MX2008007357A - Pyrazolo[1,5-a]pyridine-3-carboxylic acids as ephb and vegfr2 kinase inhibitors - Google Patents

Abstract

The invention relates to novel pyrazolo[1,5-a]pyridine-3-carboxylic acid compounds of the Formula (I) in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.

Description

PIRAZOLO-p, 5-al-PYRIDIN-3-CARBOXYLIC ACIDS AS INHIBITORS PE KINASE EphB and VEGFR2 The invention relates to pyrazolo- [1,5-a] -p? R? D? N-3-carboxylic acid compounds, when used for the treatment of diseases that respond to protein kinase modulation, or in the manufacture of pharmaceutical preparations useful in the treatment of these diseases, to pharmaceutical preparations, especially useful against said diseases, comprising said compounds and a pharmaceutically acceptable carrier, to these compounds for use in the treatment of the animal or human body. , especially against the mentioned diseases, to methods of treatment of the animal or human body comprising administering these compounds to an animal or a human being, and to processes for the manufacture of said compounds, wherein, in each case where the compounds, can be present as such and / or in the form of salts (preferably pharmaceutically acceptable) By the term "protein kinases", a class of enzymatically active roteins, it is defined where the receptor type kinases and the non-receptor type kinases can be distinguished, as well as the tyrosine and septa / threonine kinases. With respect to its location, one can distinguish nuclear, cytoplasmic, and membrane-associated kinases. Many membrane-associated tyrosine kinases are at the same time receptors for growth factors With respect to their catalytic activity, protein kinases (PKs) are enzymes that catalyze the phosphorylation of specific residues of septa, threonine, or tyrosine in cellular proteins This post-translational modification of substrate proteins normally it functions as a molecular change, which represents a step in the regulation of cell proliferation, activation, and / or differentiation. Abnormal or excessive protein kinase activity has been observed, or more generally appropriate, in various disease states, including benign and malignant proliferative disorders In many cases, it has been possible to treat in vitro diseases, and in many cases in vivo, such as the prophylactic disorders, making use of protein kinase inhibitors. Over the past years, the basic roles have been understood for the tyrosome kinases that receive Eph and its ligands, the Efpnas Various rec Different Eph epitheres are cataloged and grouped in the EphA and EphB subclasses, based on their affinity for the ligands. We identified at least 8 Efpnas that are membrane proteins, either of the type bound with zero-phosphatidyl-inositol (GPI) (EfpnaA) or of transmembrane type (EfpnaB). The signaling between the Eph receptors and their gandos seems to be restricted to direct cell-cell contact sites The result of contact is the induction of reciprocal bidirectional events between cells.

The expression of Efpnas and its receptors in certain locations has an impact on the tissue pattern and the organization of the spatially very restricted cellular locals. Specific effects include the modification of cell migration, adhesion, and the formation of somites. EphB4 (also referred to as HTK), and its ligand, Efr? NaB2 (HTKL), have important roles in the establishment and determination of vascular networks. On the venous epithelium, EphB4 is expressed in a specific manner, while, during early stages of vascular development, Efr? naB2 is expressed in a specific and reciprocal manner on arterial endothelial cells. Dysfunctional genes lead to embryonic lethality in mice, and embryos show identical defects in the formation of capillary connections in the case of any defect in Efr? naB2 and in EphB4 Both are expressed in the first site of the hematopoiesis and in the Vascular development during embogenesis An essential role for hematopoietic development has been established, endothelial, hemangioblast, and appropriate primitive mesoderm EphB4 deficiency results in an alteration in mesodermal differentiation of embryonic totipotent cells Ectopic expression of EphB4 in breast tissue results in disordered architecture, abnormal tissue function , and a predisposition to malignancy (see, for example, N Munapni et al., J Cell Sci 115, 25-37 (2002)) From these and other data, concluded that inadequate expression of EphB4 may be involved in the formation of malignancies, and therefore, that inhibition of EphB4 can be expected to be a tool for combating malignancies, eg cancer and the like The constitutively expressed viral form c- Src (from the Rous Sarcoma Virus, a retrovirus) of the tyrosome kinase c-Src that is found in cells, is an example of the way in which inadequate expression of the Src tyrosine protein kinase can lead to malignancies based on transformed cells Inhibition of tyrosine protein kinase Src can lead to inhibition of poorly regulated growth of transformed tumor cells, for example, in connective tissue tumors. Accordingly, it is also expected here that the inhibition of c-Src or the modified or mutated forms thereof, shows a beneficial effect in the treatment of proliferative diseases. It is known that VEGFRs (vascular endothelial growth factor receptors) are involved in the control of the establishment of angiogenesis Because especially solid tumors depend on a good blood supply, the inhibition of vascular endothelial growth factor receptors, and therefore of angiogenesis, is under clinical investigation in the treatment of these tumors, showing promising results Vascular endothelial growth factor is also an important participant in leukemias and lymphomas, and it is highly expressed in a variety of solid malignancies, correlating well with the progress of malignant disease Examples of tumor diseases with VEGFR-2 (KDR) expression are lung carcinomas, breast carcinomas, non-Hodgkm's lymphomas, carcinoma Ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma In addition to its angiogenic activity, the VEGFR ligand, VEGF, can promote tumor growth through direct pro-survival effects on tumor cells. Other different diseases are associated with a poorly regulated angiogenesis, for example as mentioned below The conversion of the abl proto-oncogene to an oncogene has been observed in patients with chronic myelogenous leukemia (CML) A chromosomal translocation binds the bcr gene on chromosome 22 with the abl gene of the chromosome 9, thus generating a Philadelphia chromosome The resulting fusion protein has the amino terminus of the Bcr protein bound to the carboxyl terminus of the tyrosine Abl protein kinase Accordingly, the Abl kinase domain becomes inappropriately active, promoting excessive proliferation of a hematopoietic cell clone in the bone marrow Inhibition of this tyrosine kinase by the active ingredient of Gleevec ™ or Glivec ® (registered trademarks of Novartis), an inhibitor of this fusion protein, has proven to be a highly active treatment against chronic myelogenous leukemia. Therefore, the concept could be verified In general, the inadequate expression of Abl tyrosine kinase can remedy malignancies, especially leukemias. However, many compounds used as inhibitors of protein kinases have so far shown a lack of specificity, unwanted side effects that can be caused, between other things, by inconvenient inhibitory properties against more than one type of protein kinases, a lack of efficiency due to too high a specificity, efficiency only against certain diseases, development of resistance during administration, and / or comparable undesirable properties. This leads to problem of the present invention, in view, inter alia, of the large number of protein kinase inhibitors, and of the multitude of proliferative diseases and other diseases related to protein kinase, as well as in view of the development of resistance against certain therapeutic products, there is an ever-existing need to provide new classes of compounds that are useful as protein kinase inhibitors, and therefore, in the treatment of these tyrosine protein kinase related diseases, such as the septa / threonine protein kinase. , and / or preferably PTK (protein tyrosine kinase). What is required are new classes of pharmaceutically convenient protein kinase inhibitor compounds, especially inhibitors of tyrosine protein kinase, especially with suitable properties, such as a high affinity and / or selectivity for the limited groups of activity of the unique protein kinases, also where resistance has been developed against different classes of compounds, a useful affinity profile against certain groups of kinases, or the like In other words, there is a need for novel classes of protein kinase inhibitors that may allow to meet the above-mentioned and other problems. Certain 4-substituted hydrazono-pyrazolo-pipmidines have been described for use as GSK3 kinase inhibitors in the treatment of, for example, diabetes and diseases related to the TIE-2 kinase, see International PublicatiNos. WO 04/009602, WO 04/009596 or WO 04/009597 On the other hand, certain acyl- or acyl-amino-substituted apl-amino-pyrazolo-pipmidines are have been described as p38 inhibitors, see International Publication Number WO 03/099280 General Description of the Invention It has now been found, in a manner surprisingly, that a number of protein kinases may be involved in the transmission of signals mediated by trophic factors, and in the manifestation of diseases involving the activity of protein kinases, for example in pro-growth (eg, tumor growth). ), especially as representative examples for tyrosine protein kinase kinases of the src kinase family, especially c-src kinase, endotehal vascular growth factor receptor kinase (e.g., KDR and Flt-1), kinase receptor of RET and / or receptor cells of Efpna, for example EphB2 kinase, EphB4 kinase or related kinases, also abl kinase, especially v-abl or c-abl kinase, b-raf (V599E), growth factor receptor kinases epidermal or other kinases of the epidermal growth receptor family, for example HER-1 or the c-erbB2 kinase (HER-2), Flt-3, Ick, fyn, c-erbB3 kinase, c-erbB4 kinase, the members of the family of the tyrosome protein kinases receptors for the platelet-derived growth factor, for example the platelet-derived growth factor receptor kinase, the receptor kinase CSF-1, the receptor kinase Kit (c-Kit), the kinase receptor for FGF, for example FGF-R1, FGF-R2, FGF-R3, FGF-R4, c-Raf, casein kinases (CK-1, CK-2, G-CK), Pak, ALK, ZAP70, Jak1 , Jak2, Axl, Cdk1, cdk4, cdk5, Met, FAK, Pyk2, Syk, Tie-2, insulin receptor kinase (Ins-R), the insulin-like growth factor receptor kinase (IGF-1 kinase), and / or other kinases d Sepna / threonine, for example C protein kinase (PKC), PK-B, EK-B, or cdc kinases, such as CDK1, can be inhibited by a p? razolo acid compound [1-5]. a] -p? r? d? n-3-carboxyl? co according to the invention, as well as mutated (eg, citutively activated) forms of any one or more thereof (eg, Bcr-Abl, RET / MEN2A, RET / MEN2B, RET / PCT1-9 or b-raf (V599E)) All these and other protein kinases have a part in the regulation of growth and transformation in mammalian cells, including human cells. you can find a high efficiency against cellular kinase Eph4B In view of these activities, the compounds of the invention can be used for the treatment of diseases respve to protein kinase modulation, such as diseases related to a particularly aberrant activity (eg, unregulated, poorly regulated , or citutive, or similar) or excessive of these types of kinases, especially those mentioned, and very especially those mentioned as preferred Detailed Description of the Invention The invention, in a first embodiment, refers to a compound of the formula wherein R1 is hydrogen, halogen, sulfamoyl, N-alkyl of 1 to 4 carbon atoms-sulfamoyl, N, Nd? -alkyl of 1 to 4 carbon atoms-sulfamoyl, unsubstituted or substituted alkyl, unsubstituted or substituted aplo , unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, each of R2 and R3 is, independently of the other, hydrogen, halogen, alkyl of 1 to 4 carbon atoms, methyl, alkoxy of 1 to 4 carbon atoms, or cyano, Xi. 2, X3 and 4 are CH, or up to two of them can be N, D is N (R6) (preferred), O or S, wherein R6 is hydrogen, acyl or unsubstituted or substituted alkyl, Y, is O, S, NH, CH2, N = CH, CH = N or CH = CH, Y2 is C or, if Ra is absent, it can be (also) N, Ra is absent if Y2 is N and R1 is unsubstituted alkyl with 5 or more carbon atoms, substituted alkyl, unsubstituted or substituted aplo, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, or, if Y2 is C, is hydrogen if R1 is unsubstituted alkyl with 5 or more carbon atoms, substituted alkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, or, if Y2 is C and R1 is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, sulfamoyl, N-alkyl of 1 to 4 carbon atoms-sulfamoyl, N, Nd? -alkyl of 1 to 4 carbon atoms- Sulfamoyl, or unsubstituted aplo, is a fraction of formula IA.

(IA), wherein the dotted line means the bond linking the rest of the molecule of formula I (which is indicated by the wavy line), A is C (= 0) -N (R4) or N (R4) -C ( = 0), where R4 is hydrogen or unsubstituted or substituted alkyl, Z, is O, S, NH, CH2, CH = N, N = CH or CH = CH, Z2 is nitrogen or CH, Z3 is CH or N, each R 5 present is, independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form. The invention, in a further embodiment, refers to a compound of the formula I, wherein R 1 is hydrogen, halogen, sulfamoyl, N-alkyl of 1 to 4 carbon atoms-sulfamoyl, N, Nd? -alkyl of 1 to 4 carbon atoms-sulfamoyl, unsubstituted or substituted alkyl, unsubstituted or substituted aplo, or heterocyclic unsubstituted or substituted, each of R2 and R3 is, independently of the other, hydrogen or alkyl of 1 to 4 carbon atoms, X X2I X3 and X4 are CH, D is N (R6) (preferred), O or S, in where R6 is hydróg eno, acyl or unsubstituted or substituted alkyl, Y, is O, S, NH, CH2, N = CH, CH = N or CH = CH, Y2 is C, Ra is hydrogen if R1 is unsubstituted alkyl with 5 or more carbon atoms, substituted alkyl, unsubstituted or substituted alkyl , unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, or, if R 1 is hydrogen, halogen, alkyl of 1 to 4 carbon atoms, sulfamoyl, N-alkyl of 1 to 4 carbon atoms-sulfamoyl, N, Nd? Alkyl of 1 to 4 carbon atoms-sulphamoyl, substituted or unsubstituted, is the fraction of formula IA, A is C (= 0) -N (R4) or N (R4) -C (= 0), wherein R 4 is hydrogen or unsubstituted or substituted alkyl, Z is O, S, NH, CH 2, CH = N, N = CH or CH = CH, Z 2 is nitrogen or CH, Z 3 is CH or N, each R 5 present is, independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form The invention, in a further embodiment, refers to a compound of formula I, wherein R 1 is hydrogen, N, Nd? -alot? 1 to 4 carbon atoms o-sulfamoyl, unsubstituted or substituted aplo, each of R2 and R3 is, independently of the other, hydrogen or alkyl of 1 to 4 carbon atoms, Xi. 2- 3 and X4 are CH, or up to two of them can be N; D is N (R6) (preferred), O or S, wherein R6 is hydrogen, acyl or unsubstituted or substituted alkyl, Y, is O, S, NH, CH2, N = CH, CH = N or CH = CH, Y2 is C, Ra is -hydrogen if R1 is unsubstituted alkyl with 5 or more carbon atoms, substituted alkyl, unsubstituted or substituted aplo, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclic, or, if R1 is hydrogen, N, Nd? -allo? 1 to 4 carbon atoms-sulphamoyl, or unsubstituted or substituted aplo, is the fraction of formula IA, A is C (= O) -N (R4) or N (R4) -C ( = 0), where R4 is hydrogen or unsubstituted or substituted alkyl, Z, is O, S, NH, CH2, CH = N, N = CH or CH = CH, Z2 is nitrogen or CH, Z3 is CH or N, each R5 present is, independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form The invention, in a further embodiment, refers to a compound of the formula I, wherein R 1 is hydrogen, N, Nd? -alkyl of 1 to 4 carbon atoms-sulphamoyl, unsubstituted or substituted phenyl, each of R2 and R3 is, independently of the other, hydrogen or alkyl of 1 to 4 carbon atoms, Xi, X2, X3 and X4 are CH, or up to two of them may be N, D is N (R6) (preferred), O or S, wherein R6 is hydrogen, acyl or unsubstituted or substituted alkyl, YT is O, S, NH, CH2, N-CH, CH = N or CH = CH, Y2 is C; Ra is -hydrogen, if R1 is unsubstituted or substituted phenyl, or, if R1 is hydrogen, N, Nd? -alkyl of 1 to 4 carbon atoms-sulphamoyl, or unsubstituted phenyl, is the fraction of formula IA, A is C (= O) -N (R4) or N (R4) -C (= O), wherein R4 is hydrogen or unsubstituted or substituted alkyl, Z is O, S, NH, CH2, CH = N, N = CH or CH = CH, Z2 is nitrogen or CH, Z3 is CH or N, each R5 present is, independently of the others, a substitute me, and n is 0, 1 or 2, in free form or in salt form The invention, in a further embodiment, refers to a compound of formula I, wherein R 1 is hydrogen, N, Nd? - alkyl of 1 to 4 carbon atoms-sulphamoyl, unsubstituted or substituted phenyl, each of R2 and R3 is, independently of the other, hydrogen or alkyl of 1 to 4 carbon atoms, D is NH, Y, is CH = CH, Y2 is C, Ra is -hydrogen, if R1 is substituted phenyl, or, if R1 is hydrogen, N, Nd? -alkyl of 1 to 4 carbon atoms-sulphamoyl , or unsubstituted phenyl, is the fraction of formula IA, A is C (= 0) -N (R4) or N (R4) -C (= 0), wherein R4 is hydrogen or unsubstituted or substituted alkyl, Z, is O, S, NH, CH2, CH = N, N = CH or CH = CH, Z2 is nitrogen or CH, Z3 is CH or N, each R5 present is independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form The invention, in a further embodiment, refers to a compound of formula I, wherein R 1 is hydrogen, N, Nd? - alkyl of 1 to 4 carbon atoms-sulfamoyl, unsubstituted or substituted phenyl, each of R2 and R3 is, independently of the other, hydrogen or alkyl of 1 to 4 carbon atoms, D is NH, Y, is CH = CH, Y2 is C, Ra is -hydrogen, if R1 is substituted phenyl, or, if R1 is hydrogen, N, Nd? -alkyl of 1 to 4 carbon atoms-sulphamoyl , or unsubstituted phenyl, is the fraction of formula IA, A is C (= 0) -NH or NH-C (= 0), Z, is CH = CH, Z2 is CH, Z3 is CH, each R5 present is , independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form The invention, in a further embodiment, refers to a compound of formula I, wherein R 1 is hydrogen, or substituted phenyl, each of R 2 and R 3 is, independently of the other, hydrogen or alkyl of 1 to 4 carbon atoms, X ,, X2, X3 and X4 are CH, D is NH, Y, is CH = CH, Y2 is C; Ra is hydrogen, if R1 is substituted phenyl, or, if R1 is hydrogen, or unsubstituted phenyl, is the fraction of formula IA, A is C (= 0) -NH or NH-C (-O), Z, is CH = CH, Z2 is CH, Z3 is CH, each R5 present is, independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form. The invention relates to the use of a compound of the Formula I, or a pharmaceutically acceptable salt thereof, for the treatment of diseases responsive to the modulation of Protein kinase, especially in an animal, or preferably in a human, especially a disease that responds to the inhibition of one or more tyrosine protein kinases (PTKs) mentioned under the "General Description of the Invention", more especially one or more protein tyrosome kinases selected from the family of src kinases, especially c-src kinase, endotehal vascular growth factor receptor kinase (e.g., KDR and Flt-1), RET receptor kinase or receptor kinases of Efpna, for example EphB2 kinase, EphB4 kinase or related kinases, or the mutated forms (for example, constitutively active or otherwise partially or totally poorly regulated) thereof. The invention also relates to the use of a compound of the Formula I, or a salt (preferably pharmaceutically acceptable) thereof, in the manufacture of pharmaceutical preparations useful in the treatment of the above-mentioned diseases, pharmaceutical preparations especially useful against said diseases , which comprise a compound of the Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, to a compound of the Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of the animal body. or human, especially against a disease mentioned in the preceding paragraph, to a method of treatment of the animal or human body comprising administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, to an animal or a human being, especially to a patient in need of such treatment, in an effective amount for the treatment of the aforementioned disease, and to a process for the manufacture of a compound of Formula I , or a salt (preferably pharmaceutically acceptable) thereof In Formula I, the following meanings are preferred in an independent, collective manner, or in any combination or sub-combination thereof. The general terms or symbols previously used herein and hereinafter, preferably, within the context of this disclosure, the following meanings, unless otherwise indicated The term "lower" or "from 1 to 7 carbon atoms", defines a fraction with up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, with this fraction of branched chain (one or more times) or ca dena straight. Lower alkyl or from 1 to 7 carbon atoms, for example, is normal pentyl, normal hexyl, or normal heptyl, or preferably alkyl of 1 to 4 carbon atoms, especially as methyl, ethyl, normal propyl, secondary propyl, normal butyl, isobutyl, secondary butyl, tertiary butyl In the case of lower alkenyl or lower alkynyl, lower preferably means "from 2 to 7 carbon atoms", and more preferably "from 2 to 4 carbon atoms" Halo or halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine, chlorine, or bromine, and still very preferably fluorine or chlorine Unsubstituted or substituted alkyl is preferably alkyl of 1 to 20 carbon atoms, more preferably lower alkyl, for example methyl, ethyl, or propyl, which may be linear or branched one or more times (provided that the number of carbon atoms permits), and which is unsubstituted or substituted by one or more, preferably up to three substituents independently selected from the group which consists of unsubstituted or substituted heterocyclyl as described below, especially pyrro dmo, pipepdino, pipepdino substituted by amino or by N-mono- or N, Nd? - [lower alkyl, phenyl, and / or phenyl-alkyl ? nfer? or] -am? no, unsubstituted or unsubstituted pipepdynyl substituted by N-lower alkyl bonded via a ring carbon atom, such as 1-? soprop? lp? per? d? n? 4-? lo, piperazino, alkyl-piperazmo alkyl, such as 4-methyl, ethyl, o? so prop?) -p? peraz? no, morfolmo, or thiomorpholino, unsubstituted or substituted cycloalkyl as described below, unsubstituted or substituted aplo as defined below, especially phenyl or naphthyl; lower alkenyl, lower alkyl, halogen, hydroxyl, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, phenoxy, naphthyloxy, phenyl- or naphthyl lower alkoxy, such as benzyloxy; amino-lower alkoxy, lower alkanoyloxy, benzoyloxy, naphthyloxy, nitro, cyano, cyano, carboxyl, carboxylic alkoxy, for example methoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, or terbutoxycarbonyl, phenyl- or naphthyl-alkoxy-methylcarbonyl, such as benzyloxycarbonyl, lower alkanoyl, such as acetyl, benzoyl, naphthoyl, carbamoyl, carbamoyl N-mono- or N, Nd? -sust? tu? do, such as carbamoyl N-mono-or N, Nd? -sust? tu? do, wherein the substituents are selected from lower alkyl and hydroxy-lower alkyl, amidino, guanidino, ureido, mercapto, lower thioalkyl, thiophenyl or thionaphthyl , phenyl- or napht-11-lower alkyl, lower alkylphenol alkyl, lower alkylphenol, lower alkylphenol, lower alkylphenol, phenyl- or naphthyl-sulfonyl, phenyl- Naphthyl-alkyl-sulfyl-alkyl, alkyl-phenyl-sulfyl-alkyl, alkyl-naphthyl-sulfinyl-alkyl, sulfo, m-sulphonyl-alkane, phenyl- or naphthyl-1-sulphonyl, phenyl- or naphthyl-1-alkyl? infepor-sulfonyl, alkyl phenyl sulfonyl, haloalkyl sulfone alkyl, such as tpfluoro-methanesulfonyl, sulfinamido, benzo-sulfonamido, amino, N-mono- or N, Nd? - [lower alkyl, phenyl, and / or phenyl-alkyl? nfer? or] -am? no, such as N, Nd? met? l-amino, N, Nd? et? l-am? no, 3- [N- (N, Nd? met? l-am? no) -prop? l-am? no, 2- [N- (N, Nd? met? l-am? no) -et? l-am? no, or N- (N, Nd? metal-amine) -met? l-am? no, wherein each phenyl or naphthyl (also in phenoxy or naphthoxy) mentioned above as a substituent or as part of a substituted alkyl substituent, is itself unsubstituted or substituted by one or more, for example up to 3, preferably 1 or 2 substituents independently selected from halogen, especially fluorine, chlorine, bromine, or iodine, halo-lower alkyl, such as t-fluoro-methyl, hydroxyl, lower alkoxy , amino, N-mono- or N, Nd? - (lower alkyl, phenyl, naphthyl, phenyl-lower alkyl, and / or naphthyl-lower alkyl) -amino, nitro, carboxyl, lower carbonylcarbamoyl, cyano, and / or sulfamoyl alkoxy. As R 1 in Formula I, lower alkyl, hydroxy-alkyl are especially preferred. from 1 to 4 carbon atoms, amino-lower alkyl, such as 3-aminophenol, 2-amino-ethylene, or 2-amino-methyl, N-mono- or N, Nd? - (lower alkyl, phenyl and / or phenyl-lower alkyl) -am? no-lower alkyl, such as 3- (N, Nd? met? l-am? no) ) -prop? lo, 3- (N, Nd? et? l-am? no) -prop? lo, 2- (N, Nd? met? l-am? no) -et? lo, 2- (N , Nd? Et? L-am? No) -et? Lo, N, Nd? Met? L-am? No-methyl, or N, Nd? Et? L-am? No-met? Lo, pirro dmo- lower alkyl, pipepdino-lower alkyl, 1 -alk? lp? per? d? n-4-? -alkyl lower, 4- [N-mono- or N, Nd? - (lower alkyl, phenyl , and / or of enyl-alkidyl ester) -am? no] -p? per? d? no, piperazine-lower alkyl, such as piperazine-methyl, 4-alkyl-piperazine-lower alkyl, such as - (methyl, ethyl, or? soprop? lo) -p? peraz? no-met? lo, or (morfolmo ot? omorfol? no) -alqu? lo inferior Alquilo c On 5 or more carbon atoms is in particular alkyl of 5 to 20 carbon atoms Preferably, as then the link to the conformation of the inactive enzyme is found, preferably RI is alkyl of 1 to 4 carbon atoms, or especially hydrogen, while then Y2 is C, and Ra in the formula I is a fraction of the formula IA shown above. Unsubstituted or substituted substituted is preferably an unsaturated carbocyclic system of not more than 20 carbon atoms, especially not more than 16 carbon atoms, and is preferably mono-, di-, or t-cyclic, which is unsubstituted, or, in the case of aplo substituted, is preferably substituted by one or more, preferably up to three, for example one or two substituents independently selected from the group consisting of phenyl, naphthyl, phenyl- or naphthyl-lower alkyl, such as benzyl, hydroxy-lower alkyl , such as hydroxy-methyl, lower alkoxy-lower alkyl, (lower alkoxy) -alkoxy-lower-lower alkyl, lower alkanoyl-lower alkyl, halo-lower alkyl, such as trifluoro-methyl, phenoxy- or naphthyloxy lower alkyl, faith or I- or lower-lower alkoxy-naphthyl-alkoxy, such as benzyloxy-lower alkyl, lower-carbonyloxy-lower alkyl-alkoxy, such as terbutoxy-carbonyloxy-lower alkyl, phenyl- or naphthyl-lower alkoxy-carbonyloxy lower alkyl, such as benzyloxycarbonyloxy-lower alkyl, cyano-lower alkyl, lower alkenyl, lower alkyl, lower alkanoyl, such as acetyl, halogen, hydroxyl, lower alkoxy, such as methoxy, alkoxy or-lower alkoxy, (lower alkoxy) -alcoxy, lower-lower alkoxy, phenoxy, naphthyloxy, phenyl- or naphthyl-lower alkoxy, such as benzyloxy, amino-lower alkoxy, lower alkanoyloxy, benzoyloxy, naphthyloxy, nitro , amino, mono-, di-, or tp-substituted amino (in the latter case, quaternary and positively charged), wherein the amino substituents are independently selected from lower alkyl, lower alkanoyl, lower sulfonyl alkane, such as methanesulfonyl, phenyl, naphthyl, phenyl-lower alkyl and naphthyl-lower alkyl, cyano, carboxyl, lower-carbonyl-alkoxy, for example methoxy-carbonyl, n-propoxy-carbonyl, isopropoxy-carbonyl, or terbutoxy-carbonyl, phenyl - or naphthyl-alkoxy mfeporcarbonyl, such as benzyloxycarbonyl, benzoyl, naphthoyl, carbamoyl, carbamoyl N-mono- or N, Nd? -sust? tu? do, such as carbamoyl N-mono- or N, Nd? -sust? tu? wherein the substituents are selected from lower alkyl and hydroxy-lower alkyl; amidino, guanidino, ureido, mercapto, lower thioalkyl, thiophenyl or thionaphthyl, phenyl- or naphthi 1-t-lower alkoyl, alkyl-thiophenyl alkyl, alkyl-thionaphthyl alkyl, halo-alkyl-mercapto-alkyl, alkyl-sulphonyl, phenyl - or naphthi 1-sulfonyl, phenyl- or naphtyl-alkylsulpho-sulphyl, alkyl-phenyl-sulfinyl, alkyl-naphthyl-sulfyl, sulfo, mfepor-sulphonyl alkane, phenyl- or naphthyl-sulfonyl, phenyl- or naphthyl-mfepor-sulfonyl-alkyl, mfepor-phenyl-sulfonyl-alkyl, halo-mfepor-sulfonyl-alkyl, such as trifluoro-methanesulfonyl, sulfonamido , benzo-sulfonamido, pyrro dmo, pipepdino, pipepdmo substituted by amino or by N- mono- or N, Nd? - [lower alkyl, phenyl, and / or phenyl-alkyl? nfer? or] -am? no, unsubstituted or unsubstituted p-pyridyl substituted by N-lower alkyl bonded via a ring carbon atom, such as 1-β-soprop-lp ?, per-d-4-yl, piperazino, lower-piperazino alkyl, such as - (meth, ethyl, or? soprop? l) -p? peraz? no, morpholino or thiomorph not; wherein each phenyl or naphthyl (also in phenoxy or naphthoxy) mentioned above as a substituent or as part of a substituent of substituted aplo is itself unsubstituted or substituted by one or more, for example up to 3, preferably 1 or 2 substituents independently selected from halogen, especially fluorine, chlorine, bromine, or iodine, halo-lower alkyl, such as trifluoro-methyl, hydroxyl, lower alkoxy, amino, N-mono- or N, Nd? - (lower alkyl, phenyl, naphthyl, phenyl-lower alkyl, and / or naphthyl-lower alkyl) -amino, nitro, carboxyl, lower-carbonyl-alkoxy Carbamoyl, cyano, and / or sulfolayl substituted or substituted A, especially as R 1 in Formula I, is preferably phenyl which is unsubstituted or substituted by halogen, more preferably by lower alkoxy, nitro, amino, alkanoyl, amino-amino, N -amino-sulfonyl-amino alkane, such as methanesulfonyl-amino, N-mono-, N, Nd? - or N, N, N-tr? - (lower alkyl, phenyl, and / or phenyl-alkyl) ? nfer? or) -am? no (corresponding the latter to a quaternary amino = quaternary ammonium), pyrrolidino, pipepdmo, pipepdmo substituted by amino or N-mono- or N, Nd? - [lower alkyl, phenyl, and / or phenyl-alkyl? nfer? or] -am? no, unsubstituted or unsubstituted pipepdynyl substituted by N-lower alkyl bonded via a ring carbon atom, such as 1-? soprop? lp? per? d? n- 4-? Lo, piperazino, alkyl-piperazino alkyl, such as 4- (meth? ethyl, or? soprop? l) -p? peraz? no, alkoxyl of 1 to 7 carbon atoms-carbonyl-piperazmo, for example terbutyloxy-carbonyl-piperazino, cycloalkoxy-carbonyl-piperazmo, aploxy-carbonyl-piperazino, morpholmo, or thiomorph not. Preferably, the aplo is phenyl. Preferably, the substituted aplo, for example, substituted phenyl, is substituted by one or two of the following alkoxy substituents of 1 to 7 carbon atoms, for example, alkoxy of 1 to 4 carbon atoms, morpholmo, N, Nd? -alchemy of 1 to 7 carbon-ammonium atoms, for example, N, Nd? -alkyl of 1 to 4 carbon-amino atoms, alkoxy of 1 to 7 carbon atoms- carbonyl-piperazmo, for example, terbutyloxy-carbonyl-piperazino, cycloalkoxy-carbonyl-piperazmo, aploxy-carbonyl-piperazino. In unsubstituted or substituted cycloalkyl, cycloalkyl is preferably a mono- or bi-cyclic hydrocarbon group saturated with 3 to 16, more preferably 3 to 9 ring carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo-octyl, and is substituted by one or more, preferably one to three, substituents independently selected from those described for substituted aplo or is (preferably) unsubstituted Heterocycun the unsubstituted or substituted is preferably a heterocyclic radical that is unsaturated , saturated, or partially saturated, and preferably is a monocyclic ring, or in a broader aspect of the invention, bicyclic or ticcic, and has from 3 to 24, more preferably from 4 to 16, and in a very preferably from 4 to 10 ring atoms; wherein one or more, preferably from 1 to 4, especially 1 or 2 ring atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, preferably having the ring-linkage at 12, in particular from 5 to 7 ring atoms, whose heterocyclic radical (heterocyclic) is unsubstituted or substituted by one or more, in particular by 1 to 3 substituents independently selected from the group consisting of the substituents defined above under " substituted alkyl ", and wherein the heterocyclyl is in particular a heterocyclic radical selected from from the group consisting of oxiranyl, aziphenyl, azepdmyl, 1,2-oxathiolanyl, thienyl, f-uryl, tetrahydrofuplo, pyranyl, thiopyranyl, thian-laryl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolmyl. , pyrrolidinyl, imidazolyl, imidazolidyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazoyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazole, piphodil, pyrazilyl, pipmidinyl, pipepdyl, piperazyl, pipdazinyl, morpholyl, thiomorpholinyl, (S-oxo or S, Sd) oxo) -t? omorfol? n, indohzmilo, isoindolyl, 3H-? ndol? lo, indo lo, benzimidazolilo, cumaplo, indazolilo, tpazo lo, tetrazo lo, pupnilo, 4H-qu? nol? z? n? lo, isoqumohlo, quinolyl, tetrahydrochlo lo, tetrahydroisoquinolyl, decahydroquinone, octahydroisoquin, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazmyl, naphthymidinyl, qumoxane, quinazolyl, cinolinyl, ptepd myo, carbazole, beta-carbo nyl, fenantpdinyl, acpdmilo, pepmidinyl, fenantrolmilo, furazanil, fenazmilo, fenotiazmilo, fenoxazinilo, cromenilo , isochromanyl, and chromanyl, each of these radicals being unsubstituted or substituted by 1 to 2 radicals selected from the group consisting of lower alkyl, especially methyl or tertbutyl, lower alkoxy, especially methoxy, and halogen, especially bromine or chlorine Xi, X2, X3 and X4 are preferably all CH Acyl is preferably an organic fraction selected from unsubstituted or substituted alkyl, unsubstituted or substituted aplo, unsubstituted or substituted heterocyclic, or unsubstituted or substituted cycloalkyl, each of preference as described previously, linked by means of a carbonyl group (-C (= 0) -) or sulfonyl (-S (= 0) 2-) to the rest of the molecule of the formula I, that is, a fraction derived from a organic carboxy or sulfonic acid Alkanoyl, especially lower alkanoyl, for example, acetyl, propionyl or butyroyl, benzoyl (= phenylcarbonyl), naphthyl (naphthylcarbonyl), phenyl-alkyl of 1 to 7 carbon atoms are preferred. -carbonyl, naphthyl-alkoxy of 1 to 7 carbon atoms, phenyl-sulfonyl, or mfepor-sulfonyl alkane, wherein each lower alkanoyl as acyl or each phenyl or naphthyl mentioned as part of acyl is unsubstituted or substituted by one or more, for example, up to three, preferably 1 or 2 substituents independently selected from halogen, especially fluorine, chlorine, bromine or iodine, halo-lower alkyl, such as trifluoro-methyl, hydroxyl, lower alkoxy, amino, N-mono- or N, Nd? - (lower alkyl, phenyl, naphthyl, phenyl-alkyl) lower or naphthyl-lower alkyl) -amino, nitro, carboxyl, lower-carbonyl-alkoxy, carbamoyl, cyano and / or sulfamoyl. Lower alkanoyl, benzoyl, phenyl-sulfonyl or toluol-sulfonyl Y are preferred. N = CH, CH = N or more preferably CH = CH. Y2 is C (carbon) or (if Ra is absent), it can be N, meaning that Y2-Ra can be C (Ra) or N, preferably, Y2 is C In a fraction of formula IA as shown above, "the dotted line means the link that links to the rest of the molecule of formula I (which is indicated by the wavy line), means that the dotted line corresponds to the bond linking Ra in formula I Unsubstituted or substituted alkyl R4 can be unsubstituted or substituted alkyl as defined above, lower alkyl is preferred from enyl-alko lower Z, is preferably CH = N or N = CH, or more preferably CH = CH (consequently, forming a six-membered ring) Each of Z2 and Z3 is preferably CH Substituents R5 (if present, ie, if n is 1 or 2) are preferably independently selected from the substituents mentioned above for substituted aplo, especially selected from the group consisting of lower alkyl, halogen, halo-lower alkyl, such as lower tpfluoro-methyl-alkanoyl, such as acetyl, hydroxyl, lower alkoxy, such as methoxy, nitro, amino, mono- or di-substituted amino, wherein the amino substituents are independently selected from alkyl lower and lower alkanoyl, cyano, carboxyl, methylcarbonyl, eg, methoxycarbonyl, carbamoyl, carbamoyl substituted by N-mono- or N, Nd? - (lower alkyl), amidino, guanidino, ureido, thioalkyl lower, sulfo, unsulfonyl alkane, and sulfonamido R5 is preferably alkoxy of 1 to 7 carbon atoms, and still more preferably alkoxy of 1 to 4 carbon atoms The symbol n preferably represents 0 or 1 The salts are in particular the pharmaceutically salts acceptable compounds of Formula I can be formed when there are salt-forming groups present, such as basic or acid groups, which may exist in a dissociated form at least partially, for example in a pH range of 4 to 10 in a aqueous environment, or can be isolated especially in solid form, or, when charged groups are present (eg, quaternary ammonium) - in the latter case acylate salts are formed with anions of organic or inorganic acids (e.g. as defined in the following paragraph) These salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from the compounds of Formula I, with a basic nitrogen atom, in particular pharmaceutically acceptable salts Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulphonic or sulphonic acids, for example acetic acid, propionic acid, lactic acid, fumaric acid, succinic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxy-maleic acid, methyl-maleic acid, benzoic acid, methan- or ethanesulfonic acid, ethane-1,2-d-sulfonic acid, benzenesulphonic acid, 2-naphthalene-sulphonic acid? , 1, 5-naphthalene-d? sulfon? co acid, N-cyclohexyl sulfamic acid, N-methyl-, N-ethyl-, or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid In the presence of negatively charged radicals, such as carboxyl or sulfo, salts can also be formed with bases, for example metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium salts, magnesium, or calcium, or ammonium salts with ammonia or with suitable organic amines, such as tertiary monoamines, for example tpethyl-amine or tr? - (2-hydrox? -et? l) -am? na, or bases heterocyclics, for example N-ethyl-pipepdine or N, N'-d? meth? piperazm When a basic group and an acid group are present in the same molecule, a compound of Formula I can also form internal salts. for isolation or purification, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds (where applicable, included in pharmaceutical preparations) are used. cas), and therefore, these are preferred In view of the close relationship between the compounds in free form and in the form of their salts, including salts that can be used as intermediates, for example in the purification or identification of compounds or the salts themselves, any reference to the "compounds" or to "a compound" (also including the starting materials and the "intermediates") hereinbefore and hereinafter, in especially to the compounds of Formula I, it should be understood to also refer to one or more salts thereof, or to a mixture of a free compound and one or more salts thereof, each of which is also intended to include any solvate, metabolic precursor, such as ester or amide of the compound of Formula I, or a salt of any one or more thereof, as appropriate and convenient, and if not explicitly mentioned otherwise. Different forms of crystal and solvates can be obtained , and then they are also included. When the plural form is used for the compounds, salts, pharmaceutical preparations, diseases, disorders, and the like, this is meant to include also a single compound, salt, preparation, disease, or the like, when use "a" or "an", this means that it refers to the indefinite article, or preferably to "one" In some cases, a compound of the present invention may comprise one or more the chirals in the substituents, or may show another asymmetry (leading to enantiomers), or may be able to exist otherwise in the form of more than one stereoisomer, for example due to more than one chiral center, or to more than another type of asymmetry, or due to the rings or double bonds that allow the isomepsmo Z / E (or cis-trans) (diastereomers). The present invention includes both mixtures of two or more of these isomers, such as mixtures of enantiomers, especially racemates, as well as preferably the purified isomers, in especially the purified enantiomers, or enantiomerically enriched mixtures The compounds of Formula I have valuable pharmacological properties, and are useful in the treatment of diseases that respond to the modulation of tyrosine protein kinase, especially one or more of the kinases of protein mentioned above under the "General Description of the Invention", more especially c-src kinase, vascular endothelial growth factor receptor kinase (e.g., KDR and Flt-1), RET receptor kinase, and / or receptor kinases from Efpna, for example EphB2 kinase, EphB4 kinase or related kinases, where modulation preferably means inhibition, and which respond means that the progress of a disease and / or its symptoms slows down, stops, or even reverses up to and including a complete or at least temporary cure The term "treatment" includes especially prophylaxis, including treatment eventivo, for example in patients in whom mutations or changes have been found that indicate that they are or may be susceptible to the development of a disease, or preferably therapeutic treatment (including, but not limited to, palliative, curative, alleviating the symptoms, symptom reducer, suppressor of the disease or symptoms, progress retarder, kinase regulator, and / or kinase inhibitor) of these diseases, especially any one or more of the diseases mentioned below The term "curative" as used herein, preferably means efficacy in the treatment of continuous episodes involving receptor tyrosine kinase activity (especially poorly regulated). The term "prophylactic" means preferably the prevention of the establishment or recurrence of diseases involving a poorly regulated receptor tyrosine cmase activity. The term "progress delay", as used herein, means in particular the administration of the compound active to patients who are in a previous stage or in an early phase of the disease to be treated, in whose patients, for example, a pre-form of the corresponding disease is diagnosed, or whose patients are in a condition, for example during a medical treatment, or a condition resulting from an accident, under which a corresponding disease is likely to develop, or where, for example, metastasis may be expected, without treatment. An animal of preference is a blood animal hot, more preferably a mammal A human being (which in general also falls under the general term "animal") is especially a p or a person who (for example, due to some mutation or other characteristics) is susceptible to a risk of a disease, as defined above or later When subsequently or in the foregoing the term "use" is mentioned (as a verb or name) (in relation to the use of a compound of Formula I or a pharmaceutically acceptable salt thereof), this (if not indicated in a different manner or suggested in a different manner by context) includes any one or more of the following embodiments of the invention, respectively (if not otherwise mentioned), the use in the treatment of a disease that responds to modulation (especially inhibition) of protein kinase (especially tyrosma), the use for the manufacture of pharmaceutical compositions to be used in the treatment of a disease responsive to the modulation (especially inhibition) of protein kinase, methods of using one or more compounds of Formula I in the treatment of a proliferative disease and / or responding to modulation (especially inhibition) of protein kinase, pharmaceutical preparations comprising one or more compounds of Formula I for the treatment of the disease responsive to modulation (especially inhibition) of said protein kinase, and one or more compounds of Formula I in the treatment of this disease that responds to the modulation (especially inhibition) of protein kinase, as appropriate and convenient, if not mentioned otherwise way. In particular, the diseases to be treated, and therefore, those that are preferred for the "use" of a compound of Formula I, are selected from the diseases that respond (also meaning "supported", not only "dependent", including also situations where a disease is responding to modulation, especially the inhibition of a protein kinase, ie the activity of the protein kinase supports or even causes the manifestation of the disease) to the modulation (especially inhibition) of protein kinase mentioned below, especially the proliferative diseases mentioned below When a protein kinase is mentioned, it refers to any type of protein kinase, especially one of those defined above under the "General Description of the Invention", more especially the septa / threonine kinases, and / o preferably tyrosine protein, more preferably one or more tyrosine protein kinases, especially selected from the group consisting of c-src kinase, vascular endothelial growth factor receptor kinase (e.g., KDR and Flt- 1), RET receptor kinase, or Efpna receptor kinases, for example EphB2 kinase, EphB4 kinase, or related kinases, including one or more altered or mutated or altered forms of any one or more thereof (eg, those that result in the conversion of the respective proto-oncogene to an oncogene). , such as constitutively active mutants, for example Bcr-Abl) In particular, an abnormally highly expressed, constitutively activated, or normal form is encompassed but in the given context of another regulatory mechanism in a relatively over-active patient, and / or mutated The utility of the compounds of the present invention in the modeling, especially as inhibitors, of the kinases of protein in particular and paradigmatically can be demonstrated by the following test systems for the protein kinases mentioned as preferred above In the following description of the typical example test systems, the following abbreviations have the following meanings DMSO = dimethyl sulfoxide, DTT = di tioe ptp tol, EDTA = ethylene diamine tetra acetate, MOI = multiplicity of infection, PMSF = p-toluene sulfonyl fluoride, Tps = tr? - (h? drox? -met? l) -am? non-methane An "inhibitor" is a test compound of Formula I, if not otherwise mentioned. The efficacy of the compounds of Formula I as inhibitors of the receptor kinases of Efpna B4 (EphB4), can be demonstrated as continued Generation of Bac-to-BacMR GST fusion expression vectors (Invitrogen Life Technologies, Basel, Switzerland) The entire cytoplasmic coding regions of the EphB class are amplified by polymerase chain reaction to from cDNA libraries derived from placenta or human brain, respectively. Recombinant baculoviruses are generated that express the amino acid region 566-987 of the human EphB4 receptor (SwissProt Datábase, Accession Number P54760). The GST sequence is cloned into the pFastBad® vector ( Invitrogen Life Technologies, Basel, Switzerland), and amplified by polymerase chain reaction. The cDNAs encoding the EphB4 receptor domains are respectively cloned into the 3 'frame for the GST sequence in this modified FastBad vector, to generate the pBac-to-BacMR donor vectors. Individual colonies are presented that are presented of the transformation, to give nocturnal cultures for the preparation of the plasmid on a small scale. The analysis of the restriction enzyme of the plasmid DNA reveals that several clones contain inserts of the expected size. By automated sequencing, the inserts and approximately 50 base pairs of the flanking vector sequences are confirmed in both strains. Virus production has been virus for each of the kinases according to the protocol provided by GIBCO if not mentioned otherwise. In brief, the transfer vectors containing the kinase domains are transfected into the DHIOBac cell line (GIBCO), and are applied to selective agar plates colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. Individual white colonies are collected, and viral DNA (bacmid) is isolated from the bacteria, by conventional plasmid purification procedures. Then the Sf9 cells or the Sf21 cells are transfected in 25 square cm flasks with the viral DNA, using the Cellfectin reagent according to the protocol Purification of GST-labeled kinases. The centrifuged cell lysate is loaded onto a 2 milliliter column. glutathione-Sepharose (Pharmacia), and washed three times with 10 milliliters of 25 mM Tps-HCl, pH 75, 2 mM EDTA, 1 mM DTT, 200 mM NaCl Then GST-labeled proteins are eluted by 10 applications (1 milliliter each) of 25 mM Tps-HCl, pH of 75, reduced glutathione 10 mM, 100 mM NaCl, 1 mM DTT, 10 percent glycerol , and stored at -70 ° C. Protein kinase assays Protein kinase activities are assayed in the presence or absence of the inhibitors, measuring the incorporation of 33P from [? 33P] ATP into a polymer of glutamic acid and tyrosine (poly (Glu.Tyr)) as a substrate The kinase assays with purified GST-EphB (30 nanograms) are carried out for 15 to 30 minutes at room temperature, in a final volume of 30 micro tros containing 20 mM Tps-HCl, pH 75, 10 mM MgCl 2, 3 to 50 mM MnCl 2, Na3V04 001 mM, 1 percent dimethyl sulfoxide, 1 mM DTT, 3 micrograms / milliliter of pol (Glu, Tyr ) 4 1 (Sigma, St Louis, Mo, USA), and ATP from 20 to 30 μM (? - [33P] -ATP 0 1 μCi) The assay is terminated by the addition of 20 micro-hours of EDTA 125 mM Subsequently, 40 micro-hours of the reaction mixture are transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA), previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with H3P0 at 05 hours. percent, and it is mounted on a vacuum manifold with the vacuum source disconnected After staining all the samples, the vacuum is connected, and each well is rinsed with 200 microhours of H3P0 at 05 percent The membranes are removed and washed four times on an agitator with 1 0 percent H3P04, and a once with ethanol. The membranes are counted after drying at room temperature, mounted in the 96 well Packard TopCount framework, and adding 10 microhours / well of M? Crosc? NtMR (Packard). The IC 50 values are calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, in four concentrations (usually 001, 0 1, 1, and 10 μM) One unit of protein kinase activity is defined as 1 nanomole of 33P ATP transferred from [33P] -ATP to the substrate protein per minute per milligram of protein at 37 ° C The compounds of Formula I show an inhibition of EphB4 down to 1 nM, preferably IC50 values of between 0.001 and 10.0 μM. Alternatively, the self-phosphorylation of the EphB4 receptor can be measured as follows The inhibition of the auto-phosphorylation of the EphB4 receptor can be confirmed with a m vitro experiment in cells, such as transfected A375 human melanoma cells (ATCC Number CRL -1619), which permanently express human EphB4 (SwissProt, Accession Number P54760), and are seeded in a complete culture medium (with 10% fetal calf serum = FCS) in six-well cell culture plates , and incubated at 37 ° C with 5 percent C02, until they show a confluence of about 90 percent. Then, the compounds to be tested are diluted in the culture medium (without fetal calf serum, with bovine serum albumin 0.1 percent), and add to the cells (The controls comprise the medium without the compounds e test) The auto-phosphorylation induced by the ligand is induced by the addition of 1 microgram / milliliter of soluble Efr? naB2-Fc (s-Ephr? nB2-FcR & D Biosystems, Catalog Number 496-EB), and 0.1 μM ortho-vanadate After an additional 20 minutes of incubation at 37 ° C, the cells are washed twice with ice cold PBS (phosphate-regulated serum), and immediately sanitized in 200 microliters of sis regulator per well Then the lysates are centrifuged to remove the cell nuclei, and the protein concentrations of the supernatants are determined using a commercial protein assay (PIERCE). Then the lysates can be used immediately, or if necessary, can be stored at -20 ° C A sandwich ELISA is carried out to measure the phosphorylation of EphB4 In order to capture the phosphoplated EphB4 protein, 100 nanograms / well of Efr? naB2-Fc (s-Ephr? nB2) are immobilized - Fc R & D Biosystems, Catalog Number 496-EB), on MaxiSorb ELISA plates (Nunc) Then the plates are washed, and the remaining free protein binding sites are saturated with 3 percent TopBlock® (Juro, Catalog Number TB232010) in serum regulated with phosphate, with Tween 20® (sorbitan monolaurate of pol? Ox? Et? Leno (20), ICI / Uniquema (PBST). The cell samples (100 micrograms of protein per well) are then incubated in these plates for 1 hour at room temperature. After washing the wells three times with phosphate-buffered serum, a anti-phosphotyrosm antibody coupled with alkaline phosphatase (PY 20 alkaline phosphatase conjugated ZYMED, Catalog Number 03-7722), and incubated for another hour The plates are washed again, and then the binding of the anti-phosphotyrosm antibody to the receptor is demonstrated captured phospho- phate, and quantified using 10mM D-nitro-phenyl phosphate as a substrate, and measuring the OD at 405 nanometers after 055 hours at 1 hour The difference between the positive control signal (stimulated with vanadate and s-Efr? naB2 -Fc), and that of the negative control (not stimulated) corresponds to the maximum phosphorylation of EphB4 (= 100 percent). The activity of the substances tested is calculated as the percentage of inhibition of the maximum phosphorylation of EphB4, where the concentration of the substance that induces half of the maximum inhibition is defined as the IC50 (inhibitory dose for a 50 percent inhibition). ) With the compounds of Formula I, IC50 values of between 0.0005 and 20 μM, preferably of 00005 and 10 μM can be found. The activity of the compounds of the invention as inhibitors of the KDR tyrosine protein kinase activity can be demonstrated as follows the inhibition of the receptor auto-phosphorylation induced by the vascular endotehal growth factor can be confirmed in cells such as CHO cells transfectants, which permanently express the human VEGF-R2 receptor (KDR), and are seeded in a complete culture medium (with 10 percent fetal calf serum = FCS) in six cell culture plates wells, and incubated at 37 ° C with 5 percent C02, until they show a confluence of about 80 percent. The compounds to be tested are then diluted in the culture medium (without fetal calf serum, with bovine serum albumin 0.1 percent), and are added to the cells. The controls comprise the medium without the test compounds After 2 hours of incubation at 37 ° C, the endothelial growth factor is added to the recombinant vascular, the final concentration of the vascular endothelial growth factor is 20 nanograms / milliliter. an additional incubation period of 5 minutes at 37 ° C, the cells are washed twice with ice cold PBS (phosphate buffered serum), and immediately lysed in 100 microliters of lysis buffer per well. The sados are then centrifuged to remove the cell nuclei, and the protein concentrations of the supernatants are determined using a commercial protein assay (BIORAD). Then the tissues can be used immediately, or if necessary, stored at -20 ° C. Using this protocol, it can be found that the selective compounds of Formula I show IC5o values for the inhibition of KDR which are preferably at least 1.5 times higher than for the tyrosine kinase c-Abl, more preferably more than twice higher than for the tyrosine cmase EphB4 Generally speaking, in this test system with the compounds of Formula I, IC50 values are found in the range of 0.001 to 20 μM, more preferably of 0005 to 10 μM The compounds of the formula I can also inhibit other protein kinases. The efficacy of the compounds of the invention as inhibitors of the protein tyrosine c-Abl protein kinase activity can be demonstrated as follows. An enzymatic assay m vitro is carried out in 96 well plates, as a filter binding assay, as described by Geissler et al., in Cancer fies 1992, 524492-4498, with the following modifications The His-tagged kinase domain of c-Abl is cloned and expressed in the Baculov? rus / Sf9 system as described by Bhat et al., in J Biol Chem 1997, 272 16170-16175 A 37 kD protein (cmasa c-Abl) is purified by a two-step procedure on a column of cobalt metal chelate, followed by an anion exchange column, for a yield of 1 to 2 milligrams / liter of Sf9 cells (Bhat et al., cited reference) The purity of the c-Abl kinase is > 90 percent, as judged by SDS-PAGE after staining with Coomassie blue The assay contains (total volume of 30 micro-tros) c-Abl kinase (50 nanograms), 20 mM Tps-HCl, pH 75, 10 mM MgCl 2 , Na3C04 10 μM, DTT 1 mM, and 006 μCi / assay [? 33P] -ATP (ATP 5 μM), using 30 micrograms / milliliter of poly-Al a, GI u, Lys, Tyr-6251 (Poly-ZEKY, Sigma P1152) in the presence of 1 percent dimethyl sulfoxide Reactions are terminated by the addition of 10 microliters of 250 mM EDTA, and 30 microliters of the reaction mixture are transferred to a membrane Immobilon-PVDF (Mil pore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 05% H3P04, and mounted on a vacuum manifold with the vacuum source disconnected After staining all the samples, the vacuum is connected, and each well is rinsed with 200 microhours of H3P04 at 05 percent. The membranes are removed and washed with a stirrer with H3P04 at 05 percent (4 times), and once with Ethanol The membranes are counted after drying at room temperature, mounted in a 96 well Packard TopCount frame, and adding 10 microliters / well of M? crosc? ntMR (Packard) Using this test system, the compounds of the Formula I can show IC 50 values of inhibition for the inhibition of c-Abl in the range, for example, from 0002 to 100 μM, usually between 0002 and 5 μM, the compounds of Formula I can also be used to inhibit b-raf (V599E). The activity of B-Raf-V599E is tested in the presence or in the absence of the inhibitors, measuring the incorporation of 33P from [? 33P] ATP into (H? S) -l? B The test compound is dissolved in dimethyl sulfoxide (10 mM), and stored at -20 ° C. Serial dilutions are made in fresh dimethyl sulfoxide, and further diluted with pure water to obtain test solutions concentrated three times in 3 percent dimethyl sulfoxide. The final volume (30 microliters) of the assay contains 10 microliters of test solution (1 percent dimethyl sulfoxide), 10 microliters of assay mixture (20 mM Tps-HCl, pH 75, 3 mM MnCl 2, 3 mM MgCl 2, 1 mM DTT, 3 micrograms / milliliter (H? s) -l? B, 1 percent dimethyl sulfoxide, and 35 μM ATP [? 33P] -ATP 0 1 μCi), and 10 microliters of enzyme dilution (600 nanograms of GST-B-Raf-V599E) Pipette steps are programmed to be carried out on any of the MultiPROBE hx, MultiPROBE 11 Lx, or HamiltonSTAR robots, in the 96-well format The assay is carried out as described in the literature (see C García-Echeverría et al., Cancer Cel, 5, 231-9 (2004)), and is terminated by the addition of 20 microliters of EDTA 125 mM The capture of the phospho-peptides by the filter-binding method is carried out as follows: 40 microliters of the reaction mixture are transferred to Immobilon-PVDF membranes previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes. minutes with H3P04 at 05 percent, and mounted on a vacuum manifold with the vacuum source disconnected. After all the samples are stained, the vacuum is connected, and each well is rinsed with 200 microliters of 05 percent H2P04. The free membranes are removed and washed four times on an agitator with 1 0 percent H3P04, and once with ethanol The membranes are counted after drying at room temperature, mounted in the frame of 96 Packard TopCount wells, and adding 10 microhours / well of M? crosc? ntMR The plates are eventually sealed and counted in a scintillation counter of microplates (TopCount NXT, TopCount NXT HTS) In the case of the plate method by Instantaneous evaporation, the kinase reaction is first carried out on polystyrene-based plastic plates, and then stopped after 60 minutes by the addition of 20 microliters of 125 mM EDTA. For capture (60 minutes at room temperature), the biotinylated substrate is transferred to nickel-coated flash evaporation plates. The test plates are washed three times with phosphate-buffered serum, and dried at room temperature. Then, the plates are sealed and counted in a microplate scintillation counter (TopCount NXT, TopCount NXT HTS) The IC50 values are calculated by linear regression analysis of the percent inhibition by the compound either in duplicate, in four concentrations (usually 001, 0 1, 1, and 10 μM), or as the IC50 of 8 individual points, starting at 10 μM, followed by dilutions at 1 3 For the inhibition of b-raf, the compounds of Formula I can show IC50 values on the inte RANGE OF 005 TO 50 μM The results indicate a convenient affinity profile of the compounds of the formula I There are also experiments to demonstrate the anti-tumor activity of the compounds of the Formula I m vivo For example, in order to test whether a compound of Formula I inhibits angiogenesis m vivo, its effect on the angiogenic response induced by an angiogenic factor, such as VEGF, bFGF, S-1P, PDGF, or IGF-1, is tested in an implant model of growth factor in mice, a porous Teflon chamber (volume of 0. 5 milliliters) is filled with 0.8 weight / volume agar containing hepapna (20 units / milliliter), with or without growth factor (2 micrograms / milliliter of human vascular endothelial growth factor), and implanted subcutaneously on the dorsal flank of C57 / C6 mice Mice are treated with the test compound (for example, 5, 10, 25, 50 or 100 milligrams / kilogram orally once a day), or with vehicle, starting on the day of implantation from the chamber, and continuing for 4 days afterwards At the end of the treatment, the mice are sacrificed, and the chambers are removed. The vasculated tissue that grows around the chamber is carefully removed and weighed, and the blood content is evaluated by measuring the tissue hemoglobin content (method of Drabkins, Sigma, Deisenhofer, Germany). The T? E-2 protein levels, as a measure of the endote marker at, are determined by a specific ELISA to quantify the angiogenic response. It has been previously shown that these growth factors induce dose-dependent increases in weight, in blood content, and in T? e-2 protein levels of this tissue that grows (characterized histologically by containing fibroblasts and small blood vessels (around the chambers), and that this response is blocked by neutralizing antibodies, for example that specifically neutralize the vascular endothelial growth factor (see Wood J M. et al. Cancer fies 60 (8), 2178-2189, (2000); and Schlaeppi et al., J Cancer fies. Clin Oncol 125, 336-342, (1999)) With this model, inhibition can be shown in the case of compounds of Formula I in the concentrations given above In a preferred sense of the invention, a disease that responds to modulation protein kinase is a disorder that responds, for the treated individual, in a manner beneficial to the modulation, in particular to the inhibition, of the activity of a protein kinase (preferably tyrosine), especially one characterized as preferred above. , wherein a compound of Formula I can be used, and is one or more of a pro-inflammatory disease (meaning an activity-dependent (especially inadequate) of a protein kinase), including a hyperproliferative condition, such as one or more of leukemia, hyperplasia, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, sopasis, atherosclerosis, and muscle proliferation or smooth in blood vessels, such as stenosis or restenosis following angioplasty. In addition, a compound of Formula I can be used for the treatment of thrombosis and / or scleroderma. The use of a compound of Formula I in therapy is preferred. (including prophylaxis) of a pro-inflammatory disorder (especially responsive to modulation, especially inhibition, of the activity of a protein kinase (preferably tyrosm), especially as mentioned herein as preferred), selected from of tumor diseases or cancer, in especially against a benign tumor or especially malignant tumor or cancer, more preferably solid tumors, for example carcinoma of the brain, kidney, adrenal gland, bladder, breast, stomach (especially gastric tumors), ovaries, colon, rectum, prostate, pancreas, lung (for example, microcellular or macrocellular lung carcinomas), vagina, thyroid, sarcoma, glioblastomas, multiple myeloma, or gastrointestinal cancer, especially colon carcinoma or colo-rectal adenoma, or a neck and head tumor, for example squamous carcinoma of the head and neck, including neoplasms, especially of epithelial character, for example in the case of mammary carcinoma, an epidermal hyperproliferation (different from cancer), especially sopasis, prostatic hyperplasia, or a leukemia. A compound of Formula I or its use makes it possible to cause the regression of tumors and / or prevent the formation of tumor metastases and the growth of (also m? Cro) -metasta? It is also possible to use the compounds of Formula I in the treatment of diseases of the immune system, up to where they are involved in vain, or especially the individual protein kinases (preferably of tyrosma), especially those mentioned as preferred. Additionally, the compounds of Formula I can also be used in the treatment of diseases of the central or peripheral nervous system, where signal transmission is involved by at least one protein kinase (preferably tyrosine), especially selected from the tyrosine protein kinases mentioned as preferred In chronic myelogenous leukemia (CML), a reciprocally balanced chromosomal translocation in hematopoietic totipotent cells (HSCs) produces the hybrid BCR-ABL gene This latter encodes the oncogenic fusion protein Bcr -Abl While ABL encodes a closely regulated protein tyrosome kinase, which has a fundamental role in the regulation of cell proliferation, adhesion, and apoptosis, the BCR-ABL fusion gene encodes a constitutively activated kinase that transforms totipotent hematopoietic cells to produce a phenotype that exhibits a poorly regulated clonal proliferation, a reduced ability to adhere to the bone marrow stroma, and a reduced apoptotic response to mutagenic stimuli, which make it possible to progressively accumulate more malignant transformations. The resulting granulocytes fail to develop smell up mature lymphocytes, and are released into circulation, leading to a deficiency in mature cells, and a greater susceptibility to infection. Competitive inhibitors have been described by Bcr-Abl ATP (or comparable mutated forms), which prevent the kinase from activating the pathways. mitogenic and anti-apoptotic (for example, cmasa P-3 and STAT5), which lead to the death of cells of the BCR-ABL phenotype, and therefore, they provide an effective therapy against chronic myelogenous leukemia. the Formula I useful according with the present invention as Bcr-Abl inhibitors, therefore, they are especially suitable for the therapy of diseases related to their overexpression, especially leukemias, such as leukemia, for example chronic myelogenous leukemia or acute nfocitic leukemia. Angiogenesis is considered as an absolute prerequisite for tumors that grow beyond a maximum diameter of approximately 1 to 2 millimeters, up to this limit, oxygen and nutrients can be delivered to tumor cells by diffusion. Each tumor, regardless of its origin and its cause, therefore, depends on angiogenesis for its growth, after it has reached a certain size. Three main mechanisms have an important role in the activity of inhibitors of angiogenesis against tumors 1 ) the inhibition of the growth of vessels, especially of capillaries, towards avascular resting tumors, with the result that there is no net tumor growth due to the balance achieved between apoptosis and proliferation, 2) prevention of the migration of tumor cells due to the absence of blood flow to and from tumors, and 3) the inhibition of endothelial cell proliferation, thus avoiding the stimulating effect of paracne growth exerted on the surrounding tissue by the cells endothelial cells that normally coat the vessels The compounds of Formula I, with respect to their ability to inhibit the cmasa recept from KDR and especially from Efpna, and possibly other protein kinases, and therefore, to modulate angiogenesis, are especially suitable for use against diseases or disorders related to inappropriate activity of the corresponding receptor kinase (preferably tyrosine), especially a over-expression of the same Among these diseases, especially retinopathies (eg ischemic), macular degeneration (eg, age-related), sopasis, obesity, hemangioblastoma, hemangioma, inflammatory diseases, such as diseases, are especially important. rheumatoid or rheumatic inflammatory, especially arthritis, such as rheumatoid arthritis, or other chronic inflammatory disorders, such as chronic asthma, arterial or post-transplant atherosclerosis, endometriosis, and especially neoplasic diseases, for example so-called solid tumors (especially cancers of the gastrointestinal tract, pancreas, mam a, stomach, cervix, bladder, kidney, prostate, ovaries, endometrium, lung, brain, melanoma, Kaposi's sarcoma, squamous cell carcinoma of head and neck, malignant pleural mesothelioma, lymphoma, or multiple myeloma), and other fluid tumors (e.g., leukemias) The compounds of Formula I are especially useful for preventing or treating diseases that are triggered by persistent angiogenesis, such as restenosis, for example stent-induced restenosis (vascular implant), Crohn's disease, Hodgkin; diseases of the eyes, such such as diabetic retinopathy and neovascular glaucoma, kidney diseases, such as glomerulonephritis, diabetic nephropathy, inflammatory bowel disease, malignant nephrosclerosis, thrombotic microangiopathic syndromes, transplant rejections (eg, chronic), and glomerulopathy, fibrotic diseases, such as cirrhosis of the liver pro-inflammatory diseases of mesangial cells, lesions of nervous tissue, and to inhibit re-occlusion of vessels after balloon catheter treatment, for use in vascular prostheses, or after inserting mechanical devices to keep vessels open, such such as, for example, stents (vascular implants), as immunosuppressants, as an aid in the healing of wounds without a scar, and for the treatment of age spots and contact dermatitis., the invention relates to the use of compounds of Formula I, or pharmaceutically acceptable salts thereof, in the treatment of solid tumors, as mentioned herein, and / or of liquid tumors, for example leukemias, as mentioned. in the present Due to their modulating properties of protein cmasa, such as Eph receptor kinase, the compounds of Formula I can also be used to stimulate or promote neural regeneration (neuronal regeneration, neuro-regeneration), such as axonal regeneration , or to inhibit or reverse the neural degeneration (neuronal degeneration, neurodegeneration) These uses represent additional aspects of the present invention. Accordingly, the compounds of Formula I are also useful in the treatment of conditions, diseases, or disorders that respond to protein kinase modulation, such as Eph receptor kinase, wherein stimulation or promotion of neural regeneration (neuronal regeneration, neuro-regeneration), such as axonal regeneration, or the inhibition or reversal of neural degeneration (neuronal degeneration, neurodegeneration), for example, in the treatment of lesion of spinal cord, hypoxic conditions, traumatic brain injury, infarction, embolism, multiple sclerosis, or other conditions, diseases, or neurodegenerative disorders. These uses and methods of treatment represent additional aspects of the present invention Fabrication process A compound of Formula I is prepared in a manner analogous to methods which, for other compounds, are in principle known in the art, such that, for the novel compounds of Formula I, the process is novel as a process of analogy, preferably by condensing a carbonic acid of the formula or a reactive derivative thereof, wherein R1, X (, X2, X3 and X4 are as defined for a compound of the formula I, with a compound of the formula: wherein R2, R3, D, Y, Y2, and Ra are as defined for a compound of formula I, or b) for the synthesis of a compound of formula I, wherein R1 is unsubstituted or substituted alkyl, unsubstituted aplo or substituted, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, reacting a boronic acid of the formula -R1-B (A) 2 (IV), wherein R1 is unsubstituted or substituted alkyl, unsubstituted or substituted aplo (preferred), unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl (each linked via a carbon atom), and A is hydroxyl or lower alkoxy, or B (A) 2 is 9-borab? c? clo- [33 1] -nonan? lo or -B (CHCH3CH (CH3) 2) 2, with a compound of the formula wherein R1, R2, R3, X ,, X2, X3, X4, Y ,, Y2, D and Ra are as defined for a compound of the formula I, and Hal is halogen, especially chlorine, iodine, or preferably bromine, or (perfluorinated C 1-4 alkyl) -sulfonylloxyl, and, if desired, transforming a compound of the formula I into a different compound of the formula I, transforming a salt of a compound that can be obtained from the formula I in the free compound or in a different salt, transform a free compound of the formula I that can be obtained in a salt thereof, and / or separate a mixture of isomers obtainable from a compound of the formula I in the individual isomers Preferably, the condensation reaction a) with the carbonic acid of the formula X or XIV, respectively, or a reactive derivative thereof, takes place with a reactive carbonic acid derivative which can be use as such, for example, with the reactive carbonic acid derivative in the form of an anhydride symmetric drido or mixed, an active ester, or a carbonic acid halide, for example, the acid chloride, for example, in the presence of a tertiary nitrogen base, such as a tp-lower alkyl-amine or pipdin, or can be formed in situ, for example, by condensation in the presence of reagents that form reactive esters in situ The reaction, for example, is carried out by dissolving the carbonic acids and the corresponding amine in a suitable solvent, for example a halogenated hydrocarbon , such as methylene chloride,? /,? / - d? met? l-formam? da,? /,? / - d? met? l-acetam? da,? / - met? l-2-p? R? o dona, methylene chloride, or a mixture of two or more of these solvents, and by the addition of a suitable base, for example, t-ethyl amine, di-isopropyl-ethyl-amine (DIEA) or? / -meth? l-morpholine and, if the reactive derivative of the acid of the formula II is formed in situ, a suitable coupling agent which forms a preferred reactive derivative of the carbonic acid of the formula III in situ, for example d? c? clohex? l-carbod? -? m? da / 1-h? drox? -benzo-tpazol (DCC / HOBT); b? s- (2-oxo-3-oxazole? d? n? l) -phosph? n? co (BOPCI), tetraf? uoro-borate 0- (1, 2-d? -2-oxo-1-p? Pd? L) -N, N, N ', N'-tetramethyl-uromo (TPTU); tetrafluoro-borate of O-benzotrol azol-1 -? l) -N, N, N ', N'-tetramet? l-uron? or (TBTU), hexafluoro-phosphate (benzotr? azol-1-? lox?) - tpp? rrol? d? no-phosphon? (PyBOP), 1- (3-d? met? l-am? no-prop? l) -3 hydrochloride -et? l-carbod? -? m? da / hydroxy-benzotpazol or / 1-hydrox? -7-aza-benzotr? aol (EDC / HOBT or EDC / HOAt) or HOAt alone, or with (1 - chloro-2-met? l-propen? l) -d? met? l-am? na For a review of some other possible coupling agents, see for example, Klauser, Bodansky, Synthesis 1972, 453-463 The reaction mixture is preferably stirred at a temperature between about -20 ° C and 50 ° C, especially between 0 ° C and 30 ° C, for example, at room temperature The reaction under b) takes place under Suzuki coupling or comparable conditions, for example, in the presence of a palladium catalyst, such as Pd (PPh3) 4 where Ph is phenyl or Pd (dppf) CI2 where dppf is 1 , 1 '-b? S (d? Phen? L-phosphono) -ferrocene, and a base, such as an alkali metal carbonate, for example, sodium carbonate, an alkali metal alcoholate, such as ethoxide sodium, a tertiary nitrogen base, such as t-ethyl amine, or an alkali metal phosphate, such as potassium phosphate, in the presence or absence of an appropriate solvent, for example, an ether, such as tetrahydrofuran or 1, 4-d-oxane, a hydrocarbon, for example, toluene, and / or water, for example, at an elevated temperature, for example from 30 ° C to the reflux temperature or, at higher temperatures, in a closed reaction vessel compatible with pressure Optional Reactions and Conversions A compound of Formula I can be converted to a compound other than Formula I, for example after performing one of the reactions a) ) mentioned above For example, in a compound of Formula I, wherein R 1 is halo-aplo, such as bromo-aplo, for example bromo-phenyl, the halogen can be replaced with a substituent linked by means of a nitrogen atom, for example with morphine, by reaction with a corresponding primary or secondary amine, such as morphine, in the presence of a strong base, such as an alkali metal alkoxide, for example potassium terbutoxide. , and a suitable coupling catalyst, for example a complex of 2- (d? met? l-am? no) -2-b? phen? l? -palladium (ll) / d? norborn complex? 1-phosphine, in a solvent or mixture of suitable solvents, for example an ether, such as tetrahydrofuran, preferably at elevated temperatures, for example from 30 ° C to the reflux temperature. Another example of a conversion can still be given. of a compound of Formula I, wherein a substituent of substituted nitro in R 1 is present - this nitro substituent can be reduced to a corresponding amino substituent, for example, by catalytic hydrogenation, for example in the presence of nickel Raney, in a solvent or in a solvent mixture s suitable, for example an alcohol, such as methanol or ethanol, for example at temperatures of 0 ° C to 50 ° C An amino substituent in a compound of Formula I (especially amino as a substituent of aplo R1 in Formula I ) can be converted into a mono-, di- or tp-alkylated amino substitute (in the latter case, quaternary), by reaction with a corresponding alkyl halide, for example methyl iodide, preferably in the presence of a tertiary nitrogen base, such as t-ethyl amine, in a suitable solvent or mixture of solvents, for example, an N, Nd? - (alkyl? nfepor) -alkano? lower-amide, such as N, Nd? met? l-formam? da, preferably at temperatures of 20 ° C to 80 ° C In a compound of the formula I, wherein R 1 is aplo which is substituted by iodine or bromine, and possibly one or more different substituents, such as tpfluoro, for example, wherein R 1 is 4-iodo-3-tpfluoro-met? Alternatively, the bromine or iodine can be replaced with substituted or unsubstituted aplo, such as 4-cyano-phenyl, by the coupling reaction with the corresponding substituted or unsubstituted apl-boronic acid of the formula Ar-B (OH) 2 (IV), wherein Ar is unsubstituted or substituted aplo in the presence of a catalyst, especially PdCI2 (dppf), and preferably also a base, such as an alkali metal carbonate, for example, sodium carbonate, in a solvent or mixture of suitable solvents, for example, toluene / water, for example, at elevated temperatures, for example, between 30 ° C and the reflux temperature (preferred) The salts of the compounds of the Formula I having at least one group forming salt can be prepared in a manner known per se. For example, a salt of a compound of Formula I having acidic groups can be formed by treating the compound with a metal compound, such as an alkali metal salt of a suitable organic carboxylic acid, for example the sodium salt of 2-et? l-hexane? co, with an alkali metal or organic alkaline earth metal compound, such as hydroxide, carbonate, or corresponding acid carbonate, such as sodium or potassium acid hydroxide, carbonate, or carbonate, with a corresponding calcium compound, or with ammonia or with a suitable organic amine, preferably using stoichiometric quantities or only a small excess of the forming agent salt An acid addition salt of the compounds of Formula I can be obtained in the customary manner, for example by treatment of a compound of Formula I with an acid or a suitable anion exchange reagent. Internal salts of the compounds of Formula I which contain acid and basic salt-forming groups, for example a free carboxyl group and a free amino group, for example, can be formed by neutralizing the salts, such as acid, to the isoelectric point, for example with free bases, or by its treatment with ion exchangers A salt of a compound of Formula I can be converted in the customary manner into the free compound; a metal or ammonium salt can be converted, for example, by its treatment with a suitable acid, and an acid addition salt, for example, by its treatment with a suitable basic agent. In both cases, exchangers can be used Suitable ions Stereoisomer mixtures, for example mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se, by means of appropriate separation methods. For example, diastereomeric mixtures can be separated into their individual diastereomers by of fractional crystallization, chromatography, solvent distribution, and similar procedures. This separation can take place either at the level of one of the starting compounds, or in a compound of Formula I itself. The enantiomers can be separated through the formation of diastereomeric salts, for example by salt formation with a pure chiral acid in enantiomers, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands. Intermediates and final products can be processed and / or processed in accordance with the final methods, for example they employ Chromatographic methods, distribution methods (re) cpstal? zac? on, and the like Starting Materials Starting materials are known in the art, are commercially available, or can be prepared according to methods that are known in the art. Protective groups, if not specifically mentioned, can be introduced and removed in the appropriate steps, in order to prevent functional groups, whose reaction is not desired in the step or corresponding reaction steps, employing protective groups, methods for their introduction and removal, as described above or below, for example, in the references mentioned under "General Conditions of the Process "The person skilled in the art will be able to easily decide if and which protective groups are useful or required When, in the starting materials, we use R1, R2, R3, X1, X2, X3, X4, Y, Y2, Ra, D, R6, A, R4, Z, Z2, Z3, R5 and n, these symbols preferably have the meanings given for a compound of the formula I, if not otherwise stated or otherwise dictated by the context. The starting materials, for example, can preferably be prepared as follows. For example, a material starting material of formula II, wherein R 1 is unsubstituted or substituted alkyl, unsubstituted or substituted aployl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl (and is bonded with a ring carbon atom), can be prepared from a compound (if required, in the protected carboxyl group) of the formula (Vile wherein Hal is halogen, especially chlorine, iodine, or preferably bromine, or (perfluorinated 1 to 4 carbon alkyl) -sulfonylloxyl, by reaction with a compound of formula IV as defined above in reaction b), under the preferred reaction conditions as described above for reaction b), followed by the removal of protective groups that are no longer required or desired A compound of formula III, wherein Ra is a fraction of the formula IA as defined for a compound of the formula I, and D is NH, for example, can be prepared as follows A compound of the formula III wherein D is NH, Y2 is C, and Ra is a fraction of the formula IA as defined above, wherein A is C (= 0) -N (R4), can be obtained preferably by the condensation of a carbonic acid of the formula or a reactive derivative thereof, wherein Y2 is C, with an amine of the formula to give a compound of the formula wherein Y2 is C Then a compound of the formula III can be obtained, wherein D is NH, in which a compound of the formula IX, obtained as mentioned above or by any other method, is reduced, for example, by hydrogenation catalytic, for example in the presence of Raney Nickel, in a suitable solvent or mixture of solvents, for example, an alcohol, such as methanol or ethanol, at temperatures, for example, from 0 ° C to 50 ° C, up to corresponding compound of formula III, wherein, in Ra, A is C (= 0) -N (R4) and R6 is hydrogen - wherein the latter, if desired, can then be converted to unsubstituted or substituted alkyl R6 by alkylation with an appropriate halide of the formula R6-Hal (X), wherein R6 is unsubstituted or substituted alkyl, and Hal is halogen, especially bromine or iodine, under the usual alkylation conditions Alternatively, a corresponding compound of formula III, wherein D is O or S, can be obtained by the condensation of a carbonic acid compound analogous to that of formula VII above, or a reactive derivative thereof, but wherein, instead of the nitro group (preferably protected), a hydroxyl or mercapto (preferably protected) is present, with an amine of the formula VIII as described above, and the protecting groups are removed A compound of the formula III , where D is NH, O or S, Y2 is C, and Ra is a fraction of formula IA as defined above, wherein A is N (R4) -C (= 0), can be obtained by condensation of a carbonic acid of the formula or a reactive derivative thereof, with an amino compound of the formula wherein Y2 is C, D * is amino (preferably protected), hydroxyl (preferably protected), mercapto (preferably protected), or nitro, to give a corresponding compound of the formula: wherein D * is amino (preferably protected), hydroxyl (preferably protected), mercapto (preferably protected), or nitro, and Y2 is C, which can then be converted to a corresponding compound of formula III, where either, if D * is nitro, the nitro is reduces to amino, for example, by catalytic hydrogenation, for example in the presence of Raney Nickel, in a suitable solvent or mixture of solvents, for example, an alcohol, such as methanol or ethanol, at temperatures, for example, 0 ° C at 50 ° C, to the corresponding compound of formula III, wherein, in Ra, A is N (R4) -C (= 0) and R6 is hydrogen - where the latter, if desired, can be then converting up to unsubstituted or substituted alkyl R6 by alkylation with an appropriate halide of formula X as defined above, or (a) protecting groups are removed. Reactive derivatives of carbonic acid of the formula VII or XI, as well as the reaction conditions for the condensation, are preferably selected in analogy to the reaction conditions described above for process a). Other starting materials, also those mentioned as starting materials of the intermediates above, are known in the art, are commercially available, and / or can be prepared according to conventional methods, for example, in analogy to, or by, the methods described in the Examples General Process Conditions The following applies in general to all the processes mentioned hereinabove and hereinafter, while the reaction conditions specifically mentioned above or below are preferred in any of the reactions mentioned hereinabove in the present and hereinafter, protecting groups may be used where appropriate or desired, even when this is not mentioned in a specific manner, to protect functional groups that are not intended to take part in a given reaction, and they can be introduced and / or removed in the appropriate or desired steps. Therefore, reactions comprising the use of protecting groups are included as possible, provided that reactions are described without specifically mentioning protection and / or deprotection in this memory. descriptive Within the scope of this disclosure, only one group easily removed that is not a constituent of the desired final product of Formula I, is designated as a "protective group", unless the context otherwise indicates. functional groups by such protecting groups, the protecting groups themselves, and the appropriate reactions for their removal, are described, for example, in conventional reference works, such as JFW McOmie, "Protective Groups m Organic Chemistry", Plenum Press, London and New York 1973, in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999, in "The Peptides", Volume 3 (editors E Gross and J Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th Edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H -D Jakubke and H Jeschkeit, "Aminosauren , Peptide, Proteine "(Amino Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deer-field Beach, and Basel 1982, and in Jochen Lehmann," Chemie der Kohlenhydrate Monosacchapde und Derívate "(Chemistry of monosaccharide carbohydrates and derivatives), Georg Thieme Verlag, Stuttgart 1974 A characteristic of protecting groups is that they can be easily removed (ie, without the presentation of unwanted side reactions), for example by solvation, reduction, photolysis, or alternatively, low physiological conditions (for example, by enzymatic dissociation). All of the aforementioned process steps can be carried out under reaction conditions which are known per se, preferably those mentioned in a specific manner, in the absence, or by custom, in the presence of solvents or diluents, preferably solvents or solvents. diluents which are inert towards the reactants used and dissolve them, in the absence or in the presence of catalysts, condensing or neutralizing agents, for example ion exchangers, such as cation exchangers, for example in the H + form, depending on the nature of the reaction and / or the reactants, at reduced, normal, or elevated temperature, for example in a temperature range from about -100 ° C to about 190 ° C, preferably from about -80 ° C to about 150 ° C, for example from -80 ° C to -60 ° C, at room temperature, from -20 ° C to 40 ° C, or at reflux temperature, under atmospheric pressure or in a Closed container, where appropriate under pressure, and / or in an inert atmosphere, for example under an argon or nitrogen atmosphere. Solvents from which solvents can be selected that are suitable for any particular reaction include those mentioned in a specific manner, or, for example, water, esters, such as lower alkyl lower alkanoates, for example ethyl acetate, ethers, such as ethers to phatics, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol, or 1-or 2-propanol, nitp, such as acetonitop, halogenated hydrocarbons, for example as methylene chloride or chloroform, acid amides, such as dimethyl formamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pipdin or N-met? lp? rrol? d? n-2-one, carboxylic acid anhydrides, such as acid anhydrides lower alkanoic, for example acetic anhydride, cyclic, linear, or branched hydrocarbons, such as cyclohexane, hexane, or isopentane, or mixtures thereof, for example aqueous solutions, unless otherwise indicated in the process description These solvent mixtures can also be used in the processing, for example by chromatography or division. The invention also relates to the forms of the process wherein a compound obtainable as an intermediate at any stage the process is used as a starting material, and the remaining process steps are carried out, or where a starting material is formed under the reaction conditions, or is used in the form of a derivative, by example, in a protected form, or in the form of a salt, or a compound that can be obtained by the process according to the invention is produced under the process conditions, and is further processed in situ. In the process of this invention, preferably the starting materials resulting in the compounds of Formula I described as being preferred The invention also relates to intermediates and / or novel starting materials. Particular preference is given to reaction conditions that are identical or analogous to those mentioned in Examples Preferred Modalities In Accordance With the Invention In the preferred embodiments, as well as in the preceding and following embodiments of more general scope, and also in the claims, any one or more or all of the general expressions may be replaced by the corresponding more specific definitions provided above. and below, thereby providing stronger preferred embodiments of the invention. The invention, in a preferred embodiment, refers to a compound of formula I, wherein. R1 is hydrogen, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted aplo, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, each of R2 and R3 is, independently of the other, hydrogen, halogen, alkyl of 1 to 4 carbon atoms, carbon, trifluoro-methyl, alkoxy of 1 to 4 carbon atoms, or cyano, X ,, X2, X3 and X4 are CH; D is N (R6), wherein R6 is acyl or substituted or substituted alkyl, Y2 is C, Ra is hydrogen if R1 is unsubstituted alkyl with 5 or more carbon atoms, substituted alkyl, unsubstituted or substituted aplo, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heteroocichlo, or, if R1 is hydrogen, halogen or 1 to 4 carbon atoms, is a fraction of the formula IA given above, wherein the dotted line means the bond linking the rest of the molecule of the formula I, A is C (= 0) -N (R4) or N (R4) -C (= O), wherein R4 is hydrogen or unsubstituted or substituted alkyl, Z, is CH = CH, Z2 is N or CH, Z3 is CH, each R5 is, independently of the others, a substitute , and n is 0, 1 or 2, in free form or in salt form The invention, in another preferred embodiment, refers to a compound of formula I, wherein R 1 is hydrogen, halogen or alkyl of 1 to 4 carbon atoms. carbon, each of R2 and R3 is, independently of the other, hydrogen, halogen, alkyl of 1 to 4 carbon atoms, tpfluoro- methyl, alkoxy of 1 to 4 carbon atoms, or cyano, Xi, X2 X3 and X are CH, or up to two of them may be N, D is N (R6) (preferred), O or S, wherein R6 is hydrogen, acyl or unsubstituted or substituted alkyl, Y, is O, S, NH, CH2, N = CH, CH = N or CH = CH, Y2 is C, Ra is a fraction of the formula wherein the dotted line means the bond linking the rest of the molecule of formula I (which is indicated by the wavy line), A is C (= O) -N (R4) or N (R4) -C ( = 0), where R4 is hydrogen or unsubstituted or substituted alkyl, Zi is O, S, NH, CH2, CH = N, N = CH or CH = CH, Z2 is nitrogen or CH, Z3 is CH or N, each R5 present is, independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form In an alternative preferred embodiment, the invention relates to a compound of formula I, wherein R 1 is alkyl substituted with 5 or more carbon atoms or substituted alkyl, aplo unsubstituted or substituted, unsubstituted cycloalkyl or substituted, or unsubstituted or substituted heterocyclyl, each of R2 and R3 is, independently of the other, hydrogen, halogen, alkyl of 1 to 4 carbon atoms, trifluoro-methyl, alkoxy of 1 to 4 carbon atoms, or cyano, Xi, X2 X3 and X4 are CH, or up to two of them may be N, D is N (R6) (preferred), O or S, wherein R6 is hydrogen, acyl or unsubstituted or substituted alkyl, is O, S, NH, CH2, N-CH, CH = N or CH = CH, Y2 is C or N, Ra is absent or, if Y2 is C, is hydrogen, in free form or in salt form The invention also relates to pharmaceutical preparations, to the use of a compound in the treatment or for the manufacture of a pharmaceutical preparation useful in the treatment of a disease that responds to modulation of protein kinase (especially inhibition), to a method of treatment, which comprises administering to an individual (animal or preferably human) in need of such treatment, a compound of the Formula I or a pharmaceutically acceptable salt thereof, in an amount which is efficient in the treatment of a disease that responds to modulation (especially inhibition) of a protein kinase (especially a tyrosine protein kinase), and to a process for the manufacture of a compound of formula I, or a salt thereof, in each case preferably the compound of formula I, or the (pharmaceutically acceptable) salt thereof, is a compound characterized as being preferred hereinbefore or hereinafter herein. The invention is also preferably referred to to the embodiments given in the claims (especially the dependent ones) All the claims, therefore, are included as reference herein The invention relates in particular to a compound of the Formula I given in the Examples, or a pharmaceutically acceptable salt thereof, or to its use according to the invention, as well as to the novel starting materials and processes and intermediates mentioned in the Examples Pharmaceutical Compositions The invention also relates to pharmaceutical compositions comprising a compound of Formula I (preferably novel), to its use in the therapeutic treatment (in a broader sense of the invention, also prophylactic), or to a method of treatment of a disease or disorder that depends on a protein kinase activity (especially tyrosma) inadequate, especially the disorders or preferred diseases mentioned above, to the compounds for this use, and to pharmaceutical preparations for their manufacture, especially for the mentioned uses. More generally, the pharmaceutical preparations are useful in the case of the compounds of the invention. Formula I The pharmacologically acceptable compounds of the present invention may be present in, or may be employed, for example, for the preparation of pharmaceutical compositions comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. , as an active ingredient, together or in admixture with one or more inorganic or organic, solid or liquid, pharmaceutically acceptable vehicles (carrier materials) The invention also relates to a pharmaceutical composition that is suitable for administration to a warm-blooded animal, special to a human being (or to ol cells) cellular lines derived from a warm-blooded animal, especially a human being, for example lymphocytes), for the treatment of (this, in a broader aspect of the invention, also includes the prevention of (= prophylaxis against)) a disease that responds to the inhibition of the protein kinase activity (especially tyrosma), which comprises an amount of a compound of the Formula I, or a pharmaceutically acceptable salt thereof, which is preferably effective for said inhibition , together with when minus a pharmaceutically acceptable carrier The pharmaceutical compositions according to the invention are those for enteral administration, such as nasal, rectal, or oral, or parenteral, such as intramuscular or intravenous, to warm-blooded animals (especially to a human) , which comprise an effective dose of the pharmacologically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of blood-letting animal, the body weight, the age and the condition. individual, individual pharmacokinetic data, the disease to be treated, and the mode of administration The invention also relates to a method of treatment for a disease that responds to the inhibition of a disease that depends on an inappropriate activity of a protein kinase (especially tyrosma), which comprises administering a pro or a particularly therapeutically effective one of a compound of Formula I, or a pharmaceutically acceptable salt thereof, especially to a warm-blooded animal, for example to a human being, which, taking into account one of the above-mentioned diseases, requires said treatment The dose of a compound of Formula I or a pharmaceutically acceptable salt thereof to be administered to warm-blooded animals, for example to humans of a body weight of approximately 70 kilograms, is preferably from about 3 milligrams to about 10 grams, more preferably from about 10 milligrams to about 1.5 grams, and most preferably from about 100 milligrams to about 1,000 milligrams / person / day, preferably divided into one to three individual doses, which, for example, may be the same size. Usually, children receive half the dose for adults. The pharmaceutical compositions comprise from about 1 percent to about 95 percent, preferably from about 20 percent to about 90 percent of the active ingredient. The pharmaceutical compositions according to the invention, for example, can be in a unit dose form, such as in the form of ampoules, flasks, suppositories, dragees, tablets, or capsules. the present invention are prepared in a manner known per se, for example by m It is preferred to use solutions of the active ingredient, and also suspensions, and in particular isotonic aqueous solutions or suspensions, being possible, for example, in the case of the compositions These compositions or suspensions are prepared prior to use of the active ingredient alone or together with a vehicle, for example mannitol.

Pharmaceuticals can be sterilized and / or can comprise excipients, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure, and / or pH regulators, and are prepared in a manner known per se. same, for example by means of conventional processes of dissolution or hofilization. These solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinyl pyrrolidone, or gelatin. The suspensions in oil comprise, as the oil component, the vegetable, synthetic, or semi-synthetic oils customary for injection purposes As such, esters of liquid fatty acids containing, as the acid component, a long chain fatty acid having from 8 to 22, special from 12 to 22 carbon atoms, for example laupco acid, tdedelic acid, myristic acid, pentadecyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or the corresponding unsaturated acids, for example oleic acid, elaidic, erucic acid, brasidic acid, or noleic acid, if desired with the addition of antioxidants, for example vitamin E, ß-expensive teno, or 3,5-d? terbut? l-4-h? drox? -toluene. The alcohol component of these fatty acid esters have a maximum of 6 carbon atoms, and is a mono- or polyhydroxy-, for example a mono-, di-, or tp-hydroxy-alcohol, for example methanol, ethanol, propanol, butanol, or pentanol, or the isomers thereof, but especially glycol and g cerol Accordingly, the following examples of fatty acid esters of ethyl oleate, isopropyl mmstate, isopropyl palmitate, "Labrafil M 2375" (pohoxyethylene tepopolate) should be mentioned. g cerol, Gattefossé, Paris), "Miglyol 812" (saturated fatty acid chain with a chain length of 8 to 12 carbon atoms, Huis AG, Germany), but especially vegetable oils, such as cottonseed oil , almond oil, olive oil, castor oil, sesame oil, soybean oil, and peanut oil The compositions for injection or infusion are prepared in the usual manner under sterile conditions, the same applies to the introduction of the compositions into ampoules or flasks, and to the sealing of the containers. The pharmaceutical compositions for oral administration can be obtained by the combination of the active ingredient. with solid vehicles, if desired, a resulting mixture is granulated, and the mixture is processed, if desired or necessary, after the addition of the appropriate excipients, in tablets, dragee cores, or capsules. It is also possible that they are incorporated in containers of plastic that allows the active ingredients to diffuse or be released in the measured amounts. Suitable carriers are in particular fillers, such as sugars, for example, lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example. example calcium triphosphate or calcium acid phosphate, and binders, such as starch pastes, using, for example, corn starch, wheat starch, rice starch, or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl -cellulose, sodium carboxymethyl cellulose, and / or polyvinyl pyrrolidone, and / or, if desired, disintegrants, such as the above-mentioned starches, and / or carboxymethyl starch, crosslinked pohvinyl-pyrro donate , agar, alginic acid or a salt thereof, such as sodium alginate The excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol IA the dragee cores are provided with suitable, optionally enteric coatings, using, among other things, concentrated sugar solutions, which may comprise gum arabic, talc, polyvinyl pyrro-don, pohetileng col, and / or it gave titanium oxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxy-propyl methyl cellulose phthalate Capsules are capsules dry filled made of gelatin, and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Dry filled capsules can comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and / or skimmers, such as talc or stearate magnesium, and if desired, with stabilizers In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil, or liquid polyethylene glycols, it being possible also to add stabilizers and / or antibacterial agents Dyes or pigments may be added to tablets or dragee coatings, or capsule shells, for example, for identification purposes, or to indicate a different dose of the active ingredient A compound of Formula I also it can be used advantageously in combination with other biologically active agents, preferably with other anti-proliferative agents. These anti-proliferative agents include, but are not limited to, aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors; Topoisomerase II inhibitors, active agents in microtubules; alkylating agents, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclo-oxygenase inhibitors, MPP inhibitors; mTOR inhibitors, anti-neoplastic anti-metabolites, platinum compounds, compounds that direct / reduce the activity of a protein or lipid kinase and other anti-angiogenic compounds, compounds that direct, reduce, or inhibit the activity of a phosphatase of protein or lipid; gonadorelin agonists; anti-androgens; inhibitors of methionine amino peptidase; bisphosphonates; biological response modifiers; antibodies anti-proliferative, heparanase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors, agents used in the treatment of hematological malignancies, compounds that direct, reduce, or inhibit the activity of Flt-3, Hsp90 inhibitors and temozolomide (TEMODAL®) The term "aromatase inhibitor", as used herein, refers to a compound that inhibits estrogen production, ie, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively The term includes, but is not limited to, spheroids, especially atamestane, exemestane, and formestane, and in particular non-spheroids, especially amino-glutethimide, rogletimide, pipdoglutethimide, tplostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole Exemestane can be administered, for example, in the form as it is traded, for example under the registered trademark AROMASIN Formestane can be administered, for example, in the manner in which it is traded , for example under the registered trademark LENTARON Fadrozole can be administered, for example, in the form as it is traded, for example under the registered trademark AFEMA. Anastrozole can be administered, for example, in the form as it is traded, by example under the registered trademark ARIMIDEX Letrozole can be administered, for example, in the form as it is traded, for example under the registered trademark FEMARA or FEMAR The amino-glutetimide is it can be administered, for example, in the form as it is traded, for example under the registered trademark ORIMETEN A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor, is particularly useful for the treatment of tumors positive for the hormone receptor, for example breast tumors The term "anti-estrogen", as used herein, refers to a compound that antagonizes the effect of estrogen at the level of the estrogen receptor. The term includes, but is not limited to, a, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride Tamoxifen can be administered, for example, in the form as it is marketed, for example under the registered trademark NOLVADEX Raloxifene hydrochloride can be administered, for example, in the form how it is traded, for example under the registered trademark EVISTA. The fulvestrant can be formulated as disclosed in US Pat. No. 4,659,516, or it can be administered, for example, in the form as it is traded, for example under the registered trademark FASLOREX A combination of the invention comprising a chemotherapeutic agent which is an anti-estrogen, is particularly useful for the treatment of tumors positive for the estrogen receptor, for example breast tumors The term "anti-androgen", as used herein, refers to to any substance that is capable of inhibiting the effects biologicals of androgenic hormones, and includes, but is not limited to, bicalutamide (CASODEX), which may be formulated, for example, as disclosed in U.S. Pat. No. 4,636,505. The term "agonist of gonadorelma ", as used herein, includes, but is not limited to, abare x, goserelma, and goserelma acetate. Gosere na is disclosed in U.S. Patent No. US 4,100,274, and may be administering, for example, in the way it is traded, for example under the registered trademark ZOLADEX Abarelix can be formulated, for example, as disclosed in US Pat. No. 5,843,901 The term "inhibitor" of topoisomerase I ", as used herein, includes, but is not limited to, topotecan, gimatecan, ipnotecan, camptothecin and its analogues, 9-n? tro-camptotec? na and the macromolecular camptothecin conjugate PNU-166148 ( compound A1 of International Publication Number WO99 / 17804). The ipnotecan can be administered, for example, in the way it is traded, for example under the trademark registered CAMPTOSAR The topotecan can be administered, for example, in the way it is traded, for example under the registered trademark HYCAMTIN The term "Topoisomerase M inhibitor", as used herein, includes, but is not limited to, anthracyclines, such as doxorubicin (including the liposomal formulation, by example CAELYX), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide can be administered, for example, in the form as it is traded, for example under the registered trademark ETOPOPHOS. teniposide can be administered, for example, in the form as it is traded, for example under the registered trademark VM 26-BRISTOL Doxorubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ADRIBLASTIN O ADRIAMYCIN The epirubicum can be administered, for example, in the way it is traded, for example under the registered trademark FARMORUBICIN Iridubicum can be administered, for example, in the form as it is traded, for example under the registered trademark ZAVEDOS Mitoxantrone can be administered, for example, in the form as it is traded, for example under the registered trademark NOVANTRON The term "active agent in microtubules" refers to microtubule stabilizing and microtubule destabilizing agents, and microtubulin polymerization inhibitors, including, but not limited to, taxanes, for example paclitaxel and docetaxel, vinca alkaloids, for example vinblastma, especially vmblastin sulfate, vincpstma, especially vmcpstine sulfate, and vinorelbine, discodermolyds, colchicine, and epothilones and their derivatives, for example epothilone B or a derivative thereof paclitaxel can be administered, for example, in the form as it is traded, for example TAXOL. Docetaxel can be administered, for example, in the form as it is traded, for example under the registered trademark TAXOTERE. Vmblastin sulfate can be administered, for example, in the manner in which it is traded, for example under the registered trademark VINBLASTIN RP Vincpstine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark FARMISTIN The discodermide can be obtained , for example, as disclosed in U.S. Patent No. 5,010,099 Also included are epothilone derivatives disclosed in Patent Numbers WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461, and WO 00/31247 Epothilone A and / or B are especially preferred. The term "alkylating agent", as used herein, includes, but is not limited to, a, cyclone ofosfamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel) Cyclophosphamide can be administered, for example, in the form as it is traded, for example under the registered trademark CYCLOSTIN. Ifosfamide can be administered, for example, in the way it is traded, for example under the registered trademark HOLOXAN The term "histone deacetylase inhibitors" or "HDAC inhibitors" refers to the compounds that inhibit histone deacetylase, and which have an anti-activity. pro f erati va This includes the compounds disclosed in International Publication Number WO 02/22577, especially Nh? drox? -3- [4 - [[(2-h? drox? -et? l) - [2- (1 H-? Ndol-3-? I) -et? L] -am ino] - metí liten? L] -2E-2-propenam ida, Nh? Drox? -3- [4- [ [[2- (2- metí 1-1 H-? Ndol-3-? L) -et? L] -am? No] -met? L] -fen? L] -2E-2-propenam? Da, and pharmaceutically acceptable salts thereof Suberoyl anilma hydroxyamic acid (SAHA) is especially included. The term "anti-neoplastic anti-metabolite" includes, but is not limited to, 5-fluorouracil (5- FU), capecitabine, gemcitabma, DNA demethylating agents, such as 5-azac? T? D? Na and decitabine, methotrexate, edatrexate, and foc acid antagonists, such as pemetrexed. Capecitabine can be administered, for example, in the way it is traded, for example under the registered trademark XELODA The gemcitabma can be administered, for example, in the way it is traded, for example under the registered trademark GEMZA The monoclonal antibody trastuzumab, which may be administered, for example, in the form as it is traded, for example under the registered trademark HERCEPTIN, is also included. The term "platinum compound", as used herein, includes, but it is not limited to, carboplatma, cisplatin, cisplatmo, and oxaliplatma Carboplatma can be administered, for example, in the form as it is traded, for example under the registered trademark CARBOPLAT Oxaliplatma can be administered, for example, in the form how it is traded, for example under the registered trademark ELOXATIN The term "compounds that direct / reduce the activity of a protein kinase or 11-fold and other anti-angiogenic compounds", as used herein, includes, but is not limited to, kinase inhibitors. of protein tyrosma and / or of septa and / or threonine kinase, or inhibitors of acid kinase, for example a) Compounds that direct, reduce, or inhibit the activity of platelet-derived growth factor (PDGFR) receptors, such as compounds that direct, reduce, or inhibit the activity of PDGFR, especially compounds that inhibit the receptor of the platelet-derived growth factor, for example an N-phenol-2-pipmidine-amine derivative, for example imatinib, SU101, SU6668, and GFB-111, b) Compounds that direct, reduce, or inhibit activity of fibroblast growth factor receptors (FGFR), c) Compounds that direct, reduce, or inhibit insulin-like growth factor receptor I (IGF-IR) activity, especially compounds that inhibit IGF-IR , such as the compounds disclosed in International Publication Number WO02 / 092599, d) Compounds that direct, reduce, or inhibit the activity of the receptor tyrosine kinase family Trk, e) Directing, reducing, or inhibit activity of the receptor tyrosine kinase family Axl, f) Compounds that direct, reduce, or inhibit the activity of the c-Met receptor, g) Compounds that direct, reduce, or inhibit the activity of receptor tyrosome kinases c-Kit - (part of the platelet-derived growth factor receptor family), such as compounds that direct, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit the receptor c -Kit, for example imatimb, h) Compounds that direct, reduce, or inhibit the activity of members of the c-Abl family, and their gene fusion products (eg, BCR-Abl kinase), such as compounds that direct, reduce, or inhibit the activity of members of the c-Abl family, and their gene fusion products, for example a derivative of N-phenol-2-p? r? m? d? n-am? na, for example imatinib, PD180970, AG957, NSC 680410, or PD173955 from ParkeDavis, i) Directing compounds, re duce, or inhibit the activity of the protein kinase C (PKC) members and the Raf family of sepna / threonine kinases, members of the MEK family, SRC, JAK, FAK, PDK, and Ras / MAPK, or of the kinase family Pl (3), or of the kinase family related to C-nase-PI (3), and / or members of the cyclin-dependent kinase family (CDK), and are especially derivatives of estaurospopna that are disclosed in the Patent of the United States of North America. ,093,330, for example midostaupna examples of additional compounds include, for example, UCN-01, safingol, BAY 43-9006, Bpostatin 1, Pepfosma, llmofosma, RO 318220 and RO 320432, GO 6976, Isis 3521, LY333531 / LY379196, compounds of isoqumoline, such as those disclosed in International Publication Number WO 00/09495, FTIs PD184352, or QAN697 (a P13K inhibitor), j) Compounds that direct, reduce, or inhibit the activity of a protein kinase tyrosma, such as imatimb mesylate (GLIVEC / GLEEVEC) or tirfostma A tirfostm is preferably a low molecular weight compound (Mr <1500), or a pharmaceutically acceptable salt thereof, especially a compound selected from the class of benci den-malonitplo, or of the class of S-apl-bencen-malonitplo or of cinchona of bisubstrate, but especially any compound selected from the group consisting of tirfostma A23 / RG-50810, AG 99, tirfostma AG 213 , tirfostma AG 1748, tirfostina AG 490, tirfostma B44, enantiomero tirfostma B44 (+), tirfostma AG 555, AG 494, tirfostma AG 556, AG957, and adafostma (adamantyl ester of acid 4-. { [(2,5-d? H? Drox? -fen? L) -met? L] -am? No} -benzo? co, NSC 680410, adafostma), and k) Compounds that direct, reduce, or inhibit the activity of the tyrosome kinase family of epidermal growth factor receptors (EGFR, ErbB2, ErbB3, ErbB4 as homo- or hetero-dimers) ), such as the compounds they direct, reduce, or inhibit the activity of the epidermal growth factor receptor family, which are in particular compounds, proteins, or antibodies that inhibit the members of the epidermal growth factor receptor tyrosine kinase family, for example the factor receptor epidermal growth, ErbB2, ErbB3 and ErbB4, or that bind to the epidermal growth factor or to the ligands related to epidermal growth factor, and are in particular the compounds, proteins, or generic monoclonal antibodies and specifically disclosed in International Publication Number WO 97/02266, for example the compound of Example 39, or in Patent Numbers EP 0 564409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983, and in particular WO 96/30347 (for example, the compound known as CP 358774), WO 96/33980 (for example, the compound ZD 1839), and WO 95/03283 (for example, compound ZM105180), for example trastuzumab (Herpetin®), cetuximab, Iressa, erlotmib (Tarceva ™), CI-1033, EKB-569, GW-2016, E1.1, E24, E25, E62, E64, E2 11, E63 or E763, and the 7H-pyrrolo- [2,3-d] -p? R? M? D? Na derivatives disclosed in International Publication Number WO 03/013541 Other anti-angiogenic compounds include compounds that have another mechanism for their activity, for example unrelated to the inhibition of protein kinase or lipid, for example tahdomide (THALOMID), and TNP-470 Compounds that direct, reduce, or inhibit the activity of a protein or recombinant phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25 , for example, okadaic acid or a derivative thereof Compounds that induce cell differentiation processes are, for example, retinoic acid, a-, and-, or d-tocopherol, or a-, Y-, or d-tocotpenol The term "cyclooxygenase inhibitor", as used herein, includes, but is not limited to, for example, Cox-2 inhibitors, 2-ar? L-am? No-phen? L-ace Co-substituted by 5-alkyl and its derivatives, such as celecoxib (CELEBREX), or rofecoxib (VIOXX), etopcoxib, valdecoxib, or a 5-alkyl-2-ar? l-am? no-phen ? -acetic acid, for example 5-met? l-2- (2'-chloro-6'-fluoro-an? l? no) -phen? -acetic acid, lumiracoxib The term "mTOR inhibitors" "refers to compounds that inhibit the mammalian target of rapamycin (mTOR), and which have an anti-pro-active activity, such as siro mus (Rapamune®) evero mus (Cert? canMR), CCI-779, and ABT578. Immunomodulatory drugs that may be useful in combination with a compound of the present invention include, for example, mediators, e.g., inhibitors, of mTOR activity, including rapamycin of the formula and rapamycin derivatives, for example, including 40-O-alkyl? -rapam? c? na derivatives, such as derivatives of 40-Oh? drox? -alkyl-rapam? c? na, such as 40- O- (2-h? Drox?) - et? L-rapamycin (everohmus), 32-deoxo-rapam? C? Na derivatives and 32-hydroxy-rapamycin derivatives, such as 32-deoxo-rapam? C? na, 16-O-substituted derivatives of rapamycin, such as 16-pent-2? n? lox? -32-deoxo-rapam? c? na, 16-pent-2? n? lox? -32 (S or R) -dihydro-rapamycin, 16-pent-2-? N? Lox? -32 (S or R) -d? H? Dro-40-O- (2-h? Drox? -et ?) rapamycin, rapamycin derivatives that are acylated in the oxygen group at position 40, for example, 40- [3-hydrox? -2- (hydrox? -met? l) -2-methyl-propanoate] -rapam? Cina (also known as CCI779), rapamycin derivatives that are substituted in the position 40 by heterocyclic, for example, 40-ep? - (tetrazol? l) -rapamicma (also known as ABT578), The so-called as rapalogos, for example, as disclosed in International Publications Nos. WO9802441 or WO0114387, for example, such as 40-Od? met? l-fosfinil-rapamycin, including AP23573, and the compounds that are disclosed under the name of biolimus (biolimus A9), including 40-O- (2-ethoxy?) - et? -rapam? c? na, and the compounds that are disclosed under the name of TAFA-93, preferably 40-O- (2-h? drox?) - et? l-rapam? c? na , CCI779, ABT578, or AP23573, more preferably 40-O- (2-h? Drox?) - et? L-rapam? C? Na (everohmus) Rapamycin and other rapamycin derivatives may be administered as appropriate, for example, in Dosages that are known for rapamycin or for rapamycin derivatives, for example, everohmus can be administered in dosages from 0 1 milligrams to 15 milligrams, such as from 0 1 milligrams to 10 milligrams. For example, 0 milligrams, 025 milligrams, 05 milligrams, 075 milligrams, 1 milligram, 25 milligrams, 5 milligrams, or 10 milligrams, for example, in the form of tablets (dispersible), for example, a weekly dosage may include up to 70 milligrams, depending on the disease that is being treated Other rapamycin derivatives can be given at similar dosage intervals The term "bisphosphonates", as used herein, includes, but is not limited to, etidronic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic, and zoledronic acids. "Etidronic acid" may be administered, for example, in the way it is traded, for example under the registered trademark DIDRONEL "Clodronic acid" can be administered, for example, in the way it is traded, for example under the registered trademark BONEFOS "Tiludronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark SKELID The "pamidronic acid" "can be administered, for example, in the way it is traded, for example under the registered trademark AREDIAMR" Alendronic acid "can be administered, for example, in the form as it is traded, for example under the registered trademark FOSAMAX The "ibandronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONDRANAT "Risedronic acid" can be administered, for example, in the form as it is traded, for example under the Registered trademark ACTONEL. The "zoledronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ZOMETA. The term "heparanase inhibitor", as used herein, refers to the compounds that direct, reduce, or inhibit the degradation of hepappa sulfate The term includes, but is not limited to, PI-88 The term "biological response modifier," as used herein, refers to a lymphokine or to interferons, for example, "interferon"? The term "inhibitor of Ras oncogenic isoforms", for example H-Ras, K-Ras, or N-Ras, as used herein, refers to compounds that direct, reduce, or inhibit the oncogenic activity of Ras. , for example a "farnesyl transferase inhibitor", for example L-744832, DK8G557 or R115777 (Zarnestra) The term "telomerase inhibitor", as used herein, refers to the compounds they direct, reduce, or inhibit telomerase activity Compounds that direct, reduce, or inhibit telomerase activity are especially compounds that inhibit the telomerase receptor, for example telomestatin The term "methionine aminopeptidase inhibitor", as used herein, it refers to compounds that direct, reduce, or inhibit the activity of methionine aminopeptidase. Compounds that direct, reduce, or inhibit the activity of methionine aminopeptidase are, for example, bengamide, or a derivative thereof The term "proteasome inhibitor", as used herein, refers to compounds that direct, reduce, or inhibit proteasome activity. Compounds that direct, reduce, or inhibit proteasome activity include, for example, PS -341 and MLN 341 The term "matrix metalloproteinase inhibitor" or ("MMP inhibitor"), as used herein, includes, but is not limited to, peptidomimetic and non-peptidomimetic inhibitors of collagen, tetracycline derivatives, e.g. the peptidomimetic inhibitor of hydroxamate, batimastat, and its orally bioavailable analog, mapmastate (BB-2516), ppnomastate (AG3340), metastate (NSC 686551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996 The term " agents used in the treatment of hematological malignancies, "as used herein, includes, but is not limited to, tyrosine kinase inhibitors type FMS, for example compounds that direct, reduce, or inhibit Flt activity. 3, interferon, 1-bD-arabinofuransil-cytosma (ara-C), and bisulfan, and ALK inhibitors, for example compounds that direct, reduce, or inhibit anaplastic lymphoma kinase. The term "directing compounds, reduce , or inhibit activity of Flt-3", are especially compounds, proteins, or antibodies that inhibit Flt-3, for example PKC412, midostaupna, a derivative of staurospopne, SU11248 and MLN518 The term" HSP90 inhibitors ", as used herein , includes, but is not limited to, compounds that direct, reduce, or inhibit the intrinsic ATPase activity of HSP90, which degrade, direct, reduce, or inhibit HSP90 client proteins through the ubiquitose proteasome pathway.

Compounds that direct, reduce, or inhibit the intrinsic activity of HSP90 ATPase are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, for example 17-al? -amino, 17-demethoxy? -geldanam? c? na (17AAG), a derivative of geldanamycin, other compounds related to geldanamycin, radicicol, and HDAC inhibitors. The term "anti-proliferative antibodies", as used herein, includes, but is not limited to , trastuzumab (Hercept? n R), Trastuzumab-DM1, bevacizumab (Avast? nMR), ptuximab (Rituxan®), PR064553 (ant? -CD40), and antibody 2C4 Antibodies means, for example, intact monoclonal antibodies, antibodies polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity. For the treatment of acute myeloid leukemia (AML), the compounds of Formula I can be used in Combination with conventional leukemia therapies, especially in combination with therapies used for the treatment of acute myeloid leukemia. In particular, the compounds of Formula I can be administered in combination, for example, with the farnesyl transferase inhibitors and / or other drugs useful for the treatment of acute myeloid leukemia, such as daunorubicin, adpamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatmo, and PKC412 The structure of the active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index" or from the databases, for example Patents International (for example, IMS World Publications The above-mentioned compounds, which can be used in combination with a compound of Formula I, can be prepared and administered as described in the art, such as in the documents cited above. A compound of Formula I can also be used with advantage in combination with the known therapeutic processes, for example the administration of hormones, or in particular radiation A compound of Formula I can be used in particular as a radiosensibihzante, especially for the treatment of tumors exhibiting poor sensitivity to the radiotherapy "Combination" means either a fixed combination in a unit dosage form n, or a kit of parts for combined administration, wherein a compound of Formula I and a combination component can be administered in an independent manner at the same time or separately within time intervals that allow especially that the components of combination show a cooperative effect, for example, synergistic, or any combination thereof EXAMPLES The following Examples illustrate the invention, without limiting its scope. Temperatures are measured in degrees Celsius. Unless indicated otherwise, reactions take place at room temperature. The Rf values in thin layer chromatography indicate the proportion of the distance moved. for each substance at the distance moved by the eluent front Rf values for thin layer chromatography are measured on TLC plates of 5 x 10 centimeters, silica gel F254, Merck, Darmstadt, Germany, solvent systems are marked in the Examples as follows * 10 percent methanol / 90 percent methylene chloride (CH2Cl2) ** 50 percent hexane / 50 percent ethyl acetate 100 percent methylene chloride (CH2CI2) If not Indicates otherwise, the analytical HPLC conditions are as follows Column Engineepng Column, Inc, Matrix, 3 microns, C18 150 x 46 millimeters (Lot # 205) Ultraviolet absorption detection at 215 and 254 nanometers The temperature of the column is 35 ° C, and the retention times (tR) are given in minutes Flow rate 1 milliliter / minute Gradient Water (0 to 1 percent acetic acid) / acetonitrile (0 1 percent tpfluoroacetic acid) = 98/2 for 1 minute, up to 100 percent acetonitoplo (0 1 percent tpfluoroacetic acid) in 10 minutes Stays at 100 percent for 2 minutes (total execution time 13 minutes) Abbreviations: HPLC High performance liquid chromatography Isolute Isolute® HM-N by International Solvent Technology ml M? L? L? Tro (s) Min M? Nuto (s) MS-ES Mass spectrometry with electrospray Rf Proportion of fronts in TLC RT Ambient temperature TFA Tpfluoroacetic acid TLC Thin layer chromatography tR Ultraviolet UV retention time Starting Materials General procedure for the synthesis of aniline building blocks (illustrated with the formula and the educts for the N- (3-am? No-4- met? l-fen? l) -3-tr? fluoro-met? l-benzam? da) N- (3-am? No-4-met? L-phen? L) -3-tr? Fluoromet? L- (A) (B) (C) benzamide The compound shown to the left, N- (3-amino-4-met-1-phenol) -3-trifluoro-methyl-benzamide, is obtained by the hydrogenation of the nitro compound (N- (4-met? l-3-n? tro-phen? l) -3-tr? uoro-met? l-benzamide) with Raney nickel in methanol at room temperature The product is obtained in high performance The intermediate compound of nitro (A), N- (3-n? tro-4-met? l-phen? l) -3-tr? fluoro-met? l-benzam? da, is obtained by the reaction of 4-met? l-3-n? tro-phen? l-am? na (B) and 3-tr? fluoro-methyl-benzoyl chloride (C) in methylene chloride at room temperature, and using tpethyl-amine The intermediate (A) is obtained in a good performance Previously similar and different anilines have been described in the literature and in the patents (for example, CAS No 30069-31-9) For the coupling, they are used the corresponding acid chlorides The inverted 3-amino-benzamide derivatives, 3-amino-4-meth? N- (3-tr? uoro-met? l-phen? l) -benzamide and 3-am? no-N- (4-methox? -3-tr? fluoro-met? l-phen?) -4-met? l-benzam? da, are synthesized according to the same procedure, using the starting materials corresponding commercially available Example 1: r 2 -methyl-5- (3-trifluoro-methyl-benzoyl-amino) -phenyl-amide of pyrazolo-H, 5-al-pyridyl-3-carboxylic acid of p? razolo- [1, 5-a] -p? r? d? n-3-carbon? lo (100 milligrams, 055 millimoles, Maybpdge Lot # 291259) and N- (3-am? no-4) -met? l-phenol) -3-tr? fluoro-met? l-benzamide (163 milligrams, 055 millimoles) are dissolved in 2 milliliters dry methylene chloride Tpethyl-amine (93 micro-tros, 066) is added millimoles), and the reaction mixture is stirred at room temperature. After completion of the formation of the product, the reaction mixture is quenched with water and the product is extracted with methylene chloride. The solvent is removed under reduced pressure and the crude product is stirred. absorbs in Isolute The product is purified by automated reverse phase column chromatography (Interchrom Pupflash 15 / 35U C18 column, 70 gram cartridge, water + 0.1% tpfluoroacetic acid and acetonitoplo + tpflu acid solvents) gold-acetic at 0 1 percent) and dried in the high vacuum pump, providing the title compound as a white solid HPLC tR = 1024 minutes, MS-ES (M + H) + = 439, TLC * R, = 063 Example 2: r2-Methyl-5- (3-trifluoro-methyl-phenyl-carbamoyl) -phenyl-amide of pyrazolo-l, 5-al-pyridine-3-carboxylic acid The same procedure is used as in Example 1, except that 3-amino-4-met-lN- (3-tr? uoro-met? l-phen?) -benzamide is reacted in place of the N- (3- am? no-4-met? l-phen?) -3-tpfluoro-methyl-benzamide The product is isolated by automated reverse phase column chromatography (Column-Interchrom Pupflash 15 / 35U C18, 70 gram cartridge, solvents: water + 01 percent tpfluoroacetic acid and acetonitoplo + 0.1 percent tpfluoroacetic acid), and dried in the high vacuum pump The title compound is obtained as a white solid HPLC- tR = 10.52 minutes, MS-ES: (M + H) + = 439, TLC * R, = 060 Example 3: 6-dimethyl-sulfamoyl -r 2 -methyl-5- (3-trifluoro-methyl-phenyl-carbamoyD-phenyl-amide of pyrazolo-H .5-al-pyridine-3-carboxylic acid 6-d? met? l-sulfamo chloride? lp? razolo- [1, 5-a] -p? r? d? n-3-carbonyl (200 milligrams, 035 mi moles) and 3-am? no-4-met? lN- (3-tr? fluoro-met? l-phenol) -benzamide are reacted in 2 milliliters of dry pipdin at room temperature for 18 hours. The solvent is removed under reduced pressure. The product is isolated by automated column chromatography, and dried in the high vacuum pump, providing the title compound as a single gone white HPLC. tR = 10.76 minutes; MS-ES + (M + H) + = 546, TLC ** R, = 025 The starting material is prepared as follows Step 3.1: The 6-d? Met? L-sulfamo chloride? Lp? Razolo-f1, 5 -al-p? r? d? n-3-carbon? lo The acid 6-d? met? l-sulfamo? lp? razolo- [1, 5-a] -p? r? d? n-3- carboxylic (200 milligrams, 057 millimoles) is dissolved in 4 milliliters of chloroform, and oxalyl chloride is added (97 micro-hours, 1.14 millimoles, Fluka) The reaction is refluxed for 3 hours, and then the volatiles are removed under reduced pressure. The crude product is used directly in the next step Step 32 Ac.do 6-d? met? l-sulfamo? lp? razolo-ri, 5-a1-p? r? d? n-3-carboxylic The title compound is prepared according to the literature procedure Yasumitsu Tamura, Yoshio Sumida, Yasuyoshi Miki and Masazumi Ikeda, J Chem Soc Perkm 1, 1974, 406-409 Step 33 Ethyl- Acid ester 6-d? met? l-sulfamo? lp? razolo-M, 5-al-p? r? d? n-3-carbox? l? co Potassium carbonate and ethyl propiolate are added to a suspension stirring of mesitylene sulphonate of 1 -am? no-3-d? met? l-sulfamoyl-pipdinio in chloroform at room temperature For further details, see the literature Yasumitsu Tamura, Yoshio Sumida, Yasuyoshi Miki and Masazumi Ikeda, J Chem Soc Perkm 1, 1974, 406-409 Step 34 Mesitylene sulfonate of 1 -am? No-3-d? Met? L-sulfamo? L-pyridmium The title compound is synthesized according to the typical procedure, using an equimolar mixture of a pipdin derivative and O-mesitylene-sulfonyl-hydroxylamine (MSH), see Literature Y Tamura, J Minamikawa, and Miki, S Matsugashita and M Ikeda, Tett Lett (40), 4133-4135, 1972 Example 4: r5- (4-methoxy-3-trifluoro-methyl-phenyl-carbamoyl) -2- 6-dimethyl-sulfamoyl-pyrazolo-5, 5-al-pyridine-3-carboxylic acid methylphenol-amide The same procedure is employed as described in Example 3, except that 3-amino- N- (4-methox? -3-tr? Uoro-met? L-phen? L) -4-met? L-benzamide in place of 3-am? No-4-met? LN- (3 -tr? fluoro-met? l-fen? l) -benzamide The product is isolated by automated column chromatography, and dried in the high vacuum pump, yielding the title compound as a white solid HPLC tR-1026 minutes, MS-ES + (M + H) + = 576, TLC ** R, = 0 19 Example 5: 6-phenyl-2-methyl-5- (3-trifluoro-methyl-phenyl-carbamoyl) -phenylamide of pyrazolo-M, 5-al-pyridine-3-carboxylic acid The same procedure is employed as described in Example 3, steps 34 to 3 1, except that, in step 34, the 3-phen is used. ? lp? r? d? na (Fluka) The pr The product is isolated by automated column chromatography, and dried in the high vacuum pump, yielding the title compound as a white solid HPLC tR = 11 99 minutes, MS-ES + (M + H) + -515, TLC ** R, -045 Example 6: 6-phenyl-r2-methyl-5- (3-trifluoromethyl-benzoyl-amino) -phenyl-amide of pyrazolo-p, 5-al-pyridine-3-carboxylic acid same procedure as described in Example 3, steps 34 to 3 1, except that, in step 34, the 3-f in 11-pi pdi na (Fluka) and N- (3-am? No-4-met? L-phen? L) -3-tr? Uoro-met? L -benzamide instead of 3- am? no-4-met? N- (3-tr? fluoro-met? l-phen? l) -benzamide The product is isolated by automated column chromatography and dried in the high vacuum pump to provide the compound of the title as a white solid HPLC tR-11 48 minutes, MS-ES + (M + H) + = 515, TLC ** R, = 026 Example 7: o-tolyl-amide of 6- (4-methoxy? phenyl) -pyrazolo-p.5-al-pyridine-3-carboxylic acid The o-tol? l-am? da of the acid 6-bromo-p? razolo- [1, 5-a] -p? r? d? n-3-carboxylic (50 milligrams, 0 15 millimoles), 4-methox? -phen? -boronic acid (279 milligrams, 0 18 millimoles), chloro- [2 '- (d? met? l-am? no ) -2-b? Phen? L? L] - (d? Norborn? L-phosphine) -palladium (46 milligrams, 76 micromoles, Fluka, CAS # 359803-53-5), and potassium carbonate (84 milligrams, 061 moles), are heated in 5 milliliters of dry dioxane at 130 ° C for 20 minutes in the microwave oven The product is isolated by automated column chromatography a, and dried in the high vacuum pump, yielding the title compound as a white solid HPLC tR = 11 20 minutes, MS-ES + (M + H) + = 358, TLC ** R, = 051 The The starting material is prepared as follows Example 7.1: 6-bromo-pyrazolo-ri, 5-al-pyridine-3-carboxylic acid o-tolyl-amide The same procedure is used as described in Example 3, steps 34 to 3 1 , except that in step 34, 3-bromo-p? r? d? na (Fluka) and o-tolyl-amine (Fluka) are used instead of 3-am? no- eleven 4-met? L-N- (3-tr? Uoro-met? L-phen? L) -benzamide. The product is isolated by automated column chromatography, and dried in the high vacuum pump, yielding the title compound as a white solid. HPLC- tR = 10 15 minutes, MS-ES +: (M + H) + = 331; TLC ***. R, = 032.

Example 8: 4-R4- (3-o-tolyl-carbamoyl-pyrazolo-H, 5-al-pyridin-6-yl) -phenyl-piperazine-1-carboxylic acid tert-butyl ester The same procedure is used as described in Example 7, except that the 4- [4- (4,4,5,5-tetramethyl- 1, 1,3,2] -d [oxaborolan-2] terbutil ester is used ?) -phen? -prazole-1-carboxylic acid (Maybridge) instead of 4-methox? -phen? l-boron? co. The product is isolated by automated column chromatography, and dried in the high vacuum pump, yielding the title compound as a white solid. HPLC: t R = 11 52 minutes; MS-ES + - (M + H) + = 512; TLC **: R, = 0.46.

Example 9: 6- (4-morpholin-4-yl-phenyl) -pyrazolo-r, 5-al-pyridin-3-carboxylic acid o-tolyl-amide The same procedure is used as described in Example 7, except that 4- (morpholine) -fen? L-boronic acid (Maybridge) is used in place of 4-methox? -fen? L-boron? Co acid. The product is isolated by automated column chromatography, and dried in the high vacuum pump, yielding the title compound as a white solid HPLC-tR = 9.92 minutes, MS-ES +: (M + H)? - = 413; TLC **: R, = 0.30. Example 10: 6- (3-methoxy-phenyl) -pyrazoloic acid o-tolyl-amide ri.d-al-pyridine-S-carboxylic acid The same procedure is used as described in Example 7, except that the acid 3-methox? -phen? -boron? co (Aldrich) is used instead of the acid. -metox? -fen? l-boron? co The product is isolated by automated column chromatography, and dried in the high vacuum pump, yielding the title compound as a white solid HPLC tR = 1082 minutes MS-ES + (M + H) + = 358, TLC ** R, = 065 Example 11: o-tolyl-amide of 6- (4-dimethylaminophenyl) -pyrazolo-ri.5-al-p? Ridi acid n-3-carboxylic acid The same procedure is used as described in Example 7, except that 4- (d? met? l-am? no) -phen? -boronic acid (Aldrich) is used instead of the acid 4-methox? -fen? L-boron? Co The product is isolated by automated column chromatography, and dried in the high vacuum pump, yielding the title compound as a white solid HPLC tR = 860 minutes, MS-ES + (M + H) + = 371, TLC ** R, = 057 Example 12: o-tolyl-amide of 6- ( 3,4-d-methoxy-phenyl) -pyrazolo-f1.5-a1-pyridine-3-carboxylic acid The same procedure is employed as described in Example 7, except that the acid 3,4-d? Methox? -fen? L-boron? Co (Frontier) is used in place of the 4-methox? -fen? L-boron acid? Co The product is isolated by chromatography automated column, and dried in the high vacuum pump, providing the title compound as a solid white 13 HPLC t R = 1022 minutes, MS-ES + (M + H) + = 388, TLC ** R, = 047 Example 13: Soft Capsules 5,000 soft gelatin capsules are prepared, each comprising as an active ingredient, 005 grams of any of the compounds of Formula I mentioned in any of the above Examples, as follows Composition Active ingredient 250 grams Lauroglycol 2 liters Process The pulverized active ingredient is suspended in Lauroglycol * (proprolineglycol laurate, Gattefosse SA, Saint Ppest, France), and ground in a wet pulverizer, to produce a particle size of approximately 1 to 3 microns. 0419 grams of the mixture in soft gelatin capsules, using a capsule filling machine Example 14: Tablets comprising the compounds of Formula I Tablets are prepared which comprise, as an active ingredient, 100 milligrams of any of the compounds of Formula I in any of the preceding Examples, with the following composition, following the s conventional procedures Composition Active ingredient 100 milligrams Crystalline lactose 240 milligrams Avicel 80 milligrams PVPPXL 20 milligrams Aerosil 2 milligrams Magnesium stearate 5 milligrams 447 milligrams Manufacturing The active ingredient is mixed with the carrier materials, and compressed by means of a tablet-forming machine (Korsch EKO, die diameter of 10 millimeters) Avicel® is microcreated cellulose (FMC, Philadelphia, USA) PVPPXL is polyvinyl -pohpirrolidone, cross-linked (BASF, Germany) Aerosil® is silicon dioxide (Degussa, Germany) Example 15: Inhibition of EphB4 kinase activity Using the test system described above in the general description, the compounds of Examples 1 and 2 are tested for their ability to inhibit the EphB4 kinase IC50 values are found (micromoles / hr ), especially in the interval given in the general description

Claims (1)

1. CLAIMS 1 A compound of the formula wherein R1 is hydrogen, halogen, sulfamoyl, N-alkyl of 1 to 4 carbon atoms-sulfamoyl, N, Nd? -alkyl of 1 to 4 carbon atoms-sulfamoyl, unsubstituted or substituted alkyl, unsubstituted or substituted aplo , unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclic, each of R2 and R3 is, independently of the other, hydrogen, halogen, alkyl of 1 to 4 carbon atoms, trifluoro-methyl, alkoxy of 1 to 4 carbon atoms , or cyano, Xt, X2 X3 and X4 are CH, or up to two of them may be N, D is N (R6) (preferred), O or S, wherein R6 is hydrogen, acyl or unsubstituted or substituted alkyl, and , is O, S, NH, CH2, N = CH, CH = N or CH = CH, Y2 is C or, if Ra is absent, it can be (also) N, Ra is absent if Y2 is N, and R1 is unsubstituted alkyl with 5 or more carbon atoms, substituted alkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl , or heterocyclic unsubstituted or substituted, or, if Y2 is C, is hydrogen if R1 is unsubstituted alkyl with 5 or more carbon atoms, substituted alkyl, unsubstituted aplo 0 substituted, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, or, if Y2 is C and R1 is hydrogen, halogen, 1 to 4 carbon atoms, sulfamoyl, N-alkyl of 1 to 4 carbon atoms-sulfamoyl, N, N-d? -alkyl of 1 to 4 carbon atoms-sulfamoyl, or unsubstituted aplo, is a fraction of the formula wherein the dotted line means the bond linking the rest of the molecule of formula I (which is indicated by the wavy line), A is C (= 0) -N (R4) or N (R4) -C ( = O), wherein R 4 is hydrogen or unsubstituted or substituted alkyl, 17 Z, is O, S, NH, CH2, CH = N, N = CH or CH = CH, Z2 is nitrogen or CH, Z3 is CH or N, each R5 present is, independently of the others, a substituent, and n is 0, 1 or 2, in free form or in salt form 2. A compound according to claim 1 of formula I, wherein R 1 is hydrogen, halogen, alkyl of 1 to 20 carbon atoms which is more substituted or substituted by one or more, preferably up to three substituents independently selected from the group consisting of heterocyclic unsubstituted or substituted as described below, unsubstituted or substituted cycloalkyl as described below, unsubstituted or substituted aplo as defined below, especially phenyl or naphthyl, or alkenyl of 2 to 7 carbon atoms, alkyl of 2 to 7 carbon atoms, halogen, hydroxyl, alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, (alkoxy of 1 to 7 carbon atoms) -alcoxyl from 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, phenoxy, naphthyloxy, phenyl- or naphthyl-1-alkoxy of 1 to 7 carbon atoms, amino-alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, benzoyloxy, naphthoyloxy, nitro, cyano, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl, fe ni I- or naphthyl-alkoxy is 1 to 7 carbon atoms-carbonyl, alkanoyl of 1 to 7 carbon atoms, benzoyl, naphthoyl, carbamoyl, carbamoyl N-mono- or N, Nd? -sust? tu? do, where substituents are selected from alkyl of 1 to 7 carbon atoms and hydroxy-alkyl of 1 to 7 carbon atoms, amidino, guanidino, ureido, mercapto, thioalkyl of 1 to 7 carbon atoms, thiophenyl or thionaphthyl, phenyl- or naphthyl -thioalkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-thiophenyl, alkyl of 1 to 7 carbon atoms-thionaphthyl, haloalkyl of 1 to 7 carbon atoms-mercapto, alkyl of 1 to 7 carbon atoms-sulfinyl, phenyl- or naphthi-sulphonyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfinyl, alkyl of 1 to 7 carbon atoms-phenyl-sulfinyl, alkyl of 1 to 7 carbon atoms-naphthyl-sulfinyl, sulfo, alkane of 1 to 7 carbon atoms-sulphonyl, phenyl- or naphthyl-sulf onyl, faith or I- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfonyl, alkyl of 1 to 7 carbon atoms-phenyl-sulfonyl, halo-alkyl of 1 to 7 carbon atoms-sulfonyl, sulfonamido, benzo-sulfonamido , amino, N-mono- or N, Nd? - [alkyl of 1 to 7 carbon atoms, phenyl and / or phenyl-alkyl of 1 to 7 carbon atoms] -amino, wherein each phenyl or Naphthyl, also in phenoxy or naphthoxy, mentioned above as a substituent or part of a substituted alkyl substituent, is itself unsubstituted or substituted by one or more, for example, up to three, preferably 1 or 2 substituents independently selected from halogen , haloalkyl of 1 to 7 carbon atoms, hydroxyl, alkoxy of 1 to 7 carbon atoms, amino, N-mono- or N, Nd? - (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino, nitro, carboxyl, alkoxy of 1 to 7 carbon atoms -carbonylcarbamoyl, cyano and / or sulphamoyl, unsubstituted or substituted aplo, which is an unsaturated carbocyclic system of not more than 20 carbon atoms, especially not more than 16 carbon atoms, and is mono-, bi- or or tc-cyclic, which is unsubstituted or, in the case of substituted aplo, substituted by one or more, preferably up to three, for example, one or two substituents independently selected from the group consisting of femlo, naphthyl, phenyl - or naphthi 1-alkoxy of 1 to 7 carbon atoms, hydroxy-alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, (alkoxy of 1 to 7) carbon atoms) -alcox 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms-alkyl d and 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, such as tpfluoro-methyl, phenoxy or naphthyloxy-alkyl of 1 to 7 carbon atoms, phenyl- or naphthyl-alkoxy of 1 to 7 atoms carbon-alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-carbonyloxy-alkyl of 1 to 7 carbon atoms, phenyl- or naphthyl-alkoxy of 1 to 7 carbon atoms-carbonyloxy-alkyl 1 to 7 carbon atoms, cyano-alkyl of 1 to 7 carbon atoms, alkenyl of 2 to 7 carbon atoms, alkynyl of 2 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, halogen, hydroxyl, alkoxy from 1 to 7 atoms carbon, alkoxy of 1 to 7 carbon atoms-alkoxy of 1 to 7 carbon atoms, (alkoxy of 1 to 7 carbon atoms) -alcoxyl of 1 to 7 carbon atoms- alkoxy of 1 to 7 carbon atoms , phenoxy, naphthyloxy, phenyl- or naphthyl-alkoxy of 1 to 7 carbon atoms, amino-alkoxy of 1 to 7 carbon atoms, alkanoyloxy of 1 to 7 carbon atoms, benzoyloxy, naphthyloxy, nitro, amino, amino mono- , di- or tp-substituted, wherein the amino substituents are independently selected from alkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, alkane of 1 to 7 carbon atoms-sulfonyl, phenyl , naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and naphthyl-1 -alkyl of 1 to 7 carbon atoms, cyano, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl, phenyl- or naphthyl-1-alkoxy; to 7 carbon atoms -carbonyl, benzoyl, naphthoyl, carbamoyl, carbamoyl N-mono- or N, Nd? -substituted, wherein the substituents are selected from from alkyl of 1 to 7 carbon atoms and hydroxy-alkyl of 1 to 7 carbon atoms, amidino, guanidino, ureido, mercapto, thioalkyl of 1 to 7 carbon atoms, thiophenyl or thionaphthyl, phenyl- or naphthyl-thioalkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 carbon atoms-thiophenyl, alkyl of 1 to 7 carbon atoms-thionaphthyl, haloalkyl of 1 to 7 carbon atoms-mercapto, alkyl of 1 to 7 carbon atoms -sulfinyl, phenyl- or naphthyl-sulfinyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfinyl, alkyl of 1 to 7 carbon atoms-phenyl-sulfinyl, alkyl of 1 to 7 carbon atoms-naphthyl- sulfinyl, sulfo, alkane of 1 to 7 carbon atoms-sulphonyl, phenyl- or naphthylsulfonyl, phenyl- or naphthyl-alkyl of 1 to 7 carbon atoms-sulfonyl, alkyl of 1 to 7 carbon atoms-phenylsulfonyl, haloalkyl of 1 to 7 carbon atoms-sulfonyl, sulfonamido, benzo-sulfonamido, pyrrolidino, pipepdino, pipepdino substituted by amino or N-mono- or N, Nd? - [ alkyl of 1 to 7 carbon atoms, phenyl and / or phenyl-alkyl of 1 to 7 carbon atoms] -amino, unsubstituted or unsubstituted pipepdmilo substituted by N-alkyl of 1 to 7 carbon atoms linked by means of an atom of the ring carbon, piperazmo, alkyl of 1 to 7 carbon atoms-piperazino, morpholmo or thiomorpholino, wherein each phenyl or naphthyl mentioned above as a substituent or as part of a substituent of substituted aplo is itself unsubstituted or substituted by one or more, for example, up to three, preferably 1 or 2 substituents independently selected from halogen, haloalkyl of 1 to 7 carbon atoms, hydroxyl, alkoxy of 1 to 7 carbon atoms, amino, N-mono- or N, Nd? - (alkyl of 1 to 7 carbon atoms, phenyl, naphthyl, phenyl-alkyl of 1 to 7 carbon atoms and / or naphthyl-alkyl of 1 to 7 carbon atoms) -amino, nitro, carboxyl, alkoxy of 1 to 7 carbon atoms -carbonyl, carbamoyl, cyano and / or sulfamoyl; unsubstituted or substituted cycloalkyl, wherein cycloalkyl is a mono- or bi-cyclic hydrocarbon group saturated with 3 to 16, more preferably 3 to 9 ring carbon atoms, and is substituted by one or more, preferably one to three, substituents independently selected from those described for substituted aplo, or is unsubstituted; or heterocyclic unsubstituted or substituted, wherein heterocyclyl is a heterocyclic radical that is unsaturated, saturated or partially saturated, and is a monocyclic or bicyclic or ticcic ring, and has from 3 to 24, more preferably from 4 to 16, and very preferably from 4 to 10 ring atoms, wherein one or more, preferably one to four, especially one or two ring carbon atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, the linking ring preferably having 4 to 12, especially 5 to 7 ring atoms, whose heterocyclic radical is unsubstituted or substituted by one or more, in particular 1 to 3 substituents selected independently from the group consisting of the substituents defined above under "substituted aplo", and wherein the heterocyclyl is in particular a heterocyclic radical selected from the group consisting of oxiranyl, azimni it, azipdmyl, 1,2-oxat? olanyl, thienyl, fuplo, tetrahydro-fuplo, pyranyl, thiopyranyl, thiantrenyl, isobenzo-furanyl, benzo-furanyl, chromenyl, 2H-pyrrolyl, pyrrole, pyrrolinyl , pyrrodimyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazolyl, pyrazothyl, thiazoyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazole, pipdoyl, pyrazinyl, pipmidinyl, piperazinyl, piperazinyl, pipdazmyl, morphoyl, thiomorpholyl, (S-oxo or S, Sd? Oxo) -thiomorfolmyl, indolizinyl, isomdohlo, 3H-? Ndol? Lo, indohlo, benzimidazolyl, cumaplo, indazolyl, tpazo lo, tetrazo lo, pupnil, 4H-qu? Nol? Z? N? Lo, isoquino lo, quinolilo , tetrahydro-quinolyl, tetrahydro-isoqumolyl, decahydro-quinolyl, octahydro-isoquinolyl, benzo-furanyl, dibenzo-furanyl, benzo-thiophenyl, dibenzo-thiophenyl, phthalazinyl, naphthyl nyl, quinoxalyl, n-methyl, quinazolinyl, cinolmyl, ptepdmyl, carbazo lo, beta-carboyl , fenantpdinyl, acpdinyl, pepmidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazyl, chromenyl, isochromanyl and chromanyl, each of these radicals being unsubstituted or substituted by one to three of the substituents mentioned as substituents for substituted aplo, preferably by one to two radicals selected from the group consisting of lower alkyl, especially methyl or tertiary butyl, lower alkoxy, especially methoxy, and halogen, especially bromine or chlorine, each of R2 and R3 is, independently of the other, hydrogen, halogen, alkyl of 1 to 4 carbon atoms, tpfluoro-methyl, alkoxy of 1 to 4 carbon atoms, or cyano, Xi, 2 X3 and X4 are preferably CH, or up to two of them may be N, D is N (R6) (preferred), O or S, wherein R6 is hydrogen, alkanoyl of 1 to 7 carbon atoms, benzoyl, naphthoyl, phenyl-alkanoyl of 1 to 7 atoms carbon, naphthyl-alkanoyl of 1 to 7 carbon atoms, phenyl-sulfonyl or mfepor-sulfonyl alkane, or unsubstituted or substituted alkyl as defined above, Y, is O, S, NH, CH2, N = CH, CH = N o preferably CH = CH, Y2 is preferably C or, if Ra is absent, it can be N, Ra is absent if Y2 is N and R1 is alkyl of 5 to 20 carbon atoms, substituted alkyl as defined aboveunsubstituted or substituted unsubstituted or substituted as defined above, unsubstituted or substituted cycloalkyl as defined above, or unsubstituted or substituted heterocyclic as defined above, or, if Y2 is C, is hydrogen if R1 is alkyl of 5 to 20 carbon atoms , substituted alkyl as defined above, unsubstituted or substituted aplo as defined above, unsubstituted or substituted cycloalkyl as defined above, or unsubstituted or substituted heterocyclyl as defined above, or, if Y2 is C and R1 is hydrogen, halogen or alkyl from 1 to 4 carbon atoms, is a fraction of the formula wherein the dotted line means the bond linking the rest of the molecule of formula I, A is C (= O) -N (R4) or N (R4) -C (= O), wherein R4 is hydrogen or unsubstituted or substituted alkyl as defined above, Z, is O, S, NH, CH2, CH = N, N = CH or preferably CH = CH, Z2 is nitrogen or preferably CH, Z3 is CH or N, each R5 present is, independently of the others, a substituent selected from the group consisting of alkyl of 1 to 7 carbon atoms, halogen, haloalkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, hydroxyl, alkoxy of 1 to 7 carbon atoms , nitro, amino, mono- or di-substituted amino, wherein the amino substituents are independently selected from alkyl of 1 to 7 carbon atoms and alkanoyl of 1 to 7 carbon atoms, cyano, carboxyl, alkoxy of 1 to 7 carbon atoms -carbonyl, carbamoyl, N-mono- or N, Nd? - (alkyl of 1 to 7 carbon atoms) -substituted by carbamoyl, amidino, guanidino, ureido, lower thioalkyl, sulfo, alkane of 1 to 7 carbon atoms-sulfonyl and sulfonamido, and n is 0, 1 or 2 A compound according to claim 1 of formula I, wherein R 1 is hydrogen or, halogen or alkyl of 1 to 4 carbon atoms, each of R2 and R3 is, independently of each other, hydrogen, alkyl of 1 to 4 carbon atoms, halogen or cyano, each of X ,, X2, X3 and X is CH, D is N (R6), where R6 is hydrogen, alkanoyl of 1 at 7 carbon atoms, alkyl of 1 to 7 carbon atoms or phenyl-alkyl of 1 to 7 carbon atoms, Y1 is CH = CH, Y2 is C, Ra is a fraction of the formula wherein the dotted line means the bond linking the rest of the molecule of formula I, A is C (= 0) -N (R4) or N (R4) -C (= 0), wherein R4 is hydrogen or alkyl of 1 to 7 carbon atoms, Z, is CH = CH, Z2 is N or CH, Z3 is CH, each R5 present is, independently of the others, a substituent selected from the group consisting of alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, alkanoyl of 1 to 7 carbon atoms, hydroxyl, alkoxy of 1 to 7 carbon atoms, amino, mono- or di-substituted amino, wherein the substituents of amino are independently selected from alkyl of 1 to 7 carbon atoms and alkanoyl of 1 to 7 carbon atoms, cyano, carboxyl, alkoxy of 1 to 7 carbon atoms-carbonyl, carbamoyl and carbamoyl substituted by N-mono- or N, Nd? - (alkyl of 1 to 7 carbon atoms) ), and n is 0, 1 or 2 4 A compound according to claim 1 of formula I, selected from the group consisting of [2-met? l-5- (3-tr? methyl-benzoyl-amine) -phenol] -amide of p? razolo- [1, 5-a] -p? r? d? n-3-carboxyl? co, [ 2-Met? L-5- (3-tr? Uoro-met? L-phen? L-carbamo? L) -phen? L] -amide of p? Razolo acid- [1, 5-a] -p? r? d? n-3-carbox? l? co, 6-d? I put l-sulfamo? l- [2- metí l-5- (3-tr? f luoro-metí lf in il-carbamo? l) -fen? l] -am? da of the acid p? razolo- [1, 5-a] -p? R? D? N-3-carboxy co, [5- (4-rmethox? -3-tr? Uoro-met? L-phen? L-carbamo? L) -2-met? l-phenol] -amide of 6-d? met? l-sulfamo? lp? razolo- [1, 5-a] -p? r? d? n-3-carboxylic acid, 6-phen? l- [2-met? l-5- (3-trifluoro-met? l-phen? l-carbamo? l) -phen? l] -amide of p? razolo acid- [1, 5- a] -p? r? d? n-3-carboxyl? co, 6-phen? l- [2-met? l-5- (3-tr? uoro-rmet? l-benzo? l-am? no ) -fen? l] -amide of p? razolo acid [1, 5-a] -p? r? d? n-3-carboxyl? co, o-tohl-amide of 6- (4-) acid methox? -fen? l) -p? razolo- [1, 5-a] -p? r? d? n-3-carbox? l? co, terbutil-ester of 4- [4- (3-o. -tol? l-carbamo? lp? razolo- [1,5-a] -p? r? d? n-6-? l) -fen? l] -p? peraz? n-1-carboxíl? co, o-tol-l-amide of 6- (4-morpholine-4-? l-phenol) -p? razolo- [1,5-a] -p? r? d? n- 3-carboxyl? Co, o-tol? L-am? A of 6- (3-methox? -fen? L) -p? Razolo- [1, 5-a] -p? R? D? N- 3-carboxyl? Co, o-tol? L-am? A of 6- (4-d? Met? L-am? No-phen?) -p? Razolo- [1, 5-a] -p ? r? d? n-3-carboxyl? co, and o-tolyl-amide of 6- (3,4-d? methox? -phen?) -p? razolo- [1, 5-a] - p? r? d? n-3-carbox? l? co, in each case in free form or in salt form 5 A pharmaceutical preparation, which comprises a compound as defined in claim 1 of formula I, in free form or in pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier. A compound as defined in claim 1 of formula I, in free form or in pharmaceutically acceptable salt form, for use in the diagnosis or therapeutic treatment of the animal or human body. A compound as defined in claim 1 of formula I, in free form or in pharmaceutically acceptable salt form. acceptable for use in the treatment of a disease responsive to protein kinase modulation. The use of a compound as defined in claim 1 of formula I, in free form or in pharmaceutically acceptable salt form, in the treatment of a disease that responds to protein kinase modulation or to the manufacture of a pharmaceutical preparation useful in the treatment of a disease that responds to protein kinase modulation. The use according to claim 8, wherein the disease that responds to protein kinase modulation is one or more diseases selected from the group consisting of diseases that respond to the inhibition of one or more protein kinases. tyrosma selected from the group consisting of c-src kinase, vascular endothelial growth factor receptor kinase (e.g., KDR and Flt-1), RET receptor kinase, and / or an Efpna receptor kinase, e.g. EphB2 kinase, EphB4 kinase, or related kinases The use according to claim 8 or claim 9, wherein the disease treated is one or more diseases selected from the group consisting of a pro-inflammatory disease, for example leukemia. , especially chronic myelogenous leukemia (CML), or acute lymphocytic leukemia, hyperplasia, fibrosis, such as cirrhosis of the liver, angiogenesis, sopasis, atherosclerosis, especially atherosclerosis arterial or post-transplantation, proliferation of smooth muscle in the blood vessels, such as stenosis or restenosis following angioplasty, tumor or cancer diseases, especially a benign or especially malignant tumor or cancer disease, more preferably solid tumors , for example carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, ovaries, colon, rectum, prostate, pancreas, lung, cervix, vagina, endometrium, thyroid, sarcoma, ghoblastomas, multiple myeloma, or gastrointestinal cancer, colo-rectal adenoma, melanoma, or a tumor of the neck and head, for example squamous carcinoma of head and neck, pro-fertile diseases of mesangial cells, malignant pleural mesothelioma, lymphoma, multiple myeloma, neoplasias, especially of epithelial character, for example in the case of mammary carcinoma, an epidermal hyperproliferation (different from cancer), in special sopasis, prostate hyperplasia, Kaposi's sarcoma, thrombosis, scleroderma; a disease of the immune system, a disease of the central or peripheral nervous system, wherein the signal transmission is involved by at least one protein kinase (preferably tyrosine), especially selected from the tyrosine protein kinases mentioned as preferred, retinopathies, such as diabetic retinopathy, neovascular glaucoma, or macular degeneration, obesity, hemangioblastoma, hemangioma, diabetic nephropathy, malignant nephro-sclerosis; inflammatory diseases, such as rheumatoid or rheumatic inflammatory diseases, especially arthritis, such as rheumatoid arthritis, other chronic inflammatory disorders, such as chronic asthma, endometritis, Crohn's disease, Hodgkin's disease, glomerulonephritis, inflammatory bowel disease; microangiopathic thrombotic syndromes, rejection of transplants, glomerulopathy, nerve tissue lesions; restenosis, for example stent-induced restenosis (implant vascular), and conditions, diseases, or disorders that respond to the modulation of the protein kinase, such as the Eph receptor kinase, where stimulation or promotion of neural regeneration (neuronal regeneration, neuroregeneration) is desired, such as regeneration of axons, or the inhibition or reversal of neural degeneration (neural degeneration, neurodegeneration), for example spinal cord injury, hypoxic conditions, traumatic brain injury, infarction, embolism, multiple sclerosis or other conditions, diseases, or neurodegenerative disorders 11. A method for the treatment of a disease responsive to modulation, especially inhibition, of the protein kinase, especially one or more diseases related to claim 10, which comprises administering an effective amount of a compound as defined in claim 1, of Formula I, in free form or in pharmaceutically salt form A process for the manufacture of a compound as defined in claim 1, of Formula I, in free form or in salt form, which comprises a) condensing, to an animal or a human being in need of said treatment. a carbonic acid of the formula (H) or a reactive derivative thereof, wherein R1, X ,, X2, X3 and X4 are as defined for a compound of the formula I, with a compound of the formula wherein R2, R3, D, Y, Y2, and Ra are as defined for a compound of formula I, or b) for the synthesis of a compound of formula I, wherein R1 is substituted or substituted alkyl, unsubstituted aplo or substituted, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl, reacting a boronic acid of the formula R1-B (A) 2 (IV), wherein R1 is unsubstituted or substituted alkyl, unsubstituted or substituted aplo (preferred), unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocyclyl (each linked via a carbon atom) and A is hydroxyl or lower alkoxy, or B ( A) 2 is 9-borab? C? Clo- [33 1] -nonan? Lo or -B (CHCH3CH (CH3) 2) 2, with a compound of the formula wherein R1, R2, R3, X, X2, X3, X4, Yi, Y2, D and Ra are as defined for a compound of formula I, and Hal is halogen, especially chlorine, iodine, or preferably bromine, or (perfluorinated 1 to 4 carbon alkyl) -sulfonylloxyl, and, if desired, to transform a compound of formula I into a different compound of formula I, to transform a salt of a compound which it can be obtained from the formula I in the free compound or in a different salt, to transform a free compound of the formula I that can be obtained into a salt thereof, and / or to separate a mixture of isomers that can be obtained from a compound of the formula I in the individual isomers