MXPA06009158A - Compounds and compositions as protein kinase inhibitors - Google Patents

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met kinases.

Description

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the priority benefit of Provisional Patent Application Number 60 / 544,944, filed on February 14, 2004. The full description of this application is hereby incorporated by reference in its entirety and for all purposes BACKGROUND OF THE INVENTION Field of the Invention The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods for using such compounds to treat or prevent diseases or disorders associated with abnormal or poorly regulated kinase activity, particularly diseases or disorders involving abnormal activation. of FAK kinases, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met. Protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes and maintain control over cellular function. A non-limiting, partial list of these kinases include: receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGF-R), the kinase of receptor for stem cell factor, c-kit, nerve growth receptor, trkB, c-Met, and fíbroblast growth factor receptor, FGFR3; non-receptor tyrosine kinases such as Abl and the BCR-Abl fusion kinase, focal addition kinase (FAK), Fes, Lck and Syk; and serine / threonine kinases such as b-RAF MPA (for example, MKK6) and SAPK2ß kinases. Aberrant kinase activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems. The compounds of this invention inhibit activity of one or more protein kinases and, therefore, are expected to be useful in the treatment of diseases associated with kinase.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides compounds selected from Formulas la, Ib, le, Id and le: wherein: n is selected from 0, 1 and 2; m is selected from 0, 1, 2 and 3; w is selected from -NR4 -, - S -, - 0 -, - S (0) - and -S (0) 2-; wherein R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; R1 is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms- alkyl of 0 to 4 carbon atoms and heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein any one of arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl of R-, is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, aryl of 6 to 10 carbon atoms, heteroaryl of 5 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms halo-substituted, alkoxy of 1 to 6 carbon atoms, halo-substituted, -XNR5R5, -XNR5XNR5R5, -XNR5XOR5, -XOR5, -XSR5, -XS (0) R5, -XS (O) 2R5, -XC (O) NR5R5, -XOXR6 and -XC (0) R6; wherein X is a bond or alkylene of 1 to 6 carbon atoms; R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; and R6 is selected from heterocyclyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms- alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl of 1 to 6 carbon atoms and -C (O) OH; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent of R ^ in addition is optionally substituted by 1 to 5 radicals independently selected from alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; R2 is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 10 carbon atoms -alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms-alkyl from 0 to 4 carbon atoms and heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein any of the arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl of R2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, alkyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms alkyl of 1 to 6 carbon atoms halogen-substituted, alkoxy of 1 to 6 carbon atoms halogen-substituted, heteroaryl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, -XNR5R5, -XOR5, -XSR5, -XS (O) R5, -XS (O) 2R5, -XSNR5R5, -XS (O) NR5R5, -XS (O) 2NR5R5, -XC ( O) OR5, -XOC (O) R5, -XC (O) R5, -XC (O) NR5XNR5R5, -XC (0) NR5R5, -XC (O) NR5XC (0) OR5, -XC (0) NR5XNR5C (O) R5, -XC (0) NR5XNR5C (0) OR5, -XC (0) NR5XOR5, -XC (0) N (XOR5) 2l -XNR5C (0) R5, -XC (0) ) NR5R6, -XC (0) R6, -XR7, -XR6 and -XC (O) NR5XR7, wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; R6 is selected from heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl of 1 to 6 carbon atoms and -C (O) OH; and R7 is cyano; R3 is selected from halogen, hydroxy, -XSR5, -XS (0) R5, -XS (O) 2R5, -XC (O) R5, and -XC (O) OR5, wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; and the prodrug-derived N-oxide derivatives, protected derivatives, individual isomers and mixture of isomers thereof; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of said compounds. In a second aspect, the present invention provides a pharmaceutical composition containing a compound of formula I or an N-oxide derivative, individual isomers and mixtures of isomers thereof, or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients. In a third aspect, the present invention provides a method for treating a disease in an animal wherein the inhibition of kinase activity, particularly the activity of FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and / or c-Met, can prevent, inhibit or mitigate the pathology and / or symptomatology of diseases, said element comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof . In a fourth aspect, the present invention provides the use of a compound of Formula I in the manufacture of medicament for treating a disease in an animal wherein the kinase activity, particularly the activity of FAK, Abl, BCR-Abl, PDGF -R, c-Kit, NPM-ALK, Flt-3, JAK2 and / or c-Met, contributes to the pathology and / or symptomatology of the disease. In a fifth aspect, the present invention provides a process for preparing compounds of Formula I and N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl" as a group and as a structural element to other groups, for example alkyl and halo-substituted alkoxy, can be either straight or branched chain. Alkoxy of 1 to 4 atoms carbon includes methoxy, ethoxy, and the like. The halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like. "Aryl" means a fused monocyclic aromatic ring assembly containing from 6 to 10 carbon atoms in the ring. For example, the aryl may be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group. "Heteroaryl" is as defined for the aryl, wherein one or more of the ring members is a heterogeneous atom. For example, the heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benxo [1,3] dioxyl, imidazolyl, benzoimidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, Thienyl, etc. "Cycloalkyl" means a polycyclic, monocyclic, fused bicyclic, or bridged, saturated or partially unsaturated ring assembly containing the number of ring atoms indicated. For example, the cycloalkyl of 3 to 10 carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Heterocycloalkyl" means a cycloalkyl, as defined in this application, provided that one or more of the indicated ring carbons are replaced by a selected portion of -O-, -N =, -NR-, -C (O ) -, -S-, -S (O) - or -S (O) 2-, wherein R is hydrogen, alkyl of 1 to 4 carbon atoms, or a nitrogen protecting group. For example, the heterocycloalkyl of 3 to 8 carbon atoms as used in this application to describe compounds of the invention, includes morpholino, pyrrolidinyl, piperzinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro [4.5] dec-8-yl, 1,1-dioxo-116-thiomorpholin-4-yl, etc. . "Halogen" (or halo) preferably represents chloro or fluoro, but may also be bromine or iodine. "Treat", "treating" and "treatment" refers to a method for alleviating or averting a disease and / or its present symptoms.

Description of Preferred Modalities The compounds of this invention are useful in the inhibition of kinases and are illustrated by a compound of Formula I as detailed in the brief Description of the Invention. In one embodiment, with reference to the compounds of Formula la, Ib, le and le, W is selected from -NR4- and -O-; wherein R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms. In a further embodiment, RT is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein any arylalkyl and heteroarylalkyl of R- is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, heteroaryl of 5 to 10 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , alkyl of 1 to 6 halogen-substituted carbon atoms, -XNR5R5, -XOR5, -XSR5, -XNR5XNR5R5, -XNR5XOR5 > -XC (O) NR5R5, -XOXR6 and -XC (0) R6; wherein X is a bond with an alkylene of 1 to 6 carbon atoms; R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; and R6 is selected from heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl from 1 to 6 carbon atoms and -C (O) OH; wherein any heteroaryl substituent of R-i is further optionally substituted by 1 to 5 alkyl radicals of 1 to 6 carbon atoms. In a further embodiment, R 2 is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein either arylalkyl or heteroarylalkyl of R2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, alkyl of 1 to 6 carbon atoms halogen-substituted, heteroaryl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, -XNR5R5, -XOR5, -XSR5, -XS (0) 2NR5R5, - XC (0) OR5, -XOC (O) R5, -XC (0) NR5XNR5R5, -XC (0) NR5XC (0) OR5, -XC (O) NR5XNR5C (O) R5, -XC (0) NR5XNR5C (O) ) OR5, -XC (O) NR5XOR5, -XC (O) N (XOR5) 2, -XNR5 (O) R5, -XC (0) NR5R6, -XC (O) R6, -XR7, -XR6 and -XC (O) NR5XR7; wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 1 to 6 atoms carbon and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; R6 is selected from heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl of 1 to 6 carbon atoms and -C (O) OH; and R7 is cyano. In another embodiment, R3 is selected from halogen, hydroxy, -XC (O) R5 and -XC (O) OR5; wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms. In a further embodiment, W is selected from -NH-and-O-; and R-, is selected from phenyl, benzyl, 5,6,7,8-tetrahydro-naphthalenyl, benzo [1,3] dioxy only, 1 H-indazol-7-yl, indan-4-yl and 1 H-indolyl; wherein any of the arylalkyl and heteroarylalkyl of R-, is optionally substituted by 1 to 3 independently selected methoxy radicals, methyl, amino, halogen, hydroxymethyl, hydroxy, quinoxalinyl, ethyl, puridinyl, methoxy-phenyl, piperazinyl-carbonyl, ethyl- (2-hydroxy-ethyl) -amino 2- (4-methyl-piperazin-1-yl) - ethoxy, formamyl, isopropyl, methyl-sulfanyl, tri-fluoro-methyl, ethoxy, 3-isopropylamino-propylamino, dimethylamino, porfolin, cyclopropylmethoxy, butoxy, cycloheptyl-oxy and 1,4,5,7-tetramethyl-pyrrolo [ 3,4-d] pyridazinyl. In a further embodiment, R2 is selected from pyridinyl, phenyl, thiazolyl, pyridinyl-methyl, pyridinyl-ethyl, thiophenyl, benzyl, quinolinyl, 7-oxo-5,6,7,8-tetrahydro-naphthalenyl, naphthyl and pyrimidinyl; wherein any one of the arylalkyl or heteroarylalkyl of R2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, methyl, propyl-sulfamoyl, methyl-sulphamoyl, methoxy, methyl-carboxy, 2-dimethylamino-ethyl-formamyl, carboxy, amino, cyano-ethyl, cyano-methyl, ethenyl, tri-fluoro-methyl, hydroxy-methyl, ethyl, methyl-sulfanyl, butyl, butyl, caraboxymethyl-formamidyl, 1-carboxy-ethyl-formamidyl, carboxy -ethyl, amino-ethyl-formamidyl, amino-propyl-formamidyl, dimethyl-amino-ethyl-formamidyl, dimethyl-amino-propyl-formamidyl, dimethyl-amino-butyl-formamidyl, methyl-formamidyl, ethyl-formamidyl, ethyl-formamidil -methyl, 2- (2-dimethylamino-ethylcarbamoyl) -ethyl, 2- (2-dimethylamino-formamidyl) -ethyl, 2- (amino-ethyl-formamidyl) -ethyl, 2- (amino-propyl-formamidyl) -ethyl 2- (propyl-formamidyl) -ethyl, amino-propyl-formamide and I-methyl, 2- (methyl-amino-carbamoyl) -ethyl, 2- (ethyl-amino-carbamoyl) -ethyl, morpholino-ethyl- formamidil, morpholine o-carbonyl-methyl, amino-ethyl-formamidyl-methyl, cyclobutyl-formamidyl, methyl-formamid-I-methyl, dimethyl-formamidyl-methyl, hydroxy-ethyl-formamidyl-methyl, hydroxy-propyl-formamidyl-methyl, N, N-bis- (3-hydroxy-propyl) -formamidyl, cyclopentyl-formamidyl, isobutyl-formamidyl, isobutyl-formamidyl-methyl, cyclopentyl-bromamidyl-methyl, cyano-ethyl-formamidyl, cyano-methyl-formamidyl, pyrrolidinyl-ethyl- formamidyl, 2- (isobutyl-formamidyl) -ethyl, 1H-tetrazoly, 2- (1 H-tetrazol-5-yl) -ethyl, 2- (1 H-tetrazoI-5-yl) -methyl, 2- (1 -methyl-1 H-tetrazol-5-yl) -methyl, to cetyl-to-me, non-cyclopropyl-1-methyl, hydroxy-ethyl-formamidyl, hydroxy-propyl-formamidyl, propyl- formamidyl-methyl, ethoxy-propyl-formamidyl, acetyl-amino-ethyl-formamidyl, 1-methyl-piperidin-4-yl-formamidyl, morpholino-carbonyl-ethyl, methoxy-carbonyl-methyl, methoxy-carbonyl-ethyl-formamidyl, me toxi-carbonyl-ethyl-formamidyl-methyl, methoxy-carbonyl-methyl-formamidyl-methyl, methoxy-carbonyl-methyl-formamidyl, 4-amino-cyclohexyl-formamidyl, 4-amino-cyclohexyl-formamidyl-methyl, acetyl-amino -ethyl-formamidyl-methyl, ethoxy-pro-p-methyl-methyl-methyl, methoxy-carbonyl-ethyl, 1-formyl-pyrrolidin-2-yl-carboxylic acid (1-carboxy-3-methyl-butyl) -formamidyl, 2- (methoxy-carbonyl-methyl-formamidyl) -etiyl, 1-carboxy (2,2-dimethyl-propyl) -formamidyl, 3-tert-butoxycarbonyl-amino-propyl-formamidyl, acetoxy-methyl and 1-carboxy-ethyl-formamidyl . In yet another embodiment, n is 0 or 1: m is 0 or 1; and R3 is selected from halogen, hydroxy, -C (O) OH and -C (O) OCH3. In another embodiment, compounds of the Formula Ig are described: Ig wherein R2 is selected from pyridinyl, phenyl, thiazolyl, pyrid in i-methyl, puridinyl-ethyl, thiophenyl, benzyl, quinolinyl, 7-oxo-5,6,7,8-tetrahydro-naphthalenyl, naphthyl and pyrimidinyl; wherein any one of the arylalkyl or heteroarylalkyl of R 2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, methyl, propyl-sulfamoyl, methyl-sulphamoyl, methoxy, methyl-carboxy, 2-dimethylamino-ethyl-formamyl, .carboxy, amino, cyano-ethyl, cyano-methyl, ethenyl, tri-fluoro-methyl, hydroxy-methyl, ethyl, methyl-sulfanyl, butyl, isobutyl, caraboxy-methyl-formamidyl, 1-carboxy-ethyl-formamidyl, carboxy -ethyl, amino-ethyl-formamidyl, amino-pro pil -formamidyl, dimethyl-amino-ethyl-formamidyl, dimethyl-amino-pro pil -formamidyl, dimethyl-amino-butyl-formamidyl, methyl-formamidyl, ethyl-formamidyl, ethyl -formamide-methyl, 2- (2-dimethylamino-ethylcarbamoyl) -ethyl, 2- (2-dimethylamino-formamidyl) -ethyl, 2- (amino-ethyl-formamidyl) -ethyl, 2- (amino-propyl-formamidyl) -ethyl, 2- (propyl-formamidyl) -ethyl, amino-pro pil -formamidyl-methyl, 2- (methyl-amino-carbamoyl) -ethyl, 2- (ethyl-amino-carbamoyl) -ethyl, morpholino-ethyl- formamidyl, morpholino-carbonyl-methyl, amino-ethyl-formamidyl-methyl, cyclobutyl-formamidyl, methyl-formamidyl-methyl, dimethyl-form-I-methyl, hydroxy-ethyl. formamidil-methyl, id id roxy-propyl-formam id I-methyl, N, N-bis- (3-hydroxy-propyl) -formamidyl, cyclopentyl-idyl form, isobutyl-formamidyl, isobutyl-formamidyl-methyl, cyclopentyl-fromamidyl-methyl , cyano-ethylamine, cyano-methyl-formamidyl, pyrro-lidinyl-ethyl-formamidyl, 2- (isobutyl-formamidyl) -etyl, 1H-tetrazolyl, 2- (1H-tetrazoI-5-yl) ) -ethyl, 2- (1 H-tetrazol-5-yl) -methyl, 2- (1-methyl-1 H-tetrazol-5-yl) -methyl, acetylamino, cyclopropyl-formamidyl-methyl, hydroxy- ethyl-formamidyl, hydroxy-propyl-formamidyl, propyl-formamidyl-methyl, ethoxy-propyl-formamidyl, acetyl-amino-ethyl-formamidyl, 1-methyl-piperidin-4-yl-formamidyl, morpholino-carbonyl-ethyl, methoxy- carbonyl-methyl, methoxy-carbonyl-ethyl-formamidyl, methoxy-carbonyl-ethyl-formamidyl-methyl, methoxy-carbonyl-methyl-formamidyl-methyl, methoxy-carbonyl-methyl-formamidyl, 4-amino- hexy cyclo I-form mid i lo, 4-amino-cyclohexyl-formam id i I-methyl, acetylamino, ethyl-formamidyl-methyl, ethoxy-propyl-formamidyl-methyl, methoxy-carbonyl-ethyl, 1-formyl-pyrrolidine -2-yl-carboxylic, (1-carboxy-3-methyl-butyl) -formamidyl, 2- (methoxy-carbonyl, methyl-formamidyl) -ethyl, 1-carboxy (2,2-dimethyl-pro-pil) - formamidyl, 3-tert-butoxycarbonyl-amino-propyl-formamidyl, acetoxy-methyl and 1-carboxy-ethyl-formamidyl. The preferred compounds of Formula I are described in the Examples in Table I, infra.

Pharmacology and Utility The compounds of the invention modulate protein tyrosine kinase activity and, as such, are useful for treating diseases or disorders wherein protein tyrosine kinases, particularly the FAX, Abl, BCR-Abl, PDGF kinases -R, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met, contribute to the pathology and / or symptomatology of the disease. Focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase, is located at cell-extracellular substrate (ECM) matrix contact sites that function as part of a cytoskeletal-associated network of signaling proteins (Schlaepfer, et al., Prog. Diophys., Mol., 1999, 71, 435- 478. In adherent cells, FAK is usually associated with integrins in focal additions (Schlaepfer, et al., Proc. Nati. Acad. Sci. USA, 1992, 89, 5192-5196.) FAK forforylation results in activation of the protein kinase pathway. activated by nitrogen. Overexpression of FAK is involved in the progression of cancer. High levels of FAK correlate with invasion and metastatic potential in colon tumors (Weiner, TM, et al., Lancet, 1993,342, 1024-1025), breast tumors (Owens, LV, et al., Cancer Res. , 1995, 55, 2752-2755) and oral cancers (Kornberg, LJ, Head Neck, 1998, 20, 634-639). The role of FAK in cell migration has led to speculation that they may be important in other diseases such as dysfunctions in embryonic development and angiogenic disorders (Kornberg, L.J., Head Neck, 1998,20,634-639). Abelson's tyrosine kinase (ie, Abl, c-Abl) is involved in the regulation of the cell cycle, in the cellular response to genotoxic stress, and a transmission of information about the cellular environment through integrin signaling . In summary, it seems that the Abl protein serves as a complex role with a cellular module that integrates signals from several extracellular and intracellular sources and that influences decisions regarding the apoptotic cycle of the cell. The Abelson tyrosine kinase includes derivatives of sub-types such as chimeric BCR-Abl (oncoproteins) with more regulated tyrosine kinase activity or v-Abl. BCR-Abl is critical in the pathogenesis of 95% of chronic myelogenous leukemia (CML) and 10% of acute lymphocytic leukemia. STI-571 (Gleevec) is an inhibitor of the oncogenic BCR-Abl quirocin kinase and is used for the treatment of chronic myeloid leukemia (CML). Nevertheless, some patients at the CML explosion crisis stage are resistant to STI-571 due to mutations in the BCR-Abl kinase. More than 22 mutations have been reported to date, the most common being G250E, E255V, T315I, F317L and M351T. The compounds of the present invention inhibit the abl kinase, especially the v-abl kinase. The compounds of the present invention also inhibit the wild-type BCR-Abl kinase and the BCR-Abl kinase mutations and thus are suitable for the treatment of Bcr-abl positive cancer and tumor diseases, such as leukemias (especially chronic myeloid leukemia and acute lymphoblastic leukemia, where especially apoptotic mechanisms of action are found), and also shows effects on the sub-group of leukemic stem cells as well as potential for the purification of these cells in vitro after the removal of said cells (for example, removal of bone marrow) and reimplantation of the cells once they have been removed or cleared in cancer cells (for example, reimplantation of purified bone marrow cells). PDGF (Platelet Derived Growth Factor) is a very common growth factor, which plays a very important role in normal growth as well as pathological cell proliferation, as seen in carcinogenesis and diseases of smooth muscle cells of blood vessels, for example, in atherosclerosis and thrombosis. The compounds of the invention can inhibit the activity of the PDGF receptor (PDGFR) and, therefore, they are suitable for the treatment of tumor diseases, such as gliomas, sarcomas, prostate tumors, and tumors of the colon, breast and ovary. The compounds of the present invention can be used not only as a tumor inhibitory substance, for example in small cell lung cancer, but also as an agent to treat non-malignant proliferative disorders, such as atherosclerosis, thrombosis, psoriasis, scleroderma. and fibrosis, as well as for stem cell protection, for example, to combat the hemotoxic effect of chemotherapeutic agents, such as 1-fluorouracil, and on asthma. The compounds of the invention can especially be used for the treatment of diseases that respond to an inhibition of the PDGF receptor kinase. The compounds of the present invention show useful effects in the treatment of disorders that arise as a result of a transplant, for example, allogeneic transplantation, especially tissue rejection, such as especially obliteractive bronchiolitis (OB), i.e. chronic rejection of allogeneic lung transplants. In contrast to patients with OB, those with OB usually show a high concentration of PDGF in bronchoalveolar lavage fluids. The compounds of the present invention are also effective in diseases associated with the mitigation and proliferation of vascular smooth muscle cells (wherein PDGF and PDGF-R usually also play an important role), such as restenosis and atherosclerosis. These effects and the consequences thereof for the proliferation or migration of vascular smooth muscle cells in vitro and in vivo, can be demonstrated through the administration of the compounds of the present invention, and also by investigating their effect on the thickening of intima vascular after mechanical bath in vivo. The compounds of the present invention can inhibit cell procedures involving stem cell factor (SCF, also known as c-kit ligand or steel factor), such as inhibiting SCF receptor self-formation (kit) and stimulation activation by MAPK kinase SCF (mitogen-activated protein kinase). M07e cells are a human promegakaryotic leukemia cell line, which depends on the SCF for proliferation. The compounds of the invention can inhibit autophosphorylation of SCF receptors. The Ras-Raf-MEK-ERK signaling pathway does not send the cellular response of growth signals. Ras is mutated to an oncogenic form in approximately 15% of human cancer. The Raf family belongs to the serine / threonine protein kinase and includes three members, A-Raf, B-Raf and c-Raf (or Raf-1). The focus of Raf being a drug target focused on Raf's relationship as an effector downstream of Raf. However, the latest data suggest that B-Raf may have an important role in the formation of certain tumors without any requirement for an activated Ras allele.

(Nature 417,949-954 (01 Jul 2002) In particular, B-Raf mutations have been detected in a large percentage of malignant melanomas, and existing medical treatments for melanoma are limited in their effectiveness, especially for later-stage melanomas. compounds of the present invention also inhibit cellular processes involving b-Raf kinase, providing a new therapeutic opportunity for the treatment of human cancers, especially for melanoma.The compounds of the present invention also exhibit potent inhibition of the kinase activity of anaplastic lymphoma kinase tyrosine (ALK) and NPM-ALK fusion protein.This protein tyrosine kinase results from a fusion of nucleophosmin gene (NPM) and anaplastic lymphoma kinase (ALK), presenting the activity of protein tyrosine kinase of the independent ALK ligand NPM-ALK play important role in signal transmission in a number of c Hematopoietic cells and other human cells leading to hematological and neoplastic diseases, for example in a large anaplastic cell lymphoma (ALCL) and non-Hodgkin's lymphomas (NHL), specifically in ALK + NHL or Alkomas, in inflammatory myofibroblastic tumors (IMT) and neuroblastomas (Duyster, J. et al. , 2001, Oncogene 20, 5623-5637). In addition to NPM-ALK, other gene fusions have been identified in hematological and neoplastic diseases in humans; mainly TPM3-ALK (a non-muscle tropomyosin fusion with ALK). The inhibition of Activity of the ALK tyrosine kinase can be demonstrated using known methods, for example, using the recombinant kinase domain of ALK in analogy with the VEGF-R kinase assay described in J. Wood et al. Cancer Res. 6C 2178-2189 (2000). Flt3 is a member of the tyrosine kinase family of the lll-like receptor (RTK). Flt3 (tyrosine kinase of the fms type) is also known as FLk-2 (fetal liver kinase 2). The aberrant expression of the Flt3 gene has been documented in leukemia in both adults and children including acute myeloid leukemia (AML), AML with myelodysplasia of three lines (AML / TMDS), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) . Activation mutations of the Flt3 receptor have been found in approximately 35% of patients with acute myeloblastic leukemia (AML), and are associated with poor prognosis. The most common mutation involves an in-frame duplication within the juxtamembrane domain, with an additional 5-10% of patients having a point mutation in asparagine 835. Both of these mutations are associated with constitutive activation of the tyrosine kinase activity of Flt3, and result in the proliferation and viability of signals in the absence of the ligand. Patients who express the mutant form of the receptor have been shown to have a reduced chance of cure. Thus, there is a cumulative evidence of a role for the hyper-activated (mutated) Flt3 kinase activity in leukemia in humans and myelodysplastic syndrome. This has prompted applicants to seek new inhibitors of the Flt3 receptor as a possible therapeutic aspect in these patients, for whom current drug therapies offer very little utility, and for such patients who previously have failed current available drug therapies and / or stem cell transplant techniques. Leukemias usually result from a genetic year acquired (not inherited) from the DNA of immature hematopoietic cells in the bone marrow, lymph nodes, vessel, or other organs of a blood and immune system. The effects are: accelerated growth and blockage in cell maturation, resulting in the accumulation of cells called "leukemic bursting", which do not function as normal blood cells; and a failure to produce normal bone marrow cells, leading to a deficiency of red blood cells (anemia), platelets and normal white blood cells. The burst cells are normally produced by the bone marrow and usually develop into mature blood cells, comprising about 1 percent of all cells in the bone marrow. In leukemia, the burns do not ripen properly and accumulate in the bone marrow. In acute myeloid leukemia (AML), there are so-called myeloblasts, whereas in acute lymphoblastic leukemia (ALL) they are known as lymphoblasts. Another leukemia is mixed lineage leukemia (MLL). The term "AML with myelodysplasia of three lines (AML / TMDS) "refers to an uncommon form of leukemia characterized by a dishematopoietic image that accompanies acute leukemia, a poor response to the induction of chemotherapy, and a tendency to relapse with pure myelodysplastic syndrome. Myelodysplastic syndrome (MDS) "refers to a group of disorders in the blood where the bone marrow stops normal functioning, resulting in a deficiency in the number of healthy red blood cells, compared with leukemia, where one type of blood cell red blood cells are produced in large numbers, any and sometimes all types of red blood cells are affected in the MDS.At least 10,000 new cases occur annually in the United States.Up to one third of patients diagnosed with MDS develop acute myeloid leukemia For this reason, the disease is sometimes called pre-leukemia, sometimes myelodysplastic syndrome is also called Diesmielopoiesis myelodysplasia or oligoblastic leukemia. MDS is also referred to as incandescent leukemia when high numbers of burst cells remain in the bone marrow. Myelodysplastic syndrome, like leukemia, results from genetic damage to the DNA of an individual cell in the bone marrow. Certain abnormalities in the chromosomes are present in patients with MDS. These abnormalities are called translocations, which occur when a part of a chromosome is breaks and remains attached to a separate part of a different chromosome. The same defects are often found in acute myeloid leukemia. However, MDS differs from leukemia because all of the patient's red blood cells are abnormal and all are derived from the same damaged stem cell. In patients with leukemia, the bone marrow contains a mixture of sick and healthy red blood cells. AML and advanced myeloplastic syndromes are currently treated with high doses of cytotoxic chemotherapy drugs such as cytosine-arabinoside and daunorubicin. This type of treatment induces around 70% of patients to enter a haematological remission. However, more than half of patients who go into remission will relapse later despite the administration of chemotherapy for long periods of time. Almost all patients who fail to enter remission initially, or who relapse after obtaining remission, will eventually die due to leukemia. Bone marrow transplant can cure up to 50% to 60% of patients who undergo the procedure, but only about one third of patients with AML or MDS are eligible to receive a transplant. New and effective drugs are urgently needed to treat patients who fall to remission with standard therapies, patients who subsequently relapse, and patients who are not eligible for stem cell transplantation. In addition, a new drug can be added to standard therapy with waiting It is reasonable that it will result in improved induction chemotherapy for all patients. In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, said method comprising administering to the subject a therapeutically effective amount (See, "Aministration and Pharmaceutical Compositions ", infra of a compound of Formula I or a pharmaceutically acceptable salt thereof For any of the above uses, the dosage required will vary depending on the mode of administration, the particular condition to be treated and the desired effect.

Administration and Pharmaceutical Compositions In general, the compounds of the invention will be administered in therapeutically effective amounts by any of the usual and acceptable modes known in the art, either individually or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are reported systematically at daily doses of approximately 0.03 to 2.5 mg / kg per body weight. A daily dose indicated in the higher animal, for example, humans, is on the scale of about 0.5 mg to about 100 mg, conveniently administered, for example in divided doses of up to four times a day or in a delayed manner. Suitable unit dosage forms for oral administration comprise from about 1 to 50 mg of the active ingredient. The compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, for example, orally, for example, in the forms of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions, topically, for example, in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable diluent carrier can be manufactured in a conventional manner through mixing, granulating or coating methods. . For example, the normal compositions may be tablets or gelatin capsules comprising the active ingredient together with a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example, silica, ascorbic acid talc, its magnesium or calcium salt and / or glycol polyethylenic salt; for tablets also c) binders, for example, magnesium silicate, aluminum, starch paste, gelatin, traganto, methylcellulose, carboxymethylcellulose sodium and / or polyvinylpyrrolidone; if desired d) disintegration agents, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbers, colorants, flavors and sweeteners. The injectable compositions can also be isotonic aqueous solutions or suspensions, and suppositories can be prepared from emulsions or fat suspensions. The compositions can be sterilized and / or contain auxiliaries, such as preservatives, stabilizing agents, humectants or emulsifiers, solution promoters, salts for regulating asthmatic pressure and / or pH regulators. In addition, they may also contain other therapeutically valuable substances. Formulations suitable for transdermal applications include an effective amount of a compound of the present invention with a carrier. A vehicle can include pharmacologically acceptable, absorbable solvents, to assist passage through the skin of the host. For example, the transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with vehicles, optionally a speed control barrier for delivering the compound to the skin of the host at a controlled rate and predetermined for a prolonged period of time, and means to secure the device to the skin. Transdermal matrix formulations can also be used. Formulations suitable for topical application, for example, to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well known in the art. These may contain solubilizers, stabilizers, tonicity improving agents, pH regulators and preservatives. The compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). For example, anti-inflammatory may occur Synergistic effects with other inmunoduladoras substances or any other substance used in the treatment of the diseases mentioned above, for example, when used in combination with cyclosporin, rapamycin, or ascomycin, or their immunosuppressive analogs, e.g. cyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or comparable compounds, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mixoribina, micofeninolico acid mycophenolate mofetil 15-deoxyspergualin, immunosuppressant antibodies, especially monoclonal antibodies for receptors leukocyte, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58, or their ligands, or other immunomodulatory, such as CTLA41g compounds. Where the compounds of the invention are administered in conjunction with other therapies, the doses of the co-administered compounds will, of course, vary depending on the type of co-drug employed, the specific drug employed in the condition to be treated, etc. The invention also provides a combination pharmaceutical, for example, an equiment, comprising a) a first agent that is a compound of the invention as described herein, in free form or in a pharmaceutically acceptable salt form, and b) at least one agent. The equipment may include instructions for its administration. The terms "co-administration" or "combined administration" or the like, as used herein, means that encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered through the same administration route or at the same time. The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, for example, a compound of Formula I and a co-agent, both are administered to the patient simultaneously in the form of a single dose entity. The term "non-fixed combination" means that the active ingredients, for example, a compound of Formula I and a co-agent, both administer to a patient with separate entities either simultaneously, concurrently or sequentially without specific time limits, in wherein said administration provides effective therapeutic levels of the 2 compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of 3 or more active ingredients.

Procedures for Making the Compounds of the Invention The present invention also includes processes for the preparation of the compounds of the invention. In the reactions described, it may be necessary to protect reactive functional groups, for example, hydroxy, amino, imino, thio or carboxy groups, when desired in the final product, to avoid their unwanted participation in the reactions. Other conventional protectors can be used according to standard practice, for example, see T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry". John Wiley and Sons, 1991. The compounds of Formula I, wherein W is -NR4-, can be prepared by following the following Reaction Scheme I: Reaction Scheme I where R15 R2, R3, R4 and n are as is. they defined for Formula I in the Brief Description of the Invention, and Y is a leaving group such as halogen (e.g., chlorine, and the like). A compound of the Formula can be prepared by reacting a compound of the formula 2 with a compound of the formula 3 in the presence of a suitable base (e.g., potassium tert-butoxide and diisopropylethylamine, and the like), a suitable solvent (e.g., 1,4-dioxane and butanol, and the like). The reaction is carried out at 50 to 130 ° C and can take up to 4 hours to complete. Similarly, using appropriate starting materials, reaction with a compound of formula 3 results in the compounds of Formulas Ib, le and le. The compounds of Formula I wherein W is -O-, can be prepared following the following scheme of Reaction U: Reaction Scheme II wherein R-i, R2, R3, R4 and n are as defined for Formula I in the brief description of the invention. A compound of the Formula can be treated by reacting a compound of the formula 4 with a compound of the formula 5 in the presence of a suitable solvent (for example, DMSO, and the like) and a suitable base (for example, tert-butoxide) of potassium, and the like). The reaction is carried out at 50 to 130 ° C and can take up to 4 hours to complete. Detailed descriptions of the syntheses of a compound of Formula I can be found in the Examples, infra.

Additional Methods for Making the Compounds of the Invention A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.

Alternatively, a pharmaceutically acceptable base addition salt of the compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates. The free acid and free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (for example, a solution of ammonium hydroxide, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g. hydrochloric acid, etc.). The compounds of the invention in non-oxidized form can be prepared from N-oxides of the compounds of the invention, by treating with a reducing agent (eg, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, and bromide, or the like) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) from 0 to 80 ° C. Pro-drug derivatives of the compounds of the invention can be prepared by methods known to those skilled in the art (for example, for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p.85). For example, suitable pro-drugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonate hydrochloride, para-nitrophenyl carbonate, or the like). Protected derivatives of the compounds of the invention can be made by means known to those skilled in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, "Protecting Groups in Organic Chemistry," 3rd ed., John Wiley and Sons, Inc., 1999. The compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (eg, hydrates). ). Hydrates of the compounds of the present invention can be conveniently prepared through recrystallization from a mixture of aqueous / organic solvent, using organic solvents such as dioxin, tetrahydrofuran or methanol. The compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure anantiomers. Although the resolution of the enantiomers can be accomplished using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes (e.g., crystalline diastereomeric salts) are preferred. The diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by taking advantage of these differences. The diastereomers can be separated through chromatography, or preferably, through separation / resolution techniques based on differences in solubility. The optically enantiomer could then be recovered, along with the resolving agent, by any practical means that might not result in racemization. A detailed description of the techniques applicable to the resolution of stereoisomers of the compounds from their racemic mixtures can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc. ., 1981. In summary, the compounds of Formula I can be made through a procedure, which involves: (a) that of the reaction of schemes I or II; and (b) optionally converting a compound of the invention to a pharmaceutically acceptable salt; (c) optionally converting a salt form of a compound of the invention to a non-salt form; (d) optionally converting a non-oxidized form of a compound of the invention to a pharmaceutically acceptable N-oxide; (e) optionally converting an N-oxide form of a compound of the invention to its non-oxidized form; (f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers; (g) optionally converting a non-derivatized compound of the invention to a pharmaceutically acceptable prodrug derivative; (h) optionally converting a prodrug product of a compound of the invention to its non-derivatized form. As for the production of the starting materials which is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as described in the Examples below. One skilled in the art will appreciate that the above transformations are only representative of the methods for the preparation of the compounds of the present invention, and that similarly, other well-known methods can be used.

EXAMPLES The present invention is further illustrated, but not limited to, the following examples showing the preparation of the compounds of Formula I (Examples) and intermediates (References) according to the invention.

Example 1 3NHC1 íPrOH, Reflux A. KO'Bu, THF refimetoxyaniline B. Pd2 (dba) 3l (tBu) 2blphenylphosphine, trimethoxyaniline, K3PO4, 1,4-Dioxane 90 ° C-110 ° C Synthesis of 5-Bromo-2-chloripyrimidin-4-ylamine (1): A solution of 5-bromo-2,4-dichloropyrimidine (25g, 110 mmol) in 200 mL of THF was treated with 47 mL of ammonia (330 mmol) , 7.0M solution in methanol). After stirring for 15 hours, the solution was concentrated under reduced pressure and purified through short filtration (Si02, Hexanes: Acetate e t i I o / 1: 1) to produce 21g (92%) of 1 as a white solid.

Synthesis of 2-Chloro-5- (2-ethoxyvinyl) -pyrimidin-4-ylamine (2): A 500 mL round bottom flask that was charged with 5-bromo-2-chloropyrimidin-4-ylamine (1) ( 1 Og, 48 mmol), tetrakis (triphenylphosphine) palladium (O) (2.8 g, 2.5 mmole), and toluene (200mL). Tributyl- (2-ethoxyvinyl) -stannate (22 g, 60 mmol) was added and the reaction was heated to 110 ° C with stirring for about 15 hours. After cooling to room temperature, the solution was diluted with 100 mL of ethyl acetate and washed with water and brine. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (Si02, Hexane: Ethyl acetate / 5: 1) gives 2 (4.4g, 46%) as a yellow solid.

Synthesis of 2-Chloro-7H-pyrrolo- [2,3-d] pyrimidine 3: A 500 mL round bottom flask was charged with 2-Chloro-5- (2-ethoxyvinyl) -pyrimidin-4-ylamine 2 ( 4.4 g, 20 mmol). Isopropanol (200 mL) was added followed by 25 mL of concentrated hydrochloric acid. The solution was heated to 90 ° C and stirred for two hours. After cooling to room temperature, the solution was concentrated under reduced pressure, then gassed to a pH of 9 with saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate, and the organic extracts were combined and washed with Saturated aqueous NaHC03, and brine. The organic extracts were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. Purification by short filtration (Si02, Hexane: Ethyl acetate / 1: 1) gives 3 (3.1g, 92%) as a white solid.

Synthesis of 2-Chloro-7-pyridin-2-yl-7H-pyrrolo- [2,3-d] pyrimidine 4: A suspension of 2-chloro-7H-pyrrolo ~ [2,3-d] pipmidine 3 (0.53 g, 3.5 mmol), 2-bromopyridine (0.66 mL, 1.1 g, 6.9 mmol), copper iodide (l) (0.20 g, 1.0 mmol), trans-1,2-diaminocyclohexane (0.12 mL, 0.11 g, 1.0 mmol) ), and potassium phosphate (2.2g, 10 mmol) in 10 mL of 1,4-dioxane was heated to 100 ° C and stirred for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic extract was dried over MgSO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, Hexane: ethyl acetate / 5: 1) gave 4 (0.69g, 87%) as a white solid.

Synthesis of (7-Pyridin-2-yl-7H-pyrrolo [2,3-d1-pyrimidin-2-ip- (3,4,5-trimethoxy-phenyl) -amine (5): Method 1. To a solution of 2 -chloro-7-pyridin-2-yl-7H-pyrrolo (2,3-d] pyrimidine in 1,4-dioxane was added 3,4,5-trimethoxy aniline (3 equivalents) followed by the addition of a solution of potassium tert-butoxide (1.0 M in tetrahydrofuran, 3 equivalents), dropwise After the addition, the reaction mixture was heated at 80 ° C last 2 hours. The solvent was removed and then cooled to ambient temperature. Purification by means of reverse phase HPLC gave (7-pyridin-2-yl-7H-pyrrolo [2,3-d] pyrimidin-2-yl) - (3,4,5 { Frimeioxi-phenyl) -am na as a white solid. Method 2. A round bottom flask loaded with 2-chloro-7-pyridin-2-yl-7H-pyrrolo [2,3-d] pyrimidine, 0.1 equivalents of tri (dibenzylidenaceona) dipalladium (O), 0.2 equivalents of biphenyl -2-yl-di-fer-builyl-phosphono, 3 equivalents of potassium phosphates and 1.5 equivalents of 3,4,5-?-Meioxy aniline were vaporized with niorogen followed by the addition of 1,4-dioxane. The suspension was heated at 110 ° C for 18 hours. Filiration through a Celiie pad removed the solid. The filtrate was diluted with ethyl oil, and washed with water and brine. After drying over magnesium sulfate, the product was concentrated and purified by chromatography (acetyl ether: hexanes 1: 1) to give 7-pyridin-2-yl-7H-pyrrolor-2,3-dlpyrimidin-2-yl. ) - (3,4,5-trimethoxy-phenyl) -amine as a white solid.

EXAMPLE 2 Achered 3-f2- (3,4,5-trimethoxy-n-amino) -pyrrolof2,3-d1-pyrimidin-7- n-benzoic acid A solution of 3- [2- (3,4,5-uro-methyloxy-phenylamino) -pyrrolo [2,3-d] pyrimidin-7-yl] -benzoic acid methylester in 1N of sodium hydroxide (meianol: water 1: 1) was stirred at ambient temperature for 15 hours. Acidification with 1N hydrochloric acid at a pH of 6 provides a precipitate. Filtering and washing with water provides 3- [2- (3,4,5-yrimoxy-phenylamino) -pyrrolo [2,3-d] pyrimidin-7-yl] -benzoic acid as a white solid.

Example 3 3-f2- (3,4,5-Trimethoxy-phenylamino.) - pyrrolo [2,3, d1-pyrimidin-7- illbenzoyl A dry round-bottomed maíraz loaded with 3- [2- (3,4,5-yrmethioxy-phenylamino) -pyrrolo [2,3, d] pyrimidin-7-yl] benzoyl acid was vaporized with niologen, dichloromean and added few goies of N, N'-dimeylylformamide. A solution of oxalyl chloride (2.0 M in dichloromethane) was added to leave. The reaction mixture was stirred at ambient temperature for 30 min., Resulting in a solution of 3- [2- (3,4,5-frimefoxy-phenylamino) -pyrio [2,3-d] pyrimidin-7-yl]. -benzo ilo.

EXAMPLE 4 N-I-lethyl-3-F2- (3,4,5-trimethoxy-phenylamino) -pyrrolof2,3-d-pyrmidine-7-H-benzamide To a solution of 3- [2- (3,4,5-trimethoxy-phenylamino) -pyrrolo [2,3-d] pyrimidin-7-yl] benzoyl chloride in dichloromethane was added 5 equivalents of a methylamine solution ( 2.0 M in hydrohydrofuran). After stirring at room temperature for 1 hour, the reaction was quenched with water. Removal of the solvent followed by purification with reverse phase HPLC afforded N-meityl-3- [2- (3,4,5-ynedioxy-phenylamino) -pyrrole or [2,3-d [pyri mi in-7-] il] -benzamide as a white solid. By repeating the procedures described in the previous examples, using the appropriate delivery methods, the following components of Formula I can be obtained, as identified in Table 1.

Table 1 15 20 25 15 20 15 20 25 Assays The compounds of the present invention were tested for their ability to selectively inhibit cell proliferation of 32D cells expressing BCR-Abl (32D-p210) compared to 32D cells of origin. Compounds that selectively inhibit the proliferation of these Abl transformed cells were tested for anti-proliferative activity in Ba / F3 cells expressing either wild type or Bcr-abl mutant forms. In addition, the compounds were analyzed to measure their ability to inhibit FAK, Flt-3, ALK and b-Raf.

Inhibition of cellular BCR-Abi-dependent proliferation (High Production Method) The murine cell line used is the 32D hematopoietic progenitor cell line transformed with BCR-Abl cDNA (32D-p210). These cells were maintained in RPMl / 10% fetal bovine serum (RPMI / FCS) supplemented with penicillin, 50 μg / mL, 50 μg / mL streptomycin and 200 mM L-glutamine. Similarly, untransformed 32D cells were maintained with the addition of 15% of a WEHI conditioning medium as a source of IL3. 50 μl of a cell suspension was plated 32Do 32D-p210 in 384-well Greiner cavity microplates (black) at a density of 5000 cells per well. 50 nl of the test compound (1 mM in a DMSO supply solution) was added to each well (STI571 was included as a positive control). The cells were incubated for 72 hours at 37 ° C, 5% C02. 10 μl of a 60% Alamar Blue solution (Tek diagnostics) was added to each well and the cells were incubated for a further 24 hours. The fluorescence intensity (Excitation at 530 nm, Emission at 580 nm) was quantified using the Acquest ™ system (Molecular Devices).

Inhibition of cellular BCR-Abl dependent proliferation 32D-p210 cells were placed in 96-well TC plates at a density of 15,000 cells per well. 50 μL of two double serial dilutions of the test compound (Cmax is 40 μM) was added to each well (STI571 was included as a positive control).

After incubating the cells for 48 hours at 37 ° C, 5% C02, 15 μL of MTT (Promega) was added to each well and the cells were incubated for a further 5 hours. The optical density 570nm was quantified spectrophotometrically and the IC 50 values, the concentration of the compound required for 50% inhibition, were determined from a dose-response curve.

Effects on cell cycle distribution 32D and 32D-p210 cells were placed on 6-well TC plates at 2.5x106 cells per well in 5 ml of medium and the test compound was added at 1 or 10 μM (ST1571 was incubated as a control). The cells were then incubated for 24 to 48 hours at 37 ° C, 5% CO2. 2 ml of the cell suspension was washed with PBS, were fixed in 70% EtOH for 1 hour and treated with PBS / EDTA / Rnase for 30 minutes. Propidium iodide was added (Cf = 10 μg / ml) and the fluorescence intensity was quantified through flow cytometry in the FACSscalibur ™ system (BD Biosciences).

The compounds of the present invention demonstrate an apoptotic effect on 32D-p210 cells but do not induce apoptosis in cells of 32D origin.

Effect on BCR-Abl Cellular Autophosphorylation The autophosphorylation of BCR-Abl was quantified with capture Elisa using a specific capture antibody c-abl and an anti-phosphotyrosine antibody. 323D-p210 cells were placed in plots TC of 96 cavities at 2x105 cells per cavity in 50 μL of the medium. 50 μL of two double serial dilutions of the test compounds (Cmax is 10 μM) was added to each well (STI571 was included as a positive control). The cells were incubated for 90 minutes at 37 ° C, 5% C02. The cells were then treated for 1 hour on ice with 150 μL of lysis pH buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 nM EDTA, 1 mM EGTA and 1% NP-40) containing inhibitors of protease and phosphatase. 50 μL of cell lysate was added to 96 cavity optiplates previously coated with a specific anti-abl antibody and blocked. The plates were incubated for 4 hours at 4 ° C. After washing with TBS-Tween pH regulator, 50 μL of an anti-phosphotyrosine antibody conjugated with alkaline phosphates was added and the plate was further incubated overnight at 4 ° C. After washing with the pH regulator TBS-Tween 20, 90 μL of a luminous substrate was added and the luminicence was quantified using the Acquest ™ system. The test compounds of the invention that inhibit the proliferation of BCR-Abl expressing cells, inhibit the autophosphorylation of cellular BCR-Abl in a dose-dependent manner.

Effect on Autophosphorylation of BCR-Abl Cell Effect on the proliferation of cells expressing mutant forms of Bcr-abl The compounds of the invention were tested for their effect antiproliferative in Ba / f3 cells expressing either wild type or BCR-Abl mutants (G250E, E255V, T3151, F317L, M351T) conferring resistance or decreased sensitivity to STI571. The antiproliferative effect of these compounds are cells expressing mutant-BCR-Abl and untransformed cells were tested at 10, 3.3, 1.1 and 0.37 μM as described above (in an IL3 character trait). The 1C50 values of the compounds lacking toxicity in non-transformed cells were determined from the dose-response curves obtained as described above.

Inhibition of Flt-3 The general technique involves comparing the effects of possible inhibitors on cell lines that depend on mutant Flt3 for proliferation against cell lines that do not depend on the mutant Flt3 for proliferation. Compounds having differential activity (greater than or equal to 10 times the difference in sensitivity between the FIt3 + cell lines and the Flt3 cell lines) were selected for further study.The cell lines used for the initial classification are sub- Ba / F3 cell lines that are engineered to over-express wild-type (non-mutated) mutant Flt3 after infection with a retrovirus expressing appropriate Flt3 ssDNA.The cell line of origin, Ba / F3 is dependent on interleukin-3 for proliferation, and when it lacks LL-3, cells quickly cease proliferation and die. The retrovirus expresses Flt3 from the retroviral LTR and the neo gene of an IRES site. Ba / F3 cells were selected in G418 and analyzed for Flt3 expression by fluorescence activated cell sorting (FACS). They tuned cell lines with two different mutations of Flt3. A mutant expresses an Flt-3 that has a duplication of 14 amino acids in the justmembrane domain encoded by exon 11, the specific duplication being ... VDFREYEYDLKWEF .... (called, Ba / F3-Flt3-ITD) . The second mutation has a point mutation that converts asparagine to position 835 to tyrosine (designated Ba / F3-Flt3-D835Y). Both mutations lead to the activation of the Flt-3 kinase and make it independent of L-3 and the expression cells grow in the absence of I L-3. Ba / F3 cells that express wild-type Flt3 are similarly generated and used as the "control" cell line. The cell line of origin (uninfected) and the wild-type "control" cell line remain dependent on I L-3 for proliferation. Ba / F3 cells were cultured (control, -Flt-3-ITD, or -Flt3-D835Y) up to 500,000 cells / mL in 30 mL cultures, with RPMl 1640 with 10% fetal bovine serum as the culture medium. The medium for the control cells (but not the mutant Flt3 cells) contain 10% of the conditioned medium of the VEHI-3B cell line as a source of IL-3. A "supply" solution of 10mM of each compound in sulfoxide was made Dimethyl (DMSO). Dilutions were then made in RPMl 1640 with 10% fetal bovine serum to create final drug concentrations that typically vary from InM to 10 μM. Similar dilutions of DMSO were made to serve as vehicle controls. 48 hours after the addition of the compounds, the cells were analyzed for proliferation rate and cytotoxicity.

I-Pro-1 iodide (Probes Molecule) was added to the cells at a final concentration of 2.5 μM in NaCI / Na citrate pH buffer. The cells were incubated with Yo-Pro for 10 minutes at room temperature and then read in a fluorometer for the determination of cytotoxicity. The cells were then lysed with pH regulator NP40 / EDTA / EGTA, incubated at room temperature for 90 minutes, and read for proliferation determination. Compounds that are selectively more toxic to Ba / F3-Flt3-ITD cells than to wild type control Ba / F3 cells were further tested on cells expressing Flt3-D835Y. In addition, s-Flt3 antibodies were used to immunoprecipitate the Flt3 proteins before and after exposure to various concentrations of the active compounds. The immuno-precipitated proteins were separated through sodium sulphate dudebryl polyacrylamide gels, electrophoretically transferred to a PVDF membrane and immunostained with an s-phospho-591Y-Flt3 antibody. This test determines if the compounds reduce the levels of "autophosphorylation" of Flt3 characteristic of the mutated forms of the receptor. The compounds of the invention typically exhibit antiproliferative activity against Flt3 ITD on the nanomolar scale while being non-toxic against control-Flt3 up to 10μM. The compounds of the invention also reduce the autophosphorylation activity of cellular Flt-3 at the nanomolar scale.

Inhibition of Focal Adhesion Kinase (FAK) The compounds of the invention were tested for their ability to inhibit FAK activity. The FAK kinase activities were measured in 384 well plates using a fluorescence resonance energy transfer test method based on time (TR-FRET). Full-length human FAK was expressed in E. Coli as a GST-labeled protein and purified through a column of immobilized glutathione. A biotinylated peptide, biotin-SETDDYAEHD (Synthesized by SynPep Corp.), which corresponds to the sequence of the human FAK autophosphorylation site, was used as the assay substrate. FAK kinase expressed in E. coli (2.4 μg / ml) was mixed together with the FAK peptide (133nM) in 15 μL of the assay pH buffer (20mM Hepes, pH7.4, 5mM MgCl2, 2mM MnCl2, 0.5mM Na3VO4 , 0.1% BSA, 0.1% TritonX-100). A compound of the invention (0.5 μl dissolved in DMSO) was then added to the above solution / peptide. After incubation at room temperature for 10 minutes, 5μl of 40μM was added in assay pH buffer to start the reaction. The reaction mixture was incubated at room temperature for 2 hours. Then 50μl of detection reagents containing 0.15nM of anti-phosphotyrosine antibodies labeled with Eu (PT66-Eu, PerkinElmer) and 1.5μg / ml of SA-APC (PerkinElmer) in pH-detection buffer (lOnriM Tris-HCl) were added. , pH7.4, 6mM EDTA, 0.1% BSA, 0.1% TritonX-100): The mixture was incubated at room temperature for 30 minutes and the TR-FRET signals were measured using an Acquest plate reader (Molecular Device).

Inhibition of ALK Inhibition of the tyrosine kinase activity of ALK can be demonstrated using known methods, for example, using the recombinant kinase domain in ALK in analogy with the VEGF-R kinase assay described by J. Wood et al. . Cancer Res. 6_0, 2178-2189 (2000). In vitro assays were performed using tyrosine kinase of GST-ALK protein in 96-well plates in a 20 nM Tris HCl filter binding assay, pH = 7.5.3 mM MgCl 2 10 mM MnCl 2 I mM DTT, 0.1 μd ' / assay (= 30 μl) [? - 33P] -ATP, 2 μM ATP, 3 μg / ml poly (Glu, Tyr 4: 1) Poly-EY (Sigma P-0275), 1% DMSO, 25 ng ALK over . The assays were incubated for 10 minutes at room temperature. The reactions were terminated by adding 50 μl of 125 mM EDTA, and the reaction mixture was transferred onto a MAIP Multiscreen plate (Millipore, Bedford, MA, USA), previously moistened with methanol, and rehydrated for 5 minutes with H2O. After washing (0.5% H3PO), the plates were counted in a liquid tintilation counter. The IC50 values were calculated through linear regression analysis of the inhibition percentage. Compared with the control without inhibitor, the compounds of the formula I inhibit the activity of above by 50% (IC50), for example in a concentration of 0.001 to 0.5 μM, especially 0.01 to 0.1 μM. The compounds of formula I potentially inhibit the growth of human NPM-ALK by overexpressing murine BaF3 cells (DSMZ Deutsche Sammlung von Microorganismen und Zellkulturen GmbH, Braunschweig, Germany). Expression of NPM-ALK is achieved by transfection of the BaF3 cell line with a pCIneo ™ expression vector (Promega Corp., Madison Wl, USA) coding for NPM-ALK and the subsequent selection of G418 resistant cells. The non-transfected Baf3 cells depend on I-3 for cell survival. In contrast, Baf3 cells expressing NPM-ALK (hereinafter referred to as BaF3-NPM-ALK) can proliferate in the absence of I L-3 since they obtain a proliferative signal through NPM-ALK kinase. Therefore, the putative inhibitors of the NPM-ALK kinase remove the growth signal and result in an antiproliferative activity. The antiproliferative activity of the putative inhibitors of the NPM-ALK kinase, however, can be overcome through the addition of IL-3, which provides growth signals through a mechanism independent of NPM-ALK. [For an analog cell system using FLT3 kinase see E Weisberg et al. Cancer Cell; 1_, 433-443 (2002)]. The inhibitory activity of the compounds of formula I was determined, in summary, as follows: BaF3-NPM-ALK cells (15,000 / microtiter plate cavity) were transferred to 96-well microtiter plates. The test compounds [dissolved in dimethyl sulfoxide (DMSO)] were added in a series of concentrations (dilution series) such that the final DMSO concentration is not greater than 1% (v / v). After the addition, the plates were incubated for two days, during which the control cords without the test compound could undergo two cycles of cell division. The growth of BaF3-NPM-ALK cells was measured through Yopro ™ staining [T Idziorek et al. J. Immunol. Methods; 185: 249-258 (1995) 1: 25 u I of lysis pH regulator consisting of 20mM sodium citrate, pH 4.0, 26.8mM sodium chloride, 0.4% NP40,20nM EDTA, and 20mM was added to each cavity. The lysis of the cell was completed in 60 minutes at room temperature and a total amount of Yopro bound to the DNA was determined through measurement using the 96-well reader Cytofluor II (PerSeptive Biosystems) with the following parameters: Excitation (nm) 485/20 and Emission (nm) 530/25. The IC50 values were determined through a computer-aided system using the formula: IC5o = [(ABSprUeba-ABSín¡c¡o) / (ABScontrol-ABS¡nicio)] x100. (ABS = absorption) The IC 50 value in those experiments is provided as that concentration of the test compound in question that results in a cell count that is 50% less than that obtained using the control without inhibitor. The compounds of formula I exhibit inhibitory activity with an IC 50 in the range of about 0.01 to 1 μM. The proliferative action of the compounds of formula I can also be determined in the human KARPAS-299 lymphoma cell line (DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschwieg, Germany) [described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002)] using the same methodology previously for the BaF3-NPM-ALK cell line. The compounds of formula I exhibit inhibitory activity with an IC 50 in the range of about 0.01 to 1 μM. The action of the compounds of Formula I on the autophosphorylation of ALK can be determined in the human KARPAS-299 lymphoma cell line through an immunostaining as described by WG Dirks et al. Int. J. Cancer 100, 49-56 (2002). In that test, the compounds of Formula I exhibit a 1C50 of about 0.001 to 1 μM.

Upstate KinaseProfiler ™ - Radio-Enzymatic Filter Binding Assay The compounds of the invention were analyzed for ability to inhibit individual members of a panel of kinases (a partial, non-limiting list of kinases includes: FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met The compounds were tested in triplicate at a final concentration of 10 μM following this generic protocol.Note that the composition of the kinase pH regulator and substrates vary for the different kinases included in the "Upstate KinaseProfiler ™" panel. tested in duplicate at a final concentration of 10 μM following this generic protocol Note that the composition of the kinase pH regulator and the substrates vary for the different kinases included in the "Upstate KinaseProfiler ™" panel. (2.5μL, 10x - containing MnCl2 when required), activated kinase (0.001-0.01 Units, 2.5μL), specific peptide or Acrylic polymer (Glu4-Tyr) (5-500μM or .01mg / ml) in pH regulator of Kinase kinase and pH regulator loop (50μM; 5μL) in an eppendorf flask on ice. A mixture of Mg / TP (10μL, 67.5 (or 33.75) mM MgCl2, 450 (or 225) μM ATP and 1 μCi / μl [? -32P] -ATP (3000Ci / mmoles)) was added, the reaction was incubated approximately 30 ° C for about 10 minutes. The reaction mixture was placed as a spot (20μL) on a paper of 2cmx 2cm P81 (phosphocellulose, for substrates of positively charged peptide) or Whatman No. 1 (peptide Poly (Glu4-Tyr), as substrate). The test panels were washed 4 times, for 5 minutes each time, with 0.75% phosphoric acid and washed once with acetone for 5 minutes. minutes The test frames were transferred to a flask, 5 ml of scintillation cocktail were added and the incorporation of 32P (cpm) into the peptide substrate was quantified with a Beckman scintillation counter. The percentage inhibition for each reaction was calculated. The compounds of Formula I, at a concentration of 10 μM, preferably showed a percentage of inhibition greater than 50%, preferably greater than 60%, most preferably greater than 70%, against the FAK, Abl, BCR-Abl, PDGF kinases. -R, c-Kit, NPM-ALK, Flt-3, JAK2 and / or c-Met. The compounds of Formula I, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. For example, compounds of Formula I preferably show an IC50 on a scale of 1x10"10 a 1x10"5M, most preferably less than 500mM for at least one of the following kinases: FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met. For example: (i) N- (2-Dimethylamine-ethyl) -3- [2- (3,4,5-trimethoxy-phenylamino) -pyrrolo [2,3-d] pyrimidin-7-yl] - benzamide (example 73) has an IC50 of . 38 nM for FAK. (ii). { 3- [2- (3,4,5-Trimethoxy-phenylamino) -pyrio [2,3-d] pyrimidin-7-yl] -phenyl} acetonitrile (example 104) has an IC50 of 29nM, 282nM, 342nM, 33nM, and 479nM for FLT3-ITD, FGFR3, JAK2, PDGFR-beta, and Tel-TRKC, respectively. 25 (iii). { 7- [3- (1-Methyl-1H-tetrazol-5-ylmethyl) -phenyl] -7H-pyrrolo [2,3- d] pyrimidin-2-yl] - (3,4,5-trimethoxy-phenyl) -amine (example 120) has an IC50 of 29 nM for BaF3 / PDGFR-beta. (iv) 3-. { 3- [2- (3,4,5-Trimethoxy-phenylamino) -pyrrolo [2,3-d] pyrimidin-7-yl] -phenyl} -propionitriio (example 85) has a 1C50 of 16mM for FLT3-ITD. (v) (7-Pyridin-2-yl-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-2-yl) - (3,4,5-trimethoxy-phenyl) -amine ( example 61) has an IC50 of 284mM for FGFR3. (vi) [7- (2-Chloro-pyridin-4-yl) -7H-pyrrolo [2,3-d] pyrmidin-2-yl] - (4-methoxy-2-methyl-phenyl) -amine (example 47) has IC50 of 408 nM for BCR-Abl. It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to those skilled in the art and should be included between the spirit and scope of this application and the scope of the invention. the attached claims. All publications, patents and patent applications citations are incorporated herein by reference for all purposes.

Claims (10)

1. A compound selected from Formula la, Ib, le, Id and le: wherein: n is selected from 0, 1 and 2; m is selected from 0, 1, 2 and 3; w is selected from -NR4 -, - S -, - 0 -, - S (O) - and -S (O) 2-; where R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; Ri is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms-alkyl from 0 to 4 carbon atoms and heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein any of arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyanoalkylalkyl Ri is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, aryl 6 to 10 carbon atoms, heteroaryl of 5 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, heterocycloalkyl of 3 to 8 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms carbon, alkyl of 1 to 6 carbon atoms halogen-substituted, alkoxy of 1 to 6 carbon atoms halogen-substituted, -XNR5R5, -XNR5XNR5R5, -XNR5XOR5, -XOR5, -XSR5, -XSR5, -XS (O) R5 , -XS (O) 2R5, -XC (O) NR5R5, -XOXR6 and -XC (O) R6; wherein X is a bond or alkylene of 1 to 6 carbon atoms; R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; and R6 is selected from heterocyclyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl from 1 to 6 carbon atoms and -C (O) OH; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent of Ri is further optionally substituted by 1 to 5 radicals independently selected from alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; R2 is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms, heteroaryl of 5 to 10 carbon atoms -alkyl of 0 to 4 carbon atoms, cycloalkyl of 3 to 12 carbon atoms-alkyl from 0 to 4 carbon atoms and heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein any of the arylalkyl, heteroarylalkyl, cycloalkylalkyl or Heterocycloalkylalkyl of R2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, alkyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms halogen-substituted, alkoxy of 1 to 6 carbon atoms halogen-substituted, heteroaryl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, -XNR5R5 , -XOR5, -XSR5, -XS (O) R5) -XSNR5R5, -XS (0) NR5R5, -XS (O) 2NR5R5, -XC (O) OR5, -XOC (0) R5, -XC (0) R5, -XC (O) NR5XNR5R5, -XC (O) NR5R5, -XC (0) NR5XC (O) OR5, -XC (O) NR5XNR5C (0) R5, -XC (O) NR5XNR5C (O) OR5, -XC (O) NR5XOR5, -XC (O) N (XOR5) 2, -XNR5C (O) R5, -XC (O) NR5R6, -XC (O) R6, -XR7, -XC (O) R7, -XR6 and -XC (0) NR5XR7, wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; R6 is selected from heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl of 1 to 6 carbon atoms and ~ C (O) OH; and R7 is selected from halogen and cyano; R3 is selected from halogen, hydroxy, -XSR5, -XS (O) R5, -XS (0) 2R5, -XC (0) R5, and -XC (0) OR5, wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 6 carbon atoms and cycloalkyl of 3 to 12 carbon-alkyl atoms of 0 to 4 carbon atoms; and the pharmaceutically acceptable salts and solvates, hydrates, solvates, isomers and prodrugs of said compounds.

2. The compound according to claim 1, wherein: W is selected from -NR4- and -O-; wherein R 4 is selected from hydrogen and alkyl of 1 to 6 carbon atoms; Ri is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein any arylalkyl and heteroarylalkyl of Ri is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, heteroaryl of 5 to 10 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 halogen-substituted carbon atoms, -XNR5R5, -XOR5, -XSR5, -XNR5XNR5R5, -XNR5XOR5, -XC (O) NR5R5, -XOXR6 and -XC (O) R6; wherein X is a bond with an alkylene of 1 to 6 carbon atoms; R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; and R6 is selected from heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl from 1 to 6 carbon atoms and -C (O) OH; wherein any heteroaryl substituent of R1 is further optionally substituted by 1 to 5 alkyl radicals of 1 to 6 carbon atoms; R2 is selected from aryl of 6 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms; wherein either arylalkyl or heteroarylalkyl of R2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 atoms of carbon, alkyl of 1 to 6 carbon atoms halogen-substituted, heteroaryl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms, -XNR5R5, -XOR5, -XSR5, -XS (O) 2NR5R5, - XC (O) OR5, -XOC (O) R5, -XC (O) NR5XNR5R5, -XC (O) NR5XC (O) OR5, -XC (O) NR5XNR5C (0) R5, -XC (O) NR5XNR5C (O) OR5, -XC (0) NR5XOR5, -XC ( 0) N (XOR5) 2, -XNR5 (0) R5, -XC (O) NR5R6, -XC (0) R6, -XR7, -XR6 and -XC (0) NR5XR7; wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms; R6 is selected from heterocycloalkyl of 3 to 8 carbon atoms-alkyl of 0 to 4 carbon atoms and heteroaryl of 5 to 10 carbon atoms-alkyl of 0 to 4 carbon atoms optionally substituted by 1 to 3 radicals selected from alkyl of 1 to 6 carbon atoms and -C (O) OH; and R7 is cyano; and R3 is selected from halogen, hydroxy, -XC (0) R5 and -XC (O) OR5; wherein X is a bond or alkylene of 1 to 6 carbon atoms; and R5 is selected from hydrogen, alkyl of 1 to 6 carbon atoms carbon and cycloalkyl of 3 to 12 carbon atoms-alkyl of 0 to 4 carbon atoms.

3. The compound according to claim 1, wherein W is selected from -NH- and -O-; and Ri is selected from phenyl, benzyl, 5,6,7,8-tetrahydro-naphthalenyl, benzo [1,3] dioxolyl, 1H-indazol-7-yl, indan-4-yl and H-indolyl; wherein any arylalkyl and heteroarylalkyl of Ri is optionally substituted by 1 to 3 radicals independently selected from methoxy, methyl, amino, halogen, hydroxymethyl, hydroxy, quinoxalinyl, ethyl, puridinyl, methoxy-phenyl, piperazinyl-carbonyl, ethyl- (2- hydroxyethyl) -amino 2- (4-methyl-piperazin-1-yl) -ethoxy, formamyl, isopropyl, methyl-sun-phenyl, tri-fluoro-methyl, ethoxy, 3-isopropylamino-propylamino, dimethylamino, morpholino, cyclopropyl-methoxy, butoxy, cycloheptyl-oxy and 1, 4,5,7-tetramethyl-pyrrole or [3,4-d] pyridazinyl.

4. The compound according to claim 1, wherein R2 is selected from pyridinyl, phenyl, thiazolyl, piperidyl-methyl, pyridinyl-ethyl, thiophenyl, benzyl, quinolinyl, 7-oxo-5,6,7. , 8-tetrahydido-naphthalenyl, naphthyl and pyrimidinyl; wherein any of the arylalkyl or heteroarylalkyl of R2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, methyl, propyl-sulfamoyl, methyl-sulphamoyl, methoxy, methyl-carboxy, 2-dimethylamino-ethyl-formamyl, carboxy, amino, cyano-ethyl, cyano-methyl, ethenyl, tri-fluoro-methyl, hydroxy-methyl, ethyl, methyl-sulfanyl, butyl, isobutyl, caraboxy-methyl-formamidyl, 1-carboxy-ethyl-formamidyl, carboxy- ethyl, amino-ethyl-formamidyl, amino-propyl- formamidyl, dimethyl-amino-ethyl-formamidyl, dimethyl-amino-propyl-formamidyl, dimethyl-amino-butyl-formamidyl, methyl-formamidyl, ethyl-formamidyl, ethyl-formamide-methyl, 2- (2-dimethylamino-ethylcarbamoyl) - ethyl, 2- (2-dimethylamino-formamidyl) -ethyl, 2- (amino-ethyl-formamidyl) -ethyl, 2- (amino-propyl-formamidyl) -ethyl, 2- (propyl-formamidyl) -ethyl, amino- propyl-formamidyl-methyl, 2- (methyl-amino-carbamoyl) -ethyl, 2- (ethyl-amino-carbamoyl) -ethyl, morph or I-inoy-I -formamidyl, morpholino-carbonyl-methyl, amino-ethyl- formamidil-methyl, cyclobutyl-formamidyl, met i I -formamidil-methyl, dimethyl-formamidyl-methyl, hydroxy-ethyl-formamidyl-methyl, hydroxy-propyl-formamidyl-methyl, N, N-bis- (3-hydroxy-propyl) ) -formamide, cyclopentyl-formamidyl, isobutyl-formamidyl, isobutyl-formamid-1-methyl, cyclopentyl-from-mid-I-methyl, cyano-ethyl-formamidyl, cyano-methyl-formamidyl, pyrro-lidinyl-ethyl-formamidyl, 2- (isobutyl-formamidyl) -ethyl, 1 H-tetrazolyl, 2- (1H-tetrazol-5-yl) -ethyl, 2- (1 H -tetrazol-5-ii) -methyl, 2- (1-methyl-1 H-tetrazol-5-yl) -methyl, acetyl-amino, cyclopropyl-formamidyl-methyl, hydroxy-ethyl-formamidyl, hydroxy-propyl-formamidyl , propyl-formamidyl-methyl, ethoxy-propyl-formamidyl, acetyl-amino-ethyl-formamidyl, 1-methyl-piperidin-4-yl-formamidyl, morpholino-carbonyl-ethyl, methoxy-carbonyl-methyl, methoxy-carbonyl-ethyl -formamide, methoxy-carbonyl-ethyl-formamidyl-methyl, methoxy-carbonyl-methyl-formamidyl-methyl, ethoxy-carbonyl-methyl-formamidyl, 4-amino-cyclohexyl-formamidyl, 4-amino-cyclohexyl-formamidyl-methyl, acetyl-amino, ethyl-formamidyl-methyl, ethoxy-propyl-formamidyl-methyl, methoxy-carbonyl-ethyl, 1-formyl-pyrrolidin-2-yl-carboxylic acid (1-carboxy-3-methyl-butyl) -formamidyl, 2- (methoxy-carbonyl-methyl-formamidyl) -ethyl, 1-carboxy- (2, 2-d-methylpropyl) -formamidyl, 3-tert-butoxycarbonyl-amino-propyl-formamidyl, acetoxy-methyl and 1-carboxy-ethyl-formamidyl.

5. The compound according to claim 1, wherein n is 0 or 1; m is 0 or 1; and R3 is selected from halogen, hydroxy, -C (O) OH and -C (O) OCH3.

6. The compound according to claim 1, which has the Formula Ig: ig wherein R2 is selected from pyridinyl, phenyl, thiazolyl, pyridinyl-methyl, puridinyl-ethyl, thiophenyl, benzyl, quinolinyl, 7-oxo-5,6,7,8-tetrahydro-naphthalenyl, naphthyl and pyrimidinyl; wherein any of the arylalkyl or heteroarylalkyl of R2 is optionally substituted by 1 to 3 radicals independently selected from halogen, nitro, cyano, methyl, propyl-sulfamoyl, methyl-sulphamoyl, methoxy, methyl-carboxy, 2-dimethylamine-ethyl-formamyl, carboxy, amino, cyano-ethyl, cyano-methyl, ethenyl, tri-fluoro-methyl, hydroxy-methyl, ethyl, methyl-sulfanyl, butyl, isobutyl, carboxy-methyl-formamidyl, 1-carboxy-ethyl-formamidyl, carboxy- ethyl, amino-ethyl-formamidyl, amino-pro pil -formamidyl, dimethyl-amino-ethyl-formamidyl, dimethyl-amino-pro-p-formamidyl, dimethyl-amino-butyl-formamidyl, methyl-formamidyl, ethyl-formamidyl, ethyl -formamide-methyl, 2- (2- dimethylamino-ethylcarbamoyl) -ethyl, 2- (2-dimethylamino-formamidyl) -ethyl, 2- (amino-ethyl-formamidyl) -ethyl, 2- (amino-propyl-formamidyl) -ethyl, 2- (propyl-formamidyl) -ethyl, amino-propyl-formamidyl-methyl, 2- (methyl-amino-carbamoyl) -ethyl, 2- (ethyl-amino-carbamoyl) -ethyl, morpholino-ethyl-formamidyl, morpholino-carbonyl-methyl, amino-ethyl -formamide-methyl, cyclobutyl-formamidyl, methyl-formamidyl-methyl, dimethyl-formamidyl-methyl, hydroxy-ethyl-formamidyl-methyl, hydroxy-propyl I-form-mid-I-methyl, N, N-bis- ( 3-hydroxy-propyl) -formamidyl, cyclopentyl-formamidyl, isobutyl-for-amidyl, isobutyl-formami-methyl-methyl, cyclopentyl-fromamidyl-methyl, cyano-ethyl-formamidyl, cyano-methyl-formamidyl, pyrrolidinyl-ethyl-formamidyl, - (isobutyl-formamidyl) -ethyl, IH-tetrazolyl, 2- (1 H-tetrazol-5-yl) -ethyl, 2- (1 H-tetrazol-5-yl) -methyl, 2- (1-methyl- 1 H-tetrazol-5-yl) -methyl, acetyl-amino, cyclopropyl-formamidyl-methyl, hydroxy-ethyl-formamidyl, hydroxy-propyl-formamyl, propyl-formamidyl-methyl, ethoxy-propyl-formamidyl, acetyl-amino-ethyl-formamidyl, 1-methyl-piperidin-4-yl-formamidyl, morpholino-carbonyl-ethyl, toxi-carbonyl-m ethyl, methoxy-carbonyl -ethyl-formamidyl, methoxy-carbonyl-ethyl-formamidyl-methyl, methoxy-carbonyl-methyl-formamidyl-methyl, methoxy-carbonyl-methyl-formamidyl, 4-amino-cyclohexyl-formamidyl, 4-amino-cyclohexyl-formamidyl-methyl , acetyl-amino-ethyl-formamidyl-methyl, ethoxy-propyl-formami-di-methyl, methoxy-carbonyl-ethyl, 1-formyl-pyrrolidin-2-yl-carboxylic acid, (1-carboxy-3-methyl-butyl) ) -formamide, 2- (methoxy-carbonyl-methyl-formamidyl) -ethyl, 1-carboxy (2,2-dimethyl-pro-pyl) -formamidyl, 3-tert-butoxycarbonyl-amino-propyl-formamidyl, acetoxy-methyl and 1 -carboxy-ethyl-formamidyl.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

8. A method for treating a disease in an animal, wherein the inhibition of kinase activity can prevent, inhibit or mitigate the pathology and / or symptomatology of the disease, said method comprises administering to the animal a therapeutically effective amount of a The compound according to claim 7, wherein the kinase is selected from FAK, Abl, BCR-Abl, PDGF-R, c-Kit, NPM-ALK, Flt-3, JAK2 and c-Met. The use of a compound according to claim 1, in the manufacture of a medicament for treating a disease in an animal, wherein the kinase activity of FAK, Abl, BCR-Abl, PDGF-R, c-Kit , NPM-ALK, Flt-3, JAK2 and / or c-Met contributes to the pathology and / or symptomatology of the disease.