HK1125928B - 7-substituted aza-indazoles, compositions containing same, production method and use thereof - Google Patents

Description

Substituted 7-aza-indazoles, compositions containing same, method for producing same and use thereof

The invention relates in particular to novel chemical compounds, in particular novel substituted 7-azaindoles, to compositions containing them and to their use as medicaments.

More particularly, the present invention relates to novel specific 7-azaindoles which exhibit anti-cancer activity by modulating the activity of proteins, especially kinases.

To date, most of the commercialized compounds used in chemotherapy pose considerable problems with respect to side effects and patient tolerance. These effects can be limited in methods that allow these drugs to be used to selectively act on cancer cells rather than normal cells. Thus, one of the solutions used to limit the adverse effects of these chemotherapies consists in using drugs that act on metabolic pathways or the units that make up these pathways, which are mainly expressed in cancer cells, and which will show up slightly or not at all in normal cells.

Protein kinases are a class of enzymes that catalyze the phosphorylation of the hydroxyl group of a specific residue of a protein, such as a tyrosine, serine or threonine residue. Such phosphorylation can greatly alter the function of the protein; thus, protein kinases play an important role in the regulation of a large number of different cellular processes, including in particular anabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among the different cellular functions involved in protein kinase activity, certain processes represent useful targets for the treatment of cancer and other diseases.

It is therefore an object of the present invention to provide compositions having anticancer activity by acting specifically directly on kinases. Among the kinases whose modulation of activity is being investigated, FAK, KDR and Tie2 are preferred.

These compounds correspond to the following formula (I):

formula (I)

Wherein:

1) a and Ar are independently selected from: aryl, heteroaryl, heterocyclyl, substituted aryl, substituted heteroaryl, substituted heterocyclyl, cycloalkyl, and substituted cycloalkyl;

2) l is selected from: NH, NH-SO₂、SO₂NH、NH-CH₂、CH₂-NH、NH-CO、CO-NH、CH₂-CO-NH、NH-CO-CH₂、NH-CH₂-CO、CO-CH₂-NH、NH-CO-NH、NH-CS-NH、NH-CO-O、O-CO-NH、CH₂-NH-CO-NH、NH-CO-NH-CH₂And NH-CO-CH₂-CO-NH；

3) X is N or NO;

4) r3 is selected from H and NHMR "3, wherein M is selected from: chemical bond, CO-NH, CS-NH and SO₂(ii) a And wherein R' 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocyclyl;

5) r4 is selected from: H. halogen, alkyl, substituted alkyl, OR '4, N (R' 5) (R '6), CON (R' 5) (R '6), wherein R' 4 is selected from H, phenyl, substituted phenyl, alkyl, substituted alkyl, wherein R '5 and R' 6 are independently selected from H, (C)₁-C₆) Alkyl, substituted (C)₁-C₆) Alkyl, - (C)₁-C₆) Alkyl-heterocyclyl, substituted- (C)₁-C₆) Alkyl-heterocyclyl, - (C)₁-C₆) Alkyl-heteroaryl, substituted- (C)₁-C₆) Alkyl-heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R "5 and R" 6 are linked to each other to form a saturated ring having 4 to 8 ring members containing 1 to 3 heteroatoms selected from O, S and N, optionally substituted;

6) r5 is selected from: H. halogen, R '2, CN, 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)、N(R′4)C(O)N(R′2)(R′3)、N(R′4)C(S)N(R′2)(R′3)、N(R′2)S(O₂)(R′3)、C(O)(R′2)、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(O₂)(R′2)、S(O₂)O(R′2)、S(O₂) N (R '2) (R' 3); wherein each R ' 2, R ' 3, R ' 4 is independently selected from H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, substituted heterocyclyl; and R '2 and R' 3 may be linked to each other to form a ring containing 1-3 heteroatoms selected from O, S and N;

if, when X is N, R3 is NH₂Ar and A are unsubstituted phenyl, L is NHCO attached to the para position of Ar, and R5 is H, then R4 is not selected from: phenyl, o-chlorophenyl, cinnamyl, alpha-furfuryl, o-hydroxyphenyl, p-hydroxy-m-methoxyphenyl, p-methylthiophenyl, p-methoxyphenyl, o-nitrophenyl, m-phenoxyphenyl, and if, when X is N, R5 is H, R4 is H and Ar-L-A is a groupThen R3 is not selected from: amino, acetylamino, [ (4-fluorobenzene)Yl) carbonyl]Amino, (2-methylpropionyl) amino, - (cyclopentylcarbonyl) amino, propionylamino, [ (4-methylphenyl) carbonyl]Amino, { [4- (methoxy) phenyl]Carbonyl } amino, (2-thienylcarbonyl) amino, (methylsulfonyl) amino, - [ (4-fluorophenyl) sulfonyl]Amino, (ethylsulfonyl) amino, (propylsulfonyl) amino, (3-thienylsulfonyl) amino, [ (3, 5-dimethyl-4-iso-sulfonyl)Azolyl) sulfonyl]Amino, (2-thienylsulfonyl) amino, and (1-methylethyl) amino.

Preferred products of formula (I) are those corresponding to the following definitions:

formula (I)

Wherein:

1) a and Ar are independently selected from: aryl, heteroaryl, heterocyclyl, cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocyclyl, and substituted cycloalkyl;

2) l is selected from: NH, NH-SO₂、SO₂NH、NH-CH₂、CH₂-NH、CH₂-CO-NH、NH-CO-CH₂、NH-CH₂-CO、CO-CH₂-NH、NH-CO-NH、NH-CS-NH、NH-CO-O、O-CO-NH、CH₂-NH-CO-NH、NH-CO-NH-CH₂And NH-CO-CH₂-CO-NH；

3) X is N;

4) r3 is selected from H, NH2 and NHCOR "3, and R" 3 is selected from: H. alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl, and substituted heterocyclyl;

5) r4 is selected from: H. halogen, alkyl, substituted alkyl, CON (R '5) (R' 6), wherein R '5 and R' 6 are independently selected from: H. (C)₁-C₆) Alkyl, substituted (C)₁-C₆) Alkyl, - (C)₁-C₆) Alkyl heterocyclic group, substituted- (C)₁-C₆) Alkyl heterocyclic radical, - (C)₁-C₆) Alkyl heteroaryl, substituted- (C)₁-C₆) Alkylheteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or R "5 and R" 6 are linked to each other to form a saturated ring having 4 to 8 ring members containing 1 to 3 heteroatoms selected from O, S and N, optionally substituted;

6) r5 is H.

In the product of formula (I), Ar is selected from thiazolyl, thienyl, furyl, pyrrolyl,Azolyl radical, isoAzolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolylAzolyl and benzothiazolyl; optionally substituted, or Ar is thiazolyl, or Ar-L-A is:

wherein X1, X2, X3 and X4 are independently selected from N and C-R '5, wherein R' 5 has the same definition as R5.

Preferred substituents of L-A are advantageously selected from NH-CO-NH-A and NH-SO₂-A. When L-A is NHCONH-AParticularly effective L-A combinations are obtained.

The products of the invention preferably have an a substituent selected from: phenyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl,Azolyl, thiazolyl, isoAzolyl, isothiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzoAzolyl and benzothiazolyl; optionally substituted.

More preferably, A is selected from phenyl, pyrazolyl and isoAn azole group; optionally substituted.

The A substituent is very advantageously substituted by a first substituent selected from halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, O-alkyl, O-aryl, O-heteroaryl, S-alkyl, S-aryl, S-heteroaryl, each optionally substituted by one or more substituents selected from (C)₁-C₃) Alkyl, halogen and O- (C)₁-C₃) Alkyl substituents.

The a substituent is preferably substituted with a second substituent selected from: F. cl, Br, I, OH, SH, SO₃M、COOM、CN、NO₂、CON(R8)(R9)、N(R8)CO(R9)、(C₁-C₃) alkyl-OH, (C)₁-C₃) alkyl-N (R8) (R9), (C)₁-C₃) Alkyl- (R10), (C)₁-C₃) alkyl-COOH, N (R8) (R9); wherein R8 and R9 are independently selected from H, (C)₁-C₃) Alkyl, halogenated (C)₁-C₃) Alkyl, (C)₁-C₃) Alkyl OH, (C)₁-C₃) alkyl-O (C₁-C₃) Alkyl, (C)₁-C₃) Alkyl NH₂、(C₁-C₃) Alkyl N (R8) (R9), (C)₁-C₃) Alkyl COOM, (C)₁-C₃) Alkyl SO₃M; wherein when R8 and R9 are simultaneously not H, they may be linked to form a ring having 5-7 ring members containing 1-3 heteroatoms; wherein M is H or a cation of an alkali metal selected from Li, Na and K; and wherein R10 is H or an optionally substituted non-aromatic heterocycle containing 2 to 7 carbon atoms and 1 to 3 heteroatoms selected from N, O and S.

The a substituents are particularly preferably selected from: phenyl, pyrazolyl and isoAn azole group; the A substituent may be substituted by halogen, (C)₁-C₄) Alkyl, halogenated (C)₁-C₃) Alkyl, O- (C)₁-C₄) Alkyl, S- (C)₁-C₄) Alkyl, halogenated O- (C)₁-C₄) Alkyl and halogenated S- (C)₁-C₄) Alkyl substituted. When a is disubstituted, the two substituents of a may form a ring having 5 to 7 ring members containing 0 to 3 heteroatoms selected from O, N and S.

The R4 substituent is advantageously selected from H and CON (R '5) (R' 6), R '5 and R' 6 being as defined above.

The product according to the invention may be in the form of:

a) in achiral form, or

b) In racemic form, or

c) In stereoisomerically enriched form, or

d) Enantiomerically enriched forms;

and may optionally be salified.

The products of the invention can be used for the production of medicaments for the treatment of pathological conditions, in particular cancer. One object of the present invention is a medicament, characterized in that it comprises a product of formula (I) or a pharmaceutically acceptable acid addition salt of this compound, or else a hydrate or solvate of the product of formula (I).

The invention also relates to therapeutic compositions comprising the products of the invention in combination with pharmaceutically acceptable excipients according to the chosen method of administration. The pharmaceutical composition may be in solid or liquid form or in the form of liposomes.

Among these solid compositions, powders, capsules and tablets may be mentioned. In oral forms, protected solid forms resistant to the acidic medium of the stomach may also be included. Carriers for solid forms are in particular composed of inorganic carriers such as phosphates or carbonates or organic carriers such as lactose, cellulose, starch or polymers. Liquid forms consist of suspensions or dispersions. These liquid forms contain water or an organic solvent (ethanol, NMP, etc.), or a mixture of a surfactant and a solvent, or a mixture of a complexing agent and a solvent, as the dispersing vehicle.

These liquid forms are preferably injectable and, therefore, will have a formulation acceptable for this use.

Acceptable routes of administration by injection include intravenous, intraperitoneal, intramuscular, and subcutaneous routes, with the intravenous route generally being preferred.

The dosage of the compound of the present invention to be administered will be adjusted by the practitioner according to the route of administration to the patient and the patient's condition.

Due to their low toxicity and their pharmacological and biological properties, the compounds of the invention find application in the treatment of any cancer with a considerable degree of vascularization or causing metastases, or ultimately in pathologies of the lymphoma and leukemia type.

These compounds represent a treatment of choice, either alone or in combination with appropriate chemotherapy or radiotherapy, and/or in combination with other compounds having anti-angiogenic activity, as inhibitors of VEGF or FGF. The products of general formula (I) are therefore particularly useful for the treatment or prevention of such pathological conditions, characterized in that they are administered alone or in combination with other active ingredients, in particular anticancer drugs such as cytotoxic products, cytostatic products, antiangiogenic products or antimetastatic products.

The compounds of the invention may therefore be administered alone or as a mixture with other anti-cancer agents. Among the possible combinations, mention may be made of:

alkylating agents, in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, butyl dimesylate, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozocin, dacarbazine, temozolomide, procarbazine and altretamine;

platinum derivatives, such as in particular cisplatin, carboplatin or oxaliplatin;

antibiotics, such as bleomycin, mitomycin or dactinomycin, in particular;

antimicrotubule agents, such as vinblastine, vincristine, vindesine, vinorelbine, taxanes (paclitaxel and docetaxel), among others;

anthracyclines, such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone or losoxanone, in particular;

topoisomerase I and II inhibitors, such as etoposide, teniposide, amsacrine, irinotecan, topotecan (topotecan) and raltitrexed;

fluoropyrimidines such as 5-fluorouracil, UFT or fluorouracil deoxynucleosides;

cytidine analogs such as 5-azacytidine, cytarabine, gemcitabine (gemcitabine), 6-mercaptopurine, or 6-thioguanine;

adenosine analogues such as pentostatin, cytarabine or fludarabine phosphate;

methotrexate and folinic acid;

different enzymes and compounds, such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramin, dexrazoxane, amifostine, herceptin, and also estrogens and androgens;

anti-vascular agents, such as combretastatin derivatives, for example CA4P, chalcones or colchicines, for example ZD6126 and prodrugs thereof;

anti-angiogenic agents, such as bevacizumab, sorafenib or sunitinib maleate;

therapeutic agents that inhibit other tyrosine kinases, such as imatinib, gefitinib and erlotinib.

When a compound of the invention is combined with another therapy or radiation therapy, then these therapies may be administered simultaneously, separately or sequentially. The practitioner adjusts the treatment according to the disease to be treated.

The products of the invention are useful as inhibitors of one or more kinase-catalyzed reactions. FAK, KDR and Tie2 are such kinases for which the products of the invention would be particularly useful inhibitors.

The reasons for selecting these kinases are given below: FAK

FAK is a cytoplasmic tyrosine kinase that plays an important role in the transduction of signals transmitted by integrins, and is a class of heterodimeric cell adhesion receptors. FAK and integrins are localized together in the peripheral membrane (perirembrane) structures called focal adhesions. In many cell types, it has been shown that activation of FAK, as well as its phosphorylation at tyrosine residues, especially its autophosphorylation at tyrosine 397, depends on integrin binding to its extracellular ligands and is therefore induced during cell adhesion [ Kornberg L, et al j.biol.chem.267 (33): 23439-442, (1992)]. Autophosphorylation of FAK on tyrosine 397 represents a step through its SH2 region for Src, another tyrosine kinaseSite for row binding, [ Schaller et al, mol.cell.biol.14: 1680 to 1688.1994; xing et al mol.cell.biol.5: 413-421, 1994]. Src can then phosphorylate FAK on tyrosine 925, thus supplementing Grb2 to engage proteins and causing activation of ras and MAP kinase pathways involved in the control of cell proliferation in certain cells [ 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 can also induce jun NH₂The terminal kinase (JNK) signaling pathway and leads to the development of cells to the G1 stage of the cell cycle [ Oktay et al, J, cell. biol.145: 1461-1469.1999]. phosphatidylinositol-3-OH kinase (PI 3-kinase) also binds FAK on tyrosine 397, an interaction that may be necessary for activation of PI 3-kinase [ 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 different substrates such as paxilline (paxilline) and p130CAS [ 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. Studies have revealed that FAK may have an important role in cell proliferation and/or survival in vitro. For example, in CHO cells, some authors have shown that overexpression of p125FAK leads to accelerated conversion of G1 to S, 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 cause apoptosis (Xu et al, Cell Growth Differ.4: 413-418.1996). FAK has also been shown to promote cell migration in vitro. Thus, poorly functioning fibroblasts for the expression of FAK (the "knockout" mice for FAK) show an intact morphology and a functional deficit in cell migration in response to chemotactic signals, which are eliminated by the re-expression of FAK [ DJ, Sieg et al, j.cellscience.112: 2677-91.1999]. Overexpression of the C-terminal region of FAK (FRNK) blocks extension 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 or COS cells or in human astrocytoma cells promotes cell migration. FAK is implicated in promoting cell proliferation and migration in various cell types in vitro, revealing a potential role for FAK in tumor progression. Recent studies have effectively demonstrated an increase in tumor cell proliferation in vivo following induction of FAK expression in human astrocytoma cells (Cary L.A et al J.cell Sci.109: 1787-94.1996; Wang D et al J.cell Sci.113: 4221-4230.2000). Furthermore, immunohistochemical studies of human biopsies have demonstrated that FAK is overexpressed in prostate, breast, thyroid, colon, melanoma, brain and lung cancers, with levels of FAK expression directly associated with tumors that display the most aggressive phenotype (Weiner TM, et al Lancet.342 (8878): 1024-1025.1993; Owens et al Cancer Research, 55: 2752-2755.1995; Maung K et al oncogene.18: 6824-6828, 1999; Wang D et al J.cell Sci.113: 4221-4230.2000).

KDR

KDR (kinase insertion region receptor), also known as VEGF-R2 (vascular endothelial growth factor receptor 2), is expressed only in endothelial cells. This receptor binds the angiogenic growth factor VEGF and thus serves as a mediator of the transduction signal for activation by its intracellular kinase domain. Direct inhibition of VEGF-R2 kinase activity has led to a reduction in the phenomenon of angiogenesis in the presence of exogenous VEGF (vascular endothelial growth factor) (Strawn et al Cancer Research, 1996, vol.56, p.3540-3545). This process has been demonstrated in particular with the aid of VEGF-R2 mutants (Millauer et al, Cancer Research, 1996, vol.56, p.1615-1620). The VEGF-R2 receptor appears to have no effect in adults, except for functions related to the angiogenic activity of VEGF. Therefore, a selective inhibitor of the kinase activity of VEGF-R2 would show only slight toxicity.

In addition to this major role in the dynamic process of angiogenesis, recent results revealed that VEGF expression contributes to tumor cell survival following chemotherapy and radiotherapy, emphasizing the potential synergistic effects of inhibitors of KOR and other drugs (Lee et al Cancer Research, 2000, volume 60, p.5565-5570).

Tie2

Tie-2(TEK) is a member of the tyrosine kinase receptor family and is specific for endothelial cells. Tie2 is the first receptor with tyrosine kinase activity, and agonists (angiopoietin 1 or Ang1) [ s.daw's et al (1996) Cell 87, 1161-1169] and antagonists (angiopoietin 2 or Ang2) [ p.c. maison pierre et al (1997) Science 277, 55-60] of this receptor are known to stimulate receptor autophosphorylation and Cell signaling. In the final stage of neoangiogenesis, angiopoietin 1 can act synergistically with VEGF [ Asahara T. Circ. Res. (1998) 233-. Knockout experiments and transgenic treatment of expression of Tie2 or expression of Ang1 resulted in animals exhibiting defects in vascularization [ D.J.Dumont et al, (1994) Genes Dev.8, 1897-. The binding of Ang1 to its receptor results in autophosphorylation of the Tie2 kinase region, which is essential for neovascularization and for vascular recruitment and interaction of blood vessels with pericytes and smooth muscle cells; these phenomena contribute to the maturation and stabilization of newly formed blood vessels [ p.c. maison pierre et al (1997) Science 277, 55-60 ]. Lin et al, (1997), j.clin.invest.100, 8: 2072 and Lin P. (1998), PNAS 95, 8829 and 8834, have shown inhibition of tumor growth and vascularization, as well as reduction of lung metastases, when injected or infected with adenovirus in the extracellular region of Tie-2(Tek) in melanoma and breast tumor xenograph models.

Tie2 inhibitors may be useful in situations where neovascularization or angiogenesis proceeds in an inappropriate manner, i.e., generally in these cancers, but also in certain cancers such as Kaposi's (Kaposi) sarcoma or hemangioma incertae, rheumatoid arthritis, osteoarthritis and/or associated pain (assariated pain), inflammatory diseases of the bowel such as ulcerative trigonitis or crohn's disease, symptoms of the eye such as age-related macular degeneration, diabetic retinopathy, chronic inflammation or psoriasis.

Angiogenesis is the process of creating new capillary blood vessels from existing blood vessels. Tumor angiogenesis, which is essential for tumor growth and is one of the essential elements of metastatic spread (oncogene.200)₃ May 19；22(20)：3172-9；Nat Med.1995 Jan；1(1)：27-31.)。

This neovascularization is due to migration, then proliferation and differentiation of endothelial cells under the influence of angiogenic factors secreted by cancer cells and stromal cells (Recent Prog Horm res.2000: 55: 15-35; 35-6).

The angiopoietin 1/Tie2 receptor system has a prominent role in vascular maturation by recruiting periendothelial cells in order to stabilize blood vessels (Cell, 1996 Dec 27; 87 (7): 1161-9, Recent Prog Horm Res.2004; 59: 51-71). Thus, it has been shown that administration of a soluble recombinant form of the extracellular region of the Tie-2 receptor (exTek) inhibits tumor angiogenesis and the development of metastases in murine tumor models (Proc NatI Acad Sci USA.1998 Jut 21; 95 (15): 8829-34; Cancer immunological immunol Immunother.2004 Jul; 53 (7): 60O-8). In endothelial cells in culture, stimulation by Tie-2 activates the pathway of PI3 kinase and the p42/p44 pathway involved in cell proliferation and migration; the synthetic pathway of PAF involved in proinflammatory activity is also activated (Cell Signal, 2006 Apr 14; ahead of print). Tie2 stimulation stimulates the Akt pathway and inhibits apoptosis (Exp Cell Res.2004 Aug 1; 298 (1): 167-77), the transduction pathway being known for its importance in Cell survival.

Addition of Extek (soluble receptor of Tie 2) inhibited the formation of endothelial cell pseudotubules on matrigel (matrigel) (Cancer immunological Immunother.2004 Jul; 53 (7): 600-8). These studies indicate that the Tie-2/angiogenin system is essential in the first phase of vascular bud formation in adult tissues, and that a function of the Tie-2 receptor is to enhance endothelial cell survival during the process of vascular formation. Furthermore, angiopoietin-1 stimulates lymphatic endothelial cell proliferation and lymphangiogenesis (development of lymphatic new Blood vessels), a preferential pathway for the development of metastases (Blood, 2005 Jun 15; 105 (12): 4649-56).

Thus, the process of angiogenesis has a prominent role in the development of most solid tumors. Furthermore, it has been shown that the probability of metastasis occurring increases very greatly with the increase in vascularization of the initial tumor (Br J cancer.20O)₂ May 20；86(10)；1566-77)。

The potential role of pro-angiogenic drugs (proangiogenic agents) in leukemia and lymphoma has recently been further demonstrated. In fact, it has been generally reported that cell clones in these pathologies can be naturally destroyed or switched by the immune system into an angiogenic phenotype that promotes their survival and then proliferation. The phenotypic change is due to the overexpression of angiogenic factors, in particular macrophages, and/or to the mobilization of these factors from the extracellular matrix (Thomas DA, Giles FJ, cortex J, Albitar M, Kantarjan HM, Acta Haematol, (2001), vol 207.pp 106-190).

There is a link between "extramedullary disease" in CML (chronic myelogenous leukemia) and the process of angiogenesis in the bone marrow. Different studies have demonstrated that inhibition of angiogenesis may represent a treatment of choice in these pathologies (Leuk Res, 2006 Jan; 30 (1); 54-9; Histol histopathol.2004 Oct.; 19 (4): 1245-60). Furthermore, it is strongly suggested that activation of the Tie 2/angiogenin system is involved in the development of bone marrow angiogenesis in patients suffering from multiple myeloma (blood.20o)₃ Jul 15；1O₂(2)：638-45)。

Rheumatoid arthritis is a chronic disease of unknown etiology (RA). Although it affects multiple organs, the most severe form of RA is progressive synovial inflammation of the joints leading to destruction. Angiogenesis appears to considerably affect the development of this pathology. Thus, activation of Tie2 has been shown to modulate angiogenesis in synovial tissue, which promotes the development of rheumatoid Arthritis (Arthritis Rheum.2003 Sep; 48 (9): 2461-71).

It has also been shown that the overexpression of angiopoietin 1 and Tie2 in synovial tissue of patients suffering from osteoarthritis is associated with active neovascularization (Shahrara S et al, Arthritis Res, 20O)₂(ii) a 4(3)). Thus, it has been shown that by preventing the activation of Tie2 using an adenovirus that produces extEK (soluble Tie2 receptor), it is possible to inhibit angiogenesis and the development of arthropathy, and to protect bone degradation in a mouse model in which arthropathy is induced with collagen (Arthritis Rheum.2005 May; 52 (5): 1346-8).

IBD (inflammatory bowel disease) includes two forms of chronic inflammatory disease of the intestine: UC (ulcerative colitis) and Crohn's Disease (CD). IBD is characterized by immune dysfunction resulting from inappropriate production of inflammatory cytokines that cause the establishment of a local microvascular system. This angiogenesis, which originates from inflammation, leads to intestinal ischemia caused by vasoconstriction (InflammBowel Dis.2006 Jun; 12 (6): 515-23).

Ocular pathologies associated with neovascularization, such as age-related macular degeneration, are the leading cause of blindness in developed countries. Molecular signals that control neovascularization in the eye (e.g., VEGFs or angiogenin) are selected targets in these pathologies (Camphorhiaro PA. expert Opin Biol Ther.2004 Sep; 4 (9)). Thus, it has been shown that prevention of activation of Tie2 by using an adenovirus that produces extEK (soluble Tie2 receptor) inhibits retinal and choroidal neovascularization, the most common cause of vision loss (Hum Gene Ther.2001 Jul 1; 12 (10): 1311-21).

Defining:

the term "halogen" refers to an element selected from the group consisting of F, Cl, Br and I.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbyl substituent having 1 to 12 carbon atoms. Methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-dimethylbutyl, heptyl, 1-ethylpentyl, octyl, nonyl, decyl, undecyl and lauryl substituents are examples of alkyl substituents.

The term "alkenyl" refers to a straight or branched chain hydrocarbyl substituent having one or more unsaturations and having from 2 to 12 carbon atoms. Vinyl, 1-methylvinyl, prop-1-enyl, prop-2-enyl, Z-1-methylprop-1-enyl, E-1-methylprop-1-enyl, Z-1, 2-dimethylprop-1-enyl, e-1, 2-dimethylprop-1-enyl, but-1, 3-dienyl, 1-methyldienylprop-2-enyl, Z-2-methylbut-1, 3-dienyl, E-2-methylbut-1, 3-dienyl, 2-methyl-1-methyldienylprop-2-enyl, undec-1-enyl and undec-10-enyl substituents are examples of alkenyl substituents.

The term "alkynyl" refers to a straight or branched chain hydrocarbyl substituent having at least two unsaturations borne by a pair of adjacent carbon atoms, and having from 2 to 12 carbon atoms. Ethynyl, prop-1-ynyl, prop-2-ynyl and but-1-ynyl substituents are examples of alkynyl substituents.

The term "aryl" refers to a mono-or polycyclic aromatic substituent having 6 to 14 carbon atoms. Phenyl, naphthalen-1-yl, naphthalen-2-yl, anthracen-9-yl, 1, 2, 3, 4-tetrahydronaphthalen-5-yl and 1, 2, 3, 4-tetrahydronaphthalen-6-yl substituents 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, pyrrol-2-yl, pyrrol-3-yl, furyl, thienyl, imidazolyl, pyrrolyl,Azolyl, thiazolyl, isoAzolyl, isothiazolyl, 1, 2, 4-triazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1, 3, 5-triazinyl, indolyl, benzo [ b ]]Furyl, benzo [ b ]]Thienyl, indazolyl, benzimidazolyl, azaindolyl, quinolinyl (quinonyl), isoquinolinyl (isoquinonyl), carbazolyl, and acridinyl substituents are examples of heteroaryl substituents.

The term "heteroatom" herein refers to an atom that is at least divalent and is not carbon. N, O, S and Se are examples of heteroatoms.

The term "cycloalkyl" refers to a saturated or incompletely saturated cyclic hydrocarbyl substituent having from 3 to 12 carbon atoms. Cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo [2.2.1] heptyl; cyclooctyl, bicyclo [2.2.2] octyl; adamantyl and perhydronapthyl substituents are examples of cycloalkyl substituents.

The term "heterocyclyl" refers to a saturated or incompletely saturated cyclic hydrocarbyl substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms. Preferably, a saturated or incompletely saturated cyclic hydrocarbyl substituent will be monocyclic and contain 4 or 5 carbon atoms and 1-3 heteroatoms.

The term "substituted" refers to one or more substituents other than H, such as halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, OH, O-alkyl, alkyl-OH, O-alkenyl, O-aryl, O-heteroaryl, NH₂NH-alkyl, NH-aryl, NH-heteroaryl, N-alkyl', SH, S-alkyl, S-aryl, S (O)₂)H、S(O₂) Alkyl, S (O)₂) Aryl, SO₃H、SO₃Alkyl, SO₃-aryl radicalCHO, C (O) -alkyl, C (O) -aryl, C (O) OH, C (O) O-alkyl, C (O) O-aryl, OC (O) -alkyl, OC (O) -aryl, C (O) NH₂C (O) NH-alkyl, C (O) NH-aryl, NHCHO, NHC (O) -alkyl, NHC (O) -aryl, NH-cycloalkyl and NH-heterocyclyl.

A further subject of the invention is a process for the preparation of the product of formula (I).

The products of the invention can be prepared by conventional organic chemistry methods.

The following scheme 1 is illustrative of the process used to prepare examples 1 and 3. In this respect, it does not constitute a limitation of the scope of protection of the present invention, as regards the process for preparing the claimed compounds.

Scheme 1

The following scheme 2 is illustrative of an alternative process for preparing example 1. In this respect, it does not constitute a limitation of the scope of protection of the present invention, as regards the process for preparing the claimed compounds.

Flow chart 2

The following scheme 3 is illustrative of the process used to prepare examples 6-8, 20-21, 33-35 and 38-39. In this respect, it does not constitute a limitation of the scope of protection of the present invention, as regards the process for preparing the claimed compounds.

Flow chart 3

The following scheme 4 is illustrative of the method used to prepare examples 4, 9-19, 22-32, 36-37 and 44-62. In this respect, it does not constitute a limitation of the scope of protection of the present invention, as regards the process for preparing the claimed compounds.

Flow chart 4

The following scheme 5 is illustrative of the process used to prepare examples 5 and 40-43. In this respect, it does not constitute a limitation of the scope of protection of the present invention, as regards the process for preparing the claimed compounds.

Flow chart 5

It will be appreciated by those skilled in the art that for applying the above-described method of the invention, it may be necessary to introduce amino, carboxyl and alcohol functional protecting groups in order to avoid side reactions. These groups are those which can be eliminated without altering the rest of the molecule. As examples of amino-functional protecting groups, mention may be made of tert-butylcarbamate, which can be regenerated by trifluoroacetic acid or iodotrimethylsilane, and acetyl, which can be regenerated in an acidic medium (for example, hydrochloric acid). As carboxyl-functional protecting groups, mention may be made of esters (for example, methoxymethyl esters, benzyl esters). As alcohol-functional protecting groups, mention may be made of esters which can be regenerated in an acidic medium or by catalytic hydrogenation (for example, benzoyl esters). Other protecting Groups which may be used are described by T.W.GREENE et al, Protective Groups in Organic Synthesis, third edition, 1999, Wiley-lnterscience.

A further object of the invention is a product of the general formula (II),

wherein R'₄R4 or H, -COOH or-COO- (C)₁-C₆) Alkyl, R'₃Represents H, -NH₂or-NHCO-thienyl, R'₆Represents a halogen atom, -Ar-NH₂A group wherein Ar is as defined above, or an Ar-L-A group wherein Ar, L and A are as defined above, the product of the following general formula (III):

wherein R'₄R4 or H, -COOH or-COO- (C)₁-C₆) Alkyl, and R'₆Represents a halogen atom, -Ar-NH₂A group wherein Ar is as defined above, or an Ar-L-A group wherein Ar, L and A are as defined above. These products are used, inter alia, as synthesis intermediates in the preparation of the products of the general formula (I).

The compound of formula (I) is isolated and may be purified by generally known methods, for example by crystallization, chromatography or extraction.

Enantiomers and diastereomers of the compounds of formula (I) are also part of the invention.

The compounds of formula (I) containing a basic residue may optionally be converted into addition salts with inorganic or organic acids by the action of the above-mentioned acids in solvents, for example organic solvents such as alcohols, ketones or ethers or chlorinated solvents.

The compounds of formula (I) containing an acidic residue may optionally be converted into metal salts or addition salts with a nitrogen-containing base by methods known per se. These salts may be obtained by the action of a metal base (e.g. alkali metal or alkaline earth metal), ammonium, amine or amine salt on the compound of formula (I) in a solvent. The salts formed are isolated by customary methods.

These salts are also part of the present invention.

When the product of the invention has at least one free basic functional group, pharmaceutically acceptable salts can be prepared by reaction between the product and an inorganic or organic acid. Pharmaceutically acceptable salts include chloride, nitrate, sulfate, bisulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, acetate, propionate, acrylate, 4-hydroxybutyrate, caprylate, hexanoate, decanoate, oxalate, malonate, succinate, glutarate, adipate, pimelate, maleate, fumarate, citrate, tartrate, lactate, phenylacetate, mandelate, sebacate, suberate, benzoate, salicylate, dihydrogensulfate, pyrophosphate, acetate, propionate, acrylate, 4-hydroxybutyrate, caprylate, hexanoate, decanoate, oxalate, malonate, succinate, glutarate, adipate, pimelate, maleate, fumarate, citrate, tartrate, lactate, phenylacetate, mandelate, sebacate, suberate, benzoate, salicylate, and the like, Phthalates, methanesulfonates, p-toluenesulfonates, propanesulfonates, xylenesulfonates, salicylates, cinnamates, glutamates, aspartates, glucuronates and galacturonates.

When the product of the invention has at least one free acid functional group, a pharmaceutically acceptable salt is prepared by reaction between the product and an inorganic or organic base. Pharmaceutically acceptable bases include hydroxides of cations of alkali metals or alkaline earth metals, such as Li, Na, K, Mg or Ca, basic aminated compounds such as ammonium, arginine, histidine, piperidine, morpholine, piperazine or triethylamine.

The invention is further described by the following examples which serve to illustrate the invention.

LC/MS analysis was performed on an LCT Micromass type instrument connected to an HP 1100 apparatus. The abundance of the products was measured with the aid of an HP G1315A diode array detector (at 200-600nm wavelength) and a Sedex 65 light scattering detector. Mass spectra were obtained over the range of 180-800. Data were analyzed by using Micromass MassLynx software. The separation was performed on a Hypersil BDS C18, 3 μm (50X 4.6mm) column eluting in 3.5 minutes with a 5% -90% linear gradient at a flow rate of 1ml/min using acetonitrile containing 0.05% (v/v) trifluoroacetic acid (TFA) in water containing 0.05% (v/v) trifluoroacetic acid (TFA). The total analysis time, including column reequilibration time, was 7 minutes.

MS spectra were obtained in Electrospray (ES)⁺) Obtained on a Platform II (Micromass) instrument in the mode. The major ions observed are described.

Melting points were measured by capillary tubing on a Mettler FP62 apparatus at a temperature range of 30 ℃ to 300 ℃ with a 2 ℃ temperature rise per minute.

Purification by LC/MS:

the product can be purified by LC/MS by using a Waters FractionsLynx system consisting of a Waters600 type gradient pump, a Waters515 type regeneration pump, a Waters reagent management dilution pump, a Waters2700 type auto-injector, two Rheodyne type LabPro valves, a Waters996 type diode array detector, a Waters ZMD type mass spectrometer and a Gilson 204 type fraction collector. The system is controlled by WatersFractionLynx software. The separations were performed alternately on two Waters Symmetry columns (Cis, 5. mu.M, 19X 50mm, product catalog index 186000210), one during regeneration with 95/5(v/v) water/acetonitrile mixture containing 0.07% (v/v) trifluoroacetic acid, while the other was used for separation. The elution of the column was carried out by using acetonitrile in water containing 0.07% (v/v) trifluoroacetic acid in a linear gradient of 5% to 90% at a flow rate of 10ml/min, the acetonitrile containing 0.07% (v/v)) Trifluoroacetic acid. At the exit of the separation column, one thousandth of the effluent was separated by using an LC Packing Accurate apparatus, diluted with 0.5 ml/min of methanol and sent to the detector, as 75% to the diode array detector, and the remaining 25% to the mass spectrometer. The remaining effluent (999/1000) was sent to a fraction collector where it was discarded if the amount of desired product was not detected by the FractionLynx software. The molecular formula of the expected product was supplied to the FractionLynx software when the mass signal detected matched [ M + H ]]⁺Ions and/or [ M + Na]⁺Upon ionization, the software initiates collection of the product. In some cases, according to the results of analyzing LC/MS, when the coincidence [ M +2H ] is detected]⁺Of the ion, a value equal to half the calculated molecular weight (MW/2) is also provided to the FractionLynx software. In these cases, when [ M +2H ] is detected]⁺And/or [ M + Na + H]⁺The collection is also initiated. The product was collected in tared glass tubes. After collection, the solvent was evaporated in a Savant AES 2000 or Genevac HT8 centrifugal evaporator and the mass of the product was determined by weighing the tube after evaporation of the solvent.

Example 1

1- [4- (3-amino-1H-pyrazolo [3, 4-b ] pyrimidin-6-yl) phenyl ] -3- (2-fluoro-5-trifluoromethyl-phenyl) urea

100mg (0.44mmol) of 6- (4-aminophenyl) -1H-pyrazolo [3, 4-b ] pyrimidin-3-ylamine are partly dissolved in 2.5ml of anhydrous THF. The mixture was then degassed for 15 minutes using argon. 61.55. mu.l (44.93mg, 0.44mmol, 1 eq.) of triethylamine were then added. The solution was degassed for an additional 15 minutes. Finally, 64.22. mu.l (91mg, 0.44mmol, 1 eq.) of 2-fluoro-5- (trifluoromethyl) phenyl isocyanate were added dropwise. The mixture was stirred at room temperature for 2 hours under an inert blanket gas. After the reaction, the mixture was filtered. The filtrate was concentrated. The beige (beige) solid was isolated. The crude product was then purified on a C18 silica (13g) reverse phase column by elution with a gradient of acetonitrile in water from 5% to 95%. The fractions containing the desired product were lyophilized. A white solid (10mg) was isolated.

MS(ES)MH⁺m/z＝431。

¹H NMR (DMSO-d6) delta 5.52 (width s, 2H); 7.39(m, 1H); 7.49(m partially overlapped, 1H); 7.52(d, J ═ 8,5Hz, 1H); 7.62 (width d, J ═ 8.5Hz, 2H); 8.07 (width d, J ═ 8.5Hz, 2H); 8.13(d, J ═ 8.5Hz, 1H); 8.60 (width d, J ═ 7.5Hz, 1H); 9.21 (width m, 1H); 9.63 (width m, 1H); 11.9 (width m, 1H).

6- (4-aminophenyl) -1H-pyrazolo [3, 4-b ] pyrimidin-3-ylamine:

in a suitably sized microwave reactor, 0.97mmol (222mg) of 6- (4-amino-phenyl) -2-chloronicotinonitrile was suspended in 3.3ml of 1-propanol. 0.28ml (0.290g, 5.80mmol, 6 equivalents) of hydrazine hydrate was added. The suspension was heated at 130 ℃ for 45 minutes in a microwave oven. The mixture was filtered and the solid was dried to give a green solid (215mg).

MS(EI)M⁺m/z＝225，

¹H NMR(DMSO-d6)δ5.41(sl，4H)，6.63(d，J＝8Hz，2H)，7.37(d，J＝8Hz，1H)，7.82(d，J＝8Hz，2H)，8.02(d，J＝2Hz，1H)。

6- (4-aminophenyl) -2-chloronicotinonitrile:

2.89mmol (500mg) of 2, 6-dichloronicotinic acid nitrile and 3.18mmol (551mg, 1.1 equivalents) of 4-aminophenylboronic acid are dissolved in 33.3ml of bisAn alkane. 680mg (8.09mmol, 2.8 equiv.) of sodium bicarbonate was added followed by 8.3ml of water. The mixture was stirred under an inert atmosphere for 5 minutes, then 334mg (0.29mmol, 0.1 equiv.) of tetrakis (triphenylphosphine) palladium were added. The reaction mixture was refluxed (100 ℃ C.) for 2 hours and then cooled to room temperature. The reaction medium is filtered and then extracted four times with ethyl acetate. The organic phases were combined, washed twice with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Thus, a yellow solid was obtained. This crude product was purified on a 90g silica column with a gradient of 20% to 50% ethyl acetate in heptane. The desired product was obtained as a yellow solid (531 mg).

MS(ES)MH⁺m/z＝230。

¹H NMR(DMSO-d6)δ5.94(sl，2H)，6.65(d，j＝8hz，2H)，7.89(d，j＝8hz，2H)，7.93(d，j＝8hz，1H)，8.27(d，j＝8hz，1H)。

An alternative route for the preparation of 1- [4- (3-amino-1H-pyrazolo [3, 4-b ] pyrimidin-6-yl) phenyl ] -3- (2-fluoro-5-trifluoromethylphenyl) urea (scheme 2):

0.46mmol (200mg) of 1- [4- (6-chloro-5-cyanopyrimidin-2-yl) phenyl ] -3- (2-fluoro-5-trifluoromethylphenyl) urea was suspended in 3.2ml of 1-propanol. 0.13ml (0.14g, 2.76mmol, 6 equivalents) of hydrazine hydrate was added. The suspension was heated at 80 ℃ for 10 hours. The mixture was filtered and the solid was dried to give 140mg of the desired product.

1- [4- (6-chloro-5-cyanopyrimidin-2-yl) phenyl ] -3- (2-fluoro-5-trifluoromethylphenyl) urea:

0.578mmol (100mg) of 2, 6-dichloronicotinic acid nitrile and 0.64mmol (270mg, 1.1 equiv.) of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4, 4, 5, 5-tetramethyl [1, 3, 2]]Dioxoborolan-2-yl) phenyl]Urea was dissolved in 6.6ml of bis under an inert atmosphereIn an alkane. 136mg (1.62mmol, 2.8 equivalents) of sodium bicarbonate are added, followed by 1.6ml of water. The mixture was stirred under an inert atmosphere for 5 minutes, then 33.4mg (0.029mmol, 0.05 eq) of tetrakis (triphenylphosphine) palladium were added. The mixture was refluxed (100 ℃ C.) for 2 hours and then cooled to room temperature. The reaction medium is extracted twice with ethyl acetate. The combined organic phases were washed twice with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Thus, a yellow solid was obtained. The crude product was purified on a column of 30g silica with an elution gradient between 20% and 50% of ethyl acetate in heptane. Yellow solid (175mg) was obtained.

MS(ES)MH⁺m/z＝435。

¹H NMR(DMSO-d6)δ7.40(m，1H)，7.49(m，1H)，7.68(d，J＝8Hz，2H)，8.13(d，J＝8Hz，2H)，8.16(d，J＝8Hz，1H)，8.45(d，J＝8Hz，1H)，8.56(m，1H)。

1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4, 4, 5, 5-tetramethyl [1, 3, 2] dioxaborolan-2-yl) phenyl ] urea was prepared according to the following procedure:

at room temperature 936mg of 2-fluoro-5-trifluoromethylphenyl isocyanate followed by 0.64ml of triethylamine was added to 15ml of tetrahydrofuran containing 1g of 4- (4, 4, 5, 5-tetramethyl [1, 3, 2] dioxaborolan-2-yl) aniline. The reaction medium is stirred at room temperature for 18 hours, then treated with methanol and finally evaporated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on silica by using a dichloromethane/methanol mixture (first 99.5/0.5 and then 90/10) as eluent. The fractions containing the desired product were concentrated to dryness to give 1.45g of 1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (4, 4, 5, 5-tetramethyl [1, 3, 2] dioxaborolan-2-yl) phenyl ] urea as a white solid.

MS(ES)MH⁺m/z＝425。

Example 2

Thiophene-3-carboxylic acid (6- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrazolo [3, 4-b ] pyrimidin-3-yl) amide

A solution of 1- [4- (3-amino-1H-pyrazolo [3, 4-b ] pyrimidin-6-yl) phenyl ] -3- (2-fluoro-5-trifluoromethylphenyl) urea (80.0mg, 0.186mmol) in pyridine (2ml) was cooled to 5 ℃ under argon and thiophene-3-carboxylic acid chloride (27mg, 0.186mmol, 1.0 equiv) was added. The mixture was stirred at room temperature for 5.5 h. Another equal amount of thiophene-3-carboxylic acid chloride (27mg, 0.186mmol) was added and the mixture was stirred at room temperature overnight. The reaction was supplemented with water and extracted with ethyl acetate. The organic phase was washed twice with brine solution, dried over magnesium sulfate and concentrated. An orange-yellow solid was thus obtained. The crude product was purified on a silica column with an eluent gradient of 0% to 5% methanol in dichloromethane. 13.5mg of a beige solid was obtained.

MS(ES)MH⁺m/z＝541。

¹H NMR (DMSO-d6) delta 7.40(m, 1H); 7.50(m, 1H); 7.65 (width d, J ═ 9,0Hz, 2H); 7.68(dd partially overlapping, J ═ 3.0and 50Hz, 1H); 7.71-7.75(m, 2H); 8.15 (width d, J ═ 9.0Hz, 2H); 8.39(d, J ═ 8.5Hz, 1H); 8.50 (width d, J ═ 3.0Hz, 1H); 8.61(dd, J ═ 2.5 and 7.5Hz, 1H); 9.21 (width m, 1H); 9.67 (width m, 1H); 10.9 (width m, 1H); 13.3 (width m, 1H).

Example 3

N- [4- (3-amino-1H-pyrazolo [3, 4-b ] pyrimidin-6-yl) phenyl ] -2, 3-dichlorobenzenesulfonamide:

100mg (0.44mmol) of 6- (4-aminophenyl) -1H-pyrazolo [3, 4-b ] pyrimidin-3-ylamine are dissolved in 3ml of anhydrous DMF. The solution was then degassed with argon for 15 minutes. Mu.l (89.9mg, 0.89mmol, 2 equivalents) of triethylamine are subsequently added. The solution was degassed again for 15 minutes. Finally, 0.109g (0.444mmol, 1 eq) of 2, 3-dichlorophenylsulfonyl chloride was added. The solution was stirred at room temperature under argon overnight. After the reaction was completed, 10ml of water was added. A tan precipitate formed. The mixture was filtered. The solid was dried and purified on a column of 4g silica with a gradient of 0-10% methanol in dichloromethane. An off-white solid (11mg) was isolated.

MS(ES)MH⁺m/z＝434。

¹H NMR (DMSO-d6, 373K) delta 5.09 (width s, 2H); 7.09 (width d, J ═ 8,5Hz, 2H); 7.37(d, J ═ 8,5Hz, 1H); 7.40 (width t, J ═ 8.5Hz, 1H); 7.69 (width d, J ═ 8.5Hz, 1H); 7.85 (width d, J ═ 8.5Hz, 2H); 8.02 (width d, J ═ 8.5Hz, 1H); 8.06(d, J ═ 8,5Hz, 1H); 11.5 (width m, 1H).

Example 4

The trifluoroacetate salt of 6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide:

the product of example 4 can be prepared by the method described in scheme 4:

synthesis of intermediate 1:

2-fluoro- (5-trifluoromethyl) phenyl isocyanate (4g, 19.5mmol) was added to a solution of 2-amino-thiazole-5-carbaldehyde (2.5g, 19.5mmol) in DMF (120 ml). The solution was heated at 70 ℃ for 1 hour, evaporated and purified by chromatography on a silica gel column with 1: 1 hexane/EtOAc eluent. The fractions containing intermediate 1 were combined and evaporated to give intermediate 1(4.28g) as a yellow solid.

Synthesis of intermediate 2:

to a solution of intermediate 1(88mg, 0.26mmol) in a 9: 1 mixture of ethanol/DMSO (2ml) was added a solution of 1H-pyrazol-3-ylamine (22mg, 0.26mmol) in 2ml of the same solvent mixture containing pyruvic acid (23mg, 0.26 mmol). The mixture was heated at 75 ℃ for 24 hours in the presence of oxygen, and then the reaction medium was evaporated to dryness to give intermediate 2 as an orange solid, which was used in the following step.

Preparation of the product of example 4:

intermediate 2 was dissolved in anhydrous THF (2ml) and first HOBt (36mg, 0.26mmol) was added followed by DIC (42. mu.l, 0.26 mmol). After 5 min, 2-morpholin-4-yl-ethylamine (39 μ l, 0.3mmol) was added. Stirring was continued at room temperature for 5 hours, after which the reaction medium was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column eluting with 94: 5: 1 EtOAc/MeOH/TEA and a gradient of 90: 9: 1 EtOAc/MeOH/TEA. The product containing fractions were combined and evaporated and then purified by LC/MS chromatography (reverse phase, eluent water + 0.1% TFA, gradient 25% -85% acetonitrile over 8 min). The fractions containing the desired product were combined and evaporated under reduced pressure to give the product as a yellow solid (10.6 mg).

Example 5

N- (4- (3-amino-4-methylaminocarbonyl-1H-pyrazolo [3, 4-b ] pyridin-6-yl) phenyl) -2, 3-dichlorobenzenesulfonamide:

the product of example 5 can be prepared by the method described in scheme 5 above:

synthesis of intermediate 1:

219mg of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline and 245mg (1mmol) of 2, 3-dichlorobenzenesulfonyl chloride are dissolved in 2ml of DCM and 120. mu.l (1.5. mu. mol) of pyridine. The mixture was stirred at room temperature for 6 hours, then dried in vacuo to give the desired product as a pale red solid.

MS(ES)MH⁺m/z＝428

Synthesis of intermediate 2:

84g of diethyl oxaloacetate sodium salt and 33.2g of 2-aminopyrazole are dissolved in 600ml of AcOH/H₂O (1: 3). The mixture was heated at 80 ℃ for 6 hours. The product precipitated after cooling, was filtered and dried in vacuo (17.9 g).

¹H NMR(600M Hz，DMSO-d6)δppm；13.74(s，1H)，12.39(s，1H)；8.22(s，1H)，6.70(s，1H)，4.40(q，J＝7.1Hz)2H)，1.40(t，J＝7.1Hz)3H)。

Synthesis of intermediate 3:

2.07g (10mmol) of intermediate 2, 20ml of toluene and 2.87g (10mmol) of POBr₃Heat to 110 ℃ in an oil bath while stirring. The mixture was evaporated and purified on a silica column, eluting with 20% EtOAc and 80% hexanes, to give (after evaporation) 300mg of the desired product.

¹H NMR(600MHz，DMSO-d6)δppm：14.45(s，1H)，8.41(s，1H)，7.79(s，1H)，4.49(q，J＝7.1Hz)2H)，1.46(t，J＝7.1Hz)3H)。

Synthesis of intermediate 4:

mu. mol of intermediate 3(20mg), 74. mu. mol of intermediate 1, 185. mu. mol of cesium carbonate and 7.4. mu. mol of Pd (PPh)₃) Dissolved in THF and 20% H₂O (total volume 750. mu.l). The mixture was subjected to microwave heating (power 55W) at 155 ℃ for 25 minutes. The product was evaporated and purified by LC/MS chromatography with a gradient of water containing 0.1% trifluoroacetic acid and 25% -95% acetonitrile over 9 minutes. The product was dried under vacuum.

MS(ES)MH⁺m/z＝463。

Preparation of the product of example 5

Intermediate 4(20mg, 43.3. mu. mol) and HOBt (14,6mg, 108.25. mu. mol) and DIC (16.9. mu. 108.25. mu. mol) were dissolved in DMF (0.5 ml). 0.5mmol of methylamine (1M in THF, 0.5ml) was added. The mixture was subjected to microwave heating (power 25W) at 105 ℃ for 20 minutes. The product was evaporated and purified by LC/MS chromatography with a gradient of water containing 0.1% trifluoroacetic acid and 25% -95% acetonitrile over 9 minutes. The product was dried in vacuo to give a pale yellow solid.

MS(ES)MH⁺m/z＝476。

¹H NMR(600MHz，DMSO-d6)δppm：13,79(s，1H)，11.13(s，1H)，8.35(s，1H)，8.02(s，1H)，8.13(d，J＝7.8Hz)2H)8.09(d，J＝8.27Hz)1H)，7.94(d，J＝8.05Hz)1H)，7.28(d，J＝4,31Hz)2H)，2.88(d，J＝4.31Hz)3H)，7.58(q，J＝8,08Hz)1H)，8.86(t，J＝4,43Hz)1H).

Examples 6 to 62:

by carrying out the above procedure, the products of Table 1 below were obtained

Determination of the Activity of Compounds-protocol

1.FAX

The inhibitory activity of a compound against FAK was determined by measuring the inhibition of enzyme autophosphorylation using time-resolved fluorimetry (HTRF).

The complete cDNA of human FAK, whose N-terminus has been tagged with histidine, was cloned into baculovirus-expressed, thallus pFastBac HTc. The protein was expressed and purified to about 70% homology (homology).

Kinase activity was measured by using Hepes buffer (10mM MgCl) at pH 7.2₂、100μM Na₃VO₄And 15 μ M ATP) was incubated at 37 ℃ for 1 hour for the enzyme (6.6 μ g/ml). The enzyme reaction was stopped by adding Hepes buffer containing 0.4mM KF, 133 mwetta and 0.1% BSA at pH 7.0, and labeling was performed at room temperature for 1-2 hours by adding anti-histidine antibody labeled with XL665 and phosphate-specific monoclonal antibody binding to europium cryptate (Eu-K) of tyrosine to this buffer. The characteristics of both fluorophores are available in G.Mathis et al Anticancer Research, 1997, 17, 3011-3014. The energy transfer from the excited europium cryptate to the receptor XL665 is proportional to the degree of autophosphorylation of FAK. XL-665-specific long lasting signals were measured in a Packard Discovery plate counter. All tests were performed in duplicate and the average of the two tests was calculated. The inhibition of the autophosphorylation activity of FAK using the compounds of the invention is expressed as a percentage inhibition relative to a control test, the activity of which is measured in the absence of test compound. To calculate the percentage of inhibition, the ratio [ signal at 665 nm/signal at 620nm ] is considered]

2.KDR

The inhibitory effect of the compounds was determined by measuring substrate phosphorylation by the KDR enzyme in vitro using scintillation technology (96-well plate, NEN).

The cytoplasmic domain of the human KDR enzyme was cloned as a GST fusion into the baculovirus expressed, thallus pFastBac. The protein was expressed in SF21 cells and purified to about 60% homology.

KDThe kinase activity of R is in the presence of 10mM MgCl₂、100μM Na₃VO₄And 1mM NaF, 20mM MOPS, 10mM MgCl at pH 7.2₂、10mM MnCl₂1mM DTT, 2.5mM EGTA and 10mM glycerol b-phosphate. Mu.l of compound was added to 70. mu.l of kinase buffer containing 100ng of KDR enzyme at 4 ℃. By adding 20. mu.l of a substrate containing 2. mu.g (SH 2-SH3 fragment of PLC. gamma. expressed as a GST fusion protein), 2. mu. Ci. gamma³³P[ATP]And a solution of 2. mu.M cold ATP started the reaction. After incubation for 1 hour at 37 ℃ the reaction was stopped by adding 1 volume (100. mu.l) of 200mM EDTA. The incubation buffer was removed and the wells were washed three times with 300 μ l PBS. Radioactivity was measured in each well using a TopCount NXT radioactivity counter (Packard).

Background noise was determined by measuring radioactivity in four different wells containing radioactive ATP and individual substrates.

Total Activity control contained all reactants (. gamma.)³³P-IATP]KDR and PLC γ substrates) but no compound in four different wells.

Inhibition of KDR activity using the compounds of the invention is expressed as a percentage of inhibition of control activity measured in the absence of the compound. Compound SU5614(Calbiochem) (1 μ M) was included in each plate as an inhibition control.

3.Tie2

The human Tie2 coding sequence corresponding to the intracellular domain amino acids 776-1124 was generated by PCR using cDNA isolated from the human placenta as a model. This sequence was introduced into baculovirus expressed, thallus pFastBacGT, in the form of a GST fusion protein.

The inhibitory effect of the molecule was determined by Tie2 in the assay of phosphorylation of PLC in the presence of GST-Tie2 purified to about 80% homology. The substrate was composed of SH2-SH3 fragment of PLC, which was expressed as GST fusion protein.

The kinase activity of Tie2 was in the presence of 10mM MgCl₂、10mM MnCl₂1mM DTT and 10mM glycerol phosphate in MOPS buffer at 20mM pH 7.2. A96-well scintillation plate placed on ice was plated and each well was placed with a reaction mixture consisting of 70. mu.l of kinase buffer containing 100ng of GST-Tie2 enzyme. Subsequently 10 μ l of test molecule diluted in DMSO to a concentration of up to 10% was added. For a single given concentration, each measurement was performed in quadruplicate. By adding 20. mu.l of a mixture containing 2. mu.g of GST-PLC, 2. mu.M of cold ATP and 1. mu. Ci of gamma³³P[ATP]The reaction is initiated by the solution of (a). After incubation for 1 hour at 37 ℃ the reaction was stopped by adding 1 volume (100. mu.l) of 200mM EDTA. After removing the incubation buffer, wells were washed three times with 300 μ l PBS. Radioactivity was measured on a Wallac MicroBeta 1450.

Inhibition of Tie2 activity was calculated and expressed as a percentage of inhibition relative to control activity determined in the absence of compound.

[0239]

Claims (8)

1. A product of the following general formula (I):

formula (I)

Wherein:

1) ar is selected from: thiazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and imidazolyl, or

Ar-L-A is:

wherein each of X1, X2, X3, and X4 is independently selected from N and C-R '5, wherein R' 5 has the same definition as R5,

2) a is selected from phenyl, optionally substituted, wherein A is substituted with a first substituent selected from F, Cl, Br, I, alkyl, O-alkyl, S-aryl, each optionally substituted with one or more (C)₁-C₃) Alkyl, halogen and O- (C)₁-C₃) (ii) substituent substitution of alkyl groups, wherein the alkyl groups present in the group selected for the first substituent are straight or branched chain saturated hydrocarbyl substituents having from 1 to 12 carbon atoms, and wherein a is substituted with a second substituent selected from F, Cl, Br, I, OH, CN;

3) l is selected from: NH-SO₂、NH-CO-NH；

4) X is N;

5) r3 is H;

6) r4 is CON (R '5) (R' 6), wherein R '5 and R' 6 are independently selected from H, (C)₁-C₆) Alkyl, substituted (C)₁-C₆) Alkyl, - (C)₁-C₆) Alkyl heterocyclic group, substituted- (C)₁-C₆) Alkyl heterocyclic radical, - (C)₁-C₆) (ii) alkylheteroaryl, wherein the heterocyclyl is a saturated or incompletely saturated cyclic hydrocarbyl substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms, the heteroaryl is a monocyclic or polycyclic heteroaromatic substituent having 1 to 13 carbon atoms and 1 to 4 heteroatoms, or R "5 and R" 6 are linked to each other to form a saturated ring having 4 to 8 ring members containing 1 to 3 heteroatoms selected from O, S and N, optionally substituted;

7) r5 is a hydrogen atom in the formula,

wherein the substituents in R4 are one or more substituents other than H, selected from alkyl, OH, O-alkyl, NH₂And NH-alkyl, wherein the alkyl is a straight or branched chain saturated hydrocarbyl substituent having 1 to 12 carbon atoms; and

wherein the aryl group is a monocyclic-or polycyclic aromatic substituent having 6 to 14 carbon atoms.

2. The product of claim 1, characterized in that a is selected from: a phenyl group; optionally substituted by halogen, (C)₁-C₄) Alkyl, halogenated (C)₁-C₃) Alkyl, O- (C)₁-C₄) Alkyl, S- (C)₁-C₄) Alkyl, halogenated O- (C)₁-C₄) Alkyl and halogenated S- (C)₁-C₄) Alkyl substitution.

3. Product according to any one of claims 1-2, characterized in that it is selected from:

6- {2- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide trifluoroacetate;

6- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] phenyl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid amide;

6- {4- [3- (2-fluoro-5-trifluoromethyl-phenyl) ureido ] phenyl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid methylamide;

6- {4- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- [2- (3-phenyl-ureido) thiazol-5-yl ] -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid methylamide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-dimethylaminoethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (3-dimethylamino-2, 2-dimethylpropyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid [2- (3H-imidazol-4-yl) ethyl ] amide;

1- (2-fluoro-5-trifluoromethylphenyl) -3- {5- [4- (morpholine-4-carbonyl) -1H-pyrazolo [3, 4-b ] pyridin-6-yl ] thiazol-2-yl } urea;

1- (2-fluoro-5-trifluoromethylphenyl) -3- {5- [4- (piperazine-1-carbonyl) -1H-pyrazolo [3, 4-b ] pyridin-6-yl ] -thiazol-2-yl } urea;

1- (2-fluoro-5-trifluoromethylphenyl) -3- {5- [4- (4-methylpiperazine-1-carbonyl) -1H-pyrazolo [3, 4-b ] pyridin-6-yl ] -thiazol-2-yl } urea;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2, 3-dihydroxypropyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2H-pyrazol-3-yl) amide;

6- {6- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] pyridin-3-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid methylamide;

6- {6- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] pyridin-3-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (3-morpholin-4-yl-propyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-piperazin-1-yl-ethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-piperidin-4-yl-ethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid [3- (4-methylpiperazin-1-yl) propyl ] amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-hydroxyethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-methoxyethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (pyridin-4-ylmethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (pyridin-2-ylmethyl) amide;

1- (2-fluoro-5-trifluoromethylphenyl) -3- {5- (4- (2-hydroxymethylpyrrolidine-1-carbonyl) -1H-pyrazolo [3, 4-b ] pyrimidin-6-yl ] thiazol-2-yl } urea;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid [3- (2-hydroxymethylpyrrolidin-1-yl) propyl ] amide;

1- (2-fluoro-5-trifluoromethylphenyl) -3- {5- [4- (2-hydroxymethylpiperazine-1-carbonyl) -1H-pyrazolo [3, 4-b ] pyridin-6-yl ] thiazol-2-yl } urea;

6- {3- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid methylamide;

6- {3- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] phenyl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {5- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] isoxazol-3-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-ylethyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (pyridin-3-yl-methyl) amide;

6- {2- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid [2- (4-methylpiperazin-1-yl) ethyl ] amide;

6- {5- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] [1, 3, 4] thiadiazol-2-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-ylethyl) amide;

6- {5- [3- (2-fluoro-5-trifluoromethylphenyl) ureido ] thiophen-2-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-ylethyl) amide;

6- {2- [3- (3-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (3-trifluoromethylsulfanylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (3-fluoro-5-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (4-fluoro-3-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2-chlorophenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (3-chlorophenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2-fluoro-3-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (3-chloro-4-fluoro-phenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2-methoxyphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2, 5-difluorophenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2, 4-difluorophenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (4-trifluoromethylphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (2-fluorophenyl) ureido ] thiazol-5-yl } -1H-pyrazolo (3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (3, 4-dichlorophenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (4-trifluoromethoxyphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (3-methoxyphenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide;

6- {2- [3- (4-chlorophenyl) ureido ] thiazol-5-yl } -1H-pyrazolo [3, 4-b ] pyridine-4-carboxylic acid (2-morpholin-4-yl-ethyl) amide.

4. Product, characterized in that it is selected from:

n- [4- (4- (2-morpholin-4-yl-ethyl) aminocarbonyl-1H-pyrazolo [3, 4-b ] pyridin-6-yl) phenyl ] -3-chlorobenzenesulfonamide;

n- [4- (4- (piperazine-1-carbonyl) -1H-pyrazolo [3, 4-b ] pyridin-6-yl) phenyl ] -2, 3-dichlorobenzenesulfonamide;

n- [4- (4-methylaminocarbonyl-1H-pyrazolo [3, 4-b ] pyridin-6-yl) phenyl ] -2-chloro-4-trifluoromethylbenzenesulfonamide;

n- [4- (4-methylaminocarbonyl-1H-pyrazolo [3, 4-b ] pyridin-6-yl) phenyl ] -4-fluorobenzenesulfonamide.

5. Pharmaceutical, characterized in that it comprises a product according to any one of claims 1 to 4, or an addition salt of this compound with a pharmaceutically acceptable acid.

6. A pharmaceutical composition comprising the product of any one of claims 1-4 in combination with a pharmaceutically acceptable excipient.

7. Use of a product according to any one of claims 1 to 4 in the manufacture of a medicament for inhibiting a reaction catalysed by one or more kinases, wherein the kinase is selected from FAK, KDR and Tie 2.

8. Use of a product according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of a pathological condition selected from rheumatoid arthritis, osteoarthritis and/or pain associated therewith, inflammatory diseases of the bowel, ocular pathologies, diabetic retinopathy, chronic inflammation, psoriasis and cancer.