrum: m / z = 461 [MH +] N, N ', N' - (3-cyano- Tri-tert-butyl 4-iodo-pyridin-2-yl) -hydrazine-tricarboxylate To a mixture of 925 mg of 2-Hydrazino-4-iodonicotinonitrile, 109 mg of N, N-dimethylaminopyridine and 2.6 ml of triethylamine in 45 ml of dichloromethane at 4 ° C. are added 3.9 g of diterbutyldicarbonate (Boc 2 O) in 20 ml of dichloromethane. The reaction is stirred for 30 min at 4 ° C. and then the temperature is allowed to rise to 20 ° C.. Water is added and the mixture is extracted with ethyl acetate and then dried over magnesium sulfate and concentrated under reduced pressure. The oily brown residue is purified on silica Si60 (40-63pm) (dichloromethane / methanol, 98: 2) to obtain 1.2 g of a yellow powder of N, N ', N' - (3-Cyano-4-iodo -pyridin-2-yl) -hydrazinetricarboxylate of tritertbutyl.

PF = 138 ° C (Keifler).

  MS (ES +) spectrum: m / z = 561 [MH +] Suzuki coupling (X = C) with a di-boc derivative to a solution of 110mg of (3-cyano-4-iodopyridin-2-yl) hydrazine di-tert-butyl dicarboxylate and 122 mg of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - phenyl] urea in 5.5 ml of dioxane are added 57 mg of NaHCO 3 in 1.7 ml of water. Then, 26 mg of tetrakis (triphenylphosphine) palladium are added and the reaction is refluxed at 100 ° C. After 2.5 hours the light-yellow solution is cooled to 20 ° C. and 10 ml of ethyl acetate are added. The organic phase is washed twice with 8 ml of water and then 8 ml of brine. After drying over magnesium sulphate and concentration under reduced pressure, the residual yellow oil is purified on a Biotage KP-Sil pre-filled 60Â SiO2 32-63pm column (cyclohexane / ethyl acetate, 9: 1). 114 mg of di-tert-butyl (3-cyano-4- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) -ureido] -phenyl} -pyridin-2-yl) -hydrazine dicarboxylate are obtained.

  MS (ES +) spectrum: m / z = 631 [MH +] Suzuki coupling (X = C) with a tri-boc derivative To a solution of 108mg of N, N ', N' - (3-cyano-4-iodo) tri-tert-butyl pyridin-2-yl) -hydrazinetricarboxylate and 98mg 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) -phenyl] -urea in 4.5 ml of dioxane are added 45.4 mg of NaHCO 3 in 1.4 ml of water. Then, 20.3 mg of tetrakis (triphenylphosphine) palladium are added and the reaction is refluxed at 100 ° C. After 2.5 h the light yellow solution is cooled to 20 ° C. and 10 ml of ethyl acetate are added. The organic phase is washed twice with 8 ml of water and then 8 ml of brine. After drying over magnesium sulphate and concentration under reduced pressure, the residual yellow oil is purified on a Biotage KP-Sil column of 60Â SiO2 32-63pm pre-filled (cyclohexane / ethyl acetate, 9: 1 then 7: 3). . A fraction of 86 mg of N, N ', N' - (3-cyano-4- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) -ureido] -phenyl} -pyrid in-2 is obtained. 3-Cyano-4- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -ureido] -phenyl} -pyridin-2-yl) -3-tert-butyl-3-yl; di (tertbutyl) -hydroxy-dicarboxylate.

  MS (ES +) spectrum: m / z = 731 [MH +] 1- [4- (3-Amino-1H-pyrazolo [3,4-bpyridin-4-yl] -phenyl-3- (2-fluoro-5-trifluoromethyl) -phenyl) urea (from the dibocated derivative) To a solution of 111 mg of (3-Cyano-4- {4- [3- (2-fluoro-5-trifluoromethylphenyl) -idido] -phenyl} -pyridin-2 -yl) di-tert-butyl hydrazinedicarboxylate in 4 ml of dichloromethane at 20 ° C. are added 0.3 ml of trifluoroacetic acid containing 10% of anisole and the reaction is stirred for 4 hours. The reaction medium is concentrated under reduced pressure, giving a red-orange solid. This residue is purified on a Biotage KP-Sil column of 60Â SiO2 32-63pm pre-filled (gradient dichloromethane / solution A, 95: 5 at 90:10 solution A = dichloromethane / methanol / ammonia, 38: 17: 2). 56 mg of a beige powder of 1- [4- (3-amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) is obtained. -urea, whose characteristics are as follows: IR spectrum (KBr): 3370; 3300; 1717; 1604; 1541; 1443; 1317; 1310; 1205; 1184; 1122; 1114; 1069 and 818 cm -1 Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO d6, b in ppm): 4.58 (bs, 2H); 6.91 (d, J = 5.0 Hz, 1H); 7.41 (dm, J = 9.0 Hz, 1H); 7.52 (broad t, J = 9.0 Hz, 1H); 7.56 (broad d, J = 8.5 Hz, 2H); 7.68 (broad d, J = 8.5 Hz, 2H); 8.37 (d, J = 5.0 Hz, 1H); 8.62 (broad dd, J = 2.5 and 7.5 Hz, 1H); 9.13 (m spread, 1H); 9.57 (m spread, 1H); 12.25 (bs, 1H) mp = 175 ° C dec. (Kofler).

  Similarly, 1- [4- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea can be obtained from a tribo-derivative as follows: To a solution of 81 mg of N, N ', N' - (3-cyano-4- {4- [3- (2-fluoro-5-trifluoromethyl) triethyl tert-butylphenyl) -pyridin-2-yl) -hydrazinetricarboxylate in 3 ml of dichloromethane at 20 ° C. 0.2 ml of trifluoroacetic acid containing 10% anisole is added and the reaction is stirred. a night. The reaction medium is concentrated under reduced pressure, giving a red-orange solid. This residue is purified on a Biotage KP-Sil column of 60Â SiO2 32-63pm pre-filled (gradient dichloromethane / solution A, 95: 5 then 90:10 solution A = dichloromethane / methanol / ammonia, 38: 17: 2). 27 mg of a beige powder of 1- [4- (3-amino-1Hpyrazolo [3,4-b] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) is obtained -urea

Example 2

  1- [5- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea Suzuki (X = N) To a solution of 150 mg of tri-tert-butyl N, N ', N' - (3-cyano-4-iodo-pyridin-2-yl) -hydrazine-tricarboxylate and 136 mg of 1- (2-Fluoro-5-trifluoromethyl-phenyl) -3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -pyridin-2-yl] -urea in 6.2 ml of dioxane are added 63 mg of NaHCO 3 in 1.9 ml of water.

  Then, 29 mg of tetrakis (triphenylphosphine) palladium are added and the reaction is refluxed at 100 ° C. After 2.5 hours, the yellow solution is cooled to 20 ° C. and 10 ml of ethyl acetate are added. The organic phase is washed twice with 8 ml of water and then 8 ml of brine. After drying over magnesium sulphate and concentration under reduced pressure, the residual yellow oil is purified on a Biotage KP-Sil column of pre-filled 60 SiO2 32-63 pm (gradient dichloromethane / solution A, 98: 2 at 95: 5; dichloromethane / methanol / ammonia, 38: 17: 2). 67 mg of N, N ', N' - {3'-cyano-6- [3- (2-fluoro-5-trifluoromethylphenyl) ureido] - [3,4 '] bipyridinyl-2'-yl are obtained. tritert-butyl hydrazine tricarboxylate (MS spectrum (ES +): m / z = 732 [MH +]) and 55mg of {3'-cyano-6 [3- (2-fluoro-5-trifluoromethyl-phenyl) -ureido] Di-tert-butyl [3,4 '] bipyridinyl-2'-yl} hydrazine dicarboxylate (MS spectrum (ES +): m / z = 632 [MH +]).

  1- [5- (3-Amino-1H-pyrazolof-3,4-blpyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) urea to a solution of 55mg of Di-tert-butyl 3'-cyano-6- [3 (2-fluoro-5-trifluoromethyl-phenyl) -redido] - [3,4 '] bipyridinyl-2'-yl} hydrazine dicarboxylate in 2 mL of dichloromethane at 20 C are added 0.15 ml of trifluoroacetic acid containing 10% anisole and the reaction is stirred for 2 hours.

  Separately, to a solution of 67mg of N, N ', N' - {3'-cyano-6- [3- (2-fluoro-5-trifluoromethyl-phenyl) -ureido] - [3,4 'derivative ] tri-tert-butyl bi-pyridinyl-2'-yl} hydrazine tricarboxylate in 3 mL of dichloromethane at 20 ° C. is added 0.16 mL of trifluoroacetic acid containing 10% anisole and the reaction is stirred for 2 hours.

  The red-brown reaction media are combined and concentrated under reduced pressure, giving a red-orange solid. This residue is purified on a Biotage KP-Sil column of 60Â SiO2 32-63pm pre-filled (gradient dichloromethane / solution A, 95: 5 at 90:10 then 70:30, solution A = dichloromethane / methanol / ammonia, 38:17 : 2). A product is obtained which is taken up in ethyl acetate and washed with water to remove ammonium trifluoroacetate. After drying over magnesium sulphate and concentration under reduced pressure, 58 mg of a beige yellow powder of 1- [5- (3-amino-1H-pyrazolo [3,4-b] pyridin-4-yl) pyridine is obtained. 2-yl] -3- (2-fluoro-5-trifluoromethylphenyl) urea, the characteristics of which are as follows: IR spectrum (KBr): 3209; 1708 1610 1571; 1441; 1376; 1302; 1250; 1168; 1119; 1071; 822 and 616 cm -1 Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO d6, b in ppm): 4.70 (bs, 2H); 7.00 (d, J = 5.0 Hz, 1H); 7.45 (dm, J = 9.0 Hz, 1H); 7.55 (broad t, J = 9.0 Hz, 1H); 7.65 (d, J = 8.5 Hz, 1H); 8.06 (dd, J = 2.5 and 8.5 Hz, 1H); 8.41 (d, J = 5.0 Hz, 1H); 8.54 (d, J = 2.5 Hz, 1H); 8.67 (dd, J = 2.5 and 7.5 Hz, 1H); 10.15 (bs, 1H); 1 1, 1 5 (m very spread, 1 H); 12.35 (m spread, 1H) mp => 260 ° C (Kbfler).

Example 3

  1- [4- (3-Amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea 3-Amino-1H pyrazolo [4,3-c] pyridin-4-ol A mixture of 1.2 g of 2-hydroxy-4-methoxy-nicotinonitrile and 30 ml of hydrazine hydrate is heated at 140 ° C. for 18 h in a bomb. The reaction medium is then evaporated to dryness. The residue is taken up in ethyl ether, and the resulting suspension is filtered. 1 g of 3-amino-1H-pyrazolo [4,3-c] pyridin-4-ol is obtained in the form of a gray solid.

  MS: 150+ = M +; Mp 240 C dec. (Kofler). 4-Bromo-1H-pyrazolof4,3clpyridin-3-ylamine To 3.5 g of POBr3 melted at 45 ° C., 0.4 g of 3-amino-1H-pyrazolo [4,3-c] pyridin-4-ol are added, then the suspension is raised to 70 C for 4h. It is allowed to cool and is hydrolyzed, with care, with a solution of sodium bicarbonate. The mixture is extracted with ethyl acetate. The organic phase is isolated and dried over magnesium sulphate, filtered and then concentrated under reduced pressure. 0.33 g of 4-bromo-1H-pyrazolo [4,3-c] pyridin-3-ylamine are obtained in the form of a cream solid.

  MS: 212+ = M +; PF = 230 ° C dec. (Kéifler).

  1- [4- (3-Amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -phenyl-3- (2-fluoro-5-trifluoromethyl-phenyl) urea to a solution of 53 mg of 4 1-bromo-1 Hpyrazolo [4,3-c] pyridin-3-ylamine in 6 ml of dioxane, 127 mg of 1- (2-fluoro-5-trifluoromethyl-phenyl) -3- [4- 5,5-tetramethyl-1,3,2-dioxololan-2-yl) -phenyl] urea, 60 mg of sodium bicarbonate in 1.8 ml of water and 30 mg of tetrakis (triphenylphosphine) palladium. The reaction is heated in a bath at 100 ° C. for 2 hours. It is allowed to cool and then ethyl acetate is added. The mixture is washed with water. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The oily residue is purified on a pre-filled Biotage KPSil column of 60A SiO2 32-63pm (gradient dichloromethane / solution A, 90:10 at 70:30, solution A = dichloromethane / methanol / ammonia, 38: 17: 2). 34 mg of 1- [4- (3-amino-1H-pyrazolo [4,3-c] pyridin-4yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) urea solid are obtained. cream color, the characteristics of which are as follows: MS: 431+ = MH + IR spectrum (KBr): 3354; 1717; 1605 1542; 1442; 1339; 1313; 1181; 1119; 816 and 615 cm -1 Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO d6, b in ppm): 4.72 (bs, 2H); 7.20 (d, J = 5.5 Hz, 1H); 7.41 (br m, 1H); 7.51 (broad t, J = 9.5 Hz, 1H); from 7.59 to 7.72 (m, 4H); 8.22 (d, J = 5.5 Hz, 1H); 8.65 (broad d, J = 7.5 Hz, 1H); 8.96 (brs, 1H); 9.37 (s, 1H); 12.1 (broad s, 1H).

Example 4

  1- [5- (3-Amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea 1- [5- (3-Amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea solution of 106 mg of 4-bromo-1H-pyrazolo [4,3-c] pyridin-3-ylamine in 10 ml of dioxane, 252 mg of 1- (2-fluoro-5-trifluoromethyl-phenyl) 3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -pyridin-2-yl] urea, 120 mg of sodium bicarbonate in 3 ml of water, and 60 mg of tetrakis ( triphenylphosphine) palladium. The reaction is heated in a bath at 100 ° C. for 2 hours. It is allowed to cool and then ethyl acetate is added and the mixture is washed with water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The oily residue is purified on a Biotage KP-Sil column of 60A SiO2 32-63p pre-filled (gradient dichloromethane / solution A, 90:10 at 70:30, solution A = dichloromethane / methanol / ammonia, 38: 17: 2) . 35 mg of a yellow solid of 1- [5- (3-amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro) is obtained. -5-trifluoromethyl-phenyl) -urea, the characteristics of which are as follows: MS: 432+ = MH + IR spectrum (KBr): 3404; 3224; 1693 1609 1572; 1441; 1340; 1300; 1246; 1119; 819 and 615 cm -1 Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO d6, b in ppm): 4.88 (brs, 2H); 7.25 (d, J = 6.0 Hz, 1H); 7.44 (br m, 1H); from 7.50 to 7.53 (m, 2H); 8.15 (dd, J = 2.5 and 8.5 Hz, 1H); 8.26 (d, J = 6.0 Hz, 1H); 8.63 (d, J = 2.5 Hz, 1H); 8.70 (broad, J = 7.5 Hz, 1H); 10, 15 (bs, 1H); 11.3 (very broad m, 1H); 12.2 (s wide, 1H).

Example 5

  1- [4- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -phenyl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea 1- (2-Methoxy) 4-Trifluoromethyl-phenyl) -3- (4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -phenyl-urea To a solution of 1 g of 2-methoxy-4 - (trifluoromethyl) aniline and 128 mg of 4-dimethylaminopyridine in 150 ml of tetrahydrofuran and 1.5 ml of triethylamine is added, at 20 ° C., 1.28 g of 2- (4-isocyanato-phenyl) -4,4,5,5-tetramethyl After 4 hours, the reaction mixture is evaporated to dryness under reduced pressure, the residue is taken up in a mixture of ethyl acetate and water and the organic phase is dried over magnesium sulphate. then concentrated under reduced pressure, the residual yellow oil is purified on a biotage column kp-sil of 60 to 60 psig pre-filled (eluent: cyclohexane / ethyl acetate, 8: 2). is taken up in methanol and forms a white insoluble which is separated by filtration, then the filtrate is evaporated to dryness under reduced pressure to give 0.47 g of pale yellow powder of 1- (2-methoxy-4-trifluoromethyl-phenyl) -3- [4- (4,4,5,5-tetramethyl) -1, 3,2dioxaborolan-2-yl) -phenyl] -urea.

  MS: 437+ = MH + NMR Spectrum 1H (300 MHz, (CD3) 2SO d6, b in ppm): 1.30 (s: 12H); 3.99 (s: 3H); 7.22 (d, J = 9 Hz: 1H); 7.34 (dd, J = 9 and 1 Hz: 1H); 7.50 (d, J = 9: 2H); 7.63 (d, J = 9 Hz: 2H); 8.56 (mt: 2H); 9.58 (s: 1H).

  Di-boc and tri-boc derivatives of 1- [4- (3-cyano-2-hydrazino-pyridin-4-yl) phenyl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea to a solution of 0, 27 g of tri-tert-butyl N, N ', N' - (3-cyano-4-iodo-pyridin-2-yl) -hydrazinetricarboxylate in 14 ml of dioxane at 20 ° C. are added 273 mg of (2méthoxy-4-trifluoromethyl-phenyl) -3- [4- (4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) -phenyl] -urea. To this solution is added a solution of 114 mg of sodium bicarbonate in 4 ml of water and then 51 mg of tetrakis (triphenylphosphine) palladium. The reaction is refluxed at 100 ° C. for 2.5 hours. The light yellow solution is cooled and then ethyl acetate is added. The mixture is washed with water and brine. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The orange-yellow resin obtained is purified on a biotage column kp-sil of 60 μ SiO 2 32-63 μm pre-filled (eluent: cyclohexane / ethyl acetate, 7: 3, then dichloromethane / solution a, 9: 1, solution a = dichloromethane methanol / ammonia, 38: 17: 2). 0.33 g of yellow powder is obtained from a mixture of di-boc and tri-boc derivatives of 1- [4- (3-cyano-2-hydrazinopyridin-4-yl) -phenyl] -3- (2-methoxy) -5-trifluoromethyl-phenyl) -urea.

  1- [4- (3-Amino-1H-pyrazolo [3,4-blypyridin-4-yl] -phenyl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -oleye To a solution of 272 mg of a mixture of di-boc and tri-boc derivatives of 1- [4- (3-cyano-2-hydrazinopyridin-4-yl) phenyl] -3- (2-methoxy-5-trifluoromethylphenyl) -urea in 7 7 ml of dichloromethane at 20 ° C., 0.62 ml of trifluoroacetic acid containing 10% of anisole are added. After stirring for 3 h, the red-orange medium is concentrated to dryness under reduced pressure. The residual red-orange oil is purified on a Biotage KP-Sil column of pre-filled 60A SiO 2 32-63 μm (gradient dichloromethane / solution A, 90:10 at 70:30, solution A = dichloromethane / methanol / aqueous ammonia, 38: 17: 2). A beige yellow powder is obtained which is taken up in ethyl acetate. The solution is washed with water. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure to give 61 mg of a yellow powder of 1- [4- (3-amino-1H-pyrazolo [3,4-b] pyrid-4 -yl) -phenyl] -3- (2-methoxy-5-trifluoromethyl-phenyl) urea, the characteristics of which are as follows: MS: 443+ = MH + IR spectrum (KBr): 3380; 1706; 1675; 1600; 1539; 1314; 1269; 1134; 1117; 822 and 622 cm -1 NMR spectrum (400 MHz, (CD3) 2 SO4 d6, b in ppm): 3.99 (s, 3H), 4.59 (bs, 2H), , J = 5.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.34 (broad dd, J = 2.0 and 8.5 Hz, 1H), 7, 55 (d wide, J = 8.5 Hz, 2H), 7.66 (d wide, J = 8.5 Hz, 2H), 8.37 (d, J = 5.0 Hz, 1H), 8 , 56 to 8.61 (m, 2H), 9.66 (s, 1H), 12.25 (bs, 1H), mp => 260 ° C. (Kofler), Example 6 1- [5- ( 3-Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -pyridin-2-yl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea 1- (5-B-bromine) pyridin-2-yl) -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea 3.32 g of 2-methoxy-5-trifluoromethylphenylamine in 30 ml of tetrahydrofuran are added dropwise to a solution of 1, 8 g of triphosgene in 180 ml of tetrahydrofuran at 0 ° C. 4.95 ml of triethylamine are then introduced and the reaction is stirred at this temperature for 10 min, the temperature is allowed to rise to 20 ° C. and stirred for 1 h 15 min. -drop off a solution 3 g of 2-amino-5-bromopyridine in 30 ml of THF. After 16h, the suspension is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in a mixture of ethyl acetate and water. A white insoluble precipitate is obtained which is filtered, washed with ethyl acetate and then dried under vacuum. 3.3 g of white powder of 1- (5bromo-pyridin-2-yl) -3- (2-methoxy-5-trifluoromethylphenyl) urea are obtained.

  MS: 390+ = MH + 1- (2-Methoxy-5-trifluoromethyl-phenyl) -3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -pyridin-2 To a solution of 51 mg of tricyclohexylphosphine in 12 ml of dioxane at 20 ° C., 30 mg of bis (dibenzylideneacetone) palladium are added. The brown-violet solution is stirred for 30 minutes, then 500 mg of 1- (5-bromopyridin-2-yl) -3 (2-methoxy-5-trifluoromethyl-phenyl) urea and 190 mg of potassium acetate are added. The suspension is heated under reflux for 3 h 15 and then the red-violet solution is cooled to 20 ° C. and concentrated to dryness under reduced pressure. A gray-green residue is obtained which is washed in a mixture of ethyl acetate and water. The organic phase is filtered, and the yellow filtrate is concentrated under reduced pressure. The solid residue obtained is taken up in methanol. A precipitate forms which is filtered and washed with methanol and ethyl acetate. 244 mg of pale yellow powder of 1- (2-methoxy-5-trifluoromethyl-phenyl) -3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) are obtained -pyridin-2-yl] -urea.

  MS: 437+ = M + NMR Spectrum 1H (300MHz, (CD3) 2SO d6, b in ppm): 1.32 (s: 12H); 4.03 (s: 3H); 7.25 (d, J = 9.5 Hz: 1H); 7.34 (broad d, J = 9 Hz: 1H); 7.39 (dd, J = 9.5 and 1 Hz: 1H); 7.96 (dd, J = 9 and 2 Hz: 1H); 8.52 (d, J = 1 Hz: 1H); 8.63 (d, J = 2 Hz: 1H); 10.20 (s: 1H); 11.50 (s wide: 1H).

  Di-boc and tri-boc derivatives of 1- (3'-cyano-2'-hydrazino-3,4,4 ') bipyridinyl-6-yl) -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea 234 mg of 1 (2-Methoxy-5-trifluoromethyl-phenyl) -3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxol-2-yl) -pyridin-2-yl] -urea are added at 20 ° C. to a solution of 0.3 g of tri-tert-butyl N, N ', N' - (3-cyano-4-iodopyridin-2-yl) -hydrazinetricarboxylate in 16.5 ml of dioxane . A solution of 126 mg of sodium bicarbonate in 4.5 ml of water is then added, followed by 57 mg of tetrakis (triphenylphosphine) palladium. The yellow suspension obtained is refluxed at 100 ° C. for 2.5 h. After cooling, ethyl acetate is added. The organic phase is washed with water and then with brine. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residual yellow-orange resin is purified on a pre-filled 60 μ SiO 2 32-63 μm biotage column kp-sil (eluent: cyclohexane / ethyl acetate, 7: 3, then dichloromethane / solution A, 95: 5; solution A = dichloromethane / methanol / ammonia, 38: 17: 2). 265 mg of a mixture of di-boc and tri-boc derivatives of 1- (3'-cyano-2'-hydrazino- [3,4 '] bipyridinyl-6-yl) -3- (2-methoxy) were obtained. 5-trifluoromethyl-phenyl) urea as a yellow powder.

  145- (3-Amino-1H-pyrazolof-3,4-b] pyridin-4-yl) -pyridin-2-yl] -3- (2-methoxy-trifluoromethyl-phenyl) -urea 0.8mL trifluoroacetic acid containing 10% of anisole are added at 20 ° C. to a solution of 242 mg of a mixture of di-boc and tri-boc derivatives of 1- (3'-cyano-2'-hydrazino [3,4 '] bipyrid inyl6-yl) -3- (2-methoxy-5-trifluoromethylphenyl) urea in 7 mL of dichloromethane. After stirring for 2.5 h, the reaction mixture is concentrated to dryness under reduced pressure. The residual red-orange oil is purified on a Biotage KP-Sil pre-filled 60? SiO2 32-63pm column (dichloromethane / solution A gradient, 90:10 to 70:30, solution A = dichloromethane / methanol / aqueous ammonia, 38: 17: 2). 130 mg of a beige yellow powder of 1- [5- (3-amino-1H-pyrazolo [3,4b] pyridin-4-yl) -pyridin-2-yl] -3- (2-methoxy) are obtained. 5-trifluoromethyl-phenyl) -urea, the characteristics of which are as follows: MS: 444+ = MH + IR spectrum (KBr): 3420; 3219; 1684 1613; 1586; 1438; 1303; 1271; 1247; 1136; 834 and 622 cm -1 Spectrum of R.M.N. 1H (300 MHz, (CD3) 2SO d6, b in ppm): 4.02 (s, 3H); 4.72 (very spread m, 2H); 7.01 (d, J = 5.0 Hz, 1H); 7.24 (d, J = 8.5 Hz, 1H); 7.37 (broad dd, J = 2.0 and 8.5 Hz, 1H); 7.48 (d, J = 8.5 Hz, 1H); 8.03 (dd, J = 2.5 and 8.5 Hz, 1H); 8.41 (d, J = 5.0 Hz, 1H); 8.59 (d, J = 2.5 Hz, 1H); 8.64 (d, J = 2.0 Hz, 1H); 10.2 (s, 1H); 11.5 (very spread m, 1H); 12.35 (brs, 1H) mp => 260 ° C. (Kbfler). Example 7 1- [4- (3-Amino-1H-pyrazolof3,4-b] pyridin-4-yl) phenyl-3- (2-fluoro-5-trifluoromethyl-phenyl) -urea 1-β-5 4-chloro-4-cyano-pyridin-3-yl) -phenyl-3- (2-fluoro-5-trifluoromethylphenyl) -urea: To a solution of 346 mg of 3,5-dichloroisonicotinonitrile and 959 mg of 1 (2-fluoro 5-trifluoromethyl-phenyl) -3- [4- (4,4,5,5-tetramethyl-1,3, 2-dioxololan-2-yl) -phenyl] -urea in 24 ml of dioxane are added 462 mg of NaHCO 3 in 14 g. , 4mL of water. Then, 462 mg of terataki (triphenylphosphine) palladium are added and the reaction is heated at reflux for 5 hours and then left overnight at 20 ° C. Then 20 ml of water are added and the mixture is extracted with 2 × 60 ml of ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The brown oil is purified on a Merck cartridge of 30 g of SiO 2 15-40 pm pre-filled (dichloromethane then dichloromethane / methanol, 99: 1). 290 mg of yellow crystals of 1- [4- (5-chloro-4-cyano-pyridin-3-yl) phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea are obtained.

  MS (ES +) spectrum: m / z = 435 [MH +] 1 H NMR spectrum at 400 MHz on BRUKER AVANCE DRX-400 spectrometer chemical shifts (S in ppm) solvent: (DMSO-d6) referenced at 2.50 ppm at room temperature 303K: 7.41 (m, 1H); 7.51 (dd, J = 8.5 and 10.5 Hz, 1H); 7.68 (bs, 4H); 8.62 (dd, J = 2.0 and 7.0 Hz, 1H); 8.85 (s, 1H); 8.94 (s, 1H); 9.04 (m spread, 1H); 9.49 (m spread, 1H). 1- [4- (3-Amino-1H-pyrazolof-3,4-clpyridin-4-yl) phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea To a solution of 145 mg of 1- [4 - (5-Chloro-4-cyano-pyridin-3-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea in 2 mL of EtOH at 20 ° C are added 0.05 mL of hydrate of hydrazine. The reaction is refluxed for 5:30. The reaction is incomplete and 1 mL of EtOH and 0.05 mL of hydrazine hydrate are added and the reflux is kept for 18h30. Allowed to return to 20 C and concentrated under a stream of nitrogen. The residue is purified by chromatography on silica gel: Merck cartridge of 30 g of SiO 2 15-40 pm pre-filled (dichloromethane, then dichloromethane / methanol, 95: 5, then dichloromethane / methanol, 1: 1, then dichloromethane / methanol / NH 4 OH , 82: 15: 3). An impure beige oil is recovered which is chromatographed again under the same conditions. The product is still impure and is purified by preparative HPLC basic: conditions: column: Nucleodur Gravity C18 5pm (N cat Macherey Nagel: 762101, series 4055902, batch 3044); flow rate: 20mL / min; 254 nm detection (UV118, Gilson); 10 to 95% gradient of acetonitrile in water containing 10 mM ammonium formate according to the following protocol: (t (min): acetonitrile (%)): 0: 10; 2:10; 25: 95; 33: 95; 34: 10. 19 mg of a yellow powder of 1- [4- (3-Amino-1H-pyrazolo [3,4-c] pyridin-4-yl) -phenyl] -3- (2-fluorophenyl) is obtained. 5-trifluoromethyl-phenyl) -urea.

  MP = 196 C (Koffler) MS (ES +) spectrum: m / z = 431 [MH +] 1 H NMR spectrum at 400 MHz on BRUKER AVANCE DRX-400 spectrometer, chemical shifts (8 in ppm) - solvent (DMSO-d6) referenced at 2.50 ppm at 303K: 4.61 (s, 2H); 7.40 (m, 1H); 7.50 (m, 3H); 7.66 (broad d, J = 8.5 Hz, 2H); 7.94 (s, 1H); 8.63 (dd, J = 2.0 and 7.0 Hz, 1H); 8.74 (s, 1H); 9.10 (m spread, 1H); 9.51 (s, 1H); 12.3 (spread m, 1H). R (KBr): 1610; 1531; 1443; 1340; 1314; 1265; 1195; 1166; 1118; 1069; 820 & 615 cm -1 Determination of the activity of the compounds Experimental Protocols 1. FAK The inhibitory activity of the compounds on FAK is determined by measuring the inhibition of autophosphorylation of the enzyme using a fluorescence test. resolved in time (HTRF).

  The complete human FAK cDNA, whose N-terminus was tagged with histidine, was cloned into a pFastBac HTc baculovirus expression vector. The protein has been expressed and purified to about 70% homogeneity.

  Kinase activity is determined by incubating the enzyme (6.6 μg / ml) with different concentrations of test compound in 50 mM Hepes buffer pH = 7.2, 10 mM MgCl 2, 100 μM Na 3 VO 4, 15 M ATP for 1 hour at 37 ° C. The enzymatic reaction is stopped by the addition of Hepes buffer pH = 7.0, containing 0.4 mM KF, 133 mM EDTA, 0.1% BSA and the labeling is carried out for 1 to 2 hours at room temperature by the addition in this buffer of an anti-Histidine antibody labeled with XL665 and a europium cryptate conjugated tyrosine phosphospecific monoclonal antibody (Eu-K). The characteristics of the two fluorophores 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 to the degree of autophosphorylation of FAK. The long-term specific signal of XL665 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.

  2. 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 baculovirus expression vector pFastBac. The protein was expressed in SF21 cells and purified to about 60% homogeneity.

  The kinase activity of KDR is measured in 20 mM MOPS, 10 mM MgCl 2, 10 mM MnCl 2, 1 mM DTT, 2.5 mM EGTA, 10 mM b-glycerophosphate, pH = 7.2, in the presence of 10 mM MgCl 2, 100 μM Na 3 VO 4, 1 mM NaF. 10 μl of the compound are added to 70 μl of kinase buffer containing 100 μg of KDR enzyme at 4 ° C. The reaction is started by adding 20 μl of solution containing 2 μg of substrate (SH2-SH3 fragment of PLCy expressed in the form of GST fusion protein), 2 μCi γ 33P [ATP] and 2 μM cold ATP. After 1 hour of incubation at 37 ° C., the reaction is stopped by adding 1 volume (100 μl) of 200 mM EDTA. The incubation buffer is removed, and the wells are washed three times with 300 μl 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.

  Total activity control is measured in four different wells containing all reagents (γ33P- [ATP], KDR and PLCγ substrate) but in the absence of compound.

  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.

  Compound SU5614 (Calbiochem) (1 μM) is included in each plate as inhibition control.

  3. Tie2 The human Tie2 coding sequence corresponding to amino acids of intracellular domain 776-1124 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 MgCl2, 10mM MnCl2, 1mM DTT, 10mM glycerophosphate. In a 96-well FlashPlate plate held on ice, a reaction mixture composed of 70 μl of kinase buffer containing 100 ng of GST-Tie2 enzyme per well is deposited. Then 10 μl of the test molecule diluted in DMSO at a concentration of 10% maximum are added. For a given concentration, each measurement is made in four copies. The reaction is initiated by adding 20 μl of solution containing 2 μg of GST-PLC, 2 μM of cold ATP and 1 pCi of 33P [ATP]. After 1 hour of incubation at 37 ° C., the reaction is stopped by adding 1 volume (100 μl) of EDTA at 200 mM. After removal of the incubation buffer, the wells are washed three times with 300 μl of PBS. The radioactivity is measured on a Wallac MicroBeta1450.

  Inhibition of Tie2 activity is calculated and expressed as percent inhibition over control activity determined in the absence of compound.

  Results: Table 1: FAK KDR TIE2 IC 50 Example Structure (nM IC 50 (nM) IC 50 (nM) F 1 264 50 8

F

HN

F F

HN O NH2

NOT

N N

H

  F 2 150 940 23

F

NH

F F

O NH

N NH2

NOT

N N

H

F 3 73 33 5

F

HN

F F

HN O NH2 N

NOT

NOT

H

F

NH

F F

O NH

N 4 80 218 4 NH2

N I, N

NOT

H MeO

F

HN

F F

HN 5 286 49 15 NH2

N N

H OMe

F

NH

F F

O NH 6 190 1855 27

N NH2 \ N N 'N

H

HN

F F

HN O 7 - 36 9 NH 2 \ N

N - N

H

Claims (22)

  1. Product having the following formula (I): At L \ Ar   Formula (I) wherein: 1) A and Ar are independently selected from the group consisting of: aryl, heteroaryl, substituted aryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl; 2) L is selected from the group consisting of: bond, CO, NH, CO-NH, NH-CO, NH-SO, NH-SO2, SO2NH, NH-CH2, CH2-NH, CH2-CO-NH, NH -CO-CH 2, NH-CH 2 -CO, CO-CH 2 -NH, NH-CONH, NH-CS-NH, NH-CO-O, OCO-NH; 3) One of X, Y and Z is selected from N and NO, and two others of Z, Y and X are C (R5) and C (R6); 4) R5 and R6 are independently selected from the group consisting of: H, halogen, R2, CN, O (R2), OC (O) (R2), OC (O) N (R2) (R3), OS (O2) ) (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), N ( R4) C (O) N (R2) (R3), N (R4) C (S) N (R2) (R3), N (R2) S (O2) (R3), C (O) (R2), C (O) O (R 2), C (O) N (R 2) (R 3), C (= N (R 3)) (R 2), C (= N (OR 3)) (R 2), S (R 2), S (O) (R 2), S (O 2) (R 2), S (O 2) O (R 2), S (O 2) N (R 2) (R 3); wherein each R2, R3, R4 is independently selected from the group consisting of H, alkyl, alkylene, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl, alkylene, substituted alkylene, substituted alkynyl; wherein R2 and R3 may be linked together to form a 4- to 8-membered ring containing from 1 to 3 heteroatoms selected from O, N and S. 2. Product according to claim 1, characterized in that Ar-LA is: X4 X3 X. X2 A wherein each X1, X2, X3 and X4 is independently selected from N and CR11, wherein R11 has the same definition as R5.   3. Product according to claim 2, characterized in that Ar-L-A is: X2 A, wherein X2 is selected from N, C-CH3, CF and CH.   4. Product according to claim 2 or claim 3, characterized in that R11 is selected from the group consisting of H, F, Cl, methyl, NH2, OCF3, and CONH2.   5. Product according to claim 1 or claim 2, characterized in that R5 and R6 are independently selected from H, halogen, OMe and methyl.   6. Product according to claim 5, characterized in that R5 and R6 are selected from H and F. 7. Product according to any one of claims 1 to 6, characterized in that L-A is selected from NH-CO-NHA and NH-SO2-A.   8 Product according to claim 7 characterized in that L-A is NH-CONHA.   Product according to any one of claims 1 to 8, characterized in that A is selected from the group consisting of phenyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl and indolyl. indazolyl, benzimidazolyl, benzoxazolyl, and benzothiazolyl; optionally substituted.   10. Product according to claim 9, characterized in that A is chosen from phenyl, pyrazolyl and isoxazolyl; optionally substituted.   11. Product according to any one of claims 7 to 10, characterized in that A is substituted with a first substituent selected from the group consisting of (C1-C6) alkyl, (C1-C6) halogenated alkyl, (C2-C6). ) alkylene, (C2-C6) alkynyl, aryl, halogen, heteroaryl, O- (C1-C6) alkyl, O-aryl, O-heteroaryl, S- (C1-C6) alkyl, S-aryl, S-heteroaryl, each being optionally substituted with one or more substituents selected from (C1-C3) alkyl, halogen, O- (C1-C3) alkyl.   12. Product according to any one of claims 7 to 11, characterized in that A is substituted by a second substituent selected from the group consisting of F, Cl, Br, I, OH, SH, SO3M, COOM, CN, NO2. , CON (R8) (R9), N (R8) CO (R9), (C1-C3) alkyl-OH, (C1-C3) alkyl-N (R8) (R9), (C1-C3) alkyl- ( R10), (C1-C3) alkyl-COOH, N (R8) (R9); wherein R8 and R9 are independently selected from H, (C1-C3) alkyl, (C1-C3) alkylOH, (C1-C3) alkylNH2, (C1-C3) alkyl000M, (C1-C3) alkylSO3M; wherein when R8 and R9 are simultaneously different from H, they may be linked to form a 5- to 7-membered ring having from 0 to 3 heteroatoms selected from O, N and S; wherein M is H or an alkali metal cation selected from Li, Na and K; and wherein R10 is H or an optionally substituted non-aromatic heterocycle having 2 to 7 carbon atoms and 1 to 3 heteroatoms selected from N, O and S. 13. Product according to any one of claims 7 to 12, characterized in that A is phenyl or isoxazolyl substituted by halogen, (C1-C4) alkyl, (C1-C3) halogenated alkyl, O- (C1-C4) alkyl , S- (C1-C4) alkyl, O- (C1-C4) halogenated alkyl, S- (C1-C4) halogenated alkyl.   14. Product according to claim 13, characterized in that A is 2-fluoro-5-trifluoromethyl-phenyl or 2-methoxy-5-trifluoromethyl-phenyl.   15. Product according to claim 1, characterized in that it is chosen from: 1- [4- (3-Amino-1H-pyrazolo [3,4-b] pyrid-4-yl) -phenyl] - 3- (2-fluoro-5-trifluoromethyl-phenyl) -urea; 1- [5- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea ; 1- [4- (3-Amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea; 1- [5- (3-Amino-1H-pyrazolo [4,3-c] pyridin-4-yl) -pyridin-2-yl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea; 1- [4- (3Amino-1H-pyrazolo [3,4-b] pyrid-4-yl) -phenyl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea; 1- [5- (3-Amino-1H-pyrazolo [3,4-b] pyridin-4yl) -pyridin-2-yl] -3- (2-methoxy-5-trifluoromethyl-phenyl) -urea; and 1- [4- (3Amino-1H-pyrazolo [3,4-c] pyridin-4-yl) -phenyl] -3- (2-fluoro-5-trifluoromethyl-phenyl) -urea.   16. Product according to any one of the preceding claims, characterized in that it is in the form: non-chiral, or racemic, or enriched in a stereoisomer, or enriched in an enantiomer; and in that it is eventually salified.   17. Medicament, characterized in that it comprises a product of formula (I) according to any one of claims 1 to 16, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the product of formula (I).   18. A pharmaceutical composition comprising a product according to any one of the preceding claims, in combination with a pharmaceutically acceptable excipient.   19. Use of a product according to any of claims 1 to 18 as an inhibitor of a kinase catalyzed reaction.   20. Use of a product according to claim 19, characterized in that the kinase is selected from FAK, KDR and Tie2.   21. Use of a product according to any one of claims 1 to 18, for the manufacture of a medicament useful for treating a pathological condition.   22. Use according to claim 21, characterized in that the pathological state is cancer.