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(11) Patent Number:  KE 467   
                   
(45) Date of grant: 08/09/2011   
               
(51) Int.Cl.8:    A 61K 31/437, A 61P 35/00, C 07D 213/85,       

(73) Owner:Aventis Phanna S.A. of 20 A VENUE RAYMOND-ARON F-92160 ANTONY, France       
       
(21)    Application Number:KElP/ 2008/ 000700

(72) Inventor:RONAN, Baptiste 15 Allee Des Noisetiers, F-92140 Clamart.France.    TABART, Michel  3 Rue Paul Langevin, F-91290 La   

(22) Filing Date:Norville.France. VIVIANI, Fabrice  46 Rue Jules Fossier, F-95380 01!08/2006 Louvres.France. BACQUE, Eric 123 Allee de La Clairiere, F-91190     Gif Sur Yvette.France; NAIR, Ani! 12936 North Salt Cedar Drive,    Oro Valley, Arizona 85737.U.S.A. BJERGARDE, Kristen  1!232 North Flat Granite Drive, Oro Valley, Arizona 85737.U.S.A. PATEK, Marcel  6965 N. Leonardo Da Vinci Way, Tucson, Arizona 85704.U.S.A. DODSON, Mark, 1500 East Push Wilderness Drive,   

(30) Priority data:0508316  04/08/2005    FR   
   
(74) Agent/address for correspondence:    Kaplan & Stratton Advocates,  P.O. Box 40111-00100, Nairobi                       

(54)    Title: ?-SUBSTITUTED AZA-INDAZOLES, COMPOSITIONS CONTAINING SAME, PRODUCTION METHOD AND USE THEREOF

(57) Abstract:invention relates to specific novel 7-aza-indazoles having formula (!), which modulate the activity of proteins, particularly kinases, compositions containing same and the use thereof as a medicamnt in particular as anticancer agents.

?-SUBSTITUTED AZA-INDAZOLES. COMPOSITIONS CONTAINING SAME.

PRODUCTION METHOD AND USE THEREOF

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

More particularly, the invention relates to novel specific 7-azaindazoles which exhibit an anticancer activity, via the modulation of the activity of proteins, in particular of kinases.

To  date,  most  of  the  commercial  compounds  used  in  chemotherapy  pose

10    considerable problems of side effects and of tolerance by the patients. These effects could be limited in so far as the medicaments used act selectively on cancer cells, and not on normal cells. One of the solutions for limiting the adverse effects of
chemotherapy  can  therefore  consist  of the  use  of  medicaments  which  act  on

metabolic  pathways  or  elements  which  constitute  these  pathways,  expressed

15    predominantly in cancer cells, and which will be expressed little or not at all in normal cells.

Protein kinases are a family of enzymes which catalyse the phosphorylation of hydroxyl groups of specific residues of proteins, such as tyrosine, serine or threonine residues. Such phosphorylations can greatly modify the function of proteins; thus,
20    protein kinases play an important role in the regulation of a large variety of cell processes, including in particular metabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among the various cellular functions in which the activity of a protein kinase is involved, certain processes represent attractive targets for treating cancerous diseases and other diseases.

25    Thus, one of the objects of the invention is to provide compositions which have an anticancer activity, by acting in particular with respect to kinases. Among the kinases for which a modulation of activity is desired, FAK, KDR and Tie2 are preferred.

These products correspond to formula (I) below:
 
formula (I)

in which:

1)    A  and  Ar  are  independently  selected  from  the  group  consisting  of:  aryl,

5    heteroaryl, heterocyclyl, substituted aryl, substituted heteroaryl, substituted heterocyclyl, cycloalkyl and substituted cycloalkyl;

2)    Lis selected from the group consisting of: NH, NH-S02, S02NH, 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-C0-0, 0-CO-NH, CH2-NH-CO-NH, NH-CO-NH-CH2

10    and NH-CO-CH2-CO-NH;

3)    XisNorNO;

4)    R3  is  selected from the  group consisting  of H and NHMR"3,  in which  M is

selected from the group consisting of: a bond, CO, CO-NH, CS, CS-NH and S02; and in which R"3 is selected from the group consisting of H, alkyl, alkylene,

15    alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, substituted alkyl, substituted alkylene, substituted alkynyl, substituted aryl, substituted heteroaryl, substituted cycloalkyl and substituted heterocyclyl;

5)    R4 is selected from the group consisting of: H, halogen, alkyl, substituted alkyl, OR"4, N(R"5)(R"6), CON(R"5)(R"6), in which R"4 is chosen from H, phenyl,

20    substituted phenyl, alkyl, substituted alkyl, and in which R"5 and R"6 are independently selected from the group consisting of H, (C1-C6)alkyl, substituted (C1-C6)alkyl, -(C1-C6)alkylheterocyclyl, substituted -(C1-C6)alkylheterocyclyl, -(C1-C6)alkylheteroaryl, substituted -(C1-C6)alkylheteroaryl, cycloalkyl, substituted

cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl,

25    substituted heteroaryl, or else R"5 and R"6 are linked to one another so as to form a saturated ring having from 4 to 8 ring members containing from 1 to 3 hetero atoms chosen from 0, Sand N, optionally substituted;
 
6)    RS is selected from  the group consisting  of:  H,  halogen,  R'2, CN,  O(R'2),
OC(O)(R'2), OC(O)N(R'2)(R'3), OS(02)(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(02)(R'3),  C(O)(R'2),    C(O)O(R'2),

5    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(02)(R'2), S(02)0(R'2), S(02 )N(R'2)(R'3);in which each R'2, R'3,R'4 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,

10    substituted heterocyclyl; and R'2and R'3can be linked to one another so as to

form a ring containing from 1 to 3 hetero atoms chosen from 0, S and N; provided that, when X is N, R3 is NH2, Ar and A are unsubstituted phenyl, L is

NHCO linked in the para-position with respect to Ar, and RS is H, then R4 is not chosen  from:  phenyl,  o-chlorophenyl,  cinnamyl,  a-furfuryl,  o-hydroxyphenyl, 15       p-hydroxy-m-methoxyphenyl,       p-methylthiophenyl,       p-methoxyphenyl, o-nitrophenyl, m-phenoxyphenyl~rovided that, when X is N, RS is H, R4 is

-)=I 't>

    H, and Ar-L-A is a group    , then R3 is not chosen from: amino,
    acetylamino,    [(4-fluorophenyl)carbonyl]amino,    (2-methylpropanoyl)amino,
    -( cyclopentylcarbonyl)amino,  propanoylamino,  [( 4-methylphenyl)carbonyl]amino,
20    {[4-(methyloxy)phenyl]carbonyl}amino,        (2-thienylcarbonyl)amino,
    (methylsulphonyl)amino,    -[(4-fluorophenyl)sulphonyl]amino,
    (ethylsulphonyl)amino, (propylsulphonyl)amino, (3-thienylsulphonyl)amino, [(3,5-
    dimethyl-4-isoxazolyl)sulphonyl]amino,    (2-thienylsulphonyl)amino    and    (1-
    methylethyl)amino.               

25

Products of formula (I) that are preferred correspond to the following definition:


RSx:c:R3
    I .&    '\N   
L        I   
A""  'Ar    X    ~   

formula (I)

in which:

1)    A and Ar are independently selected from the group consisting of: aryl, heteroaryl, heterocyclyl, cycloalkyl, substituted aryl, substituted heteroaryl,
5    substituted heterocyclyl and substituted cycloalkyl;

2)    Lis selected from the group consisting of: NH, NH-802, S02NH, NH-CH2, CH2-NH, CH2-CO-NH, NH-CO-CH2, NH-CH2-CO, CO-CH2-NH, NH-CO-NH, NH-CS-NH, NH-C0-0, 0-CO-NH, CH2-NH-CO-NH, NH-CO-NH-CH2 and NH-CO-CH2-CO-NH;

10    3)  X is N;

4)    R3 is selected from H , NH2 and NHCOR"3 and R"3 is 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 and substituted heterocyclyl;

15    5)  R4 is selected from the group consisting of: H, halogen, alkyl, substituted alkyl,

CON(R"5)(R"6) in which R"5 and R"6 are independently selected from the group consisting of H, (C1-C6)alkyl, substituted (C1-C6)alkyl, -(C1-C6)alkylheterocyclyl,
substituted  -(C1-C6)alkylheterocyclyl,  -(C1-C6)alkyheteroaryl,  substituted  -(C1-

C6)alkylheteroaryl,  cycloalkyl,  substituted  cycloalkyl,  heterocyclyl,  substituted

20    heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or else R"5 and R"6 are linked to one another so as to form a saturated ring having from 4 to 8 ring members containing from 1 to 3 hetero atoms chosen from 0, S and N, optionally substituted;

6)  R5 is H.

25    In the products of formula (1), Ar is chosen from a thiazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzothiazolyl; optionally substituted, or else Ar is a thiazolyl, or else Ar-L-A is:

in which X1, X2. X3 and X4 is independently chosen from N and C-R'5,in which R'5 has the same definition as R5.

L-A substituents which are preferred are advantageously chosen from NH-CO-NH-A

5    and NH-S02-A. A particularly effective L-A combination is• obtained when L-A is NHCONH-A.

Products in accordance with the invention preferably have an A substituent which is

selected from the group consisting of phenyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl,

oxazolyl,  thiazolyl,  isoxazolyl,  isothiazolyl,  pyrazolyl,  imidazolyl,  indolyl,  indazolyl,

10    benzimidazolyl, benzoxazolyl and benzothiazolyl; optionally substituted.

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

The A substituent is very advantageously substituted with a first substituent selected

from  the  group  consisting  of  halogen,  alkyl,  alkylene,  alkynyl,  aryl,  heteroaryl,

15    0-alkyl, 0-aryl, 0-heteroaryl, S-alkyl, S-aryl, S-heteroaryl, each being optionally substituted with one or more substituents chosen from (C1-C3)alkyl, halogen and O-(C1-C3)alkyl.

The A substituent is preferably substituted with a second substituent chosen from the

group consisting of F, Cl, Br, I, OH, SH, S03M, COOM, CN, N02,  CON(RB)(R9),
20    N(RB)CO(R9),  (C1-C3)alkyi-OH,  (C1-C3)alkyi-N(RB)(R9),  (C1-~)alkyi-(R1 0),  (C1-

C3)alkyi-COOH, N(RB)(R9); in which RB and R9 are independently chosen from H, (C1-C3)alkyl, halogenated (C1-C3)alkyl, (C1-C3)alkyiOH, (C1-C3)alkyi-O(C1-C3)alkyl, (C1-~)alkyiNH2, (C1-C3)alkyiN(RB)(R9), (C1-C3)alkyiCOOM, (C1-C3)alkyiS03M; in

which, when RB and R9 are simultaneously different from H, they can be linked so

25    as to form a ring having from 5 to 7 ring members containing from 1 to 3 hetero atoms; in which M is H or a cation of an alkali metal chosen from Li, Na and K; and in which R10 isH or an optionally substituted, non-aromatic heterocycle containing 2 to 7 carbon atoms and 1 to 3 hetero atoms chosen from N, 0 and S.

A substituents which are particularly preferred are chosen from phenyl, pyrazolyl and isoxazolyl; it being possible for said A substituents to be substituted with halogen, (C1-C4)alkyl, halogenated (C1-C3)alkyl, O-(C1-C4)alkyl, S-(C1-C4)alkyl, halogenated O-(C1-C4 )alkyl, and halogenated S-(C1-C4)alkyl. When A is disubstituted, the two

5    substituents of A can form a ring having from 5 to 7 ring members containing from 0 to 3 hetero atoms chosen from 0, Nand S.

An R4 substituent is advantageously selected from the group consisting of H and CON(R"5)(R"6), with R"S and R"6 as defined above.

10

    A product in accordance with the invention may be in:
    a)  non-chiral form, or
    b)    racemic form, or
    c)    a form enriched in a stereoisomer, or
15    d)    a form enriched in an enantiomer;

and may be optionally salified.

A product in accordance with the invention may be used for the manufacture of a medicament for use in the treatment of a pathological condition, in particular a

20    cancer. A subject of the present invention is a medicament, characterized in that it comprises a product of formula (I) or an addition salt of this compound with a pharmaceutically acceptable acid, or else a hydrate or a solvate of the product of formula (1).

The present invention also relates to the therapeutic compositions  comprising  a

25    product according to the invention, in combination with a pharmaceutically acceptable excipient according to the method of administration selected. The pharmaceutical composition can be in solid or liquid form or in the form of liposomes.

Among the solid compositions, mention may be made of powders, gelatin capsules

and tablets. Among the oral forms, solid forms protected against the acidic medium

30    of the stomach can also be included. The carriers used for the solid forms consist in particular of mineral carriers such as phosphates or carbonates, or of organic carriers such as lactose, celluloses, starch or polymers. The liquid forms consist of
 

solutions, of suspensions or of dispersions. As dispersive carrier they contain either water or an organic solvent (ethanol, NMP, or the like), or mixtures of surfactants
35    and solvents or of complexing agents and solvents.

The liquid forms will preferably be injectable and, as a result, will have a formulation that is acceptable for such a use.

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

The administered dose of the compounds of the invention will be adjusted by the practitioner according to the route of administration for the patient and the condition of the latter.

By virtue of their low toxicity and their pharmacological and biological properties, the

10    compounds of the present invention find their application in the treatment of any carcinoma having a considerable degree of vascularization or inducing metastases, or, finally, in pathologies of lymphoma and leukaemia type.

These compounds represent a therapy of choice, either alone or in combination with

15    suitable chemotherapy or radiotherapy, and/or in combination with other compounds having anti-angiogenic activities, such as VEGF inhibitors or FGF inhibitors. Thus, the products of general formula (I) are in particular of use for the treatment or prevention of a pathological condition characterized in that the product is
administered  alone or in  combination with  other active ingredients,  in  particular

20    anticancer agents such as cytotoxic, cytostatic, anti-angiogenic or anti-metastatic products.

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

25    • alkylating agents, and in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulphan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocin, decarbazine, temozolomide, procarbazine and hexamethylmelamine;

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

30    •   antibiotics, such as in particular bleomycin, mitomycin or dactinomycin;
 
•    antimicrotubule agents, such as in particular vinblastine, vincristine, vindesine, vinorelbine, taxoides (paclitaxel and docetaxel);

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

5    • group I and II topoisomerase inhibitors, such as etoposide, teniposide, amsacrine, irinotecan, topotecan and tomudex;

•    fluoropyrimidines such as 5-fluorouracil, UFT or floxuridine;

•    cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine or 6-thioguanine;

10    • adenosine analogues 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,  and  also

15    oestrogenic and androgenic hormones;

•    antivascular agents, such as combretastatin derivatives, for example CA4P, chalcones or colchicine, for example ZD6126, and their prodrugs;

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

• therapeutic agents which inhibit other tyrosine kinases, such as imatinib, 20 gefitinib and erlotinib.

When the compounds of the present invention are combined with another treatment or with a radiation treatment, these treatments can then be administered simultaneously, separately or sequentially. The treatment will be adjusted by the practitioner according to the disease to be treated.

25    The products of the invention are of use as agents for inhibiting a reaction catalysed by one or more kinases. 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 hereinafter:

FAK

FAK is a cytoplasmic tyrosine kinase which plays an important role in transduction of the signal transmitted by integrins, a family of heterodimeric cell adhesion receptors.

5    FAK and the integrins are located in perimembrane structures called adhesion plaques. It has been shown, in many cell types, that the activation of FAK and also the phosphorylation thereof on tyrosine residues, and in particular the autophosphorylation thereof on tyrosine 397, depend on binding of the integrins to

their extracellular ligands, and are therefore induced during cell adhesion [Kornberg

10    L, et.a/. J. Bioi. Chern. 267(33): 23439-442. (1992)]. The autophosphorylation of FAK on tyrosine 397 represents a binding site for another tyrosine kinase, Src, via its SH2 domain [Schaller eta/. Mol. Cell. Bioi. 14:1680-1688. 1994; Xing eta/. Mol. Cell. Bioi. 5:413-421. 1994]. Src can then phosphorylate FAK on tyrosine 925, thus recruiting
the Grb2 adaptor protein and inducing, in certain cells, activation of the ras and MAP

15    kinase pathway involved in the control of cell proliferation [Schlaepfer eta/. Nature; 372:786-791. 1994; Schlaepfer et a/. Prog. Biophy. Mol. Bioi. 71:435-478. 1999; Schlaepfer and Hunter, J. Bioi. Chern. 272:13189-13195. 1997]. The activation of FAK can also induce the jun NHrterminal kinase (JNK) signalling pathway and result
in the progression of cells to the G1  phase of the cell cycle [Oktay et a/., J. Cell.

20    Biol.145:1461-1469. 1999]. Phosphatidylinositoi-3-0H kinase (PI3-kinase) also binds to FAK on tyrosine 397 and this interaction could be necessary for the activation of Pl3-kinase [Chen and Guan, Proc. Nat. Acad. Sci. USA. 91:10148-10152. 1994; Ling et a/. J. Cell. Biochem. 73:533-544. 1999]. The FAK/Src complex phosphorylates

various substrates such as paxillin and p130CAS in fibroblasts [Vuori et a/. Mol. Cell.

25    Bioi. 16: 2606-2613. 1996].

The results of many studies support the hypothesis that FAK inhibitors could be useful in the treatment of cancer. Studies have suggested that FAK could play an important role in cell proliferation and/or survival in vitro. For example, in CHO cells, certain authors have demonstrated that the overexpression of p125FAK results in an

30    acceleration of G1 to S transition, suggesting that p125FAK promotes cell proliferation [Zhao J.-H eta/. J. Cell Bioi. 143:1997-2008. 1998]. Other authors have shown that tumour cells treated with FAK antisense oligonucleotides lose their adhesion and enter into apoptosis (Xu et a/, Cell Growth Differ. 4:413-418. 1996). It has also been demonstrated that FAK promotes cell migration in vitro. Thus, fibroblasts deficient for

FAK expression (FAK «knockout» mice) exhibit a rounded morphology and deficiencies in cell migration in response to chemotactic signals, and these deficiencies are eliminated by re-expression of FAK [DJ. Sieg eta/., J. Cell Science. 112:2677-91. 1999]. Overexpression of the C-terminal domain of FAK (FRNK) blocks

5    elongation 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. The involvement of FAK in promoting proliferation and migration of cells in many cell types in vitro suggests a
potential  role  for  FAK  in  neoplastic  processes.  A  recent  study  has  effectively

10    demonstrated an increase in tumour cell proliferation in vivo after induction of FAK expression in human astrocytoma cells [Cary L.A. eta/. J. Cell Sci. 109:1787-94. 1996; Wang D et a/. J. Cell Sci. 113:4221-4230. 2000]. In addition, immunohistochemical studies of human biopsies have demonstrated that FAK is overexpressed in prostate cancers, breast cancers, thyroid cancers, colon cancers,

15    melanomas, brain cancers and lung cancers, the level of expression of FAK being directly correlated with the tumours exhibiting the most aggressive phenotype [Weiner TM, et a/. Lancet. 342(8878):1024-1025. 1993; Owens et a/. Cancer Research. 55:2752-2755. 1995; Maung K. eta/. Oncogene. 18:6824-6828. 1999; Wang D eta/. J. Cell Sci. 113:4221-4230. 2000].

20    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 serves as a mediator for a

transduction signal via activation of its intracellular kinase domain. Direct inhibition of

25    the kinase activity of VEGF-R2 makes it possible to reduce 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 by means of VEGF-R2 mutants (Millauer et al.,

Cancer Research,  1996, vol. 56, p.1615-1620). The VEGF-R2 receptor seems to

30    have no function in adults other than that related to the angiogenic activity of VEGF. Consequently, a selective inhibitor of the kinase activity of VEGF-R2 should show only slight toxicity.

In addition to this central role in the dynamic angiogenic process, recent results suggest that VEGF expression contributes to tumour cell survival after chemotherapy

and radiotherapy, underlining the potential synergy of KDR inhibitors with other agents (Lee et al. Cancer Research, 2000, val. 60, p.5565-5570).

Tie2

Tie-2  (TEK)  is  a member of a family  of tyrosine  kinase  receptors,  specific for

5    endothelial cells. Tie2 is the first receptor with tyrosine kinase activity for which both the agonist (angiopoietin 1 or Ang1 ), which stimulates autophosphorylation of the receptor and cell signalling [S. Davis eta/. (1996) Cell 87, 1161-116g:j, and the antagonist (angiopoietin 2 or Ang2) [P.C. Maisonpierre eta/. (1997) Science 277, 55-

60]  are known.  Angiopoietin  1 can  synergize with  VEGF  in the final  stages of

10    neoangiogenesis [AsaharaT. Circ. Res.(1998) 233-240]. Knockout experiments and transgenic manipulations of Tie2 expression or of Ang1 expression result in animals which exhibit vascularization deficiencies [D.J. Dumont eta/. (1994) Genes Dev. 8,

1897-1909  and  C.  Suri  (1996)  Cell  87,  1171-1180].  The binding of Ang1  to  its

receptor  results in  autophosphorylation  of the  kinase  domain of Tie2,  which  is

15    essential for neovascularization and for the recruitment and the interaction of the vessels with the pericytes and the smooth muscle cells; these phenomena contribute to the maturation and stability of the newly formed vessels [P. C. Maisonpierre et a/.
(1997) Science 277, 55-60]. Lin eta/. (1997), J. C/in. Invest. 100, 8: 2072-2078 and Lin P. (1998), PNAS 95, 8829-8834, have shown an inhibition of tumour growth and

20    vascularization, and also a decrease in lung metastases, during adenoviral infections or injections of the extracellular domain of Tie-2 (Tek) in melanoma and breast tumour xenograph models.

For  the  following  reasons,  Tie2  inhibitors  can  be  used  in  situations  where

neovascularization or angiogenesis occurs inappropriately, i.e. in cancers in general,

25    but also in specific cancers such as Kaposi'ssarcoma or infantile haemangioma, rheumatoid arthritis, osteoarthritis and/or associated pain, inflammatory diseases of the intestine, such as ulcerative collitis or Crohn'sdisease, pathologies of the eye, such as age-related macular degeneration, diabetic retinopathies, chronic inflammation, or psoriasis.

30

Angiogenesis is a process for generating new blood vessels from pre-existing vessels. Tumour angiogenesis (formation of blood neovessels), which is essential for tumour growth, is also one of the essential factors of metastatic dissemination (Oncogene. 2003 May 19;22(20):3172-9; Nat Med. 1995 Jan;1(1):27-31.).

This neovascularization is due to the migration, then to the proliferation and differentiation, of the endothelial cells under the influence of angiogenic factors secreted by the cancer cells and the cells of the stroma (Recent Prog Horm Res.

5    2000;55:15-35; 35-6).

The angiopoietin 1me2 receptor system plays a predominant role in vessel maturation by allowing the recruitment of peri-endothelial cells so as to stabilize the
vessel (Cell. 1996 Dec 27;87(7):1161-9, Recent Prog Horm Res. 2004;59:51-71). It

10    has thus been shown that administration of the soluble recombinant form of the extracellular domain of the Tie-2 receptor (exTek) inhibits tumour angiogenesis in murine tumour models and also metastatic development (Proc Natl Acad Sci USA. 1998 Jul 21 ;95(15):8829-34; Cancer immunollmmunother. 2004 Jul;53(7):600-8). In endothelial cells in culture, stimulation of Tie-2 activates the Pl3 kinase pathway and

15    p42/p44 pathway, which pathways are involved in cell proliferation and migration; and the PAF synthesis pathway (Cell Signal. 2006 Apr 14; ahead of print), which pathway is involved in pro-inflammatory activity. Tie2 stimulation stimulates the Akt pathway and inhibits apoptosis (Exp Cell Res. 2004 Aug 1;298(1):167-77), a transduction pathway known to be important in cell survival.
20

The addition of Extek (soluble receptor for Tie2) inhibits the formation of endothelial cell pseudotubules on Matrigel (Cancer immunol lmmunother. 2004 Jul; 53(7): 600-8). These studies indicate that the Tie-2/angiopoietin system is necessary during the first stages of vascular bud formation in adult tissues and that one function of the

25    Tie-2 receptor is to increase endothelial cell survival during blood vessel formation. In addition, angiopoietin-1 stimulates lymphatic endothelial cell proliferation and lymphangiogenesis (development of lymphatic neovessels), a preferred route of access for metastatic development (Blood. 2005 Jun 15; 105(12): 4649-56).

30    The processes of angiogenesis thus play a predominant role in the progression of numerous solid tumours. In addition, it has been shown that the probability of appearance of metastases increases very greatly with an increase in vascularization of the primary tumour (Br J Cancer. 2002 May 20; 86(1 0): 1566-77).

35    The potential role of pro-angiogenic agents in leukaemias and lymphomas has also more recently been documented. In fact, in general, it has been reported that cell
 






13

clones in these pathologies can be either naturally destroyed by the immune system or can switch into an angiogenic phenotype which promotes their survival and then their proliferation. This change in phenotype is induced by an overexpression of angiogenic factors, in particular by macrophages, and/or mobilization of these factors

5    from the extracellular matrix (Thomas DA, Giles FJ, Cortes J, Albitar M, Kantarjian HM., Acta Haematol, (2001), vol207, pp106-190).

A correlation exists between the process of angiogenesis in the bone marrow and

"extramedullar  disease"  in  CML  (chronic  myelomonocytic  leukaemia).  Various

10    studies demonstrate that the inhibition of angiogenesis could represent a therapy of choice in this pathology (Leuk Res. 2006 Jan; 30(1 ): 54-9; Histol Histopathol. 2004 oct.;19(4): 1245-60). In addition, it is strongly suggested that activation of the Tie2/angiopoietin system is involved in the development of angiogenesis in the bone marrow in patients suffering from multiple myeloma (Blood. 2003 Jul15; 102(2): 638-
15    45).

Rheumatoid arthritis (RA) is a chronic disease with an unknown etiology. Although it affects many organs, the most severe form of RA is a progressive synovial

inflammation  of  the  joints  resulting  in  destruction.  Angiogenesis  appears  to

20    considerably affect the progression of this pathology. Thus, it has been shown that Tie2 activation regulates angiogenesis in synovial tissues, promoting the development of rheumatoid arthritis (Arthritis Rheum. 2003 Sep; 48(9): 2461-71 ).

An overexpression of angiopoietin 1 and of Tie2 in the synovial tissues of patients

25    suffering from osteoarthritis, correlated with an active neovascularization, has also been shown (Shahrara S et al. Arthritis Res. 2002;4(3)). Thus, it has been shown that, by blocking Tie2 activation using an adenovirus producing exTEK (soluble Tie2 receptor), inhibition of angiogenesis and the development of arthrosis and protection
against bone degradation  are obtained in  a mouse  model  in  which  arthrosis  is

30    induced with collagen (Arthritis Rheum. 2005 May; 52(5): 1346-8).

lBO  (inflammatory bowel disease)  comprises two forms  of chronic inflammatory
 

diseases of the intestine: UC (ulcerative colitis) and Crohn'sdisease (CD). lBO is characterized by an immune dysfunction which results in an inappropriate production 35    of  inflammatory  cytokines  inducing  the  establishment  of  a  local  microvascula
system. This angiogenesis of inflammatory origin results in intestinal ischaemia induced by vasoconstriction (lnflamm Bowel Dis. 2006 Jun;12(6):515-23).

Eye  pathologies  relating  to  neovascularization  phenomena,  such  as  age-related

5    macular degeneration, are responsible for a large majority of cases of blindness in developed countries. The molecular signals which control neovascularization phenomena in the eye, such as VEGFs or angiopoietins, are targets of choice in these pathologies (Campochiaro PA. Expert Opin Bioi Ther. 2004 Sep;4(9)). It has

thus been shown that blocking Tie2 activation using an adenovirus producing exTEK

10 (soluble Tie2 receptor) inhibits the retinal and choroidal neovascularization which is the most common cause of loss of vision (Hum Gene Ther. 2001 Jul 1; 12(1 0):1311-21 ).

Definitions

The term « halogen » refers to an element chosen from F, Cl, Br, and I.

15 The term cc alkyl» refers to a linear or branched, saturated hydrocarbon-based substituent having from 1 to 12 carbon atoms. 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,

20    2-ethylbutyl, 3,3-dimethylbutyl, heptyl, 1-ethylpentyl, cetyl, nonyl, decyl, undecyl and dodecyl substituents are examples of an alkyl substituent.

The term << alkylene » refers to a linear or branched hydrocarbon-based substituent having one or more unsaturations, and having from 2 to 12 carbon atoms. Ethylenyl, 1-methylethylenyl, prop-1-enyl, prop-2-enyl, Z-1-methylprop-1-enyl, E-1-methylprop-

25    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-methylidenylprop-2-enyl, undec-1-enyl and undec-1 0-enyl substituents are examples of an alkylene substituent.

The term cc alkynyl » refers to a linear or branched hydrocarbon-based substituent

30    having at least two unsaturations borne by a pair of vicinal 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 an alkynyl substituent.


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

5    The teim « heteroaryl » refers to a mono- or polycyclic heteroaromatic substituent having from 1 to 13 carbon atoms and from 1 to4 hetero atoms. Pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, fury!, thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, oxadiazofyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, indolyl, benzo[b)furyl, benzo[b]thienyl, indazolyl, benzimidazolyl, azaindolyl,

10    quinoleyl, isoquinoleyl, carbazolyl and acridyl substituents are examples of a heteroaryl substituent.

The term « hetero atom » refers here to an atom that is at least divalent, other than carbon. N, 0, Sand Se are examples of a hetero atom.

The  term  « cycloalkyl »  refers  to  a  saturated  or  partially  unsaturated  cyclic

15    hydrocarbon-based 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 perhydronaphthyl substituents are examples of a cycloalkyl substituent.

The  term  « heterocyclyl »  refers  to  a  saturated  or  partially  unsaturated  cyclic

20    hydrocarbon-based substituent having from 1 to 13 carbon atoms and from 1 to 4 hetero atoms. Preferably, the saturated or partially unsaturated cyclic hydrocarbon-based substituent will be monocyclic and will contain 4 or 5 carbon atoms and 1 to 3 hetero atoms.

The term « substituted » refers to one or more substituents other than H, for example

25    halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylene, alkynyl, OH, 0-alkyl, alkyi-OH, 0-alkylene, 0-aryl, 0-heteroaryl, NH2, NH-alkyl, NH-aryl, NH-

heteroaryl, N-alkyl-alkyl',SH, S-alkyl, S-aryl, S(02)H, S(02)-alkyl, S(02)-aryl, S03H,

S03-alkyl, S03-aryl, CHO, 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)NH2,  C(O)NH-alkyl, C(O)NH-aryl, NHCHO, NHC(0)-

30    alkyl, NHC(O)-aryl, NH-cycloalkyl and NH-heterocyclyl.

A subject of the present invention is the processes for preparing the products of formula (1).

The products according to the invention can be prepared using conventional organic chemistry methods.

5    Scheme 1 below is an illustration of the method used for the preparation of examples 1 and 3. In this respect, it cannot constitute a limitation to the scope of the invention, as regards the method for preparing the compounds claimed.

Scheme 1:
10    Scheme 2 below is an illustration of an alternative method used for the preparation of example 1. In this respect, it cannot constitute a limitation to the scope of the invention, as regards the methods for preparing the compounds claimed.

        Scheme 2   
                H,   
eN    Suzuki               
                   
.&                   
        57%       
C1 MC!    70%           

15    Scheme 3 below is an illustration of a method used for the preparation of examples 6 to 8, 20 to 21, 33 to 35, and 38 to 39. In this respect, it cannot constitute a limitation

to the scope of the invention, as regards the methods for preparing the compounds

claimed.

                    Scheme 3       
    H    HYO        H  .  H       
~NH2    +  R6        ~ N~NR6 _o_2__   
R3    O            75C    R3    rt   
    Jl    .OH        16-24h    0    "24h   
    "' lf            OH       
        0                   
        ~                   
        N        R6.    RaRbNH       
                           
    R3            2-18 h       
        0                   
            N-Ra    THFor DMF       
                       
Rti


5    Scheme 4 below is an illustration of a method used for the preparation of examples 4, 9 to 19, 22 to 32, 36 to 37, and 44 to 62. In this respect, it cannot constitute a limitation to the scope of the invention, as regards the methods for preparing the compounds claimed.

Scheme 4
 
..,c::::-0
F~N,... DMF
+    I ~
~    F  700C/ 1 hr

F F



JyoH 751) EIOH/DMSOCo.n. 9:1

0

+




lntennediate 1    lntennediate 2



('o           
HN~N~    N       
2           
HOBt, DtC    I "'    ('o   
    o       
N~NJ
THF/DMA 9:1, 6h,a.t.    H   
       


Scheme 5 below is an illustration of a method used for the preparation of examples 5, and 40 to 43. In this respect, it cannot constitute a limitation to the scope of the invention, as regards the methods for preparing the compounds claimed.

5    Scheme 5
 

19

        -++                        Cl   
                                Cl~   
        ¢        DCM, pyridine    ~- v   
            +    -            t"jr    l•"o   
                    0,~)01       
        NH,            ~0           
                        lntem~ediate 1   
                               
        ~1 ~""                    P0Br3    , 1oluene   
,N    NH                        110 •c. 3h   
H    '+                        -   
Nor    NaO    ..._,/                       
        0                       
                                   
                    Intermediate 2        Intermediate 3   
            6c.r~    Pd(PPh,),           
                cs,co,           
            +    -_t_                   
                    THF/water           
                00               
                l_.._    m~rt>WBVe           
                    25 min 155"C           
                               
    lnlannediate 1        Intermediate 3                lntetmediate 4   
                               
                                Cl   
                            Cl~   
            -NH2                H    W   
                            N-:;s .• o   
            HOBI, DIC                0       

DMF microwave
20 min 105'C


For those skilled in the art, it is understood that, in order to carry out the processes according to the invention described above, it may be necessary to introduce protective groups for amino, carboxyl and alcohol functions in order to prevent side

5    reactions. These groups are those which are able to be removed without the rest of the molecule being affected. As examples of amino function-protecting groups, mention may be made of tert-butylcarbamate, which can be regenerated by means of trifluoroacetic acid or of iodotrimethylsilane, and acetyl which can be regenerated in an acidic medium (hydrochloric acid, for example). As carboxyl function-protecting
 

example}. As alcohol function-protecting groups, mention may be made of esters (benzoyl ester, for example) which can be regenerated in an acidic medium or by catalytic hydrogenation. Other protective groups which can be used are described by T. W. GREENE et al. in Protective Groups in Organic Synthesis, third edition, 1999,
5    Wiley-lnterscience.


in which R' represents R4 or H, -COOH or -COO-(C,-C )alkyl,  R' represents H,
4    6    3

-NH    2    or -NHCO-thienyl, and R' represents a halogen atom, an -Ar-NH    2    group where   
        6           
20    Ar is as defined above, or an Ar-L-A group where Ar, L and A are as defined above, and the products of the general formula (Ill) below:
25    JXCN

R'e    N    Cl

30    (Ill)
in which R' represents R4 or H, -COOH or -COO-(C -C )alkyl, and R' represents a
4    1    6    6

halogen atom, an -Ar-NH2 group where Ar is as defined above, or an Ar-L-A group where Ar, L and A are as defined above. These products are in particular useful as synthesis intermediates in the processes for preparing the products of general

35    formula (1).

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.

40    The compounds of formula(!) containing a basic residue can be optionally converted into addition salts with an inorganic or organic acid, by the action of such an acid in a solvent, for example an organic solvent such as an alcohol, a ketone or an ether or a chlorinated solvent.
 
The compounds of formula (I) containing an acidic residue can be optionally converted into metal salts or into addition salts with nitrogenous bases according to the methods known per se. These salts can be obtained by the action of a metal base (alkali metal or alkaline earth metal, for example), of ammonia, of an amine or

5    of an amine salt on a compound of formula (1), 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 free basic function,

pharmaceutically acceptable salts can be prepared by reaction between said product

10    and an inorganic or organic acid. Pharmaceutically acceptable salts include chlorides, nitrates, sulphates, hydrogen sulphates, pyrosulphates, bisulphates,

sulphites, bisulphites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, acetates, propionates, acrylates, 4-hydroxybutyrates, caprylates, caproates, decanoates, oxalates, malonates,

15    succinates, glutarates, adipates, pimelates, maleates, fumarates, citrates, tartrates, lactates, phenylacetates, mandelates, sebacates, suberates, benzoates, phthalates, methanesulphonates, p-toluenesulphonates, propanesulphonates, xylenesulphonates, salicylates, cinnamates, glutamates, aspartates, glucuronates and galacturonates.

20    When a product according to the invention has at least one free acid function, pharmaceutically acceptable salts can be prepared by reaction between said 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,  and  basic  aminated  compounds  such  as  ammonia,  arginine,  histidine,

25    piperidine, morpholine, piperazine or triethylamine.

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

The LC/MS analyses were performed on an LCT Micromass machine connected to

an HP 1100 device. The abundance of the products was measured using an HP

30    G1315A diode array detector over a wavelength range of 200-600 nm and a Sedex 65 light scattering detector. The mass spectra were acquired over a range of 1BO to BOO. The data were analysed using the Micromass Masslynx software. The separation was performed on a Hypersil BDS C18, 3 J.Jm (50 x 4.6 mm) column,
 
eluting with a linear gradient of 5% to 90% acetonitrile containing 0.05% (v/v) of trifluoroacetic acid (TFA) in water containing 0.05% (v/v) of TFA, over 3.5 min at a flow rate of 1 mllmin. The total analysis time, including the column reequilibration period, is 7 min.

5    The MS spectra were acquired in electrospray (ES+) mode on a Platform II (Micromass) device. The main ions observed are described.

The melting points were measured by capillary, on a Mettler FP62 device, over the range 30°C to 300°C, with a temperature rise of 2°C per minute.

Purification by LC/MS:

10    The products may be purified by LC/MS using a Waters FractionsLynx system composed of a Waters model600 gradient pump, a Waters model 515 regeneration pump, a Waters Reagent Manager dilution pump, a Waters model2700 autoinjector, two Rheodyne model LabPro valves, a Waters model 996 diode array detector, a Waters model ZMD mass spectrometer and a Gilson model 204 fraction collector.

15    The system was controlled by the Waters FractionLynx software. The separation was performed alternately on two Waters Symmetry columns (C18, 5~M. 19x50 mm, catalogue reference 18600021 0), one column undergoing regeneration with a 95/5 (v/v) water/acetonitrile mixture containing 0.07% (v/v) of trifluoroacetic acid, while the other column was being used for separation. The columns were eluted using a linear

20    gradient of 5% to 95% of acetonitrile containing 0.07% (v/v) of trifluoroacetic acid in water containing 0.07% (v/v) of trifluoroacetic acid, at a flow rate of 10 ml/min. On leaving the separation column, one thousandth of the effluent is separated out using
an LC Packing Accurate device, diluted with methanol at a flow rate of 0.5 ml!min and conveyed to the detectors, in a proportion of 75% to the diode array detector,

25    and the remaining 25% to the mass spectrometer. The rest of the effluent (999/1 000) is conveyed to the fraction collector, where the flow is discarded if the mass of the expected product is not detected by the FractionLynx software. The molecular formulae of the expected products are supplied to the FractionLynx software, which triggers the collection of the product when the mass signal detected corresponds to

30    the [M+Ht ion and/or to the [M+Nat ion. In certain cases, depending on the analytical LC/MS results, when an intense ion corresponding to [M+2Ht• was detected, the value corresponding to half the calculated molecular mass (MW/2) is also supplied to the FractionLynx software. Under these conditions, collection is also

triggered when the mass signal of the [M+2Ht• and/or [M+Na+Ht• ion is detected. The products were collected in tared glass tubes. After collection, the solvents were evaporated off, in a Savant AES 2000 or Genevac HT8 centrifugal evaporator and the masses of the products were determined by weighing the tubes after evaporation
5    of the solvents.

Example 1

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



10    100 mg (0.44 mmol) of 6-(4-aminophenyl)-1 H-pyrazolo[3,4-b]pyridin-3-ylamine are partially solubilized in 2.5 ml of anhydrous THF. The mixture is then degassed for 15 minutes with argon. 61.55 JJI (44.93 mg, 0.44 mmol, 1 eq.) of
triethylamine are subsequently added. The solution is once again degassed for

15  minutes.  Finally,  64.22 JJI  (91 mg,  0.44 mmol,  1 eq.)  of  2-fluoro-5-

15    (trifluoromethyl)phenyl isocyanate are added dropwise. The mixture is stirred for 2 hours at ambient temperature under an inert atmosphere. After reaction, the mixture is filtered. The filtrate is concentrated. A beige solid is isolated. This crude product is subsequently purified on a C18 reverse-phase silica (13 g)
column with an eluent gradient of 5% to 95% of acetonitrile in water. The

20    fractions containing the expected product are lyophilized. A white solid is isolated (10 mg).

MS (ES) MH•m/z=431.

1H NMR (DMSO-d6) d 5.52 (broad s, 2H); 7.39 (m, 1 H); 7.49 (m partially masked, 1 H); 7.52 (d, J = 8.5 Hz, 1 H); 7.62 (broad d, J = 8.5 Hz, 2H); 8.07
25    (broad d, J = 8.5 Hz, 2H); 8.13 (d, J =8.5 Hz, 1H); 8.60 (broad d, J =7.5 Hz, 1H); 9.21 (broad m, 1H); 9.63 (broad m, 1 H); 11 ,9 (broad m, 1H).

6-(4-Aminophenyl)-1 H-pyrazolo[3,4-b]pyridin-3-ylamine:
 

In an appropriately sized microwave reactor, 0.97 mmol (222 mg) of 6-(4-amino-phenyl)-2-chloronicotinonitrile is suspended in 3.3 ml of 1-propanol. 0.28 ml (0.290 g, 5.80 mmol, 6 eq.) of hydrazine hydrate is added. The suspension is heated for 45

5    minutes at 130°C in a microwave oven. The mixture is filtered and the solid is dried so as to obtain a green solid (215 mg).
MS (EI) M+m/z=225.

1H NMR (DMSO-d6) d 5.41 (sl, 4H), 6.63 (d, J = 8 Hz, 2H), 7.37 (d, J = 8 Hz, 1 H), 7.82 (d, J = 8 Hz, 2H), 8.02 (d, J = 2 Hz, 1H).

10    6-( 4-Aminophenyl)-2-chloronicotinonitrile:



h
N    Cl


2.89 mmol (500 mg) of 2,6-dichloronicotinonitrile and 3.18 mmol (551 mg, 1.1 eq.) of 4-aminophenylboronic acid are dissolved under an inert atmosphere in 33.3 ml of dioxane. 680 mg (8.09 mmol, 2.8 eq.) of sodium bicarbonate and then 8.3 ml of

15    water are subsequently added. The mixture is stirred for 5 minutes under an inert atmosphere and then 334 mg (0.29 mmol, 0.1 eq.) of tetrakis(triphenyl-phosphine)palladium are added. The reaction mixture is brought to reflux (100°C) for 2 hours and is then cooled to ambient temperature. The reaction medium is filtered and then extracted four times with ethyl acetate. The organic phases are combined,

20    washed twice with a saturated aqueous sodium chloride solution, dried with magnesium sulphate, and concentrated. A yellow solid is then obtained. This crude is purified on a column of 90 g of silica, with an eluent gradient of 20% to 50% of ethyl acetate in heptane. The expected product is obtained in the form of a yellow

solid (531 mg).

25    MS (ES) MH+m/z=230.

1H NMR (DMSO-d6) d 5.94 (sl, 2H), 6.65 (d, j =8hz, 2H), 7.89 (d, j =8hz, 2H), 7.93 (d, j = 8 hz, 1H), 8.27 (d, j = 8 hz, 1H).


Alternative pathway for the preparation of 1-[4-(3-amino-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea (scheme 2):

NH2

~N

I
N
H



0.46 mmol   (200 mg)   of   1-[4-(6-chloro-5-cyanopyridin-2-yl)phenyl]-3-(2-fluoro-5-

5    trifluoromethylphenyl)urea is suspended in 3.2 ml of 1-propanol. 0.13 ml (0.14 g, 2.76 mmol, 6 eq.) of hydrazine hydrate is added. The suspension is heated at 8o•c for 10 h. The mixture is filtered and the solid is dried so as to obtain 140 mg of the expected product.

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

':        1~    4-N   
    0        Cl   
::,.,.    )lN    b       
~H    H           
10    F
0.578 mmol (100 mg) of 2,6-dichloronicotinonitrile and 0.64 mmol (270 mg, 1.1 eq.) of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-( 4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2-yl)phenyl]urea are dissolved under an inert atmosphere in 6.6 ml of dioxane. 136 mg (1.62 mmol, 2.8 eq.) of sodium bicarbonate and then 1.6 ml of water are

15    subsequently added. The mixture is stirred for 5 minutes under an inert atmosphere and then 33.4 mg (0.029 mmol, 0.05 eq.) of tetrakis(triphenylphosphine)palladium are added. The mixture is refluxed (1oo•q for 2 hours and is then cooled to ambient

temperature. The reaction medium is extracted twice with ethyl acetate. The organic

phases  are  combined,  washed twice with  a saturated  aqueous  sodium  chloride

20    solution, and then dried with magnesium sulphate and concentrated. A yellow solid is then obtained. The crude is purified on a column of 30 g of silica, with an eluent gradient of 20% to 40% of ethyl acetate in heptane. A yellow solid is obtained (175 mg).
MS (ES) MH+m/z=435.
 

25    1H NMR (DMSO-d6) d 7.40 (m, 1H), 7.49 (m, 1 H), 7.68 (d, J = 8 Hz, 2H), 8.13 {d, J

=8Hz, 2H), 8.16 (d, J =8Hz, 1H), 8.45 (d, J =8Hz, 1H), 8.56 (m, 1H).

The  1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-( 4, 4, 5, 5-tetramethyl[ 1, 3,2)dioxaborolan-

2-yl)phenyl)urea is prepared according to the following procedure:

936 mg   of   2-fluoro-5-trifluoromethylphenylisocyanate   and   then   0.64 ml   of

5    triethylamine are added to a solution of 1 g of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)aniline in 15 ml of tetrahydrofuran, at ambient temperature. The reaction medium is stirred at ambient temperature for 18 h, and then treated with methanol and then, finally, evaporated to dryness under reduced

pressure. The residue thus obtained is purified by chromatography on silica using, as

10    eluent, a (99.5/0.5 then 90/10) methylene chloride/methanol mixture. The fractions containing the expected product are concentrated to dryness so as to give 1.45 g of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl[1,3,2)dioxaborolan-2-yl)phenyl]urea in the form of a white solid. MS (ES) MH• m/z=425.

Example 2

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

A solution of 1-[4-(3-amino-1 H-pyrazolo[3,4-b)pyridin-6-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea (80.0 mg, 0.186 mmol) in pyridine (2 ml) is cooled to soc

20    under argon and thiophene-3-carboxylic acid chloride (27 mg, 0.186 mmol, 1.0 eq.) is added. The mixture is stirred at ambient temperature for 5.5 h. Another equivalent of thiophene-3-carboxylic acid chloride (27 mg, 0.186 mmol) is added and the mixture is stirred at ambient temperature overnight. The reaction is taken up with water, and then extracted with ethyl acetate. The organic phase is washed twice with

25    a salt solution, dried with magnesium sulphate, and concentrated. An orangey yellow solid is then obtained. The crude is purified on a silica column, with an eluent gradient of 0% to 5% of methanol in dichloromethane. A beige solid is obtained:
13.5 mg.

MS (ES) MH•mtz=541.
 

27    PCT/FR2006/001861

1H NMR (DMSO-d6) d 7.40 (m, 1H); 7.50 (m, 1H); 7.65 (broad d, J = 9.0 Hz, 2H); 7.68 (dd partially masked, J = 3.0 and 5.0 Hz, 1H); from 7.71 to 7.75 (m, 2H); 8.15 (broad d, J = 9.0 Hz, 2H); 8.39 (d, J = 8.5 Hi, 1H); 8.50 (broad d, J = 3.0 Hz, 1 H); 8.61 (dd, J = 2.5 and 7.5 Hz, 1H); 9.21 (broad m, 1H); 9.67 (broad m, 1H); 10.9

5    (broad m, 1 H); 13.3 (broad m, 1H) . Example 3

N-[ 4-(3-Am ino-1 H-pyrazolo[3 ,4-b]pyridin-6-yl}phenyl]-2, 3-dichlorobenzene-sulphonamide:

NH2

~N

~I

10    100 mg (0.44 mmol} of 6-(4-aminophenyi)-1H-pyrazolo[3,4-b]pyridin-3-ylamine are dissolved in 3 ml of anhydrous DMF. The solution is then degassed for 15 minutes with argon. 123.8 iJI (89.9 mg, 0.89 mmol, 2 eq.) of triethylamine are subsequently added. The solution is once again degassed for 15 minutes. Finally, 0.109 g (0.444 mmol, 1 eq.) of 2,3-dichlorophenylsulphonyl chloride is added. The solution is

15    stirred at ambient temperature under argon overnight. At the end of the reaction, 10 ml of water are added. A yellow-brown precipitate forms. The mixture is filtered. The solid is dried and purified on a column of 4 g of silica with an eluent gradient of 0 to 10% of methanol in dichloromethane. A beige solid is isolated (11 mg).

MS (ES) MH+ m/z=434.

20 1H NMR (DMSO-d6, 373K) d 5.09 (broads, 2H); 7.09 (broad d, J = 8.5Hz, 2H); 7.37 (d, J = 8.5 Hz, 1H); 7.40 (broad t, J = 8.5 Hz, 1H); 7.69 (broad d, J = 8.5 Hz, 1H); 7.85 (broad d, J = 8.5 Hz, 2H); 8.02 (broad d, J = 8.5 Hz, 1H); 8.06 (d, J = 8.5 Hz, 1H); 11.5 (broad m, 1 H).

Example 4

25    6-{2-[3-(2-Fiuoro-5-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4~ b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide trifluoroacetate:


The product of example 4 can be prepared  by the  process described  above  in

scheme 4:

Synthesis of intermediate 1:

5    2-Fiuoro-(5-trifluoromethyl)phenylisocyanate (4 g, 19.5 mmol) is added to a solution of 2-aminothiazole-5-carboxaldehyde (2.5 g, 19.5 mmol) in DMF (120 ml). The solution is heated at 70°C for 1 h, evaporated, and purified by chromatography on

silica gel, eluting with 1:1 hexane/EtOAc. The fractions containing intermediate 1 are

combined and evaporated so as to provide intermediate 1 in the form of a yellow

10    solid (4.28 g).

Synthesis of intermediate 2:

Added to a solution of intermediate 1 (88 mg, 0.26 mmol) in a 9:1 ethanoi/DMSO mixture (2 ml) is a solution of 1H-pyrazol-3-ylamine (22 mg, 0.26 mmol) in 2 ml of the same mixture of solvents containing pyruvic acid (23 mg, 0.26 mmol). The mixture is

15    heated at 75°C for 24 h in the presence of oxygen, and the reaction medium is then evaporated to dryness so as to provide intermediate 2 in the form of an orange solid which is used as it is in the subsequent step.
Preparation of the product of example 4:

Intermediate 2 is dissolved in dry THF (2 ml) and HOBt (36 mg, 0.26 mmol) then DIG

20    is added (42 iJI, 0.26 mmol). After 5 min, 2-morpholin-4-ylethylamine (39 iJI, 0.3 mmol) is added. The stirring is continued for 5 hat ambient temperature, and the reaction medium is then evaporated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with 94:5:1 EtOAc/MeOH/TEA using a gradient of 90:9:1 EtOAc/MeOH/TEA. The fractions containing the product are

25    combined and evaporated, and then purified by LC/MS chromatography (reverse-phase, eluent water+ 0.1% TFA with a gradient of 25% to 85% of acetonitrile over a period of 8 minutes). The fractions containing the expected product are combined and evaporated under reduced pressure so as to provide the product in the form of a yellow solid (10.6 mg).
 

30    Example 5
 
N-[4-(3-Amino-4-methylaminocarbonyl-1 H-pyrazolo[3,4-b]pyridin-6-yl}phenyl]-2,3-

dichlorobenzenesulphonamide:

c~
~~
0
N    ""

i'ti
I

The product of example 5 can be prepared by means of the process described

5    above in scheme 5: Synthesis of intermediate 1:

219 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline are dissolved with 245 mg (1 mmol) of 2,3-dichlorobenzenesulphonyl chloride in 2 ml of DCM and 120 ~I (1.5 ~mol) of pyridine. The mixture is stirred for 6 hours at ambient

10    temperature and then dried under vacuum so as to obtain the desired product in the form of a light red solid.
MS (ES) MH+ m/z=428. Synthesis of intermediate 2:
84 g of diethyl oxalacetate sodium salt are dissolved with 33.2 g of 2-aminopyrazole

15    in 600 ml of AcOH/H20 (1 :3). The mixture is heated for 6 hours at 80°C. The product

is precipitated after cooling, filtered, and dried under vacuum (17.9 g).

1H NMR (600 M Hz, DMSO-d6) 0 pprT): 13.74 (s, 1H), 12.39 (s, 1H), 8.22 (s, 1H),

6.70 (s, 1H), 4.40 (q, J = 7.1 Hz) 2H), 1.40 (t, J = 7.1 Hz) 3H). Synthesis of intermediate 3:

20    2.07 g (10 mmol) of intermediate 2, 20 ml of toluene and 2.87 g (10 mmol) of P0Br3 are heated in an oil bath to 110°C, with stirring. The mixture is evaporated and

purified on a column of silica, eluted with 20% EtOAc, 80% hexane, so as to give

(after evaporation) 300 mg of the desired product.

1H NMR (600 M Hz, DMSO-d6) ¢ppm: 14.45 (s, 1H}, 8.41 (s, 1H), 7.79 (s, 1H),

25    4.49(q,J=7.1 Hz)2H), 1.46(t,J=7.1 Hz)3H).

Synthesis of intermediate 4:

74 ~mol of intermediate 3 (20 mg), 74 ~mol of intermediate 1, 185 ~mol of cesium

carbonate and 7.4 ~mol of Pd (PPh3}4 are dissolved in THF and 20% H20 (total 30 volume 750 ~1). The mixture is heated in a microwave for 25 min at 155°C (power

55 W). The product is evaporated and purified by LC/MS chromatography in water with 0.1% of trifluoroacetic acid and a gradient of 25% to 95% acetonitrile, over 9 minutes. The product is dried under vacuum. MS (ES) MW m/z=463.

Preparation of the product of example 5

5    Intermediate 4 (20 mg, 43.31Jmol) is dissolved in DMF (0.5 ml), with HOBt (14.6 mg, 108.251-Jmol) and DIC (.16.9 IJI, 108.251-Jmol). 0.5 mmol of methylamine (1M in THF,

0.5 ml) is added. The mixture is heated. in a microwave for 20 min at 105°C (power

25 W). The product is evaporated and purified by LC/MS chromatography in water

with 0.1% of trifluoroacetic acid and a gradient of 25% to 95% acetonitrile, over 9

10    minutes. The product is dried under vacuum so as to obtain a light yellow solid. MS (ES) MH• m/z=4 76.

1H NMR (600 M Hz, DMSO-d6).opprn: 13.79 (s, 1H), 11.13 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1 H), 8.13 (d, J = 7.8 Hz) 2H) 8.09 (d, J = 8.27 Hz) 1 H), 7.94 (d, J = 8.05 Hz) 1 H), 7.28 (d, J = 4.31 Hz) 2H), 2.88 (d, J = 4.31 Hz) 3H) 7.58 (q, J = 8.08 Hz) 1 H), 8.86 (t,

15    J = 4.43 Hz) 1 H)


Examples 6 to 62:

By carrying out the procedures described above, the products of table 1 below are obtained:


Determination of the activity of the compounds- experimental protocols

1.    FAK

The inhibitory activity of the compounds on FAK is determined by measuring the

5    inhibition of autophosphorylation of the enzyme using a time resolved fluorescence assay (HTRF).

The complete eDNA of human FAK, the N-tenninal end of which had been labelled with histidine, was cloned into a baculovirus expression vector pFastBac HTc. The protein was expressed and purified to approximately 70% homogeneity.

I 0 The kinase activity is detennined by incubating the enzyme (6.6 !Jg/ml) with various concentrations of test compound in a 50 mM Hepes buffer, pH = 7.2, containing

10 mM MgCI2, 100 JJM NaN04, and 15 )lM of ATP for 1 hour at 3rC. The enzymatic reaction is stopped by the. addition of Hepes buffer, pH = 7.0, containing 0.4 mM KF, 133 mM EDTA and 0.1% BSA and the labelling is carried out, for 1 to 2 hours at ambient temperature, by the addition, to this buffer, of an anti-histidine antibody

5    labelled with XL665 and of a tyrosine phospho-specific monoclonal antibody conjugated to europium cryptate (Eu-K). The characteristics of the two fluorophores are available in G. Mathis et al., Anticancer Research, 1997, 17, pages 3011-3014.

The transfer of energy from the excited europium cryptate to the acceptor XL665 is proportional to the degree of autophosphorylation of FAK. The XL-665-specific long-

10    lasting signal is measured in a Packard Discovery plate counter. All the assays were carried out in duplicate and the mean of the two assays is calculated. The inhibition of the FAK autophosphorylation activity with compounds of the invention is expressed as percentage inhibition relative to a control, the activity of which is

measured in the absence of test compound. For calculating the % inhibition, the 15 (signal at 665 nm/signal at 620 nm] ratio is considered.

2.    KDR

The inhibitory effect of the compounds is determined in an assay of substrate phosphorylation by the KDR enzyme in vitro using a scintillation technique (96-well plate, NEN).

20    The cytoplasmic domain of the human KDR enzyme was cloned in the form of a GST fusion into the baculovirus expression vector pFastBac. The protein was expressed in SF21 cells and purified to approximately 60% homogeneity.

The kinase activity of KDR is measured in 20 mM MOPS, 10 mM MgCI2, 10 mM MnCI2, 1 mM OTT, 2.5 mM EGTA and 10 mM b-glycerophosphate, pH = 7.2, in the

25    presence of 10 mM MgCI2, 100 1JM NaN04 and 1 mM NaF. 10 J.JI of the compound are added to 70 J.ll of kinase buffer containing 100 ng of KDR enzyme at 4•c. The reaction is initiated by adding 20 J,Ji of solution containing 2 J,Jg of substrate (SH2-SH3 fragment of PLCy expressed in the form of a GST fusion protein), 2 J,JCi y 33P[ATP] and 21JM cold ATP. After incubation for 1 hour at 37"C, the reaction is stopped by

30    adding 1 volume (100 J,JI) of 200 mM EDTA. The incubation buffer is removed, and the wells are washed three times with 300 J,JI of PBS. The radioactivity is measured in each well using a Top Count NXT radioactivity counter (Packard).

The background noise is determined by measuring the radioactivity in four different wells containing radioactive ATP and. the substrate alone.

A total activity control is measured in four different wells containing all the reactants
(y3P-[ATP], KDR and PLOy substrate) but in the absence of compound.

5    The inhibition of the KDR activity with the compound of the invention is expressed as percentage inhibition of the control activity determined in the absence of compound.

The  compound  SU5614  (Calbiochem)  (1 iJM)  is  included  in  each  plate  as  an

inhibition control.

3.    Tie2

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

The  inhibitory  effect  of  the  molecules  is  determined  in  an  assay  of  PLC

15    phosphorylation by Tie2 in the presence of GST-Tie2 purified to approximately 80% of homogeneity. The substrate is composed of the SH2-SH3 fragments of PLC expressed in the form of a GST fusion protein.

The kinase activity of Tie2 is measured in a 20 mM MOPS buffer, pH 7.2, containing
10 mM  MgCI2, 10 mM  MnCI2,  1 mM  OTT and  10 mM of glycerophosphate.  In  a

20    FlashPiate 96-well plate kept on ice, a reaction mixture composed of 70 111 of kinase buffer containing 100 ng of GST -Tie2 enzyme is deposited per well. 10 111 of the test molecule diluted, in DMSO, to a concentration of at most 10% are subsequently added. For a given concentration, each measurement is carried out in quadruplicate.
The reaction is initiated by adding 20 111 of solution containing 2 IJg of GST-PLC,

25    211M of cold ATP and 1 iJCi of 33 P[ATP]. After incubation for 1 hour at 37"C, the reaction is stopped by adding 1 volume (100 IJI) of EDTA at 200 mM. After removal of the incubation buffer, the wells are washed three times with 300 111 of PBS. The radioactivity is measured on a Wallac Micro8eta1450.

The  inhibition  of the  Tie2  activity  is  calculated  and  expressed  as  percentage

30    inhibition relative to the control activity determined in the absence of compound.

Example            IC 50(nM)           
    KDR        Tie2        FAK   
1    119        192        10 000   
2    6        7           
3    10 000        75        10 000   
4    83        1        343   
                       
5    10 000        13        10 000   
9    6824        443        10 000   
                       
11    581        8        927   
12    2360        30           
13    373        4           
14    293        7           
                       
15    70        2           
16    200        7           
                       
17    46        1           
20    10 000        777           
21    10 000        6034           
    511        4           
22                       
23    527        6           
24    133        2           
                       
26    387        3               
28    4658        105               
29    160        3               
31    647        9               
33    10 000        2697               
34    10 000        4144               
55    3538        88               
 
1.  Product of general formula (I) below:

R4    R3
R5'CC'-'
L    I .--::.   /N
A/  'Ar   X    ~

H

Formula (I)

10    in which:

1)    A and Ar are independently selected from the group consisting of: aryl, heteroaryl, heterocyclyl, substituted aryl, substituted heteroaryl, substituted heterocyclyl, cycloalkyl and substituted cycloalkyl;

2)    L is selected from the group consisting of: NH, NH-S02,  S02NH, NH-CH2,
15    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-C0-0, 0-CO-NH, CH2-NH-CO-NH, NH-CO-NH-CH2, and NH-CO-CH2-CO-NH;

3)    X is N or NO;

4)    R3 is selected from the group consisting of H and NHMR"3, in which M is
20    selected from the group consisting of: a bond, CO, CO-NH, CS, CS-NH and S02, and in which R"3 is 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 and substituted heterocyclyl;

25    5) R4 is selected from the group consisting of: H, halogen, alkyl, substituted alkyl, OR"4, N(R"5)(R"6). CON(R"5)(R"6), in which R"4 is chosen from H, phenyl, substituted phenyl, alkyl, substituted alkyl, and in which R"5 and R"6 are

independently selected from the group consisting of H, (C1-Ca)alkyl, substituted
(C1-Ca)alkyl,  -(C1-Ca)alkylheterocyclyl, substituted -(C1-Ca)alkylheterocyclyl, -(C1-

30    C6)alkylheteroaryl,  substituted  -(C1-Ca)alkylheteroaryl,  cycloalkyl,  substituted
cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or else R"5 and R"6 are linked to one another so as to form a saturated ring having from 4 to 8 ring members containing from 1 to 3 hetero atoms chosen from 0, Sand N, optionally substituted;

6) R5 is selected from the group consisting of: H, halogen, R'2, CN, O(R'2), OC(O)(R'2), OC(O)N(R'2)(R'3), OS(02)(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(0)(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),
10    S(02)(R'2), S(02)0(R'2), S(02)N(R'2)(R'3);in which each R'2, R'3, R'4 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; and R'2and R'3can be linked to one another so as to

15    form a ring containing from 1 to 3 hetero atoms chosen from 0, Sand N; provided that, when X is N, R3 is NH2 , Ar and A are unsubstituted phenyl, L is

NHCO linked in the para-position with respect to Ar, and R5 is H, then R4 is not chosen from: phenyl, o-chlorophenyl, cinnamyl, a-furfuryl, o-hydroxyphenyl, p-hydroxy-m-methoxyphenyl, p-methylthiophenyl, p-methoxyphenyl,
20    o-nitrophenyl, m-phenoxyphenyl,_p\andprovided that, when X is N, R5 is H, R4 is

    H, and Ar-L-A is a group    , then R3 is not chosen from: amino,
    acetylamino,    [(4-fluorophenyl)carbonyl]amino,    (2-methylpropanoyl)amino,
    -(cyclopentylcarbonyl)amino,  propanoylamino, [(4-methylphenyl)carbonyl]amino,
    {[4-(methyloxy)phenyl]carbonyl}amino,        (2-thienylcarbonyl)amino,
25    (methylsulphonyl)amino,    -[(4-fluorophenyl)sulphonyl]amino,
    (ethylsulphonyl)amino, (propylsulphonyl)amino, (3-thienylsulphonyl)amino, [(3,5-
    dimethyl-4-isoxazolyl)sulphonyl]amino,    (2-thienylsulphonyl)amino    and    (1-
    methylethyl)amino.               

2.  Product according to Claim 1, characterized in that:

30    1) A and Ar are independently selected from the group consisting of: aryl, heteroaryl, heterocyclyl, cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocyclyl and substituted cycloalkyl;
 
2)    L is selected from the group consisting of: NH, NH-802, 802NH, NH-CH2, CH2-NH, CH 2-CO-NH, NH-CO-CH2, NH-CH2-CO, CO-CH2-NH, NH-CO-NH, NH-C8-NH, NH-C0-0, 0-CO-NH, CH2-NH-CO-NH, NH-CO-NH-CH2 and NH-CO-CH2-CO-NH;

3)    X is N;

4)    R3 is selected from H, NH2 and NHCOR"3, in which R"3 is 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  and  substituted

10    heterocyclyl;

5)    R4 is selected from the group consisting of: H, halogen, alkyl, substituted alkyl, CON(R"5)(R"6) in which R"5 and R"6 are independently selected from the group

consisting of H; (C,-C6)alkyl, substituted (C,-Cs)alkyl, -(C1-C6)alkylheterocyclyl, substituted -(C,-C6)alkylheterocyclyl, -(C,-Cs)alkylheteroaryl, substituted -(C1-

15    C6 )alkylheteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or else R"5 and R"6 are linked to one another so as to form a saturated ring having from 4 to 8 ring members containing from 1 to 3 hetero atoms chosen from 0, 8 and N, optionally substituted;

20    6)  R5 is H.

3.    Product according to Claim 1 or 2, characterized in that Ar is chosen from the group consisting of: thiazolyl, thienyl, fury!, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl and benzothiazolyl; optionally substituted.

25    4.  Product according to Claim 1 or 2, characterized in that Ar-L-A is:
-<\X=XJ-L\
4

X:;-~   A

in which each X1, X2, X3 and X4 is independently chosen from N and C-R'5,in which R'5has the same definition as R5.

30    5. Product according to Claim 1, characterized in that L-A is selected from the group consisting of NH-CO-NH-A and NH-802-A

6.    Product according to Claim 1, characterized in that A 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.

7.    Product according to Claim 6, characterized in that A is selected from the group consisting of: phenyl, pyrazolyl and isoxazolyl; optionally substituted.

8.    Product according to Claim 1, characterized in that A is substituted with a first substituent selected from the group consisting of halogen, alkyl, alkylene, alkynyl,
aryl, heteroaryl, 0-alkyl, 0-aryl, 0-heteroaryl, S-alkyl, S-aryl, S-heteroaryl, each
10    being optionally substituted with one or more substituents chosen from (C1-C3)alkyl, halogen and O-(C1-C3)alkyl.

9.    Product according to Claim 8, characterized in that A is substituted with a second
substituent selected from the group consisting of F, Cl, Br, I, OH, SH, S03M,
COOM,  CN,  N02, CON(R8)(R9),  N(R8)CO(R9),  (C1-C3)alkyi-OH,  (C1-C3)alkyl-

15    N(R8)(R9), (C1-C3)alkyi-(R10), (C1-C3)alkyi-COOH, N(R8)(R9); in which R8 and R9 are independently chosen from H, (C1-C3)alkyl, halogenated (C1-C3)alkyl, (C1-C3)alkyiOH, (C1-C3)alkyi-O(C1-C3)alkyl, (C1-C3)alkyiNH2, (C1-C3)alkyiN(R8)(R9),

(C1-~)alkyiCOOM, (C1-C3)alkyiS03M; in which, when R8 and R9 are simultaneously different from H, they can be linked so as to form a ring having

20    from 5 to 7 ring members containing from 1 to 3 hetero atoms; in which M is H or a cation of an alkali metal chosen from Li, Na and K; and in which R10 isH or an optionally substituted, non-aromatic heterocycle containing 2 to 7 carbon atoms and 1 to 3 hetero atoms chosen from N, 0 and S.

10.    Product according to Claim 1, characterized in that A is chosen from phenyl,
25    pyrazolyl and isoxazolyl; optionally substituted with halogen, (C1-C4)alkyl, halogenated (C1-C3)alkyl, O-(C1-C4)alkyl, S-(C1-C.)alkyl, halogenated O-(C1-C4)alkyl, and halogenated S-(C1-C.)alkyl, and in that, when A is disubstituted, the two substituents of A can form a ring having from 5 to 7 ring members containing from 0 to 3 hetero atoms chosen from 0, N and S.

30    11. Product according to Claim 1, characterized in that R4 is H or CON(R"5)(R"6), with R"5 and R"6 as defined above.

12.    Product according to any one of Claims 1 to 11, characterized in that it is chosen from:

1-[4-(3-a mino-1 H-pyrazolo[3,4-b]pyrid in-6-yl)phenyl]-3-(2 -fl uoro-5-trifl uo romethyl-

phenyl)urea;

thiophene-3-carboxylic acid (6-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1 H-pyrazolo[3 ,4-b]pyridin-3-yl)amide; 6-{2-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide trifluoroacetate; 6-{4-[3-(2 -fluo ro-5-trifluoro methyl phenyl)u rei do]phenyl}-1 H-pyrazolo[3 ,4-b]pyridine-4-carboxylic acid amide; 6-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido ]phenyl}-1 H-pyrazolo[3,4-

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

15    6-{2-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide;
6-{2 -[3-(2 -fluo ro-5-trifluoromethyl phenyl)u rei do ]th iazol-5-yl}-1 H-pyrazolo[3, 4-

b]pyridine-4-carboxylic acid methylamide;

6-{2-[3-(2 -flu o ro-5-trifl uoromethylphenyl)ureido ]thiazol-5-yl}-1 H-pyrazo lo[3 ,4-

20    b]pyridine-4-carboxylic acid (2-dimethylaminoethyl)amide; 6-{2-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3-dimethylamino-2,2-dimethylpropyl)amide; 6-{2 -[3-(2-fluo ro-5-trifl u oromethylphenyl)u rei do ]thiazol-5-yl}-1 H-pyrazolo[3 ,4-

b]pyridine-4-carboxylic acid [2-(3H-imidazol-4-yl)ethyl]amide;

25    1-(2-fluoro-5-trifluoromethylphenyl)-3-{5-[4-(morpholine-4-carbonyl)-1 H-pyrazolo[3,4-b]pyridin-6-yl]thiazol-2-yl}urea;

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

30    pyrazolo[3,4-b]pyridin-6-yl]-thiazol-2-yl}urea;

6-{2 -[3-(2 -flue ro-5-trifluoromethyl phenyl)u rei do ]th iazol-5-yl}-1 H-pyrazolo[3 ,4-b]pyridine-4-carboxylic acid (2,3-dihydroxypropyl)amide;

6-{2 -[3-(2 -fluo ro-5-trifl uoromethylphenyl)u reido ]thiazol-5-yl}-1 H-pyrazolo[3 ,4-

b]pyridine-4-carboxylic acid (2H-pyrazol-3-yl)amide;

35    6-{6-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]pyridin-3-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methylamide;

6-{6-[3-(2 -fluo ro-5-triflu oromethylphenyl)ureido ]pyrid in-3-yl}-1 H-pyrazolo[3 ,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(2 -fluoro-5-trifluoro methylphenyl)ureido ]thiazol-5-yl}-1 H-pyrazolo[3 ,4-

40    b]pyridine-4-carboxylic acid (3-morpholin-4-ylpropyl)amide;

6-{2-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-

b]pyridine-4-carboxylic acid (2-piperazin-1-ylethyl)amide;

6-{2 -[3-(2-fluo ro-5-trifluoromethyl phenyl)u re ido ]th iazol-5-yl}-1 H-pyrazolo[3 ,4-b]pyridine-4-carboxylic acid (2-piperidin-4-ylethyl)amide;

6-{2 -[3-(2 -fluo ro-5-trifluo ro methylphen yl) ureido ]thiazol-5-yl}-1 H-pyrazo lo[3,4-b]pyridine-4-carboxylic acid [3-( 4-methylpiperazin-1-yl)propyl]amide; 6-{2 -[3-(2 -fluo ro-5-trifl uoro methylphenyl)u rei do ]thiazol-5-yl}-1 H-pyrazo lo[3 ,4-b]pyridine-4-carboxylic acid (2-hydroxyethyl)amide; 6-{2-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-
IO    b]pyridine-4-carboxylic acid (2-methoxyethyl)amide;

6-{2 -[3-(2 -fluo ro-5-triflu oromethylphenyl) urei do ]th iazol-5-yl}-1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid (pyridin-4-ylmethyl)amide; 6-{2-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (pyridin-2-ylmethyl)amide;

15    1-(2-fluoro-5-trifluoromethylphenyl)-3-{5-[4-(2-hydroxymethylpyrrolidine-1-carbonyl)-1 H-pyrazolo[3,4-b ]pyridin-6-yl]thiazol-2-yl}urea;

6-{2 -[3-(2-fluo ro-5-trifluoromethylphenyl) u rei do ]th iazol-5-yl}-1 H-pyrazo lo[3, 4-b]pyridine-4-carboxylic acid [3-(2-hydroxymethylpyrrolidin-1-yl)propyl]amide; 1-(2-fluoro-5-trifl uoromethylphenyl)-3-{ 5-[ 4-(2-hyd roxymeth yl piperazine-1-
20    carbonyl)-1 H-pyrazolo[3,4-b]pyridin-6-yl]thiazol-2-yl}urea;

6-{3-[3-(2 -fl uoro-5-trifluoro methyl phenyl)u rei do ]phenyl}-1 H-pyrazo lo[3 ,4-b]pyridine-4-carboxylic acid methylamide;

6-{3-[3-(2 -flu o ro-5-trifluoromethylphenyl)u rei do ]phenyl}-1 H-pyrazolo [3 ,4-

b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

25    6-{ 5-[3-(2 -fluo ro-5-trifluoromethylphenyl) ureido] isoxazol-3-yl}-1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(2 -fluo ro-5-trifluo ro methylphenyl)u rei do ]thiazol-5-yl}-1 H-pyrazo lo[3 ,4-b]pyridine-4-carboxylic acid (pyridin-3-ylmethyl)amide;

6-{2 -[3-(2 -fluoro-5-trifluoromethyl pherwl)u reido ]th iazol-5-yl}-1 H-pyrazo lo [3 ,4-

30    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}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{5-[3-(2 -fluo ro-5-trifluo ro methylphenyl) ureido ]th io phen-2 -yl}-1 H-pyrazolo [3, 4-

b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

35    6-{2 -[3-(3-trifl uoro methyl phenyl) ureido ]th iazol-5-yl}-1 H-pyrazolo[3 ,4-b]pyrid ine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(3-triflu o romethylsulphanylphenyl)ureido ]th iazol-5-yl}-1 H-pyrazolo[3 ,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(3-fluoro-5-trifluoro methylphenyl)ureido ]thiazol-5-yl}-1 H-pyrazolo[3 ,4-40 b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;
 
6-{2 -[3-(4-fluo ro-3-trifluoromethylphenyl)u rei do]th iazol-5-yl}-1 H-pyrazo lo[3, 4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide; 6-{2-[3-(2-chlorophenyl)ureido ]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide; 6-{2-[3-(3-chlorophenyl)ureido ]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[ 3-(2-fluo ro-3-trifluoromethylphenyl)u rei do]th iazol-5-yl}-1 H-pyrazo lo[3, 4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(3-ch loro-4-fluorophenyl)u reido ]thiazol-5-yl}-1 H-pyrazolo[3 ,4-b ]pyrid ine-4-

IO    carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(2 -methoxyphenyl)u rei do ]thiazol-5-yl}-1 H-pyrazolo[3 ,4-b]pyrid ine-4-

carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2-[3-(2 ,5-difluorophenyl)ureido ]th iazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-

carboxylic acid (2-morpholin-4-ylethyl)amide;

15    6-{2 -[3-(2, 4-d ifluorophenyl) ureido]th iazol-5-yl}-1 H-pyrazolo[3, 4-b]pyrid ine-4-carboxylic acid (2-morpholin-4-ylethyl)amide; 6-{2-[3-(4-trifluoromethylphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2-[3-(2-fluorophenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-

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

4-carboxylic acid (2-morpholin-4-ylethyl)amide;

25    6-{2-[3-(3-cya nophenyl)ureid o ]th iazol-5-yl}-1 H-pyrazolo[3 ,4-b]pyrid i ne-4-carboxylic acid (2-morpholin-4-ylethyl)amide; 6-{2-[3-(3-methoxyphenyl)ureido]thiazol-5-yl}-1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(4-ch lorophenyl)u rei do]th iazol-5-yl}-1 H-pyrazolo[3, 4-b]pyrid ine-4-

30    carboxylic acid (2-morpholin-4-ylethyl)amide;

6-{2 -[3-(2 ,4-d imethoxyphenyl)u rei do ]th iazo 1-5-yl}-1 H-pyrazolo[3 ,4-b]pyrid i ne-4-carboxylic acid (2-morpholin-4-ylethyl)amide.

13.    Product according to any one of Claims 1 to 11, characterized in that it is chosen

from:

35    N-[4-(4-(2-morpholin-4-ylethyl)aminocarbonyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl]-3-chlorobenzenesulphonamide; N-[4-(4-(piperazine-1-carbonyl)-1 H-pyrazolo[3,4-b]pyridin-6-yl)phenyl]-2,3-

dichlorobenzenesulphonamide;

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

40    trifluoromethylbenzenesulphonamide;

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

fluorobenzenesulphonamide;

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

dichlorobenzenesulphonamide;

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

dichlorobenzenesulphonamide.

14.    Product according to any one of the preceding claims, characterized in that it is in:

a)    non-chiral form, or

b)    racemic form, or

c)    a form enriched in a stereoisomer, or

d)    a form enriched in an enantiomer; and in that it is optionally salified.
15.    Medicament, characterized in that it comprises a product of formula (I) according to any one of Claims 1 to 14, or an addition salt of this compound with a pharmaceutically acceptable acid, or else a hydrate or a solvate of the product of formula (I).

16.    Pharmaceutical composition comprising a product according to any one of the preceding claims, in combination with a pharmaceutically acceptable excipient.
 

20    17. Use of a product according to any one of Claims 1 to 14, for the manufacture of a medicament of use in the treatment of a pathological condition.

18.    Use according to Claim 17, characterized in that the pathological condition is cancer.

19.    Use according to Claim 17 or 18, characterized in that the pathological condition

25    is chosen from rheumatoid arthritis, osteoarthritis and/or its associated pain, inflammatory diseases of the intestine, such as ulcerative colitis or Crohn's disease, eye pathologies such as age-related macular degeneration, diabetic retinopathies, chronic inflammation, psoriasis, and specific cancers such as Kaposi'ssarcoma or infantile haemangioma.

30    20. Use, according to Claims 17 to 19, of a product according to any one of Claims 1 to 14, for the treatment or prevention of a pathological condition, characterized in that the product is administered alone or in combination with other active

ingredients, in particular anticancer agents such as cytotoxic, cytostatic, anti-angiogenic or anti-metastatic products.

21. Products of the general formula (II) below:
J:d~    (II)


R's    N    I

H

in which R'4represents R4 or H, -COOH or -COO-(C1-C6)alkyl, R'3represents H, -NH2 or -NHCO-thienyl, and R's represents a -phenyi-NH2 group or an Ar-L-A group where Ar, L and A are as defined in Claim 1.

10    22. Products of general formula (Ill) below:

R'
j~(
R's    N    Cl    (Ill)

in  which  R'4 represents  R4  or  H,  -COOH  or  -COO-(C -Ce)alkyl,  and  R'
1    6

15    represents an -Ar-NH2 group where Ar is as defined in Claim 1, or an Ar-L-A group where Ar, L and A are as defined in Claim 1.

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