MX2008008166A - Pyrimidinyl aryl urea derivatives being fgf inhibitors - Google Patents

Abstract

The invention relates to heteroaryl aryl ureas of the formula (IA), wherein the radicals and symbols have the meanings as defined herein, the use of such compounds in the treatment of protein kinase dependent diseases;to pharmaceutical preparations comprising said heteroaryl aryl ureas, to processes for the manufacture of such novel compounds and to methods of treatment comprising the use of such heteroaryl aryl ureas.

Description

DERIVATIVES OF PIRIMIDINIL-ARIL-UREA THAT ARE INHIBITORS OF FGF Description of the Invention The invention relates to novel compounds, formulations, methods and uses. More particularly, it refers to novel heteroaryl aryl ureas, and / or the use of, or methods comprising the use of, the compounds, which can be described as heteroaryl aryl ureas, in the treatment, or in the manufacture of pharmaceutical formulations useful in the treatment of diseases dependent on protein kinase. The invention relates to methods of using these compounds in the treatment of the aforementioned diseases, to pharmaceutical preparations comprising the heteroaryl aryl ureas, and to processes for the manufacture of these novel heteroaryl aryl ureas. The invention relates to another subject matter, as disclosed below. Background of the Invention Protein kinases (PKs) are enzymes that catalyze the phosphorylation of specific residues of serine, threonine, or tyrosine in cellular proteins. These post-translational modifications of the substrate proteins act as a molecular switch that regulates cell proliferation, activation, and / or differentiation. Abnormal or excessive activity of the protein kinase has been observed in many disease states, including benign and malignant proliferative disorders. In many cases, it has been possible to treat the diseases in vitro, and in many cases in vivo, such as proliferative disorders, making use of the protein kinase inhibitors. Kinases fall largely in two groups, those specific for phosphorylation of serine and threonine, and those specific for tyrosine phosphorylation. In addition, some kinases, referred to as "double specificity" kinases, are capable of phosphorylating tyrosine, as well as serine / threonine residues. Protein kinases can also be characterized by their location within the cell. Some kinases are transmembrane receptor proteins capable of binding to ligands external to the cell membrane. The binding of the ligands alters the catalytic activity of the receptor protein kinase. Others are non-receptor proteins that lack a transmembrane domain, and still others are ecto-kinases that have a catalytic domain on the extracellular (ecto) portion of a transmembrane protein, or that are secreted as soluble extracellular proteins. Many kinases are involved in regulatory cascades, where their substrates may include other kinases whose activities are regulated by their phosphorylation status. Accordingly, the activity of a downstream effector is modulated by the phosphorylation that results from the activation of the pathway. The receptor tyrosine protein kinases (RPTKs) are a sub-class of transmembrane extending receptors dedicated to an intrinsic tyrosine kinase activity stimulated by the ligand. The activity of receptor tyrosine protein kinases is tightly controlled. When mutated or structurally altered, receptor tyrosine protein kinases can become potent oncoproteins, causing cellular transformation, or at least poor regulation. In principle, for all receptor tyrosine protein kinases involved in cancer, poor oncogenic regulation results from the release of perturbation from one or more of the self-control mechanisms that ensure normal repression of the catalytic domains. More than half of the receptor tyrosine protein kinases have been found repeatedly in either the mutated or overexpressed forms associated with human malignancies (including sporadic cases; Blume-Jensen et al., Nature 41 1: 355-365 (2001)). Overexpression of receptor tyrosine protein kinase leads to activation of the constitutive kinase, by increasing the concentration of dimers. Examples are Neu / ErbB2, and the epidermal growth factor receptor (EGFR), which are frequently amplified in breast and lung carcinomas, and fibroblast growth factors (FGFR) associated with skeletal and proliferative disorders (Blume-Jensen et al., 2001). Angiogenesis is the mechanism by which new capillaries are formed from existing vessels. When required, the vascular system has the potential to generate new capillary networks, in order to maintain the proper functioning of tissues and organs. However, in the adult, angiogenesis is regularly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. See Merenmies et al., Cell Growth &; Differentiation, 8, 3-1 0 (1 997). On the other hand, unwanted angiogenesis is an indication of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer (solid tumors). Folkman, Nature Med., 1, 27-31 (1995). Protein kinases that have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family: VEGF-R2 (vascular endothelial growth factor-2 receptor, also known as KDR ( receptor kinase insert domain), and as FLK1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2). TEK (also known as Tie-2) is a receptor tyrosine kinase expressed only in endothelial cells, which has been shown to have a role in angiogenesis. The angiopoietin-1 factor binding results in autophosphorylation of the kinase domain of TEK, and results in a signal transduction process that appears to mediate the interaction of endothelial cells with peri-endothelial support cells, facilitating this way the maturation of newly formed blood vessels. The angiopoietin-2 factor, on the other hand, seems to antagonize the action of angiopoietin-1 on TEK, and alters angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1 997). Administration of Ad-ExTek, an extracellular domain of soluble adenoviral expression of Tie-2, inhibits tumor metastasis when delivered at the time of surgical removal of primary tumors in a clinically relevant mouse tumor metastasis model (Lin et al. , Proc. Nati, Acad. Sci. USA 95, 8829-8834 (1,998)). The inhibition of the function of Tie-2 by ExTek may be a consequence of the sequestration of the angiopoietin ligand and / or of the heterodimerization with the native Tie-2 receptor. This study demonstrates that the alteration of the Tie-2 signaling pathways, first, can be well tolerated in healthy organisms, and second, it can provide a therapeutic benefit. The Philadelphia Chromosome is an indicator of chronic myelogenous leukemia (CML), and a hybrid gene containing N-terminal exons of the bcr gene, and the larger C-terminal part (exons 2-1 1) of the c-abl gene arrives. The genetic product is a 21 0 kD protein (p21 0 Bcr-Abl). The Abl portion of the Bcr-Abl protein contains the tyrosine abl kinase, which is tightly regulated in the wild-type c-abl, but is constitutively activated in the Bcr-Abl fusion protein. This poorly regulated tyrosine kinase interacts with multiple cellular signaling pathways, leading to the transformation and poorly regulated proliferation of cells (Lugo et al., Science 241, 1079 (1990)). Mutant forms of the Bcr-Abl protein have also been identified. A detailed review of the mutant forms of Bcr-Abl has been published (Cowan-Jones et al., Mini Reviews in Medicinal Chemistry, 2004, 4 285-299). EphB4 (also known as HTK) and its ligand, ephrin B2 (HTKL) have critical roles in the establishment and determination of vascular networks. On the venous epithelium, EphB4 is specifically expressed, whereas, during the early stages of vascular development, ephrin B2 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 a defect in either Ephrin B2 or EphB4. Both are expressed in the first site of hematopoiesis and vascular development, during embryogenesis. An essential role was established for hematopoietic, endothelial, hemangioblast, and appropriate primitive mesoderm development. The deficiency of EphB4 results in an alteration in the result of the mesodermal differentiation of the totipotent embryonic cells. Ectopic expression of EphB4 in mammalian tissue results in disordered architecture, abnormal tissue function, and a predisposition to malignancy (see, for example, N. Munarini et al., J. Cell. Sci. 1 1 5, 25-37 (2002)). From these and other data, it has been concluded that the inadequate expression of EphB4 may be involved in the formation of malignancies, and therefore, that the inhibition of EphB4 can be expected to be a tool to combat malignancies, for example cancer and the like. C-Src (also known as p60 c-Src) is a cytosolic non-receptor tyrosine kinase. c-Src is involved in the transduction of mitogenic signals from a number of polypeptide growth factors, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDG F). c-Src is overexpressed in breast cancers, in pancreatic cancers, in neumoblastomas, and in others. A mutant c-Src has been identified in human colon cancer. C-Src phosphorylates a number of proteins that are involved in the regulation of noise between the extracellular matrix and the cytoplasmic actin cytoskeleton. The modulation of c-Src activity could have implications in diseases related to proliferation, differentiation, and cell death. See Bjorge, J. D., and collaborators, (2000) Oncogene 1 9 (49): 5620-5635; Halpern, M. S., et al., (1 996) Proc. Nati Acad. Sci. USA 93 (2), 824-7; Beisches, A. P., et al., (1 997) Frontiers in Bioscience [Electronic Publication] 2: D501-D51 8; Zhan, X., et al., (2001) Chemical Reviews 101: 2477-2496; Haskell, M. D., et al., (2001) Chemical Reviews 1 01: 2425-2440.

It is now recognized that tyrosine kinase receptor tyrosine kinase type fms 3 (FLT3) is a critical mediator in the pathogenesis of myeloid leukemias and some lymphoid leukemias. Activation of FLT3 on leukemic cells by the FLT3 ligand leads to receptor dimerization and signal transduction in pathways that promote cell growth and inhibit apoptosis (Blood, Volume 98, Number 3, pages 885-887 (2001)). The use of tyrosine kinase inhibitors for the therapy of acute myelogenous leukemia is impeded by the acquisition of mutations in the kinase catalytic domain, and in the case of BCR-ABL, these mutations confer resistance to imatinib. FLT3 is widely expressed in acute myeloid leukemia, and in some cases of acute lymphocytic leukemia. The activation of mutations in FLT3 contains a low risk in patients with acute myelogenous leukemia. Therefore, FLT3 is a promising target for therapeutic intervention. The tyrosine kinase receptor for platelet-derived growth factor (PDGFR) is expressed in a number of tumors, such as microcellular lung cancer, prostate cancer, and glioblastoma, as well as in the stromal and vascular compartments of many tumors. The expression of both PDGF and PDGF receptors (PDGFRs) has been observed in pancreatic cancer (Ebert M. et al., Int J Cancer, 62: 529-535 (1995)).

The serine / threonine Raf kinases are essential components of the mitogen / Ras activated protein (MAPK) protein kinase signaling module, which controls a complex transcription program in response to external cellular stimuli. The Raf genes encode highly conserved serine-threonine specific protein kinases, which are known to bind to the ras oncogene. They are part of a signal transduction pathway that is believed to consist of receptor tyrosine kinases, p21 ras, Raf protein kinases, Mek1 kinases (ERK activator, or MAPKK), and ERK kinases (MAPK), which ultimately phosphorylate the transcription factors. In this pathway, Raf kinases are activated by Ras and phosphorylate and activate two isoforms of the Mitogen Activated Protein Kinase Kinase (termed Mek1 and Mek2), which are double-specific threonine / tyrosine kinases. Both Mek isoforms activate mitogen-activated kinases 1 and 2 (MAPK, also referred to as kinase regulated by extracellular ligand 1 and 2, or Erk1 and Erk2). MAPKs phosphorylate many substrates, including transcription factors, and in doing so, establish their transcription program. The participation of the Rafe kinase pathway of Ras / MAPK, influences, and regulates many cellular functions, such as proliferation, differentiation, survival, oncogenic transformation, and apoptosis. Both the essential role and the position of Raf in many signaling pathways have been demonstrated from the studies using inhibitor Raf mutants poorly regulated and dominant in mammalian cells, as well as from studies that use biochemical techniques and Genetic in model organisms. In many cases, the activation of Raf by receptors that stimulate cellular tyrosine phosphorylation depends on the activity of Ras, indicating that Ras works upstream of Raf. After activation, Raf-1 then phosphorylates and activates Mek1, resulting in the propagation of the signal to downstream effectors, such as MAPK (mitogen-activated protein kinase) (Crews et al. (1993) Cell 74: 215 ). The serine / threonine Raf kinases are considered to be the primary effectors of Raf involved in the proliferation of animal cells (Avruch et al. (1994) Trends Biochem, Sci. 19: 279). The Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf, distinguished by their ability to interact with Ras, to activate the MAPK kinase pathway, the tissue distribution, and sub-cellular localization (Marias et al, Biochem. J. 351: 289-305, 2000; Weber et al., Oncogene 19: 169-176, 2000; Pritchard et al., Mol. Cell. Biol. 15: 6430-6442, 1995). Recent studies have shown that the B-Raf mutation in skin nevi is a critical step in the onset of melanocytic neoplasia (Pollock et al., Nature Genetics 25: 1-2, 2002). Additionally, more recent studies have revealed that an activating mutation occurs in the B-Raf kinase domain in approximately 66 percent of melanomas, in 12 percent of colon carcinoma, and in 14 percent of liver cancer (Davies et al., Nature 417: 949-954, 2002) (Yuen et al., Cancer Research 62: 6451-6455, 2002) (Brose et al., Cancer Research 62: 6997-7000, 2002). Raf / MEK / ERK pathway inhibitors at the level of Raf kinases can be potentially effective as therapeutic agents against tumors with over-expressed or mutated receptor tyrosine kinases, activated intracellular tyrosine kinases, tumors with aberrantly expressed Grb2. (an adapter protein that allows the stimulation of Ras by the Sos exchange factor), as well as tumors that harbor Ras-activating mutations itself. In early clinical studies, an inhibitor of Raf-1 kinase, which also inhibits B-Raf, has shown promise as a therapeutic agent in cancer therapy (Crump, Current Pharmaceutical Design 8: 2243-2248, 2002; and collaborators, Current Pharmaceutical Design 8: 2249-2253, 2002). The alteration of Raf expression in cell lines through the application of anti-sense RNA technology has shown to suppress tumorigenicity mediated by both Ras and Raf (Kolch et al., Nature 349: 416-428, 1991; Monia et al., Nature Medicine 2 (6): 668-675, 1996). Fibroblast Growth Factors Normal growth, as well as tissue repair and remodeling, require specific and sensitive control of the activation of growth factors and their receptors. Fibroblast growth factors (FGFs) constitute a family of more than 20 structurally related polypeptides that are developmentally regulated and that are expressed in a wide variety of tissues. Growth factors of fibroblasts stimulate proliferation, cell migration, and differentiation, and have an important role in skeletal and limb development, in wound healing, in tissue repair, in hematopoiesis, angiogenesis, and tumorigenesis (reviewed in Ornitz, Novartis Found Svmp 232: 63-76; discon 76-80, 272-82 (2001)). The biological action of fibroblast growth factors is mediated by specific cell surface receptors belonging to the family of RPTK protein kinases. These proteins consist of an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain that undergo phosphorylation by binding to fibroblast growth factor. Four fibroblast growth factor receptors have been identified to date: FGFR 1 (also referred to as Flg, fms type gene, flt-2, bFG FR, N-bFGFR or Cek1), FGFR2 (also referred to as kinase expressed in bacteria). Bek, KGFR, Ksam, Ksaml, and Cek3), FGFR3 (also referred to as Cek2), and FG FR4. All mature fibroblast growth factor receptors share a common structure consisting of an amino-terminal signal peptide, three extracellular immunoglobulin-like domains (Ig I domain, Ig II domain, Ig III domain), with an acidic region between the Ig domains (the "acid box" domain), a transmembrane domain, and intracellular kinase domains (Ullrich and Schlessinger, Cell 61: 203, 1990; Johnson and Williams (1992) Adv. Cancer Res. 60: 1-41). The different isoforms of FG FR have different binding affinities for the different ligands of the fibroblast growth factor, and therefore, FGF8 (androgen-induced growth factor) and FGF9 (glial activating factor) seem to have a higher selectivity for the FGFR3 (Chellaiah et al., J. Biol. Chem. 1 994; 269: 1, 620). Another important class of cell surface binding sites includes the binding sites for heparan sulfate proteoglycans (HSPG), which are required for the high affinity interaction and the activation of all members of the growth factor family. fibroblasts. Tissue specific expression of structural variants of heparan sulfate confer ligand-receptor specificity and FGF activity. Diseases Related to FGFR Recent discoveries show that an increasing number of skeletal abnormalities, including achondroplasia, the most common form of human dwarfism, result from mutations in FGFRs. Specific point mutations in different domains of FGF-R1, FGF-R2, and FGF-R3, are associated with autosomal dominant human skeletal dysplasias classified as craniosynostosis syndromes and dwarfism syndromes (Coumoul and Deng, Birth Defects Research 69: 286 -304 (2003)). Skeletal dysplasias associated with mutations of FGF-R3 include hypochondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD) (Webster et al., Trends Genetics 1 3 (5): 1 78-1 82 (1997), Tavormina et al., Am. J. Hum. Genet., 64: 722-731 (1999)). FGFR3 mutations have also been described in two craniosynostosis phenotypes: coronal craniosynostosis of Muenke (Bellus et al., Nature Genetics, 1 4: 1 74-1 76 (1996); Muenke et al., Am. J. Hum. Genet. , 60: 555-564 (1992)), and Crouzon syndrome with acanthosis nigricans (Meyers et al., Nature Genetics, 11: 462-464 (1995)). Crouzon syndrome is associated with specific point mutations in FGFR2, and both the familial and sporadic form of Pfeiffer syndrome are associated with mutations in FGFR1 and FGFR2 (Galvin et al., PNAS USA, 93: 7894-7899 (1996)). Schell et al., Hum. Mol. Gen., 4: 323-328 (1995)). Mutations in FGFRs result in constitutive activation of mutated receptors, and increased receptor tyrosine protein kinase activity, rendering cells and tissue incapable of differentiation. Specifically, the achondroplasia mutation results in improved stability of the mutated recapturer, which dissociates receptor activation from the decrease, leading to restricted maturation of chondrocytes and inhibition of bone growth (reviewed in Vajo et al., Endocrme Reviews, 21 (1) .23-39 (2000)). There is accumulated evidence of mutations that activate FGFR3 in different types of cancer. FGFR3 constitutively activated in two common epithelial, bladder and cervical cancers, as well as in multiple myeloma, is the first evidence of an oncogenic role for FGFR3 in carcinomas. In addition, a very recent study reports the presence of activating mutations of FGFR3 in a large proportion of benign skin tumors (Logie et al., Hum.Mol.Genet 2005). FG FR3 currently appears to be the most frequently mutated oncogene in bladder cancer, where it is mutated in nearly 50 percent of total bladder cancer cases, and in approximately 70 percent of cases that have bladder tumors superficial (Cappellen, et al, Nature Genetics 1 999, 23J 9-20; van Rhijn, et al, Cancer Research 2001, 61: 1 265-1268; Billerey, et al., Am. J. Pathol 2001, 1 58: 1955 - 1959, International Publication Number WO 2004/085676) Also, over-expression of FGFR3 in bladder cancer (superficial and invasive) has been reported (Gomez-Roman et al., Climcal Cancer Research 2005). Aberrant overexpression of FGFR3 as a consequence of chromosomal translocation t (4J 4) is reported in 1 0 to 25 percent of multiple myeloma cases (Chesi et al., Nature Genetics 1997, 16: 260-264; Richelda et al., Blood 1997, 90: 4061-4070; Sibley et al., BJH 2002, 118: 514-520; Santra et al., Blood 2003, 101: 2374-2476). Activating mutations of FGFR3 are seen in 5 aMO percent of multiple myelomas with t (4J4), and are associated with tumor progression (Chesi et al, Nature Genetics 1997, 16: 260-264; Chesi et al., Blood, 97 (3): 729-736 (2001); Intini, et al., SJH2001, 114: 362-364). In this context, the consequences of FGFR3 signaling often appear to be type-specific. In chondrocytes, the hyperactivation of FGFR3 results in growth inhibition (reviewed in Omitz, 2001), while in myeloma cells, it contributes to tumor progression (Chesi et al., 2001). It has been found that the inhibition of FGFR3 activity represents a means to treat inflammatory or autoimmune diseases mediated by T-cells, as for example, in the treatment of inflammatory or autoimmune diseases mediated by T-cells that include, but are limited to , rheumatoid arthritis (RA), collagen II arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), psoriasis, juvenile establishment diabetes, Sjogren's disease, thyroid disease, sarcoidosis, autoimmune uveitis, inflammatory bowel disease ( Crohn's disease and ulcerative colitis), celiac disease, and myasthenia gravis. See International Publication Number WO 2004/1 1 0487. Disorders resulting from mutations of FG FR3 are also described in International Publications Nos. WO 03/023004 and WO 02/1 02972. Among the diseases promoted by FGFR3, and also others FGFRs (especially in relation to, for example, with the aberrant serum levels of FGF23), we also have autosomal dominant hypophosphatemic rickets (ADHR), hypophosphatemic rickets linked to the X-chromosome (XLH), tumor-induced osteomalacia (TIO) ), fibrous bone dysplasia (FH), to be mentioned (see also X. Yu et al., Cytokine &Growth Factor Reviews 16, 221-232 (2005), and X. Yu et al., Therapeutic Apheresis and Dialysis 9 ( 4), 308-31 2 (2005)). The amplification and / or genetic over-expression of FGFR 1, FGFR2, and FGFR4, has been implicated in breast cancer (Penault-Llorca et al., Int. J. Cancer 1995, Theillet et al., Genes Chrom. Cancer 1 993; Adnane et al., Oncogene 1 991; Jaakola et al. Int J Cancer 1 993; Yamada et al., Neuro, Res. 2002). Overexpression of FGFR1 and FGFR4 is also associated with pancreatic adenocarcinomas and astrocytomas (Kobrin et al., Cancer Research 1 993; Yamanaka et al., Cancer Research 1993; Shah et al., Oncogene 2002; Yamaguchi et al., PNAS 1 994; Yamada et al., Neuro, Res. 2002). Prostate cancer has also been linked to overexpression of FGFR 1 (Giri et al., Clin. Cancer Res., 1 999). The FG Fs / FGFRs are also involved in angiogenesis. Therefore, targeting the FG FR system is also envisaged as an anti-angiogenic therapy to treat primary tumors, as well as metastases. (See, for example, Presta and collaborators, Cytokine & Growth Factors Reviews 1 6, 1 59- 1 78 (2005)). It has also been described that mutations, especially in FG FR3 (eg, FGFR3b), are responsible for the constitutive activation of these receptors in the case of oral squamous cell carcinoma (see, for example, Y. Zhang et al.

Int. J. Cancer 1 1 7, 1 66- 1 68 (2005)). It has been reported that the greater (especially bronchial) expression of FGFRs, especially FGFR 1, is associated with chronic obstructive pulmonary disease (COPD) (see, for example, Kranenburg et al., J. Pathol., 206, 28- 38 (2005)). It has been reported that chromosomal translocations involving the FGF-R 1 locus, which result in the activated forms of FGF-R 1, are responsible for the myeloproliferative syndrome 8p1 1 = eosinophilic myeloproliferative syndrome (EMS) (see D. Macdonald et al., Cross NCP (2002) Minutes Haematologica 107: 101-107). It has also been described that methods for antagonizing FGFRs, especially FGFR 1 or FGFR 4, are useful in the treatment of obesity, diabetes and / or related diseases, such as metabolic syndrome, cardiovascular diseases, hypertension, aberrant levels of cholesterol and triglycerides, dermatological disorders (eg, infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, type 2 diabetes, insulin resistance, hypercholesterolemia, cholelithiasis, orthopedic injury, thromboembolic disease, coronary or vascular restriction (eg, atherosclerosis), drowsiness during the day, sleep apnea, end-stage renal disease, gallbladder disease, gout, heat disorders, impaired immune response, impaired respiratory function, infections following wounds, infertility, liver disease , low back pain, obstetric and gynecological complications, pancr erythritis, embolism, surgical complications, incontinence with urinary tension and / or gastrointestinal disorders (see, for example, International Publication Number WO 2005/037235 A2). It has also been reported that acid fibroblast growth factor (especially FGF-1) and FGFR 1 are involved in aberrant signaling in retinoblastoma, leading to proliferation after FGF-1 binding (see, for example, S. Siffroi-et al., Arch. Ophthalmology 123, 368-376 (2005)). It has been shown that the growth of synovial sarcomas is inhibited by the interruption of the signaling pathway of fibroblast growth factor (see, for example, T. Ishibe et al., Clin. Cancer Res. 11 (7), 2702-2712). (2005)). In addition, the involvement of FGFR could be demonstrated in the case of thyroid carcinoma. Family of the Epidermal Growth Factor and Related Diseases. The epidermal growth factor receptor (EGF-R) and the ErbB2 kinase are tyrosine protein kinase receptors that, along with those of its family ErbB3 and ErbB4, have a key role in the transmission of signals in a large number of mammalian cells, including human cells, especially epithelial cells, cells of the immune system, and cells of the body. central and peripheral nervous system. For example, in different cell types, the activation of tyrosine protein kinase associated with the receptor induced by epidermal growth factor is a prerequisite for cell division, and therefore, for the proliferation of the cell population. More importantly, over-expression of EGF-R (HER-1) and / or ErbB2 (HER-2) in substantial fractions of many human tumors has been observed. For example, it was found that EGF-R is overexpressed in non-microcellular lung cancers, in squamous cell carcinoma (head and neck), in breast, gastric, ovarian, colon, and prostate cancers, as well as in gliomas. It was found that ErbB2 is over-expressed in squamous carcinoma (head and neck), in breast, gastric, and ovarian cancers, as well as in gliomas. In all the cases mentioned above, where the protein kinases are involved, it can reasonably be expected that the modulation of an aberrant activity (especially the inhibition of an activity of this kinase) is useful in the aforementioned diseases. Accordingly, there is an unmet need for high affinity and / or selective molecules capable of blocking aberrant constitutive receptor tyrosine receptor protein kinase activity, in particular the activity of FGFR, thereby resolving the clinical manifestations associated with the above mutations. mentioned, and modulating different biological functions. In view of the large number of protein kinase inhibitors, and the large number of proliferative diseases and other diseases related to protein kinase, there is an ever-existing need to provide novel classes of compounds that are useful as protein kinase inhibitors. , and therefore, in the treatment of these diseases related to protein tyrosine kinase (PTK). What is required are new classes of pharmaceutically convenient protein kinase inhibitor compounds. General Description of the Invention It has now been found that the compounds given in more detail below, which can be described as belonging to the heteroaryl-aryl-urea class, show inhibition of a number of tyrosine protein kinases, especially any kinase mentioned here, most special of FGFR. As examples of the kinases inhibited by the compounds of the invention, mention may be made in particular of FGFR1, FGFR2, FGFR3, and FGFR4. Another inhibited kinase is the recapture tyrosine kinase VEGF-R, in particular the receptor KDR of VEGF (VEGF-R2). The compounds disclosed are suitable for the inhibition of one or more of these and / or other tyrosine protein kinases, and / or for the inhibition of the mutants of these enzymes. In view of these activities, the compounds can be used for the treatment of diseases related in particular with an aberrant or excessive activity of these types of kinases, especially those mentioned. The compounds of the disclosure can exist in different forms, such as free acids, free bases, ester, and other prodrugs, salts and tautomers, for example, and the disclosure includes all variant forms of the compounds. The extension of the protection includes counterfeiting or fraudulent products that contain or are intended to contain a compound of the invention regardless of whether in fact they contain this compound, and regardless of whether any of these compounds is contained in a therapeutically effective amount. In the scope of protection, therefore, packages are included that include a description or instructions that indicate that the package contains a species or pharmaceutical formulation or composition of the invention, and a product that is or that understands or that pretends to be or to understand, this formulation, composition, or species. Throughout the description and claims of this specification, the singular encompasses the plural, unless the context otherwise requires. In particular, where the indefinite article is used, it should be understood that the descriptive memory contemplates plurality as well as singularity, unless the context requires otherwise. The features, integers, features, compounds, fractions, or chemical groups described in conjunction with a particular aspect, embodiment, or example of the invention, are to be understood as being applicable to any other aspect, embodiment, or example described herein, unless that is incompatible with it. Throughout the description and claims of this specification, the words "comprise" and "contain", and variations of words, for example "comprising" and "comprises", mean "including, but not limited to ", and do not intend to exclude (and do not) other fractions, additives, components, integers, or steps. Other aspects and modalities of the disclosure are stipulated in the following description and in the claims. Detailed Description of the Invention It has now been found that the novel compounds of Formula IA: wherein: two of X, Y, and Z are N (nitrogen), the third is CH or N (preferably Y and Z are N, and Z is CH); and wherein, any of: R1 is phenyl which is substituted hydroxyl, phenyl-alkyloxy of 1a 7 carbon atoms, piperazin-1-yl, or 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1-yl; or phenyl which is substituted by: (i) halogen or alkoxy of 1 to 7 carbon atoms, and in addition (ii) by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, N-mono- or N, N- di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, pyrrolidino-alkoxy of 1 to 7 carbon atoms, 1- (alkyl of 1 to 7 carbon atoms) -piperidine- 4-yl, morpholino-alkoxy of 1 to 7 carbon atoms, thiomorpholino-alkyl of 1 to 7 carbon atoms, piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1 -yl, 4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms carbon, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1) to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxyl of 1 to 7 carbon atoms or, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl; R2 is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or halogen; R3 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenylalkyl of 1 to 7 carbon atoms, each R4 is, independently of the others, alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms carbon, halogen, or alkoxy of 1 to 7 carbon atoms, and n is 0, 1, 2, 3, 4, or 5; or R 1 is phenyl which is substituted by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1-yl; N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, pyrrolidino-alkoxy of 1 to 7 carbon atoms, 1 - (alkyl of 1) to 7 carbon atoms) -piperidin-4-yl, morpholino-alkoxy of 1 to 7 carbon atoms, thiomorpholino-alkoxy of 1 to 7 carbon atoms, 4- (alkyl of 1 to 7 carbon atoms) -piperazin- 1-yl, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl; or phenyl bearing one of the substituents mentioned heretofore in the present paragraph, and in addition a substituent selected from halogen and alkoxy of 1 to 7 carbon atoms; R2 is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or halogen; R3 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenylalkyl of 1 to 7 carbon atoms, R5 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 7 carbon atoms , and any of: n is 3, 4, or 5, and R 4 is selected from alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, and halogen, with the proviso that at least one of each of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, and halogen; or n is 2, and one R 4 is haloalkyl of 1 to 7 carbon atoms, and the other R 4 is alkoxy of 1 to 7 carbon atoms; on is 3, 4, or 5, and R 4 is selected from halogen, iodine, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, iodine, and alkoxy is present from 1 to 7 carbon atoms; on is 3, 4, or 5, and R 4 is selected from halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms; or Y and Z are N (nitrogen), and X is CH, wherein, any of: R1 is 3-pyridyl, which is mono-substituted by N-alkyl of 1 to 7 carbon atoms-piperazin-1-yl , R 2 is hydrogen, R 3 is hydrogen, each R 4 is, independently of the others, alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halogen, or alkoxy of 1 to 7 carbon atoms, R5 is hydrogen, and n is 1.2, 3, 4, or 5; or a compound of Formula IA, wherein R 1 is 4- (2-morpholin-4-yl-ethoxy) -phenyl-amino, R 2 is hydrogen, R 3 is hydrogen, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 3- (4-methyl-piperazin-1-yl-methyl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and - and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 3- (4-ethyl-piperazin-1-yl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (2-morpholin-4-yl-ethoxy) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (1-ethyl-piperidin-4-yl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (4-ethyl-piperazin-1-yl) -phenyl-amino, R 2 is hydrogen, R 3 is ethyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH, and / or a compound of Formula IA, wherein R1 is 4- (4-ethyl-piperazine-1-carbonyl) phenyl amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R 5 is hydrogen, Y and Z are N, and X is CH; or mixtures of two or more compounds of Formula IA; or in each case of a compound of Formula IA (as mentioned above or below), the salts, pro-drugs, N-oxides, or esters thereof, are useful in the treatment of disorders related to the activity of protein kinase, especially with respect to diseases that can be treated by tyrosine protein kinase-modulating compounds, more especially FGFR-modulating compounds.

Accordingly, the invention relates to one or more of these compounds of Formula IA, salts, pro-drugs, N-oxides, or esters thereof, as well as to the uses, methods, and pharmaceutical formulations mentioned above. In particular, the present invention relates to compounds of Formula IA, wherein: two of X, Y, and Z are N (nitrogen, the third is CH or N (preferably Y and Z are N, and Z is CH ), and any of: (A) R is phenyl which is substituted by hydroxyl, by phenyl-alkyloxy of 1 to 7 carbon atoms (especially benzyloxy), by piperazin-1-yl or by 4- (phenyl-alkyl) 1 to 7 carbon atoms) -piperazin-1-yl (in particular 4-benzyl-piperazin-1-yl), or phenyl which is substituted: (i) (once) by halogen (especially fluorine or chlorine), or alkoxy of 1 to 7 carbon atoms (especially methoxy), and in addition (ii) (once) by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms (especially benzyloxy), N-mono- or N , N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms (especially dimethylamino), pyrrolidino-alkoxy of 1 to 7 carbon atoms (especially 2-pyrrolidino) -ethoxy), 1 - (alkyl of 1 to 7 carbon atoms) -piperid in-4-yl (especially 1-ethyl-piperidin-4-yl), morpholino-alkoxy of 1 to 7 carbon atoms (especially 2-morpholino-ethoxy), thiomorpholino-alkoxy of 1 to 7 carbon atoms ( in particular 2-thiomorpholino-ethoxy), piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1-yl (in particular 4-benzyl-piperazin-1-yl), - (C 1-7 alkyl) -piperazin-1-yl (in particular 4- (methyl, ethyl, or isopropyl) -piperazin-1-yl), [4- (C 1-7 -alkyl) ) -piperazin-1 -yl] -alkyl of 1 to 7 carbon atoms (especially 2- [4- (methyl or ethyl) -piperazin-1-yl] -ethyl), N-mono-or N, N- di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms (especially dimethylamino-methyl), N-mono-or N, N-di- (alkyl of 1 to 7) carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms (especially 2- (dimethylamino) -ethoxy), [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1 -yl] - alkoxy of 1 to 7 carbon atoms (especially 2- ( 4-methyl-piperazin-1-yl) -ethoxy), or [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl (in particular 4-ethi I -piperaz i n- 1 -carbonyl); R2 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or (with less preference) halogen; R3 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms (preferred), or phenyl-alkyl of 1 to 7 carbon atoms, each R4 is, independently of the others, alkyl of 1 to 7 carbon atoms, halo -alkyl of 1 to 7 carbon atoms, halogen, or alkoxy of 1 to 7 carbon atoms, R5 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms or phenyl-alkyl of 1 to 7 carbon atoms, and is 0, 1, 2, 3, 4, or 5; or (B) wherein R 1 is phenyl which is substituted by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms (especially benzyloxy), piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms ) -piperazin-1-yl (especially 4-benzyl-piperazin-1-yl), N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms (especially dimethylamino-methyl), pyrrolidino-alkoxy of 1 to 7 carbon atoms (especially 2-pyrrolidino-ethoxy), 1 - (alkyl of 1 to 7 carbon atoms) -piperidin-4- ilo (especially 1-ethyl-piperidin-4-yl), morpholino-alkoxy of 1 to 7 carbon atoms (especially 2-morpholino-ethoxy), thiomorpholino-alkoxy of 1 to 7 carbon atoms (especially 2- thiomorpholinoethoxy), 4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl (especially 4- (methyl, ethyl, or isopropyl) -piperazin-1-yl), [4- ( 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms (especially 2- [4- (methyl or ethyl) -piperazin-1 -i) l] -ethyl), N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms (especially dimethylamino-methyl), N- mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms (especially 2- (dimethylamino) -ethoxy), [4- ( 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxy from 1 to 7 carbon atoms (in particular 2- (4-methyl-piperazin-1-yl) -ethoxy), or [4- ( 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl (especially 4-ethyl-piperazin-1-carbonyl); or phenyl bearing one of the substituents mentioned heretofore for R 1 in the present paragraph, and in addition a substituent selected from halogen and alkoxy of 1 to 7 carbon atoms; R2 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or (with less preference) halogen; R3 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms (preferred), or phenyl-alkyl of 1 to 7 carbon atoms, R5 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms, or phenyl- alkyl of 1 to 7 carbon atoms, and any of: n is 3,4, or 5, and R 4 is selected from alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, and halogen, with the proviso that at least one of each of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, and halogen; or n is 2, and one R 4 is haloalkyl of 1 to 7 carbon atoms, and the other R 4 is alkoxy of 1 to 7 carbon atoms; on is 3, 4, or 5, and R 4 is selected from halogen, iodine, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, iodine, and alkoxy is present from 1 to 7 carbon atoms; or n is 3, 4, or 5, and R 4 is selected from halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms; (C) or a compound of Formula IA, under the names: 1- (2,6-dichloro-3,5-dimethoxy-phenyl) -3-. { 6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea (wherein, with reference to Formula IA, R1 is 4- (2-morpholin-4-yl-ethoxy) -phenyl-amino, R2 is hydrogen, R3 is hydrogen, R4 is 2- and 6-chloro and 3- and 5-methoxy, and n is 4 and R 5 is hydrogen), 3- (2,6-dichloro-3,5-dimethoxy-f eni I) -1-methyl-1 -. { 6- [3- (4-methyl-piperazin-1-yl-methyl) -phenyl-amino] -pyrimidin-4-yl} -urea (wherein, with reference to Formula IA, R1 is 3- (4-methyl-piperazin-1-methyl-methyl) -phenyl-amino, R2 is hydrogen, R3 is methyl, R4 is 2- and 6- chloro and 3- and 5-methoxy, and n is 4, and R5 is hydrogen), 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [3- (4-ethyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea (wherein, with reference to Formula IA, R1 is 3- (4-ethyl-piperazin-1-yl) -phenyl-amino, R2 is hydrogen, R3 is methyl, R4 is 2- and 6-chloro and 3- and 5-methoxy, and n is 4, and R5 is hydrogen), 3- (2,6-dichloro-3,5-dimethoxy-f eni I) -1-methyl-1 -. { 6- [4- (2-morpholin-4-yl-ethoxy) -phenyl-amino] -pyrimidin-4-yl} -urea (wherein, with reference to Formula IA, R1 is 4- (2-morpholin-4-M-ethoxy) -phenyl-amino, R2 is hydrogen, R3 is methyl, R4 is 2- and 6-chloro and 3- and 5-methoxy, and n is 4, and R5 is hydrogen), 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [4- (1-ethyl-piperidin-4-yl) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea (wherein, with reference to Formula IA, R1 is 4- (1-ethyl-piperidin-4-yl) -phenyl-amino, R2 is hydrogen, R3 is methyl, R4 is 2- and 6-chloro and 3- and 5-methoxy, and n is 4, and R5 is hydrogen), 3- (2,6-dichloro-3,5-dimethoxy-f eni I) -1-ethyl-1 -. { 6- [4- (4-Ethyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea (wherein, with reference to Formula IA, R1 is 4- (4-ethyl-piperazin-1-yl) -phenyl-amino, R2 is hydrogen, R3 is ethyl, R4 is 2- and 6-chloro and 3- and 5-methoxy, and n is 4, and R5 is hydrogen), or 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [4- (4-ethyl-piperazin-1 -carbonyl) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea (wherein, with reference to Formula IA, R1 is 4- (4-ethyl-piperazin-1 -carbonyl) -phenyl-amino, R2 is hydrogen, R3 is methyl, R4 is 2- and 6-chloro and 3- and 5-methoxy, and n is 4, and R5 is hydrogen), (where, in each of these compounds, the fractions corresponding to R1, R2, R3, R4, R5, X, Y and Z, and n in Formula IA, are defined by the respective meanings given for these compounds, respectively); wherein, in each of these compounds, Y and Z are nitrogen, and X is CH; and in each case of a compound of Formula IA (as mentioned above or below), the salts, pro-drugs, N-oxides, or esters thereof. In one embodiment, the present invention provides compounds of Formula IA, wherein: Y and Z are N (nitrogen), and X is CH, wherein any of: R is 3-pyridyl, which is mono-substituted by N - alkyl of 1 to 7 carbon atoms - piperazin-1-yl, R2 is hydrogen, R3 is hydrogen, each R4 is, independently of the others, alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 atoms of carbon, halogen, or alkoxy of 1 to 7 carbon atoms, R5 is hydrogen, and n is 1, 2, 3, 4, or 5. In this embodiment, preference R4 is, independently of the others, halogen or alkoxy of 1. to 7 carbon atoms, and n is preferably 3, 4, or 5, more preferably 4. Preferred Definitions The general terms used hereinbefore and hereinafter, preferably, have within the context of this disclosure, the following meanings, unless otherwise indicated: The prefix "inferior" or "Ci-C /" denotes an radical that has up to and including a maximum of 7 atoms in the chain, especially up to and including a maximum of 4 atoms in the chain. The particular alkyl and aliphatic classes comprise 1, 2, 3, or 4 carbon atoms. The radicals in question are linear or branched, with individual or multiple branching. Lower alkyl or alkyl of 1 to 7 carbon atoms is preferably alkyl with and including 1 to and including 7 carbon atoms, preferably 1, 2, 3, or 4 carbon atoms, and is straight or branched; for example, lower alkyl is butyl, such as normal butyl, secondary butyl, isobutyl, tertiary butyl, propyl, such as normal propyl or isopropyl, ethyl or methyl. The lower alkyl of example is methyl, ethyl, or isopropyl. When the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. When the phenyl is present in R1 as in ring-linking R1 with NR5 in Formula IA, preferably the substituents of hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, piperazin-1-yl, 4- (phenyl) alkyl of 1 to 7 carbon atoms) -piperazin-1-yl; N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, pyrrolidino-alkoxy of 1 to 7 carbon atoms, 1 - (alkyl of 1) to 7 carbon atoms) -piperidin-4-yl, morpholino-alkoxy of 1 to 7 carbon atoms, thiomorpholino-alkoxy of 1 to 7 carbon atoms, 4- (alkyl of 1 to 7 carbon atoms) -piperazin- 1-yl, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl, are present in position 3 or 4 in relation to the linkage with NR5. Any asymmetric carbon atoms may be present in the (R), (S), or (R, S) configuration, preferably in the (R) or (S) configuration. Radicals having any unsaturation, are present in the cis, trans, or (cis, trans) form.

Accordingly, the compounds may be present as mixtures of isomers or as the pure isomers, preferably as pure diastereomers in enantiomers. The invention also relates to the possible tautomers of the compounds disclosed. In view of the close relationship between the compounds of the Formula I in free form and in the form of their salts, including the salts that can be used as intermediates, for example in the purification or identification of the novel compounds, and the tautomers or tautomeric mixtures and their salts, any reference hereinbefore and hereinafter to these compounds, should be understood to refer also to the corresponding tautomers of these compounds, or the salts of any of the same, and as appropriate and convenient, and if not mentioned otherwise. For example, tautomers may be present in cases where amino or hydroxyl, each with at least one hydrogen bond, are bonded to the carbon atoms that are bonded to adjacent atoms by double bonds (eg. tautomerism of keto-enol or imine-enamine). When "a compound ..., a tautomer thereof, or a salt thereof," or the like, is mentioned, this means "a compound ..., a tautomer thereof, or a salt of the compound and / or the tautomer " Halogen (halo) is preferably fl uorine, chlorine, bromine, or iodine, especially (preferably in the compounds of Formula I), fluorine, chlorine, or iodine. Haloalkyl of 1 to 7 carbon atoms means an alkyl of 1 to 7 carbon atoms in which one or more hydrogen atoms are replaced by halogen atoms, for example trifluoromethyl. [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl means [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1 -yl] -C (= 0) - . The present invention relates to compounds of the Formula IA, as described above, and salts, esters, N-oxides, or pro-drugs thereof. In one aspect, therefore, the invention provides products that are compounds of Formula IA, and / or salts, esters, N-oxides, or pro-drugs thereof. The salts are in particular the pharmaceutically acceptable salts of the compounds of Formula IA (or the exemplary formula thereof), especially if they are forming salt-forming groups. The salt-forming groups are groups or radicals that have basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example basic nitrogen, such as amino, a secondary amino group that does not form a peptide bond, or tertiary amino, can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid, or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or dicarboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, or oxalic acid, or amino acids, such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, -phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-amino-salicylic acid, aromatic-aliphatic carboxylic acids, such it is like mandelic acid or cinnamic acid, hetero-aromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methan-, ethane-, or 2-hydroxy-ethanesulfonic acid, or aromatic sulfonic acids, example benzene-, p-toluene-, or naphthalene-2-sulfonic acid. When several basic groups are present, mono- or poly-acid addition salts can be formed. Compounds that have acid groups, a carboxyl group, or a phenolic hydroxyl group, can form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium, or calcium salts, or ammonium salts with ammonia or with suitable organic amines, such as tertiary monoamines, for example triethylamine or tri- (2) -hydroxy-ethyl) -amine, or heterocyclic bases, for example N-ethyl-piperidine or N, N'-dimethyl-piperazine. Mixtures of salts are possible. Compounds having both acidic and basic groups can form internal salts. For the purposes of isolation or purification, as well as in the case of the compounds that are used additionally as intermediates, it is also possible to use pharmaceutically unacceptable salts, for example the picrates. However, for therapeutic purposes, only pharmaceutically acceptable non-toxic salts can be used, and therefore, these salts are preferred. In view of the close relationship between the novel compounds or the N-oxides thereof in free form and those in the form of their salts, including the salts that can be used as intermediates, for example in the purification or identification of the compounds novel, any reference to the free compounds (including the compounds of Formula IA, the intermediates, and the starting materials) hereinbefore and hereinafter, is to be understood to also refer to the corresponding N-oxides, and / or salts, hydrates, solvates, and / or crystal forms of the compounds or their N-oxides, as appropriate and convenient. The compounds of Formula IA (or of the example formulas thereof) have valuable pharmacological properties, as described hereinabove and hereinafter. Biology The efficacy of the compounds of the invention as inhibitors of receptor tyrosine kinase activity Bcr-Abl, c-KIT, EphB4, EGF-R, VEGF-R2 (KDR), FG FR, Tie-2 (Tek), Ret, PDGFR, raf, FLT3, c-src and / or FGFR3, can be demonstrated as follows: In the following, "inhibitors", "active compounds", or the like, refer to compounds of Formula IA. Activity test against Bcr-Abl: The murine myeloid progenitor cell line 32Dcl3 transfected with the expression vector of p210 Bcr-Abl, pGDp21 0Bcr / Abl (32D-bcr / abl) was obtained from J. Griffin (Dana Faber Cancer Institute, Boston, MA, USA). The cells express the Bcr-Abl fusion protein with a constitutively active abl kinase, and the independent proliferative growth factor. The cells are expanded in RPMI 1 640 (AMI M ED), 2 percent calf fetal serum, 2 mM glutamine (Gibco) ("complete medium"), and a processing feed is prepared by freezing 2x1 aliquots. 06 cells per bottle in a freezing medium (95 percent calf fetal serum, 5 percent dimethyl sulfoxide (Sigma)). After thawing, the cells are used for a maximum of 10 to 1 2 steps for the experiments. The SH3 domain of the anti-abl antibody is used with catalog number 06-496 of Upstate Biotechnology for the ELISA. For the detection of bcr-abl phosphorylation, the anti-phosphotyrosine Ab PY20, labeled with alkaline phosphatase (PY10 (AP)) antibody from ZYMED (Catalog # 03-7722) is used. As a comparison and reference compound, (N-. {5- [4- (4-methyl-piperazino-methyl) -benzoyl-amido] -2-methyl-phenyl} -4- (3 -pyridyl) -2-pyrimidine-amine, in the form of the methanesulfonate (monosylate) salt (STI571) (marketed as Gleevec® or Glivec®, Novartis). A 10 mM sulfoxide delivery solution is prepared. dimethyl, and stored at -20 ° C. For cell assays, the delivery solution is diluted in a complete medium in two steps (1: 100 and 1:10), to provide an initial concentration of 10 μM, followed by Preparation of triple serial dilutions in a complete medium No solubility problems are found using this procedure Test compounds are treated analogously., 200,000 32D-bcr / abl cells are seeded in 50 microliters per well, in 96-well round-bottom ti culture plates. 50 microliters per well of the triple serial dilutions of the test compound are added to the cells in triplicate. The final concentration of the test compound is in the range, for example, of 5 μM down to 0.01 μM. The untreated cells are used as a control. The compound is incubated together with the cells for 90 minutes at 37 ° C, with 5 percent CO 2, followed by centrifugation of the ti culture plates at 1,300 revolutions per minute (Beckman GPR centrifuge), and the removal of the supernatants. by careful aspiration, taking care not to remove the granulated cells. The cell granules are lysed by the addition of 150 microliters of lysis buffer (50 mM Tris / HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1 percent NP-40 (non-detergent ion, Roche Diagnostics GmbH, Mannheim, Germany), 2 mM sodium ortho-vanadate, 1 mM phenyl-methyl sulfonyl fluoride, 50 micrograms / milliliter of aprotinin, and 80 micrograms / milliliter of leupeptin), and are immediately used for ELISA, or stored frozen at -20 ° C until use. The anti-abl SH3 domain antibody is coated at 200 nanograms in 50 microliters of phosphate-buffered serum per well of the black ELISA plates (black plates Packard HTRF-96, 6005207) overnight at 4 ° C. After washing three times with 200 microliters / well of phosphate-regulated serum containing 0.05 percent Tween 20 (PBST) and 0.05 percent TopBlock (Juro, Catalog #TB 23201 0), the residual protein binding sites are blocked with 200 microlitres / well of PBST, 3 percent Topblock, for 4 hours at room temperature, followed by incubation with 50 microliters of those used from cells not treated or treated with the test compounds (20 micrograms of total protein per well ) for 3 to 4 hours at 4 ° C. After washing three times, 50 microliters / well of PY20 (AP) (Zymed) diluted to 0.5 micrograms / milliliter in blocking buffer is added and incubated overnight (4 ° C). For the incubation steps, the plates are covered with plate sealers (Costar, Catalog # 3095). Finally, the plates are washed three more times with a washing regulator, and once with deionized water, before the addition of 90 microliters / well of the AP CPDStar RTU substrate with Emerald I I. The plates are now sealed with Packard Top Seal ™ R-A plate sealers (incubate for 45 minutes at room temperature in the dark, and luminescence is measured by measuring counts per second (CPS) on the Packard TopCount microplate scoring counter). For the final optimized version of the ELISA, 50 microliters of the used cells cultured, treated and used in the 96-well ti culture plates, are transferred directly from these plates to the ELISA plates that are previously coated with 50 nanograms / Well of the SH3 rabbit polyclonal anti-abl domain AB 06-466 from Upstate. The concentration of AB PY20 (anti-phosphotyrosine) (AAP) could be reduced to 0.2 micrograms / milliliter. Washing, blocking, and incubation with the luminescent substrate, are as in the above. The quantification is achieved as follows: the difference between the ELISA reading (CPS) obtained with the used ones of untreated 32D-bcr / abl cells, and the reading for the assay background (all components, but without the cellular lysate), and is taken as 100 percent, reflecting the constitutively phosphorylated bcr-abl protein present in these cells. The activity of the compound in the bcr-abl kinase activity is expressed as a percentage of bcr-abl phosphorylation reduction. The values for the IC50 are determined from the dose response curves by means of inter- or extrapolation graphically. The compounds of the invention preferably show IC 50 values in the range of 15 nM to 500 μM, more preferably from 15 nM to 200 μM. For cell assays, the compounds are dissolved in dimethyl sulfoxide, and diluted with a complete medium to provide an initial concentration of 10 μM, followed by the preparation of serial triple dilutions in a complete medium. 32D or Ba / F3 cells expressing either wild-type Bcr-Abl or Bcr-Abl mutants (e.g., T-315-1) are seeded at 200,000 cells in 50 microliters of complete medium per well in plates of 96-well round bottom tissue culture. 50 microliters per well of the triple serial dilutions of the test compound are added to the cells in triplicate. The untreated cells are used as a control. The compound is incubated together with the cells for 90 minutes at 37 ° C, with 5 percent C02, followed by centrifugation of the tissue culture plates at 1,300 revolutions per minute (Beckmann GPR centrifuge), and removal of the supernatants. by careful aspiration, taking care not to remove any of the granulated cells. The cell granules are lysed by the addition of 150 microliters of lysis buffer (50 mM Tris / HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP40, ortho-vanadate 2 mM sodium, 1 mM PMSF, 50 micrograms / milliliter of aprotinin, and 80 micrograms / milliliter of leupeptin), and are used immediately for ELISA, or stored frozen in the plates at -20 ° C until use. The rabbit anti-Abl polyclonal SH3 domain Ab 06-466 from Upstate was coated at 50 nanograms in 50 microliters of phosphate-buffered serum per well, in black ELISA plates (Packard HTRF-96 black plates); 6005207) overnight at 4 ° C. After washing three times with 200 microliters / well of phosphate-buffered serum containing 0.05 percent Tween 20 (PBST) and 0.5 percent TopBlock (Juro), the residual protein binding sites are blocked with 200 microliters / well of PBST, 3% TopBlock, for 4 hours at room temperature, followed by incubation with 50 microliters of the Untreated cells or treated with the compounds (20 micrograms of total protein per well) for 3 to 4 hours at 4 ° C. After three washes, 50 microliters / well of anti-phosphotyrosine Ab PY20 (AP) labeled with alkaline phosphatase (Zymed), diluted to 0.2 micrograms / milliliter in blocking buffer, and incubated overnight (4 ° C) are added. . For all incubation steps, the plates are covered with plate sealants (Costar). Finally, the plates are washed three more times with a washing regulator, and once with deionized water, before the addition of 90 microliters / well of the substrate-AP CDPStar RTU with Emerald II. The plates, now sealed with Packard TopSeal ™ RA plate sealers, are incubated for 45 minutes at room temperature in the dark, and the luminescence is quantified by measuring counts per second (CPS) with a Packard Top Count Microplate Cintilation Counter. Top Count). The difference between the ELISA (CPS) reading obtained is calculated with those used for untreated 32D-Bcr / Abl cells and the reading for the assay background (all components, but without the cell lysate), and is taken as 1 00 percent, reflecting the constitutively phosphorylated Bcr-Abl protein present in these cells. The activity of the compound on the activity of the Bcr-Abl kinase is expressed as the percentage reduction of Bcr-Abl phosphorylation. The IC50 (and IC90) values are determined from the dose response curves by graphical extrapolation. The compounds of the invention here preferably show IC 50 values in the range of 50 nM to 500 μM for the inhibition of autophosphorylation and for the inhibition of IL-3 independently of the proliferation of the Bcr-Abl mutants in the transfected cells. Ba / F3, in particular T315I. 32D cl3 cells are obtained from the American Type Culture Collection (ATCX CRL 11346), and Ba / F3 cells from the German Collection of Microorganisms and Cell Culture (DSMZ, Braunschweig and DSMZ No. ACC 300). Palacios et al., Nature, 309: 1984, 126, PubMed ID 6201749. Palacios et al., Cell, 41: 1985, 727, PubMed ID 3924409. Ba / F3 p210 cells and murine hematopoietic 32D cl3 cells (32D p210 cells ) are obtained by transfection of the murine Ba / F3 hematopoietic cell line dependent on IL-3 with a pGD vector containing the p210BCR-ABL cDNA (B2A2). Daley and Baltimore, 1988; Sattler et al., 1996; Okuda et al., 1 996. Daley, G. Q., Baltimore, D. (1988) Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myeloid leukemia-specific p210 BCR-ABL protein. PNAS 85.9312-931 6. Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E, and collaborators (1 996) The proto-oncogene product p 120CBL and the adapter proteins CRKL and c-CRK link c -ABL, p 190BCR-ABL and p210BCR-ABL to the phosphatidylinositol-3 'kinase pathway. Oncogene 1 2, 839-46. Okuda K, Golub T. R., Gilliland D. G. , G riffin J. D. (1 996) p210BCR-ABL, p190BCR-ABL, and TEL / ABL activate similar signal transduction pathways in hematopoietic cell Unes. Oncogene 1 3, 1 147-52. Activity Test Against c-KIT The baculovirus donor vector pFbacGOl GIBCO is used to generate a recombinant baculovirus expressing the region of amino acids 544-976 of the cytoplasmic kinase domains of human c-Kit. The coding sequences for the cytoplasmic domain of c-Kit are amplified by polymerase chain reaction, from a cDNA library of human uterus (Clontech). The amplified DNA fragment and the pFbacGOl vector are made compatible for ligation by digestion with BamH 1 and EcoRI. Ligation of these DNA fragments results in the baculovirus donor plasmid c-Kit. The production of the viruses, the expression of the proteins in Sf9 cells, and the purification of the proteins fused with GST, are carried out as follows: Production of the virus: The transfer vector pFbacG01 -c-Kit containing the domain of c-Kit kinase is transfected into the DH I OBac cell line (G IBCO), and the transfected cells are applied to selective agar plates. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. The individual white colonies are collected, and the viral DNA (bacmid) of the bacteria is isolated by conventional plasmid purification procedures. Then the Sf9 cells or the Sf21 cells, American Type Culture Collection, are transfected in 25 square centimeter flasks with the viral AN D using the Cellfectin reagent. Determination of small scale protein expression in Sf9 cells: Virus-containing medium from the transfected cell culture is harvested and used for infection in order to increase its titration. The virus-containing medium obtained after two rounds of infection is used for large-scale protein expression. For large-scale protein expression, round tissue culture plates of 100 square centimeters are seeded with 5x1 07 cells / plate, and infected with 1 milliliter of the virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the plate, and centrifuged at 500 revolutions per minute for 5 minutes. Cellular granules from 1 to 20 1-square-centimeter plates are resuspended in 50 milliliters of ice-cold lysis buffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 percent NP-40, 1 mM DTT, 1 mM PMSF). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. Purification of the GST-labeled protein: The centrifuged cell lysate is loaded onto a 2 milliliter column of glutathione-Sepharose (Pharmacia), and washed three times with 10 milliliters of 25 mM Tris-HCl, pH 7.5, EDTA 2 mM, 1 mM DTTA, 200 mM NaCl. The GST-labeled protein is eluted by ten applications (1 milliliter each) of 25 mM Tris-HCl, pH 7.5, reduced glutathione 1 0 mM, NaCl 1 00 mM, DTT 1 mM, glycerol 1 0 percent, and stored at -70 ° C. Kinase assay: Protein tyrosine kinase assays with purified GST-c-Kit are carried out in a final volume of 30 microliters containing 200 to 1. 800 milligrams of the enzyme protein (depending on the specific activity) , 20 mM Tris-HCl, pH 7.6, 3 mM MCI2, 3 mM MgCl2, 1 mM DTT, 1.0 μM Na3V04, 5 micrograms / milliliter of poly (Glu, Tyr), 4: 1, dimethyl sulfoxide 1 percent, ATP1 .0 μM, and 0J μCi of [? 33 P] ATP. The activity is assayed in the presence or in the absence of the inhibitors, by measuring the incorporation of 33P from [? 33P] ATP into the poly (Glu, Tyr) substrate, 4: 1. The assay (30 microliters) is carried out in 96-well plates at room temperature for 20 minutes, under the conditions described below, and is terminated by the addition of 20 microliters of 25 mM EDTA. Subsequently, 40 microliters of the reaction mixture is transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, and then soaked for 5 minutes with 0.5% H3P0. , 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 microliters of 0.5% H2P04. The membranes are removed and washed four times on an agitator with H P03 at 1.0 percent, and once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96-well Packard TopCount frame, and 10 microliters / well of Microscint ™ (Packard). The IC50 values are calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, in four concentrations (usually 0.01, 0J, 1, and 10 μM). One unit of protein kinase activity is defined as a nanomol of 33P ATP transferred from [33P] ATP to the substrate protein per minute per milligram of protein at 37 ° C. Values in the preferred range of between 50 nM and 500 μM can be found with a compound of Formula IA according to the invention. Activity Test Against EphB4 The efficacy of the compounds of Formula IA as inhibitors of the receptor kinases of Ephrin B4 (EphB4) can be demonstrated as follows: Generation of fusion expression vectors with GST Bac-to-BacM R (Invitrogen Life Technologies, Basel, Switzerland): The entire cytoplasmic coding regions of the EphB class are amplified by polymerase chain reaction from cDNA libraries derived from placenta or human brain, respectively. Recombinant baculoviruses expressing the amino acid region 566-967 of the human EphB4 receptor (SwissProt Datábase, Accession Number P54760) are generated. The GST sequence is cloned into the pFastBad ® vector (I nvitrogen Life Technologies, Basel, Switzerland), and amplified with polymerase chain reaction. The cDNAs encoding the EphB4 receptor domains are cloned respectively within the framework 3 'of the GST sequence in this modified FastBad vector, to generate the pBac-to-BacM R donor vectors. The individual colonies that occur in the transformation are inoculated 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 on both chains are confirmed. Virus production: The viruses for each of the kinases are made according to the protocol provided by FI BCO, if not mentioned otherwise. In brief, the transfer vectors containing the kinase domains are transferred to the DHI OBac cell line (GIBCO), and applied to selective agar plates. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. The individual white colonies are collected, and the viral DNA (bacmid) of the bacteria is isolated by conventional plasmid purification procedures. Then the Sf9 or Sf21 cells are transfected in 25 square cm flasks with the viral DNA, using the Cellfectin reagent according to the protocol. Purification of the GST-labeled kinases: The centrifuged cell lysate is loaded onto a 2 milliliter column of glutathione-Sepharose (Pharmacia), and washed three times with 1.0 milliliters of 25 mM Tris-HCl, pH 7.5, EDTA 2 mM, 1 mM DTT, 200 mM NaCl. Then the GST-labeled proteins are eluted by ten applications (1 milliliter each) of 25 mM Tris-HCl, pH 7.5, reduced glutathione 10 mM, 100 mM NaCl, 1 mM DTT, 10 percent glycerol, and they are stored at -70 ° C. Protein kinase assays: The activities of protein kinases are assayed in the presence or in the 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 the purified GST-EphB (30 nanograms) are carried out for 1 to 30 minutes at room temperature, in a final volume of 30 microliters containing 20 mM Tris-HCl, pH 7.5, 1 mM MgCl 2, MnCl2 3-50 nM, 0.5 mM Na3V04, 1 percent dimethyl sulfoxide, 1 mM DTT, 3 micrograms / milliliter of poly (Glu, Tyr), 4: 1 (Sigma, St. Louis, MO, USA), and ATP 2.0-3.0 μM (? - [33P] -ATP OJ μCi). The assay is terminated by the addition of 20 microliters of 125 mM EDTA. Subsequently, 40 microliters of the reaction mixture is transferred to a membrane I mmobilon-PVDF (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, and then soaked for 5 minutes with 0.5 H3P04. cent, and mounted on a vacuum manifold with the vacuum source disconnected. After staining all the samples, the vacuum is connected, and each well is quenched with 200 microliters of 0.5% H3P04. The membranes are removed and washed four times on a shaker with 1.0% H3P04, 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 Microscint ™ (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 0.01, 0J, 1, and 10 μM). One unit of protein kinase activity is defined as 1 nanomol of 33P ATP transferred from [? 33P] ATP to the substrate protein per minute per milligram of protein at 37 ° C. IC50 values preferably in the range of 50 mM to 500 μM can be found with the compounds of Formula IA according to the invention.

Activity Test Against EGF-R: The inhibition of EGF-R tyrosine kinase activity can be demonstrated using known methods, for example, using the recombinant intracellular domain of the EGF receptor [EGF-R, ICD; see, for example, E. McGlynn et al., Europ. J. Biochem. 207, 265-275 (1992)]. Compared to the control without inhibitor, the compounds of Formula IA inhibit the enzymatic activity by 50 percent (IC50), for example, in a concentration of 0.05 to 500 μM. As well as kinase activity is inhibited, or instead of inhibiting EGF-R tyrosine kinase activity, compounds of Formula IA also inhibit other compounds of this family of receptors, such as ErBb-2. The inhibitory activity (IC50) is approximately in the range of 0.01 to 500 μM. Inhibition of the tyrosine kinase ErbB2 (HER-2) can be determined, for example, in a manner analogous to the method employed for the protein tyrosine kinase EGF-R [see C. House and collaborators, Europ. J. Biochem. 140, 363-367 (1984)]. The ErbB-2 kinase can be isolated, and its activity can be determined, by means of protocols known per se, according to T. Akiyama et al., Science 232, 1644 (1986). Activity Test Against VEGF-R2 (KDR): Inhibition of VEGF-induced auto-phosphorylation of the receptor can be confirmed with additional in vitro experiments on cells, such as transfected CHO cells, that permanently express the human VEGF-R2 receptor ( KDR), and are seeded in a complete culture medium (with 1 0 percent fetal calf serum = FCS) in 6-well cell culture plates, and incubated at 37 ° C with 5 percent C02, until that show a confluence of approximately 80 percent. Then the compounds to be tested are diluted in the culture medium (without fetal calf serum, with bovine serum albumin at OJ percent), and added to the cells. (The controls comprise the medium without test compounds). After 2 hours of incubation at 37 ° C, the recombinant vascular endothelial growth factor is added; The final vascular endothelial growth factor concentration is 20 nanograms / milliliter. After an additional 5 minutes of incubation at 37 ° C, the cells are washed twice with ice-cold PBS (phosphate-buffered serum), and immediately lysed in 1000 microliters of lysis buffer per well. Then the used ones are centrifuged to remove the cell nuclei, and the protein concentrations of the supernatants are determined using a commercial protein assay (BIORAD). Then the used ones can be used immediately, or if necessary, they are stored at -20 ° C. A sandwich ELISA is carried out to measure the phosphorylation of VEGF-R2: A monoclonal antibody to VEGF-R2 (for example, Mab 1495J 2J 4, prepared by H. Towbin, Novartis, or a comparable monoclonal antibody) is immobilized on black ELISA plates (Opti PlateM R HTRF-96 from Packard). The plates are then washed, and the remaining free protein binding sites are saturated with 3 percent TopBlock® (Juro, Cat. # TB232010) in phosphate buffered serum, with Tween20® (polyoxyethylene sorbitan monolaurate (20) , ICI / Uniquema) (PBST). The cellular ones (20 micrograms of protein per well) are then incubated in these plates overnight at 4 ° C, together with an anti-phosphotyrosine antibody coupled with alkaline phosphatase (PY20-AP from Zymed). (The plates are washed again, and) then the binding of the anti-phosphotyrosine antibody to the captured phosphorylated receptor is demonstrated, using a luminescent AP substrate (CDF-Star, ready for use, with Emerald II, Applied Biosystems). The luminescence is measured on a Packard Top Count Microplate Cintilation Counter. The difference between the signal of the positive control (stimulated with VEGF) and that of the negative control (not stimulated with VEGF) corresponds to the VEGF-R2 phosphorylation induced by VEGF (= 100 percent). The activity of the substances tested is calculated as the percentage inhibition of the VEGF-R2 phosphorylation induced by VEGF, wherein the concentration of substance that induces half of the maximum inhibition is defined as the IC50 (inhibitory dose for a 50 percent inhibition). IC50 values preferably in the range of 20 mM to 500 μM can be found with the compounds of Formula IA, according to the invention. Activity Test Against Recombinant Protein Kinase Ret (Rat-Men2A), Tie-2 (Tek), and FGFR3-K650E: Cloning and expression of recombinant protein kinases: (Ref: the baculovirus donor vector pFB-GSTX3 is used to generate a recombinant baculovirus that expresses the amino acid region 658-1 072 of the intra-cytoplasmic kinase domain of human Ref-Men2A that corresponds to the wild-type kinase domain of Ret.The coding sequence for the cytoplasmic domain of Ret is amplified by polymerase chain reaction from the plasmid pBABEpuro RET-Men2A, which is received from Dr. James Fagin, College of Medicine, University of Cincinnati (Novartis collaboration) The amplified DNA fragments and the pFB-GSTX3 vector are made compatible for ligation by digestion with Sali and Kpnl The ligation of these DNA fragments results in the baculovi donor plasmid rus pFB-GX3-Ret (-Men2A). (Tie-2 / Tek): The baculovirus donor vector pFbacGOl is used to generate a recombinant baculovirus that expresses the amino acid region 773-1 1 24 of the cytoplasmic kinase domain of human Tek, N-terminally fused with GST (provided by Dr. Marmé, Institute of Molecular Medicine, Freiburg, Germany, based on a Research Collaboration). Tek is re-cloned into the pFbacGO 1 transfer vector by EcoRI separation and ligation in pFbacGOl digested with EcoRI (FBG-Tie2 / Tek). (FGFR-3-K650E): The baculovirus donor vector pFastBacGST2 is used to generate a recombinant baculovirus expressing the region of amino acids 41 1-806 of the cytoplasmic domain of human FGFR-3, N-terminally fused with GST (provided by Dr. Jim Griffin, Dana Farber Cancer Institute, Boston, USA, based on a research collation). The DNA encoding amino acids 41 1-806 is amplified by polymerase chain reaction, and inserted into the pFastBac-GT2 vector to provide pFB-GT2-FGFR3-wt. This plasmid in turn is used to generate a vector encoding FGFR3 (41-1806) with a mutation in K650, using the Mutagenesis Kit Di rigid to the Stratagene XL Site, to produce pFB-GT2-FGFR3-K650E. The production of the viruses, the expression of the proteins in Sf9 cells, and the purification of the proteins fused with GST, are carried out as described in the following sections. Virus production: Transfer vectors containing the kinase domains are transfected into the DH I OBac cell line (GIBCO), and 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 harvested, and viral DNA (bacmid) is isolated from bacteria by standard plasmid purification procedures. Then the Sf9 and Sf21 cells are transfected in 25 square cm flasks with the viral DNA, using the Cellfectin reagent.

Determination of small scale protein expression in Sf9 cells: The medium containing the virus is harvested from the transfected cell culture, and used for infection, in order to increase its titration. The medium containing the virus obtained after two rounds of infection is used for large-scale protein expression. For large-scale protein expression, round culture plates of 1 00 square centimeters with 5x1 07 cells / plate are seeded and infected with 1 milliliter of the virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the plate, and centrifuged at 300 revolutions per minute for 5 minutes. The cell granules of 10 to 20 plates of 10 20 square centimeters plates are resuspended in 50 milliliters of ice cold lysis buffer (25mM Tris-HCl, pH 7.5, 2mM EDTA, 1% N P-40, 1 mM DTT, 1 mM PMSF). The cells are shaken on ice for 1 5 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. Purification of GST-labeled proteins: The centrifuged cell lysate is loaded onto a 2 milliliter column of glutathione-Sepharose., and washed three times with 10 milliliters of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 2 mM DTT, 200 mM NaCl. Then the GST-labeled proteins are eluted by ten applications (1 milliliter each) of 25 mM Tris-HCl, pH of 7.5, reduced glutathione 1 0 mM, NaCl 1 00 mM, DTT 1 mM, glycerol 1 0 percent , and stored at -70 ° C.

Measurement of enzymatic activity: Tyrosine protein kinase assays with either purified GST-Ret, GST-Tek, or GST-FGFR-3-K650E, are carried out in a final volume of 30 microliters, with the final concentrations of the following components: Ret included 15 nanograms of GST-Ret, 20 mM Tris-HCl, pH of 7.5, 1 mM MnCl 2, 10 mM MgCl 2, mT DTT 1, 3 micrograms / milliliter of poly (Glu, Tyr), 4: 1 , 1 percent dimethyl sulfoxide, and 2.0 μM ATP (? - [33P] -ATP OJ μCi). Tek included 150 nanograms of GST-Tek, 20 mM Tris-HCl, pH 7.5, 3 mM MnCl2, 3 mM MgCl2, 1 mM DTT, 0.01 mM Na3V04, 250 micrograms / milliliter of PEG 20,000, 10 micrograms / milliliter of poly ( Glu, Tyr), 4: 1, 1 percent dimethyl sulfoxide, 4.0 μM ATP (? - [33P] -ATP 0J μCi). FGFR-3-K650E included 10 nanograms of GST-FGFR-3-K650E, 20 mM Tris-HCl, pH 7.5, MnCl23 mM, 3 mM MgCl2, 1 mM DTT, 20,000 0.01 mM PEG, 10 micrograms / milliliter of poly ( Glu, Tyr), 4: 1, 1 percent dimethyl sulfoxide, and 4.0 μM ATP (? - [33P] -ATP 0.1 μCi). The activity is assayed in the presence or absence of the inhibitors, measuring the incorporation of 33P from [? 33P] ATP in poly (Glu, Tyr) 4: 1. The assay is carried out in 96-well plates at room temperature for 30 minutes under the conditions described below, and is terminated by the addition of 50 microliters of 125 mM EDTA. Subsequently, 50 microliters of the reaction mixture is transferred to an Immobilon-PVDF membrane (Millipore) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5 percent H3P04, and mounted on a manifold of vacuum with the vacuum source disconnected. After staining all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of 0.5% H3P04. The membranes are removed and washed four times on a shaker with 1.0 percent H3P04, 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 Microscint ™ (Packard). The IC50 values are calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, in four concentrations (usually 0.01, 0J, 1, and 10 pM). One unit of protein kinase activity is defined as 1 nanomol of 33P ATP transferred from [? 33] ATP to the substrate protein per minute per milligram of protein at 37 ° C. IC50 values preferably in the range of 50 nM to 500 μM can be found with the compounds of Formula IA according to the invention. FGFR3 (Enzyme Assay) The assay of kinase activity with purified FGFR3 (Upstate) is carried out in a final volume of 10 microliters containing 0.25 microgram / milliliter of enzyme in kinase regulator (30 mM Tris-HCl, pH of 7.5, 15 mM MgCl2, 4.5 mM MnCl2, 15 μM Na3V0, and 50 micrograms / milliliter of bovine serum albumin), and substrates (5 micrograms / milliliter of biotin-poly-EY (Glu, Tyr) (CIS-US, Inc.) and 3μM ATP). Two solutions are made: the first 5 microliter solution contains the enzyme FGFR3 in kinase regulator, which was dosed first in a 384 well ProxiPlate® (Perkin-Elmer) format, followed by the addition of 50 nanograms of the dissolved compounds in dimethyl sulfoxide, then add 5 microliters of the second solution containing the substrate (poly-EY) and ATP in kinase buffer to each well. The reactions are incubated at room temperature for 1 hour, stopped by the addition of 10 microliters of HTRF detection mixture, containing 30 mM Tris-HCl, pH 7.5, 0.5 M KF, 50 mM EDTA, 0.2 milligrams / milliliter of bovine serum albumin, 15 micrograms / milliliter streptavidin-XL665 (CIB-US, Inc.), and 150 nanograms / milliliter anti-phosphotyrosine antibody conjugated to cryptate CIS-US, Inc.). After 1 hour of incubation at room temperature to allow the interaction of streptavidin-biotin, fluorescent signals resolved in time are read in the Analyst GT (Molecular Devices Corp.). The IC50 values are calculated by linear regression analysis of the percentage of inhibition of each compound in twelve concentrations (dilution to 1: 3, from 50 μM to 0.28 nM). In this assay, the compounds of the invention, for example, preferably have an IC 50 in the range of 2 nM to 400 μM, more preferably in the range of 5 nM to 100 μM. FGFR3 (Cell Assay) The compounds of the invention (= of Formula IA) are tested for their ability to inhibit the proliferation of transformed Ba / F3-TEL-FGFR3 cells, which depends on the activity of the cellular kinase FGFR3. . The Ba / F3-TEL-FGFR3 are cultured up to 800,000 cells / milliliter in suspension, with RPMI 1640 supplemented with 10 percent fetal bovine serum as the culture medium. The cells are dosed in a 384-well format plate, at 5,000 cells / well, in 50 microliters of the culture medium. The compounds of the invention are dissolved and diluted in dimethyl sulfoxide (DMSO). Serial 1: 3 dilutions of 12 points are made in dimethyl sulfoxide to create a gradient of concentrations typically in the range of 10 mM to 0.05 μM. The cells are added with 50 nanoliters of the diluted compounds, and incubated for 48 hours in a cell culture incubator. AlamarBIue® (TREK Diagnostic Systems) is added to the cells, which can be used to monitor the reducing environment created by the proliferating cells, at a final concentration of 10 percent. After an additional 4 hours of incubation in a cell culture incubator at 37 ° C, the fluorescent signals are quantified from the reduced AlamarBIue® (excitation at 530 nanometers, emission at 580 nanometers) in an Analyst GT (Molecular Devices Corp.) . IC5o values are calculated by linear regression analysis of the percentage of inhibition of each compound in twelve concentrations. IC50 values can be found which are preferably in the range of 2 nM to 400 μM with a compound of Formula IA according to the invention.

Upstate KinaseProfilerTM - Radio-Enzymatic Filter Linkage Assay. The compounds of the invention are evaluated for their ability to inhibit the individual members of a panel of kinases (a partial, non-limiting list of kinases includes: Abl, BCR-Abl, BMX, FGFR3, Lck, JNK1, JNK2, CSK, RAF, MKK6 and P38). The compounds are tested in duplicate at a final concentration of 10 μM following this generic protocol. Note that the kinase regulatory composition and substrates vary for the different kinases included in the "Upstate KinaseProfiler ™" panel. The kinase regulator is mixed (2.5 microliters, 1 Ox - containing MnCl2 when required), active kinase (0.001 to 0.01 Units, 2.5 microliters), specific peptide or Poly (Glu4-Tyr) (from 5 to 500 μM or 0.1 milligrams / milliliter) in kinase regulator, and kinase regulator (50 μM, 5 microliters), in an Eppendorf on ice. A mixture of Mg / ATP (10 microliters, MgCI2 67.5 (or 33.75), ATP 450 (or 225) μM, and 1 μCi / μl of [? -32P) -ATP (3,000 Ci / millimole)) is added, and the The reaction is incubated at about 30 ° C for about 10 minutes. The reaction mixture is splashed (20 microliters) on a square of paper of 2 centimeters x 2 centimeters, P81 (phosphocellulose, for positively charged peptide substrates), or Whatman No. 1 (for the peptide substrate of Poly- (Glu4- Tyr)). The test squares are washed four times, for 5 minutes each, with 0.75 percent phosphoric acid, and washed once with acetone for 5 minutes.

The test squares are transferred to a scintillation flask, 5 milliliters of scintillation cocktail are added, and the incorporation of 3 P (cpm) to the peptide substrate is quantified with a Beckman scintillation counter. The percentage of inhibition is calculated for each reaction. The compounds of Formula IA can also inhibit other tyrosine protein kinases, such as in particular the c-Src kinase which has a part in the regulation of growth and transformation in animals, especially in mammalian cells, including human cells . An appropriate assay is described in Andrejauskas-Buchdunger et al., Cancer Res. 52, 5353-8 (1992). Using this test system, the compounds of Formula IA can show IC 50 values for the inhibition of c-Src in the range, for example, from 0.05 to 500 μM. In addition, the compounds of Formula IA 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, by measuring the incorporation of 33P from [α 33P] ATP into (His) -lβB. 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 three times concentrated 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 Tris-HCl, pH 7.5, 3 mM MnCl 2, 3 mM MgCl 2. , 1 nM DTT, 3 micrograms / milliliter of (His) -l? B, 1 percent dimethyl sulfoxide, and 3.5 μM ATP [? 33P] -ATP OJ μCi), and 10 microliters of enzyme dilution (600 nanograms of GST-B-Raf-V599E). The pipette steps are programmed to be carried out on any of the MultiPROBE lix, MultiPROBE IILx, or HamiltonSTAR robots in the 96-well format. The assay is carried out as described in the literature (see C. Garcia-Echeverria et al., Cancer Cel., 5, 231-9 (2004)), and is terminated by the addition of 20 microliters of 125 mM EDTA. The capture of the phosphorylated 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 during minutes with 0.5% H3P0, 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 microliters of 0.5% H3PO. The free membranes are removed and washed four times on a shaker with 1.0 percent H3P04, 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 Microscint ™. The plates are eventually sealed and counted in a microplate scintillation counter (TopCount NXT, TopCount NXT HTS). In the case of the flash plate method, 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 instantaneous plates coated with nickel. The test plates are washed three times with phosphate-buffered serum, and dried at room temperature. Subsequently, the plates are sealed and counted in a microplate scintillation counter (TopCount NXT, TopCount NXT HTS). The IC 50 values are calculated by linear regression analysis of the percent inhibition by the compound, either in duplicate, in four concentrations (usually 0.01, 0.1, 1, and 10 μM), or as an IC50 of 8 individual points starting at 1.0 μM, followed by dilutions at 1: 3. For the inhibition of b-raf, the compounds of Formula IA preferably show IC 50 values in the range of 0.05 to 500 μM. FLT3 Receptor Kinase In order to search for compounds directed to FLT3, two different kinds of assays can be employed: The Flt3 kinase activity is determined as follows: The baculovirus donor vector pFbacGOl (GIBCO) is used to generate a recombinant baculovirus that expresses the region of amino acids 563-993 of the cytoplasmic kinase domain of human Flt3. The coding sequence for the cytoplasmic domain of Flt3 is amplified by polymerase chain reaction from human cDNA libraries (Clontech). The amplified DNA fragments and the pFbacGOl vector are made compatible for ligation by digestion with BamH1 and HindIII. Ligation of these DNA fragments results in the baculovirus donor plasmid Flt-3 (1.1). The production of the viruses, the expression of the protein in Sf9 cells, and the purification of the protein fused with GST, are carried out as follows: Production of the virus: The transfer vector (pFbacGOl -Flt-3) which contains the kinase domain Flt-3, is transfected in the BHIOBac cell line (GIBCO), and the transfected cells are applied to selective agar plates. The colonies without insertion of the fusion sequence in the viral genome (carried by the bacteria) are blue. Individual white colonies are harvested, and viral DNA (bacmid) is isolated from bacteria by standard plasmid purification procedures. Then the Sf9 or Sf21 cells (American Type Culture Collection) are transfected in flasks with the viral DNA, using the Cellfectin reagent. Determination of small scale protein expression in Sf9 cells: The medium containing the virus is transfected from the transfected cell culture, and used for inspection in order to increase its titration. The medium containing the virus obtained after two rounds of inspection is used for large-scale protein expression. For large-scale protein expression, round tissue culture plates of 100 square centimeters with 5x107 cells / plate are seeded and infected with 1 milliliter of the virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the plate, and centrifuged at 500 revolutions per minute for 5 minutes. The cell granules of 10 to 20 plates, each of 100 square centimeters, are resuspended in 50 milliliters of ice cold lysis buffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, N P-40 1 per one hundred, 1 mM DTT, 1 mM PMSF). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. Purification of the GST-labeled protein: The centrifuged cell lysate is loaded onto a 2 milliliter column of glutathione-Sepharose (Pharmacia), and washed three times with 10 milliliters of 25 mM Tris-HCl, pH 7.5, EDTA 2 mM, 1 mM DTT; NaCl 200 mM. Then the GST-labeled protein is eluted by ten applications (1 milliliter each) of 25 mM Tris-HCl, pH 7.5, reduced glutathione 10 mM, 100 mM NaCl, 1 mM DTT, 10 percent glycerol, and stored at -70 ° C. Measurement of enzymatic activity: Tyrosine protein kinase assays are carried out with the purified GST-FU2, in a final volume of 30 microliters containing from 200 to 1, 800 nanograms of the enzyme protein (depending on the specific activity), 20 mM Tris-HCl, pH 7.6, 3 mM MnCl2, 3 mM MgCl2, 1 mM DTT, 10 μM Na3V0, 3 micrograms / milliliter of poly (Glu, Tyr), 4: 1, 1 percent dimethyl sulfoxide , ATP 6.0 μM, and 0.1 μCi of [? 33P] ATP. The activity is assayed in the presence or in the absence of inhibitors, by measuring the incorporation of 33P from [? 33P] ATP into the poly (Glu, Tyr) substrate. The assay (30 microliters per well) is carried out in 96-well plates, at room temperature, for 20 minutes, under the conditions described below, and is terminated by the addition of 20 microliters of 125 mM EDTA. Subsequently, 40 microliters of each reaction mixture is transferred to a membrane I mmobilon-PVDF (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5% 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 microliters of 0.5% H3P04. The membranes are removed and washed four times on a shaker with 1.0% H3P04, and once with ethanol. The membranes are then counted individually after drying at room temperature, mounted in a 96 well Packard TopCount frame, and adding 10 microliters / well of Microscint ™ R (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 0.01, 0.1, 1, and 10 μM). A protein kinase unit is defined as a nano-mol of 33P ATP transferred from [? 33P] ATP to the substrate polypeptide per minute per milligram of protein at 37 ° C. The compounds of formula IA preferably show IC50 values in the range between 0.05 and 500 μM here.

Alternatively or in addition, a cell-based assay can be used to identify inhibitors of mutant FLT3 tyrosine kinase receptors. The general technique involves comparing the effects of potential inhibitors on cell lines that depend on the mutant FLT3 against proliferation, against cell lines that do not depend on the mutant FLT3 for proliferation. Cell lines expressing two different forms of mutated activated FLT3 are used: Ba / F3-FLT3-ITD cells that express a FLT3 mutant with an "In-Line Duplication" (ITD) within the juxtamembrane domain of the receptor. Ba / F3-FLT3-D835Y cells that express a FLT3 receptor that contains a mutation that converts asparagine to position 835 to tyrosine. Preferably, it can be shown that the compounds of the Formula IA inhibit the proliferation of both Ba / F3-FLT3-ITD cells and Ba / F3-D835Y cells at an IC50 of 50 nM to 500 μM, while on the other hand, they do not normally inhibit the growth of Ba cells. / F3 not transformed at concentrations up to 500 nM, and the inhibitory effects of growth of a compound of Formula IA on the Ba / F3-FLT3-ITD cells can be reversed by the addition of high concentrations of I L-3, for provide an alternative viability signal. At the concentrations required to inhibit the proliferation of FLT3-dependent cell lines, it can be shown that the compounds of Formula IA are not cytotoxic against several human leukemia and lymphoma cell lines, which do not have mutant FLT3 receptors (hyperactivated kinases) , suggesting that the drug has an unexpectedly high degree of specificity as a cytotoxic agent. Above all, these results indicate that compounds of Formula IA can be potent inhibitors of mutant FLT3 receptor tyrosine kinase activity, and are a promising candidate for use in the treatment of patients with mutant FLT3 receptors. In particular, it can be shown that the compounds of Formula IA inhibit the activity of receptor tyrosine kinase FLT3 in concentrations in the range of 0.05 to 500 μM. Based on the inhibition studies described hereinabove, a compound of Formula IA (or of the example formulas thereof) according to the invention, shows a therapeutic efficacy in particular against the disorders dependent on (= especially which respond to modulation, more specifically to the inhibition of) protein kinase, especially proliferative diseases, such as the diseases mentioned above under "background of the invention". There are also experiments to demonstrate the anti-tumor activity of the compounds of Formula IA in vivo. For example, in order to test whether a compound of Formula IA inhibits the growth of bladder carcinoma, the following test system can be applied: The human urinary bladder transition cell carcinoma cell line RT-1 12 is used as an in vivo model for testing the in vivo activity of the compounds described in the invention. This cell line is derived from a female patient (age unknown), with primary urinary bladder carcinoma not treated in 1973. This cell line expresses high levels of FGF-R3. 5x1 06 cells are inoculated with Matrigel subcutaneously in the flank of female hairless mice (n = 8), and tumors are allowed to develop. Tumor sizes are measured manually every 2 to 3 days using a caliper. The weight of the animal is monitored as a measure of the animal's health. Treatment with the inhibitor begins when tumor volumes reach approximately 100 cubic millimeters (approximately 7 days). The mice are randomly selected according to tumor volume, and treated with vehicle (N MP / PEG300) or with the test compound (n = 8) for 14 days. The route of administration is oral intubation, and the program is once a day / seven times a week. The antitumor activity is calculated as T / C% ((average change in tumor volume of treated animals / average change in tumor volume of control animals) x 100). The sizes of the xenograft tumors are measured manually with gauges, and the tumor volume is estimated using the formula (W x H x L) x tt / 6, where the width (W), the height (H), and the length (L) are the three largest diameters. Statistical evaluations are done using SigmaStat 2.03. If more than two groups of animals are included in an experiment, the statistical evaluation is made on absolute tumor volumes or body weights on the day of the evaluation, using the one-way ANOVA test. The Dunnett ad hoc post test is used when comparing a control group with all other treatment groups. The tests of Tukey and SNK (Student-Newman-Keuls) are used ad hoc post, when all the groups are evaluated against each other. The tumor samples are dissected and instantly frozen in liquid N2. The tumors are pulverized while they are kept frozen. An aliquot of the frozen powder is smoothed in 1% Triton extraction buffer containing protease inhibitors and phosphatase inhibitors. The used ones are clarified by centrifugation, and the protein concentration is determined. The protein lysate is used to determine the degree of inhibition of the FGFR receptor and the pathway in the tumors. The compounds of Formula IA described in this invention can inhibit tumor growth and induce regression in doses equal to and greater than 10 milligrams / kilogram. As examples of the kinases inhibited by the compounds of Formula IA, as disclosed, c-Abl and Bcr-Abl can be mentioned, in particular, the inhibition of Bcr-Abl can be mentioned.

Another inhibited kinase is the receptor tyrosine kinase VEGF-R. In particular, the KDR receptor of VEGF (VEG F-R2). The compounds of the present invention also inhibit the mutant forms of Bcr-Abl kinases. The compounds disclosed are suitable for the inhibition of one or more of these and / or other tyrosine protein kinases, and / or the non-receptor tyrosine kinase Raf, and / or for the inhibition of the mutants of these enzymes. In view of these activities, the compounds can be used for the treatment of related diseases, in particular, with an aberrant or excessive activity of these types of kinases, especially those mentioned. The ability to modulate this protein kinase activity is preferably related to the inhibition of the activity of this protein kinase. For example, as inhibitors of the VEGF receptor tyrosine kinase activity, the compounds of the invention can primarily inhibit the growth of blood vessels, and therefore, for example, are effective against a number of diseases associated with angiogenesis. poorly regulated, especially diseases caused by ocular neovascularization, especially retinopathies, such as diabetic retinopathy or age-related macular degeneration, psoriasis, hemangioblastoma, such as hemangioma, proliferative disorders of mesangial cells, such as chronic or acute renal diseases, for example diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, or rejection of transplantation, or especially inflammatory kidney disease, such as glomerulonephritis, especially mesangio-proliferative glomerulonephritis, haemolytic-uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma, and especially neoplastic diseases (solid tumors, but also leukemias and other "liquid tumors", especially those that express c-Kit, KDR, Flt-1, or Flt-3), such as in particular breast cancer, colon cancer, lung cancer (especially microcellular lung cancer), prostate cancer, or Kaposi's sarcoma. A compound of Formula IA (or an exemplary formula thereof) (or an N-oxide thereof) inhibits the growth of tumors, and especially suitable for preventing the metastatic spread of tumors and the growth of micro-metastases. One class of target kinases of the compounds of the present invention are the Bcr-Abl mutants. The mutants Glu255? Lysine, Glu255-? Valine, or Thr315- Jsoleucine, can be especially mentioned, more especially the mutant Thr315? Isoleucine. Other Bcr-Abl mutants include Met244-? Val, Phe317- > Leu, Leu248? Val, Met343- > Thr, Gly250? Ala, Met351? Thr, Gly250? Glu, Glu355? Gly, Gln252? His, Phe358? Ala, Gln252? Arg, Phe359? Val, Tyr253? His, Val379? Lle, Tyr253? Phe, Phe382? Leu, Glu255? Lys, Leu387? Met, Glu255- * Val, His396? Pro, Ph? 311? Ll ?, His396? Arg, Phe311? Leu, Ser417? Tyr, Thr315? Lle, Glu459? Lys and Phe486? Ser. The compounds of Formula IA are particularly useful for treating acute myeloid leukemia by inhibiting the tyrosine kinase domain of Flt3. A further embodiment of the present invention is a method for the treatment of acute myeloid leukemia (AML), which comprises administering a therapeutically effective amount of a claimed compound. The compounds of Formula IA (or their salts - especially pharmaceutically acceptable salts), because of their ability to inhibit FGFR, are especially useful in the treatment of (especially abnormal) growth, tissue repair, remodeling; cell migration, cell differentiation, skeletal and / or limb development, wound healing, signal transduction, hematopoiesis and / or angiogenesis, as well as tumorigenesis, or tumors or cancers, including metastasis and metastasis formation, especially in the treatment of human tumors, such as non-microcellular lung cancers, squamous cell carcinoma (head and neck), breast, gastric cancers (e.g., pancreatic, ovarian, colon, and / or prostate adenocarcinomas, as well as astrocytomas, gliomas, bladder cancer, cancers epithelial, for example from the bladder or cervix, multiple myeloma, squamous carcinoma (head and neck), such as oral squamous cell carcinoma, retinoblastoma, sarcoma, such as synovial sarcoma, and / or skin tumors; myeloproliferative syndrome 8p1 1 = eosinophilic myelo-proliferative syndrome (EMS); skeletal abnormalities, human dwarfism, including achondroplasia, craniosynostosis syndromes and dwarfism syndromes, skeletal dysplasias including hypochondroplasia, severe achondroplasia with developmental delay, acanthosis nigricans, thanatophoric dysplasia, craniosynostosis phenotypes, eg coronal craniosynostosis of Muenke or Crouzon syndrome with Acanthosis nigricans, Pfeiffer syndrome, restricted maturation of chondrocytes, inhibition of bone growth; inflammatory or autoimmune diseases, such as rheumatoid arthritis (RA), collagen II arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), psoriasis, juvenile establishment diabetes, Sjogren's disease, thyroid disease, sarcoidosis, autoimmune uveitis , inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease and / or myasthenia gravis; autosomal dominant hypophosphatemic rickets (ADHR), hypophosphatemic rickets linked with the X-chromosome (XLH), tumor-induced osteomalacia (TIO), fibrous bone dysplasia (FH), chronic obstructive pulmonary disease (COPD); obesity, diabetes, and / or diseases related thereto, such as metabolic syndrome, cardiovascular diseases, hypertension, aberrant levels of cholesterol and triglycerides, dermatological disorders (eg, infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance) , type 2 diabetes, insulin resistance, hypercholesterolemia, cholelithiasis, orthopedic injury, thromboembolic disease, coronary or vascular restriction (eg, atherosclerosis), sleepiness during the day, sleep apnea, end-stage renal disease, gallbladder disease , gout, heat disorders, impaired immune response, impaired respiratory function, infections following wounds, infertility, liver disease, lower back pain, obstetric and gynecological complications, pancreatitis, embolism, surgical complications, stress urinary incontinence , and / or gastrointestinal disorders. In International Publication Number WO2006 / 0381 1-2, a method for promoting localized neochondrogenesis in a cartilage of a mammal is described, which comprises administering certain kinase inhibitors locally to the cartilage. Surprisingly, it was found that the compounds of Formula IA, as defined herein, can be employed in the same manner. Accordingly, the present invention also relates to a method for promoting localized neochondrogenesis in a cartilage of a mammal, which comprises administering locally to cartilage, a urea derivative of Formula (IA), as defined above, or salts pharmaceutically acceptable hydrates, solvates, esters, N-oxides, protected derivatives, individual isomers, and mixtures of isomers thereof, or prodrugs thereof, in an amount that is effective to promote localized neochondrogenesis. The compound of Formula IA is also useful in the treatment of osteoarthritis in the context of neochondrogenesis.

The term "treatment" also includes prophylaxis, including preventive treatment, 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, symptom relief, symptom reducer, suppressor of disease or symptoms, progress retarder, kinase regulator, and / or kinase inhibitor) of these diseases, in particular of any one or more of the diseases mentioned above. The treatment of an animal is preferred. An animal is preferably a warm-blooded animal, more preferably a mammal. A human being (which in general also falls under the general term of "animal" is in particular a patient 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 below Pharmaceutical preparations, methods, and uses The present invention also relates to pharmaceutical compositions comprising a compound of Formula IA (or an exemplary formula thereof), or an N-oxide thereof, as an active ingredient. , and which can be used in particular in the treatment of the aforementioned diseases The pharmacologically acceptable compounds of the present invention can be used, for example, for the preparation of pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the Formula IA (or an exemplary formula thereof), or a pharmaceutically acceptable salt thereof, as an ingredient active, together or in admixture with a significant amount of one or more inorganic or organic, solid or liquid, pharmaceutically acceptable vehicles. The invention also relates to a pharmaceutical composition that is suitable for administering to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human, for example lymphocytes), for the treatment, or, in a broader aspect of the invention, the prevention of (= prophylaxis against) a disease that responds to the inhibition of tyrosine protein kinase activity, in particular one of the diseases mentioned above as preferred, for using a compound of Formula IA (or an exemplary formula thereof), which comprises an amount of a novel compound of Formula IA (or an example formula thereof), or a pharmaceutically acceptable salt thereof, which is effective for said inhibition, together with at least one pharmaceutically acceptable carrier. Especially preferred are compositions for enteral administration, such as nasal, buccal, rectal, or especially oral administration, and for parenteral administration, such as intravenous, intramuscular, or subcutaneous administration, to warm-blooded animals, especially Humans. The compositions comprise the active ingredient alone, or preferably, together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the disease to be treated, and the species, weight, age, and individual condition, the individual pharmacokinetic data, and the mode of administration. The present invention relates in particular to pharmaceutical compositions comprising a compound of Formula IA (or an exemplary formula thereof), a tautomer, an N-oxide, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof, and at least one pharmaceutically acceptable vehicle. The invention also relates to pharmaceutical compositions for use in a method for the prophylactic, or especially therapeutic, handling of the human or animal body, to a process for its preparation (especially in the form of compositions for the treatment of tumors), and to a method for the treatment of diseases (especially tumors), especially those mentioned hereinabove. The invention also relates to processes and the use of the compounds of Formula IA (or an exemplary formula thereof), or N-oxides thereof, for the preparation of pharmaceutical preparations, which comprise the compounds of Formula IA (or an exemplary formula thereof), or N-oxides thereof, as an active component (active ingredient).

The pharmaceutical compositions comprise from about 1 percent to about 95 percent active ingredient, the administration forms comprising a single dose, in the preferred embodiment, from about 20 percent to about 90 percent active ingredient. , and comprising forms other than the single dose type, in the preferred embodiment, from about 5 percent to about 20 percent active ingredient. Unit dosage forms, for example, are coated and uncoated tablets, ampoules, flasks, suppositories, or capsules. Other dosage forms are, for example, ointments, creams, pastes, foams, dyes, aerosols, etc. The examples are capsules containing from about 0.05 grams to about 1.0 grams of active ingredient. The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving, or lyophilizing processes. Preference is given to the use of the solutions of the active ingredient, and also suspensions or dispersions, especially solutions, dispersions, or isotonic aqueous suspensions, which, for example, in the case of lyophilized compositions comprising the active ingredient alone or together with a vehicle, can be reconstituted before use. The pharmaceutical compositions 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. itself, for example by means of the conventional processes of dissolution and lyophilization. These solutions or suspensions may comprise viscosity-increasing agents or solubilizers, such as carboxymethylcellulose sodium, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatin. 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, in particular from 1 to 22, carbon atoms, for example lauric acid, can be mentioned as such. , tridecylic 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 acid, erucic acid, brasidic acid, or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, β-carotene, or 3,5-diterbutyl-4-hydroxy-toluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms, and is mono- or poly-hydroxy, for example a mono-, di-, or tri-hydroxy-alcohol, for example methanol, ethanol, propanol, butanol, or pentanol, or the isomers thereof, but especially glycol and glycerol. Accordingly, the following examples of fatty acid esters can be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefossé, Paris), "Miglyol 812" (triglyceride of saturated fatty acids with a chain length of 8 to 1 2 carbon atoms, H? ls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, olive oil, castor oil, sesame oil, soybean oil, and more especially peanut oil. The compositions for injection are prepared in the customary manner under sterile conditions; The same applies also to the introduction of the compositions in ampoules or flasks, and to the sealing of the containers. Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, 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 plastic vehicles that allow the active ingredients to diffuse or be released in measured quantities. Suitable carriers are in particular fillers, such as sugars, for example lactose, sucrose, mannitol, or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium triphosphate or calcium acid phosphate, and binders, such as pastes of starch using, for example, corn starch, wheat starch, rice starch, or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinyl starch. pyrrolidone, and / or, if desired, disintegrants, such as the above-mentioned starches, and / or carboxymethyl starch, crosslinked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. The excipients are in particular flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric coatings, using, inter alia, concentrated sugar solutions, which may comprise gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and / or titanium dioxide, or solutions of coating 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. The capsules are dry filled capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry filled capsules may 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 magnesium stearate, 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 also being possible for stabilizers and / or antibacterial agents to be added. Dyes or pigments may be added to tablets or dragee coatings or capsule shells, for example, for identification purposes, or to indicate different doses of the active ingredient. Tablet cores can be provided with suitable, optionally enteric coatings through the use of, inter alia, concentrated sugar solutions, which may comprise gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and / or sodium dioxide. titanium, or coating solutions in solvents or mixtures of suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations. Pharmaceutical compositions for oral administration also include hard capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticizer. The hard capsules may contain the active ingredient in the form of granules, for example mixed with fillers, binders, and / or skimmers, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid carriers, to which stabilizers and detergents may also be added. Pharmaceutical compositions suitable for rectal administration are, for example, suppositories, which consist of a combination of the active ingredient and a suppository base. For parenteral administration, aqueous solutions of an active ingredient in a water-soluble form, for example a water-soluble salt, or aqueous suspensions for injection containing viscosity-increasing substances, for example sodium carboxy-methyl-cellulose, sorbitol, are especially suitable. , and / or dextran, and if desired, stabilizers. The active ingredient, optionally together with the excipients, may also be in the form of a lyophilisate, and may be made in a solution prior to parenteral administration by the addition of suitable solvents. Solutions can also be employed, such as are used, for example, for parenteral administration, as solutions for infusion. The invention relates in the same way to a process or a method for the treatment of one of the diseases (pathological conditions) mentioned herein, especially a disease that responds to the inhibition of a tyrosine kinase, more especially as mentioned in the foregoing, more especially FGFR, especially a corresponding neoplastic disease. The compounds of Formula IA (or an exemplary formula thereof), or the N-oxides thereof (including this also the salts, esters, or the like), may be administered as such, or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against said diseases, to an animal, preferably to a warm-blooded animal, for example to a human, each preferably requiring such treatment. In the case of an individual having a body weight of about 70 kilograms, the daily dose administered is, for example, from about 0.001 grams to about 1.2 grams, preferably, for example, from about 0 grams to about 3 grams of a compound of the present invention. "Approximately" preferably means with up to a deviation of 1 0 percent, more preferably with up to a deviation less than 1 percent, of the given number, respectively. A "responding" disease is one in which it can be shown that some beneficial effect can be found. The invention also provides a method for the treatment of a protein kinase dependent disease, which comprises administering to a warm-blooded animal, for example a human, one or more cytostatic or cytotoxic compounds, for example Glivec®, in combination with a compound of the invention, either at the same time, or at a separate time. The term "at the same time" is taken to signify in rapid succession or one immediately after the other.

The present invention also relates especially to the use of a compound of Formula IA (or an exemplary formula thereof), or N-oxides thereof, or a pharmaceutically acceptable salt thereof, especially a compound of Formula IA (or an exemplary formula thereof), which is mentioned as preferred, or a pharmaceutically acceptable salt thereof, as such, or in the form of a pharmaceutical formulation with at least one pharmaceutically acceptable carrier, for therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, preferably a disease that responds to the inhibition of a protein kinase, especially a neoplastic disease, more especially leukemia that responds to the inhibition of the tyrosine kinase Abl. The preferred dose amount, the composition, and the preparation of the pharmaceutical formulations (medicaments) to be used in each case are described above. A compound of Formula IA (or an exemplary formula thereof) may also be used with advantage in combination with other anti-proliferative agents. These anti-proliferative agents include, but are not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, inhibitors. of COX-2, MMP inhibitors, mTOR inhibitors, anti-neoplastic anti-metabolites, platinum compounds, compounds that decrease the activity of protein kinase and ATPase activity, other anti-angiogenic compounds, gonadorelin agonists , anti-androgens, bengamides, bisphosphonates, anti-proliferative antibodies, temozolomide (TEMODAL®), steroids, such as dexamethasone, proteasome inhibitors, such as velcade, and / or thalidomide. The term "aromatase inhibitors", as used herein, refers to compounds that inhibit the production of estrogen, ie, the conversion of the substrates of androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially exemestane and formestane, and in particular, non-steroids, especially amino-glutethimide, borozole, fadrozole, anastrozole, and most especially, letrozole. Exemestane can be administered, for example, in the form as it is traded, for example under the registered trademark AROMASINM R. Formestane can be administered, for example, in the form as it is traded, for example under the registered trademark LENTARONM R. Fadrozole can be administered, for example, in the form as it is traded, for example under the registered trademark AFEMAMR. Anastrozole can be administered, for example, in the form as it is traded, for example under the registered trademark ARI MI DEXM R. Letrozole can be administered, for example, in the form as it is traded, for example under the trademark registered FEMARAMR or FEMARM R. The amino-glutethimide can be administered, for example, in the form as it is traded, for example under the registered trademark ORIM ETENM R. A combination of the invention comprising an anti-neoplastic agent, which is an aromatase inhibitor, is particularly useful for the treatment of breast tumors positive for the hormone receptor. The term "anti-estrogen", as used herein, refers to compounds that antagonize the effect of estrogen at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form as it is traded, for example under the registered trademark NOLVADEXM R. Raloxifene hydrochloride can be administered, for example, in the form as it is traded, for example under the trademark registered EVISTAMR. The fulvestrant can be formulated as disclosed in the United States Patent Number US 4, 659.51 6, can be administered, for example, in the form as it is traded, for example under the registered trademark FASLODEXM R. The term "topoisomerase I inhibitors", as used herein, includes, but is not limited to, topotecan, irinotecan, 9-nitro-camptothecin, and the macromolecular camptothecin conjugate PNU-166148 (compound A1 of International Publication Number WO99 / 1 7804). The irinotecan can be administered, for example, in the way it is traded, for example under the registered trademark CAMPTOSARMR. The topotecan can be administered, for example, in the form as it is traded, for example under the registered trademark HYCAMTI NM R. The term "topoisomerase II inhibitors", as used herein, includes, but is not limited to , the anthracyclines doxorubicin (including the liposomal formulation, for example, CAELYXM R), epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. The etoposide can be administered, for example, in the form as it is traded, for example under the registered trademark ETOPHOSMR. The teniposide can be administered, for example, in the form as it is traded, for example under the registered trademark VM 26-BR ISTOLM R. Doxorubicin can be administered, for example, in the form as it is traded, for example under the Registered trademark ADRIBLASTI NM R. Epirubicin can be administered, for example, in the form as it is traded, for example under the registered trademark FARMORUB ICI NM R. Idarubicin can be administered, for example, in the form in which it is traded , for example under the registered trademark ZAVEDOSM R. Mitoxantrone can be administered, for example, in the form as it is traded, for example under the registered trademark NOVANTRONM R. The term "microtubule active agents" refers to microtubule stabilizing and microtubule destabilizing agents, including, but not limited to, the taxanes paclitaxel and docetaxel; vinca alkaloids, for example vinblastine, especially vinblastine sulfate, vincristine, especially vincristine sulfate, and vinorelbine, discodermolide and epothilones, such as epothilones B and D. Docetaxel can be administered, for example, in the form trade, for example under the registered trademark TAXOTEREMR. The vinblastine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark VINBLASTIN R. R.MR. The vincristine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark FARMISTIN ™. The term "alkylating agents", as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, and melphalan. 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 form as it is traded, for example under the registered trademark HOLOXANMR. The term "histone deacetylase inhibitors" refers to compounds that inhibit histone deacetylase, and which possess anti-proliferative activity. The term "farnesyl transferase inhibitors" refers to compounds that inhibit farnesyl transferase and that possess anti-proliferative activity.

The term "COX-2 inhibitors" refers to compounds that inhibit the enzyme cyclo-oxygenase type 2 (COX-2), or that possess an anti-proliferative activity, such as celecoxib (Celebrex®), rofecoxib (Vioxx ®), and lumiracoxib (COX189). The term "MMP inhibitors" refers to compounds that inhibit matrix metalloproteinase (MMP) and that possess anti-proliferative activity. The term "mTOR inhibitors" refers to compounds that inhibit the mammalian target of rapamycin (mTOR), and which possess anti-proliferative activity, such as sirolimus (Rapamune®), everolimus (Certican ™), CCI-779 and ABT578. The term "anti-neoplastic anti-metabolites" includes, but is not limited to, 5-fluoro-ur, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gemcitabine, 6-mercapto-purine, hydroxy urea , methotrexate, edatrexate, and the salts of these compounds and in addition ZD 1694 (RALTITREXEDMR), LY231514 (ALIMTAMR), LY264618 (LOMOTREXOLMR) and OGT719. The term "platinum compounds", as used herein, includes, but is not limited to, carboplatin, cisplatin, and oxaliplatin. Carboplatin can be administered, for example, in the form as it is traded, for example under the registered trademark CARBOPLAT R. Oxaliplatin can be administered, for example, in the form as it is traded, for example under the registered trademark ELOXATIN ™ . The term "compounds that decrease the activity of protein kinase, and other anti-angiogenic compounds", as used herein, includes, but is not limited to, compounds that decrease the activity, for example, of the factor of vascular endothelial growth (VEGF), epidermal growth factor (EGF), c-Src, protein kinase C, platelet-derived growth factor (PDG F), Bcr-Abl, c-Kit, Flt-3, Insulin-like growth factor receptor I (IGF-I R), and cyclin-dependent kinases (CDKs), phosphatidyl-inositol 3 (PI3K) kinase inhibitors, and protein kinase B (PKB) inhibitors (PKB) ( for example, as mentioned in International Publications Nos. WO 2005/054238 and WO 2005/054237), inhibitors of heat shock protein 90 (HSP90) (an enzyme of ATPase), and anti-angiogenic compounds having another mechanism of action different from decreasing the activity of protein kinase na. Compounds that decrease the activity of vascular endothelial growth factor are especially compounds that inhibit the VEGF receptor, especially the tyrosine kinase activity of the VEGF receptor, and the compounds that bind to VEGF, and are in particular the compounds, proteins, and generic monoclonal antibodies and specifically disclosed in Patent Numbers WO 98/35958, WO 00/09495, WO 00/27820, WO 00/59509, WO 98/1 1223, WO 00/2781 9 , WO 01/551 1 4, WO 01/58899 and EP 0 769 947; those described by M. Prewett et al., In Cancer Research 59 (1999) 5209-5218, by F. Yuan et al., In Proc. Nati Acad. Sci. USA, volume 93, pages 1 4765-14770, December 1 996, by Z. Zhu et al., In Cancer Res. 58, 1 998, 3209-321 4, and by J. Mordenti et al., In Toxicologic Pathology, volume 27, number 1, pages 14-21, 1999; in International Publications Nos. WO 00/37502 and WO 94/10202; AngiostatinM R, described by M. S. O'Reilly et al., Cell 79, 1 994, 315-328; and Endostatin ™ R, described by M. S. O'Reilly et al., Cell 88, 1 997, 277-285; the compounds that reduce the epidermal growth factor activity are in particular the compounds that inhibit the EGF receptor, especially the activity of the tyrosine kinase of the EGF receptor, and the compounds that bind to the EGF, and are in particular the generic and specifically disclosed compounds in Patent Numbers WO 97/02266, EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, WO 98 / 10767, WO 97/30034, WO 97/49688, WO 97/38983 and in particular WO 96/33980; Compounds that reduce the activity of c-Src include, but are not limited to, compounds that inhibit the activity of protein tyrosine c-Src kinase as defined below, and inhibitors that interact with SH2, such as which are disclosed in International Publications Nos. WO97 / 071 31 and WO97 / 081 93; Compounds that inhibit the tyrosine c-Src protein kinase activity include, but are not limited to, the compounds belonging to the structure classes of the pyrrolo-pyrimidines, especially pyrrolo- [2,3-d] - pyrimidines, purines, pyrazo-pyrimidines, especially pyrazo- [3,4-d] -pyrimidines, pyrazo-pyrimidines, in particular pyrazo- [3,4-d] -pyrimidines and pyrido-pyrimidines, especially pyrido- [2 , 3-d] -pyrimidines. Preferably, the term refers to the compounds disclosed in International Publications Nos. WO 96/10028, WO 97/28161, W097 / 32879 and WO97 / 49706; the compounds that reduce the activity of protein kinase C are in particular the staurosporine derivatives disclosed in European Patent Number EP 0296 110 (the pharmaceutical preparation described in International Publication Number WO 00/48571), which compounds are inhibitors of protein kinase C; other specific compounds that decrease the activity of the protein kinase, and which can also be used in combination with the compounds of the present invention, are imatinib (GleevecO / Glivec®), PKC412, lressa ™ (ZD1839), PKI166, PTK787, ZD6474 , GW2016, CHIR-200131, CEP-7055 / CEP-5214, CP-547632, KRN-633 and SU5416; Anti-angiogenic compounds that have another mechanism of action other than reducing the activity of the protein kinase include, but are not limited to, thalidomide (THALOMID), celecoxib (Celebrex), and ZD6126. The term "gonadorelin agonist", as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is disclosed in U.S. Patent No. US 4,100,274, and may be administered, for example, in the form as it is traded, for example under the registered trademark ZOLADEXM R. The abarelix is it can be formulated, for example, as disclosed in U.S. Patent No. 5,843,901. The term "anti-androgens", as used herein, includes, but is not limited to, bicalutamide (CASODEXM R), which may be formulated, for example, as disclosed in the US Pat. North America Number 4,636,505. The term "bengamides" refers to the bengamides and derivatives thereof which have anti-proliferative properties. The term "bisphosphonates", as used herein, includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zolendronic acid. The "etidronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark DI DRONELMR. The "clodronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONEFOSM R. The "tiludronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark SKELI DM R. The "pamidronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark AREDIA R. The "alendronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark FOSAMAXM R. The "ibandronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONDRANATM R. The "risedronic acid" "can be administered, for example, in the way it is traded, for example under the registered trademark ACTON ELM R. The" zoledronic acid "can be administered, for example, in the way it is traded, for example under the registered trademark ZOMETAMR. The term "anti-proliferative antibodies," as used herein, includes, but is not limited to, trastuzumab (Herceptin ™), Trastuzumab-DM 1, erlotinib (Tarceva ™ R), bevacizumab (Avastin ™ R), rituximab (Rituxan ®), PR064553 (anti-CD40), and the 2C4 antibody. For the treatment of acute myeloid leukemia (AML), the compounds of Formula IA (or an exemplary formula thereof) can be used in combination with conventional leukemia therapies, especially in combination with the therapies employed for the treatment of acute myeloid leukemia. In particular, the compounds of Formula IA (or an exemplary formula thereof) can be administered in combination, for example, with farnesyl transferase inhibitors, and / or other drugs useful for the treatment of acute myeloid leukemia, such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatin, 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 I international (for example, IMS World Publications). The above-mentioned compounds, which can be used in combination with a compound of Formula IA (or an exemplary formula thereof), can be prepared and administered as described in the art, such as in the documents cited above. The terms "co-administration" or "combined administration", or the like, as used herein, are intended to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens wherein the agents are not necessarily administer by the same route of administration or at the same time. When the term "use" (as a verb or as a name) is subsequently or in the foregoing mentioned (in connection with the use of a compound of Formula IA, or a salt (especially pharmaceutically acceptable) thereof, this (if not indicated in a different way or suggested in a different way by the context) includes any one or more of the following embodiments of the invention, respectively (if not otherwise mentioned): use in the treatment of a disease that Respond to the modulation (especially inhibition) of the protein kinase (especially tyrosine), the use for the manufacture of pharmaceutical compositions for use in the treatment of a disease that responds to the modulation (especially inhibition) of the protein kinase , methods of using one or more compounds of Formula IA in the treatment of a disease that responds to the modulation (especially inhibition) of the protein and / or proliferative kinase. , pharmaceutical preparations comprising one or more compounds of Formula IA for the treatment of this disease that responds to the modulation (especially inhibition) of the protein kinase, and one or more compounds of Formula IA in the treatment of said disease which responds to the modulation (especially inhibition) of the protein kinase, as appropriate and convenient, if not otherwise mentioned. In particular, the diseases to be treated, and therefore those preferred for the "use" of a compound of Formula IA, are selected from the diseases that respond (meaning also "supported", not only " "dependent", also including situations where a disease is responding to the modulation, especially the inhibition, of a protein kinase, ie the activity of the protein kinase supports or even causes the manifestation of the disease) the modulation (especially inhibition) of the protein kinase (especially tyrosine) mentioned above, or especially the proliferative diseases mentioned above or below. Preferably, a disease that responds to the modulation (especially inhibition) of the protein kinase is one that responds to the inhibition of one or more of the kinases mentioned above and below, more preferably FGFR. Manufacturing Process A compound of Formula IA is prepared in a manner analogous to methods which, for other compounds, are in principle known in the art, such that, for novel compounds of Formula IA, the process is novel as an analogy process, preferably by: reacting an aniline compound of the Formula NA: wherein R4 and n are as defined for a compound of Formula IA, with an amine of the MIA Formula: R2 wherein R1, R2, R3, R5, X, Y, and Z are as defined for a compound of Formula IA, in the presence of a bis-reactive carbonic acid derivative; and, if desired, transforming a compound of Formula IA into a compound different from Formula IA, transforming a salt of a compound that can be obtained from Formula IA into the free compound or into a different salt, transforming a free compound that can be obtained from Formula IA into a salt thereof, and / or separating a mixture of isomers that can be obtained from a compound of Formula IA in the individual isomers. In the reaction, the bis-reactive carbonic acid derivative is preferably a carbonic acid anhydride, and more preferably a carbon dioxide, especially carbonic dichloride (phosgene). The reaction of preference can take place by reacting first of a compound of the formula NA (preferred), or of a compound of the formula II IA, with the bis-reactive carbonic acid derivative, up to the corresponding isocyanate, to which then the other compound (of Formula M ÍA or NA, respectively) is added. The first preferred reaction takes place in a suitable solvent, such as an ether, for example dioxane, at elevated temperatures, for example from 20 ° C to the reflux temperature of the reaction mixture, and can preferably be followed by the concentration of the resulting isocyanate solution, to provide the isocyanate in a solid or oil preference form. The second isocyanate reaction then takes place after the addition of a suitable solvent, in particular N-methylpyrrolidone (NMP), and / or toluene, at an elevated temperature, for example from 20 ° C to the reflux temperature of the mixture. of reaction, and the addition of the complementary amine of Formula M ÍA or MA, respectively. Both reactions preferably take place under a protective gas, especially nitrogen or argon. Reactions and Optional Conversions A compound of Formula IA can be converted to a compound other than Formula IA. For example, in a compound of Formula IA, wherein R 1 is benzyloxy-phenyl-amino or 4-benzyl-piperazin-1-phenyl-amino, the benzyl fraction can be removed by hydrogenation, for example in the presence of a noble metal catalyst, such as palladium on carbon, in a suitable solvent, such as an alcohol, for example methanol, at appropriate temperatures, for example from 0 ° C to 50 ° C, in the case of nitrogen removal of piperazine, in the additional presence of an acid, for example HCl, to provide the corresponding compound, wherein in place of the benzyl fraction, a hydrogen is present. A compound of Formula IA can be converted to a corresponding N-oxide. The reaction is carried out with a suitable oxidizing agent, preferably a peroxide, for example m-chloroperbenzoic acid, in a suitable solvent, for example a halogenated hydrocarbon, typically chloroform or dichloromethane, and in a lower alkane acid. -carboxylic, typically acetic acid, preferably at a temperature between 0 ° C and the boiling temperature of the reaction mixture, especially at about room temperature.

The compounds of the invention in unoxidized form can be prepared from N-oxides of the compounds of the invention by treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, borohydride lithium , sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) of 0 ° C to 80 ° C. Salts of the compounds of Formula IA having at least one salt-forming group can be prepared in a manner known per se. For example, an acid addition salt of the compounds of Formula IA with basic groups (eg, basic nitrogen), can be obtained in the customary manner, for example by treating a compound of Formula IA with an acid or with suitable anion exchange reagent. A salt of a compound of the Formula IA 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 the acid. ethyl-hexanoic acid, with an alkali metal compound or alkaline earth metal organic, such as the hydroxide, carbonate, or carbonate corresponding acid, such as hydroxide, carbonate, or sodium hydrogen carbonate or potassium, with a compound corresponding calcium , or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt forming agent. Internal salts of the compounds of Formula IA containing acidic and basic salt forming groups, for example a free carboxyl group and a free amino group can be formed, for example, by the neutralization of the salts, such as the addition salts of acid, up to the isoelectric point, for example, with weak bases, or by treatment with ion exchangers. A salt of a compound of Formula IA (= a compound of the invention) 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 a different salt. In both cases, suitable ion exchangers can be used. Stereoisomeric 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. The diastereomeric mixtures, for example, can be separated into their individual diastereomers, by means 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 IA itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by H PLC, using chromatographic substrates with chiral ligands. A more detailed description of the techniques applicable to the resolution of the stereoisomers of the compounds can be found from their racemic mixture in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, I nc. , 1981 . Pro-drug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (for example, for further details, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Volume 4, page 1 985). For example, appropriate pro-drugs can be prepared by reacting a non-derivative compound of the invention with a suitable carbamylating agent (e.g., 1, 1 -acyloxy-alkyl-carbano-chlorhidate, para-nitrophenyl carbonate, or the like). The protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of the protecting groups and their removal can be found in TW Greene, "Protecting Groups in Organic Chemistry", 3rd Edition, John Wiley and Sons, Inc., 1 999. The compounds of The present invention can be conveniently prepared, or can be formed, during the process of the invention, as solvates (eg, hydrates). The hydrates of the compounds of the present invention can be conveniently prepared by recrystallization from a mixture of aqueous / organic solvents, using organic solvents such as dioxin, tetrahydrofuran, or methanol. Intermediates and final products can be processed and / or processed according to conventional methods, for example using chromatographic methods, distribution methods, (re-) crystallization, and the like. Starting Materials The starting materials and the intermediates (in each case, including the salts thereof), especially of the Formulas MA and MIA, can be prepared in analogy to the methods described in the Examples, in accordance with, or in analogy to, the methods that are known in the art, and / or that are commercially available. The starting materials, for example, can be prepared as follows: When R1, R2, R3, R4, R5, X, Y, Z, and n are used in the starting materials and intermediates, these symbols preferably have the meanings given for a compound of Formula IA, if not indicated otherwise. A compound of Formula IA carrying one or more halogen moieties, for example, can be prepared by halogenation, for example, with an inorganic acid halide, such as sulfuryl chloride, in a suitable solvent, for example acetonitrile, dichlor - methane, and / or tetrahydrofuran, preferably at temperatures in the range of -40 ° C to 25 ° C, of a corresponding compound of Formula I IA, where up to four other R4 fractions selected from alkyl are present. 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halogen, and alkoxy of 1 to 7 carbon atoms, and the amino group is protected, for example, by acetyl or terbutoxy-carbonyl (for introduction of protecting groups, see, for example, in the Examples, or under the General Process Conditions below), followed by the removal of the protecting group (eg, acetyl by treatment with an alkali metal hydroxide, such as potassium hydroxide, in a suitable solvent, such as ethanol, at elevated temperatures, for example from 30 ° C to the reflux temperature of the mixture; terbutoxycarbonyl by reaction with an acid, for example HCl, in a suitable solvent, for example dioxane, at temperatures, for example, -20 ° C to 30 ° C). R4 = alkyl of 1 to 7 carbon atoms, especially methyl, can be introduced by the alkylation of the phenyl ring (especially when the alkoxyl fractions of 1 to 7 carbon atoms R4 are already present), in a precursor compound corresponding, also of the Formula MA (with protection and deprotection of the amino group as in the previous paragraph), with an alkyl halide of 1 to 7 carbon atoms (for example, iodide), in a suitable solvent, for example tetrahydrofuran, at temperatures preferably from -50 ° C to 25 ° C, after the reaction of the precursor compound of Formula 11 with a strong base, for example butyl- or tert-butyl-lithium, in a suitable solvent, for example pentane and tetrahydrofuran, at preferred temperatures in the range of -80 ° C to 0 ° C. A compound of the MIA Formula, for example, can be prepared as follows, by reacting a compound of the Formula VIA: R3 wherein Hal is halogen, especially chlorine or bromine, with an amine of the Formula VA: 'R1 NH (VA) in the presence of an acid, for example acetic acid or hydrochloric acid, in a suitable solvent, for example water or dioxane, at elevated temperatures, for example in the range of 50 ° C to 160 ° C (if requires, in a tube). Alternatively, a compound of the MIA Formula, wherein R 1 is phenyl substituted by [4- (C 1-7 alkyl) -piperazin-1-yl] -carbonyl, can be obtained by the reaction of a composed of the Formula IVA, as defined above, with a compound of the Formula VIA: wherein A is hydrogen, alkoxy of 1 to 7 carbon atoms, or halogen, preferably in the presence of an acid, for example HCl, in a suitable solvent, for example dioxane, at elevated temperatures, for example 50 ° C at 170 ° C (e.g., in a microwave oven), and then the resulting compound of Formula Vi l A is reacted: wherein the fractions are as defined under the IVA and VIA Formulas, in the presence of a coupling agent, such as propyl phosphonic anhydride, in an appropriate solvent, such as N, N-dimethyl formamide, in the presence of a nitrogen base, for example triethylamine and / or 4-dimethylaminopyridine, preferably at temperatures in the range of 0 ° C to 50 ° C, to obtain the corresponding compound of Formula I MA. A compound of the formula VA, wherein R5 is hydrogen, by example, it can be obtained by reducing a corresponding compound, wherein, in place of the amino group (NR3), a nitro group is present, for example, with iron powder in ethanol, water, and acetic acid, at temperatures high, for example, from 30 ° C to 1 00 ° C, or with hydrogen in the presence of a catalyst, for example Raney nickel in methanol, at temperatures, for example, from 0 ° C to 50 ° C. In both cases, other customary solvents are possible. A corresponding compound of the formula VA can then be obtained, wherein R5 is alkyl of 1 to 7 carbon atoms, by alkylation, for example, with a corresponding alkyl halide of 1 to 7 carbon atoms. The corresponding starting materials, as well as other compounds of Formula IA, can be obtained in analogy to, or by the methods described in, the Examples, according to procedures known in the art, or are commercially available. 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 above in the present and later herein, protective groups may be used where appropriate or where 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 can be introduced and / or removed at the appropriate or desired stages. Reactions comprising the use of protecting groups, therefore, are included as possible, provided that reactions are described without specifically mentioning the protection and / or deprotection in this specification. Within the scope of this disclosure, only an easily removable group that is not a constituent of the particular desired end product of Formula IA is designated as a "protecting group," unless the context otherwise dictates. The protection of the functional groups by these 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 in Organic Chemistry", Plenum Press, London and New York 1 973, in TW Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1 999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1 981, in "Methoden der organischen Chemie" (Methods of organic chemistry), Houben Weyl, 4th Edition, Volume 1 5 / 1, Georg Thieme Verlag, Stuttgart 1 974, in H-D. Jakubke and H. Jeschkeit, "Aminosáuren, Peptide, Proteine" (Amino Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1 982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Carbohydrate Chemistry: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be easily removed (ie without undesired side reactions), for example, by solvolysis, reduction, photolysis, or in a manner alternative, under physiological conditions (for example, by enzymatic dissociation). All the steps of the aforementioned process 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 agents, 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 -1 00 ° C to about 1 90 ° C, preferably from about -80 ° C at 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 reci closed pin, 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 aliphatic ethers, 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, nitriles , such as acetonitrile, 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 pyridine or N-methyl-pyrrolidin- 2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear hydrocarbons, or branched, 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 that can be obtained as an intermediate at any stage of the process, is used as a starting material, and the remaining process steps are carried out, or where a starting material under the reaction conditions, or it is used in the form of a derivative, for example, in a protected form or in the form of a salt, or a compound is produced which can be obtained by the process in accordance with the invention under the process conditions and is further processed in situ. In the process of the present invention, preference is given to using starting materials that result in the compounds of Formula IA described as being preferred. The invention also relates to novel intermediates and / or novel materials. A special preference is given to reaction conditions and novel intermediates that are identical or analogous to those mentioned in the Examples. Preferred Modalities in Accordance with thevention: In the preferred embodiments, as well as in the foregoing and following embodiments of a more general scope, and also in the claims, any or more of the general symbolic expressions, independently of others may be replaced by the corresponding more specific definitions provided above and below, thus producing more preferred embodiments of the invention. The modalities given in the claims are preferred, which, therefore, are incorporated herein by reference. Especially preferred is a compound of Formula IA, as given in any of the above groups A, B, or C. One or more compounds of the Formula IA given in the Examples, as well as the salts (especially pharmaceutically acceptable salts) thereof, are highly preferred. Examples: The following Examples serve to illustrate the invention without limiting its scope. Temperatures are measured in degrees Celsius. Unless indicated otherwise, the reactions take place at room temperature. The Rf values that indicate the proportion of the distance moved by each substance to the distance moved by the eluent front, are determined in thin layer chromatography plates of 5x10 centimeters, of silica gel F254 (Merck, Darmstadt, Germany), by thin layer chromatography, using the solvent systems indicated below. Analytical HPLC Conditions: System 1 Linear gradient from 20 to 100 percent CH3CN in 5 minutes + 1.5 minutes with 100 percent CH3CN (0J percent trifluoroacetic acid); detection at 215 nanometers, flow rate of 1 milliliter / minute at 30 ° C. Column: Nucleosil 100-3 C18 (70x4.0 millimeters). Abbreviations and Acronyms AcOH Acetic acid. API-MS Mass spectroscopy with ionization at atmospheric pressure. Brine Saturated NaCl solution in water. Celite Celite® (The Celite Corporation) = filter aid based on diatomaceous earth.

CH3CN Acetonitrile. DCM Dichloromethane. Conc. Concentrate. DIEA Di-isopropyl-ethyl-amine. DMAP 4-dimethyl-amino-pyridine. DMF Dimethyl-formamide. DMP 1, 3-dimethyl-3,4,5,6-tetrahydro-2- (1 H) -pyrimidinone.

DMSO Dimethyl sulfoxide. Equiv. Equivalent (s) ESI-MS Mass spectroscopy with electrospray ionization. Et3N Triethylamine. EtOAc Ethyl acetate. EtOH Ethanol. HN04 Nitric acid. H2S04 Sulfuric acid. h Hours. Hexano Hex. HCl Hydrochloric acid. H20 Water. HPLC High pressure liquid chromatography. L Liters LiOH Lithium hydroxide. I Metilo. MeOH Methanol. mL Milliliters. Min Minutes P. f. Melting point. MPLC Medium pressure liquid chromatography.

MS Mass spectrum. NaH Sodium hydride. Na2C03 Sodium carbonate. NaHC03 Sodium bicarbonate. Na2S04 Sodium sulfate. NH3ac Aqueous ammonia. NMP 1-methyl-2-pyrrolidone. NMR Nuclear magnetic resonance. PdCl2 (dppf) [1 J'-bis- (diphenyl-phosphino) -ferrocene] -dichloro-palladium (II). Pd (PPh3) 4 Tetrakis- (triphenyl-phosphine) -palladium (0). Pd (PhCN) 2 Cl 2 Bis- (benzonitrile) -palladium (II) Chloride.

Ph Phenyl. Rf Proportion of fronts (TLC). RT Ambient temperature. TBTU 0- (Benzotriazol-1 -yl) - N, N, N ', N'-tetramethyl-uronium tetrafluoroborate. TFA CF3COOH (trifluoroacetic acid). THF Tetrahydrofuran. TLC Thin layer chromatography. TR Retention time. wt Weight. Microwave Appliance: Emrys Optimizer (Biotage) Example for the Reaction Scheme AcOH / H, 0 CA ° J, OL, Example 1: 1- (2,6-dichloro-3,5-dimethoxy-phenyl) -3-f6-r4- (2-morpholin-4-yl-ethoxy) -phenyl- amino1-pyrimidin-4-urea-urea Phosgene (20 percent in toluene, 0.8 milliliters, 1.58 mmol, 2.4 equivalents) is added to a solution of 2,6-dichloro-3,5-dimethoxy-aniline (175 milligrams) , 0.79 millimoles, 1.2 equivalents) in dioxane (2.5 milliliters), under an argon atmosphere. The mixture is heated to reflux, stirred for 1 hour, allowed to cool to room temperature, and concentrated in vacuo. The resulting isocyanate is added to a solution of N- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrimidine-4,6-diamine (208.5 milligrams, 0.66 mmol) in NMP (2 milliliters), at 75 ° C, and under an argon atmosphere. The reaction mixture is stirred at 75 ° C for 2 hours, allowed to cool to room temperature, and then diluted with dichloromethane and a saturated solution of NaHCO 3. The aqueous layer is separated and extracted with dichloromethane. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 96: 4), followed by trituration of the resulting material in MeOH, gives the title compound as a white solid: ESI-MS: 562.9 / 564.9 [MH] +; tR = 2.99 minutes (purity: 100 percent, system 1); TLC: Rf = 0.36 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Step 1.1: N-r4- (2-morpholin-4-yl-ethoxy) -phenyl-pyrimidine-4,6-diamine A mixture of 6-chloro-pyrimidin-4-yl-amine (194 milligrams, 1.5 mmol, 1.3 equivalents), 4- (2-morpholin-4-yl-ethoxy) -phenylamine (256 milligrams, 1J5 mmol) in H20 (1 milliliter), and glacial acetic acid (5 milliliters), is stirred for 16 hours at 100 ° C. After evaporation of the solvent, the residue is taken up in dichloromethane, and diluted with a saturated aqueous solution of NaHCO 3. The aqueous layer is separated and extracted with dichloromethane. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The residue is triturated in EtOAc to give the title compound as a gray solid: ESI-MS: 316.2 [MH] +; tR = 1.00 minutes (purity: 95 percent, system 1); TLC: Rf = 0.22 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Step 1.2: 4- (2-morpholin-4-yl-ethoxy) -phenyl-amine 4- (2-Chloro-ethyl) -morpholine hydrochloride (4.2 grams, 22 mmol, 1.2 equivalents) in one portion, a a mixture of 4-amino-phenol (2 grams, 18.3 mmol), and finely powdered sodium hydroxide (1.87 grams), 45.8 mmol, 2.5 equivalents) in dimethyl formamide (32 milliliters), under an argon atmosphere. The reaction mixture is stirred for 23.5 hours at room temperature. The resulting dark suspension is filtered. The filtrate is diluted with dichloromethane (200 milliliters), and washed with brine (60 milliliters, twice). The organic phase is dried (sodium sulfate), filtered, and concentrated. Purification of the residue by silica gel column chromatography (DCM / EtOH, 95: 5 - >; 7: 3), provides the title compound as a yellow-brown solid: API-MS: 223.2 [MH] +; TLC: R, = 0.31 (DCM / EtOH, 9: 1). Step 1.3: 2.6-dichloro-3,5-dimethoxy-aniline To a solution of N-82,6-dichloro-3,5-dimethoxy-phenyl) -acetamide (34.5 grams, 264 mmol) in ethanol (1.3 liters), Add 2M KOH (0.72 liters). Then, the reaction mixture is heated to reflux, stirred for 44 hours at reflux, and then allowed to cool to room temperature. The resulting suspension is cooled to 0 ° C, stirred for 1 hour, and filtered. The residue is washed with a small portion of cold EtOH / H20 (1: 1), and with cold H20 until neutral, and dried to provide the title compound as a white solid: ESI-MS: 222.0 / 224.0 [MH ] +, TLC: R, = 0.52 (Hex / EtOAc, 1: 1). Step 1.4: N- (2,6-dichloro-3,5-dimethoxy-phenyD-acetamide) Sulfuryl chloride (26.9 milliliters, 325 mmol, 1.93 equivalents) (in 7 minutes) is added to a cold suspension (0 ° C) ) of N- (3,5-dimethoxy-phenyl) -acetamide (32.9 grams, 169 mmol) in CH3CN (500 milliliters) under an argon atmosphere.The resulting yellowish mixture is allowed to stir for 30 minutes, and is quenched by the dropwise addition of a saturated aqueous solution of sodium bicarbonate (250 milliliters) The resulting precipitate is collected by vacuum filtration, washed with H20 (300 milliliters), and dried to provide 20 grams of the desired product (lot 1) The filtrate is diluted with a saturated aqueous solution of NaHCO3 (300 milliliters), and extracted with EtOAc (300 milliliters, twice), the organic phase is washed with H20 and brine, dried (Na2SO4), filtered, and The residue is purified by column chromatography on silica gel (EtOAc / Hex, 1: 1 → 2: 1), to provide 8.8 grams of the product (lot 2). Batch 1 and 2 are combined and stirred in hexane. The solid is collected by filtration, washed with hexane, and dried to provide the title compound as a white solid. ESI-MS: 264.0 / 266.0 [MH] +, TLC: R, = 0J5 (Hex / EtOAc, 1: 1). Step 1.5: N- (3,5-dimethoxy-phene-acetamide) Acetic anhydride (13 milliliters, 137 millimoles, 1.05 equivalents) is added (in 15 minutes) to a suspension of 3,5-dimethoxy-aniline (20 grams, 131 millimoles ) in toluene (110 milliliters), maintaining the internal temperature in the range of 35 ° C to 45 ° C. The reaction mixture is left stirring for 20 hours at room temperature The resulting thick gray suspension is diluted with hexane (55). milliliters), and filtered.The filter residue is washed with toluene / hexanes (2: 1, 70 milliliters), and with hexanes, and dried to provide the title compound as a white solid. API-ES-MS: 196.1 [MH] +, t R = 3.03 minutes (purity: 100 percent, system 1) Example 2: 3- (2,6-d-chloro-3,5-dimethoxy-f in yl) -1-methyl-1-fß-T3 - (4-Methyl-piperazin-1-yl-methyl) -phenyl-amino-1-pyrimidin-4-yl) -urea Phosgene (20 percent in toluene, 1 milliliter, 2.0 mmol, 2.4 equivalents) is added to a solution of 2,6-dichloro-3,5-dimethoxy i-aniline (221 milligrams, 1.0 millimoles, 1.2 equivalents) in dioxane (2.5 milliliters), under an argon atmosphere. The mixture is heated to reflux, stirred for 1 hour, allowed to cool to room temperature, and concentrated in vacuo. The resulting isocyanate is added to a solution of N-methyl-N '- [3- (4-methyl-piperazin-1-yl-methyl) -phenyl] -pyrimidine-4,6-diamine (step 2.1) (259 milligrams , 0.83 mmol) in toluene (5 milliliters), at reflux, and under an argon atmosphere. The reaction mixture is stirred at reflux for 3 hours, allowed to cool to room temperature, and diluted with dichloromethane and a saturated aqueous solution of NaHCO 3. The aqueous layer is separated and extracted with dichloromethane. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 95: 5), gives the title compound as a yellow solid: ESI-MS: 560.0 / 562.0 [MH] J tR = 3.26 minutes (purity: 99 percent, system 1); TLC: Rf = 0.37 (DCM / MeOH + 1 percent aqueous NH3, 9: 1). Step 2J: N-methyl-N'-33- (4-methyl-piperazin-1-yl-methyl-phenyl-pyrimidine-4,6-diamine) A mixture of (6-chloro-pyrimidin-4-yl) -methyl -amine (385 milligrams, 2.68 millimoles, 1.1 equivalents), 3- (4-methyl-piperazin-1-methyl-methyl) -phenylamine (500 milligrams, 2.44 millimoles) and 4N HCl in dioxane (7 milliliters), heat in a sealed tube at 150 ° C for 17.5 hours.The solvent is removed, and the residue is diluted with dichloromethane and a saturated aqueous solution of NaHCO3 The aqueous layer is separated and extracted with dichloromethane and DCM /. MeOH (95: 5) The organic phase is washed with brine, dried (Na 2 SO 4), filtered, and concentrated The purification of the residue by MPLC on silica gel (DCM / MeOH + 1 percent aqueous NH 3, 95: 5), gives the title compound as a beige solid: ESI-MS: 313.2 [MH] +; tR = 1.00 minutes (purity: 100 percent, system 1); TLC: Rf = 0.05 (DCM / MeOH + 1 percent aqueous NH3, 9: 1) Step 2.2: 3- (4-methyl-piperazin-1-yl-metip-phenyl-amine A to a suspension of 1-methyl-4- (3-nitro-benzyl) -piperazine (6.9 grams, 29.14 mmol) and Raney's nickel (2 grams) in MeOH (150 milliliters), stir for 5 hours at room temperature, under an atmosphere of hydrogen. The reaction mixture is filtered through a pad of Celite, and concentrated to give the title compound as a yellow solid: ESI-MS: 206.1 [MH] X Step 2.3: 1 -methyl-4- (3-nitro) -benzyl) -piperazine A mixture of 3-nido-benzyl chloride (5 grams, 29.14 millimoles), N-methyl-piperazine (3.9 millimeters, 34.97 millimoles, 1.2 equivalents), potassium carbonate (8 grams, 58.28 millimoles, 2 equivalents), and acetone (100 milliliters) is stirred for 15 hours at reflux. The reaction mixture is allowed to cool to room temperature, filtered and concentrated. The residue is purified by MPLC on silica gel (DCM / MeOH + 1 percent aqueous NH3, 95: 5), to give the title compound as a brown oil: ESI-MS: 236.0 [MH] J tR = 1.40 minutes (purity: 100 percent, system 1); TLC: Rf = 0.31 (DCM / MeOH + 1 percent aqueous NH3, 9: 1). Example 3: 3- (2,6-I Chloro-3,5-d-methoxy-phenyl) -1- (6-r 3 - (4-ethyl-piperazin-1-yl) -phenyl-amino-1-pyrimidin-4-yl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 559.9 / 561.9 [MH] J t R = 3.75 minutes (purity: 100 percent, system 1); TLC: Rf = 0.37 (DCM / MeOH + 1 percent aqueous NH3, 92: 8). Step 3J: N-3- (4-ethyl-piperazin-1-yl) -phenylH-N'-methyl-pyrimidin-4,6-diamine The title compound is prepared in analogy to the procedure described in step 2J: ESI-MS : 313.2 [MH] J tR = 1.20 minutes (purity: 100 percent, system 1); TLC: R, = EYE (DCM / MeOH + 1 percent aqueous NH3, 9: 1). Step 3.2: 3- (4-ethyl-piperazin-1-l) -phenyl-amine The title compound is prepared in analogy to the procedure described in step 2.2: API-MS: 206.2 [MH] J TLC: R, = 0.31 (DCM / EtOH, 9: 1). Step 3.3: 1-ethyl-4- (3-nitro-phenyl-piperazine) A mixture of 1-fluoro-3-nitro-benzene (3.2 milliliters, 29.7 millimoles) and N-ethyl-piperazine (7.6 milliliters, 59.4 millimoles, 2 The reaction mixture is allowed to cool to room temperature and is diluted with H20 (40 milliliters) and DCM / MeOH (9: 1, 80 milliliters). The aqueous phase is separated and extracted with DCM / MeOH (9: 1) .The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated, purification of the crude product by silica gel column chromatography. (DCM / MeOH, 1: 0 → 95: 5), gives the title compound as a brown oil: ESI-MS: 236.0 [MH] +; tR = 2.49 minutes (purity: 99 percent, system 1); TLC: Rf = 0.26 (DCM / MeOH, 95: 5). Example 4: 3- (2,6-dichloro-3,5-dimethoxy-f in i l) -1-methyl-1 -. { 6-T4- (2-morpholin-4-yl-ethoxy) -phenyl-amino-1-pyrimidin-4-yl) -urea The title compound is prepared in analogy to the procedure described in Example 1: ESI-MS: 577.0 / 579.0 [MH] +; tR = 3.53 minutes (purity: 95 percent, system 1); TLC: Rf = 0.40 (DCM / MeOH + 1 percent aqueous NH3 93: 7). Step 4J: N-methyl-N'-44- (2-morpholin-4-yl-ethoxy) -phenylH-pyrimid-4,6-diamine The title compound is prepared in analogy to the procedure described in step 1J: ESI-MS: 330.2 [MH] +; tR = 1.10 minutes (purity: 100%, system 1); TLC: Rf = 0J6 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Example 5:? .f6- (4-benzyloxy-phenyl-amino) -pyrimidin-4-ill-3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 553.9 / 555.9 [MH] J t R = 5J6 minutes (purity: 100 percent, system 1). Step 5J: N- (4-benzyloxy-phenD-N'-methyl-pyrimidine-4,6-diamine) The title compound is prepared in analogy to the procedure described in step 1J: ESI-MS: 307.2 [MH] +; tR = 3.72 minutes (purity: 100 percent, system 1). Example 6: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-r6- (4-hydroxy-phen i-am i no) -pyrim id i n-4-i 11-1 -methyl -urea A suspension of 1- [6- (4-benzyloxy-phenyl-amino) -pyrimidin-4-yl] -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-methyl-urea (Example 5) (67 milligrams, 0J21 mmol), palladium on carbon (20 milligrams), and MeOH (3.5 milliliters), is stirred for 3 hours at room temperature, under an atmosphere of hydrogen. The reaction mixture is filtered through a pad of Celite, and concentrated. The residue is purified by silica gel column chromatography to provide the title compound as a brown solid: ESI-MS: 464.2 / 466.2 [MH] J t R = 3.91 minutes (purity: 100 percent, system 1). Example 7: 1- (2-chloro-3,5-dimethoxy-6-methyl-phenyl) -3- (6-r4- (4-ethyl-piperazin-1-yl) -phenyl-aminol-pyrimidin-4-yl) -urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 526.1 / 528.1 [MH] J tR = 3J2 minutes (purity: 100 percent, system 1); TLC: R (= 0J3 (DCM / MeOH + 1 percent aqueous NH3, 93: 7) Step 7.1: N-4 - (4-ethyl-piperazin-1-yl) -phenyl-pyrimidine-4,6-diamine The compound of the title is prepared in analogy to the procedure described in step 1.1: ESI-MS: 299.1 [MH] +; tR = 1.00 minutes (purity:> 95 percent, system 1) Step 7.2: 4- (4- ethyl-piperazin-1-yl) -aniline A suspension of 1-ethyl-4- (4-nitro-phenyl) -piperazine (6.2 grams, 26.35 mmol) and Raney's nickel (2 grams) in MeOH (120 milliliters) is stirred for 7 hours at room temperature under a hydrogen atmosphere, the reaction mixture is filtered through a pad of Celite, and concentrated to give the title compound as a violet solid: ESI-MS: 206J [MH] J TLC: R, = 0.15 (DCM / MeOH + 1 percent aqueous NH3, 9: 1) Step 7.3: 1-ethyl-4- (4-nitro-phenyl-piperazine A mixture of 1-bromine -4-nitro-benzene (6 grams, 29.7 millimoles) and 1-ethyl-piperazine (7.6 milliliters, 59.4 millimoles, 2 equivalents), s and heated at 80 ° C for 15 hours. After cooling to room temperature, the reaction mixture is diluted with water and DCM / MeOH, 9: 1. The aqueous layer is separated and extracted with DCM / MeOH, 9: 1. The organic phase is washed with brine, dried (sodium sulfate), filtered, and concentrated. Purification of the residue by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 9: 1), gives the title compound as a yellow solid: ESI-MS: 236.0 [MH] +; tR = 2.35 minutes (purity: 100 percent, system 1); TLC: Rf = 0.50 (DCM / MeOH + 1 percent aqueous NH3, 9: 1). Step 7.4: 2-chloro-3,5-dimethoxy-6-methyl-phenyl-amine HCl is added dropwise (91 milliliters, 360 millimoles, 8 equivalents, 4N in dioxane) to a cooled solution (10 ° C) of the terbutil - (2-Chloro-3,5-dimethoxy-6-methyl-phenyl) -carbamic acid ester (13.8 grams), 45.7 millimoles) in dioxane (150 milliliters), under an argon atmosphere. The reaction mixture is allowed to warm to room temperature, stirred for 24 hours, and concentrated. The residue is diluted with EtOAc, washed with a saturated aqueous solution of NaHCO 3 and brine, dried (Na 2 SO 4), filtered, and concentrated. The residue is purified by crystallization from DCM / hexanes to give the title compound. ESI-MS: 202.0 [MH] +, TLC: R, = 0.37 (DCM). Step 7.5: (2-Chloro-3,5-dimethoxy-6-methyl-phenyl-carbamic acid tertiary butyl ester A solution of sulfuryl chloride (6.7 milliliters, 79.8 mmol, 1.05 equivalents) in dichloromethane (140 milliliters), add drip (75 milliliters) to a cold solution (-15 ° C) of the acid ester (3,5-dimethoxy-2-methyl-phenyl) -carbamic acid (20.4 grams, 76.3 millimoles) in tetrahydrofuran (330 milliliters) under an atmosphere of argon, the reaction mixture is left stirring for 3 hours at -15 ° C, and then it is poured onto a mixture of ice / H20 (400 milliliters), a saturated aqueous solution of NaHCO3 (400 milliliters), and EtOAc (400 milliliters) The layers are separated, and the aqueous phase is extracted with EtOAc (200 milliliters, twice) The combined organic phase is washed with H20 (200 milliliters, three times) and brine (200 milliliters), it is dried (Na 2 SO 4), filtered and concentrated, the residue is purified by trituration in diethyl ether, followed by column chromatography. a silica gel (hexanes / acetone, 95: 5), to provide the title compound. ESI-MS: 302.2 [MH] +, TLC: Rf = 0J3 (hexanes / acetone, 9: 1). Step 7.6: Terbutil-acid ester (3,5-dimethoxy-2-methyl-phenyl) -carbamic A solution of terbutyl lithium (200 milliliters, 340 millimoles, 2.4 equivalents, 1.7M in pentane) is added dropwise to a cold solution (-65 ° C) of the (3,5-dimethoxy-phenyl) -carbamic acid tertiary butyl ester (36J grams, 142 mmol) in tetrahydrofuran (200 milliliters), under an argon atmosphere. The mixture is stirred for 15 minutes at -65 ° C, and then allowed to warm to -25 ° C. Then a solution of methyl iodide (10.7 milliliters, 171 millimoles, 1.2 equivalents) in tetrahydrofuran (140 milliliters) is added. The reaction mixture is allowed to stir for 1 hour at -25 ° C, and then poured onto a mixture of ice / H20 (300 milliliters) and EtOAc (300 milliliters). The layers are separated, and the aqueous phase is extracted with EtOAc (150 milliliters, twice). The combined organic phase is washed with H20 (150 milliliters, three times), and brine (200 milliliters), dried (Na2SO), filtered, and concentrated. The residue is purified by silica gel column chromatography (hexanes / acetone, 95: 5 → 9: 1 → 4: 1), to give the title compound. ESI-MS: 268.1 [MH] +, TLC: R, = 0.25 (hexanes / acetone, 9: 1). Step 7.7: (3,5-Dimethoxy-phenyl) -carbamic acid terbutilide A solution of diterbutyl dicarbonate (145 grams, 651 mmol, 1.3 equivalents) in tetrahydrofuran (200 milliliters) is added dropwise to a solution of 3,5-Dimethoxyaniline (78.2 grams, 500 millimoles) in tetrahydrofuran (1.5 liters) at room temperature, under an argon atmosphere. The reaction mixture is heated to reflux for 4.5 hours (after heating, a considerable gas evolution is observed), it is allowed to cool to room temperature, and concentrated. The residue is diluted with EtOAc (800 milliliters) and H20 (800 milliliters). The layers are separated, and the aqueous phase is extracted with EtOAc (200 milliliters, twice). The combined organic phase is washed with HCl 0JN (200 milliliters), H20, and brine, dried (Na2SO4), filtered, and concentrated. The residue is crystallized from dichloromethane / hexanes, to provide the title compound. ESI-MS: 252J [MH] ", TLC: Rf = 0.34 (Hexanes / EtOAc, 3: 1) Example 8: 3- (2-Chloro-3,5-dimethoxy-6-methyl-phenyl) -1- {.6-r4- (4-ethyl-piperazin-1-yl) -phenyl-amino-1-pyrimidin-4-yl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 1 : ESI-MS: 540J / 542J [MH] +; tR = 3.56 minutes (purity: 100 percent, system 1); TLC: Rf = 0J3 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Example 9: 3- (2-Chloro-3,5-dimethoxy-6-methyl-phenyl) -1-y6-r4- (2-dimethylamino-ethoxy) -phenyl-amino-1-pyrimidin-4-yl) - 1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 1: ESI-MS: 515.2 / 517.2 [MH] J t R = 3.47 minutes (purity:> 95 percent, system 1). Step 9.1: N-r4- (2-Dimethyl-amino-ethoxy) -phenyl-N'-methyl-pyrimidine-4.6-diamine The title compound is prepared in analogy to the procedure described in step 1.1: ESI-MS: 288.2 [MH] +; tR = 0.95 minutes (purity: 95 percent, system 1). Step 9.2: 4- (2-Dimethyl-amino-ethoxy) -phenyl-amine The title compound is prepared in analogy to the procedure described in step 1.2: ESI-MS: 181.2 [MH] +; TLC: R (= 0.18 (DCM / MeOH, 7: 3) Example 10: 3- (2-Cl-3-methoxy-6-met-1-methyl-3,5-methoxy) -1- methy1- (6- ( 4-r2- (4-methyl-piperazin-1-yl) -ethoxy-phenyl-amino) -pyrimidin-4-yl) -urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS : 570.0 [MH] +; tR = 3.20 minutes (purity: 90 percent, system 1), TLC: Rf = 0J3 (DCM / MeOH + 1 percent aqueous NH3, 93: 7).

Step 1 OJ: N-methyl-N '- (4-r2- (4-methyl-pi-erazin-1 -D-ethoxyl-phenyl) -pyrimidine-4.6-diamine The title compound is prepared in analogy to the procedure described in step 1J: ESI-MS: 343.2 [MH] +; tR = 1.00 minutes (purity: 95 percent, system 1), TLC: Rf = 0.23 (DCM / MeOH + 1 percent aqueous NH3, 9: 1 Example 11: 3- (2-chloro-6-iodo-3,5-dimethoxy-phenyl) -1-. {6-r4- (4-ethyl-piperazin-1 -h-phenol- amino) -pyridin-4-yl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 1: ESI-MS: 651.8 / 653.7 [MH] J tR = 3.20 minutes (purity: 95 percent, system 1), TLC: Rf = 0.18 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Step 11.1: N-f4- (4-Ethyl-piperazin-1-yl) -phene-p'-N'-methyl-pyrimidine-4,6-diamine The title compound is prepared in analogy to the procedure described in Step 1J: ESI-MS: 313.2 [MH] +; tR = 1.10 minutes (system 1); TLC: R, = 0.21 (DCM / MeOH, 93: 7). Pasol 1.2: 2-chloro-6-vodo-3,5-dimethoxy-phenyl-amine HCl (6.46 milliliters, 26 millimoles, 9J equivalents, 4N in dioxane) is added to a cooled solution (10 ° C) of the terbutil-ester of (2-chloro-3,5-dimethoxy-6-methyl-phenyl) -carbamic acid (1.28 grams, 2. 85 millimoles, purity of 92 percent) in dioxane (10 milliliters), under an argon atmosphere. The reaction mixture is allowed to warm to room temperature, and then it is stirred for 1.5 hours. The residue is diluted with EtOAc and ice / water, and made basic by the addition of a saturated aqueous solution of NaHCO3). The layers are separated. The aqueous layer is extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by silica gel column chromatography (dichloromethane) to give the title compound. API-ES-MS: 314.0 [MH] J TLC: R, = 0.53 (DCM). Step 11.3: (2-Chloro-6-vodo-3,5-dimethoxy-pheno-carbamic acid tertiary butyl ester A solution of sulfuryl chloride (0.92 milliliters, 11.0 mmol, 1.18 equivalents) in dichloromethane (20 milliliters) it is added dropwise (30 minutes) to a cold solution (-15 ° C) of (2-iodo-3,5-dimethoxy-phenyl) -carbamic acid tertiary butyl ester (3.6 grams, 9.49 millimoles) in tetrahydrofuran (48) milliliters), under an argon atmosphere, the reaction mixture is left stirring for 1 hour at -15 ° C, and then it is poured onto a mixture of ice / H20 (100 milliliters), a saturated aqueous solution of NaHCO3 (80 milliliters). ), and EtOAc (100 milliliters) The layers are separated, and the aqueous phase is extracted with EtOAc (100 milliliters, twice) The combined organic phase is washed with H20 (60 milliliters, three times) and brine (60 milliliters). ), dried (Na2SO4), filtered, and concentrated The residue was purified by silica gel column chromatography (dichloromethane), followed by talization from dichloromethane / hexanes, to provide the title compound. ESI-MS: 411.9, 413.9 [MH] ", TLC: R, = 0J8 (DCM / Hexanes, 7: 3) Step 11.4: Terbutil-ester of (2-iodo-3,5-dimethoxy-phenol) ) - carbamic A solution of terbutyl lithium (14J milliliters, 24 millimoles, 2.4 equivalents, 1.7M in pentane) is added dropwise (15 minutes) to a cold solution (-65 ° C) of the terbutil-ester of the acid (3) , 5-dimethoxy-phenyl) -carbamic acid (2.53 grams, 10 mmol) in tetrahydrofuran (18 milliliters), under an argon atmosphere.The mixture is stirred for 15 minutes at -65 ° C, and then allowed to warm to -25 C. An excess of trifluoromethyl iodide is bubbled into the yellow reaction mixture.The resulting dark mixture is poured onto a mixture of ice / H20 (60 milliliters) and EtOAc (60 milliliters) .The layers are separated, and The aqueous phase is extracted with EtOAc (30 milliliters, twice) The combined organic phase is washed with H20 (40 milliliters, three times) and brine (60 milliliters), dried (Na2SO4), filtered, and concentrated. The residue is purified by column chromatography on silica gel (dichloromethane / hexanes, 2: 1), to provide the title compound. ESI-MS: 380J [MH] +TLC: Rf = 0.27 (DCM / Hex, 2: 1). Step 11.5: (3,5-Dimethoxy-phenyl) -carbamic acid tertiary butyl ester A solution of diterbutyl dicarbonate (69.5 grams, 312 millimoles, 1.3 equivalents) in tetrahydrofuran (100 milliliters) is added to a solution of 3.5 -dimethoxy-aniline (37.5 grams, 240 millimoles) in tetrahydrofuran (600 milliliters). The reaction mixture is refluxed for 3 hours, allowed to cool to room temperature, stirred overnight, and concentrated. The residue is partitioned between EtOAc (500 milliliters) and H20 (500 milliliters). The layers are separated, and the aqueous phase is extracted with EtOAc (100 milliliters, twice). The combined organic phase is washed with HCl OJN (100 milliliters, twice), H20, and brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by trituration with hexane, to provide the title compound. ESI-MS: 254J [MH] +, TLC: R, = 0.42 (Hex / EtOAc, 3: 1). Example 12: 3- (2-chloro-3,5-dimethoxy-6-methyl-phenyl) -1-l6-y4- (4-isopropyl-piperazin-1-yO-phenyl-aminol-pyrim-di-4) -yl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 1: ESI-MS: 554.0 / 555.0 [MH] J t R = 3.49 minutes (purity: >95 percent, system 1), TLC: Rf = 0.13 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Step 12J: N-r4- (4-lsopropyl-piperazin-1-p-fenip-N'-methyl-pyrimidin-4,6-diamine) The title compound is prepared in analogy to the procedure described in step 1J: ESI -MS: 288.2 [MH] +; tR = 0.95 minutes (purity: 95 percent, system 1) Step 12.2: 4- (4-isopropyl-piperazin-1-iD-aniline A suspension of 1-isopropyl- 4- (4-nitro-phenyl) -piperazine (5J8 grams, 20.80 mmol) and 5 percent palladium on carbon (0.5 grams) in MeOH (100 milliliters) is stirred for 2.7 hours at room temperature, under a hydrogen atmosphere The reaction mixture is filtered through a pad of Celite, and concentrated to provide the title compound as a violet-colored solid: ESI-MS: 220J [MH] J tR = 0.95 minutes (system 1).

Step 12.3: 1-isopropyl-4- (4-nitro-phen-piperazine) A mixture of 1-bromo-4-nitro-benzene (6 grams, 29.7 mmol) and 1-ethyl-piperazine (7.6 milliliters, 59.4 mmol) , 2 equivalents), is heated at 80 ° C for 15 hours.After cooling to room temperature, the reaction mixture is concentrated.The purification of the residue by silica gel column chromatography (DCM / MeOH, 95: 5) , gives the title compound as a yellow solid: ESI-MS: 250.1 [MH] +; tR = 2.57 minutes (purity: 100 percent, system 1); TLC: Rf = 0J6 (DCM / MeOH, 95: 5) Example 13: 1- (6-R4- (4-benzyl-piperazin-1-yl) -phenyl-amino-1-pyrimidin-4-yl) -3- (2,6-dichloro-3,5-di methoxy) fen i I) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 621.9 / 623.9 [MH] +; tR = 4.04 minutes (purity: 100 percent, system 1) Step 13.1: N-4 (4-benzyl-piperazin-1-yl) -phenylH-N'-methyl-pyrimidin-4,6-diamine The title compound is prepared in analogy to the procedure described in step 1.1: ESI-MS: 375J [MH] +; tR = 2.36 minutes (purity: 95 percent, system 1). Step 13.2: 4- (4-benzyl-piperazin-1-yl) -phenyl-amine Iron powder (5.4 grams, 97 mmol, 4 equivalents) is added in portions to a mixture at 80 ° C of 1 -benzyl-4 phenyl-piperazine (7.2 grams, 24.2 mmol), EtOH (150 milliliters), H20 (40 milliliters), and AcOH (20 milliliters). The reaction mixture is stirred for 1.75 hours at 80 ° C, allowed to cool to room temperature and concentrated. The residue is diluted with EtOAc and a saturated aqueous solution of Na 2 CO 3. The layers are separated, and the aqueous phase is extracted with EtOAC. The combined organic phase is washed with brine, dried (Na2SO), filtered, and concentrated to provide the title compound: ES-MS: 268.3 [MH] +; a single peak at tR = 1.30 minutes (system 1). Step 13.3: 1 -benzyl-4- (4-nitro-phenyl) -piperazine A mixture of 1-bromo-4-nitro-benzene (5 grams, 24.8 millimoles) and 1-benzyl-piperazine (8.6 milliliters, 49.5 millimoles, 2 equivalents) is heated at 80 ° C for 17 hours. The reaction mixture is allowed to cool to room temperature, and is diluted with dichloromethane / H20. The layers are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phase is washed with brine, dried (Na 2 SO 4), filtered, and concentrated. Purification of the residue by silica gel column chromatography (hexanes / EtOAc, 1: 1) gives the title compound as a yellow solid: ESI-MS: 298.3 [MH] J tR = 3.25 minutes (purity: 100 percent , system 1). Example 14: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1-r6- (4-piperazin-1-yl-f-en-1-amino) -pyrimidin-4-ill -urea A suspension of the 1 -. { 6- [4- (4-benzyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -3- (2,6-dichloro-3,5-dimethoxy-6-methyl-phenyl) -1-methyl-urea (100 milligrams, 0J61 mmol) (Example 13), palladium on carbon (30 milligrams), MeOH ( 6 milliliters), and HCl (37 percent, 16 microliters), is stirred for 5 days at room temperature under a hydrogen atmosphere. The reaction mixture is filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM / 2N NH3 in MeOH, 95: 5), gives the title compound as a beige solid: ESI-MS: 532.0 / 534.0 [MH] J tR = 3.39 minutes (purity: 100 percent, system 1). Example 15: 3- (2-chloro-3,5-dimethoxy-6-methyl-phenyl) -1-r6- (3-dimethyl-amyne-methyl-phenyl-amino) -pyrimidin-4-i 11- 1 -methyl I-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 485.0 / 487.0 [MH] J t R = 3.69 minutes (purity: 100 percent, system 1). Example 16: 3- (2-Chloro-3,5-dimethoxy-6-methyl-phenyl-1- (6-r3- (4-ethyl-piperazin-1-yl) -phenyl-aminol-pyrimidin-4-yl) - 1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 540.0 / 542.0 [MH] J t R = 3.74 minutes (purity: 100 percent, system 1) Example 17: 3- (2-chloro-3,5-dimethoxy-6-methyl-phenyl-1-methyl-1- (6-r4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-aminol-pyrimidin-4-) il) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 541.0 / 543.0 [MH] J t R = 3.66 minutes (purity: 100 percent, system 1). Step 17.1: N-methyl-N'-r4- (2-pyrrolidin-1-yl-ethoxy) -phene-pyrimidine-4,6-diamine The title compound is prepared in analogy to the procedure described in step 2.1: ESI -MS: 314.1 [MH] J tR = 1.15 minutes (system 1); TLC: Rf = 0.15 (DCM / MeOH + 1 percent aqueous NH3, 9: 1). Step 17.2: 4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-amine The title compound is prepared in analogy to the procedure described in step 1.2: ESI-MS: 207.1 [MH] +; TLC: Rf = 0.22 (DCM / MeOH, 1: 1). Example 18: 3- (2-chloro-3,5-dimethoxy-6-methyl-phenyl) -1-methyl-1-f6-r3-fluoro-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl -aminol-pyrimidin-4-yl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 578.9 / 580.9 [MH] +; tR = 3.96 minutes (purity: 100 percent, system 1); TLC: Rf = 0.38 (DCM / MeOH + 1 percent aqueous NH3, 92: 8). Step 18J: N-f3-fluoro-4- (2-pyrrolidin-1-yl-ethoxy) -phenn-N'-methyl-pyrimidin-4,6-diamine The title compound is prepared in analogy to the procedure described in step 1.1: ESI-MS: 332.2 [MH] +; tR = 1.30 minutes (system 1); TLC: Rf = 0.37 (DCM / MeOH + 1 percent aqueous NH3, 99: 1). Step 18.2: 3-Fluoro-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-amine A suspension of 1- [2- (2-fluoro-4-nitro-phenoxy) -ethyl] -pyrrolidine ( 1.25 grams, 4.92 mmol) and 10 percent palladium on carbon (0.2 grams) in EtOH (20 milliliters) is stirred for 1 hour at room temperature, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite, and concentrated to provide the title compound as a brown oil: ESI-MS: 225.1 [MH] +; tR = 0.80 minutes (system 1). Step 18.3: 1 -f2- (2-fluoro-4-nitro-phenoxy) -etill-pyrrolidine 1- (2-Chloro-ethyl) -pyrrolidine hydrochloride (1.2 grams, 7. 0 mmol, 1 J equivalents) to a suspension of 2-fluoro-4-nitro-phenol (1 gram, 6.4 mmol) and cesium carbonate (5.2 grams, 15.9 mmol, 2.5 equivalents) in dimethyl formamide (20 milliliters). The resulting mixture is heated to 80 ° C, and stirred for 18 hours. Additional 1- (2-chloro-ethyl) -pyrrolidine hydrochloride (1 gram) is added, and the mixture is stirred for 3 hours at 80 ° C. The reaction mixture is cooled to room temperature, diluted with EtOAc and H20. The layers are separated, and the aqueous layer is extracted with EtOAc. The organic phase is washed with H20, dried (Na2SO4), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 95: 5), to give the title compound as a yellow solid. ESI-MS: 255.1 [MH] J tR = 2.57 minutes (system 1); TLC: R, = 0.55 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Example 19: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-f6-r4- (1-ethyl-pi peridin-4-yl) -phenyl-am i nol-pyrim id i n-4-il ) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 558.9 / 560.9 [MH] J t R = 3.85 minutes (purity: 100 percent, system 1); TLC: Rf = 0J4 (DCM / MeOH + 1 percent aqueous NH3, 95: 5).

Step 19J: N-r4- (1-ethyl-piperidin-4-yl) -phenyl-N'-methyl-pyrimidin-4,6-diamine The title compound is prepared in analogy to the procedure described in step 1J: ESI -MS: 312.2 [MH] +; tR = 1.3 minutes (system 1); TLC: Rf = 0.27 (DCM / MeOH + 1 percent aqueous NH3, 92: 8). Step 19.2: 4- (1-ethyl-piperidin-4-yl) -phenyl-amine A suspension of 1-ethyl-4- (4-nitro-phenyl) -piperidine (0.8 grams, 4.92 mmol), and palladium al 10 percent on charcoal (OJ grams) in EtOH (10 milliliters), is stirred for 3 hours at room temperature, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 95: 5), to provide the title compound. ESI-MS: 205.1 [MH] +; TLC: Rf = 0.29 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Step 19.3: 1-ethyl-4- (4-n-phenyl) -piperidine Sodium triacetoxy borohydride (3.1 grams, 14.6 millimoles, 3 equivalents) is added to a cold (5 ° C) solution of 4- ( 4-nitro-phenyl) -piperidine (1 gram, 4.9 mmol) and acetaldehyde (0.82 milliliters), 14.6 millimoles, 3 equivalents) in dichloromethane (20 milliliters). The reaction mixture is stirred for 1 hour at 5 ° C, and then diluted with dichloromethane and a saturated aqueous solution of NaHCO 3. The layers are separated, and the aqueous layer is extracted with dichloromethane. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 98: 2), to provide the title compound as a yellow oil. ESI-MS: 235J [MH] +; tR = 2.64 minutes (purity: 85 percent, system 1); TLC: Rf = 0J4 (DCM / MeOH + 1 percent aqueous NH3, 98: 2). Step 19.4: 4- (4-nitro-phenyl) -pyridine A solution of concentrated H2SO4 (2.65 milliliters) in AcOH (40 milliliters), and a solution of concentrated HN03 (2J milliliters) in AcOH (20 milliliters), add in sequence and dropwise to a solution of 4-phenyl-piperidine in AcOH (40 milliliters), keeping the temperature below 20 ° C. Then H2S04 concentrate (40 milliliters) is added (no cooling is applied, the internal temperature reaches 60 ° C). The reaction mixture is allowed to cool to room temperature, poured onto ice / water (100 grams), neutralized by the addition of solid NaHCO 3 (150 grams), and extracted with dichloromethane. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by trituration in Et20, to give the title compound as a yellow solid: ESI-MS: 207J [MH] J tR = 2.42 minutes (system A Example 20: 3- (2,6-Dichloro-3,5-dimethoxy-phen-p-1-ethyl-1-f6-r4- (4-ethyl-piperazin-1-yl) -phenyl-amino-1-pyrimidin-4 -yl) -urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 573.9 / 575.9 [MH] J t R = 3.69 minutes (purity: 100 percent, system 1). Step 20J: N-Ethyl-N'-β4- (4-ethyl-piperazin-1-yl) -phenyl-pyrimidin-4,6-diamine The title compound is prepared in analogy to the procedure described in step 1J: ESI-MS : 327.2 [MH] +; tR = 1.5 minutes (system 1). Example 21: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-f6-r2-fluoro-4- (2-pi rrol idin-1 -i l-ethoxy) -phen i-aminol- pyrim id i n-4-yl-1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: ESI-MS: 578.9 / 580.9 [MH] J t R = 3.79 minutes (purity: 100 percent, system 1). Step 21 J: N-r2-fluoro-4- (2-pyrrolidin-1-yl-etoxH-phenyl-N'-methyl-pyrimidin-4,6-diamine) The title compound is prepared in analogy to the procedure described in step 2.1: ESI-MS: 332.2 [MH] X Step 21.2: 2-fluoro-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-amine A suspension of 1- [2- (3- fluoro-4-nitro-phenoxy) -ethyl] -pyrrolidine (1.96 grams, 7.7 mmol) and 10 percent palladium on carbon (0.2 grams) in MeOH (40 milliliters), stir for 0.5 hours at room temperature, under a hydrogen atmosphere.

The reaction mixture is filtered through a pad of Celite, and concentrated to provide the title compound. ESI-MS: 225J [MH] +; tR = 0.95 minutes (system 1). Step 21.2: 1 -2- (3-fluoro-4-nitro-phenoxy) -etip-pyrrolidine 1- (2-Chloro-ethyl) -pyrrolidine hydrochloride (2.6 grams, 15.4 millimoles, 1.3 equivalents) is added to a mixture of 2-fluoro-4-nitro-phenol (1.84 grams, 11.7 millimoles) and cesium carbonate (9J grams, 27.9 millimoles, 2.5 equivalents) in dimethyl formamide (40 milliliters). The resulting mixture is heated to 80 ° C, and stirred for 3 hours. The reaction mixture is cooled to room temperature, and then diluted with dichloromethane and H20. The layers are separated, and the aqueous layer is extracted with dichloromethane. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 97: 3), to give 1.96 grams of the title compound as a dark yellow solid. ESI-MS: 255J [MH] +; tR = 2.55 minutes (purity: 93 percent, system 1); TLC: Rf = 0.40 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Example 22: 3- (2,6-dichloro-3,5-dimethoxy-phenin-1- (6-r 4 - (4-ethyl-piperazin-1-yl) -2-methoxy-phenyl-am i nol-pyrim id i n- 4-11-1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: API-MS: 589.9 / 591.8 [MH] J t R = 3.59 minutes (system 1); TLC: R, = 0J3 (DCM / MeOH + 0.5 percent aqueous NH3, 95: 5) Step 22 J: N-4 - (4-ethyl-piperazin-1-yl) -2-methoxy-phenyl-N'-methyl- pyrimidine-4,6-diamine The title compound is prepared in analogy to the procedure described in step 1.1: ESI-MS: 343.2 [MH] +; tR = 1.30 minutes (system 1).

Step 22.2: 4- (4-ethyl-piperazin-1-yl-2-methoxy-phenyl-amine) A suspension of 1-ethyl-4- (3-methoxy-4-nitro-phenyl) -piperazine (4 grams, 15J millimoles) and Raney nickel (1 gram) in MeOH (80 milliliters), stir for 10.5 hours at room temperature, under a hydrogen atmosphere, the reaction mixture is filtered through a pad of Celite, and concentrated to give the title compound as a brown oil: ESI-MS: 236.2 [MH] +; tR = 0.95 minutes (system 1) Step 22.3: 1-ethyl-4- (3-methoxy-4-nitro-phenyl) ) -piperazine The title compound is prepared in analogy to the procedure described in step 248.3: ESI-MS: 266.1 [MH] X Example 23: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1 -f6-f4- (4-ethyl-piperazin-1 -carbonyl) phenyl-am iol-pyrimidin-4-y 11-1 -methyl-urea The title compound is prepared analogously to the process described in Example 23: API-MS: 587.8 / 589.8 [MH] J tR = 3.58 minutes (purity: 94.8 percent, system 1); TLC: Rf = 0.47 (DCM / 2N NH 3 in MeOH, 9: 1). Step 23 J: (4-Ethyl-piperazin-1-ylH4- (6-methyl-amino-pyrimidin-4-yl-amino-hexyl-methanone) Propyl-phosphonic anhydride (50 percent in dimethylformamide, 2.72 milliliters, 4.7 mmol, 2 equivalents), to a solution of 4- (6-methyl-amino-pyrimidin-4-yl-amino) -benzoic acid (0.570 grams, 2.33 mmol), N-ethyl-piperazine (0.33 milliliters, 2.57 mmol) , 1J equivalents), DMAP (7 milligrams), and Et3N (3.3 milliliters, 23.3 millimoles, 10 equivalents) in dimethyl formamide (25 milliliters), at room temperature and under an argon atmosphere.The reaction mixture is stirred at room temperature environment for 1 hour, diluted with EtOAc, and washed with H20.The aqueous layer is extracted with EtOAc.The combined organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. by silica gel column chromatography (DCM? DCM2 / 2N in MeOH, 86:14), to give the title compound as a yellow foam: ES-MS: 341.2 [ MH] +; tR = 1.00 minutes (system 1); R, = 0.33 (CH2Cl2 / 2N NH3 in MeOH, 9: 1). Step 23.2: 4- (6-Methyl-amino-pyrimidin-4-ylamino) -benzoic acid The title compound is prepared in analogy to the procedure described in step 2J: ESI-MS: 245.0 [MH] +; tR = 1.58 minutes (system 1). Example 24: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6-l4- (4-ethyl-pi) -zinzin-1-yl) -3-fluoro-phenyl-am-nol-pyrimidin-4-yl-1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2: API-MS: 577.9 / 579.9 [MH] +; tR = 3.87 minutes (purity: 90 percent, system 1); TLC: Rf = 0.20 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Step 24 J: N-r4- (4-ethyl-piperazin-1 -i I) -3-f luoro-f enyl-N'-methyl-pi rimidin-4,6-diamine The title compound is prepared in analogy to the procedure described in step 2J, but stirring the reaction mixture for 15 minutes at 160 ° C in a microwave apparatus. The crude product is purified by trituration in EtOAc to give the title compound: ESI-MS: 331.2 [MH] X Step 24.2: 4- (4-ethyl-piperazin-1-ip-3-fluoro-f-phenyl-amine A suspension of 1-ethyl-4- (2-fluoro-4-nitro-phenyl) -piperazine (1.24 grams, 15.1 mmol) and Raney's nickel (13 milligrams) in MeOH (6 milliliters) is stirred for 17 hours at Room temperature under a hydrogen atmosphere The reaction mixture is filtered through a pad of Celite, and concentrated to give the title compound as a purple oil: ESI-MS: 224J [MH] J tR = 0.90 minutes (system 1) Step 24.3: 1 -ethyl-4- (2-fluoro-4-nitro-phenyl) -piperazine N-Ethyl-piperazine (0.96 milliliters, 7.6 mmol, 1.2 equivalents) is added to a mixture of 3 , 4-difluoro-nitro-benzene (0.7 milliliters, 6.32 mmol) and potassium carbonate (1.74 grams, 12.6 mmol, 2 equivalents) in dimethylformamide (10 milliliters) The reaction mixture is stirred at 90 ° C for 17 minutes. hours, it is left to cool to room temperature, diluted with H20, and extracted with dichloromethane. The organic phase is washed with brine, dried (Na 2 SO 4), filtered, and concentrated. The residue is purified by silica gel column chromatography (DDCM / MeOH + 1 percent aqueous NH3, 97: 3), to give the title compound as a yellow solid: ES-MS: 254.1 [MH] +; tR = 2.65 minutes (system 1); Rf = 0.30 (DCM / MeOH + 1 percent aqueous NH3, 93: 7). Example 25: 3- (2,4-dichloro-5-methoxy-3-trifluoromethyl-phenyl-1- (6-f4- (4-ethyl-piperazin-1-M) -phenyl-amynol-pyrimidine -4-ill-1-methyl-urea Phosgene (20 percent in toluene, 0.54 milliliters, 1.0 mmol, 2.0 equivalents) is added to a solution of 2,4-dichloro-5-methoxy-3-trifluoromethyl- Aniline (156 milligrams, 0.60 millimole, 1.2 equivalents) in dioxane (2 milliliters), under a nitrogen atmosphere.The mixture is heated to reflux, stirred for 75 minutes, allowed to cool to room temperature, and concentrated in vacuo. The resulting solid of 2,4-dichloro-5-methoxy-3-trifluoromethyl-phenyl isocyanate is added in portions to a solution of N- [4- (4-ethyl-piperazin-1-yl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine (156 milligrams, 0.50 millimoles; for preparation see step 25.5), in 6 milliliters of toluene, under a nitrogen atmosphere. The reaction mixture is stirred at 110 ° C for 3.3 hours, allowed to cool to room temperature, and diluted with dichloromethane and a saturated aqueous solution of NaHCO 3. The aqueous layer is separated and extracted twice with dichloromethane. The organic phase is washed with brine, dried (Na 2 SO), filtered, and concentrated. Trituration of the resulting solid with two portions of MeOH gives the title compound: ESI-MS: 598/600 [MH] +; tR = 5.1 minutes (purity: 97 percent, system 1). Step 25J: 2,4-Dichloro-5-methoxy-3-trifluoromethyl-aniline A solution of 2M KOH in water (1.87 milliliters) is added to a solution of N- (2,4-dichloro-5-methoxy). 3-trifluoro-methyl-phenyl) -acetamide (104 milligrams, 0.344 mmol) in EtOH (3 milliliters). After stirring for 3.5 hours at 80 ° C, followed by cooling to room temperature, the solvent is evaporated, and the residue is taken up in EtOAc and a saturated aqueous solution of NaHCO 3. The separated aqueous layer is extracted twice with EtOAc. The organic phases are washed with brine, dried (Na2SO4), filtered, and concentrated to give the title compound: ESI-MS: 258/260 [MH] "; tR = 4.8 minutes (system 1); TLC: R, = 0.54 (EtOAc) Step 25.2: N- (2,4-dichloro-5-methoxy-3-trifluoromethyl-phenyl) -acetamide A solution of N- (5-methoxy-3-trifluoromethyl) phenyl) -acetamide (233 milligrams, 1.0 mmol) under a nitrogen atmosphere, cooled in an ice bath (precipitation), then 1.93 milliliters of a 1M solution of S02CI2 in dichloromethane was added. add another 1.93 milliliters of the S02CI2 solution, and stirring is continued for a total of 4 hours at 0 ° C. The suspension is diluted with dichloromethane and a saturated aqueous solution of NaHCO3 The separated inorganic phase is extracted twice The organic phases are washed with water and brine, dried (Na 2 SO 4), filtered and concentrated, column chromatography (hexane / EtOAc, 7: 3), c) the title compound: P. f .: 143-144 ° C; API-MS: 300/302 [M-H] '; TLC: R, = 0.23 (Hex / EtOAc, 1: 1); 1 H-NMR (DMSO-d 6) d 2 J 3 (s, H 3 C), 3.88 (S, H3C), 7.84 (S, H, ßniio), 9-81 (s, HN). Step 25.3: N- (5-methoxy-3-trifluoromethyl-phenyl) -acetamide Acetic anhydride (1.22 milliliters, 12.8 mmol) is added over 10 minutes to a solution of 5-methoxy-3-trifluoro-methyl-aniline. (2.29 grams, 12.0 mmol) in toluene (10 milliliters), at a temperature of 25 ° C to 33 ° C. After 90 minutes at room temperature, hexane (10 milliliters) is added, and the suspension is stirred for 20 minutes. Filtration, washing with toluene / hexane, 2: 1, and hexane, gives the title compound: P.f .: 123-124 ° C; API-MS: 234 [MH] J TLC: R, = 0.27 (Hex / EtOAc, 1: 1). Step 25.4: 5-methoxy-3-trifluoro-methyl-aniline Hydrogenation of a solution of 3-methoxy-5-nitro-benzo-trifluoride (6.19 grams, 28 mmol), in MeOH (140 milliliters), in the presence of Pd-C (0.62 grams, 10 percent), removal of the catalyst by filtration, and concentration in vacuo of the resulting filtrate, gives the title compound: API-MS: 190 [MH] "; TLC: R, = 0.7 (EtOAc) Step 25.5: N-4 - (4-ethyl-piperazin-1-yl) -phenyl-N'-methyl-pyrimidine-4,6-diamine A mixture of 4- (4-ethyl-piperazin-1-) il) -aniline (1 gram, 4.88 millimoles) (prepared in analogy to Example 238, step 238.1), (6-chloro-pyrimidin-4-yl) -methyl-amine (1.81 grams, 12.68 mmol, 1.3 equivalents), and 4N HCl in dioxane (15 milliliters) is heated in a sealed tube at 150 ° C for 5 hours.The reaction mixture is concentrated, diluted with dichloromethane and a saturated aqueous solution of sodium bicarbonate. The mixture is separated and extracted with dichloromethane. Wash with brine, dry (sodium sulfate), filter, and concentrate. Purification of the residue by silica gel column chromatography (DCM / MeOH, 93: 7), followed by trituration in diethyl ether, gives the title compound as a white solid: ESI-MS: 313.2 [MH] +; tR = 1.10 minutes (system 1); TLC: R, = 0.21 (DCM / MeOH, 93: 7). Example 26: 3- (5-methoxy-3-trifluoromethyl-phenyl-1- (6-r4- (4-ethyl-pi-perazin-1-yl) -phenyl-am-nol-pyrimid i-4-) 11-1-methyl-urea Phosgene is added (20 percent in toluene, 1.62 milliliters, 3. 0 mmol, 2.0 equivalents) to a solution of 5-methoxy-3-trifluoromethyl-aniline (344 milligrams, 1.8 mmol, 1.2 equivalents) in dioxane (6 milliliters) under a nitrogen atmosphere. The mixture is heated to reflux, stirred for 80 minutes, allowed to cool to room temperature, and concentrated in vacuo. For 45 minutes, a concentrated solution of the resulting oily-5-methoxy-3-trifluoromethyl-phenyl isocyanate solution in toluene is added portionwise to a boiling solution of N- [4- (4-ethyl-piperazin-1-yl. ) -phenyl] -N'-methyl-pyrimidine-4,6-diamine (468 milligrams, 1.50 millimole, step 242J) in 18 milliliters of toluene, under a nitrogen atmosphere. The reaction mixture is stirred at 110 ° C for 4 hours, allowed to cool to room temperature, and diluted with dichloromethane and a saturated aqueous solution of NaHCO 3. The aqueous layer is separated and extracted twice with dichloromethane. The organic phases are washed with brine, dried (Na 2 SO 4), filtered and concentrated. Column chromatography (DCM / MeOH, 49: 1 → 24: 1) provides the title compound: API-MS: 530/532 [MH] +; TLC: R, = 0.4 (DCM / MeOH, 9: 1); tR = 4.3 minutes (purity: 100 percent, system 1). Example 27: 3- (5-methoxy-3-trifluoromethyl-phenyl) -1- (6-r3-chloro-4- (4-ethyl-piperazin-1-yl) -phen i-am i-1- pyrimidin-4-yl) -1-methyl-urea 0.4-milliliter portions of a solution of 1M S02CI2 in dichloromethane are added repeatedly over a period of 27 hours to a freezing solution of 3- (5-methoxy-3-). t fluoro-methyl-phenyl) -1-. { 6- [4- (4-ethyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} - 1-methyl-urea (105 milligrams, 0.20 mmol) (Example 26) in acetonitrile (6 milliliters). The reaction is followed by HPLC analysis. The reaction mixture (which still contains starting material) is diluted with dichloromethane and a saturated aqueous solution of NaHCO 3. The aqueous layer is separated and extracted twice with dichloromethane. The organic phases are washed with brine, they are dried (Na2SO4), filtered, and concentrated. Reversed-phase MPLC (H20 / CH3CN + 0J percent trifluoroacetic acid) provides, after neutralization of the fractions containing the product with NaHCO3, the partial concentration and extraction with dichloromethane, the title compound : API-MS: 564/566 [MH] J TLC: R, = 0.28 (DCM / MeOH + 1 percent aqueous NH3, 95: 5); 1 H-NMR (DMSO-d 6) d 1.02 (t, H 3 C), 2.37 (q, H2C), 2.51 (m, 4 H), 2.92 (m, 4 H), 3.33 (s, H 3 C), 3.82 (s, H 3 C) , 6.48 (s, 1H), 6.90 (s, 1H), 7J2 (d, 1H), 7.43 (m, 2H), 7.59 (s, 1H), 7.82 (s, 1H), 8.55 (s, 1H), 9.66 (s, HN), 12.33 (s, HN). Example 28: 1-. { 6-r2-chloro-4- (4-ethyl-piperazin-1-yl) -phenyl-amino-1-pyrimidin-4-yl} -3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1 -methyl-urea The title compound is prepared in analogy to the procedure described in Example 2 (1 hour with 20 minutes of refluxing): ESI-MS: 593.8 / 595.8 [MH] +; tR = 3.80 minutes (purity: 95 percent, system 1); TLC: Rf = 0.45 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Step 28J: N-r2-Chloro-4- (4-ethyl-piperazin-1-yl) -phenyl-N'-methyl-pyrimidin-4,6-diamine The title compound is prepared in analogy to the procedure described in step 1.1: ESI-MS: 347.1 / 349.1 [MH] +; TLC: Rf = 0.15 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Step 28.2: 2-chloro-4- (4-ethyl-piperazin-1-yl) -phenyl-amine A suspension of 1-chloro-4-nitro-phenyl-4-ethyl-piperazine (1 gram, 3.7 mmol) and Raney nickel (OJ grams) in MeOH (20 milliliters) is stirred for 8 hours at room temperature, under an atmosphere of hydrogen. The reaction mixture is filtered through a pad of Celite, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 95: 5), to give the title compound as a grayish solid: ESI-MS: 240J / 242J [MH] +; tR = 0.90 minutes (system 1); TLC: R, = 0.46 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Step 28.3: 1- (3-chloro-4-nitro-phenyl) -4-ethyl-piperazine N-Ethyl-piperazine (4.3 grams, 34.3 mmol, 1.2 equivalents) is added to a mixture of 2-chloro-4-fluoro -nitro-benzene (5 grams, 28.6 millimoles) and potassium carbonate (7.9 grams, 57.1 millimoles, 2 equivalents) in dimethyl formamide (50 milliliters). The reaction mixture is stirred at 100 ° C for 6 hours, allowed to cool to room temperature, diluted with H20, and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The residue is purified by trituration in diethylether to give 5.6 grams of the title compound as a yellow solid: ES-MS: 270.0 [MH] +; tR = 2.90 minutes (system 1). Example 29: 3- (2,6-dichloro-3,5-dimethoxy-phenyI-1- (6-r4- (4-ethyl-pi per azi n-1-yl) -2-f luoro-f in i l-am i nol-pyrimidin-4-i 11-1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 2 (one hour of refluxing, and EtOAc is used instead of dichloro- methane to extract the product): ESI-MS: 577.9 / 579.9 [MH] +; tR = 4.00 minutes (purity:> 95 percent, system 1); TLC: Rf = 0.35 (DCM / MeOH + 1 percent of NH3 aqueous, 97: 3) Step 29.1: N-r4- (4-ethyl-piperazin-1 -i I) -2-f luoro-f enyl-N'-methyl-pi rimidin-4,6-diamine The compound of the title is prepared in analogy to the procedure described in step 2.1, but by stirring the reaction mixture for 1 hour at 160 ° C in a microwave apparatus, and using EtOAc in place of dichloromethane to extract the product. title: ESI-MS: 331J [MH] J TLC: R, = EYE (DCM / MeOH + 1 percent aqueous NH3, 95: 5) Step 29.2: 4- (4-ethyl-piperazin-1-yl) -2-fluoro-phenyl -a min a A suspension of 1-ethyl-4- (3-fluoro-4-nitro-phenyl) -piperazine (7 grams, 27.7 mmol), and Pd (10 percent) on carbon (0.35 grams) in MeOH (140 milliliters) ), it is stirred for 3 hours at room temperature, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 95: 5), to give the title compound as a white solid: ESI-MS: 224J [MH] +; TLC: R, = 0.54 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Step 29.3: 1-ethyl-4- (3-fluoro-4-nitro-phenyl) -piperazine N-Ethyl-piperazine (4.8 milliliters, 37.7 mmol, 1.2 equivalents) is added to a mixture of 2,4-difluoro-nitro -benzene (5 grams, 31.4 millimoles), and potassium carbonate (8.7 grams, 62.9 millimoles, 2 equivalents) in dimethyl formamide (50 milliliters). The reaction mixture is stirred at 100 ° C for 2 hours, it is allowed to cool to room temperature, diluted with H20, and extracted with EtOAc. The organic phase is washed with brine, dried (Na 2 SO), filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH + 1 percent aqueous NH3, 95: 5), to give the title compound as a yellow oil: ES-MS: 254.1 [MH] J TLC : Rf = 0.67 (DCM / MeOH + 1 percent aqueous NH3, 95: 5). Example 30: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-f6-r6- (4-isopropyl-piperazin-1 -i I) -pyr id i n-3-yl-aminol-pirim id i n-4-yl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 1 (2 equivalents of phosgene for the formation of the isocyanate, 16 hours of stirring at 70 ° C in the next step, and EtOAc is used in place of dichloromethane to extract the product): ESI-MS: 574.8 / 576.8 [MH] +; tR = 3.32 minutes (system 1); TLC: R, = EYE (DCM / MeOH / aqueous NH3, 94: 5: 1). Step 30J: N-r6- (4-isopropyl-piperazin-1-yl) -pyridin-3-ill-N'-methyl-pyrimidine-4.6-diamine The title compound is prepared in analogy to the procedure described in step 1.1 . Title compound: ESI-MS: 328.2 [MH] X Step 30.2: 6- (4-isopropyl-piperazin-1 -iO-pyridin-3-yl-amine A mixture of iron powder (1.4 grams, 25.3 mmol, 4 equivalents), 1-isopropyl-4- (5-nitro-pyridin-2-yl) -piperazine (1.58 grams, 6.32 mmol), EtOH (20 milliliters), H20 (5 milliliters), and AcOH (2.5 milliliters), stir for 2 hours at 90 ° C, allow to cool to room temperature, basify by the addition of aqueous ammonia, filter through a pad of Celite, and partially concentrate to remove the EtOH. The organic phase is washed with brine, dried (Na 2 SO 4), filtered, and concentrated, The residue is purified by silica gel column chromatography (DCM) and extracted with EtOAc and dichloromethane. / MeOH / aqueous NH 3, 91: 8: 1), to provide the title compound as a purple solid: ESI-MS: 221.1 [MH] J TLC: R, = 0.20 (DCM / MeOH / aqueous NH 3, 91: 8: 1.) Step 30.3: 1 -iso propyl-4- (5-nitro-pyridin-2-iP-piperazine (NVP-BKT293) N-isopropyl-piperazine (1.8 milliliters, 12.7 millimoles, 2 equivalents) is added to a cold (5 ° C) mixture of 2- chloro-5-nitro-pyridine (1 gram, 6.3 mmol) in dichloromethane (5 milliliters). The reaction mixture is allowed to warm to room temperature, stirred for 16 hours, diluted with dichloromethane / H20, and extracted with dichloromethane. The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated to give the title compound as a yellow solid: ES-MS: 251.2 [MH] +; tR = 2.20 minutes (system 1). Example 31: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6-rß- (4-ethyl-pi perazi n-1 -i p-pyridin-3-yl-am i nol-pyrimid i n-4-yl) -1-methyl-urea The title compound is prepared in analogy to the procedure described in Example 1 (2 equivalents of phosgene for isocyanate formation, 4 hours of refluxing in the next step, and EtOAc is used in place of dichloromethane to extract the product): ESI-MS: 560.8 /562.8 [MH] J tR = 3.20 minutes (system 1); TLC: Rf = 0.35 (DCM / MeOH / aqueous NH3, 94: 5: 1). Step 31 J: N-r6- (4-Ethyl-piperazin-1-yl) -pyridin-3-iH-N'-methyl-pyrimidine-4,6-diamine The title compound is prepared analogously to the process described in step 1J: Title compound: ESI-MS: 314.2 [MH] +; TLC: R, = 0.20 (DCM / MeOH / aqueous NH3, 91: 8: 1). Step 31.2: 6- (4-Ethyl-piperazin-1-yl) -pyridin-3-yl-amine A suspension of 1-ethyl-4- (5-nitro-pyridin-2-yl) -piperazine (1.4 grams) and Raney nickel (140 milligrams) in MeOH (30 milliliters) is stirred for 10 hours at room temperature, under an atmosphere of hydrogen. The reaction mixture is filtered through a pad of Celite, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH / aqueous NH3, 94: 5: 1), to give the title compound as a purple oil: ESI-MS: 207.1 [MH] +; TLC: R, = 0.26 (DCM / MeOH / aqueous NH3, 94: 5: 1). Step 31.3: 1-ethyl-4- (5-nitro-pyridin-2-yl) -piperazine The title compound is prepared in analogy to the procedure described in step 30.3, but using N-ethyl-piperazine. The title compound: ES-MS: 237.1 [MH] +; TLC: Rf = 0.25 (DCM / MeOH / aqueous NH3, 96: 3: 1). EXAMPLE 32: Soft Capsules 5,000 soft gelatin capsules are prepared, each comprising, as an active ingredient, 0.05 grams of any of the compounds of Formula IA mentioned in any of Examples 1 to 29 or earlier, as follows: Composition Active ingredient 250 grams. Lauroglicol 2 liters. Preparation process: The pulverized active ingredient is suspended in Lauroglykol * (propylene glycol laurate, Gattefossé S.A., Saint Priest, France), and ground in a wet pulverizer, to produce a particle size of about 1 to 3 microns. Then, portions of 0.419 grams of the mixture are filled into soft gelatin capsules, using a capsule filling machine. Example 33: Tablets comprising the com ponents of the Formula IA Tablets are prepared which comprise, as an active ingredient, 1 00 milligrams of any of the compounds of Formula IA of any of Examples 1 to 29 above, with the following composition, following the conventional procedures: Composition Active ingredient 1 00 milligrams. Crystal lactose 240 milligrams. Avicel 50 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 microcrystalline cellulose (FMC, Philadelphia, USA). PVPPXL is polyvinyl-polypyrrolidone, cross-linked (BASF, Germany). Aerosil® is silicon dioxide (Degussa, Germany).

Claims (9)

1. CLAIMS wherein: two of X, Y, and Z are N (nitrogen), the third is CH or N (preferably Y and Z are N, and Z is CH); and wherein, any of: R 1 is phenyl which is substituted hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, piperazin-1-yl, or 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1 -ilo; or phenyl which is substituted by: (i) halogen or alkoxy of 1 to 7 carbon atoms, and in addition (ii) by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, N-mono- or N, N- di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, pyrrolidino-alkoxy of 1 to 7 carbon atoms, 1- (alkyl of 1 to 7 carbon atoms) -piperidine- 4-yl, morpholino-alkoxy of 1 to 7 carbon atoms, thiomorpholino-alkyl of 1 to 7 carbon atoms, piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1 -yl, 4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms carbon, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1) to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxy of 1 to 7 carbon atoms , [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl; Rz is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or halogen; R3 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 7 carbon atoms, each R4 is, independently of the others, alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon, halogen, or alkoxy atoms of 1 to 7 carbon atoms, and n is 0, 1, 2, 3, 4, or 5; or R 1 is phenyl which is substituted by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1-yl; N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, pyrrolidino-alkoxy of 1 to 7 carbon atoms, 1 - (alkyl of 1) to 7 carbon atoms) -piperidin-4-yl, morpholino-alkoxy of 1 to 7 carbon atoms, thiomorpholino-alkoxy of 1 to 7 carbon atoms, 4- (alkyl of 1 to 7 carbon atoms) -piperazin- 1-yl, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl; or phenyl bearing one of the substituents mentioned heretofore in the present paragraph, and in addition a substituent selected from halogen and alkoxy of 1 to 7 carbon atoms; R2 is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or halogen; R3 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 7 carbon atoms, R5 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 7 atoms carbon, and any of: n is 3, 4, or 5, and R 4 is selected from alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, and halogen, with the proviso that when unless one of each of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, and halogen is present; or n is 2, and one R 4 is haloalkyl of 1 to 7 carbon atoms, and the other R 4 is alkoxy of 1 to 7 carbon atoms; on is 3, 4, or 5, and R 4 is selected from halogen, iodine, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, iodine, and alkoxy is present from 1 to 7 carbon atoms; on is 3, 4, or 5, and R 4 is selected from halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms; or Y and Z are N (nitrogen), and X is CH, wherein, any of: R1 is 3-pyridyl, which is mono-substituted by N-alkyl of 1 to 7 carbon atoms-piperazin-1-yl , R 2 is hydrogen, R 3 is hydrogen, each R 4 is, independently of the others, alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halogen, or alkoxy of 1 to 7 carbon atoms, R5 is hydrogen, and n is 1, 2, 3, 4, or 5; or a compound of Formula IA, wherein R 1 is 4- (2-morpholin-4-yl-ethoxy) -phenyl-amino, R 2 is hydrogen, R 3 is hydrogen, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 3- (4-methyl-piperazin-1-yl-methyl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and - and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 3- (4-ethyl-piperazin-1-yl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (2-morpholin-4-yl-ethoxy) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (1 -et i I -piperidin-4-yl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and - and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (4-ethyl-piperazin-1-yl) -phenyl-amino, R 2 is hydrogen, R 3 is ethyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH, and / or a compound of Formula IA, wherein R1 is 4- (4-ethyl-piperazine-1-carbonyl) phenyl amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R 5 is hydrogen, Y and Z are N, and X is CH; or mixtures of two or more compounds of Formula IA; or a salt, a prodrug, an N-oxide, and / or an ester thereof.
2. 2. A compound according to claim 1, of Formula IA, wherein: two of X, Y, and Z are N (nitrogen), the third is CH or N (preferably Y and Z are N, and Z is CH); and wherein, any of: R 1 is phenyl which is substituted by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, piperazin-1-yl, or 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin -1 -yl; or phenyl which is substituted by: (i) halogen or alkoxy of 1 to 7 carbon atoms, and in addition (ii) by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, N-mono- or N, N- di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, pyrrolidino-alkoxy of 1 to 7 carbon atoms, 1- (alkyl of 1 to 7 carbon atoms) -piperidine- 4-yl, morpholino-alkoxy of 1 to 7 carbon atoms, thiomorpholino-alkoxy of 1 to 7 carbon atoms, piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1 -yl, 4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms carbon, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1) to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -carbonyl; R2 is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or halogen; R3 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 7 carbon atoms, each R4 is, independently of the others, alkyl of 1 to 7 carbon atoms, haloalkyl of 1 to 7 carbon atoms, halogen, or alkoxy of 1 to 7 carbon atoms, R5 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms, phenyl-alkyl of 1 to 7 carbon atoms, and n is 0, 1, 2 , 3, 4, or 5; or R1 is phenyl which is substituted by hydroxyl, phenyl-alkyloxy of 1 to 7 carbon atoms, piperazin-1-yl, 4- (phenyl-alkyl of 1 to 7 carbon atoms) -piperazin-1-yl; N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, pyrrolidino-alkoxy of 1 to 7 carbon atoms, 1 - (alkyl of 1) to 7 carbon atoms) -piperidin-4-yl, morpholino-alkoxy of 1 to 7 carbon atoms, thiomorpholino-alkoxy of 1 to 7 carbon atoms, 4- (alkyl of 1 to 7 carbon atoms) -piperazin- 1-yl, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkyl of 1 to 7 carbon atoms, N-mono- or N, N-di- (alkyl of 1 to 7 carbon atoms) -amino-alkoxy of 1 to 7 carbon atoms carbon, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1-yl] -alkoxy of 1 to 7 carbon atoms, [4- (alkyl of 1 to 7 carbon atoms) -piperazin-1- il] -carbonyl; or phenyl bearing one of the substituents mentioned heretofore in the present paragraph, and in addition a substituent selected from halogen and alkoxy of 1 to 7 carbon atoms; R2 is hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, or halogen; R3 is hydrogen, alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 7 carbon atoms; R5 is hydrogen (preferred), alkyl of 1 to 7 carbon atoms, or phenyl-alkyl of 1 to 7 carbon atoms, and any of: n is 3.4, or 5, and R4 is selected from alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, and halogen, with the proviso that at least one of each of alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms is present , and halogen; or n is 2, and one R 4 is haloalkyl of 1 to 7 carbon atoms, and the other R 4 is alkoxy of 1 to 7 carbon atoms; on is 3, 4, or 5, and R 4 is selected from halogen, iodine, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, iodine, and alkoxy is present from 1 to 7 carbon atoms; on is 3, 4, or 5, and R 4 is selected from halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms, with the proviso that at least one of each of halogen, haloalkyl of 1 to 7 carbon atoms, and alkoxy of 1 to 7 carbon atoms; or a compound of Formula IA, wherein R 1 is 4- (2-morpholin-4-yl-ethoxy) -phenyl-amino, R 2 is hydrogen, R 3 is hydrogen, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 3- (4-methyl-piperazin-1-yl-methyl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and - and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 3- (4-ethyl-piperazin-1-yl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (2-morpholin-4-yl-ethoxy) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (1-ethyl-piperidin-4-yl) -phenyl-amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH; or a compound of Formula IA, wherein R 1 is 4- (4-ethyl-piperazin-1-yl) -phenyl-amino, R 2 is hydrogen, R 3 is ethyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R5 is hydrogen, Y and Z are N, and X is CH, and / or a compound of Formula IA, wherein R1 is 4- (4-ethyl-piperazine-1-carbonyl) phenyl amino, R 2 is hydrogen, R 3 is methyl, R 4 is 2- and 6-chloro and 3- and 5-methoxy, n is 4, R 5 is hydrogen, Y and Z are N, and X is CH; or mixtures of two or more compounds of Formula IA; or a salt, a prodrug, an N-oxide, and / or an ester thereof.
3. 3. A compound of Formula IA, according to claim 1, selected from the group of compounds consisting of: 1- [6- (4-benzyloxy-phenyl-amino) -pyrimidin-4-yl] -3 -(2, 6-dichloro-3,5-dimethoxy-phenyl) -1-methyl-urea, 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1- [6- (4-hydroxy-phenyl- amino) -pyrimidin-4-yl] -1-methyl-urea, 1-. { 6- [4- (4-benzyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -3- (2,6-dioxide ro-3,5-di methoxy-f-enyl) -1-methyl-urea, 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-methyl -1- [6- (4-pi pe razin-1-phenyl-amino) -pyrimidin-4-yl] -urea, 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1 -. { 6- [2-fluoro-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea, 3- (2,6-dichloro-3,5-d-methoxy-phenyl) -1-. { 6- [4- (4-eti I- pipe razin- 1 -i l) -2-methoxy-phenyl-amino] -pyridin-4-yl} -1-Iam I-urea, 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [4- (4-ethyl-piperazin-1 -i I) -3-f luoro-f-enyl-amino] -pyrimidin-4-yl} - 1-methyl-urea, 3- (5-methoxy-3-trifluoro-methyl -fe or I) -1-. { 6- [3-chloro-4- (4-ethyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} - 1-methyl-urea, 1-. { 6- [2-Chloro-4- (4-ethyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -3- (2,6-dichloro-3,5-dimethoxy-f-enyl) -1-methyl-urea, and 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [4- (4-ethyl-piperazin-1-yl) -2-f luoro-f-enyl-am i] -pyrimidin-4-yl} - 1-methyl-urea; or a salt, a prodrug, an N-oxide, and / or an ester thereof.
4. 4. A compound of Formula IA, according to claim 1, selected from the group of compounds consisting of: 1- 2-chloro-3,5-dimethoxy-6-methyl-phenyl) -3-. { 6- [4- (4-ethyl-piperazin-1-yl-phenyl-amino] -pyrimidin-4-yl}. -urea, 3- 2-chloro-3,5-dimethoxy-6-methyl-phenyl) -1-. { 6- [4- (4-ethyl-piperazin-1-yl-phenyl-amino] -pyrimidin-4-yl.} - 1-methyl-urea, 3- 2-chloro-3,5-dimethoxy-6- methyl-phenyl) -1-. { 6- [4- (2-Dimethyl-amino-ethoxy) -enyl-amino] -pyrimidin-4-yl} -1-methyl-urea, 3- 2-chloro-3,5-dimethoxy-6-methyl-phenyl) -1-methyl- (6- { 4- [2- (4-methyl-piperaz n-1 -yl) -ethoxy] -phenyl-amino.} - pyrimidin-4-yl) -urea, 3- 2-chloro-6-iodo-3,5-dimethoxy-phenyl) -1-. { 6- [4- (4-ethyl-piperazin-1-yl) -phene-amino} -pyrimidin-4-yl} -1-methyl-urea, 3- 2-chloro-3,5-dimethoxy -6-methyl-phenyl) -1-. { 6- [4- (4-Isopropyl-piperazin-1-yl-phenyl-amino] -pyrimidin-4-yl}. -1-methyl-urea, 3- 2-chloro-3,5-dimethoxy-6- methyl-phenyl) -1- [6- (3-dimethyl-amino-methyl-f-enyl-amino) -pyrimidin-4-yl] -1-methyl-urea, 3- 2-chloro-3,5-dimethoxy- 6-methyl-phenyl) -1-. { 6- [3- (4-ethyl-piperazin-1-yl-phenyl-amino] -pyrimidin-4-yl.} - 1-methyl-urea, 3- 2-chloro-3,5-dimethoxy-6- methyl-phenyl) -1-methyl-1-. { 6- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea, 3- (2-chloro-3,5-dimethoxy-6-methyl-f-enyl) -1-methyl-1 -. { 6- [3-fluoro-4- (2-pyrrolidin-1-yl-ethoxy) -f eni-amino] -pyrimidin-4-yl} - 1-methyl-urea, 3- (2,4-dichloro-5-methoxy-3-trifluoromethyl-phenyl) -1-. { 6- [4- (4-eti I-pipe-reason-n-1 -yl) -phenyl-amin or] -pyrimidin-4-yl} -1-methyl-urea, and 3- (5- methoxy-3-trifluo ro-meti I -fen i I) - 1-. { 6- [4- (4-eti I -piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea; or a salt, a prodrug, an N-oxide, and / or an ester thereof.
5. 5. A compound of Formula IA, according to claim 1, selected from the group of compounds consisting of: 1- (2,6-dichloro-3,5-dimethoxy-phenyl) -3-. { 6- [4- (2-morpholin-4-yl-ethoxy) -phenyl-amino] -pyrimidin-4-yl} -urea, 3- (2,6-dichloro-3,5-dimethoxy-f-enyl) -1-methyl-1 -. { 6- [3- (4-methyl-piperazin-1-yl-m-ethyl) -phenyl-amin or] -pyrimidin-4-yl} -u re a, 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [3- (4-ethyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea, 3- (2,6-dichloro-3,5-dimethoxy-f eni I) -1-methyl-1 -. { 6- [4- (2-morpholin-4-yl-ethoxy) -phenyl-amino] -pyrimidin-4-yl} -urea, 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [4- (1-ethyl-piperidin-4-yl) -phenyl-amino] -pyrimidin-4-yl} -1-methyl-urea, 3- (2,6-dichloro-3,5-dimethoxy-f eni I) -1-ethyl-1 -. { 6- [4- (4-ethyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; and 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [4- (4-Ethyl-piperazin-1 -carbonyl) phenyl-amino] -pyrimidin-4-i I.}. - 1 -methyl-urea; or a salt, a prodrug, an N-oxide, and / or an ester thereof.
6. 6. A compound of Formula IA, according to claim 1, selected from the group of compounds consisting of: 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [6- (4-ethyl-piperazin-1-yl) -pyridin-3-yl-amino] -pyrimidin-4-yl} -1-methyl-urea; and 3- (2,6-dichloro-3,5-dimethoxy-phenyl) -1-. { 6- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl-amino] -pyrimidin-4-yl} -1-methyl-urea, or a salt, a prodrug, an N-oxide, and / or an ester thereof.
7. 7. A pharmaceutical preparation, which comprises a compound of Formula IA, or a pharmaceutically acceptable salt, pro-drug, N-oxide, or ester thereof, according to any of claims 1 to 6, and at least one pharmaceutically acceptable vehicle.
8. 8. A compound of Formula IA, or a pharmaceutically acceptable salt, pro-drug, N-oxide, or ester thereof, according to any of claims 1 to 6, for use in the treatment of the animal or human body, especially for the treatment of diseases that respond to the inhibition of FGFR.
9. 9. The use of a compound of Formula IA, or a pharmaceutically acceptable salt, pro-drug, N-oxide, or ester thereof, according to claim 1, for the manufacture of a pharmaceutical preparation for the treatment of dependent diseases of protein kinase, especially FGFR. 1 0. A method for the manufacture of a compound of Formula IA, according to any of claims 1 to 6, which comprises: reacting an aniline compound of the Formula MA: wherein R 4 and n are as defined for a compound of the Formula IA, with an amine of the Formula M ÍA: R R 3 HN NH (IIIA) R2 wherein R1, R2, R3, X, Y, and Z are as defined for a compound of Formula IA, in the presence of a bis-reactive carbonic acid derivative; and, if desired, transforming a compound of Formula IA into a different compound of Formula IA, transforming a salt of a compound that can be obtained from Formula IA into the free compound or into a different salt, transforming a free compound which can be obtained from Formula IA in a salt thereof, and / or separating a mixture of isomers that can be obtained from a compound of Formula IA in the individual isomers. eleven . A method for the treatment of a tyrosine kinase dependent disease (especially FGFR), which comprises administering to a person in need of such treatment, an effective amount for this treatment, of a compound of Formula IA, an N- oxide, a salt, an ester, or a prodrug thereof, according to any of claims 1 to 6.