MXPA06009395A - 7h-pyrrolopyrimidine derivatives - Google Patents

Abstract

The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives of formula (I), wherein the symbols and substituents are as defined in the description, to processes for the preparation thereof, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives - alone or in combination with one or more other pharmaceutically active compounds - for the preparation of pharmaceutical compositions for the treatment especially of a proliferative disease, such as a tumour.

Description

DERIVATIVES OF 7H-PIRROLOP1RIMI DINA The present invention refers to 7H-pyrrolopyrimidine derivatives and to the use of said derivatives as medicaments, to their pharmaceutical preparation and to their manufacturing process. In accordance with the above, the present invention provides compounds of the formula I wherein Ri and R2 are independently a hydrogen atom, a halo radical; or a lower alkyl, heterocycle, amino or cycloalkyl radical, all of which may be substituted or unsubstituted; or Ri and R2 together can form a substituted or unsubstituted N-heterocycle ring; Y is a group (R3) n-X- or A (R3) (R3) C-; wherein X is a lower alkyl, amino, amido or carbonyl radical; A is a hydroxy, amino, halo or lower alkyl radical; R3 is a lower alkyl, lower alkoxy, carbonyl, amino, hydroxy, heterocycle or heteroaryl radical, all of which may be substituted or unsubstituted; n has a value of 1 or 2; or a pharmaceutically acceptable salt or ester thereof. Preferably, R ^ and R2 are independently a hydrogen atom; or a lower alkyl, heterocycle, amino or cycloalkyl radical, all of which may be substituted or unsubstituted; or Ri and R2 together can form a substituted or unsubstituted N-heterocycle ring; And it is a group (R3) "- X- or A (R3) (R3) C-. In previous paragraphs and later in the present description, the following terms have the following meanings. The term "lower" in relation to radicals or organic compounds, means a compound or a radical which may be branched or unbranched with up to 7 carbon atoms inclusive, preferably 1 to 4 carbon atoms. A lower alkyl group is branched or unbranched and contains from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. A lower alkyl represents, for example, a methyl, ethyl, propyl, butyl, isopropyl, isobutyl or tertiary butyl radical. A lower alkoxy group is branched or unbranched and contains from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms. A lower alkoxy represents, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or tertiary butoxy radicals. A carbonyl radical is a radical -C (O) -. An unsubstituted carbonyl is a radical -C (O) H and a substituted carbonyl is a radical -C (O) R3. A hydroxy radical is -OH, which is unsubstituted or substituted. When substituted, the hydroxy radical is one in which the hydrogen has been replaced by a substituent, e.g. a lower alkyl radical, cycloalkyl or heterocycle. A halo or halogen radical represents chlorine, fluorine, bromine, but it can also be iodine. A heteroaryl radical is a cyclic aromatic hydrocarbon radical of 5 to 1 8 ring atoms, of which one or more, preferably 1 or 2, are heteroatoms selected from the group consisting of O, N or S. It can be a heteroaryl monocyclic or bicyclic. The heterocyclic aryl represents, for example, pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl or thienyl radicals, including any of said substituted radicals. A cycloalkyl radical represents a cyclic hydrocarbon radical containing from 3 to 12 ring atoms, preferably from 3 to 6 ring atoms. A cycloalkyl represents, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radicals, independently substituted or unsubstituted. A heterocycle radical represents a monocyclic, bicyclic or tricyclic hydrocarbon radical, which is unsaturated or partially or completely saturated and contains one or more, preferably 1 to 3, heteroatoms which are selected from the group consisting of O, N or S and preference contains 3 to 18 atoms in the ring; for example, a heterocycle is a pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, pyranyl, pyrazolidinyl, oxiranyl, dioxanyl, imidazolinyl or imidazolidinyl radical or especially piperidinyl, morpholinyl or piperazinyl. A radical N-heterocycle represents a monocyclic, bicyclic or tricyclic hydrocarbon radical, which is unsaturated or fully or partially saturated and contains at least one nitrogen atom. An N-heterocycle may contain one or more, preferably 0, 1, 2 or 3 different heteroatoms which are selected from the group consisting of O, N or S and preferably contain from 3 to 18 ring atoms; for example a monocyclic hydrocarbon radical with 5 or 6 members in the ring, at least one of which is a nitrogen atom, which is not saturated or is completely or partially saturated and may contain 1 or 2 different heteroatoms which are selected from the A group consisting of N, O and S. A radical N-heterocycle is for example pyrrolidine, imidazoline, imidazolidine, piperidine, morpholino or piperazine, especially piperidine, morpholino or piperazine. An amino radical is a -NH2- substituted or unsubstituted radical, wherein the substituents are for example lower alkyl radicals. An amido radical is a H2NC (O) -substituted or unsubstituted radical, or an unsubstituted or substituted -C (O) -NH radical, wherein the substituents are, for example, lower alkyl radicals. The substituents, e.g. 1-6 substituents, preferably 1 -3 substituents on the radical R3 are one or more substituents that are independently selected from the group consisting of halo, lower alkyl, lower alkoxy, amino, hydroxy and heterocycle radicals; all of which, except the halo radical, are substituted or unsubstituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of halo, hydroxy, lower alkoxy radicals , amino, lower alkyl and heterocycle; all of which, except the halo radical, are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy and lower alkoxy. The substituents, e.g. 1-6, preferably 1-3 substituents on the Ri and R2 radicals are one or more substituents that are independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, cycloalkyl, heterocycle and heteroaryl radicals; all of which, except the halo radical, are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of halo, hydroxy, alkyl radicals lower, lower alkoxy, amino, heterocycle and heteroaryl; all of which, except the halo radical, are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of halo, hydroxy, alkyl radicals lower and amino. The compounds of Formula I and those listed below are referred to herein as agents of the invention.

The pharmaceutically acceptable salts of the acidic agents of the invention are salts formed with bases, mainly cationic salts such as salts with alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium salts, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium and tris- (hydroxymethyl) -methylammonium. Similarly, the acid addition salts, such as salts of mineral acids, organic carboxylic acids and organic sulfonic acids, for example hydrochloric acid, methanesulfonic acid, maleic acid, may also contain a basic group, such as a pyridyl, which is part of the structure. For purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. Only salts that are pharmaceutically acceptable and non-toxic (at the appropriate doses) are used therapeutically and, therefore, those salts are preferred. Agents of the invention comprising free hydroxyl groups may also exist in the form of pharmaceutically acceptable and physiologically degradable esters and as such are included within the scope of the invention. Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, which can be transformed by solvolysis or cleavage under physiological conditions, to obtain the corresponding Agents of the invention comprising free hydroxyl groups. Proper pharmaceutically acceptable and suitable esters are those derived from a carboxylic acid, a monoester of carbonic acid or a carbamic acid, advantageously esters derived from a substituted or unsubstituted lower alkanoic acid or an arylcarboxylic acid. The compounds of Formula I exhibit valuable pharmacological properties in mammals and are particularly useful as inhibitors of Bcr-Abl. In chronic myelogenous leukemia (CML), a reciprocally balanced chromosomal translocation in hematopoietic stem cells (HSCs), produces the hybrid BCR-ABL gene. The latter codes for the oncogenic fusion protein Bcr-Abl. While the ABL gene codes for a well-regulated protein tyrosine kinase, which plays a fundamental role in the regulation of cell proliferation, adhesion and apoptosis, the BCR-ABL fusion gene codes for a constitutively activated kinase, the which transforms the CMHs so that they produce a phenotype that exhibits a deregulated clonal proliferation, a reduced ability to adhere to the stroma of the bone marrow and reduces the apoptotic response to mutagenic stimuli, which makes it possible for more malignant transformations to accumulate progressively. The resulting granulocytes fail to develop as mature lymphocytes and are released into the circulation, causing a deficiency of mature cells and an increased susceptibility to infections. The ATP-competitive inhibitors of Bcr-Abl prevented the kinase from activating mitogenic and antiapoptotic pathways (eg P-3 kinase and STAT5), causing the death of cells with BCR-ABL phenotype and thus providing an effective therapy against LMC. An agent of the invention, as an inhibitor of Bcr-Abl, is especially suitable for the therapy of diseases related to excessive expression of Bcr-Abl, especially leukemias, such as CML or ALL. The compounds of Formula I have valuable pharmaceutical properties, as described above and as will be described below. The efficacy of the compounds of the invention as inhibitors of c-Abl, Bcr-Abl, Raf and VEGF receptor tyrosine kinase activity, can be demonstrated as follows: Activity test against c-Abl tyrosine kinase protein. The test is carried out as a filter paper binding assay, in the following manner: the His-tagged kinase domain of c-Abl is cloned and expressed in the baculovirus / Sf9 system, as described in Bhat et al. , J. Biol. Chem. A 37 kD protein (c-Abl kinase) is purified by a two step procedure, in a cobalt metal chelate column, followed by an anion exchange column, in a yield of 1 - 2 mg / L of Sf9 cells. The purity of the c-Abl kinase is >90%, determined by EGPA-DSS after a stain with Coomassie blue. The assay contains: c-Abl kinase (50 ng), 20 mM Tris-HCl, pH 7.5, 10 mM MgCl2, 1.0 μM Na3VO4, 1 mM DTT and 0.06 μCi / [? 33 P] -ATP assay (ATP 5 μM), using 30 μg / mL of poly-Ala, Glu, Lys, Tyr-6: 2: 5: 1 (Poly-AEKY, Sigma P1 152), in the presence of 1% DMSO, in a total volume of 30 μL. Reactions are stopped by adding 10 μL of 250 mM EDTA, and 30 μL of the reaction mixture is transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously submerged for 5 minutes in methanol, rinsed with water and then submerged for 5 minutes in 0.5% H3PO4 and mounted in a vacuum apparatus with the vacuum source disconnected. After transferring all the samples, the vacuum is applied and each well is rinsed with 20 μL of 0.5% H3PO4. The membranes are removed and washed with shaking with 0.5% H3PO4 (4 times) and once with ethanol. The membranes are counted after drying at room temperature, mounted in a Packard 96-well counting apparatus, and adding 10 μL / well of Microscint ™ (Packard). The Cl5o values that can be found for the compounds of Formula I are in the range of 1 to 10,000 nM, preferably in the range of 1 to 1, 000 nM and more preferably in the range of 1 to 1 00 nM. Activity test against Bcr-Abl. L line of murine myeloid progenitor cells 32Dcl3 transfected with the expression vector p21 0 Bcr-Abl, to obtain pGDp21 0Bcr / Abl (32D-bcr / abl), was obtained in J. Griffin (Dana Faber Cancer Institute, Boston, MA, USA). The cells express the Bcr-Abl fusion protein with a constitutively active Abl kinase and proliferation independent of the growth factor. The cells are cultured in RPMI 1640 (AMIMED), 10% fetal calf serum, 2 mM glutamine (Gibco) ("complete medium") and a working solution prepared, freezing aliquots of 2 x 106 cells per vial, in freezing medium (95% SFT, 5% DMSO (SIGMA)). After thawing, the cells are used for maximum 10-12 passes for the experiments. For cell assays, the compounds are dissolved in DMSO and diluted with complete medium, to obtain an initial concentration of 1.0 μM, followed by the preparation of serial dilutions in factors of 3, in complete medium. 200,000 32D-Bcr / Abl cells were seeded in 50 μL of complete medium, per well, in a 96 well round-bottom tissue culture plate. 50 μL per well of the serial dilutions in factor 3 of the test compound are added to the cells in triplicate. As control untreated cells are used. The compound is incubated together with the cells for 90 minutes at 37 ° C, 5% CO2, followed by a centrifugation of the tissue culture plates at 1300 rpm (Beckman GPR centrifuge) and the supernatant is removed by careful aspiration, taking care not to remove any of the compacted cells. The cell pellets are lysed by the addition of 150 μL of lysis buffer (tris / 50 mM HCl, pH 7.4, 1 50 mM sodium chloride, 5 mM EDTA, 1 mM AEGT, 1% NP-40, ortho - 2 mM sodium vanadate, 1 mM PMSF, 50 μg / mL aprotinin and 80 μg / mL leupeptin) and were used immediately for an ELISA test, or stored frozen in the plates at -20 ° C until their use. A series of black ELISA plates (Packard HTRF-96 black plates) were coated overnight at 4 ° C, with 50 ng / well of rabbit polyclonal serum against the abl-SH3 domain, the said serum being referred to as Ab 06-466 of Upstate, in 50 μL of SRF. After washing 3 times with 200 μL / well of SRF containing 0.05% Tween 20 (PBST) and 0.5% TopBlock (Juro), the binding sites of the residual protein were blocked with 200 μL / well of PBST, 3 % of TopBlock for 4 hours at room temperature, followed by an incubation with 50 μL of lysate of untreated cells or cells treated with the compound (20 μg total protein per well), for 3-4 hours at 4 ° C. After 3 washes, 50 μL / well of the antiphosphotyrosine antibody Ab PY20 (AP) labeled with alkaline phosphatase (Zymed), was diluted to 0.2 μg / mL with blocking buffer, added to the plates and incubated overnight ( 4 ° C). For all incubation steps, the plates were covered with plate sealer (Costar). Finally, the plates were washed three more times with washing buffer and once with deionized water, before adding 90 μL / well of the AP-substrate CDPStar RTU, with Emerald I I. The plates now sealed with Packard TopSeal ™ -A were incubated for 45 minutes at room temperature in the dark and the luminescence was quantified by measuring counts per second (cps), with a Packard Top Count Microplate Scintillation Counter (Top Count). The difference between the ELISA (cps) reading obtained with the Untreated 32D-Bcr / Abl cells and the background reading of the assay (all components, but without the cell lysate) is calculated and taken as 100% , reflecting the phosphorylated Bcr-Abl protein constitutively present in these cells. The activity of the compound on the activity of Bcr-Abl kinase is expressed as percent reduction in Bcr-Abl phosphorylation. The IC50 and Cl90 values were determined from dose-response curves by extrapolation in graphs. The Cl 50 values that can be found with the compounds of Formula I are in the range of 1 to 10,000 nM, preferably in the range of 1 to 5,000 nM, even more preferably in the range of 1 to 1, 000 nM. Activity test against the Bcr-Abl mutant: the activity of the compounds on the Bcr-Abl mutant M351 T kinase, was evaluated in the manner described above, except that the 32Dcl3 cells were transfected with mutant Bcr-Abl, instead of p21 0 Bcr-Abl. C-Raf-1 protein kinase assay: The recombinant c-Raf-1 protein was obtained by triple infection of Sf21 cells with recombinant baculovirus GST-c-Raf-1, together with recombinant baculoviruses v-Src and v-Ras , which are required to activate the production of c-Raf-1 kinase (Williams et ai, PNAS 1 992; 89: 2922-6). The active Ras (v-Ras) is required to recruit c-Raf-1 in the cell membrane and v-Src to phosphorylate the c-Raf-1, to activate it completely. The cells are inoculated at 2.5 x 107 cells per 150 mm plate and allowed to adhere to the bottom of the 150 mm plate for 1 hour at room temperature. The medium was aspirated (SF900I I containing 1.0% SFB) and the recombinant baculoviruses GST-c-Raf-1, v-Ras and v-Src were added to MOI of 3.0, 2.5 and 2.5, respectively, in a total volume of 4-5 mL. The cells were incubated for 1 hour at room temperature and then 15 mL of the medium was added. The infected cells were incubated for 48-72 hours at 27 ° C. The infected Sf21 cells were scraped and collected in a 50 mL test tube and centrifuged for 1 0 min at 4 ° C, at 1, 1000 g, in a Sorvail centrifuge. The cell pellet was washed once with ice cold SRF and lysed with 0.6 mL of lysis buffer by 2.5 x 1 07 cells. Complete lysis of the cells was achieved after 10 min. on ice, with occasional agitation by pipetting. The cellular ones were centrifuged for 10 min. at 4 ° C, at 14,500 g, in a Sorvall centrifuge with a SS-34 rotor and the supernatant was transferred to a clean test tube and stored at -80 ° C. C-Raf-1 was purified from the used cells, using 100 μL of packaged glutathione-sepharose 4B, equilibrated with ice cold SRF for 2.5 x 10 7 cells. The GST-c-Raf-1 was allowed to bind to the beads at 4 ° C for 1 hour, with shaking. The GST-c-Raf-1 attached to the accounts was transferred to a column. The column was washed once with a lysis buffer and twice with ice-cold Tris buffer. Ice-cooled elution buffer was added and the column flow stopped to allow free glutathione to interrupt the interaction of GST-c-Raf-1 with the glutathione-sepharose beads. Fractions (1 mL) were collected in previously cooled tubes. Each tube contained 10% glycerol) (final concentration) to maintain kinase activity during the freeze and thaw cycles. The purified fractions of the GST-c-Raf-1 kinase protein were stored at -80 ° C. L? B was used as substrate for c-Raf-1 kinase. L? B is expressed in bacteria as a His-tagged BL21 protein. LysS bacteria containing the plasmid L? B were grown to an OD600 optical density of 0.6, in LB medium and then induced to express L? B with I PTG (final concentration of 1 mM) for 3 hours at 37 °. C, and then the bacteria were used by sonication (establishing the microtip boundary at 1 minute for three times), in sonication buffer [Tris 50 mM, pH 8.0, 1 mM DTT, 1 mM EDTA] and centrifuged at 10,000 g for 15 minutes. The supernatant was mixed with ammonium sulfate to obtain a final concentration of 30%. This mixture was stirred for 15 minutes at 4 ° C and then centrifuged at 10,000 g for 15 minutes. The pellet was resuspended in binding buffer (Novagen) containing 1 mM ASB. This solution was applied to Ni-agarose (Novagen) and washed according to the Novagen manual. L? B was eluted from the column, using elution buffer (0.4M imidazole, 0.2M NaCl, 8mM Tris, pH 7.9). Fractions containing protein were dialysed in 50 mM Tris, pH 8, 1 mM DTT. The activity of the c-Raf-1-kinase protein was tested in the presence or absence of inhibitors, measuring the incorporation of 33P from [? 33P] ATP into the L? B. The assay was carried out in 96-well plates at room temperature, for 60 minutes. Contains (in a total volume of 30 μL): c-Raf-1 kinase (400 ng), 25 mM Tris-HCl, pH 7.5, 5 mM MgCl2, 5 mM MnCl2, 10 μM Na3VO4, 1 mM DTT and 0.3 μCi / assay [? 33P] -ATP (ATP 10 μM), using 600 ng of L? B in the presence of 1% DMSO. Reactions were stopped by adding 10 μL of 250 mM EDTA, and 30 μL of the reaction mixture was transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously submerged for 5 minutes in methanol, rinsed with water and then submerged for 5 minutes in 0.5% H3PO4 and then mounted in a vacuum apparatus with the vacuum source disconnected. After transferring all the samples, the vacuum was connected and each well was rinsed with 200 μL of 0.5% H3PO4. The membranes were removed and washed 4 times, with stirring, with 0.5% H3PO4 and once with ethanol. The membranes were counted after drying at room temperature, mounted in a Packard TopCount 96-well counter, and adding 10 μL / well of Microscint ™ (Packard). The values of% > of inhibition at 10M, which can be found for the compounds of Formula I, are in the range of 10 to 100%, preferably in the range of 25 to 1 00%, even more preferably in the range of 50. at 1 00%. Activity test against the VEGF receptor tyrosine kinase. The test is performed using the VEGF receptor of the tyrosine kinase Flt-3. The detailed procedure is as follows: 30 μL of kinase solution (1 0 ng of the kinase domain of Flt-3) is incubated, Shibuya et al., Oncogene 5, 51 9-24 [1990] in 20 mM Tris-HCl, pH 7.5, 3 mM manganese dichloride (MnCl 2), 3 mM magnesium chloride (MgCl 2), 10 μM sodium vanadate. , 0.25 mg / mL of polyethylene glycol (PEG) 20000, 1 mM dithiothreitol and 3 μg / μL of poly (Glu, Tyr) 4: 1 (sigma, Buchs, Switzerland), [33P] -ATP 8 μM (0.2 μCi), 1% DMSO and from 0 to 1000 μM of the compound to be tested, for 10 minutes at room temperature. Then, the reaction is stopped by the addition of 1.0 μL of ethylenediaminetetraacetate (EDTA) 0.25M, pH 7. Using a multichannel jet (LAB SYSTEMS, USA), a 20 μL aliquot is applied to a difluoride membrane of polyvinyl (PVDF) Immobilon P (Millipore, Bedford, USA), through a Gibco-BRL microtiter filter connected to a vacuum source. After completing the liquid removal, the membrane is washed four times successively in a bath containing 0.5% phosphoric acid) (H3PO) and once with ethanol, incubated for 1 0 minutes each time under stirring and then mounted in a TopCount Hewlett Packard counter and the radioactivity is measured after the addition of 10 μL of Microscint® (liquid for β-scintillation). Cl50 values are determined by linear regression analysis of the percentages of inhibition of each compound, in at least four concentrations (as a rule, 0.01, 0.1, 1.0 and 1.0 μM). The Cl 50 values that can be found in the compounds of Formula I are in the range of 1 to 1,000,000 nM, preferably in the range of 1 to 5,000 nM, even more preferably in the range of 1 to 1. , 000 nM and still more preferably in the range of 1 to 500 nM. The inhibition of autophosphorylation of the KDR receptor induced by VEGF, can be confirmed by an additional in vitro experiment in cells: transfected CHO cells are inoculated, which permanently express the human VEGF receptor (KDR) in complete culture medium with 10% of fetal calf serum (SFT), in 6-well cell culture plates, and incubated at 37 ° C under an atmosphere of 5% CO2, until they show approximately 80% confluency. Then, the compounds to be tested are diluted in culture medium (withSFT, with 0.1% bovine serum albumin) and added to the cells (the controls comprise medium withthe test compounds). After two hours of incubation at 37 ° C, recombinant VEGF is added (the final concentration being VEGF 20 ng / mL). After another incubation for 5 minutes at 37 ° C, the cells are washed twice with ice-cold SRF (phosphate buffer saline) and immediately lysed in 100 μL of lysis buffer per well. The Used ones are centrifuged to remove the nuclei of the cells and the protein concentration of the supernatants is determined by a commercial protein assay (BIORAD). The Used ones can be used immediately or, if necessary, they can be stored at -20 ° C. A sandwich ELISA test is performed to measure phosphorylation of the KDR receptor: a monoclonal antibody against KDR (eg MAb 1495.12.14) is immobilized on black ELISA plates (OptiPlate ™ HTRF-96 from Packard) . The plates are then washed and the remaining free protein binding sites are saturated with 1% ASB in SRF. The used cells (20 μg of protein per well), subsequently, are incubated in these plates overnight at 4 ° C, together with an antiphosphotyrosine antibody coupled with alkaline phosphatase (PY20: AP from Transduction Laboratories). The plates are washed again and the binding of the antiphosphotyrosine antibody with the captured phosphorylated receptor is demonstrated by the use of a luminescent AP substrate (CDP-Star, ready for use, with Emerald I I; TROP1X). The luminescence is measured on a Top Count Packard Microplate Scintillation Counter (Top Count). The difference between the signal of the positive control (stimulated with VEGF) and that of the negative control (not stimulated with VEGF), corresponds to the phosphorylation of the KDR receptor induced by VEGF (= 1 00%). The activity of the tested substances is calculated as the% inhibition of KDR receptor phosphorylation induced by VEGF, where the concentration of the substance that induces half of the maximum inhibition is defined as the IC5o (inhibitory concentration for 50% ). The Cl 50 values that can be found in the compounds of the formula I are in the range of 1 to 10,000 nM, preferably in the range of 1 to 5,000 nM, even more preferably in the range of 1 to 2,000 nM. The% inhibition values that can be found in the compounds of Formula I are in the range of 10 to 100%, preferably in the range of 30 to 1 00%, even more preferably in the range of 50 to 100. 1 00%. An agent of the invention inhibits in addition to BHCR-Abl and c-Abl, also other tyrosine kinases in various degrees, which are involved in signal transduction that are mediated by trophic factors, for example Raf kinase, Arg, derived kinases of the Src family, especially c-Src kinase, Lck and Fyn; also kinases of the EGF family, for example c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; insulin-like growth factor receptor kinase (IGF-1 kinase), especially members of the PDGF receptor tyrosine kinase family, such as the PDGF receptor kinase, CSF-1 receptor kinase, receptor kinase Kit and VEGF receptor kinase; and also serine / threonine kinases, all of which play a role in the regulation of growth and transformation of mammalian cells, including human cells. Inhibition of the c-erbB2 tyrosine kinase (HER-2) can be measured, for example, in the same manner as the inhibition of the EGF-R protein kinase, using known procedures. Based on these studies, an agent of the invention shows therapeutic efficacy especially against disorders that depend on the deregulation of protein kinases, especially leukemias and proliferative diseases. An agent of the invention is also effective against a number of diseases, for example a number of diseases related to the deregulation of the protein kinase, especially neoplastic diseases, e.g. solid tumors, leukemias and other "liquid tumors", especially those that express c-kit, KDR, Flt-1 or Flt-3, such as especially breast cancer, colon cancer, lung cancer (especially small cell lung cancer) , prostate cancer or Kaposi's sarcoma. An agent of the invention also inhibits the growth of tumors, and is especially suitable for preventing the metastatic spread of tumors and the growth of micrometastases. For example, Raf kinase, Arg, kinases of the Src family, especially c-Src kinase, Lck and Fyn; also kinases of the EGF family, for example c-erbB2 kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; Insulin-like growth factor receptor kinase (IGF-1 kinase), especially members of the PDGF receptor tyrosine kinase family, such as the PDGF receptor kinase, CSF-1 receptor kinase, receptor kinase Kit and VEGF receptor kinase; and also serine / threonine kinases, all of which play a role in the regulation of growth and transformation of mammalian cells, including human cells. An agent of the invention is also effective against diseases caused by ocular neovascularization, especially retinopathies, such as diabetic retinopathy or age-related macular degeneration, psoriasis, hemangioblastoma, such as hemangioma, mesangial cell proliferative disorders, such as chronic or acute kidney diseases, e.g. diabetic nephropathy, malignant nephrosclerosis, syndromes of thrombotic microangiopathy or rejection of transplantation, or especially renal inflammatory disease, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, haemolytic-uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, diabetes , endometriosis, chronic asthma. An agent of the invention is not only for the handling (prophylactic and preferably therapeutic) of humans, but also for the treatment of other warm-blooded animals, for example animals of commercial use, for example rodents, such as mice, rabbits or rats, or guinea pigs. Such a compound can also be used as a reference standard in the test systems described above, to allow a comparison with other compounds. The present invention also relates especially to the use of an agent of the invention, or a pharmaceutically acceptable salt thereof, especially an agent of the invention which is said to be preferred, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the therapeutic and also prophylactic management of one or more of the aforementioned diseases, especially a neoplastic disease, in particular if said disease responds to an inhibition of a protein tyrosine kinase, especially to the inhibition of Bcr-Abl. In accordance with the aforementioned, the present invention also provides, in another series of embodiments: A. A method for inhibiting Bcr-Abl in a subject (e.g., a mammal, especially a human) in need of such treatment , wherein the method comprises administering to the subject an effective amount of an agent of the invention, or a method for the treatment of any of the above-mentioned disorders, particularly a method for the treatment of a proliferative disease or disorder, or to alleviate a or more symptoms of any of the above-mentioned disorders. B. An agent of the invention for use as a pharmaceutical substance, or for use in the prevention, improvement or treatment of any disease or disorder such as those described above, for example a disease or proliferative disorder. A pharmaceutical composition comprising an agent of the invention, in association with a pharmaceutically acceptable diluent or carrier, for example for use as an antiproliferative agent or for use in the prevention, improvement or treatment of any disease or disorder such as those described above , for example a disease or proliferative disorder. D. The use of an agent of the invention in the manufacture of a medicament for use as an antiproliferative agent or for use in the prevention, improvement or treatment of any disease or disorder such as those described above, for example a disease or proliferative disorder. An agent of the invention may also be administered on its own or in combination with one or more other therapeutic agents, wherein the possible combination therapy may be with fixed combinations or by administration of a compound of the invention and one or more of other therapeutic agents in a staggered manner or independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents. An agent of the invention can additionally be administered especially for the therapy of tumors, such as leukemia therapy, in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention or a combination thereof. Long-term therapy is equally possible as help therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the state of the patient after a tumor regression, or even chemopreventive therapy, for example in patients at risk. An agent of the invention can be administered on its own or in combination with one or more other therapeutic agents. Such therapeutic agents include, but are not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase I I inhibitors, microtubule active agents., alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that decrease the activity of protein kinase and other anti-angiogenic compounds , gonadorelin agonists, antiandrogens, bengamides, bisphosphonates, antiproliferative antibodies and temozolomide (TEMODAL®). The term "aromatase inhibitors" as used herein, refers to compounds that inhibit the production of estrogens, for example the transformation of the substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially exemestane and formestane and, in particular, non-steroids, especially amioglutethimide, vorozole, fadrozole, anastrozole and, most notably, letrozole. Exemestane can be administered e.g. , in the way it is marketed, for example with the trademark AROMASIN ™. Formestane can be administered, e.g. , in the form in which it is marketed, for example under the trademark LENTARON ™. Fadrozole can be administered, e.g. , in the way it is marketed, for example under the trademark .AFEMA ™. Anastrozole can be administered, e.g. , in the way it is marketed, for example with the trademark ARIMIDEZ ™. Letrozole can be administered, e.g. , in the way it is marketed, for example with the trademark FEMARA ™ or FEMAR ™. The aminoglutethimide can be administered, e.g. , in the way it is marketed, for example under the trademark ORIMETEN ™. A combination of the invention comprising an antineoplastic agent which is an aromatase inhibitor, is particularly useful for the treatment of mammary tumors positive to hormone receptors. The term "antiestrogen" as used herein, refers to compounds that antagonize the effect of estrogens, at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, e.g. , in the way it is marketed, for example with the trademark NOLVADEZ ™. Raloxifene hydrochloride can be administered, e.g. , in the way it is marketed, for example with the trademark EVISTA ™. The fulvestrant can be formulated in the manner described in US Patent No. 4,659,516, or it can be administered, for example, in the form in which it is marketed, for example under the trademark FASLODEX ™. The term "topoisomerase I inhibitors" as used herein, includes but is not limited to topotecan, irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in International Patent Application WO 99 / 17804). Irinotecan can be administered, e.g. , in the way it is marketed, for example with the trademark CAMPTOSAR ™. Topotecan can be administered, e.g. , in the form in which it is marketed, for example under the trademark HYCAMTIN ™. The term "topoisomerase M inhibitors" as used herein, includes but is not limited to the anthracyclines doxorubicin (including the liposomal formulation, eg CAELYX ™), epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. The etoposide can be administered, e.g. , in the way it is marketed, for example with the trademark ETOPOPHOS ™. The teniposide can be administered, e.g. , in the way it is marketed, for example with the trademark VM 26-BRISTOL ™. Doxorubicin can be administered e.g. , in the form in which it is marketed, for example with the trademark ADR1BLASTIN ™. Epirubicin can be administered, e.g. , in the form in which it is marketed, for example under the trademark FARMORUBICIN ™. Idarubicin can be administered, e.g. , in the way it is marketed, for example under the registered trademark ZAVEDOX ™. Mitoxantrone can be administered, e.g. , in the way it is marketed, for example with the registered NOVANTRON ™ ark. The term "microtubule-active agents" refers to microtubule-stabilizing and microtubule-destabilizing agents, including but not limited to the taxanes paclitaxel and docetaxel, the vinca alkaloids, e.g. vinblastine, especially vinblastine sulfate, vincristine, especially vincristine sulfate and vinorelbine, discodermolide and epothilones, such as epothilone B and D. Docetaxel can be administered, e.g. in the way it is marketed, for example under the trademark TAXOTERE ™. Vinblastine sulfate can be administered e.g. in the way it is marketed, for example with the trademark VI NBLASTI N R. P. ™. Vincristine sulfate can be administered, e.g. in the form in which it is marketed for example under the trademark FARMISTIN ™. The discodermolide can be obtained, e.g. in the manner described in US Patent No. 5,010,099. The term "alkylating agents" as used herein includes but is not limited to cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide can be administered, e.g. in the way it is marketed, for example with the trademark CYCLOSTI N ™. Ifosfamide can be administered, e.g. in the way it is marketed, for example with the trademark HOLOXAN ™. The term "histone deacetylase inhibitors" refers to compounds that inhibit the enzyme histone deacetylase and that possess antiproliferative activity. The term "farnesyl transferase inhibitors" refers to compounds that inhibit the farnesyl transferase enzyme and that possess antiproliferative activity. The term "COX-2 inhibitors" refers to compounds that inhibit the enzyme cyclooxygenase type 2 (COX-2) and that possess antiproliferative activity, such as celecoxib (Celebrex®), rofecoxib (Vioxx®) and lumiracoxib (COX189) . The term "MMP inhibitors" refers to compounds that inhibit the matrix metalloproteinase (MMP) enzyme and that possess antiproliferative activity. The term "mTOR inhibitors" refers to compounds that inhibit the target of rapamycin in mammals (mTOR) and which possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican ™), CCI-779 and ABT578.

The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate, and salts of such compounds, and also ZD 1694 (RALTITREXED ™), LY231 514 (ALIMTA ™), LY26461 8 (LOMOTREXOL ™) and OGT71 9. The term "platinum compounds" as used herein, includes but is not limited to carboplatin, cis-platinum and oxaliplatin. Carboplatin can be administered, e.g. , in the way it is marketed, for example with the trademark CARBOPLAT ™. Oxaliplatin can be administered, e.g. , in the form in which it is marketed, for example under the trademark ELOXATI N ™. The term "compounds that decrease the activity of protein kinase and other anti-angiogenic compounds" as used herein, includes but is not limited to compounds that decrease the activity of, for example, Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF), c-Src, protein kinase C, Platelet Derived Growth Factor (PDGF), Bcr-Abl tyrosine kinase, c-kit, Flt-3 and Growth Factor Receptor similar to Insulin I (IGF-IR) and cyclin-dependent kinases (CDKs) and angiogenic compounds that have another mechanism of action different from the decrease in protein kinase activity. Compounds that decrease the activity of VEGF are especially compounds that inhibit the VEGF receptor, especially the tyrosine kinase activity of the VEGF receptor, and compounds that bind to VEGF, and in particular those compounds, proteins and monoclonal antibodies that are generically and specifically described in International Patent Application WO 98/35958 (which describes compounds of Formula I), International Patent Applications WO 00/09495, WO 00/27820, WO 00/59509, WO 98/1 1223, WO 00/27819 , WO 01/551 14, WO 01/58899 and European Patent EP 0 769 947; those described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan etai in Proc. Nati Acad. Sci. USA, vol. 93, pgs. 14765-14770, December 1 996, by Z. Zhu et al in Cancer Res. 58, 1 998, 3209-3214, and by J. Mordenti et al in Toxicologic Pathology, vol. 27, no. 1, pgs. 14-21, 1 999; in International Patent Applications WO 00/37502 and WO 94/1 0202; Angiostatin ™, described by M. S. O'Reilly et al. , Cell 79, 1994, 31 5-328; and Endostatin ™, described by M. S. O'Reilly et al. , Cell 88, 1 997, 277-285; compounds that decrease the activity of EGF are especially compounds that inhibit the EGF receptor, especially the tyrosine kinase activity of the EGF receptor, and compounds that bind to EGF, and in particular those compounds generically and specifically described in the International Patent Application WO 97 / 02266 (which describes compounds of Formula IV), European Patent EP 0 564 409, International Patent Application WO 99/03854, European Patents EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063; International Patent Applications WO 98/1 0767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/33980; Compounds that decrease the activity of c-Src include, but are not limited to compounds that inhibit the activity of the c-Src tyrosine kinase protein, as described below and inhibitors of the SH2 interaction such as those described in International Patent Applications WO 97/07131 and WO 97/08193; Compounds that inhibit the activity of the c-Src tyrosine kinase protein include, but are not limited to compounds belonging to the structure classes of the pyrrolopyrimidines, especially pyrrolo [2,3-d] -pyrimidines, purines, pyrazopyrimidines, especially pyrazo [3,4-d] -pyrimidines, pyrazopyrimidines, especially pyrazo [3,4-d] -pyrimidines and pyridopyrimidines, especially pyrido [2,3-d] pyrimidines. Preferably, the term refers to those compounds described in International Patent Applications WO 96/1 0028, WO 97/28161, WO 97/32879 and WO 97/49706; the compounds that decrease the activity of protein kinase C are especially those derived from staurosporine described in European Patent 0 296 1 10 (pharmaceutical preparation described in the International Patent Application WO 00/48571), which corresponds to inhibitors of the protein kinase C; in addition, specific compounds that decrease protein kinase activity and that can also be used in combination with the compounds of the present invention, are Imatinib (Gleevec® / Glivec®), PKC412, Iressa ™ (ZD1839), PKI 1 66, PTK787, ZD6474, GW2016, CHIR-200131, CEP-7055 / CEP-5214, CP-547632 and KRN-633; Anti-angiogenic compounds that have another mechanism of action other than the decrease in protein kinase activity include, but are not limited to, for example, thalidomide (THALOMID), celecoxib (Celebrex), SU5416 and ZD6126.

The term "gonadorelin agonist" as used herein, includes but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is described in US Patent No. US 4, 100,274 and can be administered, e.g. , in the way it is marketed, for example with the ZOLADEX ™ trademark. Abarelix can be formulated, e.g. , in the manner described in US Patent No. US 5,843,901. The term "antiandrogens" as described herein, includes but is not limited to bicalutamide (CASODEX ™), which may be formulated, for example, in the manner described in US Patent No. US 4,636,505. The term "bengamides" refers to bengamides and derivatives thereof, which have antiproliferative properties. The term "bisphosphonates" as used herein, includes but is not limited to etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, resedronic acid, and zoledronic acid. The "etridonic acid" can be administered, e.g. , in the way it is marketed, for example, under the registered trademark DIDRONEL ™. The "clodronic acid" can be administered, e.g. , in the way it is marketed, for example, under the trademark BONEFOS ™. The "tiludronic acid" can be administered, e.g. , in the form in which it is marketed, for example, under the trademark SKELI D ™. The "pamidronic acid" can be administered, e.g. , in the way it is marketed, for example, under the trademark AREDIA ™. The "alendronic acid" can be administered, e.g. , in the way it is marketed, for example, under the trademark FOSAMAX ™. The "ibandronic acid" can be administered, e.g. , in the form in which it is marketed, for example, under the trademark BONDRANAT ™. The "risedronic acid" can be administered, e.g. , in the way it is marketed, for example, under the trademark ACTONEL ™. The "zoledronic acid" can be administered, e.g. , in the way it is marketed, for example, under the trademark ZOMETA ™. The term "antiproliferative antibodies" as used herein, includes but is not limited to trastuzumab (Herceptin ™), Trastuzumab-DM 1, erlotinib (Tarceva ™), bevacizumab (Avastin ™), rituximab (Rituxan®), PRO64553 (anti-CD40) and Antibody 2C4. For the treatment of acute myelocytic leukemia (AML), the compounds of Formula I can be used in combination with normal leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, the compounds of Formula I can be administered in combination with, for example, farnesyl transferase inhibitors and / or other drugs used for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, imitoxantrone, Idarubicin, Carboplatin and PKC412. The structure of the active agents identified by key numbers, generic or commercial names, can be obtained in the current edition of the standard compendium "The Merck Index" or in databases, for example Patents International (e.g. IMS World Publications).

The aforementioned compounds, which can be used in combination with the agent of the invention, can be prepared and administered in the manner described in the art, for example in the aforementioned documents. Preference is given to compounds of the formula I wherein A is preferably a hydroxy, amino, halo or lower alkyl radical; R? and R2 are preferably and independently a hydrogen atom; or a lower alkyl, heterocycle, amino or cycloalkyl radical, all of which may be substituted or unsubstituted; or Ri and R2 together can form a substituted or unsubstituted N-heterocycle ring; R3 is preferably a lower alkyl, lower alkoxy, amino, hydroxy, heterocycle or heteroaryl radical, all of which may be substituted or unsubstituted. Preferably, R-, and R2 may be substituted or unsubstituted with one or more substituents, e.g. 1-6, preferably 1 -3 substituents, which are independently selected from the group consisting of hydroxy, lower alkyl, lower alkoxy, amino, cycloalkyl, heterocycle and heteroaryl radicals; all of which are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of lower alkyl, lower alkoxy, amino, heterocycle and heteroaryl; all of which are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of hydroxy and lower alkyl radicals. Preferably, R 3 is unsubstituted or substituted by 1 -6, preferably 1 -3 substituents, which are independently selected from the group consisting of lower alkyl, lower alkoxy, amino, hydroxy and heterocycle radicals; all of which are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of hydroxy, amino, lower alkyl, lower alkoxy and heterocycle; all of which are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of lower alkyl, lower alkoxy, hydroxy and lower alkoxy radicals. In a preferred embodiment, the invention provides compounds of Formula I, wherein R 1 and R 2 are independently a hydrogen atom, a halo radical; or lower alkyl, heterocycle, which are selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino, and piperazine, amino or cycloalkyl which are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; all of which may or may not be substituted; or R, and R2 can be joined to together form a substituted or unsubstituted N-heterocycle which is selected from pyrrolidine, imidazoline, imidazolidine, piperidine, pyran, morpholino and piperazine; Y is a group (R3) n-X- or of the formula I I; wherein X is a lower alkyl, amino, amido or carbonyl group; A is a hydroxy, amino, halo, or lower alkyl group; R3 is a lower alkyl, lower alkoxy, carbonyl, amino, hydroxy, heterocycle group which are selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino, and piperazine, or heteroaryl which is selected pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl and thienyl, all of which may or may not be substituted; n has a value of 1 or 2. Substituents, e.g. 1-6 substituents, preferably 1 -3 substituents on the radical R3 are one or more substituents which are independently selected from the group consisting of halo, lower alkyl, lower alkoxy, amino, hydroxy and heterocycle radicals which are selected from pyrrolidine, tetrahydrothiophene , tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine; all of which, except the halo radical, are substituted or unsubstituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of halo, hydroxy, lower alkoxy radicals , amino, lower alkyl and heterocycle selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, midazolidine, morpholino and piperazine; all of which, except the halo radical, are unsubstituted or substituted by one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of halo radicals, lower alkyl, lower alkoxy, hydroxy and lower alkoxy. The substituents, e.g. 1 -6, preferably 1 -3 substituents in the R1 and R2 radicals are one or more substituents independently selected from the group consisting of halo radicals, hydroxy, lower alkyl, lower alkoxy, amino, cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, ciciohexilo, cycloheptyl and cyclooctyl, heterocycle is selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine and heteroaryl is selected from pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl and thienyl, all of which, except the radical halo, are unsubstituted or substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which select ind ependientemente the group consisting of halo radicals, hydroxy, lower alkoxy, amino, heterocycle selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine and heteroaryl alkyl is selected from pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl and thienyl, all of which, except the radical halo, they may or may not be substituted with one or more substituents, for example from 1 to 6, preferably from 1 to 3 substituents, which independently select from the group consisting of halo, hydroxy, lower alkyl and amino radicals, or a pharmaceutically acceptable salt or ester acceptable of them. In another preferred embodiment, the invention provides compounds of Formula I, wherein R-i and R2 are independently a hydrogen atom, a lower alkyl radical lower-lower lower alkyl-lower alkyl, cycloalkyl, lower hydroxyalkyl, alkoxy, alkylamino, lower heterocycloalkyl; or R | and R2 can be joined together to form an N-heterocycle or lower alkyl-N-heterocycle; Y is a group (R3) "- X- or A (R3) (R3) C-; wherein X is a lower alkyl or carbonyl radical; A is a hydroxy radical; n has a value of 1; R3 is a lower alkyl, lower alkoxy, amino, heterocycle, heteroaryl, lower alkyl-heterocycle, lower alkylamino-lower alkyl, heterocycle-lower alkylamino, lower alkylamino, hydroxyalkylamino lower, amino substituted with lower alkoxy-lower alkyl and lower alkyl group; or a pharmaceutically acceptable salt or ester thereof. In yet another preferred embodiment, the invention also provides compounds of Formula I, wherein Ri and R 2 are independently a hydrogen atom, a methyl, ethyl, propyl, cyclopropyl, hydroxypropyl, dimethylaminoethyl, morpholinylpropyl, methoxyethyl, pyrrolidinylpropyl radical; or Ri and R2 may be joined together to form a piperazinyl or methylpiperazinyl group, preferably N-methylpiperazinyl; Y is (R3) n-X- or A (R3) (R3) C-; wherein X is CH2 or -C (O) -; A is a hydroxy radical; n has a value of 1; R3 is a methyl, ethyl, butoxy, morpholinyl, piperazinyl, pyrrolyl, tetrazolyl, imidazolyl, methylpiperazinyl, diethylaminopropyl, morpholinpropylamino, methylamino, hydroxypropylamino, (methoxy-ethyl) methylamino group; or a pharmaceutically acceptable salt or ester thereof. In still another preferred embodiment, the invention provides compounds of Formula I, wherein R- and R 2 are independently a hydrogen atom, a methyl, ethyl or propyl group; Y is (R3) n-X- or A (R3) (R3) C-; wherein X is CH2 or -C (O) -; A is a hydroxy radical; n has a value of 1; R3 is a methyl, piperazinyl, morpholino or imidazolyl group, all of which may or may not be substituted; wherein the substituents, for example 1 -6, preferably 1 -3 and more preferably 1, in the radical R3, are a methyl group; or a pharmaceutically acceptable salt or ester thereof. In particular, the invention includes a compound that is selected from: Methyl-. { 6- [4- (4-Methyl-piperazin-1-methyl-phenyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -propylamine; [4- (4-methylamino-7 H -pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] morpholin-4-yl-methanone; [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-methyl-piperazin-1-yl) -methanone; Dimethyl-. { 6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; N- (3-diethylaminopropyl) -4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrim id i n-6-i I) benzamide; [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] -morpholin-4-yl-methanone; 4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -N- (3-morpholin-4-yl-propyl) -benzamide; (4-methylpiperazin-1-yl) -. { 4- [4- (4-methyl-piperazin-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} -metanone; 4- (4-methyl-piperazin-1-yl) -6- [4- (4-methyl-piperazin-1-methyl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidine; . { 4- [4- (ethyl-methyl-amino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; [4- (4-isopropylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-methyl-piperazin-1-yl) -methanone; [4- (4-methylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-methyl-piperazin-1-yl) -methanone; lsopropyl-. { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; ethyl-methyl-. { 6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; . { 4- [4- (3-hydroxypropylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; methyl-. { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; (4-methyl-piperazin-1-yl) - [4- (4-propylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] -methanone; . { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -propi laminate; Methyl-. { 6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3- d] pyrimidin-4-yl} -propyl amine; [4- (4-cyclopropylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-methyl-piperazin-1-yl) -methanone; N-methyl-4- (4-methalamine-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -benzamide; . { 4- [4- (2-dimethylamino-ethylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; N, N-dimethyl-N'-. { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -ethane-1, 2-diamine; [6- (4-imidazol-1-methyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -dimethylamine; Dimethyl-. { 6- [4- (1 H -pyrrol-2-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} amine; [6- (4-butoxymethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -dimethylamine; Dimethyl- [6- (4-tetrazol-1-yl-methylphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] amine; 3- [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -benzylamino] propan-1-ol; [6- (4-. {[[(2-methoxyethyl) -methylamino] methyl} - phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -dimethylamine; 3-. { 4- [4- (3-morpholin-4-yl-propylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} pentan-3-ol; 2- (4-. {4- [bis- (2-methoxyethyl) amino] -7H-pyrrolo [2,3-d] pyrimidin-6-yl.} - phenyl) propan-2-ol; 3- (4- { 4- [bis- (2-methoxyethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidin-6-yl}. -phenyl) -pentan-3 ol; 3-. { 4- [4- (3-pyrrol-1-yl-propylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] phenyl} -pentan-3-ol; 2- [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] -propan-2-ol; 2- [4- (4-methylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] propan-2-ol; or a pharmaceutically acceptable salt or ester thereof. The agents of the invention can be prepared by the processes described below: a) reduction of a compound of Formula I I for example with a reducing agent, for example lithium aluminum hydride, preferably in an inert solvent such as THF and advantageously under an inert atmosphere such as nitrogen. b) coupling a compound of the Formula Vi l with a compound of Formula Vlla, H-R3 (Vl la) wherein the radical R3 of Formula Vl is unsubstituted or substituted by amino, heterocycle or heteroaryl. For example, in an inert solvent such as butanol and advantageously in the presence of Nal, preferably at an increased temperature, for example at reflux temperature. c) for compounds wherein Y in Formula I is A (R3) (R3) C-. The transformation of a compound of Formula XI I for example with an organometallic compound, e.g. a compound of Formula XI I I R3-MgZ (XIII) wherein Z is a halide and R3 is previously defined, for example, ethylmagnesium bromide. For example, in an inert solvent such as THF and advantageously at a reduced temperature, and also advantageously under an inert atmosphere. The raw material of Formula I I can be prepared by hydrolysis of a compound of Formula VI to obtain a compound of Formula V, for example with LiOH and H2O in a solvent such as MeOH. The compound of Formula VI can be prepared, for example, as set forth on pages 70-71 in the International Patent Application WO 97/02266. Then, a compound of Formula V is coupled with a compound of Formula Vl to H-R3 (Vl la) wherein R3 of Formula V1 is unsubstituted or substituted with an amino, heterocycle or heteroaryl group, to obtain a compound of the Formula lll (III) for example, by first forming the activated acid of a compound of Formula V, for example by treating it with oxalyl chloride, advantageously in an inert solvent and preferably under an inert atmosphere. The activated acid is then treated with the compound of Formula VII, advantageously in the presence of a base such as triethylamine, preferably at a reduced temperature. Then, the compound of Formula I is coupled with a compound of Formula IV to form the desired raw material of Formula I I. For example, in an inert solvent such as butanol, and advantageously at an increased temperature, for example 50-120 ° C. The raw material of Formula VI can be prepared by treating a compound of Formula VI with a compound of Formula XI Í N 'H (XI) to obtain the compound of Formula IX advantageously in a sealed tube, and preferably at an elevated temperature. The compound of Formula VI can be prepared, for example, as set forth on pages 70-71 in International Patent Application WO 97/02266. The compound of Formula 10 is reduced to obtain a compound of Formula VI I I for example with a reducing agent, for example lithium aluminum hydride in an inert solvent, such as THF, advantageously at an elevated temperature, for example 30 to 70 ° C and preferably under an inert atmosphere such as argon. Then, the compound of Formula VII is transformed into the desired raw material of Formula VII. For example, treating a compound of Formula VII I with a reagent such as thionyl chloride in an inert solvent, such as toluene, and advantageously at a reduced temperature, e.g. , 1 0 - (- 20 ° C). Method C The raw material of Formula XI I can be prepared by treating a compound of Formula VI with a compound of Formula XI i H (X for example in an inert solvent such as butanol, advantageously at an elevated temperature, e.g. , from 60 to 100 ° C. The compound of Formula VI can be prepared, for example, as set forth on pages 70-71 in International Patent Application WO 97/02266. The invention also relates to processes and the use of a reagent of the invention, or a pharmaceutically acceptable salt thereof, for the preparation of pharmaceutical compositions comprising an agent of the invention, or a pharmaceutically acceptable salt thereof, as an active component. (active ingredient).

If desired, the pharmaceutical compositions may also contain additional active components, for example, cytostatic agents, and / or may be used in combination with known therapeutic processes, for example in the administration of hormones or radiation. Preference is given to a pharmaceutical composition that is suitable for administration to warm-blooded animals, especially humans or animals of commercial utility suffering from a disease that responds to an inhibition of a protein tyrosine kinase, especially to a BCR inhibition. -Abl, etc. , which comprises an effective amount of an agent of the invention for the inhibition of a protein tyrosine kinase, especially for the inhibition of Bcr-Abl, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier. A pharmaceutical composition for the prophylactic or especially therapeutic management of neoplastic diseases and other proliferative diseases of a warm-blooded animal, especially a human being or a mammal of commercial use requiring such treatment, especially suffering from such a disease, comprising active ingredient an amount that is prophylactic or especially therapeutically active against said diseases; similarly, an agent of the invention or a pharmaceutically acceptable salt thereof is preferred. The pharmaceutical compositions comprise from about 1 to 95% of the active ingredient, the single dose dosage forms comprise, in the preferred embodiment, from about 20 to about 90% of the active ingredient, and the forms that are not of the single dose type they comprise, in the preferred embodiment, from about 5 to about 20% of the active ingredient. The unit dosage forms are, for example, coated and uncoated tablets, ampoules, flasks, suppositories or capsules. Some examples are capsules containing from about 0.05 g to about 1.0 g of the active substance. The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by mixing, granulating, coating, dissolving or lyophilizing processes. In the same way, the invention relates to a process or a method for the treatment of one of the pathological disorders mentioned hereinabove, especially to a disease that responds to an inhibition of a protein tyrosine kinase, especially for the inhibition of Bcr-Abl, especially a corresponding neoplastic disease. An agent of the invention, or a pharmaceutically acceptable salt thereof, can be administered as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against said diseases, to a warm-blooded animal, for example a human being, which requires such treatment, the compounds especially are useful in the form of pharmaceutical compositions. In the case of an individual having a body weight of about 70 kg, the daily dose administered is from about 0.1 to about 5 g, preferably from about 0.5 to about 2 g, of a compound of the present invention. The present invention also relates especially to the use of an agent of the invention, or a pharmaceutically acceptable salt thereof, especially an agent of the invention which is said to be preferred, or a pharmaceutically acceptable salt thereof as such or in form of a pharmaceutical composition with at least one pharmaceutically acceptable carrier, for the therapeutic management and also the prophylactic management of one or more of the above-mentioned diseases herein, preferably a disease that responds to an inhibition of the protein tyrosine kinase, especially to an inhibition of Bcr-Abl, especially a neoplastic disease, in particular if said disease responds to an inhibition of the protein tyrosine kinase, especially to the inhibition of Bcr-Abl. Additionally, the invention is described in the following non-limiting examples. Experimental Section The preparation of the 7H-pyrrolopyrimidine derivatives and their intermediates are illustrated in the following reaction schemes and in Examples 1-35. Abbreviations: DMF: N, N-dimethylformamide HCl: Hydrochloric acid NaOH: Sodium hydroxide LiOH: Lithium hydroxide THF: Tetrahydrofuran Examples Example 1: (4-Methylpiperazin-1-yl) - was dissolved. { 4 - [- (Methylpropyl-amino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} methanone (43 mg, 0.1 1 mmol) in THF (1 mL) at room temperature and LiAIH4 (17 mg, 0.44 mmol) was added in small portions under an argon atmosphere. Subsequently, the reaction mixture was allowed to stir for 2 h and was processed by the careful addition of ethyl acetate and H2O. The phases were separated and the aqueous phase was repeatedly extracted with ethyl acetate. The organic extracts were combined and the combined was washed with brine and dried over MgSO4. After filtering and removing the solvents in vacuo, methyl- was obtained. { 6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} propylamine, in the form of a white powder. C22H28N6: M + H = 379.2; 1 H-NMR (400 MHz, DMSO-d 6); 12.01 (s, 1 H, NH), 8.15 (s, 1 H), 7.80 (d, 2H), 7.34 (d, 2H), 6.99 (s, 1 H), 3.72-3.65 (m, 2H), 3.41 (s, 2H), 2.59-2.21 (m, 8H), 2.17 (s, 3H), 1 .78-1 .59 (m, 2H), 1 .71 -1 .60 (m, 2H), 0.96 ( t, 3H). p.f. = 220-221 ° C.

The raw material is obtained as follows: Example 1, step 1: 4- (4-Chloro-7H-pyrrolo [2,3-d] -pyrimidin-6-yl) benzoic acid Ethyl ester of 4- (4-chloro-7H-pyrrolo [2,3] -pyrimidin-6-yl) benzoic acid (WO 97/02266, 10.0 g, 33.14 mmol) was suspended in MeOH (70 mL) and treated with a solution of LiOH x H 2 O (3.48 g, 82.55 mmol) in H 2 O (55 mL) at room temperature and stirred for 16 hours. The reaction mixture was subsequently acidified with a solution of 4N aqueous HCl to pH 2, and the precipitated product was isolated by filtration, washed with cold H2O and dried under vacuum at 60 ° C, to obtain the title compound in the form of a white powder. C 13 H 8 CIN 3 O 2: M + H = 274.1; 1 H NMR (400 MHz, DMSO-d 6): 13.19 (s, 1 H), 8.61 (s, 1 H), 8.17 (d, 2 H), 8.01 (d, 2 H), 7.22 (s, 1 H). Example 1, step 2: 4- (4-chloro-7H-pyrrolor-2,3-dl-pyrimidin-6-yl) -phenp- (4-methyl-piperazin-1-yl) -metanone 4- (4-Chloro-7H-pyrrolo [2,3-d] pyrimidin-6-yl) benzoic acid (500 mg, 1.86 mmol) was suspended in anhydrous THF (20 mL) under an argon atmosphere, and oxalyl chloride (0.37 mL, 4.57 mmol) was added at room temperature, followed by 4-5 drops of DMF. The reaction mixture was heated at 50 ° C for 1 hour, then cooled to room temperature and all volatile compounds were removed under vacuum, to obtain a yellow solid residue, which was suspended in THF (30 mL). This suspension was added dropwise to a solution of N-methylpiperazine (0.51 mL, 4.57 mmol) and triethylamine (1.10 mL, 7.66 mmol) in H2O (1 mL) at 0 ° C. The reaction was allowed to stir for 1 hour at room temperature. Then, all volatile compounds were removed in vacuo and the residual crude product was taken up in ethyl acetate, washed with H2O and dried over MgSO4. After filtering and removing the solvents in vacuo, the product was crystallized from ethyl acetate / hexanes, to obtain a white powder. 1 H NMR (400 MHz, DMSO-d 6): 1 3.01 (s, 1 H, NH), 8.61 (s, 1 H), 8.1 1 (d, 2 H), 7.54 (d, 2 H), 7.21 (s) , 1 H), 3.71 -3.45 (m, 4H), 2.39-2.21 (m, 4H), 2.1 9 (s, 3H). p.f. = > 320 ° C. Example 1; Step 3: 4- (Methylpiperazin-1-yl) - (4- | '- (methyl ropil-amine) -7H-pyrroloyl-2,3-d1-pyrimidin-6-p-phenyl) -metanone 4- (4-Chloro-7H-pyrrolo [2,3-d] pyrimidin-6-yl) - (4-methylpiperazin-1-yl) -methanone (99 mg, 0.28 mmol) was suspended in n-butanol (10%). mL) and N-methylpropylamine was added at room temperature. The mixture was heated in a sealed tube at 80 ° C for 16 hours. The reaction mixture was subsequently allowed to cool to room temperature again, and the precipitated product was collected by filtration and washed with cold diethyl ether. It was dried in vacuo to obtain the title compound as a white powder. C 22 H 28 N 6 O: M + H = 393.2; 1 H NMR (400 MHz, DMSO-de): 12.19 (s, 1 H), 8.16 (s, 1 H), 7.97 (s, 2 H), 7.40 (d, 2 H), 7.17 (s, 1 H) , 3.72 (t, 2H), 3.61 -3.38 (m, 4H), 3.34 (s, 3H), 2.41 -2.21 (m, 4H), 2.19 (s, 3H), 1 .79-1 .59 (m, 2H), 0.98 (t, 3H). p.f. = 222-224 ° C. The compounds of Examples 2-23, wherein Y of Formula I is (R3) nX-, were synthesized in analogy to the above procedures (for the compounds wherein X = -C (O) -, for the raw material , only steps 1 -3 were carried out, all the steps were carried out for X = CH2, Table 1 lists the structures, yields and analytical data.

Example 24: r6- (4-imidazol-1-yl-methyl-phenyl) -7H-pyrroloyl-2,3-dl-pyrimidin-4-yl-di-methylamine [6- (4-Chloromethylphenyl) -7H-pyrrolo [2,3] pyrimidin-4-yl] -dimethylamine (170 mg, 0.59 mmol) was dissolved in n-butanol (7 mL) at room temperature. Imidazole (326 mg, 4.80 mmol) and a catalytic amount of Nal were added, and the mixture was heated to reflux for 1.5 hours. It was allowed to cool to room temperature again, concentrated in vacuo, to obtain a yellow solid, which was purified by flash chromatography (SiO2, ethyl acetate / MeOH 7: 3) to obtain [6- (4-imidazole -1-methyl-methylphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] dimethylamine, in the form of a yellow solid. C? 8H18N6: M + H = 393.0; 1 H-NMR (400 MHz, DMSO-d 6). 12.1 1 (s, 1 H, NH), 8.1 1 (s, 1 H), 7.86 (d, 2 H), 7.77 (s, 1 H), 7.31 (d, 2 H), 7.21 (s, 1 H), 7.13 (s, 1 H), 6.91 (s, 1 H), 5.20 (s, 2H), 3.32 (s, 6H). p.f. = 273-275 ° C. Example 24, Step 1: Ethyl ester of 4- (4-dimethylamino-7H-pyrrolof 2,3-dlpyrim id i n-6-i I-benzoic acid Ethyl ester of 4- (4-chloro-7H-pyrrolo [2,3] pyrimidin-6-yl) benzoic acid (WO 97/02266, 900 mg, 3.00 mmol) was suspended in an aqueous solution of 40% dimethylamine (1 0 mL) and heated to 60 ° C in a sealed tube. The raw material was dissolved gradually with simultaneous precipitation of the product. The reaction mixture was stirred for 1 hour at 60 ° C and then cooled to room temperature again. The product was isolated by filtration and washed with cold diethyl ether. After drying in vacuo, the title compound was obtained as a yellow solid. C17H18N4O2: M + H = 31.1.1; 1 H NMR (400 MHz, DMSO-d 6): 12.31 (s, 1 H, NH), 8. 17 (s, 1 H), 8.02 (d, 2 H), 7.95 (d, 2 H), 7.35 (s, 1 H), 4.29 (q, 2H), 1.35 (t, 3H). p.f. = 293-296 ° C. Example 24, step 2: f4- (4-dimethylamino-7H-pyrrolor-2,3-dlpyrimidin-6-iQ-phenylemethanol Li [AIH4] (660 mg, 17.40 mmol) in THF (70 mL) was suspended.

The suspension was cooled in an ice bath and small portions of 4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl-benzoic acid ethyl ester were added under an argon atmosphere. it was stirred for 30 minutes at room temperature and then heated at 50 ° C for a further 30 minutes, then cooled to room temperature again and the reaction was stopped by careful addition of a dilute aqueous solution of NaOH. stirred for 30 minutes and then all the inorganic salts were removed by filtration The remaining solution was concentrated in vacuo to obtain a yellow solid, which was triturated with hexanes.The product was isolated by filtration and dried under vacuum, obtain a white powder C15H16N4O: M + H = 269.1; 1 H-NMR (400 MHz, DMSO-d6): 13.01 (s, 1 H, NH), 8.23 (s, 1 H), 7.89 (d, 2H), 7.39 (d, 2H), 7.19 (s, 1 H), 5.21 (s, 1 H, OH), 4.55 (d, 2H), 3.35 (s, 6H) p.f. = 306-309 ° C. Rf (ethyl acetate / MeOH, 9: 1) = 0.30. Example 24, step 3: r6- (4-chloromethylphenyl) -7H-pyrrolor2,31-pirim id in-4-i lid ¡metí lamina 60c j [4- (4-Dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) phenyl] methanol (51.0 mg, 1.90 mmol) was dissolved in toluene (15 mL) and cooled at -1 0 ° C. Thionyl chloride (2.70 mL, 38.0 mmol) was added dropwise and the reaction was stirred for 1 hour at 0 ° C and then for an additional hour at room temperature, resulting in a yellow suspension. The precipitate was isolated by filtration. Subsequently, it was subjected to extraction by partition in ethyl acetate and H2O. The phases were separated and the aqueous phase was repeatedly extracted with ethyl acetate. The extracts were combined and the combined was washed with brine and dried over MgSO, filtered and concentrated to obtain a yellow solid, which was dried under vacuum to obtain the title compound. C15H15CIN4: M + H = 287.1; 1 H-NMR (400 MHz, DMSO-d 6): 12.1 1 (s, 1 H), 8.12 (s, 1 H), 7.89 (d, 2 H), 7.42 (d, 2 H), 7.18 (s, 1 H) , 4.79 (s, 2H), 3.38 (s, 6H). Rf (ethyl acetate / MeOH, 9: 1) = 0.60. Examples 25-29 (wherein R ^ and R2 are methyl), wherein Y of Formula I is (R3) nX, wherein X is CH2, were prepared from [6- (4-chloromethylphenyl) - 7H-pyrrolo [2,3] pyrimidin-4-yl] dimethylamine, in accordance with the above procedure (Example 24). The analytical data are listed in Table 2.

Example 30: 2-r4- (4- (3-morpholin-4-yl-propylamino) -7H-pyrrolo1- [2,3-d1-pyrimidin-6-infenillpentan-3-ol Ethyl ester of 4- [4- (3-morpholin-4-yl-propylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -benzoic acid (147 mg, 0.36 mmol) was suspended in THF and cooled to -70 ° C under an argon atmosphere. Ethylmagnesium bromide (2.2 mL, solution in 1 M THF) was added dropwise through a cannula. The reaction mixture was stirred for 30 minutes at -70 ° C and then allowed to warm to room temperature. It was stirred an additional 1 hour and then worked up by the addition of ethyl acetate, dilute aqueous HCl and H2O. The phases were separated and the aqueous phase was repeatedly extracted with ethyl acetate. The organic extracts were combined and the combined was washed with brine and dried over MgSO4. After filtration, all volatile compounds were removed in vacuo to obtain 2- [4- (4- (3-morpholin-4-yl-propylamino) -7H-pyrroio] [2,3-d] pyrimidin-6-yl. ] -phenyl] -pentan-3-ol, in the form of a white powder C24H33N5O2: M + H = 424.3; 1 H-NMR (400 MHz, DMSO-d 6): 1 1 .95 (s, 1 H, NH), 8.1 5 (s, 1 H), 7.71 (d, 2 H), 7.42-7.39 (m, 3 H), 6.83 (s, 1 H), 4.58 (s, 1 H, OH), 3.59 (q, 4H), 3.51 -3.43 (m, 2H), 2.39-2.23 (m, 6H), 1 .81 -1 .62 (m, 6H), 0.62 (t, 6H). p.f. 175-177 ° C. Example 30, Step 1: Ethyl ester of 4-r4- (3-morpholin-4-yl-propylamino) -7H-pyrrolor-2,3-dlpyridin-6-OH benzoic acid Ethyl ester of 4- (4-chloro-7H-pyrrolo [2,3] pyrimidin-6-yl) benzoic acid (WO 97/02266, 271 mg, 6.64 mmol) was suspended in n-butanol (30 mL). 3-Aminopropylmorpholine (519 mg, 3.6 mmol) was added. The reaction mixture was heated at 80 ° C for 72 hours and then allowed to cool to 0 ° C and the yellow precipitate was isolated by filtration, washed with cold diethyl ether and dried under vacuum to obtain the title compound. Title in the form of a yellow powder. C 22 H 27 N 5 O 3: M + H = 410.2; 1 H-NMR (400 MHz, DMSO-d6). 12.20 (s, 1 H, NH), 8.17 (s, 1 H), 8.00 (d, 2H), 7.91 (d, 2H), 7.60 (t, 1 H, NH), 7.16 (s, 1 H), 4.31 (q, 2H), 3.59-3.53 (m, 4H), 3.51 -3.42 (m, 2H), 2.41 -2.25 (m, 6H), 1 .81 -1 .70 (m, 2H), 1 .37 (t, 3H). p.f. = 231-234 ° C. Example 30, step 2: 2- [4- (4- (3-morpholin-4-yl-propylamino) -7H-pyrrololf2.3-dlpyrimidin-6-yl-1-phenyl-1-pentan-3-ol Examples 31-35, wherein Y is of the Formula were prepared from 4- (4-chloro-7H-pyrrolo [2,3] pyrimidin-6-yl) benzoic acid ethyl ester, in accordance with the above procedure . The analytical data are listed in Table 3.

Example 36: Dry filled capsules of 5,000 capsules, each comprising 0.25 g of one of the compounds of the Formula I mentioned in the preceding Examples as active ingredient, were prepared as follows: Composition Active ingredient 1250 g Talc 180 g Wheat starch 120 g Magnesium stearate 80 g Lactose 20 g Preparation process: The mentioned substances were pulverized and passed through a sieve with a mesh size of 0.6 mm. Portions of 0.33 g of the mixture were introduced into the gelatin capsules, using a capsule filling machine. Example 37: Soft capsules 5,000 soft gelatin capsules, each comprising 0.05 g of one of the compounds of Formula I mentioned in the preceding Examples as active ingredient, were prepared as follows: Composition Active ingredient 250 g PEG 400 1 liter Tween 80 1 liter Preparation process: The active ingredient was pulverized and suspended in PEG 400 (polyethylene glycol having a Mr from about 380 to about 420, Fluka, Switzerland) and Tween®80 (polyoxyethylene sorbitan monolaurate, Atlas, Chem. Ind. Inc., USA, supplied by Fluka, Switzerland) and ground in a wet sprayer at a particle size of about 1 to 3 μm. Subsequently, 0.43 g portions of the mixture were introduced into the soft gelatin capsules, using a capsule filling machine. Example 38: Inhibition of tyrosine kinase activity of BcrAbl, c-Abl, c-Raf-1, EGF-R (HER-1), ErbB-1 (HER-2) and VEGF receptor (KDR).

Claims (17)

1. CLAIMS A compound of Formula I, wherein RT and R2 are independently a hydrogen atom, a halo radical; or a lower alkyl, heterocycle, amino or cycloalkyl radical, all of which may be substituted or unsubstituted; or Ri and R2 together can form a substituted or unsubstituted N-heterocycle ring; Y is a group (R3) n-X- or A (R3) (R3) C-; wherein X is a lower alkyl, amino, amido or carbonyl radical; A is a hydroxy, amino, halo or lower alkyl radical; R3 is a lower alkyl, lower alkoxy, carbonyl, amino, hydroxy, heterocycle or heteroaryl radical, all of which may be substituted or unsubstituted; n has a value of 1 or 2; the substituents on the radical R3 are one or more substituents that are independently selected from the group consisting of halo, lower alkyl, lower alkoxy, amino, hydroxy and heterocycle radicals; all of which, except the halo radical, are unsubstituted or substituted with one or more substituents which are independently selected from the group consisting of halo, hydroxy, lower alkoxy, amino, lower alkyl and heterocycle radicals; all of which, except the halo radical, are unsubstituted or substituted with one or more substituents which are independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy and lower alkoxy radicals; the substituents on the radicals R ^ and R2 are one or more substituents which are independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, cycloalkyl, heterocycle and heteroaryl radicals; all of which, except the halo radical, are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, heterocycle and heteroaryl radicals; all of which, except the halo radical, are unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, lower alkyl and amino radicals or a pharmaceutically acceptable salt or ester thereof.
2. 2. A compound of Formula I, according to claim 1, wherein R-1 and R2 are independently a hydrogen atom, a halo radical; or lower alkyl, heterocycle, which are selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, midazoline, imidazolidine, morpholino and piperazine, amino or cycloalkyl which are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; all of which may or may not be substituted; or R-i and R2 can be joined to together form a substituted or unsubstituted N-heterocycle which is selected from pyrrolidine, imidazoline, imidazolidine, piperidine, morpholino and piperazine; Y is a group (R3) n-X- or A (R3) (R3) C-; wherein X is a lower alkyl, amino, amido or carbonyl radical; A is a hydroxy, amino, halo or lower alkyl radical; R3 is lower alkyl, lower alkoxy, carbonyl, amino, hydroxy, heterocycle selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine or heteroaryl selected from pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl and thienyl, all of which may or may not be substituted; n has a value of 1 or 2; the substituents on the radical R3 are one or more substituents which are independently selected from the group consisting of halo, lower alkyl, lower alkoxy, amino, hydroxy and heterocycle radicals which are selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine; all of which, except the halo radical, are substituted or unsubstituted with one or more substituents independently selected from the group consisting of halo, hydroxy, lower alkoxy, amino, lower alkyl and heterocycle radicals which are selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran , piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine; all of which, except the halo radical, are unsubstituted or substituted by one or more substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy and lower alkoxy radicals; the substituents on the Ri and R2 radicals are one or more substituents which are independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkoxy, amino, cycloalkyl radicals which are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, heterocycle selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine, and heteroaryl selected from pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl and thienyl, all of which, except the halo radical, are unsubstituted or substituted by one or more substituents independently selected from the group consists of halo, hydroxy, lower alkyl radicals , lower alkoxy, amino, heterocycle which are selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, imidazolidine, morpholino and piperazine and heteroaryl selected from pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, midazolyl and thienyl, all of which, except the halo radical, are unsubstituted or substituted by one or more substituents independently selected of the group consisting of halo, hydroxy, lower alkyl and amino radicals; or a pharmaceutically acceptable salt or ester thereof.
3. 3. A compound of Formula I according to claim 1, wherein R ^ and R2 are independently a hydrogen atom, a lower alkyl radical, cycloalkyl, hydroxyalkyl lower, lower alkoxy-lower alkyl, lower alkylamino-lower alkyl, lower heterocycloalkyl; or R, and R2 can be joined together to form an N-heterocycle or lower alkyl-N-heterocycle; Y is a group (R3) n-X- or A (R3) (R3) C-; wherein X is a lower alkyl or carbonyl radical; A is a hydroxy radical; n has a value of 1; R3 is a lower alkyl, lower alkoxy, amino, heterocycle, heteroaryl, lower alkyl-heterocycle, heterocycle-lower alkyl, lower alkylamino-lower alkyl, heterocycle-lower alkylamino, lower alkylamino, hydroxyalkylamino lower, amino substituted with lower alkoxy-alkyl group lower and lower alkyl; or a pharmaceutically acceptable salt or ester thereof; heterocycle selected from pyrrolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, pyran, pyrazolidine, oxirane, dioxane, imidazoline, midazolidine, morpholino and piperazine; cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; N-heterocycle is selected from pyrrolidine, imidazoline, imidazolidine, piperidine, morpholino and piperazine; heteroaryl selected from pyridyl, indoyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl and thienyl.
4. 4. A compound of Formula I according to claim 1, 2 or 3, RT and R2 are independently a hydrogen atom, a methyl, ethyl, propyl, cyclopropyl, hydroxypropyl, dimethylaminoethyl, morpholinylpropyl, methoxyethyl, pyrrolidinylpropyl radical.; or R-i and R2 may be joined to together form a piperazinyl or methylpiperazinyl group, preferably N-methylpiperazinyl; Y is (R3) n-X- or A (R3) (R3) C-; wherein X is CH2 or -C (O) -; A is a hydroxy radical; n has a value of 1; R3 is a methyl, ethyl, butoxy, morpholinyl, piperazinyl, pyrrolyl, tetrazolyl, imidazolyl, methylpiperazinyl, diethylaminopropyl, morpholinpropylamino, methylamino, hydroxypropylamino, (methoxy-ethyl) methylamino group; or a pharmaceutically acceptable salt or ester thereof.
5. 5. A compound of Formula I according to claim 1, 2, 3 or 4, which is selected from the group consisting of Methyl-. { 6- [4- (4-Methyl-piperazin-1-methyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -propylamine; [4- (4-methylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] morpholin-4-yl-methanone; [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-methylpiperazin-1-yl) -m-ethanone; Dimethyl-. { 6- [4- (4-methyl-piperazin-1-methyl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; N- (3-diethylaminopropyl) -4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) benzamide; [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] -morpholin-4-yl-methanone; 4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -N- (3-morpholin-4-yl-propyl) -benzamide; (4-methylpiperazin-1-yl) -. { 4- [4- (4-methyl-piperazin-1-yl) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} -metanone; 4- (4-methyl-piperazin-1-yl) -6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7 H -pyrrolo [2,3-d] pyrimidine; . { 4- [4- (ethyl-methyl-amino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; [4- (4-isopropylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-methyl-piperazin-1-yl) -methanone; [4- (4-methylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-methyl-piperazin-1-yl) -methane? A; lsopropyl-. { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; ethyl-methyl-. { 6- [4- (4-Rethyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; . { 4- [4- (3-hydroxypropylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; methyl-. { 6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; (4-M-ethyl-piperazin-1-yl) - [4- (4-propylamine or-7 H -pyrrole or [2,3-dpyrimidin-6-yl] -phenyl] -m-ethanone; . { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -propyl amine; Methyl-. { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -propylamine; [4- (4-cyclopropylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] - (4-m ethy-l-piperazin-1-yl) -m-ethanone; N-methyl-4- (4-methylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -benzamide; . { 4- [4- (2-dimethylamino-ethylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} - (4-methyl-piperazin-1-yl) methanone; N, N-dimethyl-N, -. { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -ethane-1, 2-diamine; [6- (4-imidazol-1-methyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -dimethylamine; Dimethyl-. { 6- [4- (1 H -pyrrol-2-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} amine; [6- (4-butoxymethyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -dimethylamine; Dimethyl- [6- (4-tetrazol-1-methyl-methyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -amine; 3- [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-M) -benzylamino] propan-1 -ol; [6- (4-. {[[(2-methoxyethyl) -methylamino] methyl} - phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -dimethylamine; 3-. { 4- [4- (3-morpholin-4-yl-propylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} pentan-3-ol; 2- (4-. {4- [bis- (2-methoxyethyl) amino] -7H-pyrrolo [2,3-d] pyrimidin-6-yl.} - phenyl) propan-2-ol; 3- (4-. {4- [bis- (2-methoxyethyl) -amino] -7H-pyrrolo [2,3-d] pyrimidin-6-yl} -phenyl) -pentan-3-ol; 3-. { 4- [4- (3-pyrrol-1-yl-propylamino) -7H-pyrroIo [2,3-d] pyrimidin-6-ii] phenyl} -pentan-3-ol; 2- [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] -propan-2-ol; 2- [4- (4-methylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] propan-2-oI; or a pharmaceutically acceptable salt or ester thereof.
6. 6. A compound of Formula I according to claim 1, 2, 3, 4 or 5, which is selected from the group consisting of [4- (4-methylamino-7H-pyrrolo [2,3-d] pyrimidine. -6-l) -phenyl] -morpholin-4-yl-methanone; [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] -morpholin-4-yl-methanone; . { 4- [4- (ethyl-methylamino) -7H-pyrrolo [2,3-d] pyrimidin-6-yl] -phenyl} - (4-methyl-piperazin-1-yl) -methanone; lsopropyl-. { 6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; ethyl-methyl-. { 6- [4- (4-methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; methyl-. { 6- [4- (4-Methyl-piperazin-1-yl-methyl) -phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-yl} -amine; [6- (4-imidazol-1-methyl-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yl] -dimethylamine; 2- [4- (4-dimethylamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) -phenyl] -propan-2-ol; or a pharmaceutically acceptable salt thereof.
7. 7. A compound of Formula I, or a pharmaceutically acceptable salt thereof, according to any of the claims 1 to 6, for use in a method for the treatment of the body of a human being or an animal.
8. 8. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof according to any of claims 1 to 6, together with at least one pharmaceutically acceptable carrier.
9. 9. A compound of Formula I according to any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical composition.
10. 10. The use of a compound of Formula I according to any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease. eleven .
11. The use of a compound of Formula I according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of a disease, which responds to an inhibition of a protein tyrosine kinase.
12. 12. A method of inhibiting Bcr-Abl in a subject in need of such treatment, which method comprises administering to the subject an effective amount of an agent of the invention, or a method for the treatment of any of the above-mentioned disorders, particularly a method for the treatment of a proliferative disease or disorder, or for alleviating one or more symptoms of any of the above-mentioned disorders.
13. 13. A compound according to claim 1, for use as a pharmaceutical composition or for use in the prevention, improvement or treatment of any disease or disorder such as those described above.
14. 14. A pharmaceutical composition comprising an agent of the invention in association with a pharmaceutically acceptable diluent or carrier, for example to be used as an antiproliferative agent or for use in the prevention, improvement or treatment of any disease or disorder such as those described above.
15. 15. The use of a compound according to claim 1, in the manufacture of a medicament for use as an antiproliferative agent or for use in the prevention, improvement or treatment of any disease or disorder such as those described above.
16. 16. A process for the preparation of a compound of Formula I according to claim 1 or a salt thereof, wherein a) reduction of a compound of Formula II b) coupling a compound of the Formula VII with a compound of the Formula Vlla, H-R3 (Vl la) wherein the radical R3 of the Formula Vlla is unsubstituted or substituted by amino, heterocycle or heteroaryl. c) for the compounds wherein Y in Formula I is from the Formula II as defined above. The transformation of a compound of Formula XII with an organometallic compound of Formula XI I I R3-MgZ (XI I I) wherein Z is a halide and R3 is as previously defined.
17. 17. All novel compounds, methods, processes and uses substantially as those described above, with particular reference to the Examples.