AU2004212733B2

AU2004212733B2 - Novel purine derivatives, preparation method thereof, application of same as medicaments, pharmaceutical compositions and novel use

Info

Publication number: AU2004212733B2
Application number: AU2004212733A
Authority: AU
Inventors: Florence Bordon-Pallier; Jean-Luc Haesslein
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 2003-02-18
Filing date: 2004-02-13
Publication date: 2009-12-24
Anticipated expiration: 2024-02-13
Also published as: DE602004017580D1; CA2515610A1; FR2851248B1; IL170318A; BRPI0407578A; WO2004073595A2; EP1597258B1; MXPA05007519A; JP2006517955A; ATE413401T1; EP1597258A2; FR2851248A1; WO2004073595A3; AU2004212733A1

Abstract

Purine derivatives (I), are new. Purine derivatives of formula (I), their racemic mixtures, enantiomers, diastereoisomers and salts with acids and bases, are new. [Image] Y : N, O, S, CHR 3or =CR 3; R, R 1upto 6C alkyl or upto 6C alkoxy (both optionally substituted by at least one T), or aryl or heteroaryl (both optionally substituted by at least one T or T 1and optionally aryl substituted by dioxolyl), H, halo, OH, , CN, NO 2, NR 4R 5, CF 3, CF 3O, or S(O) n-NR 4R 5; n : 0-2; R 3upto 6C alkyl (optionally substituted by at least one T) or aryl (optionally substituted by at least one T, T 1or dioxolyl), H, halo, CN, NO 2, NR 4R 5, CF 3or CF 3O; R 2R 4, OR 4, SR or NR 4R 5; R 4, R 5upto 6C alkyl or upto 6C cycloalkyl (both optionally substituted by at least one T) or aryl (optionally substituted by at least one T, T 1or dioxolyl), or H, or NR 4R 54-6 membered heterocyclyl optionally containing at least one O, N or S heteroatom (optionally substituted by at least one T or T 1); T : halo, OH, CN, CF 3, CF 3O, upto 6C alkoxy, aryl, heterocyclyl, acid groups, NHR 4, N-alkyl-R 4, COR 4, COOR 4, CON-(upto 6C alkyl)-R 4or CONHR 4, and T 1alkyl, hydroxyalkyl or phenylalkyl. An independent claim is also included for the preparation of (I). ACTIVITY : Fungicide; Dermatological; Antipsoriatic; Cytostatic; Nootropic; Neuroprotective; Antiallergic; Immunosuppressive; Vasotropic; Antiinflammatory; Cardiovascular-Gen. MECHANISM OF ACTION : Protein kinase inhibitor. In a test for determining inhibition of JNK3 kinase, results showed that trans-N-[6-(5,6-dichloro-2,3-dihydro-1H-indol-1-yl)-9H-purin-2-yl]-1,4-cyclohexane diamine dihydrochloride (Ia) exhibited an IC 50value of 0.29 mu M.

Description

WO 2004/073595 PCT/FR2004/000330 1 NOVEL PURINE DERIVATIVES, PREPARATION METHOD THEREOF, APPLICATION OF SAME AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE The present invention relates to novel purine 5 derivatives, to the method for preparing them, to the novel intermediates obtained, to their application as medicinal products, to the pharmaceutical compositions containing them and to the novel use of such purine derivatives. 10 A subject of the invention is thus novel purine derivatives. The products of the present invention have protein kinase-inhibiting properties. Among the kinases inhibited, mention may in 15 particular be made of cyclin-dependent protein kinases called 'cdk', in particular CDKl and CDK2, GSK, GSK3Beta, CIV1, SARC, SRC kinase ()Abl kinase, CAM kinase II, casein kinase II, EGF-tyrosine kinase, IRK kinase, Map kinase (ERK 42), MEKl kinase, PKA, Protein kinase 20 p5611ck, Zap70, AKT; FAK, JNK3, PLK1. Protein kinases are a family of enzymes which catalyze the phosphorylation of hydroxyl groups of specific protein residues such as tyrosine, serine or threonine residues. Such phosphorylations can widely 25 modify the function of the protein; thus, protein kinases play an important role in regulating a large variety of cell processes, including in particular metabolism, cell proliferation, cell differentiation, cell migration or cell survival. Among the various of cell functions in 30 which the activity of a protein kinase is involved, some processes represent attractive targets for treating cancer-related diseases and also other diseases. Thus, one of the objects of the present invention is to provide compositions which have anticancer activity by 35 acting in particular with respect to kinases. Among the 2 kinases for which a modulation of the activity is sought, mention may in particular be made of FAK (Focal Adhesion Kinase). FAK is a cytoplasmic tyrosine kinase which plays an 5 important role in transduction of the signal transmitted by integrins, a family of heterodimeric cell adhesion receptors. FAK and the integrins are colocalized in perimembrane structures called adhesion plaques. It has been shown, in many cell types, that the activation of 10 FAK, and also its phosphorylation on tyrosine residues and in particular its autophosphorylation on tyrosine 397, are dependent on binding of the integrins to their extracellular ligands and are therefore induced during cell adhesion [Kornberg L, et al. J. Biol. Chem. 267(33): 15 23439-442. (1992)]. The autophosphorylation on tyrosine. 397 of FAK represents a binding site for another tyrosine kinase, Src, via its SH 2 domain [Schaller et al. Mol. Cell. Biol. 14: 1680-1688. 1994; Xing et al. Mol. Cell. Biol. 5: 413-421. 1994]. Src can then phosphorylate FAK 20 on tyrosine 925, thus recruiting the adapter protein Grb2 and inducing, in some cells, activation of the ras and MAP Kinase pathway involved in the control of cell proliferation [Schlaepfer et al. Nature; 372:786-791. 1994; Schlaepfer et al. Prog. Biophy. Mol. Biol. 71:435 25 478. 1999; Schlaepfer and Hunter, J. Biol. Chem. 272:13189-13195. 1997] . The activation of FAK can also induce the jun NH 2 -terminal kinase (JNK) signaling pathway and result in progression of the cells toward the G1 phase of the cell cycle [Oktay et al., J. Cell. 30 Biol.145: 1461-1469. 1999]. Phosphatidylinositol-3-OH kinase (P13-kinase) also binds to FAK on tyrosine 397 and this interaction might be necessary for the activation of P13-kinase [Chen and Guan, Proc. Nat. Acad. Sci. USA. 91: 10148-10152. 1994; Ling et al. J. Cell. Biochem. 73: 35 533-544. 1999]. The FAK/Src complex phosphorylates various substrates such as paxillin and p130CAS in 3 fibroblasts [Vuori et al. Mol. Cell. Biol. 16: 2606-2613. 1996]. The results of many studies support the hypothesis that FAK inhibitors might be useful in the treatment of 5 cancer. Studies have suggested that FAK might play an important role in cell proliferation and/or survival in vitro. For example, in CHO cells, some authors have demonstrated that overexpression of p125FAK leads to an acceleration in G1 to S transition, suggesting that 10 p125FAK promotes cell proliferation [Zhao J.-H et al. J. Cell Biol. 143:1997-2008. 1998]. Other authors have shown that tumor cells treated with FAK antisense oligonucleotides lose their adhesion and enter into apoptosis (Xu et al, Cell Growth Differ. 4:413-418. 15 1996). It has also been demonstrated that FAK promotes cell migration in vitro. Thus, fibroblasts deficient for FAK expression (mice which are knockout for FAK) exhibit a rounded morphology and deficiencies in cell migration in response to chemotactic signals, and these 20 deficiencies are suppressed by re-expression of FAK [DJ. Sieg et al., J. Cell Science. 112: 2677-91, 1999]. Overexpression of the C-terminal domain of FAK (FRNK) blocks the elongation of adherent cells and reduces cell migration in vitro [Richardson A. and Parsons J.T. 25 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 cell proliferation and migration in many cell types in vitro suggests a potential role for FAK in neoplastic 30 processes. A recent study has effectively demonstrated an increase in tumor cell proliferation in vivo after induction of FAK expression in human astrocytoma cells [Cary L.A. et al. J. Cell Sci. 109: 1787-94, 1996; Wang D et al. J. Cell Sci. 113: 4221-4230, 2000]. In addition, 35 immunohistochemical studies of human biopsies have demonstrated that FAK is overexpressed in prostate, 4 breast, thyroid, colon, melanoma, brain and lung cancers, the level of expression of FAK being directly correlated with the tumors exhibiting the most aggressive phenotype [Weiner TM, et al. Lancet 342(8878): 1024-1025. 1993; 5 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]. Studying the molecular mechanisms which control the cell cycle has made it possible to demonstrate the role 10 of the cdks thus defined: these Cdks are essential regulators of the cycle of cell division; cdks are proteins consisting of at least two subunits, a catalytic subunit (of which cdc2 is the prototype) and a regulatory subunit (cyclin) . A certain number of cdks are thus 15 known. Cdks therefore form protein complexes, each one of which is involved in a phase of the cell cycle. Many documents in the literature describe the existence and the role of cdks and, by way of example, mention may in particular be made of document 20 WO 97/20842. Several kinase inhibitors have been described, such as butyrolactone, flavopiridol and 2(2-hydroxyethyl amino)-6-benzylamino-9-methylpurine (called olomoucine). Such Cdk-activating protein kinases are in 25 particular those of pathogenic fungi which cause infectious diseases in a human organism. In the context of the present invention, as pathogenic fungi, mention may be made of Candida albicans, but, for example, and equally: Candida 30 stellatoidea, Candida tropicalis, Candida parapsilosis, Candida krusei, Candida pseudotropicalis, Candida quillermondii, Candida glabrata, Candida lusianiae or Candida rugosa or else mycetes of the Saccharomyces cerevisiae type, or of the Aspergillus or Cryptococcus 35 type, and in particular, for example, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, 5 Histoplasma capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliens and Sporothrix schenckii or else mycetes of the phycomycetes or eumycetes classes, in particular the subclasses of basidiomycetes, ascomycetes, 5 mehiascomycetales (yeast) and plectascales, gymnascales (fungi of the skin and of the hair), or of the hyphomycetes class, in particular the subclasses conidiosporales and thallosporales, among which the following species: mucor, rhizopus, coccidioides, 10 paracoccidioides (blastomyces, brasiliensis), endomyces (blastomyces), aspergillus, menicilium (scopulariopsis), trichophyton, epidermophton, microsporon, piedraia, hormodendron, phialophora, sporotrichon, cryptococcus, candida, geotrichum, trichosporon or else toropsulosis, 15 pityriasis Versicolor or Erythrasma. Among such pathogenic fungi, mention may be made most particularly of Candida albicans. It may be noted that the first Cdk-activating kinases of fungi were identified in Saccharomyces 20 cerevisiae and Schizosaccharomyces pombe. The activation of Cdks requires both the binding of a cycline molecule and the phosphorylation of the Cdk on a conserved threonine residue, located in a region referred to as 'T loop' . It has been shown that this phosphorylation is 25 carried out by a kinase referred to as 'Cdk-activating kinase' or 'CAK'. By way of additional information regarding these 'CAKs', mention may be made of the contents of the documents referenced as follows: - 'Solomon, Trends Biochem. Sci. 19, 496-500 (1994) 30 - 'Buck et al, EMBO J., 14(24), 6173-83 (1995) - 'Damagnez et al, EMBO J., 14(24), 6164-72 (1995) In the yeast Saccharomyces cerevisiae, a kinase responsible for CAK activity has been identified, and named CIV1. 35 By way of additional information regarding these 'CIVl's, mention may be made of the contents of the 6 documents referenced as follows: - Thuret et al, Cell, 86(4), (1996) - Kaldis et al, Cell, 86(4), 553-564 (1996), - Espinosa et al, Science, 273(5282), 1714-1717 (1996) 5 Such a CAK activity as defined above, essential for cell survival and division, has been found and identified in pathogenic fungi such as in particular Candida albicans: the sequence of the gene encoding this CIVl protein in Candida albicans, called CaCIV1, and the 10 CaCIV1 protein, have been identified. Such a sequence and its protein are clearly defined in French patent application No. 9710287. Such protein kinase inhibitors can in particular have antiproliferative properties. 15 Products of formula (I) as defined below which have fungal CIV1 protein kinase-inhibiting properties have now been found, these protein kinases being Cdk-activating, and this is in particular the subject of the present invention. 20 Thus, the present invention relates to products of formula (I) as defined below which can in particular have inhibitory properties for such a CIV1 protein which can be found in various fungi as defined above. The present invention thus in particular relates to 25 products of formula (I) as defined below which may have more particularly inhibitory properties for the CaCIV1 protein kinase of Candida albicans as defined above and described in French patent application No. 9710287. Such inhibitors of a CIV1 protein essential for cell 30 survival in yeasts can be used as antifungal agents, either as medicinal products or on an industrial scale. Their inhibitory properties thus make it possible to use products of the present invention as fungicides for treating diseases caused by such pathogenic fungi. 35 The spectrum of known fungal infections extends from fungal attack of the skin or the nails to more serious 7 mycotic infections of internal organs. Such infections and the diseases which result therefrom are identified as mycoses. Antimycotic substances with fungistatic or fungicidal effects are used to treat these mycoses. 5 The present invention also relates to the method for preparing such inhibitors, their use as an antifungal agent and the pharmaceutical compositions containing such inhibitors. A subject of the present invention is thus the 10 products of formula (I) : y DORi N N N NI N" R2 H N in which: 15 Y represents N, 0, S, CHR3 or =CR3 the dashed line on the ring indicating that the corresponding bond is single or double, R and R1, which may be identical or different, represent hydrogen, halogen, hydroxyl, alkyl, alkoxy, cyano, NO 2 , 20 NR4R5, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, -S(O)n-NR4R5, acyl, -NH-CO-alkyl or -NH-CO-NH-phenyl in which the alkyl and phenyl radicals are optionally substituted with one or more radicals chosen from thienyl and phenyl which is itself optionally 25 substituted, these phenyl radicals being themselves optionally substituted with one or more radicals chosen from halogen atoms and the radicals -NH2, -NHAlk and -N(Alk)2, n represents an integer of 0 to 2, 30 R3 represents hydrogen, halogen, alkyl, cyano, NO 2 , NR4R5, trifluoromethyl, aryl, 8 R2 represents a radical R4, OR4, SR4 or NR4R5 in which R4 represents a hydrogen atom or an alkyl, cycloalkyl or aryl radical, NR4R5 being such that either R4 and R5, which may be 5 identical or different, are chosen from the values for R4 or R4 and R5 form, together with the nitrogen atom to which they are attached, a cyclic radical containing 4 to 6 ring members containing one or more hetero atoms, which may be identical or different, chosen from N, 0 and S, 10 all the alkyl, alkoxy, cycloalkyl, aryl and heterocyclic radicals defined above being optionally substituted with one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, aryl and heterocyclic radicals, radicals with an acid and acid 15 isostere function and the radicals -NHR4, -NalkR4, -COR4, -COOR4, -CONalkR4 and -CONHR4 in which R4 has the meaning given above and alk represents an alkyl radical, all the aryl and heterocyclic radicals defined above also being optionally substituted with one or more alkyl, 20 hydroxyalkyl and phenylalkyl radicals, all the aryl radicals defined above also being optionally substituted with a dioxol radical, all the alkyl and alkoxy radicals defined above being linear or branched and containing at most 6 carbon atoms, 25 all the cycloalkyl radicals defined above containing at most 6 carbon atoms, wherein R, R1, R2 and R3 are not hydrogen, said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, 30 and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I). A subject of the present invention is thus the products 35 of formula (I) as defined above, in which: Y represents N, 0, S, CHR3 or =CR3 the dashed line on the ring indicating that the 9 corresponding bond is single or double, R and R1, which may be identical or different, represent hydrogen, halogen, hydroxyl, alkyl, alkoxy, cyano, NO 2 , NR4R5, trifluoromethyl, trifluoromethoxy, aryl, hetero 5 aryl, -S (0) n-NR4R5, n represents an integer of 0 to 2, R3 represents hydrogen, halogen, alkyl, cyano, NO 2 , NR4R5, trifluoromethyl, aryl, 10 R2 represents a radical R4, OR4, SR4 or NR4R5 in which R4 represents a hydrogen atom or an alkyl, cycloalkyl or aryl radical, NR4R5 being such that either R4 and R5, which may be identical or different, are chosen from the values for R4 15 or R4 and R5 form, together with the nitrogen atom to which they are attached, a cyclic radical containing 4 to 6 ring members containing one or more hetero atoms, which may be identical or different, chosen from N, 0 and S, all the alkyl, alkoxy, cycloalkyl, aryl and heterocyclic 20 radicals defined above being optionally substituted with one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy, aryl and heterocyclic radicals, radicals with an acid or acid isostere function and the radicals -NHR4, -NalkR4, -COR4, 25 -COOR4, -CONalkR4 and -CONHR4 in which R4 has the meaning given above and alk represents an alkyl radical, all the aryl and heterocyclic radicals defined above also being optionally substituted with one or more alkyl, hydroxyalkyl and phenylalkyl radicals, 30 all the aryl radicals defined above also being optionally substituted with a dioxol radical, all the alkyl and alkoxy radicals defined above being linear or branched and containing at most 6 carbon atoms, all the cycloalkyl radicals defined above also containing 35 at most 6 carbon atoms, said products of formula (I) being in all the possible 10 racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I). 5 In the products of formula (I) and in the following text: - the term 'linear or branched alkyl radical' denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl 10 radicals and also heptyl, octyl, nonyl and decyl radicals and their linear or branched positional isomers, - the term 'linear or branched alkoxy radical' denotes methoxy, ethoxy, propoxy, isopropoxy and linear, secondary or tertiary butoxy radicals and pentoxy or 15 hexoxy radicals and their linear or branched positional isomers, - the term 'acyl radical or radical r-CO-' denotes a linear or branched radical containing at most 12 carbon atoms, in which the radical r represents a hydrogen atom, 20 or an alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, these radicals having the optionally substituted values given above or below: thus, the acyl radical represents in particular CO-alkyl, CO-aryl or CO-heteroaryl. Mention 25 may be made, for example, of formyl, acetyl, propionyl, butyryl or benzoyl, or else valeryl, hexanoyl, acryloyl, crotonoyl, carbamoyl, pyrrolidinylcarboxyl or else furyl carboxyl radicals, - the term 'halogen atom' preferably denotes a chlorine 30 atom, but may also represent a fluorine, bromine or iodine atom, - the term 'cycloalkyl radical' denotes cyclopropyl and cyclobutyl radicals and most particularly cyclopentyl and cyclohexyl radicals, 35 - the term 'aryl radical' denotes unsaturated radicals, monocyclic radicals or radicals consisting of condensed 11 rings which are carbocyclic. As examples of such an aryl radical, mention may be made of phenyl or naphthyl radicals, - the term 'heterocyclic radical' denotes a saturated or 5 unsaturated radical consisting at most of 6 ring members such that one or more of the ring members represents an oxygen, sulfur or nitrogen atom: such a heterocyclic radical thus denotes a carbocyclic radical interrupted with one or more hetero atoms chosen from oxygen, 10 nitrogen and sulfur atoms, it being understood that the heterocyclic radicals can contain one or more hetero atoms chosen from oxygen, nitrogen and sulfur atoms and that, when these heterocyclic radicals comprise more than one hetero atom, the hetero atoms of these heterocyclic 15 radicals may be identical or different. Mention may in particular be made of the dioxolane, dioxane, dithiolane, thiooxolane, thiooxane or piperazinyl radical, the piperazinyl radical substituted with a linear or branched alkyl radical containing at most 4 carbon atoms, the 20 thienyl radical such as 2-thienyl and 3-thienyl, the furyl radical such as 2-furyl, the pyridyl radical such as 2-pyridyl, 3-pyridyl or 4-pyridyl, and the pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl, tetrazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, 25 oxadiazolyl, 3-isoxazolyl or 4-isoxazolyl radical; mention may also be made of condensed heterocyclic groups containing at least one hetero atom chosen from sulfur, nitrogen and oxygen, for example benzothienyl such as 3-benzothienyl, benzofuryl, benzopyrrolyl, 30 benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl. Mention may most particularly be made of thienyl radicals such as 2-thienyl and 3-thienyl, furyl radicals such as 2-furyl, and tetrahydrofuryl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl and pyrrolidinyl 35 radicals, - the term 'acid or acid isostere function' denotes a 12 free, salified or esterified carboxyl radical, a free or salified tetrazolyl radical, or the radicals:

-SO

3 H, -PO (OH) 2, NH-S0 2

-CF

3 , -NH-S0 2 -NH-V, NH-S0 2

-NH-CO

V, NH-CO-V, -NH-CO-NH-V, -NH-CO-NH-SO 2 -V, -S0 2 -NH-, 5 -S0 2 -NH-CO-V, -S0 2 -NH-CO-NH-V, -CO-NH-V, -CO-NH-OH, -CO NH-S0 2 -V in which V represents a linear or branched alkyl or alkenyl radical containing at most 6 carbon atoms or a phenyl radical, these alkyl, alkenyl and phenyl radicals 10 represented by V optionally being substituted with the substituents indicated above for the alkyl and phenyl radicals of the products of formula (I). The carboxyl radical(s) of the products of formula (I) may be salified or esterified with diverse groups 15 known to those skilled in the art, among which mention may, for example, be made of: - among the salification compounds, inorganic bases such as, for example, an equivalent of sodium, of potassium, of lithium, of calcium, of magnesium or of ammonium, or 20 organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclo hexylamine, morpholine, benzylamine, procaine, lysine, 25 arginine, histidine or N-methylglucamine, - among the esterification compounds, the alkyl radicals for forming alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals possibly being 30 substituted with radicals chosen, for example, from halogen atoms, and hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, 35 benzyl or phenethyl groups. The addition salts with inorganic or organic acids 13 of the products of formula (I) may, for example, be the salts formed with hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic, maleic, fumaric, 5 succinic, tartaric, citric, oxalic, glyoxylic, aspartic or ascorbic acids, alkylmonosulfonic acids such as, for example, methanesulfonic acid, ethanesulfonic acid or propanesulfonic acid, alkyldisulfonic acids such as, for example, methanedisulfonic acid, alpha,beta 10 ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid, and aryldisulfonic acid. It may be recalled that stereoisomerism can be defined, in its broad sense, as the isomerism of compounds having the same structural formulae, but the 15 various groups of which are arranged differently in space, such as, in particular, in monosubstituted cyclohexanes, the substituent of which may be in the axial or equatorial position, and the various possible rotational conformations of ethane derivatives. However, 20 another type of stereoisomerism exists, due to the different spatial arrangements of substituents attached either on double bonds or on rings, which is often referred to as geometrical isomerism or cis-trans isomerism. The term 'stereoisomers' is used in the 25 present application in its broadest sense and therefore concerns all of the compounds indicated above. A particular subject of the present invention is the products of formula (I) as defined above, corresponding to formula (Ia): R a 3a Ra Raa R a N N R a (1a) H N 2 30 0 14 in which: Ya represents N, 0, S, CHR3a or =CR3a the dashed line on the ring indicating that the corresponding bond is single or double, 5 Ra and Rla, which may be identical or different, represent hydrogen, halogen, hydroxyl, alkyl, alkoxy, cyano, NO 2 , NR4aR5a, trifluoromethyl, trifluoromethoxy, phenyl, heteroaryl, -S (0) n-NR4aR5a, 10 n represents an integer of 0 to 2, R3a represents hydrogen, halogen, alkyl, cyano, NO 2 , amino, alkylamino, dialkylamino, trifluoromethyl and phenyl, R2a represents a radical R4a, OR4a, SR4a or NR4aR5a in 15 which R4a represents a hydrogen atom or an alkyl, cycloalkyl or phenyl radical, NR4aR5a being such that either R4a and R5a, which may be identical or different, are chosen from the values for R4a, or R4a and R5a form, together with the nitrogen atom 20 to which they are attached, an optionally substituted piperidyl, morpholinyl, pyrrolidinyl or piperazinyl radical, all the alkyl, alkoxy, cycloalkyl, phenyl, phenylalkyl and heterocyclic radicals defined above being optionally substituted with one or more radicals chosen 25 from halogen atoms, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy and phenyl radicals, a heterocyclic radical such as, for example, tetrahydropyranyl or piperidyl optionally substituted on N or C with a carboxyl radical which is free, salified or 30 esterified with an alkyl radical, the radicals SO 3 H,

PO(OH)

2 , NH-S0 2

-CF

3 , NH-S 2 -NH-V and NH-S0 2 -NH-CO-V in which V represents a phenyl, alkyl or alkenyl radical, the alkenyl radicals being linear or branched containing at most 6 carbon atoms, and the radicals -NalkR4a, 35 -NHR4a, -COR4a, -COOR4a, -CONalkR4a and -CONHR4a in which R4a has the meaning indicated above and alk represents an 15 alkyl radical, all the phenyl and heterocyclic radicals defined above also being optionally substituted with one or more alkyl, hydroxyalkyl or phenylalkyl radicals, 5 all the phenyl radicals defined above also being optionally substituted with a dioxol radical, all the alkyl and alkoxy radicals defined above being linear or branched and containing at most 6 carbon atoms, all the cycloalkyl radicals defined above containing 5 or 10 6 carbon atoms, said products of formula (Ia) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and 15 organic bases of said products of formula (Ia). It may be noted that, when R2a represents a radical NR4aR5a, R2a represents in particular the radical NH-Rya in which Rya represents the radical: D~a_ 2 20 in which Dla and D2a, which may be identical or different, are either chosen from a hydrogen atom, a hydroxyl radical, linear or branched alkyl or alkoxy radicals containing at most 6 carbon atoms, and the radicals NHR5a, or together form the radical =0 or 25 =N-OR4a, R4a represents a hydrogen atom, or an alkyl, cycloalkyl or phenyl radical, R5a represents a hydrogen atom, an alkyl or cycloalkyl radical or the radical -COOtBu (Boc). 30 A more particular subject of the present invention is the products of formula (I) as defined above, corresponding to formula (Ib): 16 Ra b Rb R 3 b-, -Rb N N1 N N N R2b (Ib) N H in which: Yb represents N, CHR3b or =CR3b the dashed line on the ring indicating that the 5 corresponding bond is single or double, Rb and Rlb, which may be identical or different, represent hydrogen, halogen, hydroxyl, alkyl, alkoxy, cyano, NO 2 , trifluoromethyl, trifluoromethoxy, phenyl, -S (O)n-NR4bR5b, 10 n represents an integer of 0 to 2, R3b represents hydrogen, halogen, alkyl, cyano, NO 2 , amino, alkylamino, dialkylamino, trifluoromethyl and phenyl, R2b represents a radical R4b or NR4bR5b in which R4b 15 represents a hydrogen atom or an alkyl, cycloalkyl or phenyl radical, NR4bR5b being such that either R4b and R5b, which may be identical or different, are chosen from the values for R4b, or R4b and R5b form, together with the nitrogen atom 20 to which they are attached, an optionally substituted piperidyl, morpholinyl or pyrrolidinyl radical, all the alkyl, alkoxy, cycloalkyl, phenyl and phenylalkyl radicals and heterocyclic radicals, such as piperidyl, morpholinyl and pyrrolidinyl, defined above being 25 optionally substituted with one or two radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkoxy and phenyl radicals, and tetrahydropyranyl and piperidyl radicals, themselves optionally substituted on N or C with a carboxyl radical 30 which is free, salified or esterified with an alkyl radical, and the radicals -NalkR4a, -NHR4a and -COOR4a in 17 which R4a has the meaning indicated above and alk represents an alkyl radical, all the phenyl and heterocyclic radicals defined above also being optionally substituted with one or more alkyl, 5 hydroxyalkyl and phenylalkyl radicals, all the alkyl and alkoxy radicals defined above being linear or branched and containing at most 4 carbon atoms, all the cycloalkyl radicals defined above containing 5 or 6 carbon atoms, 10 said products of formula (Ib) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (Ib). 15 It may be noted that, when R2b represents a radical NR4bR5b, R2b represents in particular the radical NH-Ryb in which Ryb represents the radical: D b

D

2 in which Dlb and D2b, which may be identical or 20 different, are either chosen from a hydrogen atom, a hydroxyl radical, linear or branched alkyl and alkoxy radicals containing at most 4 carbon atoms, and the radicals NHR5b, or together form the radical =0 or =N-OR4b, 25 R4b represents a hydrogen atom, an alkyl radical containing at most 4 carbon atoms, phenyl, -CH 2 -phenyl or a cycloalkyl radical containing at most 6 carbon atoms optionally substituted with the radical -NHR3b, R5b represents a hydrogen atom, an alkyl or cycloalkyl 30 radical containing at most 6 carbon atoms, or the radial -COOtBu (Boc). An even more particular subject of the present invention is the products of formula (I) as defined above, corresponding to formula (Ic): 18 YC Rc N N N

R

2 c (c) H N in which: Yc represents N, CH 2 or CH=, the dashed line on the ring indicating that the 5 corresponding bond is single or double, Rc and Rlc, which may be identical or different, represent hydrogen, halogen, hydroxyl, alkyl, alkoxy, phenylalkoxy, phenylalkyl, cyano, NO 2 , trifluoromethyl, trifluoromethoxy, phenyl, -S (O)n-NH 2 optionally 10 substituted on the nitrogen atom with one or two alkyl radicals and n represents an integer of 0 to 2, R3c represents hydrogen, halogen, alkyl, cyano, NO 2 , trifluoromethyl and phenyl, R2c represents a radical NR4cR5c in which either R4c and 15 R5c, which may be identical or different, are such that R4c represents a hydrogen atom or an alkyl, cycloalkyl, phenyl or phenylalkyl radical, the alkyl, cycloalkyl, phenyl and phenylalkyl radicals being optionally substituted with one or more radicals 20 chosen from hydroxyl, amino or carboxyl which is free, salified or esterified with an alkyl radical, tetrahydropyrannyl radical or piperidyl radical, optionally substituted on N or C with a carboxyl radical which is free, salified or esterified with an alkyl 25 radical, and R5c represents a hydrogen atom or an alkyl radical, or R4c and R5c form, together with the nitrogen atom to which they are attached, a piperidyl, morpholinyl or pyrrolidinyl radical, these radicals being optionally 30 substituted with an alkyl, hydroxyalkyl, amino, monoalkylamino or dialkylamino radical, 19 all the alkyl and alkoxy radicals defined above being linear or branched containing at most 4 carbon atoms, said products of formula (Ic) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, 5 and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (Ic). It may be noted that, when Ryc represents the radical: D 2 C 10 in which Dlc and D2c, which may be identical or different, are either chosen from a hydrogen atom, a hydroxyl radical, linear or branched alkyl and alkoxy radicals containing at most 4 carbon atoms, and the 15 radicals -NH 2 , -NH-COOtBu or -NHalkyl in which the linear or branched alkyl radical contains at most 4 carbon atoms, or together form the radical =0 or =N-Oalkyl, in which the linear or branched alkyl radical contains at most 4 carbon atoms. 20 Ryd represents in particular the radical:

D

1d

D

2 d_ in which Did and D2d, which may be identical or different, are chosen from a hydrogen atom, a hydroxyl radical, linear or branched alkyl and alkoxy radicals 25 containing at most 4 carbon atoms, and the radicals -NH 2 , -NH-COOtBu or -NHalkyl in which the linear or branched alkyl radical contains at most 4 carbon atoms, or together form the radical =0 or =N-Oalkyl, in which the linear or branched alkyl radical contains at most 4 30 carbon atoms. Rye represents in particular the radical: 20

D

2 e , : in which one of Die and D2e represents a hydrogen atom and the other the radical -NH 2 optionally substituted with a radical -COOtBu or -alkyl in which the linear or 5 branched alkyl radical contains at most 4 carbon atoms. A most particular subject of the present invention is the products of formula (I) as defined above, corresponding to formula (Id): Rad d R-Rd R 3 d Rd N N N N R d (Id) N: 2 H 10 in which: Yd represents N, CH 2 or CH=, the dashed line on the ring indicating that the corresponding bond is single or double, Rd and Rld, which may be identical or different, 15 represent hydrogen, halogen, alkyl, alkoxy, phenylalkoxy,

NO

2 , dialkylaminosulfonyl, -NH 2 , trifluoromethyl, -CO-CH 3 , -NH-CO-alkyl or -NH-CO-NH-phenyl in which the alkyl radical is optionally substituted with a thienyl or phenyl radical and the phenyl radical is optionally 20 substituted with one or more radicals chosen from the halogen atoms and the radicals -NH 2 , -NHAlk and N(Alk)2, R3d represents hydrogen or alkyl, R2d represents a radical NR4dR5d in which either R4d and R5d, which may be identical or different, are such that 25 R4d represents a hydrogen atom, a linear or branched alkyl radical containing 1 to 4 carbon atoms and optionally substituted with one or two hydroxyl(s), a cycloalkyl radical optionally substituted with an amino or hydroxyl radical or a phenyl or phenylalkyl (1 to 4 C) 21 radical with phenyl optionally substituted with a carboxyl radical which is free, salified or esterified with an alkyl radical, a tetrahydropyranalkyl radical (Ex 28), or a piperidylalkyl radical (Ex 31, 36) 5 optionally substituted on N or C with a carboxyl radical, and R5d represents a hydrogen atom or an alkyl radical, or R4d and R5d form, together with the nitrogen atom to which they are attached, a piperidyl radical optionally substituted with an amino radical, a morpholinyl radical 10 or a pyrrolidinyl radical optionally substituted with a hydroxyalkyl radical, all the alkyl and alkoxy radicals defined above being linear or branched containing at most 4 carbon atoms, said products of formula (Id) being in all the possible 15 racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (Id). A subject of the present invention is thus most 20 particularly the products of formula (I) as defined above, corresponding to formula (Id) in which: Yd represents N, CH 2 or CH=, the dashed line on the ring indicating that the corresponding bond is single or double, 25 Rd and Rld, which may be identical or different, represent hydrogen, halogen, alkyl, alkoxy, phenylalkoxy,

NO

2 , dialkylaminosulfonyl, R3d represents hydrogen or alkyl, R2d represents a radical NR4dR5d in which either R4d and 30 R5d, which may be identical or different, are such that R4d represents a hydrogen atom, a linear or branched alkyl radical containing 1 to 4 carbon atoms and optionally substituted with one or two hydroxyl(s), a cycloalkyl radical optionally substituted with an amino 35 or hydroxyl radical, a phenyl radical or a phenyl (Ci-C 4 ) alkyl radical with phenyl optionally 22 substituted with a carboxyl radical which is free, salified or esterified with an alkyl radical, tetrahydropyranalkyl radical or piperidylalkyl radical, optionally substituted on N or C with a carboxyl radical, 5 and R5d represents a hydrogen atom or an alkyl radical, or R4d and R5d form, together with the nitrogen atom to which they are attached, a piperidyl radical optionally substituted with an amino radical, morpholinyl radical or pyrrolidinyl radical optionally substituted with a 10 hydroxyalkyl radical, all the alkyl and alkoxy radicals defined above being linear or branched containing at most 4 carbon atoms, said products of formula (Id) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the 15 pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (Id). A most particular object of the present invention is the products of formula (I) as defined above, having the 20 following names: - trans-N-[6-(5,6-dichloro-2,3-dihydro-lH-indol-1-yl)-9H purin-2-yll-1,4-cyclohexanediamine dihydrochloride - trans-N-[6-(1H-benzimidazol-1-yl)-9H-purin-2-yl]-1,4 cyclohexanediamine dihydrochloride 25 - trans-N-[6-(5,6-dimethyl-lH-benzimidazol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine - trans-N-[6-(5,6-dichloro-lH-benzimidazol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine hydrochloride - trans-N-[6-(5-methoxy-lH-benzimidazol-1-yl)-9H-purin-2 30 yll-1,4-cyclohexanediamine dihydrochloride - trans-N-[6-(lH-indol-1-yl)-9H-purin-2-yl]-1,4-cyclo hexanediamine dihydrochloride - trans-N-[6-[6-(phenylmethoxy)-1H-benzimidazol-1-yl]-9H purin-2-yl]-1,4-cyclohexanediamine 35 - trans-N- [6- [5- (phenylmethoxy) -1H-benzimidazol-1-yl]-9H purin-2-yl]-1,4-cyclohexanediamine 23 - trans-4-[[6-(1H-benzimidazol-1-yl)-9H-purin-2-yl] amino]cyclohexanol - trans-N-[6-(2,3-dihydro-5-nitro-lH-indol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine dihydrochloride 5 - trans-N-[6-[2,3-dihydro-6-(trifluoromethyl)-1H-indol-l yl-9H-purin-2-yl]-1,4-cyclohexanediamine (Ex 40) - trans-N- [1- [2- [ (4-aminocyclohexyl)amino]-9H-purin-6 yl]-2,3-dihydro-lH-indol-5-yl]-2-thiopheneacetamide (Ex 41) 10 - trans-N-[6-(6-nitro-2,3-dihydro-lH-indol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine (Ex 44) A subject of the present invention is also a method for preparing the products of formula (I) as defined above, wherein the compound of formula (II): CI N N C1 N N 15 H is subjected to the action of a compound of formula (III): ly R'(I) R N H in which R', R1' and R3' have the meanings indicated 20 respectively in claim 1 for R, R1 and R3, in which the optional reactive functions are optionally protected with protective groups, and Y has the meaning indicated in claim 1, so as to obtain a product of formula (IV): 24 3 N N N (IV) N -CI H N' in which R', Rl', R3' and Y have the meanings indicated above, which product of formula (IV) is subjected to a reaction 5 with a compound of formula (V): R2'-H (V) in which R2' has the meaning indicated in claim 1 for R2 in which the optional reactive functions are optionally protected with protective groups, 10 so as to obtain a product of formula (I'): R 3 R N N N N1 N 2 in which R', R1', R2', R3' and Y' have the meanings indicated above, the products of formula (I') having the meaning indicated 15 in claim 1 for the products of formula (I) in which the optional reactive functions are optionally protected with protective groups, which products of formula (I') can be products of formula (I) and which, so as to obtain other product(s) of 20 formula (I), can be subjected, if desired and if necessary, to one or more of the following conversion reactions, in any order: a) a reaction of esterification of an acid function, b) a reaction of saponification of an ester function to 25 an acid function, 25 c) a reaction of oxidation of an alkylthio group to a corresponding sulfoxide or sulfone, d) a reaction of conversion of a ketone function to an oxime function, 5 e) a reaction of reduction of the free or esterified carboxyl function to an alcohol function, f) a reaction of conversion of an alkoxy function to a hydroxyl function, or else of a hydroxyl function to an alkoxy function, 10 g) a reaction of oxidation of an alkyl function to an aldehyde, acid or ketone function, h) a reaction of conversion of a nitrile radical to a tetrazolyl, i) a reaction of removal of protective groups which the 15 protected reactive functions may carry, j) a reaction of salification with an inorganic or organic acid or with a base so as to obtain the corresponding salt, k) a reaction to resolve the racemic forms into resolved 20 products, said products of formula (I) thus obtained being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms. The products of formula (I') having the meaning 25 indicated above for the products of formula (I) in which the optional reactive functions are optionally protected with protective groups, which products of formula (I') can be products of formula (I) and which, so as to obtain other product(s) of 30 formula (I), can be subjected, if desired and if necessary, to one or more of the following conversion reactions, in any order: a) a reaction of esterification of an acid function, b) a reaction of saponification of an ester function to 35 an acid function, c) a reaction of oxidation of an alkylthio group to a 26 corresponding sulfoxide or sulfone, d) a reaction of conversion of a ketone function to an oxime function, e) a reaction of reduction of the free or esterified 5 carboxyl function to an alcohol function, f) a reaction of conversion of an alkoxy function to a hydroxyl function, or else of a hydroxyl function to an alkoxy function, g) a reaction of oxidation of an alkyl function to an 10 aldehyde, acid or ketone function, h) a reaction of conversion of a nitrile radical to a tetrazolyl, i) a reaction of removal of protective groups which the protected reactive functions may carry, 15 j) a reaction of salification with an inorganic or organic acid or with a base so as to obtain the corresponding salt, k) a reaction to resolve the racemic forms into resolved products, 20 said products of formula (I) thus obtained being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms. It may be noted that such reactions of conversion of the substituents to other substituents can also be 25 carried out on the starting products and also on the intermediates as defined above, before continuing the synthesis according to the reactions indicated in the method described above. Under preferential conditions for implementing the 30 invention, the method described above can be carried out in the following way: The product of formula (II) is therefore 2,6-di chloropurine, which is a commercially available product. The product of formula (II) is subjected to the 35 action of the product of formula (III) as defined above, in particular in an alcohol such as butanol, at a 27 temperature of approximately 80 0 C or at a temperature of approximately 750C for approximately 2 to 3 hours, or in DMF, so as to give a product of formula (IV) as defined above. 5 The product thus obtained, of formula (IV) as defined above, is subjected to the action of a compound of formula (V) under the conditions defined in the experimental section and in particular as indicated below. 10 The compound of formula (V) may in particular represent a compound of formula (XIV), (XV) or (XVI) as defined below: R ' D' (XIV) 1 NR'H D2' R 6' D' OH (XV) 15 D 2 ' R 6' D SH (XVI) D2' compounds of formula (XIV) , (XV) or (XVI) in which D 1 1 ,

D

2 ' and R' 5 have the meanings indicated in claim 1 20 respectively for D1, D2 and R5 in which the optional reactive functions are optionally protected with protective groups and R6' representing one or more substituents which the cycloalkyl radical may carry, in which the optional reactive functions are optionally 25 protected with protective groups. The product of formula (V), namely R2-H, may in particular represent the product (XIV): 28

NH

2 (XIV) D210 in which Dl' and D2' have the meanings indicated above respectively for Dl and D2 in which the optional reactive functions are optionally protected with protective 5 groups. Thus, found among the products of formula (I') are in particular the products of formula (I"): R3- N N N N W in which R', R1', R3', D1', D2' and Y' have the meanings 10 indicated above, in which the optional reactive functions are optionally protected with protective groups, and W represents NH, S or 0, which can be prepared in particular by reacting a product of formula (IV) as defined above with a product of formula (XIV), (XV) or 15 (XVI) as defined above. The reaction of the product of formula (IV) with a compound of formula (XIV), (XV) or (XVI) as defined above, so as to give a product of formula (I'), may in particular be carried out according to a condensation 20 reaction which, where appropriate, may be carried out at a temperature of approximately 140 0 C without solvent: such a condensation reaction may be followed by a reaction of salification in the presence of hydrochloric acid for example or else of tartaric acid, citric acid or 25 methanesulfonic acid, in an alcohol such as, for example, ethanol or methanol, so as to give products of formula (I') as defined above. The amine function of the compounds of formula (I') 29 as defined above can be protected with a group such as Boc or CH 2 -phenyl, and can then be freed under the usual conditions known to those skilled in the art. The saponification reaction can be carried out 5 according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide. The reactions of reduction or oxidation of the 10 product of formula (I') to a product of formula (I) can be carried out according to the usual methods known to those skilled in the art. Depending on the values for Y', R', Rl', R2', R3', D1' and D2', the products of formulae (I') may or may not 15 constitute products of formula (I) and can give products of formula (I) or be converted into other products of formula (I) by being subjected to one or more of the reactions a) to k) indicated above. Thus, the various reactive functions which some 20 compounds of the reactions defined above may carry can, if necessary, be protected: these are, for example, free carboxyl, acyl or hydroxyl radicals or else amino and monoalkylamino radicals which can be protected with the appropriate protective groups. 25 The following nonexhaustive list of examples of protection of reactive functions may be mentioned: - the hydroxyl groups can be protected, for example, with alkyl radicals such as tert-butyl, trimethylsilyl, tert butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, 30 benzyl or acetyl, - the amino groups can be protected, for example, with acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyl oxycarbonyl or phthalimido radicals or other radicals known in peptide chemistry, 35 - the acyl groups, such as the formyl group, can be protected, for example, in the form of ketals or of 30 thioketals which may be cyclic or noncyclic, such as dimethyl or diethyl ketal or ethylene dioxy ketal or diethyl thioketal or ethylene dithioketal, - the acid functions of the products described above can, 5 if desired, be amidated with a primary or secondary amine, for example in methylene chloride in the presence, for example, of 1-ethyl-3- (dimethylaminopropyl) carbo diimide hydrochloride at ambient temperature: - the acid functions can be protected, for example, in 10 the form of esters formed with readily cleavable esters such as benzyl esters or tert-butyl esters or esters known in peptide chemistry. The reactions to which the products of formula (I') as defined above can be subjected, if desired or if 15 necessary, can be carried out, for example, as indicated below. a) The products described above can, if desired, be the subject, on the optional carboxyl functions, of esterification reactions which can be carried out 20 according to the usual methods known to those skilled in the art. b) The optional conversions of ester functions to acid functions of the products described above can, if desired, be carried out under the usual conditions known 25 to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or potassium hydroxide in an alcoholic medium, such as, for example, in methanol, or else with hydrochloric or sulfuric acid. 30 c) The optional alkylthio groups of the products described above can, if desired, be converted into the corresponding sulfoxide or sulfone functions under the usual conditions known to those skilled in the art, such as, for example, with peracids, such as, for example 35 peracetic acid or meta-chloroperbenzoic acid, or else with oxone, sodium periodate in a solvent such as for 31 example methylene chloride or dioxane, at ambient temperature. The obtaining of the sulfoxide function can be promoted with an equimolar mixture of the product 5 containing an alkylthio group and of the reagent such as in particular a peracid. The obtaining of the sulfone function can be promoted with a mixture of the product containing an alkylthio group with an excess of the reagent such as in 10 particular a peracid. d) The reaction of conversion of a ketone function to an oxime function can be carried out under the usual conditions known to those skilled in the art, such as in particular action in the presence of an optionally 0 15 substituted hydroxylamine in an alcohol such as, for example, ethanol, at ambient temperature or by heating. e) The optional free or esterified carboxyl functions of the products described above can, if desired, be reduced to alcohol functions by the methods known to those 20 skilled in the art: the optional esterified carboxyl functions can, if desired, be reduced to alcohol functions by the methods known to those skilled in the art and in particular with lithium aluminum hydride in a solvent such as, for example, tetrahydrofuran or else 25 dioxane or ethyl ether. The optional free carboxyl functions of the products described above can, if desired, be reduced to alcohol functions in particular with boron hydride derivatives. f) The optional alkoxy functions, such as in particular 30 methoxy functions, of the products described above can, if desired, be converted into hydroxyl functions under the usual conditions known to those skilled in the art, for example with boron tribromide in a solvent such as, for example, methylene chloride, with pyridine 35 hydrobromide or hydrochloride, or else with hydrobromic or hydrochloric acid in water or trifluoroacetic acid at 32 ref lux. g) The optional alcohol functions of the products described above can, if desired, be converted into aldehyde or acid functions by oxidation under the usual 5 conditions known to those skilled in the art, such as, for example, by the action of manganese oxide so as to obtain aldehydes or of Jones reagent so as to obtain acids. h) The optional nitrile functions of the products 10 described above can, if desired, be converted into tetrazolyl under the usual conditions known to those skilled in the art, such as, for example, by cycloaddition of a metal azide, such as, for example, sodium azide or an azide of trialkyltin, onto the nitrile 15 function, as indicated in the method described in the article referenced as follows: J. Organometallic Chemistry 33, 337 (1971) KOZIMA S. et al. It may be noted that the reaction of conversion of a 20 carbamate to urea, and in particular of a sulfonylcarbamate to sulfonylurea, can be carried out, for example, at the reflux of a solvent such as, for example, toluene in the presence of the appropriate amine. 25 It is understood that the reactions described above can be carried out as indicated or else, where appropriate, according to other usual methods known to those skilled in the art. i) The removal of protective groups, such as, for 30 example, those indicated above, can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric, benzenesulfonic or para toluenesulfonic acid, or formic or trifluoroacetic acid, 35 or else by catalytic hydrogenation. The phthalimido group can be removed with hydrazine.

33 A list of various protective groups which can be used will for example be found in patent FR 2 499 995. j) The products described above can, if desired, be the subject of salification reactions, for example with an 5 inorganic or organic acid or with an inorganic or organic base, according to the usual methods known to those skilled in the art. k) The optional optically active forms of the products described above can be prepared by resolving the racemic 10 mixtures according to the usual methods known to those skilled in the art. The starting product of formula (II), namely 2,6 dichloropurine, is known and commercially available. Among the starting products of formulae (III) and 15 (V) , some are known and can be obtained commercially or can be prepared according to the usual methods known to those skilled in the art. Among the commercially available starting products of formulae (III), (V), (XIV), (XV) and (XVI), mention 20 may, for example, be made of the following products: as commercially available products of formula (XIV), mention may be made of trans-1,4-diaminocyclohexane, trans-4-aminocyclohexanol or else benzylamine, para methoxybenzylamine or para-fluorobenzylamine. 25 It is also possible in particular to prepare some starting products from commercially available products, for example by subjecting them to one or more of the reactions described above in a) to k), carried out under the conditions also described above. 30 By way of example, mention may also be made of: examples of products of formula (II) as defined above are given below in the preparation of the examples of the present invention. The experimental section below gives examples of such 35 starting products. Finally, a subject of the present invention is, as 34 new industrial products, the compounds of formula (IV) such as in particular the product 6-(lH-benzimidazol-1 yl)-2-chloro-9H-purine. Illustrations of such reactions defined above are 5 given in the preparation of the examples described below. The products of formula (I) as defined above, and also their addition salts with acids, exhibit advantageous pharmacological properties. The products of the present invention as defined 10 above have kinase-inhibiting properties with great selectivity. Cdks play a central role in initiating, developing and concluding the events of the cell cycle and, thus, cdk inhibiting molecules are capable of limiting undesired 15 cell proliferations such as those observed in cancers, psoriasis, fungal growth, and growth of parasites (animals, protists): such cdk-inhibiting molecules are thus also capable of intervening in the regulation of neurodegenerative diseases such as Alzheimer's disease. 20 Kinases which are particularly sensitive to the inhibitory effects of the derivatives of the present invention are in particular cdkl, cdk2, cdk4, cdk5 and cdk7. The products of the present invention therefore 25 possess antimitotic properties. The products of the present invention have, in addition to their kinase-specific inhibiting properties, advantageous cellular effects such as antiproliferative properties and in particular effects on apoptosis. 30 It is known, through studies described in the literature, such as in WO 97/20842, that relationships exist between the cell cycle and apoptosis. Among the pathways leading to apoptosis, some are kinase-dependent. The products of the present invention are in 35 particular of use for the treatment of tumors. The products of the invention can thus also increase 35 the therapeutic effects of commonly used antitumor agents. The products of formula (I) of the present invention therefore have most particularly antimitotic and 5 antineurodegenerative properties. The products of formula (I) as defined above can therefore be used as tyrosine kinase inhibitors: such tyrosine kinases can belong to diverse families such as, for example, the Src family in which are found in 10 particular Src, Fyn, Lck, Yes, Fgr, Hck and Yrk, or else, for example, the Csk, Btk, Abl, Fak, Jak, Syk, Fps, Zap 70, EGF, PDGF and CSF families. Such a list of protein tyrosine kinases is not exhaustive. Among these tyrosine kinase proteins, it may be 15 noted that tyrosine kinase proteins associated with receptors, such as, for example, EGF, PDGF or CSF, and cytoplasmic tyrosine kinase proteins, among which in particular Src, Fyn, Lck, Yes, Fgr, Hck and Yrk, or else Csk, Btk, Abl, Fak, Jak, Syk, Fps and Zap 70, are 20 distinguished. The products of formula (I) as defined above can also be used to inhibit the catalytic (tyrosine kinase) domain of the Src protein, the method consisting in administering, to the patient whose treatment requires 25 inhibition of the catalytic (tyrosine kinase) domain of the Src protein, an inhibitory amount of one or more products of formula (I) as defined above. The products of formula (I) as defined above are most particularly inhibitors of the Src catalytic domain: 30 such inhibitors are thus in particular capable of inhibiting the adhesion of osteoclasts to the surface of bone and thus bone resorption by osteoclasts. The bone diseases for which treatment or prevention requires the use of the products of formula (I) as 35 defined above are in particular osteoporosis, hypercalcemia, osteopenia, for example caused by bone 36 metastases, dental disorders, for example periodontal diseases, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, and immobilization-induced osteopenia. In addition, the 5 products of formula (I) as defined above can be used to relieve, prevent or treat bone disorders which are caused by treatments, by glucocorticoids, therapies associated with the taking of steroids or corticosteroids, or by male or female sex hormone deficiencies. 10 All these disorders are characterized by bone loss, which is based on a deficiency in balance between bone formation and bone destruction and which can be favorably influenced by inhibiting bone resorption by osteoclasts. The products of formula (I) as defined above, by 15 virtue of their affinity with the catalytic (tyrosine kinase) domain of Src, can also be used in other therapeutic applications. For example, it is known that platelets and neurones are tissues which also express the Src protein. In addition, since several proteins of this 20 family are mostly expressed in the hematopoietic system, many applications in the treatment of immunity, of infection, of allergy and of autoimmune diseases can be envisioned. Finally, the products of formula (I) as defined above can 25 also be used to inhibit the catalytic (tyrosine kinase) domain of proteins other than Src, the method consisting in administering, to the patient whose treatment requires inhibition of the catalytic (tyrosine kinase) domain, an inhibitory amount of one or more products of formula (I) 30 as defined above. Such proteins containing the catalytic (tyrosine kinase) domain, other than Src, can therefore be chosen in particular from Fyn, Lck, Yes, Fgr, Hck, Yrk, Csk, Btk, Abl, Fak, Jak, Syk, Fps, Zap 70, EGF, PDGF and CSF. 35 Such a list of protein tyrosine kinases is not exhaustive.

37 The products of formula (I) as defined above can also be used to inhibit the serine/threonine kinase catalytic domain in particular among CDKs. The products of formula (I) as defined above can 5 thus be used in the treatment of diseases such as proliferative diseases, cancer, restenosis, inflammation; allergies or cardiovascular diseases. The products of the present invention as defined above have protein kinase-inhibiting properties as 10 indicated above and in particular inhibitory properties for CIV1 as defined above. CIVls play a central role in entry into the cell cycle via Cdk activation and, thus, the CIVl-inhibiting molecules are capable of limiting undesired cell 15 proliferations such as those observed in fungal growths. The products of formula (I) of the present invention can therefore have antimitotic properties. These properties justify their application in therapeutics, and a subject of the invention is 20 particularly, as medicinal products, the products of formula (I) as defined above, said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the pharmaceutically acceptable addition salts with inorganic 25 and organic acids or with inorganic and organic bases of said products of formula (I). A subject of the invention is more particularly, as medicinal products, the products as defined by formula (Id) as defined above. 30 A subject of the invention is most particularly, as medicinal products, the products described below in the examples, and in particular the products of formula (I) as defined above, corresponding to the following formulae: 35 - trans-N-[6-(5,6-dichloro-2,3-dihydro-lH-indol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine dihydrochloride 38 - trans-N-[6-(1H-benzimidazol-1-yl)-9H-purin-2-yl]-1,4 cyclohexanediamine dihydrochloride - trans-N-[6-(5,6-dimethyl-lH-benzimidazol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine 5 - trans-N-[6-(5,6-dichloro-lH-benzimidazol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine hydrochloride - trans-N-[6-(5-methoxy-1H-benzimidazol-1-yl)-9H-purin-2 yl]-1,4-cyclohexanediamine dihydrochloride - trans-N-[6-(1H-indol-1-yl)-9H-purin-2-yl]-1,4 10 cyclohexanediamine dihydrochloride - trans-N-[6-[6-(phenylmethoxy)-lH-benzimidazol-1-yl]-9H purin-2-yl]-1,4-cyclohexanediamine - trans-N-[6-[5-(phenylmethoxy)-1H-benzimidazol-1-yl]-9H purin-2-yl]-1,4-cyclohexanediamine 15 - trans-4-[[6-(1H-benzimidazol-1-yl)-9H-purin-2 yl]amino]cyclohexanol - trans-N-[6-(2,3-dihydro-5-nitro-lH-indol-1-yl)-9H purin-2-yl]-1,4-cyclohexanediamine dihydrochloride - trans-N-[6-[2,3-dihydro-6-(trifluoromethyl)-1H-indol-1 20 yl)-9H-purin-2-yl]-1,4-cyclohexanediamine (Ex 40) - trans-N-[1-[2-[(4-aminocyclohexyl)amino]-9H-purin-6 yl]-2,3-dihydro-lH-indol-5-yl]-2-thiopheneacetamide (Ex 41) - trans-N-[6-(6-nitro-2,3-dihydro-1H-indol-1-yl)-9H 25 purin-2-yl]-1,4-cyclohexanediamine (Ex 44) The medicinal products, which are the subject of the invention, are, for example, of use, as antimitotics, in cancer chemotherapy or else in the treatment of psoriasis or of parasitic diseases such as those due to protists or 30 to fungi, or else in the treatment of Alzheimer's disease or in the treatment of neuronal apoptosis. The medicinal products, which are a subject of the invention, are of use in particular in the treatment of diseases due to fungi, such as candidosis, aspergillosis, 35 histoplasmosis and coccidiosis. The invention extends to the pharmaceutical 39 compositions containing, as active principle, at least one of the medicinal products as defined above. Such compositions can in particular be useful for treating topical and systemic fungal infections. 5 The pharmaceutical compositions indicated above can be administered orally, rectally, parenterally or locally by topical application to the skin and the mucous membranes, or by intravenous or intramuscular injection. These compositions may be solid or liquid and may be in 10 all the pharmaceutical forms commonly used in human medicine, such as, for example, simple or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels, aerosol preparations, vaginal pessaries and gynecological 15 capsules. These compositions are prepared according to the usual methods. The active principle may be incorporated therein in excipients conventionally used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa 20 butter, aqueous or nonaqueous vehicles, fatty substances of animal or plant origin, paraffin derivatives, glycols, various wetting agents, dispersing agents or emulsifiers, or preserving agents. The dosage will be variable depending on the product 25 used, the individual treated and the ailment in question, and can be, for example, from 0.05 to 5 g per day in adults, or preferably from 0.1 to 2 g per day. A subject of the invention is therefore particularly the pharmaceutical compositions as defined above, which 30 are used as medicinal products. A subject of the invention is thus in particular the use of the products of formula (I) as defined above, and/or of their pharmaceutically acceptable salts, for preparing medicinal products intended for the prevention 35 or treatment of fungal diseases such as mycoses due to fungi chosen in particular from the fungi defined above.

40 A subject of the invention is more precisely the use of the products of formula (I) as defined above, and/or of their pharmaceutically acceptable salts, for preparing medicinal products intended for the prevention or 5 treatment of fungal diseases such as in particular candidiasis, aspergillosis, histoplasmosis and coccidiosis. A subject of the invention is particularly the use of the products of formula (I) as defined above, and/or 10 of their pharmaceutically acceptable salts, for preparing medicinal products intended for the prevention or treatment of diseases caused by Candida albicans, and in particular intended for the prevention or treatment of systemic candidiosis. 15 A subject of the invention is thus the products of formula (I) as defined above having antifungal properties, as inhibitors of Candida albicans CIV1 protein kinases. A subject of the invention is thus the 20 pharmaceutical compositions containing, as active principle, at least one inhibitor of Candida albicans CIV1 protein kinases as defined above. A subject of the present invention is in particular the use of the compositions as defined above, as 25 antifungal agents. A subject of the present invention is thus the pharmaceutical compositions as defined above, which are used as antimitotic medicinal products, in particular for cancer chemotherapy or else for the treatment of 30 psoriasis, of parasitic diseases such as those due to fungi or to protists, or of Alzheimer's disease. A subject of the present invention is thus the pharmaceutical compositions as defined above, which are used as antineurodegenerative, in particular anti 35 neuronal apoptosis, medicinal products. A subject of the present invention is also the use 41 of the products of formula (I) as defined above, and/or of their pharmaceutically acceptable salts, for preparing medicinal products intended for cancer chemotherapy, for the treatment of psoriasis or of parasitic diseases such 5 as those due to fungi or to protists, for the treatment of Alzheimer's disease or for the treatment of neurodegenerative disorders, in particular neuronal apoptosis. A subject of the present invention is also the use 10 of the products of formula (I) as defined above, and/or of their pharmaceutically acceptable salts as defined above, for preparing medicinal products intended for the prevention or treatment of diseases associated with a disturbance of the secretion and/or of the activity of 15 protein tyrosine kinases and of serine/threonine kinases. A subject of the present invention is also the use of the products of formula (I) as defined above, and/or of their pharmaceutically acceptable salts, for preparing medicinal products intended for the treatment or 20 prevention of immunity, infection, allergy, and autoimmune diseases. A subject of the present invention is also the use of the products of formula (I) as defined above, and/or of their pharmaceutically acceptable salts, for preparing 25 medicinal products intended for the treatment or prevention of diseases such as proliferative diseases, cancer, restenosis, inflammation, allergies or cardiovascular diseases. The present invention also relates to a method for 30 screening antifungal products according to the present invention, which comprises a step in which the activity of a given protein kinase is measured, and then the products having an inhibitory affect on this activity are selected, thus determining the antifungal properties of 35 the products according to the present invention. The following examples of products of formula (I) 42 according to the present invention illustrate the invention without however limiting it. Experimental section: EXAMPLE 1: Trans-N- [6- (5, 6-dichloro-2,3-dihydro-lH-indol 5 1-yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine dihydrochloride Stage 1: 2-chloro-6-(2,3-dihydro-lH-indol-1-yl)-9H-purine 189 mg of 2,6-dichloropurine, 4 ml of butanol and 143 mg (1.2 equivalents) of indoline are mixed and 10 brought to a temperature of 800C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 262 mg of expected product are obtained in the form of beige 15 colored crystals. Stage 2: Trans-N-[6-(5,6-dichloro-2,3-dihydro-lH-indol-l yl)-9H-purin-2-yl]-1,4-cyclohexanediamine dihydrochloride 800 mg of trans-1,4-diaminocyclohexane are brought to its melting temperature (700C), 190 mg of product 20 obtained in stage 1 above are added in a single step, and the mixture is then heated at 1400C for approximately 6 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by 25 chromatography on silica with an MeOH-NH 4 0H : 98-2 mixture for eluent. 4 ml of ethanol and 4 ml of HCl-EtOH (hydrochloric acid-ethanol) are added and washing is carried out with ethanol. Drying is carried out under vacuum at 500C. 67 mg of expected product are obtained. 30 EXAMPLE 2: Trans-N-[6-(1H-benzimidazol-1-yl)-9H-purin-2 yl] -1,4-cyclohexanediamine dihydrochloride Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine The same procedure as in Example 1 is carried out, starting from 1.89 g of 2,6-dichloropurine, 40 ml of 43 butanol and 1.30 g of benzimidazole. 1.1 g of expected product are obtained. Stage 2: Trans-N-[6-(lH-benzimidazol-1-yl)-9H-purin-2 yl]-1,4-cyclohexanediamine dihydrochloride 5 2.52 g of trans-1,4-diaminocyclohexane are brought to its melting temperature (700C), 865 mg of product obtained in stage 1 above are added, and the mixture is then heated at 140 0 C for approximately 5 hours. The mixture is allowed to return to ambient 10 temperature. Purification is carried out by chromatography on silica with a CH 2 C1 2 -MeOH-NH 4 0H : 78-20-2 mixture for eluent. 10 ml of ethanol and 6 ml of HCl-EtOH (hydrochloric acid-ethanol) are added. Evaporation to dryness is carried out and a paste is then 15 formed in ethyl ether. This paste is dried under vacuum. 397 mg of expected product are obtained. EXAMPLE 3: 6- (1H-benzimidazol-1-yl) -9H-purin-2-amine 500 mg of 2-amino-6-purine, 5 ml of butanol and 383 mg of benzimidazole are mixed and brought to a 20 temperature of 90 0 C for approximately 48 hours, and then 140 0 C for 48 hours. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H 95-5-0.3 mixture for eluent. A paste is formed in methanol. 250 mg of expected 25 product are obtained. EXAMPLE 4: 6-(lH-benzimidazol-1-yl)-N,N-dimethyl-9H purin-2-amine Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 30 5.5 g of benzimidazole are mixed and brought to a temperature of 80OC for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are 35 obtained.

44 Stage 2: 6- (1H-benzimidazol-1-yl) -N,N-dimethyl-9H-purin 2-amine 300 mg of product obtained in stage 1 above are mixed with 3 ml of DMF (dimethylformamide) and 0.17 ml 5 (1.1 equivalents) of TEA (triethylamine). The mixture is heated at 900C for 2 hours. The precipitate is filtered off. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 90-9-9 mixture for eluent. 298 mg of expected product are obtained. 10 EXAMPLE 5: Trans-N- [6- (5, 6-dimethyl-1H-benzimidazol-1 yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine Stage 1: 2-chloro-6-(5,6-dimethyl-1H-benzimidazol-1-yl) 9H-purine 283 mg of 2,6-dichloropurine, 5 ml of butanol and 15 219 mg of 5,6-dimethylbenzimidazole are mixed and brought to a temperature of 1000C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with isopropanol and drying under vacuum at 50 0 C are carried out, and 194 mg of expected 20 product are obtained, in the form of cream-colored crystals. Stage 2: Trans-N-[6-(5,6-dimethyl-lH-benzimidazol-1-yl) 9H-purin-2-yl]-1,4-cyclohexanediamine 570 mg of trans-1,4-diaminocyclohexane are brought 25 to its melting temperature (700C), 149 mg of product obtained in stage 1 above are added in a single step, and the mixture is then heated at 1400C for approximately 18 hours. The mixture is allowed to return to ambient 30 temperature. Purification is carried out by chromatography on silica with an MeOH-NH 4 0H : 98-2 mixture for eluent. 40 mg of expected product are obtained, in the form of beige-colored crystals. EXAMPLE 6: Ethyl 3-[[6-(lH-benzimidazol-1-yl)-9H-purin-2 35 yl]amino]benzoate 45 Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80 0 C for approximately 17 hours. The 5 mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: Ethyl 3-[[6-(lH-benzimidazol-1-yl)-9H-purin-2 10 yl]amino]benzoate 300 mg of product obtained in stage 1 above are mixed with 0.83 ml (5 equivalents) of ethyl 3-amino benzoate and 0.166 mg of NaI, and the mixture is then heated at 1400C for approximately 4 days. 15 The mixture is allowed to return to ambient temperature and stirring is carried out at ambient temperature for 2 days. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 95-5-0.3 mixture for eluent. 25.2 mg of expected product 20 are obtained. EXAMPLE 7: Trans-N- [6- (5-chloro-2,3-dihydro-1H-indol-1 yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine Stage 1: 2-chloro-6-(5-chloro-2,3-dihydro-lH-indol-1-yl) 25 9H-purine The same procedure as in stage 1 of Example 1 is carried out, starting from 756 mg of 2,6-dichloropurine, 12 ml of butanol and 737 mg of 5-chloro-2,3-dihydro-lH indole. 30 The mixture is brought to a temperature of 800C for approximately 20 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with isopropanol, and drying are carried out. 1.67 g of expected product 35 are thus obtained. Stage 2: Trans-N-[6-(5-chloro-2,3-dihydro-1H-indol-1-yl)- 46 9H-purin-2-yl]-1,4-cyclohexanediamine The same procedure as in stage 2 of Example 1 is carried out, starting from 1.14 g of trans-1,4 diaminocyclohexane and 306 mg of the product obtained in 5 stage 1 above; the mixture is then heated at 1200C for approximately 6 hours. 140 mg of expected product are obtained, in the form of beige-colored crystals. EXAMPLE 8: Trans-N- [6- (5, 6-dichloro-lH-benzimidazol-1 10 yl) -9H-purin-2-yl] -1,4-cyclohexanediamine hydrochloride Stage 1: 2-chloro-6-(5,6-dichloro-lH-benzimidazol-1-yl) 9H-purine 567 mg of 2,6-dichloropurine, 6 ml of butanol and 617 mg of 5,6-dichlorobenzimidazole are mixed and brought 15 to a temperature of 1000C for approximately 24 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with isopropanol and drying under vacuum at 50OC are carried out, and 548 mg of expected product are obtained, in the form of gray/black-colored 20 crystals. Stage 2: trans-N-[6-(5,6-dichloro-lH-benzimidazol-1-yl) 9H-purin-2-yl]-1,4-cyclohexanediamine hydrochloride 570 mg of trans-1,4-diaminocyclohexane are brought to its melting temperature (700C), 170 mg of product 25 obtained in stage 1 above are added in a single step, and the mixture is then heated at 110 0 C for approximately 24 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with an MeOH-NH 4 0H : 98-2 30 mixture for eluent. The purified product is dissolved in ethanol and HCl-AcOEt (hydrochloric acid-ethyl acetate) is then added. Partial drying and drying under vacuum at 500C are carried out. 34 mg of expected product are obtained in the form of brown-colored crystals. 35 EXAMPLE 9: 6- (1H-benzimidazol-1-yl) -N- (phenylmethyl) -9H- 47 purin-2-amine Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a 5 temperature of 80OC for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. 10 Stage 2: 6-(lH-benzimidazol-1-yl)-N-(phenylmethyl)-9H purin-2-amine 300 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.27 g (5 equivalents) of n-butylamine, and the mixture is then heated at 120 0 C for 15 approximately 48 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. 351 mg of expected 20 product are obtained. EXAMPLE 10: 6- (1H-benzimidazol-1-yl) -N-butyl-9H-purin-2 amine Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 25 5.5 g of benzimidazole are mixed and brought to a temperature of 80 0 C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are 30 obtained. Stage 2: 6-(lH-benzimidazol-1-yl)-N-butyl-9H-purin-2 amine 200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 0.6 ml (5 equivalents) of 35 benzylamine, and the mixture is then heated at 120OC for 48 approximately 60 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:90-9-1 mixture for eluent. Evaporation is carried out and a 5 paste is formed in methylene chloride. Partial drying and drying under vacuum at 50 0 C are carried out. 105 mg of expected product are obtained. EXAMPLE 11: 2-[ [6-(1H-benzimidazol-1-yl)-9H-purin-2-yl] amino]ethanol 10 Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80 0 C for approximately 17 hours. The mixture is allowed to return to ambient temperature. 15 Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 2-[[6-(lH-benzimidazol-1-yl)-9H-purin-2-yl] amino] ethanol 20 210 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.3 ml of ethanolamine, and the mixture is then heated at 120 0 C for approximately 48 hours with stirring. The mixture is allowed to return to ambient temperature. Purification is carried out by 25 chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride-methanol (5-5). Partial drying and drying under vacuum at 50 0 C are carried out. 118 mg of expected product are obtained. 30 EXAMPLE 12: 6-(1H-benzimidazol-1-yl)-N-methyl-9H-purin-2 amine Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a 35 temperature of 800C for approximately 17 hours. The 49 mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. 5 Stage 2: 6-(lH-benzimidazol-1-yl)-N-methyl-9H-purin-2 amine 200 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.115 ml (5 equivalents) of methylamine, and the mixture is then heated at 120 0 C for 10 approximately 18 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and 15 drying under vacuum at 50 0 C are carried out. 190 mg of expected product are obtained. EXAMPLE 13: 6- (lH-benzimidazol-1-yl) -N-cyclohexyl-9H purin-2-amine Stage 1: 6-(1H-benzimidazol-1-yl)-2-chloro-9H-purine 20 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80 0 C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under 25 vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 6- (lH-benzimidazol-1-yl) -N-cyclohexyl-9H-purin 2-amine 200 mg of product obtained in stage 1 above are 30 mixed with 2 ml of DMSO and 0.42 ml of cyclohexylamine, and the mixture is then heated at 110 0 C for approximately 48 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:90-9-1 35 mixture for eluent. 84.7 mg of expected product are 50 obtained. EXAMPLE 14: 2,2'-[[6-(1H-benzimidazol-1-yl)-9H-purin-2 yl]imino]bisethanol Stage 1: 6-(1H-benzimidazol-1-yl)-2-chloro-9H-purine 5 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80 0 C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under 10 vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 2,2'-[[6-(lH-benzimidazol-1-yl)-9H-purin-2-yl] imino]bisethanol 200 mg of product obtained in stage 1 above are 15 mixed with 3 ml of DMSO and 0.388 mg (5 equivalents) of diethanolamine, and the mixture is then heated at 1200C for approximately 48 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 20 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and drying under vacuum at 500C are carried out. 88.2 mg of expected product are obtained. EXAMPLE 15: Trans-N- [6- (5-methoxy-1H-benzimidazol-1-yl) 25 9H-purin-2-yl] -1, 4-cyclohexanediamine dihydrochloride Stage 1: 2-chloro-6- (5-methoxy-lH-benzimidazol-1-yl) -9H purine 567 mg of 2,6-dichloropurine, 15 ml of butanol and 999 mg of 5-OCH 3 -benzimidazole are mixed and brought to a 30 temperature of 120 0 C for approximately 24 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with H 2 C1 2 and drying under vacuum at 500C are carried out. The product is taken up in H 2 0; 1 ml of NH 4 0H is added and then extraction is carried out 35 with CH 2 Cl 2 and a saturated aqueous NaCl solution is 51 added. Drying is carried out over sodium sulfate and the product is brought to dryness. 60 mg of expected product are obtained, in the form of white-colored crystals. Stage 2: Trans-N- [6- (5-methoxy-lH-benzimidazol-1-yl) -9H 5 purin-2-yl]-1,4-cyclohexanediamine dihydrochloride 969 mg of trans-1,4-diaminocyclohexane are brought to its melting temperature (70 0 C), 5100 mg of product obtained in stage 1 above (no name) and 10 ml of DMSO are added in a single step, and the mixture is then heated at 10 120 0 C for approximately 72 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with an MeOH-NH 4 0H:98-2 mixture for eluent. The purified product is dissolved in ethanol and HCl-AcOEt is then added. Partial drying and 15 drying under vacuum at 60 0 C are carried out. Purification is carried out by chromatography on silica with a

CH

2 Cl 2 -MeOH-NH 4 0H:75-23-2 mixture for eluent. 258 mg of expected product are obtained, in the form of beige colored crystals. 20 EXAMPLE 16: Trans-N-[6-(1H-indol-1-yl)-9H-purin-2-yl] 1, 4-cyclohexanediamine dihydrochloride Stage 1: 2-chloro-6-(lH-indol-1-yl)-9H-purine 236 mg of product obtained in stage 1 of Example 1 in 20 ml of dioxane are heated over siliparite with 25 227 mg of DDQ (dichlorodicyanobenzoquinone), for 60 hours at 800C. The dioxane is evaporated off and then purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH:95-5 mixture for eluent. 142 mg of expected product are obtained, in the form of beige 30 colored crystals. Stage 2: Trans-N-(6-(1H-indol-1-yl)-9H-purin-2-yl]-1,4 cyclohexanediamine dihydrochloride 1.31 g of trans-1,4-diaminocyclohexane are brought to its melting temperature (700C), 310 mg of product 35 obtained in stage 1 above are added, and the mixture is 52 then heated at 140 0 C for approximately 18 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with an MeOH-NH 4 0H:98-2 mixture for eluent. 4 ml of 5 ethanol and then 2 ml of hydrochloric acid-ethanol (8N) are added. Partial drying followed by washing with ethanol are carried out. Drying is carried out under vacuum. 23 mg of expected product are obtained, in the form of beige-colored crystals. 10 EXAMPLE 17: 6- (1H-benzimidazol-1-yl) -N-phenyl-9H-purin-2 amine Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a 15 temperature of 80 0 C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. 20 Stage 2: 6-(lH-benzimidazol-1-yl)-N-phenyl-9H-purin-2 amine 300 mg of product obtained in stage 1 above are mixed with 0.52 ml of aniline and the mixture is then heated at 140 0 C for approximately 72 hours. The mixture 25 is allowed to return to ambient temperature for 48 hours. A paste is formed in methylene chloride and partial drying is carried out. 48 mg of expected product are obtained. EXAMPLE 18: 2- [[6- (1H-benzimidazol-1-yl) -9H-purin-2 30 yl] amino] -1,3-propanediol Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80 0 C for approximately 17 hours. The 35 mixture is allowed to return to ambient temperature.

53 Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 2-[[6-(lH-benzimidazol-1-yl)-9H-purin-2 5 yl]amino]-1,3-propanediol 200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 336 mg (5 equivalents) of 2-amino-1,3-propanediol, and the mixture is then heated at 1200C for approximately 72 hours. The mixture is 10 allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a

CH

2 Cl 2 -MeOH-NH 4 0H:90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride-methanol:50-50. Partial drying and drying under 15 vacuum at 500C are carried out. 91.4 mg of expected product are obtained. EXAMPLE 19: Trans-N- [6- [6- (phenylmethoxy) -1H benzimidazol-1-yl] -9H-purin-2-yl] -1, 4-cyclohexanediamine Stage 1: 2,6-dichloro-9-[ [2-(trimethylsilyl)ethoxy] 20 methyl]-9H-purine 945 mg of 2,6-dichloropurine, 15 ml of DMF (dimethylformamide) and 288 mg of NaH are mixed and left at ambient temperature for 2 hours. 1.06 ml of 2-chloromethoxyethyltrimethylsilane are then added. The 25 mixture is stirred for 18 hours at ambient temperature. The DMF is evaporated off. The product is taken up in methylene chloride. Washing is carried out with a saturated sodium bicarbonate solution and then once with H20 and, finally, with a saturated NaCl solution. Drying 30 over Na 2

SO

4 and evaporation to dryness are carried out. Purification is carried out by chromatography on silica with a CHCl 3 -AcOEt:5-5 mixture for eluent. 876 mg of expected product are obtained, in the form of a yellow colored oil. 35 Stage 2: 2-chloro-6- (6- (phenylmethoxy) -lH-benzimidazol-l- 54 yl) -9- [[2- (trimethylsilyl) ethoxy]methyl] -9H-purine 860 mg of product obtained in stage 1 above are mixed with 605 mg of 5-(phenylmethoxy)-lH-benzimidazole (benzyl ether in the 5-position of benzimidazole) and 5 15 ml of butanol. The mixture is heated at 120 0 C for 24 hours. Partial drying, washing with H 2 0 and then drying under vacuum at 50 0 C are carried out. 667 mg of 2-chloro 6- (6- (phenylmethoxy) -lH-benzimidazol-1-yl) -9- [[2- (tri methylsilyl)ethoxy]methyl]-9H-purine are obtained, in the 10 form of beige-colored crystals. Stage 3: Trans-N- [6- [6- (phenylmethoxy)-lH-benzimidazol-l yl]-9H-purin-2-yl]-1,4-cyclohexanediamine 1 g of trans-1,4-diaminocyclohexane is brought to its melting temperature (700C), 15 ml of DMSO and 530 mg 15 of product obtained in stage 1 above are added, and the mixture is then heated at 1200C for approximately 21 hours. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:85-13.5-l.5 mixture for eluent. 38 mg of expected product are obtained, in the 20 form of beige-colored crystals. EXAMPLE 20: Trans-N- [6- [5- (phenylmethoxy) -1H benzimidazol-1-yl] -9H-purin-2-yl] -1, 4-cyclohexanediamine Stage 1: 2,6-dichloro-9-[[2-(trimethylsilyl)ethoxy] methyl] -9H-purine 25 945 mg of 2,6-dichloropurine, 15 ml of DMF (dimethylformamide) and 288 mg of NaH are mixed and left at ambient temperature for 2 hours. 1.06 ml of 2-chloro methoxyethyltrimethylsilane are then added. Stirring is carried out for 18 hours at ambient temperature. The DMF 30 is evaporated off. The product is taken up in methylene chloride. Washing is carried out with a saturated sodium bicarbonate solution, then once with H 2 0 and, finally, with a saturated NaCl solution. Drying over Na 2

SO

4 and evaporation to dryness are carried out. Purification is 35 carried out by chromatography on silica with a 55 CHCl 3 -AcOEt:5-5 mixture for eluent. 876 mg of expected product are obtained, in the form of a yellow-colored oil. Stage 2: 2-chloro-6- (5- (phenylmethoxy)-lH-benzimidazol-l 5 yl) -9- [[2- (trimethylsilyl)ethoxy]methyl] -9H-purine 860 mg of product obtained in stage 1 above are mixed with 605 mg of 5-(phenylmethoxy)-lH-benzimidazole (benzyl ether in the 5-position of benzimidazole) and 15 ml of butanol. The mixture is heated at 120 0 C for 24 10 hours. Partial drying, washing with H 2 0 and then drying under vacuum at 50 0 C are carried out. 667 mg of 2-chloro 6- (5- (phenylmethoxy) -1H-benzimidazol-1-yl) -9- [[2- (tri methylsilyl)ethoxy]methyl]-9H-purine are obtained, in the form of beige-colored crystals. 15 Stage 3: Trans-N-[6-[5-(phenylmethoxy)-1H-benzimidazol-l yl]-9H-purin-2-yl]-1,4-cyclohexanediamine 1 g of trans-1,4-diaminocyclohexane is brought to its melting temperature (70 0 C), 15 ml of DMSO and 530 mg of product obtained in stage 1 above are added, and the 20 mixture is then heated at 120 0 C for approximately 21 hours. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:85-13.5-1.5 mixture for eluent. 39 mg of expected product are obtained, in the form of beige-colored crystals. 25 EXAMPLE 21: Trans-N- [6- (1H-benzimidazol-1-yl) -9H-purin-2 yl] -1, 2-cyclohexanediamine dihydrochloride Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a 30 temperature of 80 0 C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. 35 Stage 2: Trans-N-[6-(lH-benzimidazol-1-yl)-9H-purin-2- 56 yl]-1,2-cyclohexanediamine dihydrochloride 200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 420 mg (5 equivalents) of (lS,2S)-(-)-1,2-diaminocyclohexane, and the mixture is 5 then heated at 120 0 C for approximately 4 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:95-5-0.33 mixture for eluent. 4 ml of ethanol and 4 ml of HCl-EtOH (hydrochloric acid 10 ethanol) are added. Evaporation to dryness is carried out and a paste is then formed in ethyl ether. Drying is carried out under vacuum. 116 mg of expected product are obtained. EXAMPLE 22: 1,1-dimethylethyl [1-[6-(1H-benzimidazol-1 15 yl) -9H-purin-2-yl] -4-piperidinyl]carbamate Stage 1 : 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 800C for approximately 17 hours. The 20 mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 1,1-dimethylethyl [1-[6-(1H-benzimidazol-1-yl) 25 9H-purin-2-yl]-4-piperidinyl]carbamate 200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 740 mg (5 equivalents) of Boc-4-aminopiperidine, and the mixture is then heated at 120 0 C for approximately 4 hours. The mixture is allowed 30 to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 90-9-1 mixture for eluent. Evaporation to dryness is carried out and then a paste is formed in dichloromethane.. Drying is carried out under vacuum. 35 252 mg of expected product are obtained.

57 EXAMPLE 23: Cis-N- [6- (1H-benzimidazol-1-yl) -9H-purin-2 yl] -1, 2-cyclohexanediamine dihydrochloride Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5 5.5 g of benzimidazole are mixed and brought to a temperature of 800C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are 10 obtained. Stage 2: Cis-N-[6-(lH-benzimidazol-1-yl)-9H-purin-2-yl] 1,2-cyclohexanediamine dihydrochloride 200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 0.5 ml (5 equivalents) of 15 cis-1,2-diaminocyclohexane, and the mixture is then heated at 1200C for approximately 3 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a

CH

2 Cl 2 -MeOH-NH 4 0H:85-15-1.5 mixture for eluent. 3 ml of 20 ethanol and 3 ml of HCl-EtOH (hydrochloric acid-ethanol) are added. 34.3 mg of expected product are obtained. EXAMPLE 24: Trans-4- [[6- (1H-benzimidazol-1-yl) -9H-purin 2-yl] amino] cyclohexanol Stage 1: 6-(1H-benzimidazol-1-yl)-2-chloro-9H-purine 25 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80 0 C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under 30 vacuum are carried out, and 3 g of expected product are obtained. Stage 2: Trans-4-[[6-(lH-benzimidazol-1-yl)-9H-purin-2 yl]amino]cyclohexanol 200 mg of product obtained in stage 1 above are 35 mixed with 3 ml of DMSO and 586 mg (5 equivalents) of 58 trans-4-aminocyclohexanol, and the mixture is then heated at 120 0 C for approximately 4 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 5 85-15-1.5 mixture for eluent. 45 mg of expected product are obtained. EXAMPLE 25: 1-[6-(1H-benzimidazol-1-yl)-9H-purin-2-yl]-4 piperidinamine bis (trifluoroacetate) 100 mg of product obtained in Example 22 are mixed 10 with 3 ml of methylene chloride and 1.5 ml of trifluoroacetic acid containing 10% of anisole. The mixture is stirred at ambient temperature for 5 hours. It is concentrated to dryness and co-evaporation with toluene and then with methylene chloride is carried out. 15 Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:90-9-1 mixture for eluent. 128 mg of expected product are obtained. EXAMPLE 26: Trans-N- [6- (2-methyl-1H-indol-1-yl) -9H-purin 2-yl] -1, 4-cyclohexanediamine dihydrochloride 20 Stage 1: 6-(2-methyl-lH-indol-1-yl)-2-chloro-9H-purine The same procedure as in stage 1 of Example 1 is carried out, mixing 189 mg of 2,6-dichloropurine, 5 ml of butanol and 0.16 g of 2-methylindoline. The mixture is heated at 130 0 C for approximately 1 hour and allowed to 25 return to ambient temperature. Partial drying is carried out, followed by washing with isopropanol. The product is dried and 174 mg of expected product are thus obtained. Stage 2 : Trans-N-[6-(2-methyl-lH-indol-1-yl)-9H-purin-2 yl]-1,4-cyclohexanediamine dihydrochloride 30 The same procedure as in stage 2 of Example 1 is carried out, starting from 638 mg of trans-1,4 diaminocyclohexane and 161 mg of the product obtained in stage 1 above, and the mixture is heated at 120 0 C for 29 hours. Purification is carried out on silica with 35 MeOH-NH 4 0H:98-2 for eluent, and 190 mg of product are 59 thus obtained, in the form of a brown-colored resin, the product is dissolved in ethanol and HCl-AcOEt are added, the hydrochloride precipitates, 3 ml of AcOEt are added, and partial drying and drying under vacuum at 500C are 5 carried out. 222 mg of the expected product are thus obtained, in the form of beige-colored crystals. EXAMPLE 27: (2S)-2-[[6-(lH-benzimidazol-1-yl)-9H-purin-2 yl] amino] -1-butanol 10 Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 800C for approximately 17 hours. The mixture is allowed to return to ambient temperature. 15 Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: (2S)-2-[[6-(lH-benzimidazol-1-yl)-9H-purin-2 yl]amino]-1-butanol 20 200 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 350 gl (5 equivalents) of (+/-)-2-amino-1-butanol, and the mixture is then heated at 1200C for approximately 2 days. The mixture is allowed to return to ambient temperature. Purification is carried 25 out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 95-5-0.3 mixture for eluent. 40 mg of expected product are obtained. EXAMPLE 28: 6- (lH-benzimidazol-1-yl) -N- [(tetrahydro-2H pyran-4-yl )methyl] -9H-purin-2-amine 30 Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 800C for approximately 17 hours. The mixture is allowed to return to ambient temperature.

60 Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 6- (lH-benzimidazol-1-yl) -N- [ (tetrahydro-2H 5 pyran-4-yl)methyl]-9H-purin-2-amine 250 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 531 mg l of 4-aminomethyl tetrahydropyran, and the mixture is then heated at 120 0 C for approximately 2 days. The mixture is allowed to 10 return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H 90-9-1 mixture for eluent. 142 mg of expected product are obtained. EXAMPLE 29: Trans-N- [6- (2-methyl-1H-indol-1-yl) -9H-purin 15 2-yl] -1,4-cyclohexanediamine Stage 1: 6-(2-methyl-lH-indol-1-yl)-2-chloro-9H-purine The same procedure as in stage 1 of Example 1 is carried out, mixing 378 mg of 2,6-dichloropurine, 10 ml of butanol and 0.32 of dimethylindoline. The mixture is 20 heated at 100 0 C for approximately 5 hours and allowed to return to ambient temperature. Partial drying and washing with isopropanol are carried out. The product is dried and 423 mg of expected product are thus obtained. Stage 2: 6-(2-methyl-1H-indol-1-yl)-2-chloro-1H-purine 25 140 mg of product obtained in stage 1 above are mixed with 170 mg of DDQ (dichlorodicyanobenzoquinone) and 5 ml of dioxane. The mixture is brought to 80-90 0 C and then allowed to return to ambient temperature. Filtration, rinsing and drying are carried out. 30 Purification is carried on silica with CHCl 3 -EtOH-AcOEt : 90-5-5 for eluent. 170 mg of the expected product are thus obtained. Stage 3: Trans-N-[6-(2-methyl-lH-indol-1-yl)-9H-purin-2 yl]-1,4-cyclohexanediamine 35 The same procedure as in stage 2 of Example 1 is 61 carried out, starting from 684 mg of trans-1,4 diaminocyclohexane and 166 mg of the product obtained in stage 2 above, and the mixture is heated at 1400C for 6 hours. Purification is carried out on silica with 5 MeOH-NH 4 0H:98-2 for eluent, and 51 mg of expected product are thus obtained, in the form of beige-colored crystals. EXAMPLE 30: Trans-N- [6- (2,3-dihydro-5-nitro-1H-indol-1 yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine dihydrochloride Stage 1: 2-chloro-6-(2,3-dihydro-5-nitro-lH-indol-1-yl) 10 9H-purine 567 mg of 2,6-dichloropurine, 10 ml of butanol and 590 mg of 5-nitroindole are mixed. The mixture is heated to 80 0 C for approximately 17 hours and allowed to return to ambient temperature. Purification is carried out by 15 chromatography on silica with a CHCl 3 -ethanol:95-5 mixture for eluent. 834 mg of expected product are thus obtained, in the form of yellowish-colored crystals. Stage 2: Trans-N-[6-(2,3-dihydro-5-nitro-lH-indol-1-yl) 20 9H-purin-2-yl]-1,4-cyclohexanediamine dihydrochloride 421 mg of the product obtained in stage 1 above are mixed with 1.14 g of trans-1,4-diaminocyclohexane and 10 ml of DMSO. The mixture is heated at 120 0 C for approximately 29 hours. Drying under vacuum at 500C is 25 carried out and the dry product is purified by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H : 85-13.5-1.5 mixture for eluent. A paste is formed in ethanol and 2 ml of HC1-ethanol are then added. Drying is carried out under vacuum. 30 113 mg of expected product are thus obtained, in the form of mustard yellow-colored crystals. EXAMPLE 31: 1,1-dimethylethyl 4-[[[6-(1H-benzimidazol-1 yl) -9H-purin-2-yl] amino]methyl] -1-piperidinecarboxylate Stage 1: 6-(1H-benzimidazol-1-yl)-2-chloro-9H-purine 35 8 g of 2,6-dichloropurine, 150 ml of butanol and 62 5.5 g of benzimidazole are mixed and brought to a temperature of 800C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under 5 vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 1,1-dimethylethyl 4-[[[6-(lH-benzimidazol-l-yl) 9H-purin-2-yl]amino]methyl]-1-piperidinecarboxylate 200 mg of product obtained in stage 1 above are 10 mixed with 5 ml of DMSO and 790 mg (5 equivalents) of 4-aminomethyl-N-Boc-piperidine, and the mixture is then heated at 1000C for approximately 3 days. The mixture is allowed to return to ambient temperature. The DMSO is concentrated to dryness and the dry product is taken up 15 in CH 2 Cl 2 . Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H:95-5-0.33 mixture for eluent. 56 mg of expected product are thus obtained. EXAMPLE 32: Trans-N-[6-(5-bromo-2,3-dihydro-lH-indol-1 yl)-9H-purin-2-yl]-1,4-cyclohexanediamine 20 Stage 1: 6-(5-bromo-2,3-dihydro-9H-indol-1-yl)-2-chloro 9H-purine The same procedure as in stage 1 of Example 7 is carried out, using 950 mg of 5-bromo-2,3-dihydro-lH indole in place of 737 mg of 5-chloro-2,3-dihydro-lH 25 indole. 1.32 g of expected product are thus obtained. Stage 2 : Trans-N-[6-(5-bromo-2,3-dihydro-1H-indol-1-yl) 9H-purin-2-yl]-1,4-cyclohexanediamine The same procedure as in stage 2 of Example 7 is carried out, using 350 mg of the product obtained in 30 stage 1 above instead of 306 mg of the product obtained in stage 1 of Example 7. 35 mg of expected product are obtained, in the form of brown-colored crystals. EXAMPLE 33: 6-(lH-benzimidazol-1-yl)-2-(4-morpholinyl) 9H-purine dihydrochloride 35 Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 63 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 800C for approximately 17 hours. The mixture is allowed to return to ambient temperature. 5 Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: 6-(lH-benzimidazol-1-yl)-2-(4-morpholinyl)-9H purine dihydrochloride 10 230 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 370 mg (5 equivalents) of morpholine, and the mixture is then heated at 1200C for approximately 16 hours. The mixture is allowed to return to ambient temperature. The DMSO is concentrated to 15 dryness. A paste is formed in CH 2 Cl 2 (methylene chloride) . Drying is carried out under vacuum. The dry product is taken up in 5 ml of HCl (8M) and 10 ml of ethanol and concentrated to dryness, and 209 mg of expected product are obtained. 20 EXAMPLE 34: (2S)-1-[6-(lH-benzimidazol-1-yl)-9H-purin-2 yl] -2 -pyrrolidinemethanol Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a 25 temperature of 800C for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. 30 Stage 2: (2S)-1-[6-(1H-benzimidazol-1-yl)-9H-purin-2-yl] 2-pyrrolidinemethanol 250 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 470 mg of (S)-(+)-2 pyrrolidinemethanol. The mixture is then heated at 110C 35 for approximately 16 hours. The mixture is allowed to 64 return to ambient temperature. A paste is formed in CH 2 Cl 2 (methylene chloride). Drying is carried out under vacuum. 200 mg of expected product are obtained. EXAMPLE 35: (2R)-1-[6-(1H-benzimidazol-1-yl)-9H-purin-2 5 yl]-2-pyrrolidinemethanol Stage 1: 6-(lH-benzimidazol-1-yl)-2-chloro-9H-purine 8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80OC for approximately 17 hours. The 10 mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained. Stage 2: (2R)-l-[6-(lH-benzimidazol-1-yl)-9H-purin-2-yl] 15 2-pyrrolidinemethanol 250 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 400 ml (4 equivalents) of (R)-(-)-2-pyrrolidinemethanol, and the mixture is then heated at 1200C for approximately 5 hours. The mixture is 20 allowed to return to ambient temperature. The DMSO is concentrated to dryness and the dry product is taken up in CH 2 Cl 2 , then partial drying is carried out. 258 mg of expected product are obtained. EXAMPLE 36: 6-(1H-benzimidazol-1-yl)-N-(4-piperidinyl 25 methyl)-9H-purin-2-amine bis(trifluoroacetate) 35 mg of the product of Example 31 are mixed with 1 ml of CH 2 Cl 2 and 0.5 ml of TFA containing 10% of anisole. The mixture is left to stir for 2 hours at ambient temperature, followed by concentrating to dryness 30 in the presence of toluene and of CH 2 C1 2 . 40 mg of expected product are thus obtained. EXAMPLE 37: Trans-1-[2-[(4-aminocyclohexyl)amino]-9H purin-6-yl]-2,3-dihydro-N,N-dimethyl-1H-indole-5 sulfonamide dihydrochloride 65 Stage 1: 1-(2-chloro-9H-purin-6-yl)-2,3-dihydro-N,N dimethyl-9H-indole-5-sulfonamide The same procedure as in stage 1 of Example 7 is carried out, using 1.08 g of 2,3-dihydro-N,N-dimethyl-lH 5 indole-5-sulfonamide in place of 737 mg of 5-chloro-2,3 dihydro-1H-indole. The mixture is brought to a temperature of 80 0 C for approximately 20 hours. 1.628 g of expected product are thus obtained. Stage 2: Trans-l-[2-[(4-aminocyclohexyl)amino]-9H-purin 10 6-yl]-2,3-dihydro-N,N-dimethyl-lH-indole-5-sulfonamide dihydrochloride The same procedure as in stage 2 of Example 7 is carried out, using 379 mg of the product obtained in stage 1 above in place of 306 mg of the product obtained 15 in stage 1 of Example 7. 150 mg of expected product are obtained, in the form of cream-colored crystals. EXAMPLE 38: Trans-N- [6- (5-f luoro-2, 3-dihydro-1H-indol-1 yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine dihydrochloride 20 Stage 1: 2-chloro-6-(5-fluoro-2,3-dihydro-lH-indol-1-yl) 9H-purine The same procedure as in stage 1 of Example 7 is carried out, using 658 mg of 5-fluoro-2,3-dihydro-1H indole instead of 737 mg of 5-chloro-2,3-dihydro-1IH 25 indole. 1.088 g of expected product are thus obtained. Stage 2: Trans-N-[6-(5-fluoro-2,3-dihydro-1H-indol-1-yl) 9H-purin-2-yl]-1,4-cyclohexanediamine dihydrochloride The same procedure as in stage 2 of Example 7 is carried out, using 290 mg of the product obtained in 30 stage 1 above instead of 306 mg of the product obtained in stage 1 of Example 7. 87 mg of expected product are obtained, in the form of beige-colored crystals.

66 Nomenclature Examples Trans-l- [1- [2- [(4-amino- Example cyclohexyl)amino]-9H- 39 N N N N NH purin-6-yl]-2,3-dihydro- 840694 < N9 H2 1H-indol-5-yl]ethanone SNH ( CFa Trans-N- [6- [2, 3-dihydro N 6-(trifluoromethyl)-lH- Example N ,H indol-1-yl) -9H-purin-2- 40 <9 I 3 N) yl]-l,4 N N N H H cyclohexanediamine H Trans-N- [1- [2- [(4-amino O / cyclohexyl) amino] -9H purin-6-yl]-2,3-dihydro- Example N N NH 2 1H-indol-5-yl]-2-thio- 41 N( NN pheneacetamide H H Trans-N-[1-[2-[(4-amino J - cyclohexyl) amino] -9H 0 purin-6-yl]-2,3-dihydro- Example N 1H-indol-5-yl]benzene- 42 N -"N 1 2 NH2 propanamide H H C Trans-N-[1-[2-[(4-amino _ N G cf cyclohexyl)amino] -9H purin-6-yl] -2, 3-dihydro- Example N 1H-indol-5-yl]-N'-(3,4- 43 N H2 dichlorophenyl)urea H Trans-N-[6-(6-nitro-2,3 N N2 dihydro-lH-indol-1-yl) - Example NH 9H-purin-2-yl] -1,4- 44 (/ N NH cyclohexanediamine N N HOO HH_ _ _ _ _ _ _ _ _ _ 67 H j' Trans-N- [1-[2- [(4-amino NN cyclohexyl) amino] -9H purin-6-yl] -2, 3-dihydro- Example N 1H-indol-5-yl]-N'-[4- 45 S(dimethylamino)phenyl] H Hurea

NH

2 Trans-N-[6-(5-amino-2,3 dihydro-lH-indol-1-yl) N 9H-purin-2-yl]-1,4- Example N N NH 2 cyclohexanediamine 46 H H EXAMPLE 39: Trans-1- [1- [2- [ (4 -aminocyclohexyl) amino] -9H purin-6-yl] -2, 3-dihydro-1H-indol-5-yl] ethanone Stage 1: 2-chloro-1-[l-(9H-purin-6-yl)-2,3-dihydro-lH 5 indol-5-yl]ethanone 1.10 g of 2,6-dichloropurine, 12 ml of butanol and 1.13 g of acetylindoline are mixed and brought to a temperature of 90 0 C for approximately 3.5 hours. The mixture is allowed to return to ambient temperature. 10 Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 1.94 g of expected product are obtained. Stage 2: Trans-l- [l-[2-[ (4-aminocyclohexyl)amino]-9H purin-6-yl]-2,3-dihydro-1H-indol-5-yl]ethanone 15 1.88 g of product obtained in stage 1 above are mixed with 4.8 g of trans-1,4-diaminocyclohexane and the mixture is then heated at 140 0 C for approximately 72 hours. The mixture is allowed to return to ambient temperature for 48 hours. A paste is formed in water, and 20 is dried under vacuum at 50OC. 2.7 g of expected product are obtained, in the form of a beige powder. EXAMPLE 40: Trans-N- [6- [2,3-dihydro-6- (trifluoromethyl) 1H-indol-1-yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine 68 Stage 1: 2-chloro-6-[2,3-dihydro-6-(trifluoromethyl)-lH indol-1-yl]-9H-purine 756 mg of 2,6-dichloropurine, 8 ml of butanol and 897 mg of 6-(trifluoromethyl)indoline are mixed and 5 brought to a temperature of 90 0 C for approximately 23 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 50 0 C are carried out, and 1.256 g of expected product are obtained, in the form of beige 10 crystals. Stage 2: Trans-N-[6-[2,3-dihydro-6-(trifluoromethyl)-lH indol-1-yl]-9H-purin-2-yl]-1,4-cyclohexanediamine 340 mg of product obtained in stage 1 above are mixed with 800 mg of trans-1,4-diaminocyclohexane and the 15 mixture is then heated at 140 0 C for approximately 8 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H: 85-15-1.5 mixture as eluent. 275 mg of product are 20 recovered, and a paste is formed in HCl/ethanol ethanol: 50-50. Partial drying and drying under vacuum at 50 0 C are carried out. 244 mg of expected product are obtained. EXAMPLE 41: Trans-N- [1- [2- [ (4-aminocyclohexyl) amino] -9H purin-6-yl] -2, 3-dihydro-1H-indol-5-yl] -2-thiophene 25 acetamide Stage 1: 2-chloro-6- (2, 3 -dihydro-5-nitro-1H-indol-1-yl) 9H-purine 37.8 g of 2,6-dichloropurine, 700 ml of butanol and 32.8 g of 5-nitroindoline are mixed and brought to a 30 temperature of 90 0 C for approximately 3 days. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 50 0 C are carried out, and 57.3 g of expected product are obtained, in the form of beige crystals. 35 Stage 2: Trans-N-[6-(2,3-dihydro-5-nitro-1H-indol-1-yl) 9H-purin-2-yl]-1,4-cyclohexanediamine 69 56 g of product obtained in stage 1 above are mixed with 140 g of trans-1,4-diaminocyclohexane and the mixture is then heated at 1400C for approximately 55 hours. The mixture is allowed to return to ambient 5 temperature. Purification is carried out by chromatography on silica with a CH 2 Cl 2 -MeOH-NH 4 0H: 85-15-1.5 mixture as eluent. 19.7 g of product are recovered. Stage 3: 1, 1-dimethylethyl trans-6- (2, 3-dihydro-5-nitro 10 1H-indol-1-yl)-2-[ [4-[ [ (1,1-dimethylethoxy)carbonyl] amino]cyclohexyl]amino]-9H-purine-9-carboxylate 9.46 g of product obtained in stage 2 above are mixed with 160 ml of chloroform and 2.4 ml of triethyl amine. The mixture is cooled to 0 0 C, then 31.43 g of 15 Boc 2 0 are added in a single step, and the mixture is left at 0 0 C for 10 minutes and then refluxed for 3 hours. The mixture is allowed to return to ambient temperature, 70 ml of water are added, and the mixture is extracted with 150 ml of dichloromethane. The organic phase is 20 washed with 70 ml of saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and evaporated to dryness. 12.92 g of expected product are thus obtained. Stage 4: 1,1-dimethylethyl trans-6- (5-amino-2,3-dihydro 1H-indol-1-yl) -2- [[4- [[(1, 1-dimethylethoxy) carbonyl] 25 amino] cyclohexyl] amino] -9H-purine-9-carboxylate 12.65 g of product obtained in stage 3 above, in 130 ml of methanol, are introduced into a round-bottomed hydrogenating flask; 500 mg of Pd/C are added and the mixture is stirred under a pressure of 1400 mbar of 30 hydrogen for 12 hours. The mixture is filtered through clarcel and the solvent is then evaporated off. The residue is chromatographed on 600 g of silica, with 60/40 dichloromethane/ethyl acetate as eluent. 6 g of expected product are thus obtained. 35 Stage 5: 1,1-dimethylethyl trans-6-[2,3-dihydro-5-[(2 thienylacetyl)amino]-lH-indol-1-yl]-2-[[4-[[(1,1-di- 70 methylethoxy)carbonyl]amino]cyclohexyl]amino]-9H-purine 9-carboxylate 40 mg of product obtained in stage 4 are mixed with 11.4 mg of 2-thiophene acetyl chloride, 25 y1 of diiso 5 propylethylamine and 2 ml of dichloromethane. The mixture is stirred at ambient temperature for 1 hour, and then washed with brine, dried over magnesium sulfate and evaporated to dryness. Stage 6: Trans-N-[1-[2-[(4-aminocyclohexyl)amino]-9H 10 purin-6-yl]-2,3-dihydro-lH-indol-5-yl]-2-thiophene acetamide The product obtained in stage 5 is dissolved in 2 ml of methanol. 2 ml of a 2N solution of hydrochloric acid in methanol are added. The mixture is stirred at ambient 15 temperature for 48 hours, and then evaporated to dryness. The residue is chromatographed on an Xterra LCMSprep column, elution being carried out with acetonitrile/ ammonium hydrogen carbonate buffer at 0.2% as a gradient. 6 mg of expected product, example 41, are thus recovered. 20 EXAMPLE 42: Trans-N-[1-[2-[(4-aminocyclohexyl)amino]-9H purin-6-yl]-2,3-dihydro-1H-indol-5-yl]benzenepropanamide Stage 1: 1,1-dimethylethyl trans-6-[2,3-dihydro-5-[(1 oxo-3-phenylpropyl)amino]-lH-indol-1-yl]-2-[[4-[[(1,1-di methylethoxy)carbonyl]amino]cyclohexyl]amino]-9H-purine 25 9-carboxylate 40 mg of product obtained in stage 4 of example 41 are mixed with 11.97 mg of hydrocinnamoyl chloride, 25 gl of diisopropylethylamine and 2 ml of dichloromethane. The mixture is stirred at ambient temperature for 1 hour, and 30 then washed with brine, dried over magnesium sulfate and evaporated to dryness. Stage 2: Trans-N-[1-[2-[(4-aminocyclohexyl)amino]-9H purin-6-yl]-2,3-dihydro-lH-indol-5-yl]benzenepropanamide The product obtained in stage 1 is dissolved in 2 ml 35 of methanol. 2 ml of a 2N solution of hydrochloric acid in methanol are added. The mixture is stirred at ambient 71 temperature for 48 hours, and then evaporated to dryness. The residue is chromatographed on an Xterra LCMSprep column, elution being carried out with acetonitrile/ ammonium hydrogen carbonate buffer at 0.2% as a gradient. 5 4 mg of expected product, example 42, are thus recovered. EXAMPLE 43: Trans-N- [1- [2- [ (4-aminocyclohexyl) amino] -9H purin-6-yl] -2, 3-dihydro-1H-indol-5-yl] -N' -(3, 4-dichloro phenyl)urea Stage 1: 1,1-dimethylethyl trans-6-[5-[[[(3,4-dichloro 10 phenyl)amino]carbonyl]amino]-2,3-dihydro-lH-indol-1-yl] 2-[[4-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexyl] amino] -9H-purine-9-carboxylate 80 mg of product obtained in stage 4 of example 41 are mixed with 37.3 mg of 3,4-dichlorophenyl isocyanate 15 and 5 ml of dichloromethane. The mixture is stirred at ambient temperature for 2 hours, 0.5 ml of water are added, and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, elution being carried out with acetonitrile/ammonium 20 hydrogen carbonate buffer pH 9. 35 mg of expected product are obtained. Stage 2: Trans-N- [1- [2- [ (4-aminocyclohexyl)amino] -9H purin-6-yl] -2, 3-dihydro-lH-indol-5-yl] -N' -(3, 4-dichloro phenyl)urea 25 The product obtained in stage 1 is dissolved in 5 ml of methanol. 5 ml of a 2N solution of hydrochloric acid in methanol are added. The mixture is stirred at ambient temperature for 48 hours, and then evaporated to dryness. The residue is chromatographed on an Xterra LCMSprep 30 column, elution being carried out with acetonitrile/ ammonium hydrogen carbonate buffer at 0.2% as a gradient. 30 mg of expected product, example 43, are thus recovered. EXAMPLE 44: Trans-N- [6- (6-nitro-2,3-dihydro-1H-indol-1 35 yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine Stage 1: 2-chloro- (6-nitro-2,3-dihydro-lH-indol-1-yl) -9H- 72 purine 378 mg of 2,6-dichloropurine, 7 ml of butanol and 328 mg of 6-nitroindoline are mixed and brought to a temperature of 900C for approximately 3 days. The mixture 5 is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 500C are carried out, and 573 mg of expected product are obtained, in the form of beige crystals. Stage 2: Trans-N-[6-(6-nitro-2,3-dihydro-lH-indol-1-yl) 10 9H-purin-2-yl] -1, 4-cyclohexanediamine 560 mg of product obtained in stage 1 above are mixed with 1.40 g of trans-1,4-diaminocyclohexane, and the mixture is then heated at 1400C for approximately 55 hours. The mixture is allowed to return to ambient 15 temperature. Purification is carried out by chromato graphy on silica gel with a CH 2 Cl 2 -MeOH-NH 4 0H:85-15-1.5 mixture as eluent. 197 mg of product are recovered, to which product 10 ml of methanol/CH 2 Cl 2 and 6 ml of HCl/ ethanol are added. Partial drying and drying under vacuum 20 at 35 0 C are carried out. 27 mg of expected product are obtained. EXAMPLE 45: Trans-N- [1- [2- [ (4-aminocyclohexyl) amino] -9H purin-6-yl] -2, 3-dihydro-1H-indol-5-yl] -N' - [4- (dimethyl amino)phenyl]urea 25 Stage 1: 1,1-dimethylethyl trans-6-[5-[[[[4-(dimethyl amino)phenyl]amino]carbonyl]amino]-2,3-dihydro-lH-indol 1-yl]-2-[ [4-[[ (1,1-dimethylethoxy)carbonyl]amino]cyclo hexyl]amino]-9H-purine-9-carboxylate 80 mg of product obtained in stage 4 of example 41 30 are mixed with 32.2 mg of 4-dimethylaminophenyl iso cyanate and 5 ml of dichloromethane. The mixture is stirred at ambient temperature for 20 hours, 0.5 ml of water is added, and the mixture is evaporated to dryness. Purification is carried out on an Xterra LCMSprep column, 35 elution being carried out with acetonitrile/ammonium hydrogen carbonate buffer, pH 9. 55 mg of expected 73 product are obtained. Stage 2: Trans-N- [1- [2-[ (4-aminocyclohexyl)amino]-9H purin-6-yl] -2, 3-dihydro-lH-indol-5-yl] -N' - [4- (dimethyl amino)phenyl]urea 5 The product obtained in stage 1 is dissolved in 5 ml of methanol. 5 ml of a 2N solution of hydrochloric acid in methanol are added. The mixture is stirred at ambient temperature for 48 hours, and then evaporated to dryness. The residue is chromatographed on an Xterra LCMSprep 10 column, elution being carried out with acetonitrile/ ammonium hydrogen carbonate buffer at 0.2% as a gradient. 42 mg of expected product, example 45, are thus recovered. EXAMPLE 46: Trans-N-[6-(5-amino-2,3-dihydro-1H-indol-1 15 yl) -9H-purin-2-yl] -1, 4-cyclohexanediamine 200 mg of product obtained in stage 4 of example 41 are dissolved in 5 ml of methanol. 5 ml of a 2N solution of hydrochloric acid in methanol are added. The mixture is stirred at ambient temperature for 48 hours, and then 20 evaporated to dryness. The residue is chromatographed on a silica column, elution being carried out with dichloromethane, methanol, aqueous ammonia 85/15/1.5. The product obtained is taken up in 10 ml of a 50/50 methanol/dichloromethane mixture, 6 ml of 1M solution of 25 HCl in ethyl acetate are added, and the mixture is left to crystallize and is filtered, and 87 mg of expected product are thus recovered. EXAMPLE 47: PHARMACEUTICAL COMPOSITION: Tablets were prepared corresponding to the following 30 formula: Product of Example 1 ............................. 0.2 g Excipient for a finished tablet at .......... 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

74 PHARMACOLOGICAL SECTION: The proteins used in the assays described below are obtained according to the usual methods known to those skilled in the art. 5 1) Assay for inhibition of CIV-CDK (CIV1) activity a) Preparation of the reagents -(1)- 3X enzyme cocktail 10 967 l buffer [50 mM Tris-HC1 - 0.1M NaCl - pH 7.5] - 0.1% BSA + 30 gl Cdk2 (1 mg/ml) + 3 gl CaCivl (0.4 mg/ml) 15 -(2)- 3X inhibitor cocktail A 3X range of inhibitor is prepared in 3% DMSO-buffer [50 mM Tris-HCl - 0.1M NaCl - pH 7.5] - 0.1% BSA 20 EXAMPLE of range: 200; 100; 30; 20; 10; 3; 2; 1; 0.3; 0 AM -(3)- 3X ATP cocktail 25 12.2 gl [ 33 P]ATP + 305 gl 1X kinase buffer + 700 l water 1OX kinase buffer = 0.5M Tris - 0.1M MgCl 2 - 1 mM Na 3

VO

4 10 mM DTT - 15 gM ATP - pH 7.5 + 1 tablet of protease inhibitors (Complete EDTA FreeTM per 5 ml of buffer). 30 b) Carrying out the assay 1) - 30 gl of the 3X enzyme cocktail (1) are mixed with 30 gl of the 3X inhibitor cocktail (2); 2)- 30 l of the 3X ATP cocktail (3) are added (start of the reaction); 35 3)- the mixture is incubated for 30 min at ambient temperature (20 to 25 0

C);

75 4)- the reaction is stopped by adding 250 4 of buffer [50 mM Tris-HCl - 0.1M NaCl - pH 7.5] - 0.1% BSA - 25 mM EDTA; 5)- 100 yl are distributed into a plate coated with 5 antibodies directed against the substrate of the reaction; 6)- the plate is incubated for 60 min at ambient TO, with gentle agitation, and then washed 3 times with 300 yl of buffer [50 mM Tris-HCl - 0.1M NaCl - pH 7.5] - 0.05% 10 Tween 20; 9)- the plate is left to dry for 30 min at 37 0 C; 10)- the plate is counted in a scintillation counter. c) Results obtained expressed as IC50s expressed as 15 micromolar Product IC50 as micromolar Example 1 0.8 Example 2 0.5 20 Example 5 1.1 Example 7 3.6 Example 8 1.3 Example 15 0.3 Example 16 0.31 25 Example 18 3.9 Example 19 0.78 Example 20 1.7 Example 24 0.39 Example 27 4.3 30 Example 30 0.1 Example 39 3.6 Example 40 0.2 Example 41 0.95 Example 42 3.3 35 Example 43 4.4 Example 44 0.02 76 Example 45 1.3 Example 46 2.00 2) Assay for inhibition of SRC kinase activity The inhibition is determined by fluorescence 5 polarization, the Abl kinase phosphorylates a peptide detected by adding an anti-phosphopeptide antibody coupled to a fluorescent label. The assay is carried out in a final volume of 50 gl; all the reagents are prepared in a buffer: 10 m 25 mHepes/NaOH pH 7.6 " 5 mM MgCl 2 " 2 mM MnCl 2 " 50 gM Na 2

VO

4 5 gl of the 10-times concentrated inhibitor are added to 15 25 yl of enzyme (12 U/ml final concentration) , (Upstate Biotechnology ref 14-117). After incubation for 5 minutes at ambient temperature, 10 gl of PolyGluTyr 4/1 (150 ng/ml final concentration) and 10 gl of ATP (5 gM final concentration) are added. The detection is carried 20 out after incubation for 20 minutes at ambient temperature. > Results obtained expressed as percentage inhibition at 20 gM Example 8 98% 25 Example 15 99% Example 20 99% Example 24 99% Example 27 95% Example 30 99% 30 Example 32 100% Example 38 95% 3) Assay for inhibition of CDK2 activity The inhibition of the kinase activity of Cyclin Dependent kinase 2 (CDK2) is determined by measuring the 77 phosphorylation of its substrate peptide. The assay is carried out in a final volume of 50 gl. The incubation buffer as follows: " 50 mHepes/NaOH pH 7.5 5 " 10 MM MgCl 2 " 1 mM DTT 5 gl of the 10-times concentrated inhibitor are added to 25 gl of incubation buffer containing 0.8 U/gL final concentration of the enzyme; 10 aL of incubation buffer 10 containing 0.0025 mg/ml of peptide substrate are then added and, finally, 10 gL of incubation buffer containing 2 mM ATP and radiolabeled ATP, ["P]ATP (0.25 gCi), are added. The reaction is stopped after incubation for 10 minutes at 37 0 C. 15 > Results obtained expressed as percentage inhibition at 20 gM Example 2 97% Example 27 97% Example 30 99% 20 4) Assay for inhibition of CDK1 activity The inhibition of the kinase activity of Cyclin Dependent kinase 1 (CDK1) is determined by measuring the phosphorylation of its substrate peptide. The test is carried out in a final volume of 50 gl. 25 The incubation buffer is as follows: * 50 mM Tris/HCl pH 7.5 * 10 mM MgCl 2 * 100 gM Na 2

VO

4 * 2 mM DTT 30 * 40 mM Beta-glycerophosphate * 0.1 mg/ml BSA 5 yl of the 10-times concentrated inhibitor are added to 25 gl of incubation buffer containing 0.04 U/gl final concentration of the enzyme; 10 gl of incubation buffer 35 containing 12.5 gM final concentration of peptide 78 substrate are then added and, finally, 10 gl of incubation buffer containing 50 MM ATP and radiolabeled ATP, ["P]ATP (0.5 iCi), are added. The reaction is stopped after incubation 'for 40 minutes at ambient 5 temperature. > Results obtained expressed as percentage inhibition at 20 gM Example 8 93% Example 30 99% 10 5) Assay for inhibition of Abl activity The inhibition of the kinase activity is determined by fluorescence polarization, the Abl kinase phosphorylates a peptide detected by adding an anti phosphopeptide antibody coupled to a fluorescent label. 15 The assay is carried out in a final volume of 50 gl; all the reagents are prepared in a buffer: * 20 mHepes/NaOH pH 7.5 * 5 mM MgCl 2 * 100 yM Na 2

VO

4 20 a 1 mM DTT * 100 AM EDTA/NaOH * 0.01% Brij35 5 gl of the 10-times concentrated inhibitor are added to 25 gl of enzyme (1000 U/ml final concentration), 25 (Calbiochem ref 102555). After incubation for 5 minutes at ambient temperature, 10 ML of PolyGT (400 ng/ml final concentration) and 10 gL of ATP (5 AM final concentration) are added. The detection is carried out after incubation for 15 minutes at 30 0 C. 30 > Results obtained expressed as percentage inhibition at 20 yM Example 24 100% Example 2 100% Example 32 100% 79 6) Assay for inhibition of ZAP kinase activity The inhibition of the kinase activity is determined by fluorescence polarization, the ZAP kinase phosphorylates a peptide detected by adding an anti 5 phosphopeptide antibody coupled to a fluorescent label. The assay is carried out in a final volume of 50 4l; all the reagents are prepared in a buffer: " 20 mTris/HCl pH 7.7 N 7 M MnCl 2 10 " 50 gM Na 2

VO

4 5 gl of the 10-times concentrated inhibitor are added to 25 y1 of enzyme (0.7 gg/ml final concentration) (Panvera ref P2782) . After incubation for 5 minutes at ambient temperature, 10 gl of PolyGT (300 ng/ml final 15 concentration) and 10 y1 of ATP (0.25 AM final concentration) are added. The detection is carried out after incubation for 15 minutes at ambient temperature. > Results obtained expressed as percentage inhibition at 20 gM 20 Example 8 98% Example 20 95% Example 24 96% 7) Assay for inhibition of Casein kinase II activity The inhibition of the kinase activity is determined 25 by measuring the phosphorylation of its substrate peptide. The assay is carried out in a final volume of 50 4l. The incubation buffer is as follows: " 30 mM MES pH 6.9 30 " 15 M MgCl 2 " 195 mM KCl - 7.25 mM DTT 5 gl of the 10-times concentrated inhibitor are added to 25 gl of incubation buffer containing 1 U/gl final 35 concentration of the enzyme (Tebu, SE-124); 10 gl of 80 incubation buffer containing 60 AM final concentration of peptide substrate are then added, and, finally, 10 yl of incubation buffer containing 25 yM ATP and radiolabeled ATP, ["P]ATP (0.25 gCi), are added. The reaction is 5 stopped after incubation for 30 minutes at ambient temperature. > Results obtained expressed as percentage inhibition at 20 gM Example 8 93% 10 Example 30 97% 8) Assay for inhibition for CAM kinase II activity The inhibition of the kinase activity is determined by measuring the phosphorylation of its substrate peptide. 15 The assay is carried out in a final volume of 50 gl. The incubation buffer is as follows: " 20 mM MOPS pH 7.4 " 5 mM MgC1 2 " 5 mM CaCl 2 20 " 1 mM DTT " 100 gM Na 2

VO

4 " 25 mM Beta-glycerophosphate 5 gl of the 10-times concentrated inhibitor are added to 25 gl of incubation buffer containing 0.2 gg/gl final 25 concentration of the enzyme (Tebu, SE-134); 10 gl of incubation buffer containing 5 gM final concentration of substrate and 1600 U/ml final concentration of calmodulin are then added and, finally, 10 gl of incubation buffer containing 20 gM ATP and radiolabeled ATP, ["P]ATP 30 (0.05 gCi), are added. The reaction is stopped after incubation for 40 minutes at ambient temperature. > Results obtained expressed as percentage inhibition at 20 jM Example 30 98% 81 9) Assay for inhibition of EGF tyr kinase activity The inhibition of the kinase activity is determined by measuring the phosphorylation of its substrate peptide. 5 The assay is carried out in a final volume of 100 4l. The incubation buffer is as follows: " 5 mM Hepes/Tris pH 7.4 " 2% Glycerol 10 " 0.2% triton X100 10 gl of the 10-times concentrated inhibitor are added to 20 gl of incubation buffer containing 1 U/gl final concentration of the enzyme (Tebu, SE-124); 30 gl of incubation buffer containing 0.43 mg/ml final 15 concentration of peptide substrate are then added along with 20 gl of incubation buffer containing 0.4 AM of enzyme and, finally, 20 gl of 6 mM tris/HCl pH 7.4, 15 mM MgCl 2 buffer containing 10 yM ATP and radiolabeled ATP, ["P]ATP (0.25 gCi), are added. The reaction is stopped 20 after incubation for 60 minutes at 30 0 C. > Results obtained expressed as percentage inhibition at 20 AM Example 20 100% 10) Assay for inhibition of AKT activity 25 The inhibition of the kinase activity is determined by fluorescence polarization, the AKT kinase phosphorylates a peptide detected by adding an anti phosphopeptide antibody coupled to a fluorescent label. The assay is carried out in a final volume of 30 gl; 30 all the reagents are prepared in a buffer: a 50 m HEPES pH 7.5 " 0.03% triton X100 m 10 mM MgCl 2 " 5% Glycerol 35 " 1 mM DTT 82 10 gl of the 10-times concentrated inhibitor are added to 5 gl of enzyme (20 ng final concentration), and 5 gl of peptide (1 gM final concentration) and 10 l of ATP (80 gM final concentration) are added. The detection is 5 carried out after incubation for 20 minutes at 250C. > Results obtained expressed as IC50s expressed as micromolar Example 8 0.46 gM 11) Assay for inhibition of FAK activity 10 The inhibition of the kinase activity is determined by fluorescence polarization, the autophosphorylation of FAK is detected by adding an anti-phosphoprotein antibody coupled to a fluorescent label. The assay is carried out in a final volume of 30 pl; 15 all the reagents are prepared in a buffer: " 50 m HEPES pH 7.5 " 0.03% triton X100 " 10 mM MgCl 2 " 5% Glycerol 20 " 1 mM DTT 10 y1 of the 10-times concentrated inhibitor are added to 5 gl of enzyme (100 ng final concentration), and 5 l of incubation buffer and 10 l of ATP (1 gM final concentration) are added. The detection is carried out 25 after incubation for 10 minutes at 25 0 C. > Results obtained expressed as IC50s expressed as micromolar Example 8 2 yM Example 20 1.6 gM 30 Example 30 1 AM 12) Assay for inhibition of JNK3 activity The inhibition of the kinase activity is determined by fluorescence polarization, the JNK3 kinase 83 phosphorylates a peptide detected by adding an anti phosphopeptide antibody coupled to a fluorescent label. The assay is carried out in a final volume of 30 g1; all the reagents are prepared in a buffer: 5 " 50 m HEPES pH 7.5 " 0.03% triton X100 " 10 mM MgC1 2 " 5% Glycerol 0 1 mM DTT 10 10 y1 of the 10-times concentrated inhibitor are added to 5 gl of enzyme (40 ng final concentration), and 5 l of incubation buffer containing 100 ng of substrate and 10 gl of ATP (6 gM final concentration) are added. The detection is carried out after incubation for 30 minutes 15 at 250C. > Results obtained expressed as IC50s expressed as micromolar Example 8 0.84 gM Example 1 0.29 gM 20 Example 15 0.5 gM Example 38 0.42 gM Example 26 0.31 gM Example 27 0.29 AM 13) Assay for inhibition of GSK3beta activity 25 The inhibition of the kinase activity is determined by measuring the phosphorylation of its substrate peptide. The assay is carried out in a final volume of 40 gl; all the reagents are prepared in a buffer: 30 " 50 m HEPES pH 7.5 " 0.03% triton X100 " 10 mM MgC1 2 " 5% Glycerol " 1 mM DTT 35 10 gl of the 10-times concentrated inhibitor are added to 84 5 yl of enzyme (20 ng final concentration) , and 5 gl of peptide (1 AM final concentration) then 2.5 yl of incubation buffer containing 16 MM ATP and 2.5 gl of radiolabeled ATP, ["P]ATP (50 nCi) are added. After 5 incubation for 15 minutes at ambient temperature, 10 Al of incubation buffer* containing 1 gM of substrate. The reaction is stopped after incubation for 30 minutes at 30 0 C. > Results obtained expressed as IC50s expressed as 10 micromolar Example 2 0.6 gM Example 26 1.3 gM Example 30 1.5 AM 14) Assay for inhibition of PLK1 activity 15 The inhibition of the kinase activity is determined by measuring the phosphorylation of its substrate peptide. The assay is carried out in a final volume of 40 gl; all the reagents are prepared in a buffer: 20 m 50 m HEPES pH 7.5 " 0.03% triton X100 " 10 mM MgCl 2 " 5% Glycerol " 1 mM DTT 25 10 gl of the 10-times concentrated inhibitor are added to 5 gl of enzyme (75 ng final concentration), and 5 Ml of peptide (1 MM final concentration), then 2.5 Ml of incubation buffer containing 40 AM ATP and 2.5 Ml of radiolabeled ATP, [ 33 P]ATP (500 nCi), are added. After 30 incubation for 15 minutes at ambient temperature, 10 gl of incubation buffer containing 192 nim of substrate. The reaction is stopped after incubation for 60 minutes at 37 0 C. > Results obtained expressed as IC50s expressed as 85 micromolar Example 18 0.16 yM Example 1 0.21 gM 15) Determination of the minimum inhibitory concentration 5 in order to test the sensitivity of fungi to antifungal agents in liquid medium: micro method Principle: A constant number of cells of a given strain is placed in the presence of increasing concentrations of an antifungal agent, under conditions taken from the 10 NCCLS (National Committee for Clinical Laboratory Standards, 1997. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved Standard M27-A. NCCLS, Villanova, Pa.); the minimum concentration with which a visible decrease is observed 15 in the cloudiness of the cell growth (at least 80% compared to a control without product) is the Minimum Inhibitory Concentration (MIC) of the antifungal agent with respect to the strain tested. RPMI 1640 medium (liquid) without L-glutamine is 20 supplemented with L-glutamine (0.3 g/l or 10.5 ml of a solution at 200 mM) and buffered with 34.54 g/l (0.165 M) of morpholinepropanesulfonic acid (MOPS). The medium is sterilized by filtration. 100 gl of RPMI medium are distributed into each well of a 96-well plate. The 25 appropriate volume of the antifungal solution is distributed in the first column of the microplate and supplemented with 200 gl of medium. Doubling dilutions are made so as to establish a range of 11 concentrations in each line of the microplate. The 12th well of each row 30 will serve as a growth control. The cell suspension is prepared from a culture (liquid or agar) or from a frozen vial, and is diluted in RPMI medium so as to obtain a cell suspension at 5 x 10' - 2 x 10' cells/ml. 100 gl of the cell suspension are distributed in the microplate. 35 For all species of Candida, the MIC is read after 24- 86 48 h, and for Cryptococcus and Aspergillus after 48-72 h, of incubation at 37 0 C in a normal atmosphere. The MIC is read by visual reading, determining the well which contains the lowest dose of antifungal agent which causes 5 at least 80% inhibition of the growth of the fungus. Results of the MICs > Example 5: MIC Candida glabrata 64 gg/ml; Candida albicans 64 gg/ml > Example 8: MIC Candida glabrata 16 gg/ml; Candida 10 albicans 16 gg/ml; Aspergillus fumigatus 32 gg/ml > Example 19: MIC Candida glabrata 32 yg/ml; Candida albicans 16 gg/ml; Aspergillus fumigatus 32 gg/ml > Example 20: MIC Candida glabrata 16 gg/ml; Candida albicans 32 gg/ml; Aspergillus fumigatus 32 gg/ml 15 > Example 30: MIC Candida glabrata 64 gg/ml; Candida albicans 32 yg/ml > Example 32: MIC Candida glabrata 64 yg/ml; Candida albicans 64 gg/ml