ES2371921T3 - PIRIMIDINA UREA DERIVATIVES AS QUINASA INHIBITORS. - Google Patents

Abstract

A compound of Formula (I): where the following fragments hereinafter referred to as "left ring" and "right ring", respectively: The left hand ring the right hand ring where X is C- R5, and Y and Z are both N, whereby the ring on the left has the structure of Fragment (A): Fragment (A) n is 0, 1, 2, 3, 4 or 5; X1 is oxygen. where R1 is of the formula R2-NRa- where Ra is hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, where hydrocarbyl has 1 to 15 carbon atoms, is optionally interrupted by an -O- or -NH- bond and is unsubstituted or it is substituted by hydroxy, halo, amino or mono- or di- (C1-C4) alkylamino, alkanoyl having 4 chain atoms, trifluoromethyl, cyano, azo or nitro; and R2 is selected from (i) linear or branched alkyl having 1, 2, 3 or 4 carbon atoms, (ii) linear or branched alkyl having 1, 2, 3 or 4 carbon atoms substituted by one or more halogens and / or one or two functional groups selected from hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, lower acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, groups hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano which are in turn optionally substituted in at least one heteroatom by one or, when possible, more alkyl groups linear or branched having 1, 2, 3 or 4 carbon atoms, (iii) a group of the formula where: ring A represents a 6-membered carbocyclic or heterocyclic ring; m is 0, 1 or 2; the or each Rb is independently selected from -L2-NRcRd; -L2-RING where RING is a substituted mono or bicyclic ring as defined below; halogen; hydroxy; protected hydroxyl; Not me; amidino; guanidino; hydroxyguanidino; formamidine; isothioureido; ureido; mercapto; acyl having 4 chain atoms; acyloxy having 4 chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; or nitro; and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isotioureido , ureido, mercapto, acyl having 4 chain atoms, acyloxy having 4 chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are optionally substituted on at least one heteroatom by one or, when possible, more aliphatic C1-C7 groups, where L2 is a direct link; a link selected from -O-; -S-; -CO)-; -OC (O) -; -NRaC (O) -; -C (O) -NRa -; -OC (O) - NRa -; cyclopropyl and -NRa-; or is a linear or branched group having 1, 2, 3 or 4 carbon atoms optionally interrupted and / or terminated at a single end or at both ends by a said link; and where Rc and Rd are each independently selected from hydrogen, and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens, by a 5- or 6-membered heterocyclic or carbocyclic ring optionally substituted, and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 chain atoms, acyloxy having 4 chain atoms, carboxy , sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups which are optionally substituted on at least one heteroatom with one or more C1-C7 aliphatic groups, or Rc and Rd together with their attached nitrogen form a 5 or 6-membered ring optionally substituted as described below, and said rings being optionally substituted independently of one another by 0, 1, 2, 3, 4 or 5 halogen selected substituents; hydroxy; protected hydroxy; Not me; amidino; guanidino; hydroxyguanidino; formamidine; isothioureido; ureido; mercapto; acyl having 4 chain atoms; acyloxy having 4 chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; C1-C7 aliphatic optionally substituted by one or more halogens and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isotioureido, ureido, mercapto, acyl that has 4 chain atoms, acyloxy having 4 chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of the above being hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and carbamoyl groups in turn optionally substituted on at least one heteroatom by one or, when possible , more aliphatic C1-C7 groups; R2 is H, halo, alkyl, alkyl interrupted by an -O- or -NH- bond and / or linked to the left ring by a said bond, trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl structural unit (interrupted or not) having 1, 2, 3 or 4 carbon atoms; R3 is H, a straight or branched C1-C4 alkyl or a straight or branched C1-C4 alkyl substituted by a saturated or unsaturated 5 or 6 membered carbocyclic or heterocyclic ring; R4 is selected from hydroxy, protected hydroxy, alkoxy, alkyl, trifluoromethyl and halo, where alkyl and the alkyl part of the alkoxy is a straight or branched chain and has 1, 2, 3, or 4 carbon atoms; R5 is H, halo, alkyl, alkyl interrupted by an -O- or -NH- bond and / or linked to the left ring by a said bond, trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl structural unit (interrupted or not) having 1, 2, 3 or 4 carbon atoms, or salts, hydrates, solvates, esters, N-oxides, protected derivatives, individual stereoisomers and pharmaceutically acceptable stereoisomer mixtures thereof.

Description

Pyrimidine urea derivatives as kinase inhibitors

Field of the Invention

The invention relates to compounds, formulations, methods and novel uses. More particularly it relates to compounds, which can be described as heteroaryl aryl ureas, useful for the treatment of protein kinase dependent diseases or for the manufacture of pharmaceutical compositions for use in the treatment of said diseases. The invention further relates to methods of using such compounds in the treatment of said diseases, pharmaceutical preparations comprising heteroaryl aryl ureas and processes for the manufacture of heteroaryl aryl ureas. The invention relates to other matters as disclosed below.

Background

Protein kinases (PK) are enzymes that catalyze phosphorylation of specific serine, threonine and chyrosine residues in cellular proteins. These post-translational modifications of substrate proteins act as molecular switches that regulate cell proliferation, activation and / or differentiation. An aberrant activity

or excessive PK has been observed in many disease states that include benign and malignant proliferative disorders. In many cases, it has been possible to treat diseases in vitro and in many cases in vivo, such as proliferative disorders, making use of PK inhibitors.

The kinases are mainly divided into two groups, those specific for phosphorylation of serine and threonine, and those specific for phosphorylation of tyrosine. Some kinases, referred to as "double specificity" kinases, are capable of phosphorylating tyrosine residues as well as serine / threonine.

Protein kinases can also be characterized by their location within the cell. Some kinases are transmembrane receptor proteins capable of binding external ligands to the cell membrane. Ligand binding alters the catalytic activity of the protein kinase receptor. Others are non-receptor proteins that lack a transmembrane domain and still others are ectokinases that have a catalytic domain over the extracellular portion (ecto) of a transmembrane protein or that are secreted as soluble extracellular proteins.

Many kinases are involved in regulatory cascades where their substrates can include other kinases whose activities are regulated by their phosphorylation status. Thus, the activity of a downstream effector is modulated by phosphorylation resulting from route activation.

The protein tyrosine kinase receptors (RPTK) are a subclass of transmembrane scanning receptors related to the intrinsic activity of ligand-stimulating tyrosine kinase. The activity of the RPTKs is controlled in a tight manner. When they undergo mutations or are structurally altered, RPTKs can become potent oncoproteins, producing cellular transformation. In principle, for all RPTKs involved in cancer, oncogenic deregulation comes from the relief or disturbance of one or more of the self-control mechanisms that ensure normal repression of the catalytic domains. More than half of the known RPTKs have been found repeatedly in their forms either mutated or overexpressed associated with malignant diseases in humans (including sporadic cases); Blume-Jensen et al., Nature 411: 355-365 (2001).

Overexpression of the RPTK leads to the constitutive activation of the kinase by increasing the concentration of the dimers. Examples are Neu / ErbB2 and the epidermal growth factor receptor (EGFR) that 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. In adults, however, angiogenesis is quite limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. See Merenmies et al., Cell Growth & Differentiation, 8, 3-10 (1997). On the other hand, unwanted angiogenesis is evidence 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 tyrosine kinase receptor family: VEGF-R2 (factor receptor Two vascular endothelial growth, also known as KDR (kinase insert domain receptor) and as FLK-1; FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2).

TEK (also known as Tie-2) is a tyrosine kinase receptor expressed only in endothelial cells that has been shown to play a role in angiogenesis. The binding of the angiopoietin-1 factor results in an autophosphorylation of the TEK kinase domain and results in a signal transduction process that appears to mediate the interaction of endothelial cells with periendothelial support cells, thereby facilitating maturation. of newly formed blood vessels. The angiopoietin-2 factor, on the other hand, seems to antagonize the action of angiopoietin-1 in TEK and interrupts angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997).

Administration of Ad-ExTek, an expressed soluble adenoviral extracellular domain of Tie-2, inhibits tumor metastasis when administered at the time of surgical removal of primary tumors in a clinically relevant mouse model of tumor metastasis (Lin et al., Proc Natl Acad Sci USA 95, 8829-8834 (1998) The inhibition of the function of Tie-2 by ExTek may be a consequence of the kidnapping of the angiopoietin ligand and / or heterodimerization of the native Tie-2 receptor This study demonstrates that disruption of the Tie-2 signaling pathway, first, can be well tolerated in healthy organisms, and, second, can provide a therapeutic benefit.

The Philadelphia Chromosome in an evidence for chronic myelogenous leukemia (CML) and carries a hybrid gene that contains N-terminal exons of the bcr gene and the main C-terminal part (exons 2-11) of the c-abl gene. The genetic product is a 210 KD protein (p 210 Bcr-Abl). The Abl part of the Bcr-Abl protein contains the Abl-tyrosine kinase that is strictly regulated in the wild-type c-abl, but constitutively activated in the Bcr-Abl fusion protein. This deregulated tyrosine kinase interacts with multiple cell signaling pathways leading to the transformation and deregulated proliferation of cells (Lugo et al., Science 247, 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 called HTK) and its ligand, ephrinB2 (HTKL) have critical roles in the establishment and determination of vascular networks. On the venous epithelium, EphB4 is specifically expressed, while during the primary stages of vascular development, ephrinB2 is specifically and reciprocally expressed in 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 defective ephrinB2 and EphB4. Both are expressed at the first site of hematopoiesis and vascular development during embryogenesis. An essential role is established for proper hematopoietic, endothelial, hemangioblastic and primitive mesoderm development. EphB4 deficiency results in an alteration in mesodermal differentiation from embryonic stem cells. Ectopic expression of EphB4 in breast tissues results in a disordered architecture, abnormal tissue function and a predisposition to malignancy (see, for example, N. Munarini et al., J. Cell. Sci. 115, 25-37 ( 2002)). From these and other data it has been concluded that an inappropriate expression of EphB4 may be involved in the formation of malignant diseases and so the inhibition of EphB4 can be expected as a tool to combat malignancies, for example, cancer and the like.

C-Src (also known as p60 c-Src) is a cytosolic tyrosine kinase without a receptor. 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 (PDGF). C-Src is overexpressed in breast cancers, pancreatic cancers, neuroblastomas and others. The mutant c-Src has been identified in human colon cancer. The c-Src phosphorylates a certain number of proteins that are involved in the regulatory conversation between the extracellular matrix and the cytoplasmic actin cytoskeleton. Modulation of c-Src activity may have implications in diseases related to cell proliferation, differentiation and death. See Bjorge, J. D., et. to the. (2000) Oncogene 19 (49): 5620-5635; Halpern, M. S., et. to the. (1996) Proc. Natl Acad. Sci. U. S. A. 93 (2), 824-7; Belsches, A. P., et. to the. (1997) Frontiers in Bioscience [Electronic Publication] 2: D501-D518; Zhan, X., et. al (2001) Chemical Reviews 101: 2477-2496; Haskell, M. D., et. to the. (2001) Chemical Reviews 101: 2425-2440.

The fms-like tyrosine kinase receptor (FLT3) tyrosine kinase is now recognized as a critical mediator in the pathogenesis of myeloid leukemias and some lymphoids. The activation of FLT3 on leukemic cells by the FLT3 ligand leads to receptor dimerization and signal transduction in routes that promote cell growth and inhibit apoptosis (Blood, Vol. 98, No. 3, pp. 885 -887 (2001)).

The use of tyrosine kinase inhibitors in AML therapy is impeded by the acquisition of mutations in the catalytic domain of the kinase, and in the case of BCR-ABL, these mutations confer resistance to imatinib.

FLT3 is widely expressed in AML and in some cases of acute lymphocytic leukemia. Activation mutations in FLT3 confer a poor risk in patients with AML. Thus, FLT3 is a promising objective for therapeutic intervention.

Platelet-derived growth factor receptor tyrosine kinase (PDGFR) is expressed in a number of tumors such as small cell lung cancer, prostate cancer and glioblastomas as well as stromal and vascular compartments of many tumors. Expression of both PDGF and PDGF receptors (PDGFR) has been observed in pancreatic cancer (Ebert M et al., Int J Cancer, 62: 529-535 (1995).

Fibroblast Growth Factor

Normal growth, as well as tissue repair and remodeling, require specific and delicate control of activation growth factors and their receptors. Fibroblast growth factors (FGF) constitute a family of more than twenty structurally related polypeptides that are regulated by development and are expressed in a wide variety of tissues. FGF stimulate cell proliferation, migration and differentiation and play a major role in skeletal and limb development, wound healing, tissue repair, hematopoiesis, angiogenesis and tumorigenesis (reviewed Ornitz, Novartis Found Svmp 232: 6376; discussion 76 -80, 272-82 (2001)).

The biological action of FGF is mediated by specific cell surface receptors that belong to the RPTK family of protein kinases. These proteins consist of an extracellular ligand binding domain, an individual transmembrane domain and an intracellular tyrosine kinase domain that undergoes phosphorylation by FGF binding. Four FGFR have been identified to date: it is FGFR1 (also called Flg, fms-like gene, flt-2, bFGFR, N-bFGFR orCek1), FGFR2 (also called Expressed bacterial Bek-kinase -, KGFR, Ksam, Ksaml and Cek3), FGFR3 (also called Cek2) and FGFR4. All mature FGFRs share a common structure that contains an amino terminal signal peptide, three extracellular immunoglobulin-like domains (domain ig I, domain ig II, domain ig III), with an acid region between ig domains (the domain of the "Acid box", 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 distinctive isoforms of FGFR have different binding affinities for the different ligands of FGF, thus FGF8 (androgen-induced growth factor) and FGF9 (glial activation factor), appear to have an increased selectivity for FGFR3 (Chellaiah et al. J Biol. Chem 1994; 269: 11620).

Another major class of binding sites on the cell surface include binding sites for heparan sulfatoproteoglycans (HSPG) that are required for interaction with high affinity and activation of all members of the FGF family. Specific tissue expression of heparan sulfate structural variants confer ligand-receptor specificity and FGF activity.

FGFR related diseases

Recent findings show that an increasing number of skeletal abnormalities, including achondroplasia, the most common form of human dwarfism, come from mutations in FGFRs.

Mutations at specific points in different domains of FGFR3 are associated with autosomal dominant human skeleton disorders including hypochondroplasia, severe achondroplasia and developmental delay and acanthosis nigricans (SADDAN) and tanatophoreic dysplasia (TD) (Cappellen et al., Nature Genetics, 23 : 18-20 (1999); Webster et al., Trends Genetics 13 (5): 178-182 (1997); Tavormina et al., Am. J. Hum. Genet., 64: 722-731 (1999)) . FGFR3 mutations have also been described in two craniosynostosis phenotypes: Muenke's crown craniosynostosis (Bellus et al., Nature Genetics, 14: 174-176 (1996); Muenke et al., Am. J. Hum. Genet ., 60: 555564 (1997)) and Crouzon syndrome with acanthosis nigricans (Meyers et al., Nature Genetics, 11: 462-464 (1995)), Cruozon syndrome is associated with specific point mutations in FGFR2 and with both familiar and sporadic forms of Pfeiffer syndrome that 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 (nineteen ninety five)). FGFR mutations result in constitutive activation of mutated receptors and increase the activity of the protein tyrosine kinase receptor, making cells and tissues unable to differentiate.

Specifically, the achondroplasia mutation results in enhanced stability of the mutated receptor, dissociating the activation of the subregulation receptor, leading to restricted chondrocyte maturation and inhibition in bone growth (reviewed in Vajo et al., Endocrine Reviews , 21 (1): 23-39 (2000)).

There is accumulated evidence regarding FGFR3 that activates mutations in various types of cancer.

FGFR3 constitutively activated in two common epithelial cancers, bladder and cervix 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 FGFR3 activating mutations in a large proportion of benign skin tumors (Logie et al., Hum Mol Genet 2005). FGFR3 currently appears to be the mutated oncogene that appears most frequently in bladder cancer when it is mutated in almost 50% of total bladder cancer cases and in approximately 70% of cases that have superficial bladder tumors (Cappellen, et al., Nature Genetics 1999, 23; 19-20; van Rhijn, et al., Cancer Research 2001, 61: 1265-1268; Billerey, et al, Am. J. Pathol. 2001, 158: 1955-1959, WO 2004/085676). Aberrant overexpression of FGFR3 as a consequence of t-chromosomal translocation (4, 14) is reported in 10-25% of cases of multiple myeloma (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). FGFR3 activating mutations are seen in 5-10% of multiple myelomas with t (4, 14) 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, BJH 2001, 114: 362-364).

In this context, the consequences of FGFR3 signaling appear to be cell type specific. In chondrocytes, hyperactivation of FGFR3 results in growth inhibition (reviewed in Omitz 2001), while in the myeloma cell it contributes to tumor progression.

It has been found that inhibition of FGFR3 activity represents a means to treat inflammatory or autoimmune diseases mediated by T cells, such as in the treatment of inflammatory or autoimmune diseases mediated by T cells that include but are not limited to rheumatoid arthritis (RA ), collagen II arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), psoriasis, juvenile onset diabetes, Sjogren's disease, thyroid disease, sarcoidosis, autoimmune uveitis, inflammatory bowel disease (ulcerative Crohn's colitis ), celiac disease and myasthenia gravis. See WO 2004/110487.

Disorders resulting from mutations in FGFR3 are also described in WO 03/023004 and WO 02/102972.

The amplification of the gene and / or expression of FGFR1, FGFR2 and FGFR4 has been implicated in breast cancer (Penault-Llorca et al., Int J Cancer 1995; Theillet et al., Genes Chrom. Cancer 1993; Adnane et al. , Oncogene 1991; Jaakola et al., Int J Cancer 1993; Yamada et al., Neuro Res 2002). Overexpression of FGFR1 and FGFR4 is also associated with pancreatic adenocarcinomas and astrocytomas (Kobrin et al., Cancer Research 1993; Yamanaka et al., Cancer Research 1993; Shah et al., Oncogene 2002; Yamaguchi et al., PNAS 1994; Yamada et al., Neuro Res 2002). Prostate cancer has also been linked to overexpression of FGFR1 (Giri et al., Clin Cancer Res 1999).

There is a need not met by highly selective molecules capable of blocking the activity of the constitutive aberrant block tyrosine kinase receptor protein, in particular the activity of FGFR, thus pointing to the clinical manifestations associated with the aforementioned mutations, and modulating various biological functions

In view of the large number of protein kinase inhibitors and the multitude of proliferative and other PK-related diseases, there is a permanent need to provide novel classes of compounds that are useful as PK inhibitors and thus in the treatment of these related diseases. with the protein tyrosine kinase (PTK). What is required are new classes of pharmaceutically advantageous PK inhibitor compounds.

Family of epidermal growth factor and related diseases

The epidermal growth factor receptor (EGF-R) and ErbB-2 kinase are receptors for the protein tyrosine kinase, which together with their family members ErbB-3 and ErbB-4, play a key role in the transmission of signals in a large number of mammalian cells, including human cells, especially epithelial cells, immune system cells and central and peripheral nervous system cells. For example, in various cell types, EGF-induced activation of the receptor-associated tyrosine kinase protein is a prerequisite for cell division and therefore for cell population proliferation. More importantly, overexpression of EGF-R (HER-1) and / or ErbB-2 (HER-2) has been observed in substantial fractions of many human tumors. EGF-R, for example, was found to be overexpressed in non-small lung cell cancers, squamous cell carcinoma (head and neck), breast, gastric, ovarian, colon and prostate, as well as gliomas. ErbB-2 was found to be overexpressed in squamous cell carcinoma (head and neck), breast, gastric and ovarian, as well as in gliomas.

The citation of any document here is not intended to be an admission that such a document is a relevant prior art, or material considered against the patentability of any claim of the present application. Any statement regarding the content or date of any document based on the information available to the applicant at the time of filing does not constitute an admission as to the correctness of said statement.

Summary of the Invention

The present invention provides a compound of formula (I): wherein

the following fragments are referred to hereafter as "left ring" and "right ring", respectively

ring on the left ring on the right

X is C-R9, and Y and Z are both N, so the ring on the left has the structure of the Fragment (A):

10 n is 0, 1, 2, 3, 4 or 5.

X1 is oxygen,

where R1 is of the formula R2-NRa- where Ra is hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, where hydrocarbyl has 1 to 15 carbon atoms, is optionally interrupted by an -O- or -NH- bond and is unsubstituted or it is substituted by hydroxy, halo, amino or mono- or di- (C1-C4) alkylamino, alkanoyl having 4 chain atoms,

Trifluoromethyl, cyano, azo or nitro;

and R2 is selected from

(i)

 linear or branched alkyl having 1, 2, 3 or 4 carbon atoms,

(ii)

 linear or branched alkyl having 1, 2, 3 or 4 carbon atoms substituted by one or more halogens and / or one or two functional groups selected from hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino,

20 isothioureido, ureido, mercapto, lower acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, hydroxy groups, amino, amidino, guanidino, hydroxyguanidino, formamidino, isotioureido, ureido, mercapto, carboxy, sulfo , sulfamoyl, carbamoyl and cyano which are in turn optionally substituted on at least one heteroatom by one or, where possible, more linear or branched alkyl groups having 1, 2, 3 or 4 carbon atoms,

(iii) a group of the formula where:

Ring A represents a 6-membered carbocyclic or heterocyclic ring;

m is 0, 1 or 2;

the or each Rb is independently selected from -L2-NRcRd; -L2-RING where RING is a substituted mono or bicyclic ring as defined below; halogen, hydroxy; protected hydroxyl; Not me; amidino; guanidino; hydroxyguanidino; formamidine; isothioureido; ureido; mercapto; acyl having 4 chain atoms; acyloxy having 4 chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; or nitro; and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isotioureido , ureido, mercapto, acyl having 4 chain atoms, acyloxy having 4 chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are optionally substituted on at least one heteroatom by one or, when possible, more C1-C7 aliphatic groups, where L2 is a direct link; a link selected from -O-; -S-; -CO)-; -OC (O) -; -NRaC (O) -: C (O) -NRa-: -OC (O) -NRa-; cyclopropyl and -NRa-; or is a linear or branched group having 1, 2, 3 or 4 carbon atoms optionally interrupted and / or terminated at a single end or at both ends by a said link;

and where Rc and Rd are each independently selected from hydrogen, and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens, by a 5- or 6-membered heterocyclic or carbocyclic ring optionally substituted, and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 chain atoms, acyloxy having 4 chain atoms, carboxy , sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups which are optionally substituted on at least one heteroatom for one or more C1-C7 aliphatic groups,

or Rc and Rd together with their attached nitrogen form an optionally substituted 5 or 6 member ring as described below.

said rings being optionally substituted independently of one another by 0, 1, 2, 3, 4 or 5 halogen selected substituents; hydroxy; protected hydroxy; Not me; amidino; guanidino; hydroxyguanidino; formamidine; isothioureido; ureido; mercapto; acyl having 4 chain atoms; acyloxy having 4 chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; C1-C7 aliphatic optionally substituted by one or more halogens and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isotioureido, ureido, mercapto, acyl that has 4 chain atoms, acyloxy having 4 chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of the above hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and carbamoyl groups substituted on at least one heteroatom by one or, when possible, more C1 groups -C7 aliphatic;

R2 is H, halo, alkyl, alkyl interrupted by an -O- or -NH- bond and / or linked to the left ring by a said bond, trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl structural unit (interrupted

or not) having 1, 2, 3 or 4 carbon atoms;

R3 is H, a straight or branched C1-C4 alkyl or a straight or branched C1-C4 alkyl substituted by a saturated or unsaturated 5 or 6 membered carbocyclic or heterocyclic ring;

R4 is selected from hydroxy, protected hydroxy, alkoxy, alkyl, trifluoromethyl and halo, where alkyl and the alkyl part of the alkoxy is a straight or branched chain and has 1, 2, 3, or 4 carbon atoms;

R5 is H, halo, alkyl, alkyl interrupted by an -O- or -NH- bond and / or linked to the left ring by a said bond, trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl structural unit (interrupted

or not) that has 1, 2, 3 or 4 carbon atoms,

or salts, hydrates, solvates, esters, N-oxides, protected derivatives, individual stereoisomers and mixture of pharmaceutically acceptable stereoisomers thereof.

It has now been found that the above compounds, which can be described as belonging to the heteroaryl aryl urea class, show inhibition of a certain number of protein tyrosine kinases.

The compounds of the invention are provided for use in a method for the treatment of a protein kinase dependent disease in a warm-blooded animal, for example a human, which comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a salt, ester, N-oxide

or prodrug thereof.

Also included is the use of a compound of Formula I or a salt, ester, N-oxide or prodrug thereof for the manufacture of a medicament for use in the treatment of a protein kinase dependent disease.

As another aspect of the invention, oral pharmaceutical compositions comprising compounds of Formula I or salts, esters, N-oxides or prodrugs thereof may be mentioned. Intravenous pharmaceutical formulations comprising compounds of formula I or salts, esters, N-oxides or prodrugs thereof should also be mentioned as an additional aspect.

In embodiments of the method, use and formulations mentioned above, the compound is in the form of the compound of formula (I) as such. In other embodiments, the compound is in the form of a salt, ester, N-oxide or prodrug thereof. Thus, in certain embodiments the compound is in the form of a salt, while in others it is not.

The compounds of the formula (I) (or example formulas thereof), described below in more detail, show especially inhibition of protein kinases for example, tyrosine kinase proteins. As examples of kinases inhibited by the compounds of the disclosure, FGFR1, FGFR2, FGFR3 and FGFR4 may be mentioned. Another inhibited kinase is the VEGF-R tyrosine kinase receptor. In particular the VEGF KDR receiver (VEGF-R2). The disclosed compounds are suitable for the inhibition of one or more of these and / or other tyrosine kinases and / or for the inhibition of mutants of these enzymes. In view of these activities, the compounds can be used for the treatment of diseases related to, especially, aberrant or excessive activity of such types of kinases, especially those mentioned.

The compounds of the disclosure may exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the disclosure includes all variant forms of the compounds.

The degree of protection includes false or fraudulent products that contain or are intended to contain a compound of the invention regardless of whether they indeed contain such a compound and regardless of whether such a compound is contained in a therapeutically effective amount. It is included within the scope of the invention therefore all packages that include a description or instructions indicating that the package contains a species or pharmaceutical formulation or composition of the invention and a product that is or comprises, or is intended to be or comprise such formulation, composition or species.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, when the indefinite article is used, the specification should be understood as if it contemplated plurality as well as singularity, unless the context requires otherwise.

Features, integers, features, compounds, chemical structural units or groups described in conjunction with a particular aspect, embodiment, or example of the invention should be understood as applicable to any other aspect, embodiment or example described herein unless it is incompatible with them. .

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of words, for example, "which includes" and "comprises" means "including but not limited to", and does not intend (and does not) exclude other structural units, additives, components, integers or stages.

Additional aspects and embodiments of the disclosure are defined in the following description and claims.

Detailed description

The present invention relates to compounds of Formula I as described above and salts. esters, N-oxides or prodrugs thereof. In one aspect, therefore, the invention provides products that are compounds of the formula I and salts, esters, N-oxides or prodrugs thereof.

R5 is H, halo, hydroxy, amino, mono- or dialkylamino, alkyl (eg methyl), alkyl interrupted by a -O- or -NH- bond and / or linked to the left ring by a said bond (eg to form alkoxy, for example methoxy), trifluoromethyl, hydroxy, amino, mono- or dialkylamino; Any alkyl structural unit (interrupted or not) typically has 1, 2, 3 or 4 carbon atoms.

In a class of compounds, R5 is H or halo, particularly H, F or Cl, for example it is H or F. In a particular class of compounds, the or each R5 is H.

R2 substituent

Considering again the left ring without restriction, R2 can be any structural unit described above in relation to R5 and of course R2 and R5 can be the same or different.

R2 and R5 are independently H, halo, alkyl, alkyl interrupted by an -O- or -NH- bond and / or linked to the left ring by a said bond, trifluoromethyl, hydroxy, amino, mono- or dialkylamino; Any alkyl structural unit (interrupted or not) typically has 1, 2, 3 or 4 carbon atoms.

In a class of compounds, both R2 and R5 are independently H or halo, particularly H, F or Cl, for example they are H or F. In a particular class of compounds, R2 and the or each of the R5 are H.

It will be understood from the above description that a particular left and right structure is fragment (B):

R1 substituent A common left ring structure is represented by the fragment (C):

where Ra is as described above and preferably H, and R2 is as mentioned above and as further described below.

R1 is of the formula R2-NRa-and R2 is selected from the categories (i), (ii) and (iii) above. In a class of compounds, alkyl is, for example, a linear or branched alkyl having 1, 2, 3 or 4 carbon atoms; linear alkyl is more common, regardless of the number of carbon atoms.

In a subclass of these compounds where R1 is of the formula R2-NRa-, R2 is alkyl, for example, linear or branched alkyl having 1, 2, 3 or 4 carbon atoms; the most common linear alkyl, regardless of the number of carbon atoms.

Turning now to those compounds in which R2 is a group of category (iii), that is, it is of the formula

Ring A is a 6-membered carbocyclic or heterocyclic ring, particularly phenyl, cyclohexyl or cyclohexenyl. Of these, phenyl is preferred. Other example residues that form ring A are pyridyl and pyrimidyl.

The integer m can be 0.

The integer m is frequently 1. When m is greater than 1, all Rb groups or all Rb groups except one are frequently halogen (mainly F or Cl), methyl or trifluoromethyl. Hydroxy and amino should also be included in this aspect. Frequently, a simple Rb group is selected from -L2-NRaRd and L2-RING and there are 0, 1 or 2 additional substituents that are not -L2-L2-NRcRd or -L2-RING, but are, for example, halogen (mainly F or Cl), lower alkyl (for example methyl), lower alkyl (for example, methoxy), hydroxy, amino or trifluoromethyl.

In accordance with the foregoing, the invention includes compounds in which R2 is, for example, a 6-membered carbocyclic ring (mainly phenyl) substituted by 1, 2, 3, 4 or 5 halogens, for example selected from F, Cl and Br; typically such phenyl rings are mono or disubstituted, for example they are substituted at 2- and / or 4- by F or substituted at 3- by Cl. In some cases of halogen plural substitution, all halogens are the same. Thus, in a class of compounds R2 is a monocyclic ring, particularly a 6-membered carbocyclic ring (mainly phenyl), substituted only by one or more halogens, particularly selected from F and Cl, sometimes the one or each of the halogens is F but in some other cases the or each of the halogens is Cl.

In another class of compounds, R2 is a monocyclic ring, particularly a 6-membered carbocyclic ring (mainly phenyl), substituted by 1, 2, 3, 4 or 5 substituents, for example 1 or 2 substituents, selected from alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono or dialkylamino, cyano, halogen, hydroxy or protected hydroxy, where alkyl or the alkyl part of alkoxy and alkanoyl (Oxi) has 1, 2, 3 or 4 carbon atoms; Example substituents in this case are methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain of such rings have 0, 1 or 2 substituents, for example, 0 or 1.

In a class of compounds, L2 is a direct bond, linear alkyl, terminated linear alkyl adjacent to ring A by such a bond, or is such a bond. In a subclass, any such union is -O- or -C (O) -, of which -O- can be mentioned in particular.

The invention includes a class of compound in which ring A is a 6-membered ring, particularly phenyl, cyclohexyl or cyclohexenyl and has one or two Rb substituents independently selected from Rb-L2-NRcRd and L2-RING, as defined. previously. In a subclass, there is an individual substituent in, in particular, position 3 or position 4, selected from -L2-NRcRd and L2-RING, such that the ring on the left has a structure corresponding to the fragments (D1 ), (D2), (E1) or (E2):

As previously described, Ra is commonly H. Also as previously described, the phenyl ring may be replaced by cyclohexyl or cyclohexenyl, particularly cyclohexyl. It may alternatively be replaced by a 5- or 6-membered heterocycle, particularly pyridine.

In some embodiments, the phenyl ring of the above fragments (or other replacement phenyl ring) has 1, 2, 3 or 4 additional substituents, for example selected from halogen (particularly F or Cl), methyl, methoxy or trifluoromethyl. e.g. 1 or 2 such substituents. Hydroxy and amino may also be mentioned in this aspect.

L2 is as previously described, a direct link; a link selected from -O-; -S-; -C (O) -: -OC (O) -: -N RaC (O) -: -C (O) -NRa -; -OC (O) -NRa -; cyclopropyl and -NRa-; or C1-C7 aliphatic optionally interrupted and / or terminated at a single end or at both ends by a said link (Ra is as previously defined and is typically H). Any aliphatic structural unit is often alkyl. e.g. alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as in the subclass of linkers L2 in which the aliphatic structural units are methyl, ethyl or n-propyl.

In particular fragments (D) and (E), L2 is a direct linear alkyl bond, linear alkyl terminated adjacent to the phenyl ring in the above representations of the fragments by a said union, or is a said union, suitable but not necessarily any of said union is -O- or -C (O) -, of which -O- can be mentioned in particular. Thus, the above fragments (D) and (E) may comprise subfragments - PH-NRcRd, -Ph-RING, -Ph-O-alkyl-NRcRd, -Ph-O-alkyl-RING, -Ph-alkyl-NRcRd, -Ph-alkyl-RIN G, and also to mention are the sub-fragments -Ph-O-NRcRd, -Ph-O-RING, -Ph-C (O) - NRcRd and -Ph-C (O) -RING, where , in all these subfragments containing alkyl, alkyl can be, for example, methyl, ethyl or n-propyl, or n-butyl.

Now considering in more detail the fragments (D1) and (D2), these contain a RING structural unit which is a cyclic structural unit and in many cases a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted as previously defined. Example rings are saturated, for example, cyclopentane

or cyclohexane. In particular compounds, RING is a 5- or 6- membered heterocycle, which frequently contains one or two heteroatoms, typically selected from O and N; in a subclass, the heterocycles contain one or two nitrogen and where there is an individual nitrogen, optionally an oxygen. Particular heterocycles include a nitrogen that is not a member of a double bond and are more particularly saturated heterocycles. As heterocycles, pyrrolidine, piperidine, piperazine and morpholine can be mentioned; In some compounds, RING is piperidine that has its nitrogen in position 4 with respect to L2. As described above, RING can be substituted and, in a class of compounds, is substituted by 0, 1, 2, 3, 4 or 5 substituents, for example, selected from C1-C7 aliphatic groups, optionally substituted as described more above, and less frequently C1-C7 aliphatic oxy of which the aliphatic group is optionally substituted as described above. Any aliphatic group is often alkyl (straight or branched chain), for example alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as in the case of a subclass of fragments (D1) and (D2) which have substituents that are methyl, ethyl or n-propyl. Substituents of RING examples include C1, C2, C3 or C4 straight or branched chain alkyl such as, for example, methyl, ethyl, n-propyl, isopropyl or t-butyl of which methyl, halogen can be mentioned in particular (mainly F or Cl) and C1, C2, C3 or C4 alkoxy; hydroxy and amino may also be mentioned. The alkyl structural units may be unsubstituted or substituted, for example, by halogen (mainly F or Cl) or in some cases by hydroxy or amino.

In some classes of RING structural units, there are 0, 1, 2, 3, 4 or 5 of such substituents selected from alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy or protected hydroxy, where alkyl or the alkyl part of alkoxy and alkanoyl (oxy) has 1, 2, 3 or 4 carbon atoms; Example substituents in this case are methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain RING structural units have 0, 1 or 2 substituents, e.g. 0 or 1

Now considering in more detail the fragments (E1) and (E2), contain a structural unit NRcRd. Rc and Rd are as previously described. In one class of these fragments, Rc and Rd are the same or different (but more usually the same) and are selected from C1-C7, for example, C1-C4 aliphatic groups, optionally substituted as described above. As aliphatic structural units Rc and Rd may be mentioned alkyl, for example having 1, 2, 3 or 4 carbon atoms, as in the case of a subclass of fragments (E1) and (E2) having substituents in which they are methyl , ethyl or n-propyl. Alkyl or other aliphatic structural units may be substituted for example by amino or mono or di (C1-C4) alkylamino, or for example by a 5- or 6-membered heterocyclic or carbocyclic ring optionally substituted as previously described, or unsubstituted. Thus particularly L2NRcRd structural units are - OCH2NMe2, -OCH2NEt2, -OCH2CH2NMe2, -OCH2CH2NEt2, -OCH2CH2CH2NMe2, -OCH2CH2C H2NEt2, -CH 2 NMe 2, -CH 2 NEt 2, -CH2CH2NMe2, -CH2CH2NEt2, -CH2CH2CH2NMe2 and -CH2CH2CH2NEt2.

In another class of fragments (E1) and (E2), Rc and Rd together with the adjacent nitrogen form a heterocyclic structural unit (usually a 5- or 6- membered heterocyclic ring), optionally substituted as described above. In addition to the nitrogen of the NRcRd structural unit, the heterocyclic ring may contain at least one additional heteroatom, and often exactly one additional heteroatom, in any case typically selected from O and N, in a subclass, the heterocycles together contain one or two nitrogens and , when there is an individual nitrogen, optionally an oxygen. Particular heterocycles include a nitrogen that is not a member of a double bond and are more particularly saturated heterocycles. As heterocycles, pyrrolidine, piperidine, piperazine and morpholine can be mentioned; of these particular heterocycles are piperazine and morpholine. As described above, the heterocycle can be substituted and, in a class of compounds, is substituted by 0, 1, 2, 3, 4 or 5 substituents, for example, selected from C1-C7 aliphatic groups, optionally substituted as described above, and less frequently aliphatic-C1-C7 oxy of which the aliphatic group is optionally substituted as described above. Any aliphatic group is often alkyl (straight or branched chain), for example alkyl or other aliphatic having 1, 2, 3 or 4 carbon atoms, as in the case of a subclass of cyclic fragments (E1) and (E2) that they have substituents that are methyl, ethyl or n-propyl. Substituents

Examples of cyclic (E1) and (E2) fragments include straight, branched or straight chain C1, C2, C3 or C4 alkyl such as, for example, methyl, ethyl, n-propyl, isopropyl or t-butyl, of which the Methyl may be mentioned in particular, halogen (mainly F or Cl) and C1, C2, C3 or C4 alkoxy; Hydroxy and amino should also be mentioned. The alkyl structural units may be unsubstituted or substituted, for example by halogen (mainly F or Cl) in some cases by hydroxy or amino.

In some classes of cyclic fragments (E1) and (E2) (i.e. fragments in which Rc and Rc together with the adjacent nitrogen form a ring), there are 0, 1, 2, 3, 4 or 5 of such substituents selected from alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono or dialkylamino, cyano, halogen, hydroxy or hydroxy protected, where alkyl or the alkyl part of alkoxy and alkanoyl (Oxi) has 1, 2, 3 or 4 carbon atoms; Example substituents in this case are methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH. Certain cyclic fragments have 0, 1 or 2 substituents, for example 0 or 1.

L2NRcRd structural units are Pip, -Morf, -OCH2Pip, -OCH2Morf, -OCH2CH2Pip, -OCH2CH2Morf, -OCH2CH2CH2Pip, -OCH2CH2CH2Morf, -CH2Pip, -CH2Morf, -CH2CH2Pip, -CH2CH2Morf, -CH2CH2CH2Pip and -CH2CH2CH2Morf. You can also mention -C (O) Pip and -C (O) Morf. The abbreviation " Pip " means piperazine and "Morf" morpholine, and these rings can be substituted as previously described. In particular, piperazine is optionally substituted in N. Piperazine and morpholine can be substituted by a C1-C7 aliphatic group as mentioned in the previous paragraph, for example a straight, branched or branched C1, C2, C3 or C4 structural unit selected from alkyl and haloalkyl such as, for example, methyl, trifluoromethyl, ethyl n-propyl, isopropyl

or t-butyl, of which methyl and trifluoromethyl are examples. As described above, Ra is in particular hydrogen.

Among the classes of compounds that should be mentioned in particular are those in which the ring on the left and the ring on the right have structures corresponding to the fragment (D1) or (E1). Particularly as examples are compounds such that they have a fragment (E1) in which Ra and Rd together with the adjacent nitrogen form a 5- or 6- membered heterocyclic ring as described above. These rings can be substituted as previously described. In particular they are optionally substituted in N by a C1-C7 aliphatic group, as mentioned above, for example, a straight, branched or straight chain C1, C2, C3 or C4 structural unit selected from alkyl and haloalkyl such as, for example, methyl , trifluoromethyl, ethyl n-propyl, isopropyl or t-butyl, of which methyl and trifluoromethyl are examples. As described above, Ra is in particular hydrogen.

It will be apparent from the foregoing that the invention includes compounds having a left and right ring having the structure of the following fragment (F):

Fragment (F)

where L2NRcRd is particularly Pip, -Morf, -OCH2Pip, -OCH2Morf, -OCH2CH2Pip, -OCH2CH2Morf, -OCH2CH2CH2Pip, -OCH2CH2CH2Morf, -CH2Pip, -CH2Morf, -CH2CH2Pip, -CH2CH2Morf, -CH2CH2CH2Pip and -CH2CH2CH2Morf, or C (O) Pip or -C (O) Morf. " Pip " and "Morf" They are as described in the last paragraph.

R3 substituent

Substituent R3 is as previously described in relation to Formula (I).

R3 is H or a straight or branched C1-C4 alkyl such as, for example, methyl, ethyl or n-propyl, of which methyl is an example. In other compounds, R3 is a straight or branched C1-C4 alkyl such as, for example, methyl, ethyl or n-propyl substituted by a saturated or unsaturated 5- or 6- membered carbocyclic or heterocyclic ring, for example by phenyl, pyrrolidine, piperidine, piperazine, morpholine, thiophene, furan, pyrrole, pyridine, pyrazine

or pineapple R3 can therefore be a straight chain alkyl (or other straight chain aliphatic group, for example, in any case with up to 4 carbon atoms) substituted at its free end by such a mono or bicyclic ring.

The right ring

By "right ring" the fragment is understood: The integer n is more usually 1, 2, 3 or 4, for example, 2, 3 or 4. In particular, there are frequently substituted R4 groups in both ortho positions and optionally in at least one or two positions, for example, there may be an individual substituent meta or para.

R4 is particularly selected from hydroxy, protected hydroxy, lower alkoxy, lower alkyl, trifluoromethyl and halo, mainly F or Cl. R4 can also be Br, alkyl and the alkyl part of the alkoxy can be branched or, more usually a straight chain, and frequently it has 1, 2, 3 or 4 carbon atoms, as for example in the case of methyl, ethyl, methoxy and ethoxy. R4 is especially selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl, for example, is selected from Cl, F, methyl, methoxy and trifluoromethyl, as in those compounds where R4 is Cl, F,

10 methyl or methoxy. In some of the compounds mentioned in this paragraph, chlorine is the only halogen, in some others fluorine is the only halogen. The reader is reminded that, when there are plural R4 groups, they may be the same or different.

Compounds in which halogen selected from F and Cl are included in one or both ortho positions.

Rings on the right corresponding to the fragment (G) are mentioned:

Fragment (G) where: Q is selected from F and Cl; U is selected from H, F. Cl, methyl, trifluoromethyl and methoxy, and particularly Q and U are the same or different and both

20 are selected from F and Cl;

T and V are the same or different and are selected from H, methyl, trifluoromethyl and methoxy, e.g. of H, methyl and methoxy.

In some fragments (G), U, T and V are all H. In other fragments (G), Q and U are the same and selected

of F and Cl. A particular ring on the right is the Fragment (H):

The rings on the right corresponding to Fragment (I) must be mentioned:

Fragment (I) where: Q is selected from F and Cl,

5 Ua and Ub are each independently selected from H, F, Cl, methyl, trifluoromethyl and methoxy; in some compounds Ua and Uc are the same.

In example fragment structures (I), all Q, Ua and Ub are the same and are fluorine or more particularly chlorine. In other example structures, Q is F or particularly Cl while Ua and Ub are the same or different and are selected from methyl, trifluoromethyl and methoxy; both Ua and Ub can be the same, for example both can be

10 methoxy.

The compounds of formula (I)

It has been described above how the compounds of the formula (I) have the following variable domains:

• Ring on the left

• R2 15 • Right ring

Various structural units have been described for each of these variable domains and it will be clear that Any combination of such structural units is permissible. Compounds that have the following combinations, among many others, can be mentioned:

Ring on the left

R3 Right ring

Fragment (A)

H, C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (B)

H, C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

(continued) (continued) (continued) (continued)

Ring on the left

R3 Right ring

Fragment (C)

H, C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (C), R3 = H, Rz = category (i) or (ii)

H, C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (C), Ra = H, R2 = category (iii)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F. hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (D1)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (D2)

C1-C4 alkyl or C1-C4 alkyl n = 1, 2, 3, or 4.

replaced by an optionally substituted 5 or 6 member ring

R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (E1)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (E2)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (F)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Ring on the left

R3 Right ring

Fragment (C), R3 typically = H, R2 = category (iii)

H n = 1, 2, 3. or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl

Fragment (D1); Ra typically = H,

H n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl,

Fragment (D2); Ra typically = H,

H n = 1, 2. 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (E1); Ra typically = H,

H n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (E2); Ra typically H = H,

H n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl,

Fragment (F)

H n = 1, 2, 3, or 4. R4 = selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

Fragment (A)

H, C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I).

Fragment (B)

H, C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G). (H) or (I).

Fragment (C)

H, C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G): (H) or (I).

Ring on the left

R3 Right ring

Fragment (C), Ra = H. Rz = category (i) or (ii)

H = C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I).

Fragment (C), R3 = H, Rz = category (iii)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I).

Fragment (D1)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I)

Fragment (02)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I).

Fragment (E1)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I).

Fragment (E2)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I).

Fragment (F)

C1-C4 alkyl or C1-C4 alkyl substituted by an optionally substituted 5 or 6-membered ring R4 is Fragment (G), (H) or (I).

Fragment (C), R3 typically = H, R2 = category (iii)

H R4 is Fragment (G), (H) or (I).

Ring on the left

R3 Right ring

Fragment (D1): Ra typically = H,

H R4 is Fragment (G), (H) or (I).

Fragment (D2): Ra typically = H,

H R4 is Fragment (G), (H) or (I).

Fragment (E1); Ra typically = H,

H R4 is Fragment (G), (H) or (I).

Fragment (E2): Ra typically = H,

H R4 is Fragment (G), (H) or (I).

Fragment (F)

H R4 is Fragment (G), (H) or (I).

Each row of the preceding table provides support for an individual patent claim, filed by itself or with one or more additional claims, each corresponding to a respective row of the table. He

The previous text provides support for the dependent claims of such claims by describing subclasses of the respective characteristics or combinations of characteristics of each row. For each row in the table, a patent claim or claims can be written to individually protect a subclass or subclasses of the matter represented by the row.

It will be apparent from the foregoing that a subset of the compounds of formula (I) are of the following formulas (II) 10 and (III):

In the formulas (II) and (III) the case is frequent in which X is CH, Y and Z are N and R2 is H. Ring A is typically phenyl or a completely or partially hydrogenated analog thereof. Alternatively it can be a heterocycle, typically six members, for example, pyridine or pyrimidine. The integer m may be 0, 1 or 2, for example 1. In some cases there are one or more structural units Rb that are F or Cl, as previously described, for example, the only structural units Rb may be one or two structural units selected from F and Cl.

In accordance with the above, formulas (II) and (III) cover the following subclasses, among others:

1) X is CH, Y and Z are N, R2 is H, ring A is phenyl or a partially or totally hydrogenated analog thereof, m is 0, 1 or 2, e.g. one;

2) X is CH, Y and Z are N, R2 is H, ring A is a heterocycle, typically of six members, e.g. pyridine or pyrimidine, m is 0, 1 or 2, e.g. one,

In some cases of subclasses 1) and 2) there is one or more structural units Rb that are F or Cl, as previously described, for example the only structural units Rb may be one of the selected structural units of F and Cl.

More commonly, ring A is replaced by one or two structural units Rb (and usually a single structural unit Rb) comprising -L2-RING-L2 or NRcRd-, and optionally other substituents (for example, numbering 1, 2 or 3) selected from eg halogen; hydroxy; protected hydroxy for example trialkylsilylhydroxy; amino, amidino, guanidino, hydroxyguanidino; formamidine; isothioureido; ureido; mercapto; C (O) H or other lower acyl; lower acyloxy; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; whose substituents are in turn optionally substituted in at least one heteroatom by one or, where possible, more C1, C2, C3 or C4 alkyl groups. Additional substituents in particular are ring A are halogen, lower alkyl (for example methyl), lower alkoxy (for example, methoxy), hydroxy, amino or trifluoromethyl.

Compounds of the following formulas (IV), (V), (VI) and (VII) may also be mentioned:

where

10 L2NRcRd is in particular -Pip, -Morf, -

OCH2Pip, -OCH2Morf, -OCH2CH3Pip, -OCH2CH2Morf, -OCH2CH2CH2Pip, -OCH2CH2CH2Morf, -CH2Pip, -CH2Morf, -CH2CH2Pip, -CH2CH2Morf, -CH2CH2CH2-O2, O-P2, O-P2) Morf (or of course these heterocycles are replaced by another described herein, or in other embodiments Rc and Rd form a non-cyclic structure as previously described);

15 L2RING is in particular-RING, -OCH2RING, -OCH2CH2RING, -OCH2CH2CH2RING, -CH2RING, -CH2CH3RING, -CH2CH2CH2RING, or is -C (O) RING, where RING is in particular pyrrolidine, piperidine, piperazine or morpholine be another RING structural unit disclosed here:

R3 is as previously described and is particularly but not necessarily H: R4 is as previously described and is particularly but not necessarily selected from Cl, F, hydroxy, methyl, methoxy and

Trifluoromethyl;

n is 0, 1, 2, 3, 4 or 5, e.g. It is 1, 2, 3, or 4.

In embodiments, RING or a heterocycle consisting of L2NRcRd is substituted by 1, 2, 3, 4 or 5 substituents, e.g. 1 or 2 substituents, selected from alkyl, alkoxy, alkanoyl, alkanoyloxy, haloalkyl, amino, mono- or di-alkylamino, cyano, halogen, hydroxy or hydroxy protected, where alkyl or the alkyl part of alkoxy and alkanoyl (oxy) has 1 , 2, 3 or 4

25 carbon atoms; Example substituents in this case are methyl, ethyl, methoxy, ethoxy, acetyl, trifluoromethyl, cyano, F, Cl and OH, piperazine or N-alkyl substituted piperadine are examples, as are the RING structural units as a class substituted by one or two substituents or more, selected from alkyl and haloalkyl (eg trifluoromethyl). As an alternative to substitution, there may be no substitution.

The present invention also relates to the use of a claimed compound in a method of treating acute myeloid leukemia (AML), which comprises administering a therapeutically effective amount of a claimed compound.

RAF serine / threonine kinases are essential components of the Ras / Mitogen activated protein kinase signaling module (MAPK) that controls a complex transcriptional program in response to external cellular stimuli. Raf genes encode highly conserved serine-threonine specific protein kinases that are known to bind the ras oncogene. They are part of a transduction signal pathway that is believed to consist of tyrosine kinase receptor, p21 ras, Raf protein kinases, MEK1 (ERK activator or MAPKK) kinases and ERK (MAPK) kinases, which ultimately phosphorylate transcription factors. In this route, Raf kinases are activated by Ras and diactive phosphorylate in two isoforms of the mitogen-activated protein kinase (called MEK1 and MEK2), which are specific threonine / tyrosine kinases. Both isoforms of Mek activate mitogen-activated kinases 1 and 2 (MAPK, also called extracellular kinase regulated by ligand 1 and 2 or ERK1 and ERK2). MAPKs phosphorylate many substrates including transcription factors and thus establishing their transcriptional program, Raf kinase participation in the Ras / MAPK pathway 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 demonstrated from studies the use of deregulated Raf mutants and dominant inhibitors in mammalian cells as well as from studies using biochemical and genetic techniques of model organisms. In many cases, Raf activation by receptors that simulate cell tyrosine phosphorylation depends on Ras activity indicating that Ras functions drag those of Raf. By activation, Raf-1 phosphorylates and then 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 ). Raf serine / threonine kinases are considered as the primary Ras effectors involved in the proliferation of animal cells (Avruch et al. (1994) Trends Biochem. Sci. 19: 279).

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, tissue distribution and subcellular location ( Marías et al., Biochem. J. 351: 289-305, 2000; Weber et. Al., Oncogene 19: 169-176, 2000; Pritchard et al., Mol. Cell. Biol. 15: 64306442, 1995).

Recent studies have shown that the B-Raf mutation in the skin nevi is a critical stage in the initiation of melanocytic neoplasia (Pollock et al, Nature Genetics 25: 1-2, 2002). Additionally, more recent studies have emerged that activation of the mutation in the B-Raf kinase domain occurs in approximately 66% of melanomas. 12% of colon carcinoma and 14% 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 Raf kinase level can potentially be effective as therapeutic agents against overexpressed or mutated tyrosine kinase receptor tumors, activated intracellular tyrosine kinases, aberrantly expressed Grb2 tumors (a protein adapter that allows the stimulation of Ras by the exchange factor Sos), as well as tumors that receive activation of mutations of the Raf itself. In previous clinical trials of Raf-1 kinase, which also inhibits B-Raf, the promise of a therapeutic agent in cancer therapy has been shown (Crump, Current Pharmaceutical Design 8: 2243-2248. 2002; Sebastien et. Al ., Current Pharmaceutical Design 8: 2249-2253, 2002).

The interruption of the expression of RAF in cell lines through the application of antisense RNA technology has been 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).

As examples of kinases inhibited by the compounds of the disclosure, c-Abl and Bcr-Abl can be mentioned, in particular, the inhibition of Bcr-Abl can be mentioned. Another inhibited kinase is the VEGF-R tyrosine kinase receptor, in particular the VEGF KDR receptor (VEGF-R2). The compounds of the present invention also inhibit the mutant forms of the BCR-ABL kinases. The disclosed compounds are suitable for the inhibition of one or more of these and / or other tyrosine kinase and / or non-receptor tyrosine kinase Raf proteins, and / or for the inhibition of mutants of these enzymes. In view of these activities, the compounds can be used for the treatment of diseases related especially to aberrant or excessive activity of such types of kinases, especially those mentioned.

For example, as inhibitors of the activity of the VEGF receptor tyrosine kinase, the compounds of the invention can primarily inhibit blood vessel growth and are thus, for example, effective against a number of diseases associated with deregulated angiogenesis, especially diseases. caused by ocular neovascularization, especially retinopathies, such as diabetic retinopathy or age-related macula 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 transplant rejection, or especially renal inflammatory diseases, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, uremic hemolytic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma and especially neoplastic diseases (solid tumors, but also leukemia and other "liquid tumors", especially those expressing c-kit, KDR, Flt-1 or FLT-3 ), such as especially breast cancer, colon cancer, lung cancer (especially small cell lung cancer), prostate cancer or Kaposi's sarcoma. A compound of the formula I *, II *, III *, IV *, V *, VI *, VII *, VIII * or IX * (or example formulas thereof) (or an N-oxide thereof) They inhibit the growth of tumors and is especially suitable to prevent metastatic spread of tumors and the growth of micrometastases.

A class of target kinases of the compounds of the present invention are the Bcr-Abl mutants. The mutants Glu255 ---> Lysine, Glu255 ---> Valine or hr315 ---> Isoleucine can be mentioned especially, most especially the Thr315 mutant ---> Isoleucine.

Other mutants of Bcr-Abl 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 ---> Ile , Tyr253 ---> Phe, Phe382 ---> Leu, Glu255 ---> Lys, Leu387 ---> Met, Glu255 ---> Val, His396 ---> Pro, Phe311 ---> Ile, His396 ---> Arg, Phe311 ---> Leu, Ser417 ---> Tyr, Thr315-Ile, Glu459 ---> Lys and Phe486 ---> Ser.

Substituents

The following definitions apply to the compounds of the invention as appropriate and consistent and if nothing else is mentioned.

"Substituted", whenever used for a structural unit, means that one or more hydrogen atoms in the respective structural unit, especially up to 5, more especially 1, 2 or 3 hydrogen atoms are independently replaced from each other by the corresponding number of substituents that are preferably independently selected from the group consisting of lower alkyl, for example, methyl, ethyl or propyl, lower haloalkyl, for example, trifluoromethyl, C6-C18 aryl, especially phenyl pyridine.

C6-C16-aryl is unsubstituted or substituted by one or more, especially 1, 2 or 3 structural units selected from, for example, lower alkyl, halogen, carboxy, lower alkoxycarbonyl, hydroxy, etherified or esterified hydroxy, lower alkoxy, phenyl - lower alkoxy, lower alkanoyloxy, lower alkanoyl, amino, mono or disubstituted amino, halo, lower haloalkyl, eg trifluoromethyl, sulfo, sulfamoyl, carbamoyl, N-monosubstituted or N, N-disubstituted Carbamoyl, lower N-alkylcarbamoyl, N- (hydroxy-lower alkyl) -carbamoyl, such as N- (2-hydroxyethyl) -carbamoyl, cyano, lower cyanoalkyl and nitro;

Substituents also include hydroxy, C3-C10-cycloalkyl, especially cyclopropyl or cyclohexyl, hydroxy-C3-C8cytoalkyl, such as hydroxy-cyclohexyl, heterocyclyl with 5 or 6 ring atoms and 1 to 3 ring heteroatoms selected from O, N and S, especially piperidinyl, especially piperidin-1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl, especially morpholin-1-yl, hydroxy, lower alkoxy, for example methoxy, halo-lower alkoxy, especially 2,2,2-trifluoroethoxy , phenyl-lower alkoxy, lower amino-alkoxy, such as 2-eminoethoxy; lower alkanoyloxy, hydroxy-lower alkyl, such as hydroxymethyl or 2-hydroxyethyl, amino, mono or disubstituted amino, carbamoyl-lower alkoxy, N-alkylcarbamoyl-lower, lower alkoxy or N, N-di-lower alkylcarbamoyl-lower alkoxy, amidino , ureido, mercapto, N-hydroxy-amidino, guanidino, amidino-lower alkyl, such as 2-amidinoethyl, Nhydroxyamidino-lower alkyl, such as N-hydroxy-amidino-methyl or -2-ethyl, halogen, for example fluoro, chlorine, bromine or iodine, carboxy, esterified carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, benzoyl, lower alkanoyl, sulfo, lower alkanesulfonyl, for example methanesulfonyl (CH3S (O) 2-) , lower alkylthio, phenylthio, lower phenyl-alkylthio, lower alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl, phenyl-lower alkylsulfinyl, lower alkylphenylsulfinyl, halogenoalkylmercapto, lower halogenoalkylsulfonyl, such as special Trifluoromethanesulfonyl, dihydroxyboro (-B (OH) 2), phosphono (-P (= O) (OH) 2), hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, mono- or di- (hydroxy-lower alkyl) -carbamoyl, sulfamoyl, mono- or di-lower alkylaminosulfonyl, nitro, cyano-lower alkyl, such as cyanomethyl, and cyano, lower alkenyl, lower alkynyl.

Needless to say, the substituents are only in the positions where they are chemically possible, being the person skilled in the art able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are possible and which are not. For example, amino or hydroxy groups with free hydrogen may be unstable if they are bonded to carbon atoms with unsaturated bonds (eg, olefinic,). Additionally, it will of course be understood that the substituents as listed above may themselves be substituted by a substituent, subject to the aforementioned restriction for appropriate substitutions as recognized by the experienced person.

Other definitions

The general terms used here before and below preferably have the following meanings within the concept of this disclosure, unless otherwise indicated:

The prefix "lower" denotes a 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. Particular classes of alkyl and aliphatic comprise 1, 2, 3 or 4 carbon atoms. The radicals in question can be either linear or branched with single or multiple branching.

Lower alkyl is preferably alkyl with from and including 1 to and including 7 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms, and is linear or branched; for example, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tertbutyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Example lower alkyl is methyl, propyl or tert-butyl.

When the plural form is used for the compounds, salts and the like, it is also taken to mean an individual compound, salt or the like.

Any asymmetric carbon atom 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. The compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomerically pure diastereomers.

The invention also relates to possible tautomers of the disclosed compounds.

In view of the close relationship between heteroaryl aryl ureas in the free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of new compounds, tautomers or tautomeric mixtures and its salts, any reference hereinbefore or hereinafter to those compounds, should be understood as referring also to the corresponding tautomers of these compounds, or salts of any of these, as appropriate and subsequent and if nothing else is mentioned .

Tautomers, for example, may be present in cases where amino or hydroxy, each with at least one hydrogen bound, are attached to carbon atoms that are linked to adjacent atoms by double bonds (eg, keto-enol or imine tautomerism). enamina).

When "a compound is mentioned", a tautomer thereof; or a salt thereof ", this means," a compound ..., a tautomer thereof, or a salt of the compound or tautomer ".

By acyl is meant an organic radical corresponding to the residue of, for example, an organic acid from which the hydroxyl group has been removed, that is, a radical having the formula RC (O) -, where R may in particular be aliphatic or substituted aliphatic, or may for example be a substituted or unsubstituted mono or bicyclic ring. Thus, R may be selected from C1-C8 alkyl, C3-C7 cycloalkyl, phenyl, benzyl or phenethyl group. Among others, an example acyl is alkylcarbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. Lower acyl is for example formyl or lower alkylcarbonyl, in particular acetyl.

The aliphatic may have up to 20, for example up to 12, carbon atoms and is linear or branched one or more times; lower aliphatic, especially C1-C4 aliphatic, is preferred. The aliphatic structural units may be alkyl, alkenyl or alkynyl; the alkenyl and alkynyl may contain one or more, for example, one or two, unsaturated carbon carbon bonds.

Alkyl may have up to 20, for example up to 12, carbon atoms and is linear or branched one or more times; lower alkyl, especially C1-C4 alkyl, in particular methyl, ethyl or bi-propyl or t-butyl is preferred. Where alkyl can be substituted by one or more substituents independently selected from those mentioned above under the heading "substituents". Especially preferred is unsubstituted alkyl, preferably lower alkyl. The term "alkyl" also encompasses cycloalkyl as further defined below:

Alkyl can be optionally interrupted by one or more heteroatoms within the chain, for example, -O-, thus forming, for example, an ether bond.

Cycloalkyl is preferably C3-C10 cycloalkyl, especially cyclopropyl, dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl which is unsubstituted or substituted by one or more, especially 1, 2

or 3 substituents independently selected from the group consisting of the substituents defined above under the heading "substituents".

Alkenyl may have one or more double bonds and preferably has 2 to 20, more preferably up to 12, carbon atoms, is linear or branched one or more times (as much as possible in view of the number of carbon atoms). C2-C7 alkenyl, especially C3 or C4 alkenyl, such as allyl or crotyl, is preferred. The alkenyl may be unsubstituted or substituted, especially by one or more, more especially up to three, of the substituents mentioned above under the heading "substituents". Substituents such as amino or hydroxy (with a dissociable free hydrogen) are preferably not linked to carbon atoms that participate in a double bond, and also other substituents that are not sufficiently stable are preferentially excluded. Unsubstituted alkenyl, in particular C2-C7 alkenyl, is preferred.

Alkynyl is a preferable structural unit with one or more triple bonds and preferably has from 2 to 20, more preferably up to 12, carbon atoms; it is linear or branched one or more times (as much as possible in view of the number of carbon atoms). C2-C7 alkynyl is preferred, especially C3 or C4 alkynyl such as ethynyl

or propin-2-yl. The alkynyl may be unsubstituted or substituted, especially by one or more, more especially up to three, of the substituents mentioned above under the heading "substituents". Substituents such as amino or hydroxy (with a dissociable free hydrogen) are preferably not linked to carbon atoms that participate in a triple bond, and other substituents that are not sufficiently stable are also preferably excluded. Unsubstituted alkynyl is preferred, in particular C2-C7 alkynyl.

An aryl group is an aromatic radical and can be heterocyclic or carbocyclic. Preferably, aryl is carbocyclic and is linked to the molecule through a bond located on a carbon atom of the aromatic ring of the radical (or optionally linked through a linking group, such as -O- or -CH2-). Preferably aryl has a ring system of no more than 16 carbon atoms and is preferably mono- or tricyclic and can be completely or partially substituted, for example, substituted by at least two substituents. Preferably aryl is selected from phenyl, naphthyl, indenyl, azulenyl and antryl, and is preferably in each case unsubstituted or lower alkyl, especially methyl, ethyl or n-propyl, halo (especially fluoro, chloro, bromo or iodo), halo- lower alkyl (especially trifluoromethyl), hydroxy, lower alkoxy (especially methoxy), lower halo-alkoxy (especially 2,2,2-trifluoroethoxy), lower amino-alkoxy (especially 2-amino-ethoxy), lower alkyl (especially methyl or ethyl) carbamoyl, N- (lower alkyl hydroxy) -carbamoyl (especially N- (2-hydroxyethyl) -carbamoyl) and / or sulfamoyl substituted aryl, especially a corresponding phenyl substituted or unsubstituted phenyl. Also, heterocyclic groups may be mentioned herein, as defined below.

Any carbocyclic group especially comprises 3, 4, 5, 6 or 7 carbon atoms in the ring and can be aromatic (aryl) or non-aromatic. When the carbocycle is not aromatic, it can be saturated or unsaturated. Especially preferred carbocycles are phenyl, cyclohexyl and cyclopentyl.

Heterocyclyl (or heterocyclic group) is preferably a radical heterocyclic radical that is unsaturated, saturated or partially saturated and is preferably a monocyclic ring or in a broader aspect of the invention, bicyclic or tricyclic; it has 3 to 24, more preferably 4 to 16 ring atoms. Heterocycles may contain one

or more, preferably one to four, especially one or two ring-forming heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the ring preferably having 4 to 12, especially 5 to 7 ring atoms. The heterocycles may be unsubstituted or substituted by one or more, especially 1 to 3, substituents independently selected from the group consisting of the substituents defined above under the heading "Substituents". A heterocycle especially is a radical selected from the group consisting of oxyranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thiantrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, , imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, pyraniol, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, especially piperidin-1-yl, pyridyl-1-yl, pyridrazine , morpholinyl, especially morpholino, thiomorpholinyl, especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl , dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinolinyl, pteridinyl, carbazolyl, �-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenantholinyl, furazanyl, phenazinyl, phenoxyanzyl, phenyl, triazyl, yostyl, yinyl, yosinyl, yosinyl, yosinyl, yosinyl, yosinyl, yosinyl, yosinyl, yosinyl, yosinyl, yosinyl, y, nyl, yinyl, y, nyl, yinyl, y, nyl, y, n, yy, n, y, n, yy,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,. or substituted by one or two radicals selected from the group consisting of lower alkyl, especially methyl or tert-butyl, lower alkoxy, especially methoxy, and halo, especially bromine or chlorine. Unsubstituted heterocyclyl is preferred, especially piperidyl, piperazinyl, thiomorpholino or morpholino.

Any especially heterocyclic group comprises five or six chain atoms of which at least one is a heteroatom selected from N, O or S. Especially preferred heterocycles are pyridine, pyrrolidine, piperidine and morpholine. Mono or disubstituted terms may be an amino group substituted by one or more of the substituents as listed under the heading "Substituents" and can form a secondary amine group

or tertiary and / or is especially an amino having the formula NRK2, NRKOH, NRKCORK (eg NHCO-alQuil), NRKCOORK (eg NRKCOO-alQuil), NRKC (NRK) H (eg NHC (NH) H), NRKC (NRK ) NRKOH (eg NHC (NH) NHOH), NRKC (NRK) NRKCN, (eg NHC (NH) NHCN), NRKC (NRK) NRKCORK, (eg NHC (NH) NHCORK), NRKC (NRK) NRKR2, (eg NHC (NH) NHRK), N (COORK) C (NH2) = NCOORK, (eg N (COORK) C (NH2) = NCOORK), where each RK is selected

regardless of the substituents as listed under the heading "Substituents" and may be especially selected from hydrogen, hydroxy, alkyl, substituted alkyl, lower alkyl, such as methyl; lower hydroxyalkyl, such as 2-hydroxyethyl; halo-lower alkyl, lower alkoxy lower alkyl, such as ethyl methoxy; alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl. Substituted cycloalkyl, heteroaryl, heterocyclyl, lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, phenyl, phenyl-lower alkyl, such as benzyl or 2-phenylethyl.

Any Rk group may be substituted by the substituents as defined under the heading "Substituents" and the substituents may be selected from, preferably one or two of, nitro, amino, halogen, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower alkoxycarbonyl.

As such, exemplary substituted amino groups are N-lower alkylamino, such as N-methylamino, N, N-dialkylamino, N-lower alkylaminoamino-lower alkyl, such as aminomethyl or 2-aminoethyl, lower hydroxyalkylamino, such as 2- hydroxyethylamino or 2-hydroxypropyl, lower alkoxy lower alkyl, such as methoxy ethyl, phenyl-lower alkylamino, such as benzylamino, N, N-di-lower alkylamino, N-phenyl-lower alkyl-N-lower alkylamino, N, N- di-lower alkylphenylamino, lower alkanoylamino, such as acetylamino, benzoylamino, phenylalkoxycarbonylamino, carbamoyl or aminocarbonylamino, amino-lower alkyloxy-phenyl-amino, sulfamoylphenylamino, [N- (hydroxy-lower alkyl) -carbamoyl] -phenylamino. An example of a substituted amino is an amino substituted by a 4-substituted cyclohexyl, for example cyclohexan-4-ol.

A disubstituted amino can also be lower alkylene-amino, e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; oxaalkylene-lower amino, e.g. morpholine, or lower azaalkylene amino, e.g. N-substituted piperazino or piperazino, such as N-methylpiperazine, N-methoxycarbonylpiperazino, N-monosubstituted Carbamoyl or N, N-disubstituted, N-lower alkyl-carbamoyl or N- (lower hydroxy-alkyl) -carbamoyl, such as N- (2-hydroxyethyl) -carbamoyl. It is also contemplated that an alkanoylamino extends to carbamate, such as carbamic acid methyl ester.

Halogen (halo) is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine, most especially chlorine or fluorine.

Etherified hydroxy, especially C3-C20 alkyloxy, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy, halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic heteroaryl comprising one or two nitrogen atoms, preferably lower alkoxy which is substituted by imidazolyl, such as 1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3isoquinolinyl, quinolinyl, indolyl or thiazolyl.

Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tertbutoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy.

Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.

Alkanoyl is alkylcarbonyl, especially lower alkanoyl, e.g. acetyl. The alkyl part of the alkanoyl group can be substituted to form an R10 structural unit.

Carbamoyl N-Mono- or N, N-disubstituted is especially substituted by one or two substituents independently selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa lower alkylene

or lower alkylene aza optionally substituted on the terminal nitrogen atom.

The salts are especially pharmaceutically acceptable salts of the compounds of the formula (I) (or formulations of examples thereof), especially if they are forming salt forming groups.

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 amino, a secondary amino group that does not form a peptide bond or a pyridyl radical, can form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example mono or dicarboxylic aliphatic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, acid hydroximaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, carboxylic aromatic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4 aminosalicylic acid , aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, acid heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethanesulfonic acid, or aromatic sulfonic acids, for example benzene-, ptoluene or naphthalene-2-sulfonic acid. When several basic groups are present, mono or polyacid addition salts can be formed. Compounds having acidic groups, a carboxy group or a phenolic hydroxy group, can form metal or ammonium salts, such as alkali or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with suitable ammonia or organic amines, such as tertiary monoamines, for example triethylamine or tri- (2-hydroxyethyl) -amine, or heterocyclic bases, for example, N-ethylpiperidine or N, N'-dimethylpiperazine. Salt mixtures are possible

Compounds that have both acidic and basic groups can form internal salts.

For the purposes of isolation or purification, as well as in the case of compounds that are additionally used as intermediates, it is also possible to use pharmaceutically unacceptable salts, for example picrates. However, pharmaceutically acceptable, non-toxic salts can be used for therapeutic purposes, and those salts are therefore preferred.

Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of the Formula (I) (or an example formula thereof) with a basic denitrogen atom, especially the salts pharmaceutically acceptable. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, acid pimelic, subic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroximaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, acid 4 aminosalicylic, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene acid -disulfonic acid, 2-, 3-or 4-methylbenzenesulfonic acid, methylsulfuric acid, e acid tilsulfuric, dodecylsulfuric acid, N-cyclohexylsulfamic, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, for example, 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 suitable organic amines, such as tertiary monoamines, for example, triethylamine or tri (2-hydroxyethyl) amine, or heterocyclic bases, for example N-ethylpiperidine or N, N'-dimethylpiperazine.

When a basic or acidic group is present in the same molecule, a compound of formula (I) (or an example formula thereof) can also form internal salts.

For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are used (when applicable in the form of pharmaceutical preparations), and therefore these are preferred.

In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the new compounds, any reference to the compounds Free above or hereafter should be understood as referring also to the corresponding salts, as appropriate and consistent.

The compounds of the formula (I) (or example formulas thereof) and N-oxides thereof have valuable pharmacological properties, as described above and hereafter.

biology

The efficacy of the compounds of the invention as inhibitors of Bcr-Abl, EGF-R, VEGF-R2 (KDR) and FGFR3 (KDR) as a tyrosine kinase receptor can be demonstrated as follows:

Test for activity against Bcr-Abl:

The murine 32Dcl3 myeloid progenitor cell line transfected with the expression vector p210 Bcr-Abl pGDp210Bcr / Abl (32D-bcr / abl) was obtained from J. Griffin (Dana Faber Cancer Institue, Boston, MA, USA). The cells express the Bcr-Abl fusion protein with a consecutively active abl kinase and an independent proliferation growth factor. The cells are expressed in RPMI 1640 (AMIMED), 10% fetal calf serum, 2 mM glutamine (Gibco) ("complete medium"), and a working pool is prepared by freezing aliquots of 2 x 106 cells per vial in a freezing medium (95% FCS, 5% DMSO (Sigma)). After thawing, the cells are used for a maximum of 10 to 12 steps for the experiments. The anti abl SH3 antibody domain catalog # 05-466 from Upstate Biotechnology is used for ELISA. For the detection of phosphorylation of bcr-abl, the alkaline phosphatase antibody PY20, labeled with alkaline phosphatase (PY10 (AP)) of ZYMED (catalog # 03-7722) is used. By way of comparison and reference compound, (N- {5- [4- (4-methyl-piperazino-methyl) benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidine-amine is used , in the form of methane sulphonate (monomesylate) salt (STI571) (marketed as Gleevec® or Glivec®, Novartis.) A stock solution of 10 mM in DMSO is prepared and stored at -20 ° C. For cell tests, The stock solution is dissolved in complete medium in two stages (1: 100 and 1:10) to produce a starting concentration of 10 μM followed by the preparation of serial dilutions three times in complete medium No solubility problems were found using This procedure The test compounds are treated analogously For the test, 200,000 32D-bcr / abl cells are planted in 50 μl per well in 96-well round-bottom tissue culture plates 50 μl per well are added of the three-fold serial dilutions of the test compound to the cells in triplicates. The final test compound varies, for example, from 5 μm to 0.01 μm. Untreated cells are used as control. The compound is incubated together with the cells for 90 minutes at 37 ° C, 5% CO2, followed by centrifugation of the tissue culture plates at 1300 rpm (Beckman GPR centrifuge) and removal of supernatants with careful aspiration being careful not to withdraw None of the cells in pella. The cell pellets are lysed by the addition of 150 μl of lysis regulator (50 mM Tris / HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40 (non-ionic detergent) , Roche Diagnostics GmbH, Mannheim, Germany), 2 mM sodium orthovanadate, 1 mM phenylmethyl sulfonylfluoride, 50 μg / ml aprotinin and 80 μg / ml leupeptin), and was used immediately for ELISA or stored frozen at -20ºC until use. The anti-abl SH3 domain antibody is coated with 200 ng in 50 µl of PBS per well in black ELISA plates (Packard HTRF-96 black plates; 6005207) overnight at 4 ° C. After washing 3 times with 200 μl / well of PBS containing 0.05% of Tween 20 (PBST) 0.5% of TopBlock (Juro, catalog # TB 232010), the residual binding sites of the protein are blocked with 200 μl / well of PBST, 3% TopBlock for 4 hours at room temperature, followed by incubation with 50 μl of untreated cell lysates or test compound (20 μg of total protein per well) for 3-4 hours at 4 ° C. After 3 washes, 50 μl / well of PY20 (AP) (Zymed) diluted to 0.5 μg / ml in blocking regulator is added and incubated overnight (4 IC). For all incubation stages, the plates are coated with plate sealers (Costar, catalog # 3095). Finally the plates are washed another three times with a wash regulator and once with deionized water before the addition of 90 μl / well of the AP CPDStar TAU substrate with Emerald II. The plates now sealed with Packard Top Seal ™ -A plate sealers (catalog # 6005185) are incubated for 45 minutes at room temperature in the dark and the luminescence is quantified by measuring the counts per second (CPS) with a microplate scintillation counter Packard Top Count. For the final optimized version of the ELISA, 50 µl of the lysates of the cultured, treated and lysed cells are transferred in 96-well tissue culture plates, directly from these plates to the ELISA plates that are precoated with 50 ng / well of domain AB 06-466 rabbit anti-abl-SH3 polyclonal. The concentration of AB PY20 (AP) antiphosphotyrosine can be reduced to 0.2 μg / ml. Washing, blocking and incubation of the luminescent substrate is done as indicated above. Quantification is achieved as follows: The difference between the ELISA reading (CPS) obtained from the lysates of the untreated 32D-bcr / abl cells and the reading of the background assay (all components, but without cell lysate) 100% reflection of the phosphorylated bcr-abl protein constitutively present in these cells is calculated and taken. The activity of the compound in the activity of bcr-abl kinase is expressed as a percentage reduction of phosphorylation of bcr-abl. The values for the IC50 are determined from the dose response curves by inter or graphic extrapolation. The compounds of the invention here preferably show IC50 values in the range of 15 nm to 500 μM, most preferably 15 nm to 200 μM.

For cell assays, the compounds are dissolved in DMSO and diluted with complete medium to produce a starting concentration of 10 μM followed by the preparation of 3-fold serial dilutions in complete medium. 32D or Ba / F3 cells that expressed either mutants "wt" -Bcr-Abl or Bcr-Abl (eg, T-315-I) were seeded at 200,000 cells in 50 µl of complete medium per well in culture plates of round bottom fabrics of 96 wells. 50 µl per well of the 3-fold serial dilutions of the test compound were added to the triplicate cells. As control untreated cells were used. The compound is incubated together with the cells for 90 minutes at 37 ° C, 5% CO2, followed by centrifugation of the culture plates at 1300 rpm (Beckmann GPR centrifuge) and removal of the supernatants by careful aspiration being careful not to remove any of The cell pellets. The cell pellets are lysed by the addition of 150 μl of lysis regulator (50 μM Tris / HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1% NP-40, orthovanadate 2 mM sodium, 1 mM PMSF, 50 mg / ml aprotinin and 80 mg / ml leupeptin) and were either used immediately for ELISA or stored frozen in plates at -20 ° C until use.

The Upstate rabbit polyclonal anti-abl-SH3 Ab 06-466 domain was coated at 50 ng in 50 µl of PBS per well in black ELISA plates (Packard HTRF-96 black plates; 6005207) overnight at 4 ° C. After washing three times with 200 μl / well, containing 0.05% Tween 20 (PBST) and 0.5% TopBlock (Juro), the residual binding sites of the protein were blocked with 200 μL / PBST well, 3% of TopBlock for 4 hours at room temperature followed by incubation with 50 μL of lysates from untreated or treated cells with the compound (20 μg of total protein per well) for 3-4 hours at 4 ° C. After three washes, 50 μl / well of Ab PY20 (AP) antiphosphotyrosine with alkaline phosphatase (Zymed) diluted to 0.2 μg / ml was labeled: a blocking regulator is added and incubated overnight (4 ° C). For all stages of incubation the plates are covered with plate sealants (Costar). Finally, the plates were washed another three times with a wash regulator and once with deionized water before the addition of 90 μl / well of the AP CDPStar TAU substrate with Emerald II. The plates, now sealed with the TopSeal ™ -A Packard were incubated for 45 minutes at room temperature in the dark and the luminescence was quantified by measuring the counts per second (CPS) with a Packard Top Count (Top Count) microplate scintillation counter .

The difference between the ELISA reading (CPS) obtained for the lysates of the untreated 32D-Bcr / Abl cells and the reading of the background assay (all components, but without cell lysate) is calculated by taking as 100% reflection the Constitutively phosphorylated Bcr-Abl protein present in cells. The activity of the compound on the activity of Bcr-Abl kinase is expressed as a percentage reduction of phosphorylation of Bcr-Abl. The IC50 (and IC60) values are determined from the dose response curves by graphic extrapolation.

The compounds of the invention preferably here show IC50 values below 500 nm for inhibition of autophosphorylation and inhibition of IL-3 independent proliferation of Bcr-Abl mutants in cells transfected with Ba / F3, in particular T315I .

32D cl3 cells were obtained from the American Type Culture Collection (ATCC CRL11346) and Ba / F3 cells from the German Collection of Microorganisms and Cell Cultures (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 32D cl3 hematopoietic murine cells (32D p210 cells) were obtained by transfecting the IL-3-dependent murine Ba / F3 cell line with a pGD vector containing p210BCR-ABL (B2A2) cDNA

Daley and Baltimore, 1988; Sattler et al., 1996; Okuda et al., 1996.

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 85.9312-9316

Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E, et al. (1996) The protooncogene product p120CBL and the adapter proteins CRKL and c-CRK link c-ABL, p190BCR-ABL and p210BCR-ABL to the phosphatidilinositol-3 ’kinase pathway. Oncogene 12, 839-46.

Okuda K, Golub TR, Gilliland DG, Griffin JD. (1996) p210BCR-ABL, p190BCR-ABL, and TEL / ABL activate similar signal transduction pathways in hematopoietic cell lines. Oncogene 13, 1147-52.

Test for activity against c-KIT

The pFbacG01 vector of GIBCO donor of baculovirus was used to generate a recombinant baculovirus that expresses the amino acids of the amino acid region 544-976 of the cytoplasmic kinase domains of human c-KIT. The coding sequences for the cytoplasmic domain of c-Kit is amplified by PCR from a human uterus cDNA library (Clontech). The amplified DNA fragment and the vector pFbacG01 were made compatible by ligation by digestion with BamH1 and EcoRI. Ligation of these DNA fragments resulted in the donor c-Kit baculovirus plasmid. Virus production, protein expression in Sf9 cells and purification of fused proteins in GST were carried out as follows:

Virus production: The transfer vector pFbacG01-c-Kit containing the c-Kit kinase domain is transfected into the DH10Bac cell line (GIBCO) and the transfected cells are plated on plates on selective agar plates Colonies without insertion of the Fusion sequence in the viral genome (carried by the bacteria) are blue. The individual white colonies are selected and the viral DNA (bacmid) of the bacteria is isolated by standard plasmid purification procedures. The Sf9 cells or the Sf21 American Type Culture Collection cells are then transferred in 25 cm3 flasks with the viral DNA using the Cellfectin reagent.

Determination of small-scale protein expression in Sf9 cells: The medium containing the virus is collected from the culture of transfected cells and used for infection in order to increase its titer. Media containing the virus obtained after two rounds of infection is used for large-scale protein expression. For a large-scale protein expression, 100 cm2 round tissue culture plates are seeded with 5 x 107 cells / plate and infected with 1 ml of virus-containing medium (approximately 5 MOIs). After 3 days the cells are scraped off the plate and centrifuged at 500 rpm for 5 minutes. The 10-20 x 100 cm2 cell pellets are resuspended in 50 ml of cold ice lysis regulator (25 mM Tris-HCl, pH 7.5. 2 mM EDTA, 1% NP-40, 1 mM DTT, PMSF 1 mM). The cells are shaken on ice for 15 minutes and then centrifuged at 5000 rpm for 20 minutes.

Purification of GST-targeted protein: The centrifuged cell lysate is loaded onto a 2 ml glutathione phosphate column (Pharmacia) and washed three times with 10 ml of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The GST-labeled protein is eluted with 10 applications (1 ml each) of Tris-HCl, pH 25 25 mM, 10 mM reduced glutathione, 100 mM NaCl, 1 mM DTT, 10% glycerol and stored at -70 ° C.

Kinase test: The tyrosine protein kinase assays were purified with GST-c-Kit being carried out in a final volume of 30 ml containing 200-1800 ng of enzymatic protein (depending on the specific activity), Tris-HCl, pH 7.6 20 mM, 3mM MnCl2, 3 mM MgCl2, 1 mM DTT, 4 mg Na3VO410, 4 mg / ml 4: 1 poly, 1% DMSO, 1.0 μM ATP and 0.1 μCi [l33P] ATP. The activity is assayed in the presence or absence of inhibitors by measuring the incorporation of 33P from [l33P] ATP into the 4: 1 poly (Glu, Tir) substrate. The test (30 μl) is carried out in 96-well plates at room temperature for 20 minutes under conditions described below and terminated by the addition of 20 μl of 125 mM EDTA. Subsequently, 40 μl of the reaction mixture is transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA), previously immersed for 5 minutes in methanol, rinsed with water, then immersed for 5 minutes with H3PO4 at 0.5% and mounted on a vacuum distributor with vacuum source disconnected. After detecting these samples, it is connected in vacuo and each well is rinsed with 200 μl of 0.5% H3PO4. The membranes are removed and washed 4 times on a shaker with 1.0% H3PO4 and once with ethanol. The membranes are counted after drying at room temperature, mounted on a 96-well Packard TopCount frame, and the addition of 10 μl / well of Microscint TM (Packard). IC50 values will be calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, at four concentrations (usually 0.01, 0.1, 1 and 10 μm). One unit of protein kinase activity is defined as a 33 mol of PATP transferred from [l33P] ATP to the protein substrate per minute per mg of protein at 37 ° C.

Test for activity against EphB4

The efficacy of the compounds of the formula I as inhibitors of the Efrin B4 receptor kinases (EphB4) can be demonstrated as follows:

Generation of Bac-to-Bac ™ (Invitrogen Life Technologies, Basel, Switzerland) GST fusion expression vectors: The complete cytoplasmic coding regions of the EphB class are amplified by PCR from cDNA libraries derived from placenta or brain human, respectively. Recombinant Baculoviruses are generated that express the 566-987 amino acid region of the human EphB4 receptor (SwissProt Database, Accession No. P54760). The GST sequence is cloned into the pFastBac1® vector (Invitrogen Life Technologies, Basel, Switzerland) and amplified by PCR. The cDNAs encoding the EphB4 receptor domains, respectively, are cloned in the 3'prim framework primer to the GST sequence in their modified FastBac1 vector to generate the pBAC-to-Bac ™ donor vectors. The individual colonies that arise from the transformation are inoculated to give overnight cultures for small-scale plasmid preparation. Analysis of restriction enzymes of the DNA plasmid reveals several clones containing inserts from the expected sites. By automated sequencing the inserts of approximately 50 bp of the flank vector sequences are confirmed in both chains.

Virus production: Viruses for each of the kinases are made according to the protocol provided by GIBCO if nothing else is established. To summarize, transfer vectors containing the kinase domains are transfected into the DH10Bac (GIBCO) cell line and plated on selective agar plates. Colonies without insertion of the fusion sequence into the viral genome (carried out by bacteria) are blue. The individual white colonies are selected and the viral DNA (bacmido) is isolated from the bacteria by standard plasmid purification procedures. Sf9 or Sf21 cells are transfected in 25 cm2 flasks with the viral DNA using the Cellfectin reagent according to the protocol.

Purification of GST labeled kinases: The centrifuged cell lysate is loaded onto a 2 μl glutathione-sepharose column (Pharmacia) and washed three times with 10 ml of TrisHCl, pH 7.5 25 mM, 2 mM EDTA, 1 mM DTT, NaCl 200 mM The labeled GST proteins are then eluted for 10 applications (1 ml each) of 25 mM Tris-HCl, pH 7.5, 10 mM reduced glutathione, 100 mM NaCl, 1 mM DTT, 10% glycerol and stored at -70 ° C.

Protein kinase tests: Protein kinase activities are tested in the presence or absence of inhibitors, measuring the incorporation of 33P from [l33P] ATP into a polymer of glutamic acid and tyrosine (poly (Glu, Tir)) as a substrate . Kinase tests with purified GST-EphB (30ng) are carried out for 15-30 minutes at room temperature in a final volume of 30 μl containing 20 mM Tris HCl, pH 7.5, 10 mM MgCl2, 3-50 mM MnCl2 , 0.01 mM Na3VO4, 1% DMSO, 1 mM DTT, 3 μg / mL poly (Glu, Tyr) 4: 1 (Sigma; St. Louis, Mo., USA) and 2.0-3.0 μM ATP (l- [33P] -ATP 0.1 μCi). The test is terminated by the addition of 20 μl of 125 mM EDTA.

Subsequently, 40 μl of the reaction mixture is transferred onto the Immobilon-PVDF membrane (Millipore, Bedford, MA, USA), previously immersed for 5 minutes in methanol, rinsed with water, then immersed for 5 minutes with H3PO4 at 0.5% and mounted on a vacuum distributor with the vacuum source disconnected. After observing all the samples, it is connected to the vacuum and each well rinsed well with 200 μl of 0.5% H3PO4. The membranes are removed and washed 4 times on a stirrer with 1.0% H3PO4 and once with ethanol. The membranes are counted after drying at room temperature, assembling a Packard TopCount96 well frame and also 10 μl / well of Microscint ™ (Packard). The IC50 values were calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate at four concentrations (usually 0.01, 0.1, 1 and 10 μm). One unit of protein kinase activity is defined as 1 nmol of 33P ATP transferred from [l33P] ATP to the substrate protein per minute per mg of protein at 37 ° C.

Test for activity against EGF-R:

Inhibition of the activity of EGF-R tyrosine kinase can be demonstrated using known methods, for example using the recombinant intracellular domain of EGF receptor [EGF-R ICD; see, for example E. McGlynn et al., Europ. J. Biochem. 207, 265-275 (1992)]. Compared to control without inhibitor, the compounds of the formula I inhibit enzyme activity by 50% (IC50), for example in a concentration ranging from 0.0005 to 0.5 μM, especially 0.001 to 0.1 μM.

Just as or instead of inhibiting the activity of EGF-R tyrosine kinase, the compounds of formula I also inhibit other members of the receptor family, such as ErbB-2. The inhibitory activity (IC50) is approximately in the range of 0.001 to 0.5 μM. The inhibition of ErbB-2 tyrosine kinase (HER-2) can be determined, for example, analogously to the method used for the EGF-R tyrosine kinase protein [see C. House et al., Europ. J. Biochem. 140, 363-367 (1984)]. ErbB-2 kinase can be isolated, and its activity determined, by means of protocols known per se, for example according to T. Akiyama et al., Science 232, 1644 (1985).

Test for activity against VEGF-R2 (KDR):

The inhibition of VEGF-induced receptor autophosphorylation can be confirmed with an additional in vitro experiment in cells such as transfected CHO cells, which are permanently expressed in the human VEGF-R2 receptor (KDR), which are seeded in complete culture medium ( with 10% fetal calf serum = FCS) in 6-well cell culture plates and incubate at 37 ° C under 5% CO2, until they show approximately 80% confluence. The compounds to be tested are then diluted in culture medium (without FCS, with 0.1% bovine serum albumin) and added to the cells. (Controls comprise medium without test compound). After 2 hours of incubation at 37 ° C, recombinant VEGF is added; The final concentration of VEGF is 20 ng / ml. After an additional 5 minutes of incubation at 37 ° C, the cells are washed twice with ice-cold PBS (phosphate-regulated saline solution) and immediately lysed in 100 µl of lysis regulator per well. The lysates are then centrifuged to remove cell nuclei, and protein concentrations of the supernatants are determined using a commercial protein test (BIORAD). The lysates can then be used immediately or, if necessary, stored at -20 ° C.

A sandwich ELISA is carried out to measure phosphorylation of VEGF-R2: a monoclonal antibody to VEGF-R2 is immobilized (for example Mab 1495.12.14; prepared by H. Towbin, Novartis or a comparable monoclonal antibody) on plaques of Black ELISA (Packard OptiPlateTM HTRF-96). The cells are then washed and the remaining protein-free sites are saturated with 3% TopBlock® (Juro catalog No TB232010) in phosphate saline solution with Tween 20® (polyoxyethylene monolaurate (20) sorbitan, ICI / Uniquema) (PBST ). Cell lysates (20 μg of protein per well) are then incubated in these plates overnight at 4 ° C together with an alkaline phosphatase-coupled antiphosphotyrosine antibody (PY20: Zymed AP). The plates are washed again and the binding of the antiphosphotyrosine antibody to the captured phosphorylated receptor is then demonstrated using a luminescent AP substrate (CDP-Star, ready to use, with Emerald II; Applied Biosystems). The luminescence is measured in a Packard Top Count Microplate Scintillation Counter. The difference between the positive control signal (stimulated with VEGF) and that of the negative control (not stimulated with VEGF) corresponds to the phosphorylation of VEGF-R2 induced by VEGF (= 100%). The activity of the tested substances is calculated as percentage inhibition of VEGF-R2 phosphorylation induced by VEGF, where the concentration of substance that induces half of the maximum inhibition is defined as the IC50 (single dose for 50% inhibition) .

Activity test against recombinant protein kinases Ret (Ret-Men2A), Tie-2 (Tek) and FGFR3-K650E:

Cloning and expression of recombinant protein kinases: (Ret); the donor vector of baculovirus pFB-GSTX3 was used to generate a recombinant baculovirus expressing the B58-1072 amino acid region of the human Ret-Men2A intracytoplasmic kinase domain corresponding to the wild type kinase domain of Ret. The coding sequence for the cytoplasmic domain of Ret was amplified by PCR from the pure pBAB plasmid Ret-Men2A which was received from Dr. James Fagin, College of Medicine, University of Cincinati (collaboration for NovaTAis). The amplified DNA fragments and the vector pBF-GSTX3 became compatible for ligation by digestion with Sall and Kpnl. Ligation of these DNA fragments resulted in the donor plasmid of baculovirus pFB-GX3-Ret (-Men2A).

(Tie-2 / Tek): The baculovirus donor vector pFbacG01 was used to generate a recombinant baculovirus that expressed the amino acids of the 773-1124 amino acid region of the human Tek cytoplasmic kinase domain, fused by the N to GST terminal ( provided by Dr. Marmè, Institute of Molecular Medicine, Freiburg, Germany based on a research collaboration). The Tek was recloned in the transfer vector pFbacG01 by cleavage of EcoRl and ligation with pFbacG01 digested with EcoRI (FBG-Tie2 / Tek).

(FGFR-3-K650E): The baculovirus donor vector pFastbacGST2 was used to generate a recombinant baculovirus that expressed amino acids from the amino acid region (aa) 411-806 of the cytoplasmic domain of FGFR-3 fused through an N terminal with GST (provided by Dr. Jim Griffin, Dana Farber Cancer Institute, Boston, USA based on research collaboration). The DNA encoding amino acids 411-806 was amplified by PCR, inserted into the vector pFastbac-GT2 to produce pFB-GT2-FGFR3-wt. The plasmid in turn was used to generate a vector encoding FGFR3 (411-806) without a mutation in K650 using the Stratagene XL-Site mutagenesis kit to produce pFB-GT2-FGFR3-K650E. Virus production, protein expression in Sf9 cells and purification of cells fused with GST were carried out as described in the following sections.

Virus production: Transfer vectors containing the kinase domains were transfected into the DH10Bac cell line (GIBCO) and seeded on plates on selective agar plates. Colonies without insertion of the fusion sequence in the viral genome (carried by bacteria) are blue. Individual white colonies were selected and the viral DNA (bacmid) was isolated from the bacteria by standard plasmid purification procedures. Sf9 cells or Sf21 cells were then transfected in 25 cm3 flasks with the viral DNA used by the Cellfectin reagent.

Determination of small-scale protein expression in Sf9 cells: Media containing the virus was collected from the transfected cell culture and used for infection in order to increase its titer. Media containing the virus obtained after two rounds of infection were used for large-scale protein expression. For large-scale protein expression, 100 cm2 round tissue culture plates were seeded with 5x107 cells / plates and infected with 1 ml of medium containing virus (approx. 5 Mois). After 3 days the cells were scraped off the plate and centrifuged at 500 rpm for 5 minutes. The cell pellets of 10-20 100 cm2 plates were resuspended in 50 ml of the ice-cold lysis regulator (25mMTris-HCl, pH7.5, 2mMEDTA, 1% NP-40, 1mM DTT, 1mMP MSF). The cells were shaken on ice for 15 minutes and then centrifuged at 5000 rpm for 20 minutes.

Purification of GST-labeled proteins: The centrifuged cell lysate was loaded onto a 2 ml column of glutathione sepharose and washed three times with 10 ml of 25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The GST-labeled proteins were then eluted with 10 applications (1 ml each of 25 mM tris-HCl, pH 7.5, 10 mM reduced glutathione, 100 mM NaCL, 1 mM DTT, 10% glycerol and stored at 70 ° C .

Measurement of enzyme activity: Tyrosine protein kinase tests with purified GST-Ret, GST-Tek or GST-FGFR-3-K650E were carried out in a final volume of 30 μL with final concentrations of the following components: Ret included 15 ng of GST-Ret, 20 mM Tris-HCl, pH 7.5, 1 mM MnCl2, 10 mM MgCl2, 1 mM DTT, 3 mg / mL poly (Glu, Tyr) 4: 1, 1% DMSO and 2.0 mM ATP ( l- [33P] -ATP 0.1 mCi). Tek included 150 ng of GST-Tek, 20 mM Tris-HCl, pH 7.5, 3 mM MnCl2, 3 mM MgCl2, 1 mM DTT, 0.01 mM Na3VO4, 250 mg / mL PEG 20'000, 10 mg / mL poly (Glu , Tyr) 4: 1, 1% DMSO and 4.0 mM ATP (l- [33P] -ATP 0.1 mCi). FGFR-3-K650E including 10 ng of GST-FGFR-3-K650E, 20 mM Tris-HCl, pH 7.5, 3 mM MnCl2, 3 mM MgCl2, 1 mM DTT, 0.01 mM PEG 20'000, 10 mg / mL poly (Glu, Tyr) 4: 1; 1% DMSO and 4.0 mM ATP (l- [33P] -ATP 0.1 mCi). The activity was tested in the presence or absence of inhibitors, measuring the incorporation of 33P of [l33P] ATP in poly (Glu, Tyr) 4: 1. The test was carried out in 96-well plates at room temperature for 30 minutes under the conditions described below and was determined by the addition of 50 µL of 125 mM EDTA. Subsequently, 60 μL of the reaction mixture was transferred onto an Immobilon-PVDF (Millipore) membrane previously immersed for 5 minutes in methanol, rinsed with water, then immersed for 5 minutes in 0.5% H3PO4 and mounted on a vacuum distributor with vacuum source disconnected. After sowing all the samples, the vacuum was connected and each well was rinsed with 200 μL of 0.5% H3PO4. The membranes were removed and washed four times on a stirrer with 1.0% H3PO4, once with ethanol. The membranes were counted after drying at room temperature, mounted on a 96-well Packard TopCount frame, and the addition of 10 μL / well of Microscint TM (Packard). IC50 values were calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, at 4 concentrations (usually 0.01, 0.1, 1 and 10 μM). One unit of protein kinase activity is defined as a 33P ATP nmol transferred from [l33P] ATP to the substrate protein per minute per mg of protein at 37 ° C.

On the basis of the inhibitory studies described herein, a compound of the formula (I) or (I *) or (example formulas thereof) according to the invention shows therapeutic efficacy especially against protein kinase dependent disorders, especially proliferative diseases

The heteroaryl aryl ureas useful in accordance with the invention, especially the compounds of the formula (I) (or example formulas thereof), which inhibit the activities of the protein kinase mentioned especially the tyrosine protein kinases mentioned above and below, they can therefore be used for the treatment of protein kinase dependent diseases. Protein kinase-dependent diseases are especially proliferative diseases, preferably benign or especially malignant tumors (for example carcinoma of the liver, adrenal glands, bladder, breast, stomach, ovaries, colon, rectum, prostate, pancreas, lungs, vagina or thyroid, sarcoma, glioblastomas and numerous tumors of the neck and head, as well as leukemia). They are able to approach the regression of tumors and prevent the formation of tumor metastases and the growth of metastases (also micro). They can also be used in epidermal hyperproliferation (for example, psoriasis), in prostatic hyperplasia and in the treatment of neoplasms, especially epithelial, for example breast carcinoma. It is also possible to use the compounds of the formula (I) (or example formulas thereof) in the treatment of diseases of the immune system in which several or, especially, individual tyrosine protein kinases are involved; additionally, the compounds of the formula (I) (or formulas of examples thereof) can be used in the treatment of diseases of the central or peripheral nervous system where signal transmission by at least one tyrosine protein kinase, especially selected from those specifically mentioned.

The expression of FGFR1 (also known as "Fig"), FGFR2 (also known as "Bek"), and the like belonging to a family of fibroblast growth factor receptors is reported as present in various cancers such as tumors of brain, lung cancer, breast cancer, gastric cancer, head and neck cancer, and prostate cancer (Proc. Natl. Acad. Sci. USA, 87: 5710-5714 (1990); Oncogene. 1997 August 14; 15 ( 7): 817-26; Cancer Res. 1994 January 15; 54 (2): 523-30; Cancer Res. 1992 February 1; 52 (3): 571-7). In particular, it is reported for gastric cancer that overexpression of FGFR2 correlates with poor prognosis mainly in poorly differentiated cancers such as cancers of gastric scirrhus. (lin Cancer Res. 1996 August; 2 (8): 1373-81; J Cancer Res Clin Oncol. 2001 April; 127 (4): 207-16; Int Rev Cytol. 2001;

204: 49-95). Additional diseases associated with FGFR1 and FGFR4 are diabetes and obesity.

The diseases related to FGFR1, FGFR2, FGFR3 and FGFR4 have been described here previously under the heading "BACKGROUND", and as inhibitors of these kinases the compounds of the invention can find application in the treatment of those diseases.

As inhibitors of VEGF tyrosine kinase receptor activity, the compounds of the invention can primarily inhibit blood vessel growth and are therefore, for example, effective against a number of diseases associated with deregulated angiogenesis, especially diseases caused. by ocular neovascularization, especially retinopathies, such as diabetic retinopathy or age-related macula degeneration, psoriasis, hemangioblastoma, such as hemangioma, mesangial cell proliferative disorders, such as chronic or acute renal diseases, for example, diabetic kidney disease, malignant nephrosclerosis , thrombotic microangiopathy syndromes or transplant rejection, or especially inflammatory renal diseases, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, hemolytic-uremic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, re arterial stenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma and especially neoplastic diseases (solid tumors, but also leukemias and other "liquid tumors", especially those that express KDR), such as especially breast cancer, colon cancer, cancer of lungs (especially small cell lung cancer), prostate cancer or sarcoma is Kaposi. A compound of the formula

(I) or (or example formulas thereof) (or an n-oxide thereof) inhibits the growth of tumors and is especially suitable for preventing metastatic dispersion of tumors and the growth of micrometastases.

The two vascular endothelial growth factor receptor (VEGF-R2; KDR) is selectively expressed in the primary vascular endothelium and is essential for normal vascular development. In order to grow beyond their minimum size, tumors must generate new vascular supply. Angiogenesis, or the outbreak of new blood vessels, is a central process in the growth of solid tumors. For many types of cancer, the degree of vascularization of a tumor is a negative prognostic indicator that means aggressive disease and the potential increase in metastasis. Recent efforts to understand the molecular basis of tumor-related angiogenesis have identified several potential therapeutic agents, including the tyrosine kinase receptor for vascular endothelial growth factor of angiogenic factor (VEGF) (see Zeng et al.,

J. Biol. Chem. 276 (35), 32714-32719 (2001)). The heteroaryl aryl ureas according to the present invention, especially the compounds of the formula (I) (or example formulas thereof) for use as KDR inhibitors are thus especially suitable for therapy of diseases related to VEGF receptor overexpression. of tyrosine kinase. Among these diseases, especially retinopathies, age-related macula degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory diseases, such as rheumatoid or rheumatic inflammatory diseases, especially arthritis, such as rheumatoid arthritis, or other chronic disorders, are especially important. , such as chronic asthma, arterial or post-transplant atherosclerosis, endometriosis and especially neoplastic diseases, for example, so-called solid tumors (especially cancers of the gastrointestinal tract, pancreas, sinus, stomach, cervix, bladder, kidney, prostate, ovaries, endometrium , lungs, brain, melanoma, Kaposi's sarcoma, squamous cell carcinoma of the head and neck, malignant pleural mesoterioma, lymphoma or multiple myeloma) and liquid tumors (for example leukemia).

In particular, the present invention is relevant to the use of a compound of the formula I for the manufacture of a medicament for the treatment of a proliferative disorder, a skeletal disorder, a cancer, a solid tumor, especially an epithelial cancer, a disease inflammatory or autoimmune T-cell mediated.

In chronic myelogenous leukemia (CML), a reciprocally balanced chromosomal translocation in hematopoietic stem cells (HCS) produces the hybrid BCR-ABL gene. The latter encodes the oncogenic fusion protein Bcr-Abl. While ABL encodes a tightly regulated tyrosine kinase protein, which plays a fundamental role in regulating cell proliferation, adhesion and apoptosis, the BCR-ABL fusion gene encodes a constitutively activated kinase, which transforms HSC to produce a phenotype. It exhibits deregulated clonal proliferation, reduced capacity to adhere to the stroma of the bone marrow and reduces the apoptotic response to mutagenic stimuli, allowing more malignant transformations to accumulate progressively. The resulting granulocytes fail to develop into mature lymphocytes and are released into the circulation, leading to a deficiency in mature cells and an increased susceptibility to infection. Competitive Bcr-Abl ATP inhibitors have been described in a manner that prevents mitogenic activation of the kinase and antiapoptotic pathways (e.g., P-3 and SATT5 kinase), leading to the death of Bcr-Abl phenotype cells and therefore providing an effective therapy against CML. The heteroaryl aryl ureas according to the present invention, especially the compounds of the formula (I) (or example formulas thereof) are therefore especially suitable for the therapy of diseases related to their overexpression, especially leukemia, such as leukemia, for example CML or ALL.

The compounds of the formulas l *, ll *, lll *. IV *, V *, V *, VII *, VIII * or IX * (or example formulas thereof), in view of their activity as PDGF receptor inhibitors, are also especially suitable for the treatment of proliferative diseases, especially small cell lung cancer, atherosclerosis, thrombosis, psoriasis, scleroderma or fibrosis.

There are also experiments that demonstrate the antitumor activity of the compounds of the formula (I) (or example formulas thereof) in vivo. Live antitumor activity is tested, for example using breast carcinoma cell lines, such as human estrogen-dependent breast carcinoma (MCF-7 (ATCC: HTB22) or ZR-75-1 (ATCC: CRL1500), or estrogen independent breast carcinomas MDA-MB468 (ATCC: HTB132) or MDA-MB231 (ATCC: HTB26); colon carcinoma cell lines (205 (ATCC: CCL222); glioblastoma cell lines, such as U-glioblastomas) 87MG (ATCC: HTB14) or U-373MG (ATCC: HTB17); lung carcinoma cell lines, such as small cell lung carcinomas (NCI-H69 (ATCC: HTB119) or NCl-H209 (ATCC: HTB172) , or NCI-H596 lung carcinoma (ATCC: HTB178): skin tumor cell lines, such as Hs294T (ATCC: HTB140) or A375 (ATCC: CRL 1619) melanomas; tumor cell lines of the genitourinary system, such as NIH-Ovcar3 ovarian carcinoma (ATCC: HTB161), as well as DU145 (ATCC: HTB81) or PC-3 prostate carcinomas (ATCC: CR L 1435), or T24 bladder carcinoma (ATCC: HTB4); epithelial carcinomas, such as KB31 epithelial carcinoma; or (especially with respect to leukemia) K562 cells (American Type Culture Collection, Mannassas, VA) or human CFU-G cells (CFU-G means granulocyte colony forming unit, and represents an early precursor cell but committed to formation of granules in the bloodstream or in the bone marrow) each of which is transplanted into female Balb / c hairless male or female mice. Other cell lines include leukemic cell lines such as K-562, SUPB15, MEG01, Ku812F, MOLM-13, BaF3, CEM / 0, JURKAT / 0 or U87MG.

Tumors are obtained after subcutaneous injection of the respective cells (minimum 2x106 cells in 100 ml of phosphate-regulated physiological saline) in carrier mice (for example, 4-8 mice per cell line). The resulting tumors are passed serially through at least three subsequent transplants before treatment begins. Tumor fragments (approximately 25 mg each are injected subcutaneously into the left flank of the animals using a 13 gauge Trocar needle under narcosis with Forene (Abbott, Switzerland) for implantation. Mice transplanted with the dependent tumor of estrogen they also receive an estrogen pellet (1.0 cm from a tube with an appropriate amount for medical purposes, Dow Chemicals, with 5 mg of estradiol, Sigma). Treatment is started routinely (this is with a low or intermediate tumor load), as soon as the tumor has reached an average size of 100 mm 3. Tumor growth is determined once, twice or three times a week (depending on the tumor growth of the cell line) and 24 hours after the last treatment by measuring the perpendicular diameter In the case of tumors, tumor volumes were determined according to the formula L x D xp / 6 (see Evans, BD, Smit h, I.E., Shorthouse, A.J. and Millar, J.J., Brit. J. Cancer, 45: 466-468, 1982). The antitumor activity is expressed as T / C% (average increase in the tumor volume of treated animals divided by the average increase in tumor volume in control animals multiplied by 100). Tumor regression (%) represents the smallest average tumor volume compared to the mean tumor volume at the start of treatment. Each animal in which the tumor reaches a diameter of more than 1.5 to 2 cm3 is sacrificed. The leukemia burden is established by examining both the peripheral white blood cell count and the weight of the spleen and thymus in animals tumorized with leukemia cell lines.

An example programming (although not limiting) for the administration of a heteroaryl aryl urea, especially of the formula (I) (or example formulas thereof), or a salt thereof, is the daily administration, preferably with a at three dosages for a longer time, possibly until the disease is cured or, if only palliative treatment is achieved, for as long as required; alternatively, treatment is possible for example for 5 days, and / or administration on days 1, 4 and 9, with eventual repetition after a certain time without treatment. Alternatively, treatments are possible several times a day (for example 2 to 5 times) or treatment by continuous administration (for example infusion), for example at the time points indicated in the last sentence. In general, Administration is oral, or parenteral, preferably oral. The test compounds are preferably diluted in water or in 0.9% sterile saline.

All human tumor cell lines are obtained from the American Type Culture Collection (ATCC, Rockville, MD., USA) if nothing else is indicated and grown in the media suggested with the corresponding additives (ATCC culture conditions), if not something else is mentioned. BALB / c 3T3 c-sis and b-sis transformed cells are obtained from Dr. C. Stiles (Dana Farber Cancer Institute, Boston, MA, USA). "Modified Dulvecco Eagle (DMEM") medium, which is supplemented with 10% calf serum and hygromycin B in a concentration of 0.2 mg / ml or G418 in a concentration of 0.5 mg / ml BALB / c AMuLV cells are cultured A.6R.1 (ATCC) is maintained in DMEM, supplemented with 10% fetal calf serum.

The pharmacological activity of a heteroaryl aryl urea of the formula (I) (or example formulas thereof) can, for example, be demonstrated in a clinical study in a test procedure as essentially described below. Suitable clinical studies are, for example, non-randomized open-label studies, with dose escalation in patients with one of the tumor diseases mentioned above. Beneficial examples of proliferative diseases can be determined directly through the results in these studies or by changes in the study design that are known as such to a person skilled in the art. The efficacy of the treatment can be determined in such studies, for example, in the case of tumors after 18 or 24 weeks by radiological evaluation of the tumors every 6 weeks, in case of leukemia, for example, by determination of the aberrant white blood cell count , and by staining of mononuclear cells and / or by means of the determination of residual disease (MRD), for example, by FACS-LPC MRD

or PCR.

Alternatively, a double-blind, placebo-controlled study may be used in order to prove the benefits of heteroaryl aryl ureas useful in accordance with the invention, especially the compounds of formula (I) (or example formulas thereof) mentioned herein. .

The trk family of neurotrophin receptors (trkA, trkB, trkC) promotes survival, growth and differentiation of neuronal and non-neuronal tissues. The trkB protein is expressed in neuroendocrine-like cells in the small intestine and colon, in the alpha cells of the pancreas, in the monocytes and macrophages of the lymph nodes and spleen, and in the granular layers of the epidermis (Shibayama and Koizumi . nineteen ninety six). TrkB protein expression has been associated with an unfavorable progression of Wilms tumor and neuroblastomas. In addition, trkB is expressed in cancer prostate cells but not in normal cells. The downstream signaling path of trk receptors involves the MAPK activation cascade through the Shc, activated Ras, ERK-1 and ERK-2 genes, and the PLC-range I transduction route (Sugimoto et al., 2001).

The c-Src kinase transmits the oncogenic signals of many receptors. For example, overexpression of EGFR or HER3 / neu in tumors leads to constitutive activation of c-Src, which is characteristic of the malignant cell but is absent in normal cells. On the other hand, mice deficient in the expression of c-Src exhibit an osteopetrotic phenotype, indicating a key participation of c-Src in the function of osteclasts and a possible participation in related disorders.

The Tec kinase family, Bmx, a non-receptor tyrosine kinase protein, controls the proliferation of mammary epithelial cancer cells.

Receptor three of the fibroblast growth factor was shown to exert a negative regulatory effect on bone growth and an inhibition of chondrocyte proliferation. Tanatophoreic dysplasia is caused by different mutations in the three fibroblast growth factor receptor, and one mutation, the TDII FGFR35, has a constitutive tyrosine kinase activity that activates the Stat1 transcription factor, which carries the expression of an inhibitor of the cell cycle, growth arrest and abnormal bone development (Su et al., Nature, 1997, 386, 288-292). FGFR35 is also frequently expressed in multiple myeloma-like cancers.

The activity of glucocorticoid-regulated serum and kinase (SGK) correlates with the activities of the ion channels, in particular the sodium and / or potassium channels and the compounds of the invention may be useful for the treatment of hypertension.

Lin et al (1997) J. Clin. Invest. 100, 8: 2072-2078 and P. Lin (1998), have shown an inhibition of tumor growth and vascularization and also a decrease in lung metastasis during adenoviral infections or during injections of the Tie-2 extracellular domain (Tek ) in breast tumors and in xenograft models in melanoma. Tie2 inhibitors can be used in situations where neovascularization occurs inappropriately (that is, in diabetic retinopathy, chronic inflammation, psoriasis, Kaposi's sarcoma, chronic neovascularization due to macular degeneration, rheumatoid arthritis, childhood hemangioma and cancers).

Lck plays a role in signaling T cells. Mice lacking the Lck gene have a poor ability to develop thymocytes. The role of Lck as a positive activator of T-cell signaling suggests that Lck inhibitors may be useful for the treatment of autoimmune diseases such as rheumatoid arthritis.

JNK, along with other MAPKs, have been implicated in having a role in the cellular mediation response to cancer, platelet aggregation induced by thrombin, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. The therapeutic objectives related to the activation of the JNK pathway include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases. As a result of the importance of JNK activation associated with liver diseases or episodes of liver ischemia, the compounds of the invention may also be useful in the treatment of various liver disorders. A role for JNK in cardiovascular diseases such as myocardial infarction or congestive heart failure has also been reported in that they demonstrate that JNK mediates hypertrophic responses for various forms of cardiac tension. The JNK cascade has also been shown to play a role in the activation of T cells, including the activation of the IL-2 promoter. Thus, JNK inhibitors may have therapeutic value to alter pathological immune responses. A role for the activation of JNK in various cancers has also been established, suggesting the potential use of JNK inhibitors in cancer. For example, constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis [Oncogene 13: 135-42 (1996)]. JNK can play a role in Kaposi's sarcoma (KS). Other proliferative effects of other cytokines involved in the proliferation of KS, such as vascular endothelial growth factor (VEGF), and L-6 and TNF, can also be mediated by JNK. In addition, the regulation of the c-jun gene in transformed P210 BCR-ABL cells corresponds to JNK activity, suggesting a role for JNK inhibitors in the treatment of chronic myelogenous leukemia (CML) [Blood 92: 2450-60 (1998 )].

It is believed that certain abnormal proliferative conditions are associated with the expression of raf and are, therefore, as believed responsible for the inhibition of raf expression. Abnormally high levels of raf protein expression are also involved in the transformation and abnormal proliferation of cells. It is also believed that these abnormal proliferative conditions respond to the inhibition of raf expression. For example, it is believed that c-Raf protein expression plays a role in abnormal cell proliferation since it has already been reported that 60% of all lung carcinoma cell lines express usually high levels of mRNA and protein c -raf. Additional examples of abnormal proliferative conditions are hyperproliferative disorders such as cancers, tumors, hyperplasia, pulmonary fibrosis, angiogenesis, psoriasis, atherosclerosis and cellular proliferation of smooth muscles in the blood vessels, such as stenosis or restenosis after angioplasty. The cellular signaling pathway of which raf is a part has been implicated in inflammatory disorders characterized by T cell proliferation (activation and growth of T cells), such as tissue graft rejection, endotoxin shock and glomerular nephritis, by example.

The stress-activated protein kinases (SAPK) are a family of protein kinases that represent the penultimate stage in signal transduction pathways that result in the activation of the c-jun transcription factor and the expression of c-jun regulated genes . In particular, c-jun is involved in the transcription of genes that encode proteins involved in the repair of DNA that is damaged due to genotoxic aggressions. Therefore, agents that inhibit SAPK activity in a cell prevent DNA repair and sensitize the cell against agents that induce DNA deterioration or inhibit DNA synthesis and induce apoptosis of a cell or inhibit cell proliferation

The mitogen-activated protein kinases (MAPK) are members of conserved signal transduction pathways that activate transcription factors, translation factors and other target molecules in response to a variety of phosphorylation-activated MAPK extracellular signals in a double phosphorylation structure. which has the sequence Thr-X-Tyr by mitogen activated proteins kinases (MKK). In higher eukaryotes, the physiological role of MAPK signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. In accordance with the above, the ability to regulate signal transduction through these routes (particularly through MKK4 and MKK6) could lead to the development of preventive treatments and therapies for human diseases associated with MAPK signaling, such as diseases inflammatory, autoimmune diseases and cancer.

A compound of the formula (I) (or example formulas thereof) may be administered alone or in combination with one or more other therapeutic agents, possible combination therapy that takes the form of fixed combinations or the administration of a compound of the invention. and one or more other therapeutic agents that are supplied staggered or independently of one another, or the combined administration of fixed combinations and one or more therapeutic agents. A compound of the formula (I) (or example formulas thereof) may additionally or additionally be administered especially for tumor therapy, such as leukemia therapy, in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention or a combination thereof. . Long-term therapies are also possible since it is an adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapies to maintain the patient's status after tumor regression, or even chemopreventive therapy for example in patients at risk.

The therapeutic agents for possible combination are especially one or more cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several selected from the group comprising indarubicin, cytarabine, interferon, hydroxyurea, bisulfan, or a polyamine biosynthesis inhibitor, an inhibitor of protein kinase, especially serine / threonine protein kinase, such as protein kinase C, or tyrosine protein kinase, such as the epidermal tyrosine kinase growth factor receptor, a cytokine, a negative growth regulator, such as TGF-� or IFN-�, an aromatase inhibitor, a classic cytostatic, and an inhibitor of the interaction of an SH2 domain with a phosphorylated protein. A specific example of a combination agent is (N- {5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidinaamine (Glivec® / Gleevec®).

A compound according to the invention is not only for the management (prophylactic and preferably therapeutic) of humans, but also for the treatment of other warm-blooded animals, for example, of commercially useful animals, for example rodents, such as mice , rabbits or rats or guinea pigs. Such a compound can also be used as a reference standard in the test systems described above to allow a comparison with other compounds.

In general, the invention also relates to the use of a compound of formula (I) (or example formulas thereof) or an N-oxide thereof for the inhibition of tyrosine kinase activity, either in vitro or in vivo .

With the groups of preferred compounds of the formula (I) (or example formulas thereof) and N-oxides thereof, the definitions of the substituents of the general definitions mentioned hereinbefore can be reasonably used, for example, to replace more general definitions with more specific definitions or especially with definitions characterized by being preferred.

Especially, the invention relates to the use of a compound of the formula (I) (or example formulas thereof) or of an N-oxide or a possible tautomer thereof or a pharmaceutically acceptable salt of such compound for the preparation of a pharmaceutical composition for the treatment of a disease that responds to an inhibition of protein kinase activity, where the disease is a neoplastic disease.

More particularly, the invention relates to the use of a compound of the formula (I) (or example formulas thereof) or of an N-oxide or a possible tautomer thereof; or of a pharmaceutically acceptable salt of such a compound for the preparation of a pharmaceutical composition for the treatment of leukemia, which corresponds to an inhibition of Abl, Abl-Bcr, including mutant forms thereof and the activity of tyrosine kinase VEGF- R2.

Particular active products are compounds named in the examples and salts, esters, N-oxides or prodrugs thereof.

Furthermore, the invention provides a method for the treatment of a disease that responds to an inhibition of a protein kinase activity, which comprises administering a compound of formula (I) (or example formulas thereof) or an N-oxide or a pharmaceutically acceptable salt thereof, where the radicals and symbols have the meanings as defined above, in an amount effective against said disease, to a warm-blooded animal that requires such treatment.

A compound of the invention can be prepared by processes that, although not yet applied for the new compounds of the present invention, are known per se, where the compounds and intermediates can also be present with functional groups in protected form if necessary. and / or in the form of salts, assuming that a salt forming group is present and that the salt reaction is possible;

any protecting group in a protected derivative of a compound of the formula (I) (or example formulas thereof) is removed;

and, if desired, a compound obtainable from the formula (I) (or example formulas thereof) is converted into another compound of the formula (I) (or example formulas thereof) or an N-oxide thereof, a free compound of the formula (I) (or example formulas thereof) is converted into a salt, a salt obtainable from a compound of the formula (I) (or example formulas thereof) is converted into the free compound or another salt, and / or a mixture of isomeric compounds of the formula (I) (or example formulas thereof) is separated into the individual isomers.

The compounds of the invention in non-oxidized form can be prepared from N-oxides of the compound of the invention by treatment with a reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, trichloride phosphorus, tribromide, or the like) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 ° C.

Prodrug derivatives of the compounds of the invention can be prepared by methods known to persons of ordinary skill in the art (for example, for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a compound not derived from the invention with a suitable carbamilating agent (for example, 1,1-acyloxyalkylcarbanhydrochloride, para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be prepared by means known to a person of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their elimination can be found in T. W Greene, " Protecting Groups in Organic Chemistry ", 3rd edition, John Wiley and Sons, Inc., 1999.

The compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (eg, hydrates). 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.

The compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolution agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering their optically pure enantiomers. While the resolution of the enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes (for example, crystalline diastereomeric salts) are preferred. Diastereomers have distinctive physical properties (for example, melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography, or preferably, by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, together with the resolution agent, by any practical means that does not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, " Enantiomers, Racemates and Resolutions ", John Wiley and Sons, Inc ., 1981.

Although the production of the starting materials has not been particularly described, the compounds are known

or they can be prepared analogously to methods known in the art or as disclosed in the examples below.

A person skilled in the art will note that the above transformations are only representative of methods for the preparation of the compounds of the present invention, and that other well known methods can be used in the same way.

Protective groups

If one or more other functional groups, for example carboxy, hydroxy, amino, or mercapto, are or need to be protected in a compound of the formula (I) (or example formulas thereof), since they should not take part in the reaction, there are groups such that are normally used in the synthesis of amides, in particular peptide compounds, and also of cephalosporins and penicillins, as well as derivatives of nucleic acids and sugars.

Protective groups may already be present in precursors and should protect related functional groups against unwanted side reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protective groups that lend themselves easily, that is, without unwanted side reactions, to elimination, typically by sololysis, reduction, photolysis or also by enzymatic activity, for example under conditions analogous to physiological conditions, and They are not present in the final products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and below.

The protection of such functional groups by such protecting groups, the protecting groups themselves, and their elimination reactions are described for example in standard reference books for peptide synthesis as cited hereinafter, and especially books on groups protectors such as JFW McOmie. " Protective Groups in Organic Chemistry ", Plenum Press, London and New York 1973, in " Methoden der organischen Chemie " (Methods of organic chemistry), Houben-Weilo, 4th edition, Volume 15 / l, Georg Tieme Verlag. Stuttgart 1974, and in T. W. Greene, " Protective Groups in Organic Synthesis ". Wiley, New York.

Pharmaceutical preparations, methods and uses

The present invention also relates to pharmaceutical compositions comprising a compound of the formula (I) (or example formulas thereof) or an N-oxide thereof as an active ingredient and which can be used especially 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 (I) (or example formulas thereof), or a pharmaceutically acceptable salt of the same, an active ingredient together or in admixture with a significant amount of one or more inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.

The invention also relates to a pharmaceutical composition that is suitable for the administration of 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, prevention of (= prophylaxis against) a disease that responds to the inhibition of tyrosine protein kinase activity, especially one of the diseases mentioned above as preferred for use of a compound of the formula (I) (or example formulas thereof), comprising an amount of a novel compound of the formula (I) (or example formulas 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 enteric administration, such as nasal, oral, 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, its age, weight and condition of the individual, individual pharmacokinetic data, and the mode of administration.

The present invention relates especially to pharmaceutical compositions comprising a compound of the formula (I) (or example formulas thereof), a tautomer, a 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 management of the human or animal body, a process for the preparation thereof (especially in the form of compositions for the treatment of tumors) and with a method for the treatment of tumor diseases, especially those mentioned above.

The invention also relates to processes for the use of compounds of the formula (I) (or example formulas thereof) or N-oxides thereof for the preparation of pharmaceutical preparations comprising the compounds of the formula (I) (or example formulas thereof) or N-oxides thereof as active component (active ingredient).

The pharmaceutical compositions comprise from about 1% to about 95% active ingredient, the individual dose administration forms comprising in the preferred embodiment from about 20% to about 90% active ingredient and forms that are not of the individual dose type that they comprise in the preferred embodiment from about 5% to about 20% active ingredient. Unit dosage forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules. Additional dosage forms are, for example, ointments, creams, pastes, foams, tinctures, sprays, etc. Examples are capsules containing from about 0.05 g to about 1.0 g 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, granulation, coating, dissolving or lyophilization processes.

Preference is given to the use of solutions of the active ingredient, and also suspensions or dispersions, especially isotonic aqueous dispersions or suspensions solutions, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a vehicle that can be handled before use. . The pharmaceutical compositions may be sterilized and / or may comprise excipients, for example preservatives, stabilizers, wetting and / or emulsifying agents, solubilizers, salts for regulating osmotic pressure and / or regulators and are prepared in a manner known per se, for example by means of conventional dissolution and lyophilization processes. Said solutions or suspensions may comprise viscosity increasing agents or solubilizers, such as sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone or gelatin.

The oil suspensions comprise as an oily component the vegetable, synthetic, or semi-synthetic oils usually for injection purposes. Mention may be made as such especially esters of liquid fatty acids containing as acid component a long chain fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example tauric acid, tridecyl acid, pentadecyl acid, acid palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, carbonic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, �-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydroxy alcohol, for example, a mono, di or trihydroxy, for example methanol, ethanol, propanol, butanol or pentanol

or isomers thereof, but especially glycol and glycerol. The following examples of fatty acid esters are therefore mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattephossé Paris), "Mygliol 812" (fatty acid triglyceride saturated with a chain length of C8 to C12, Huls AG, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially oil of peanut.

Compositions for injection are usually prepared under sterile conditions. The same also applies to introducing the compositions in ampoules or vials and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired by granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, in tablets, dragee cores or capsules It is also possible to incorporate them in plastic vehicles that allow the active ingredient to diffuse or be released in measured quantities.

Suitable carriers are especially fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binding agents such as starch pastes using for example corn starch, wheat, rice

or potato, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and / or if desired, disintegrating agents, such as the aforementioned starches, and / or carboxymethyl starch, cross-linked polyvinyl pyrrolidone , agar, alginic acid or a salt thereof, such as sodium alginate. The excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings, optionally enteric, using, inter alia, concentrated sugar solutions that may comprise gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, or suitable organic solvent coating solutions , or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropyl methylcellulose phthalate. The capsules are dry filled capsules made of gelatin and sealed flexible capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. 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 glidants, such as talc or magnesium stearate, and if desired with stabilizers. . In the flexible capsules the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty acids, paraffin oil or liquid polyethylene glycols, also making it possible to add stabilizers and / or antibacterial agents. Dyes or pigments can be added to the tablets

or dragee coatings or capsule shells, for example for identification purposes or to indicate different doses of the active ingredient.

The tablet cores may be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions that may comprise gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, or solutions of coating in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, suitable cellulose preparation solutions.

Pharmaceutical compositions suitable for rectal administration are, for example, suppositories consisting of a combination of the active ingredient and a suppository base. For parenteral administration, aqueous solutions of an active ingredient in water soluble form, for example of a water soluble salt, aqueous injection suspensions containing substances that increase viscosity, for example sodium carboxymethyl cellulose, sorbitol and / or dextran, and, if desired, stabilizers. The active ingredient, together with optionally excipients, may also be in the form of a lyophilisate and may be constituted as a solution before parenteral administration by the addition of suitable solvents.

Solutions that are used, for example, for parenteral administration can also be used for infusion solutions.

The invention relates in the same way to a process or method for the treatment of one of the pathological conditions mentioned above, especially a disease that responds to an inhibition of a tyrosine kinase, especially a corresponding neoplastic disease. The compounds of the formula

(I) (or example formulas thereof) or N-oxides can therefore be administered in such or especially in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against said diseases, to an animal of warm blood, for example a human who requires such treatment. In the case of an individual having a body weight of about 70 kg the daily dose administered is about 0.05 g to about 5 g, preferably from about

0.25 g to about 1.5 g, of a compound of the present invention.

The invention also provides a method for treating a protein kinase dependent disease, which comprises administration to a warm-blooded animal, for example a human, of 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 "the same time" is understood as in rapid succession or immediately after one another.

The present invention also relates especially to the use of a compound of the formula (I) (or example formulas thereof) or N-oxides thereof, or a pharmaceutically acceptable salt thereof, especially a compound of formula (I) (or example formulas thereof) which is said to be 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 prophylactic management of one or more of the diseases mentioned above, preferably a disease that responds to an inhibition of a protein kinase, especially a neoplastic disease, more especially leukemia which responds to an inhibition of the tyrosine kinase Abl.

The amount of preferred dose, composition and preparation of the pharmaceutical formulations (medicines) used in each case are described above.

A compound of the formula (I) (or example formulas thereof) can be used advantageously in combination with other antiproliferative agents. Such antiproliferative agents include, but are not limited to aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubular active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors. , MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that decrease the activity of the protein kinase and additionally antiangiogenic compounds, agonists of agonadorrein, antiandrogens, bengamides, bisphosphonates, antiproliferative antibodies and temolozomide (TEMODAL®).

The term "aromatase inhibitors" as used herein refers to compounds that inhibit estrogen production, that is, the conversion of androstenedione and testosterone substrates into estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially exemestane and formestane, and, in particular, non-steroids, especially aminoglutehimide, vorozol, fadrozol, anastrozole and, most especially, letrozole. Exemestane can be administered, for example, in the form that is marketed, for example under the brand name AROMASIMTM. Formestane can be administered, for example, in the form in which it is marketed, for example under the brand name LENTARONTM. Fadrozole can be administered, for example, in the form as it is marketed, for example under the AFEMATM brand. Anastrazole can be administered, for example, in the form in which it is marketed, for example under the brand name ARIMIDEXTM. Letrozole can be administered for example, in the form that is marketed, for example under the brand name FEMARATM or FEMATAM. Aminogluteimide can be administered, for example, in the form that is marketed, for example under the trademark ORIMETENTM.

A combination of the invention comprising an antineoplastic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor-positive breast tumors. The term "antiestrogens" 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 in which it is marketed, for example under the brand name NOLVADEXTM, raloxifene hydrochloride can be administered, for example in the form as it is marketed, for example under the brand EVISTATM. Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, for example, in the form in which it is marketed, for example under the trademark FASLODEXTM.

The term "topoisomerase I inhibitors" as used herein includes, but is not limited to topotecan, irinotecan, 9-nitrocanfothecin and the macromular canfothecin conjugate PNU-166148 (compound A1 in WO 99/17804). Irinotecan can be administered, for example in the form in which it is marketed, for example under the brand CAMPTOSATAM. Topotecan can be administered, for example, in the form in which it is marketed, for example under the HYCAMTINTM brand.

The term "topoisomerase II inhibitors" as used herein, includes but is not limited to doxorubicin anthracyclines (including the liposomal formulation, for example CAELYXTM), epirubicin, and darrubicin and nemorubicin, anthraquinones mitoxantrone and losoxantronex, and podophyllinase etoposide and teniposide. The etoposide can be administered, for example, in the form as it is marketed, for example under the trademark ETOPOPHOSTM. Teniposide can be administered, for example, in the form as it is marketed, for example under the brand VM26-BRISTOLTM. Doxorubicin can be administered, for example in the form in which it is marketed, for example under the name ADRIBLASTINTM. Epirubicin can be administered, for example, in the form in which it is marketed, for example under the brand name FARMORUBICINTM. Idarubicin can be administered, for example, in the form in which it is marketed, for example under the brand name ZAVEDOSTM. Mitoxantrone can be administered, for example, in the form in which it is marketed, for example under the NOVANTRONTM brand.

The term "microtubular active agents" refers to stabilizing agents of micro tubules and destabilizing micro tubules that include, but are not limited to, the paclitaxel and docetaxel taxanes, the vinca alkaloids, for example vinblastine, especially vinblastine sulfate, especially vincristine sulfate. of vincristine, and vinorrelbine, discodermolide and epitolones, such as epitolone B and D. The dosetaxel can be administered, for example in the form in which it is marketed, for example under the trademark TAXOTERETM. Vinblastine sulfate can be administered, for example, in the form in which it is marketed, for example under the trademark VINBLASTIN R.P.TM. Vincristine sulfate can be administered, for example, in the form in which it is marketed, for example under the brand name FARMISTINTM.

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 in which it is marketed, for example under the brand name CY-CLOSTINTM. Ifosfamide can be administered, for example, in the form as it is marketed, for example under the HOLOXANTM brand.

The term "histone deacetylase inhibitors" refers to compounds that inhibit histone deacetylase and possess antiproliferative activity.

The term "farmesyl transferase inhibitors" refers to compounds that inhibit farmesyl transferase and possess antiproliferative activity.

The term "COX-2 inhibitors" refers to compounds that inhibit the enzyme cyclooxygenase type 2 (COX-2) that possess antiproliferative activity such as celecoxib (Celebrex®), rofecoxib (Vioxx®) and lumiracoxib (COX189).

The term "MMP inhibitors" is related to compounds that inhibit the metalloproteinase matrix (MMP) and that possess antiproliferative activity.

The term "m-TOR inhibitors" refers to compounds that inhibit the objective of rapamycin mammals (mTOR) and possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CetricanTM), CCI-779 and AB578.

The term "antineoplastic antimetabolites" includes, but is not limited to 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gencitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts of such compounds, ZD1694 (RALTITREXED ™), LY231514 (ALIMTA ™), LY264618 (LOMOTREXOL ™) and OGT719.

The term "platinum compounds" as used herein includes, but is not limited to carboplatin, cis-platinum and oxaliplatin. Carboplatin can be administered, for example, in the form that is marketed, for example under the CARBOPLATTM brand. Oxaliplatin can be administered, for example, in the form that is marketed for example under the trademark ELOXATINTM.

The term "compounds that decrease the activity of protein kinase and additional anti-angiogenic compounds" as used herein, includes but is not limited to compounds that decrease the activity of, for example, Endothelial Vascular Growth Factor (VEGF). , Epidermal Growth Factor (EGF), c-Src, protein kinase C, platelet-derived growth factor (PDGF), Bcr-Abl, c-kit, Flt-3, the growth factor 1 receptor similar to insulin (IGF-IR) and cyclin-dependent kinases (CDK), and antiangiogenic compounds that have other mechanisms of action that decrease protein kinase activity.

The compounds that decrease the activity of VEGF are especially compounds that inhibit the VEGF receptor, especially the tyrosine kinase activity of the VEGF receptor, and compounds that bind to VEGF, and are in particular those compounds, proteins and generic monoclonal antibodies and specifically disclosed in WO 98/35958. WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0 769947; as described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Natl Acad. Sci. USA, vol. 93, pp. 14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al in Toxicologic Pathology, vol. 27. no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202; Angiostatin ™, described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; and Endostatin ™, described by M. S. O'Reilly et al. Cell 88, 1997, 277-285:

Compounds that decrease EGF activity are especially compounds that inhibit the EGF receptor, especially the EGF receptor tyrosine kinase activity, and compounds that bind to EGF, and are in particular those compounds that are disclosed generically and specifically in 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, especially, WO 96/33980;

Compounds that decrease c-Src activity include, but are not limited to, compounds that inhibit c-Src tyrosine kinase protein activity as defined below, and SH2 interaction inhibitors such as those disclosed in WO. 97/07131 and WO 97/08193;

Compounds that inhibit the activity of the protein tyrosine kinase c-Src include, but are not limited to, compounds that belong to the pyrrolopyrimidine structure classes, especially pyrrolo [2,3-d] pyrimidines, purines, pyrazopyrimidines, especially pyrazo [ 3,4-d] pyrimidines. pyrazopyrimidines, especially pyrazo [3,4-d] pyrimidines and pyridopyrimidines, especially pyrido [2,3-d] pyrimidines. Preferably, the term relates to those compounds disclosed in WO 96/10028, WO 97/28161. WO97 / 32879 and WO97 / 49706;

compounds that decrease the activity of protein kinase C are especially those derived from staurosporin disclosed in EP 0296110 (pharmaceutical preparation described in WO 00148571) compounds that are inhibitors of protein kinase C;

Additional specific compounds that decrease protein kinase activity and that can also be used in combination with the compounds of the present invention are imatinib (Gleevec® / Glivec®) PKC412, Iressa ™ (ZD1839), PK1166. PTK787, ZD6474, GW2016, CHIR-200131, CEP-70551CEP-5214, CP547632, KRN-633 and SU5416;

Antiangiogenic compounds that have another mechanism of action that decrease protein kinase activity include, but are not limited to, for example, thalidomide (THALOMID) celecoxib (CELEBREX) and ZD 6126.

The term "agonist agonist" as used herein includes, but is not limited to abarelix, goserrelin and goserrelin acetate. Goserrelin is disclosed in US 4,100,274 and can be administered, for example, in the form as it is marketed, for example under the brand name ZOLADEXTM. Abarelix can be formulated, for example, as disclosed in US 5,843,901.

The term "antiandrogens" as used herein includes, but is not limited to bicalutamide (CASODEXTM), which can be formulated, for example, as disclosed in US 4,636,505.

The term "bengamides" refers to bengamides and derivatives thereof that have antiproliferative activities.

The term "bisphosphonate" as used herein includes but is not limited to etridonic acid, clodronic acid, tiludronic acid, panidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. "Etridonic acid" can be administered, for example in the form, e.g., in the form in which it is marketed, for example, under the brand name DIDRONEL ™. " Clodronic " it can be administered, for example, in the form in which it is marketed, for example, under the brand name BONEFOS ™, "Tiludronic". it can be administered, for example, in the form in which it is marketed, for example, under the SKELID ™ brand. "Pamidronic" it can be administered, for example, in the form in which it is marketed, for example, under the AREDIA ™ brand. " Alendronic " it can be administered, for example, in the form in which it is marketed, for example, under the brand name FOSAMAX ™. "Ibandronic" it can be administered, for example, in the form in which it is marketed, for example, under the brand name BONDRANAT ™, "Risedronic" may

administered, for example, in the form in which it is marketed, for example, under the ACTONEL ™ brand. "Zoledronic" it can be administered, for example, in the form in which it is marketed, for example, under the ZOMETA ™ brand.

The term "anti-proliferative antibodies" as used herein includes, but is not limited to trastuzumab (HerceptinTM). Trastuzumab-DM1, erlotinib (Tarceva ™), bevacizumab (Avastin ™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibody.

For the treatment of acute myeloid leukemia (AML), the compounds of the formula (I) (or example formulas thereof) can be used in combination with standard therapies for leukemia, especially in combination with therapies used for the treatment of AML. In particular, the compounds of the formula (I) (or example formulas thereof) can be administered in combination with for example farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara- C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatio and PKC412.

The structure of the active agents identified by the code numbers, commercial generic names can be taken from the current edition of the standard compendium “The Merck Index " or databases, for example Patents International (for example, IMS World Publications).

The aforementioned compounds that can be used in combination with a compound of the formula (I) (or example formulas thereof), can be prepared and administered as described in the art as in the documents cited above.

General Process Conditions

All the process steps described herein can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such that they are inert to the reagents used and capable of dissolving them, in absence or presence of catalysts, condensing agents or neutralizing agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and / or the reagents at reduced, normal or elevated temperatures , for example in the range of 100 ° C to about 190 ° C, preferably from about 80 ° C to about 150 ° C, for example at -80 ° C to -60 ° C, at room temperature, at -20 ° C to 40 ° C, or at the boiling point of the solvent used, under atmospheric pressure or in a closed container, when appropriate under pressure, and / or n an inert atmosphere, for example under argon or nitrogen.

It should be emphasized that reactions analogous to the conversions mentioned in this chapter can also take place at the level of the appropriate intermediaries.

Detailed Description of the Process

The heteroaryl ureas of the present invention can be prepared according to methods known in the art.

According to a general example process, compounds having the structure of the general formula (I) can be prepared by reacting a hetero aryl amine of General formula (VIII) with aryl isocyanate of general formula (IX):

The reaction can for example be carried out in an aprotic solvent, such as toluene, for example. An example procedure is shown below:

A preferred embodiment is as follows

Additional stages of the process

In the additional steps of the process, carried out as desired, the functional groups of the starting compounds that should not take part in the reaction may be present in an unprotected form or may be protected for example by one or more of the groups. protectors mentioned above under "protective groups". The protecting groups are therefore totally or partially removed according to one of the methods described there.

The salts of a compound of the formula (I) (or example formulas thereof) with a salt forming group can be prepared in a manner known per se. The acid addition salts of compounds of the formula (1) (or example formulas thereof) can thus be obtained by treatment with an acid or with a reagent suitable for anion exchange.

The salts can usually be converted into free compounds, for example, by treatment with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate or sodium hydroxide.

Stereoisomeric mixtures, for example, mixtures of diastereomers, can be separated into their corresponding isomers in a manner known per se by means of suitable separation methods. Diastereomeric mixtures, for example, can be separated into their individual diastereomers by fractional crystallization, chromatography, solvent distribution and similar procedures. This separation can take place either at the level of the starting compound or in a compound of the formula (I) (or example formulas thereof) itself. The enantiomers can be separated through the formation of diastereomeric salts, for example by salt formation with a pure enantiomeric chiral acid or by chromatography, for example by MPLC, using chromatographic substrates with chiral ligands.

A compound of the invention where hydrogen is present can be converted into the respective compound wherein R 3 or R 4 is lower alkyl by reaction for example with a diazo compound lower alkyl, especially diazomethane, in an inert solvent, preferably in the presence of a catalyst of a noble metal, especially in dispersed form, for example copper, or a salt of a noble metal, for example copper (I) chloride or copper (II) sulfate. It is also possible to react with lower alkyl halides, or with other lower alkanes bearing leaving groups, for example, lower alkyl alcohols esterified by a strong organic sulfonic acid, such as a lower alkanesulfonic acid (optionally substituted by halogen, such as fluoro), an aromatic sulfonic acid, for example an unsubstituted or substituted benzenesulfonic acid, the substituents being preferably selected from lower alkyl, such as methyl, halogen, such as bromine, and / or nitro, for example, esterified by methanesulfonic acid, or p-acid -toluenesulfonic. The alkylation takes place under usual conditions for the alkylation of amides, especially in aqueous solution and / or in the presence of polar solvents, typically alcohols, for example methanol, ethanol, isopropanol or ethylene glycol, or dipolar aprotic solvents, for example tetrahydrofuran, dioxane or dimethylformamide, when applicable in the presence of acidic or basic catalysts, generally at temperatures ranging from about 0 ° C to the boiling temperature of the corresponding reaction mixture, preferably between 20 ° C and the reflux temperature, if necessary under increased pressure , for example, in a sealed tube and / or under an inert gas, typically nitrogen or argon.

The salts may be present in all the compounds of items and transients, if they contain salt-forming groups. Salts may also be present during the reaction of such compounds, assuming that the reaction is not disturbed by it.

At all stages of the reaction, the isomeric mixtures that are presented can be separated into their individual isomers, for example diastereomers or enantiomers, or into any mixture of isomers, for example racemates or diastereomeric mixtures.

The invention also relates to those forms of the process in which part is obtained from a compound obtainable at any stage as a transient and the missing stages are carried out, or the process is interrupted at any stage, or forms a low starting material. the reaction conditions, or use said starting material in the form of a derivative or reactive salt, or produce a compound obtainable by means of the process according to the invention and said compound is processed in situ. In the preferred embodiment, part of the starting materials leading to the compounds described hereinbefore is preferred, particularly as especially preferred, are primarily preferred and / or preferred above all.

In the preferred embodiment, a compound of the formula (I) (or example formulas thereof) is prepared in accordance with or in analogy with the processes and process steps defined in the examples.

The compounds of the formula (I) (or example formulas thereof), including their salts, can also be obtained in the form of hydrates, or their crystals may include for example the solvent used for crystallization (present as solvates).

Examples

The following examples serve to illustrate the invention without limiting the scope thereof.

Temperatures are measured in degrees Celsius. Unless otherwise indicated, the reactions take place at room temperature under N2 atmosphere.

The R1 values, which indicate the proportion of the distance traveled by each substance versus the distance traveled by the front of the eluent are determined on thin silica gel plates (Merck. Darmstadt, Germany) by thin layer chromatography using the systems of respective solvents mentioned.

Most of the respective anilines are described in WO 03/099771 or can be prepared analogously with the derivatives cited therein as examples. All others are described somewhere else.

General synthesis scheme:

HPLC conditions

10 Gradient A: Carried out in a Waters system equipped with a CTC Analytics HTS PAL autosampler, 515 pumps, and a 996 DAD detector operated at 210 nm. Column: CC70 / 3 Nucleosil 100-3 C18 (3 μ, 70 x 3 mm, Macherey-Nagel, order # 721791.30), temperature; 45 ° C, flow 1.2 mL. min1 Eluents: A Water + 0.2% H3PO4 (85%, (Merck 100552) + 2% Me4NOH, (10%. Merck 108123), B: Acetonitrile + 20% water + 0.1% H3PO4 (85%) + 1% Me4NOH ( 10%) Gradient: 0% B to 95% B for 6.6 min., Then 95% B 4.4 min.

Gradient B: Linear gradient 20-100% CH3CN (0.1% TFA) and H2O (0.1% TFA) in 7 min + 2 min 100% CH3CN (0.1% TFA); detection at 215 nm, flow rate 1 mL / min at 30 ° C. Column: Nucleosil 100-3 C18 (125 x 4.0mm).

Gradient C: Column: (50 x 4.6 mm) packed with C18-Nucleosil reverse phase material

(Interchrom UP3ODB-5QS, Optisphere 3 μM ODB). UV Absorption Detection at 215 nm. Retention times 20 (tR) are given in minutes. Flow rate: 2 ml / min. Gradient: 20% -100% a) in b) for 14 min + 5 min100% a). a): Acetonitrile + 0.1% TFA; b): water + 01% TFA.

Gradient D: Column: (50 x 4.6 mm) packed with C18-Nucleosil reverse phase material (Interchrom UP3ODBSQS, Optisphere 3 μM ODB). UV Absorption Detection at 215 nm. Retention times (tR) are given

in minutes. Flow rate: 2 ml / min. Gradient 15% - 100% a) in b) for 2.25 min + 1.25 min 100% a). a): Acetonitrile + 0.1% TFA; b): water + 0.1% TFA ..

Gradient E: Column: (50 x 4.6 mm) packed with C18-Nucleosil reverse phase material (Interchrom UP3ODB5QS, Optisphere 3 μM ODB). UV Absorption Detection at 215 nm. Retention times (tR) are given in minutes. Flow rate: 2 ml / min. Gradient 5% -60% a) in b) for 9 min + 7 min 60% a). a): Acetonitrile + 0.1% TFA: b): water + 0.1% TFA.

Gradient F: Column: (125 x 4 mm) packed with Nucleosil 100-5 C18 AB. UV Absorption Detection at 215 nm. Retention times (tR) are given in minutes. Flow rate: 1.5 ml / min Linear gradient 5% -100% CH3CN (0.1% TFA) and H2O (0.1% TFA) in 5 min, then 100% CH3CN (0.1% TFA) for 1 min.

Gradient G: Column: (125 x 4 mm) packed with Nucleosil 100-5 C18 AB. UV Absorption Detection at 215 nm. Retention times (tR) are given in minutes. Flow rate: 1.5 ml / min Linear gradient: 10% -100% CH3CN (0.1% TFA) and H2O (0.1% TFA) in 5 min, then 100% CH3CN (0.1% TFA) for 1 min.

Gradient H: Column: (125 x 4 mm) packed with Nucleosil 100-5 C18 AB. UV Absorption Detection at 215 nm. Retention times (tR) are given in minutes. Flow rate: 15 ml / min Linear gradient: 30% -100% CH3CN (0.1% TFA) and H2O (0.1% TFA) in 5 min, then 100% CH3CN (0.9% TFA) for 1 min.

Gradient I: Column: (250 x 4 mm) packed with Nucleosil 100-5 C18 AB. UV Absorption Detection at 215 nm. Retention times (tR) are given in minutes. Flow rate: 2 ml / min. Linear gradient: 2% .100% CH3CN (0.1% TFA) and H2O (0.1% TFA) in 10 min, then 100% CH3CN (0.1% TFA) for 3 min.

Gradient J: Linear gradient 2.0-100% CH3CN in 5 min + 1.5 min 100% CH3CN (0.1% TFA); detection at 215 nm, flow rate 1 ml / min at 30 ° C. Column: Nucleosil 100-3 C18 (70 x 4.0mm) Abbreviations Ac = Acetyl AcCn Acetonitrile Elemental analysis (for indicated atoms, difference between calculated and measured value � of 0.4%) Brine = Saturated sodium chloride solution conc D-day concentrate ( s) DCM = Dichloromethane DIPE Diisopropyl ether DIPEA = N, N-Diisopropylethylamine DMAP Dimethylaminopyridine DMEU 1,3-dimethyl-2-imidazolidinone DMF dimethyl formamide DMSO = Dimethylsulfoxide EE = Ethyl acetate ESI-MS = Electro ion mass spectrometry diethyl ether

EtOAc

Ethyl acetate

EtOH =

Ethanol

Et3N

Triethylamine

Former.

Example

h

hours)

HATU =

O- (7-Azobenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate

HPLC =

High performance liquid chromatography

Hx

Hexanes

L

liter (s)

I

methyl

MeOH =

Methanol

min

minute (s)

m.p. =

Melting point

MPLC

Medium pressure liquid chromatography

-

 Combi Flash system: normal phase of SiQ2

-

 Gilson System: Nucleosil C18 (H2O / CH3CN + TFA) in reverse phase, product generally obtained as free base after neutralization with NaHCO3. MS Mass spectrum NEt3 Triethylamine NMP = N-methyl-pyrrolidinone NMR = Nuclear magnetic resonance spectroscopy Pd (PhCN) 2Cl2 = Bis (benzonitrile) palladium chloride (II) Rf = Retention factor (TLC)

TA = ambient temperature sat. saturated

TBME = tert-Butyl methyl ether

TFA = Trifluoroacetic Acid

THF = Tetrahydrofuran

TLC = Thin layer chromatography

tR = Retention time (HPLC)

bis (trichloromethyl) triphosgene carbonate

Preparations

The compounds of examples 76, 95, 171-195, 197-215, 216 (compounds 1-54) and 227-230 are provided for reference purposes.

Preparation 1: 2,6-Dichloro-3-methoxycyanate

To a solution of 2,6-dichloro-3-methoxyaniline (0.25 g, 1.30 mmol, 1.0 eq.) In dioxane (7.5 ml) is added a 20% phosgene solution in toluene (0.69 ml, 1.30 mmol, 1.0 eq .) through a hypodermic syringe. The light brown reaction mixture is stirred under nitrogen at room temperature overnight. The clear solution obtained is evaporated under high vacuum using a rotary evaporator at 45 ° C in a temperature bath to produce a brown oil that solidifies on standing: 400 MHz 1H-NMR (CDCl3) 5: 3.90 (s, 3H, OMe), 6.72 (d, 1H, Ar-H4), 7.27 (d, 1H. Ar-H5).

2,6-Dichloro-3-methoxyaniline

To a solution of 2,4-dichloro-3-aminophenol hydrochloride (GLSynthesis, 7.70 g, 35.9 mmol, 1.0 eq.) In acetone is added 85% powdered potassium hydroxide (9.48 g, 143.6 mmol, 4.0 eq.) In little portions. Then, dimethyl sulfate (5.13 ml, 53.9 mmol, 1.5 eq.) Is added at a rate such that the internal temperature does not rise above 30 ° C. After 1 hour of stirring at room temperature, water (50 ml) is added and stirring is continued for another hour. The solvent is evaporated and the residue is distributed between ethyl acetate (150 ml) and water (100 ml). The organic layer is isolated, dried over Na2SO4 and evaporated to give a yellow oil. Kugelrohr distillation produces the desired product in the form of a colorless oil: e.g. 150º / 0.3 mbar, HPLC: tR =

5.61 min (purity: 90%. Gradient A), 400 MHz 1H-NMR (CDCl3) 5: 3.87 (s, 3H, OMe), 4.49 (br s, 2H, NH2), 6.30 (d, 1H, Ar-H4 ), 7.11 (d, 1H, Ar-H5).

Preparation 2: 2,6-Dichloro-3,5-dimethoxyaniline

To a solution of N- (2-chloro-3,5-dimethoxy-phenyl) -acetamide (6.72 g, 25.4 mmol) in ethanol (400 ml) is added 3M KOH (134 ml). Then, the reaction mixture is refluxed for 90 hours. After cooling, water (270 ml) is added and dropwise with vigorous stirring. The precipitate formed is filtered off, washed (1x EtOH / water 1: 1, 50 ml, 1x 100 ml) and dried under vacuum at 50 ° C overnight. The title compound was obtained as colorless crystals: HPLC: t R = 5.43 min (purity:> 99%, gradient A). ESI-MS: 221.9 / 223.9 / 225.8 [MH] +, 400 MHz 1H-NMR (CDCl3) 5: 3.89 (s, 6H, 2x OMa), 4.56 (br s, 2H, NH2), 6.03 (s, 1H, Ar-H4).

N- (2-Chloro-3,5-dimethoxy-phenyl) -acetamide

Sulfuryl chloride (26.9 ml, 325 mmol, 1.93 eq.) (And for 7 minutes) is added to a cold suspension (0 ° C) of NN- (3,5-dimethoxyphenyl-acetamide (32.9 g, 169 mmol) in ACCN ( 500 ml), under an inert atmosphere The resulting yellowish solution is stirred for 30 minutes and stopped by the dropwise addition of a saturated aqueous solution of sodium bicarbonate (250 ml) The resulting precipitate is collected by vacuum filtration , washed with water (300 ml) and dried to produce 20 g of the desired product (lot 1) The filtrate is eluted with a saturated aqueous solution of sodium bicarbonate (300 ml) and extracted with EE (2 x 300 ml) The organic phase is washed with water and brine, dried (sodium sulfate), filtered and concentrated.The residue is purified by silica gel column chromatography (EE / Hx, 1: 1 - 2: 1) to produce 8.8 g of the product (lot 2), lots 1 and 2 are combined and stirred in hexane.The solid is collected by filtration, washed with hexa no and dried to produce 25.8 g of the title compound as a white solid. ESI-MS: 264.0 / 266.0 [MH] +.

Preparation 3: N- (3-Amino-4-meth-phenyl) -3-trifluoromethyl-benzamide

A suspension of N- (3-Amino-4-meth-phenyl) -3-trifluoromethyl-benzamide (9.91 g, 30.6 mmol) and 10% palladium on carbon (990 mg) in ethanol (180 ml) is hydrogenated under pressure atmospheric at room temperature. After 2 hours the reaction is complete, the catalyst is filtered off through Celite, and the filtrate is evaporated to dryness. Recrystallization of the crude product from ethyl acetate / hexanes followed by vacuum drying at 45 overnight produces the title compound as light gray spongy needles, HPLC: tR =

5.38 min (purity:> 99%, gradient A), ESI-MS: 295.3 [MH] +

-

(4-methyl- 3-nitro-phenyl) - 3-trifluoromethyl-benzamide

To a solution of 4-methyl-3-nitroanilline (5 g, 32.2 mmol, 1.0 eq.) And triethylamine (5.38 ml, 38.6 mmol, 1.2 eq.) In dichloromethane (100 ml) is added a chloride solution of 3- trifluoromethylbenzoyl (33.8 mmol, 1.05 eq.) for 30 minutes. The solution formed is stirred for 1 hour at room temperature. Then, the reaction mixture is diluted with dichloromethane (800 ml) and extracted with water (100 ml), 2M aqueous Na2CO3 (100 ml), 2M HCl (100 ml), water (100 ml). The organic layer is dried over Na2SO4, evaporated to a volume of approximately 100 ml and diluted with hexanes (100 ml). The precipitate is filtered off, washed with hexanes / dichloromethane 1: 1 and hexanes. Vacuum drying overnight at room temperature produces fine light yellow needles: HPLC: t R = 6.72 min (purity:> 99%, gradient A), ESI-MS: 325.2 [MH] +

Preparation 4: 4- (4-Methyl-piperazin-1-ylmethyl) -3-trifluomethyl-benzoic acid

To a solution of 4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-benzoate (7.23 g, 21.1 mmol, 1.0 eq) in ethanol (40 ml) is added 1M NaOH (30.6 ml, 30.6 mmol, 1.4 eq.). After stirring for 2 hours at room temperature a clear pale yellow solution is obtained. The mixture is evaporated to a volume of 30 ml. Then, the solution is adjusted to pH 7 by the addition of 1M HCl and the solvent is removed. The residue is taken up to three times in toluene (70 ml) and evaporated. The crude material is dissolved in 1: 9 ethanol / THF (150 ml), filtered, evaporated, triturated with ethyl acetate and dried in vacuo at 60 ° C overnight to produce a beige powder. HPLC: tR =

3.61 min (purity:> 99%, gradient A), ESI-MS: 303.3 [MH] +

Ethyl 4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-benzoate

To a solution of N-methylpiperazine (5.8 g, 57.9 mmol. 1.0 eq.) In tetrahydrofuran (225 ml) containing finely ground anhydrous potassium carbonate (10.4 g, 75.2 mmol, 1.3 eq.) Is added a solution of ethyl 4 -bromomethyl-3trifluoromethylbenzoate (18.0 g, 57.9 mmol, 1.0 eq.) in tetrahydrofuran with vigorous mechanical stirring for 20 minutes. Stirring is continued at room temperature for 20 hours. The suspension obtained is filtered, and the filtrate is evaporated to give a brown oil. The crude product is purified by medium pressure chromatography (290 g of silica gel, gradient: TBME to EtOH / TBME 1: 4 for 30 minutes, and then 25 NH3 / ETOH / TBME

1:19:80 for 60 minutes). Fractions containing the title compound are combined and evaporated to provide a yellow oil: HPLC: t R = 4.75 min (purity:> 99%, gradient A), ESI-MS: 331.4 [MH] +.

Ethyl 4-bromomethyl-3-trifluoromethyl-benzoate

A mixture of ethyl 4-methyl-3-trifluoromethylbenzoate (25.19 g, 108.5 mmol, 1.0 eq.), N-bromosuccinimide (19.94 g, 112, 02 mmol, 1.03 eq.) And benzoyl peroxide (0.21 g, 0.83 mmol, 0.75% mol) is heated to reflux and illuminated by a 100 W daylight lamp for 7 hours. After cooling to room temperature, the succinimide formed is filtered off. The filtrate is evaporated to dryness giving a yellow oil. Flash chromatography (TBME / hexanes) gives a colorless oil that solidifies on standing: HPLC: tR = 7.17 min (purity: 97%, gradient A), TLC; Rf = 0.30 (TBME / hexanes 1: 9).

Ethyl 4-methyl-3-trifluoromethylbenzoate

A solution of commercially available 4-methyl-3-trifluoromethylbenzoic acid (2.4.5 g, 120 mmol) and concentrated sulfuric acid (6.5 ml) in dry ethanol (245 ml) is refluxed for 23 hours. After reaching room temperature the solvent evaporates and the residue is neutralized by the addition of saturated aqueous NaHCO3 solution. The mixture is extracted with ethyl acetate (3 x 40 ml). The organic extracts are combined, dried over Na2SO4 and evaporated to dryness to yield a pale yellow oil: HPLC: t R = 7.15 min (purity:> 96%, gradient A), ESI-MS: 233.3 [MH] +.

Example 1: 3- (2,6-Dichloro-3-methoxy-phenyl) -1-methyl-1- {6-4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin4-yl} - urea

To a solution of 2,6-dichloro-3, methoxyphenyl isocyanate (preparation 1, 52.3 mg, 0.24 mmol, 1.2 eq) in toluene (2.5 ml) is added N-methyl-N- [4- (4-methyl-piperazine- 1-yl) -phenyl] -pyrimidine-4,6-diamine (59.7 mg, 0.2 mmol, 1.0 eq.). The suspension obtained is stirred under argon at 110 ° C for 17 hours. After cooling the crude product is filtered and purified by flash chromatography (100% DCM to 5% MeOH in DCM for 35 min). The fractions contained in the product are combined and evaporated to dryness. The residue is triturated with ether (2 ml) and treated with ultrasound until a homogeneous suspension is obtained. The precipitate is filtered and dried in vacuo at 60 ° C overnight to produce the title compound as a colorless powder: m.p. 161.5-163 ° C, HPLC: tR =

5.07 min (purity:> 99%, gradient A). ESI-MS: 516.6 / 518.5 / 520.4 [MH] +.

N-Methyl-N- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrimidine-4,6-diamine

A solution of (6-chloro-pyrimidin-4-yl) -methyl-amine (1.65 g, 11.5 mmol, 1.1 eq.) And 4- (4-methylpiperazin-1-yl) -aniline

(2.0 g. 10.5 mmol, 1.0 eq.) Commercially available in a mixture of water (4 ml) and glacial acetic acid (16 ml) is heated to an internal temperature of 100 ° C for 16 hours. After cooling, the solvent evaporates.

The residue is taken in methanol (50 ml) and made alkaline by the addition of 25% NH3 in water. To this silica gel (11 g) is added and the solvent evaporates. The crude product adsorbed on the silica is purified by medium pressure liquid chromatography (A: TBME; B: MeOH-NH3 99: 1; gradient: 5% B -> 25% B in 180 minutes). The fractions containing the product are combined and evaporated to dryness. The residue is triturated with ether. The product is filtered, washed with ether, and dried in vacuo at 50 ° C overnight to give the title compound as a pale yellow powder. tR = 3.04 min (purity: 97%, gradient A), ESI-MS: 299.3 [MH].

(6-Chloro-pyrimidin-4-yl) -methyl-amine

This material was prepared by a modified procedure published in the literature (J. Appl Chem, 1955, 5, 358.): To a suspension of 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) Commercially available from isopropanol (60 ml) 33% methylamine in ethanol (40.1 ml, 328.9 mmol, 2.5 eq.) Is added at such a rate that the internal temperature does not rise above 50 ° C. After finishing the addition the reaction mixture is stirred for 1 hour at room temperature. Then, water (50 ml) is added and the suspension formed is cooled in a water bath at 5 ° C. The precipitated product is filtered, washed with cold isopropanol / water of 2: 1 (45 ml) and water. The collected material is dried under vacuum overnight at 45 ° C to produce the title compound as a colorless powder: tR = 3.57 min (purity:> 99%, gradient A), ESI, MS: 144.3 /146.2 [MH] +.

Example 2: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin- 4-il} urea

To a solution of 2,6-dichloro-3,5-dimethoxyaniline (preparation 2.74 mg, 0.34 mmol, 1.25 eq.) In dioxane is added 20% phosgene solution in toluene (191 ml, 0.36 mmol, 1.35 eq .) under argon. The reaction mixture is stirred for an additional 6 hours at room temperature under argon. Then, the solvent is evaporated and the colorless crystalline residue is taken in dry toluene (2.5 ml). After the addition of N-methyl-N- [4- (4-methyl-piperazin-1-yl) -phenylpyrimidine-4,6-diamine (see example 1, 80 mg, 0.27 mmol, 1.0 eq) the solution is Stir at 70 ° C for 36 hours under argon. After cooling, the precipitate is filtered, washed with toluene, methanol / ether 1: 1 and ether to give a beige powder. The crude product is purified by flash chromatography (1% MsOH in DCM at 16% MeOH in DCM for 30 min). The fractions containing the product are combined, evaporated and crushed with ether. The precipitate is filtered, washed (1x methanol / cold ether 1: 1, 1x ether), and dried under vacuum at 45 ° C overnight to yield the title compound as a colorless powder: m.p. 221º (dec.), ESIMS: 546.1 / 548.0 / 550.0 [MH] +.

Following the procedures of examples 1 and 2 but using the appropriate starting materials, examples 3 -

Example 3: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl }-urea

Colorless powder, m.p. 157-160 ° C, ESI-MS: 546.1 / 547.8 / 549.9 [MH] +. Example 4: 1- (2,6-Dichloro-phenyl) -3 {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 3.84 min (purity:> 99%, gradient B), ESI-MS: 472/474/476 [MH] +. Example 5: 1- (2,6-Dichloro-phenyl) -3-6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Beige powder, m.p. 209-212 ° C, TLC: Rf = 0.36 (DCM / MeOH / 25% NH3 350: 50: 1). ESI-MS: 472/474/476 [MH] +. Example 6: 1- (2-Chloro-6-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.41 (DCM / MeOH / 25% NH3 350: 50: 1), HPLC: tR = 10.39 min (purity: 98%, Gradient C), ESI-MS; 452/454 [MH] +.

Example 7: 1- (2-Chloro-6-methyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.29 (DCM / MeOH / 25% NH3 350: 50: 1), HPLC: tR = 7.91 min (purity: 99%, Gradient C), 20 ESIMS: 452/454 [MH] +.

Example 8: 1- (3-Methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] - py-rimidin-4-yl} -urea

Beige powder, HPLC: t R = 4.52 min (purity:> 99%, gradient A). ESI-MS: 434.4 [MH] +. Example 9: 1- (3-Methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] - py-rimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.20 (TBME / MeOH / NH2 90: 9: 1), HPLC: tR = 4.67 min (purity:> 99%, gradient A), ESI-MS: 434.4 [MH] +.

Example 10: 1- (3,5-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

10 Colorless powder, MPLC: t R = 5.62 min (purity:> 99%, gradient A), ESI-MS: 472.3 / 474.2 [MH] +. Example 11: 1- (3,5-Dichloro-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 5.71 min (purity:> 99%, gradient A), ESI-MS: 472.4 / 474.2 [MH] +. Example 12: 1- (2,5-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.44 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.76 min (purity: 90%, gradient A), ESI-MS: 464.4 [MH] +.

Example 13: 1- (2,5-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea Colorless powder , TLC: Rf = 0.27 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.90 min (purity:> 99%, gradient A), ESIMS: 464.4 [MH] +.

Example 14: 1- {6- [4- (4-Methyl-piperazin-1-yl) -phenylamino] -piperazin-4-yl} -3- (3,4,5-trimethoxy-phenyl) -urea

Colorless powder, TLC: Rf = 0.30 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.36 min (purity:> 99%, gradient A), ESIMS: 494.5 [MH] +.

Example 15: 1- {6- [3- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (3,4,5-trimethoxy-phenyl) -urea

10 Colorless powder, HPLC: t R = 4.72 min (purity:> 99%, gradient A), ESI-MS: 494.5 [MH] +. Example 16: 1- (2,4-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.24 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.60 min (purity:> 99%, gradient A), ESIMS: 464.4 [MH] +.

Example 17: 1- (2,4-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: tR = 4.75 mln (purity:> 95%, gradient A), ESI-MS: 464.4 [MH] +. Example 18: 1- (3,5-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.19 (TBME / MeOH / NH3 80: 18: 2). HPLC: t R = 4.66 min (purity:> 99%, gradient A), ESIMS: 464.4 [MH] +.

Example 19: 1- (3,5-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 4.78 min (purity;> 99%, gradient A), ESI-MS: 464.4 [MH] +. Example 20: 1- (3,5-Bis-trifluoromethyl-phenyl) -3-6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

10 Colorless powder, HPLC: t R = 5.86 min (purity:> 99%, gradient A). ESI-MS: 540.4 [MH] +. Example 21: 1- (3,5-Bis-trifluoromethyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 5.98 min (purity:> 99%, gradient A). ESI-MS: 540.3 [MH] +. Example 22: 1- (3,5-Dimethyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.69 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.05 min (purity:> 99%, gradient A), ESIMS: 432.4 [MH] +.

Example 23: 1- (3,5-Dimethyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.31 (TBME / MeOH / NH3 90: 9: 1), HPLC: tR = 5.33 min (purity:> 99%, gradient A), ESI-MS: 432.4 [MH] +.

Example 24: 1- (3-Chloro-4-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.17 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.79 min (purity:> 99%, gradient A), ESIMS: 468.3 / 470.4 [MH] +.

Example 25: 1- (3-Chloro-4-methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.57 (TBME / MeOH / NH3 90: 9: 1), HPLC: tR = 4.96 min (purity:> 99%, gradient A), ESI-MS: 468.3 / 470.3 [MH] +.

Example 26: 1- (5-Methoxy-2-methyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

15 light gray powder, HPLC: t R = 4.87 min (purity:> 99%, gradient A), ESI-MS: 448.4 [MH] +. Example 27: 1- (5-Methoxy-2-methyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.63 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.95 min (purity:> 99%, gradient A). ESIMS: 448.5 [MH] +.

Example 28: 1- (2-Chloro-5-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 5.35 min (purity:> 99%, gradient A), ESI-MS: 468.3 / 470.4 [MH] +. Example 29: 1- (2-Chloro-5-methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 5.33 min (purity:> 99%, gradient A), ESI-MS: 468.4 / 470.5 [MH] +. Example 30: 1- (3,4-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] pyrimidin-4-yl} -urea

Light yellow powder, TLC: Rf = 0.32 (TBME / MeOH / NH3 80: 18: 2), UPLC: tR = 5.34 min (purity: 98%, gradient A), 10 ESIMS: 464.4 [MH] +.

Example 31: 1- (3,4-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1yl) -phenyl-amino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.36 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 4.62 min (purity: 98%, gradient A), ESI-MS: 464.4 [MH] +.

Example 32: 1- (4-Fluoro-3-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.63 (TBME / MeOH / NH3 70: 27: 3), HPLC: tR = 4.58 min (purity:> 99%, gradient A), ESIMS: 452.4 [MH] +.

Example 33: 1- (4-Fluoro-3-methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1yl) -phenylamino] -pyrimidin-4-yl} -urea

Light yellow powder, TLC: Rf = 0.31 (TBME / MeO / NH3 80: 18: 2), HPLC: tR = 4.91 min (purity:> 99%, gradient A), ESIMS:

452.4 [MH] +. Example 34: 1- (4,5-Dimethoxy-2-methyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.27 (TBME / MeOH / NH3 70: 27: 3), HPLC: tR = 4.62 min (purity:> 99%, gradient A), ESIMS: 478.4 [MH] +.

Example 35: 1- (4,5-Dimethoxy-2-methyl-phenyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} - urea

Light yellow powder, TLC: Rf = 0.32 (TBME / MeOH / NH3 80: 18: 2). HPLC: t R = 4.77 min (purity:> 99%, gradient A), ESIMS: 478.4 [MH] +.

Example 36: 1- (2,6-Dichloro-3-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-yl) -phenylamino] -pyrimidin-4-yl} urea

Colorless powder, TLC: Rf = 0.30 (DCM / MeOH 80:20), HPLC: tR = 4.83 min (purity:> 100%, gradient A), ESI-MS: 502.6 / 504.4 / 506.4 [MH] +.

Example 37: 1- (2,6-Dichloro-3-methoxy-phenyl) -3- {6- [3- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

20 Light yellow powder. TLC: Rf = 0.63 (DCM / MeOH 80:20), HPLC: tR = 4.84 min (purity: 89%, gradient A), ESI-MS: 533.6 / 535.5 / 537.5 [MH] +.

Example 38: 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- (6-methylamino-pyrimidin-4-yl) -urea

Colorless powder, TLC: Rf = 0.47 (TBME / MeOH / NH3 90: 9: 1), HPLC: tR = 5.21 min (purity:> 100%, gradient A), ESIMS: 338.3 / 340.4 [MH] +.

Example 39: 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- (6-phenylamino-pyrimidin-4-yl) -urea

Colorless powder, HPLC: t R = 6.60 min (purity:> 99%, gradient A), ESI-MS: 400.4 / 402.4 [MH] +. Example 40: 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

10 Colorless powder, TLC: Rf = 0.52 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.27 min (purity:> 99%, gradient A), ESIMS: 498.4 / 500.2 [MH] +.

Example 41: 1- (2-Chlolo-3,5-dimethoxy-2-methyl-phenyl) -3- {6- [3- (4-methyl) -piperazin-1-yl) -phenyl-amino] -pyrimidin -4-il} -urea

Colorless powder, TLC: Rf = 0.47 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.29 min (purity:> 99%, gradient A), 15 ESIMS: 498.4 / 500.3 [MH] +.

Example 42: 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.60 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.49 min (purity:> 99%, gradient A), ESIMS: 515.5 / 517.4 [MH] +.

Example 43: 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [3- (2-dimethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.20 (TBME / MeOH 30:70), HPLC; tR = 5.38 min (purity:> 99%, gradient A), ESI-MS: 487.4 / 489.4 [MH] +.

Example 44: 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 5.30 min (purity: 96%, gradient A), ESI-MS: 529.4 / 531.3 [MH] +. Example 45: 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [3- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

10 Colorless powder, TLC: Rf = 0.40 (TBME / MeOH 75:25), HPLC: tR = 5.29 min (purity:> 99%, gradient A), ESI-MS: 529.4 / 531.4 [MH] + .

Example 46: 3- (2,3-Dimethoxy-phenyl) -1-ethyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.57 (DCM / MeOH 85:15), HPLC: tR = 5.29 min (purity: 98%, gradient A), ESI-MS: 492.2 [MH] +.

Example 47: 3- (3,5-Dimethoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Light yellow powder, TLC: Rf = 0.38 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.13 min (purity; 95%, gradient A), ESIMS: 478.5 [MH] +.

Example 48: 3- (3,5-Dimethoxy-phenyl) -1-methyl-1- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.48 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.21 min (purity: 95%, gradient A), ESI-MS: 478.4 [MH] +.

Example 49: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1-methyl-1- (6-phenylamino-pyrimidin-4-yl) -urea

Colorless powder, HPLC: t R = 7.38 min (purity: 96%, gradient A), ESI-MS: 414.5 / 416.4 [MH] +. Example 50: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4il} -urea

10 Colorless powder, HPLC: t R = 5.65 min (purity: 95%, gradient A), ESI-MS: 512.4 / 514.3 [MH] +. Example 51: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4- il} -urea

Colorless powder, TLC: Rf = 0.53 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.63 min (purity:> 99%, gradient A), ESIMS: 512.5 / 514.4 [MH] +.

Example 52: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazine-1-carbonyl) -phenylamino] -pyrimidin-4 -il} urea

Colorless powder, TLC: Rf = 0.45 (OCM / MeOH 80:20), HPLC: tR = 5.33 min (purity: 90%, gradient A), ESI-MS: 540.5 / 542.4 [MH] +.

Example 53: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- {6- [4- (2-diethylamino-ethoxy): phenylamino] -pyrimidin-4-yl} -1-methyl-urea

Colorless powder, TLC: Rf = 0.22 (TBME / MeOH 75:25), HPLC; tR = 5.74 min (purity:> 99%, gradient A), ESI-MS: 529.4 / 531.3 [MH] +.

Example 54: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- {6- [3- (2-dimethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -1-methyl-urea

Colorless powder, TLC: Rf = 0.34 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.57 min (purity:> 99%, gradient A), ESIMS: 501 4 / 503.3 [MH] +.

Example 55: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1-ethyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4- il} -urea

Colorless powder, TLC: Rf = 0.26 (DCM / MeOH 90:10), HPLC: tR = 5.69 min (purity:> 100%, gradient A), ESI-MS: 526.5 / 528.4 [MH] +.

Example 56: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -1 -tiofen-2-ylmethylurea

Colorless powder, TLC: Rf = 0.36 (DCM / MeOH 90:10), HPLC: tR = 6.10 min (purity:> 100%, gradient A), ESI-MS: 594.5 / 596.4 [MH] +.

Example 57: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- [2- (4-methyl-piperazin-1-yl) -ethyl] -1- (6-phenylamino-pyrimidin-4- il) -urea

Colorless powder, TLC: Rf = 0.15 (TBME / MeOH 50:50), HPLC: tR = 5.82 min (purity:> 100%, gradient A), ESI-MS: 526.5 / 528.4 [MH] +.

Example 58: 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- (6-phenylamino-pyrimidin-4yl) -1- (2-pyridin-2-yl-ethyl) -urea

Colorless powder, HPLC: t R = 7.30 min (purity: 95%, gradient A), ESI-MS: 505.4 / 507.4 [MH] +. Example 59: 3- (2,6-Dichloro-3-methoxy-phenyl) -1ethyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

10 Yellow foam, TLC: Rf = 0.26 (TBME / MeOH 40:60), HPLC: tR = 5.37 min (purity: 96%, gradient A), ESI-MS: 530.1 / 532.0 / 534.0 [MH] +.

Example 60: 3- (2,6-Dichloro-3-methoxy-Phenyl) -1-methyl-1- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4- il} -urea

Colorless powder, TLC: Rf = 0.15 (TBME / MeOH 60:40), HPLC: tR = 5.31 min (purity: 97%, gradient A), ESI-MS: 15 516.1 / 518.0 / 520.1 [MH] +.

Example 61: 3- (2,6-Dichloro-3-methoxy-phenyl) -1-methyl-1- {6- [3- (4-methyl-piperazin-1-carbonyl) -phenylamino] -pyrimidin-4- il} urea

Colorless powder, TLC: Rf = 0.67 (DCM / MeOH 80:20), HPLC: tR = 5.11 min (purity: 91%, gradient A), ESI-MS: 544.4 / 546.3 / 548.4 [MH] +.

Example 62: 3- (2,6-Dichloro-3-methoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4- il} -urea

Beige powder, HPLC: t R = 5.14 min (purity: 93%, gradient A), ESI-MS: 529.2 / 531.0 / 533.1 [MH] +.

Example 63: 3- (2,6-Dichloro-3-methoxy-phenyl) -1- (6-methoxy-pyridin-3-ylmethyl) -1- {6- [4- (4-methyl-piperazin-1- il) -phenylamino] 10 pyrimidin-4-yl} -urea

Colorless powder, TLC: Rf = 0.56 (DCM / MeOH 80:20), HPLC: tR = 5.69 min (purity:> 99%, gradient A), ESI-MS: 623.0 / 625.5 / 627.3 [MH] +.

Example 64: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-ethyl-1- {6- [4- (4-methyl-piperazine-carbonyl) -phenylamino] -pyrimidin-4- il} 15 urea

Colorless powder, TLC: Rf = 0.44 (DCM / MeOH 85:15), HPLC: tR = 5.23 min (purity:> 99%, gradient A), ESI-MS: 588.5 / 590.1 / 592.2 [MH] +.

Example 65: 1- (2-Chloro-6-methyl-phenyl) -3- (6-isopropylamino-pyrimidin-4-yl) -urea

Beige powder, m.p. 233-233 ° C, TLC: Rf = 0.55 (DCM / MeOH / 25% NH, 350: 50: 1), ESI-MS: 319/321 [MH] +. Example 66: (2,6-dichlro-phenyl) -carbamic acid 4- {6- [3- (2,6-dichloro-phenyl) -ureido] - pyrimidin-4-ylamino} -cyclohexyl ester

Colorless powder, m.p. 222-224 ° C, ESI-MS: 582/584/586 [MH] +. Example 67: 1- (6-Isopropylamino-pyrimidin-4-yl) -3- (2,4,6-trichloro-phenyl) -urea

Colorless powder, m.p. 218-220 ° C, HPLC: t R = 9.92 min (purity: 100%, gradient C). Example 68: 1- (2,6-Dichloro-phenyl) -3- (6-isopropylamino-pyrimidin-4-yl) -urea

Colorless powder, m.p. 203-204 ° C, ESI-MS: 340/342/586 [MH] +. Example 69: 1- {6- [4- (1-Methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea

Slightly yellow powder, m.p. 189-191 ° C, ESI-MS: 535/537/539 [MH] +. Example 70: 1- (2-Chloro-6-methyl-phenyl) -3- {6- [4- (1-methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Slightly yellow powder, m.p. 178-180 ° C, ESI-MS: 481/483 [MH] +. Example 71: 1- (2,6-Dichloro-phenyl) -3- {6- [4- (1-methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-y} -urea

Colorless powder, m.p. 183-185 ° C, ESI-MS: 501/503 [MH] +. Example 72: 1- (2,5-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, m.p. 223-225 ° C, ESI-MS: 472/474 [MH] +. Example 73: 1- {6- [4- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea

Colorless powder, m.p. 209-211 ° C, ESI-MS: 506/508/510 [MH] +. Example 74: 1- {6- [4 - (- Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,5-trichloro-phenyl) -urea

Colorless powder, m.p. 252-254 ° C, ESI-MS: 506/508/510 [MH] +. Example 75: 1- (3,4-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, m.p. 260-262 ° C, ESI-MS: 472/474 [MH] +. Example 76: 1- (6-Amino-pyrimidin-4-yl} -3- (2,3-dichloro-phenyl) -1- [4- (4-methyl-piperazin-1-yl} -phenyl] - urea

Colorless powder, m.p. 280-282 ° C, ESI-MS: 472/474 [MH] +. Example 77: 1- (2,3-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, m.p. 279-281 ° C, ESI-MS: 472/474 [MH] +. Example 78: 1- (5-Chloro-2-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless resin, TLC: Rf = 0.41 (DCM / MeOH / 25% NH3 350: 50: 1), HPLC: tR = 13.25 min (purity: 100%, gradient E), ESIMS: 468/470 [MH] +. Example 79: 1- (2-Chloro-6-methyl-phenyl) -3- {6- [3- (1-methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, m.p. 200-204 ° C, ESI-MS: 481/483 [MH] +. Example 80: 1- (2,6-Dichloro-phenyl) -3- {6- [3- (1-methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, m.p. 198-200 ° C, ESI-MS: 501/503 [MH] +. Example 81: 1- {6- [3- (1-Methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea

Colorless powder, m.p. 222-225 ° C, ESI-MS: 535/537/539 [MH] +. Example 82: 1- (2-Chloro-6-methyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, m.p. 199-201 ° C, ESI-MS: 466/468 [MH] +. Example 83: 1- (2,6-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, m.p. 199-201 ° C, ESI-MS: 466/468 [MH] +. Example 84: 1- {6- [4- (4-Methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea

Yellowish powder, m.p. 194-196 ° C, ESI-MS: 520/522/524 [MH] +. Example 85: 1- {6- [4- (4-Methyl-piperazin-1-carbonyl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea

Amorphous material, m.p. 165-175 ° C, TLC: Rf = 0.61 (DCM / MeOH / 25% NH3 150: 50: 1), HPLC: tR = 8.63 min (purity: 98.8%, gradient C), ESI-MS: 534/536 / 538 [MH] +.

Example 86: 1- {6- [3- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea

Yellowish amorphous material, m.p. 138-142 ° C, TLC: Rf = 0.41 (DCM / MeOH / 25% NH3 350: 50: 1), HPLC; tR = 8.92 min (purity: 99%, gradient C), ESI-MS: 506/508/510 [MH] +.

Example 87: 1- {6 - [(tran) -4- (tert-Butyl-dimethyl-silanyloxy) -cyclohexylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea

Colorless powder, m.p. 198-198 ° C, ESI-MS: 570/572/574 [MH] +. Example 88: 1- [6 - ((trans) -4-Hydroxy-cyclohexylamino) -pyrimidin-4-yl] -3- (2,4,6-trichloro-phenyl) -urea

Colorless powder, m.p. 171-173 ° C, ESI-MS: 430/432/434 [MH] +. Example 89: 1- {6 - [(trans) -4- (tert-Butyl-dimethyl-silanyloxy) -cyclohexylamino] -pyrimidin-4-yl} -3- (2-chloro-6-methylphenyl) -urea

15 Beige powder, m.p. 218-220 ° C, TLC: Rf = 0.74 (ethyl acetate / methanol 95: 5), HPLC: tR = 13.92 min (purity: 93.9%, gradient C), ESI-MS: 490/492 [MH] +.

Example 90: 1- (2-Chloro-6-methyl-phenyl) -3- [6 - ((trans) -4-hydroxy-cyclohexylamino) -pyrimidin-4-yl] -urea

Colorless powder, m.p. 149-152 ° C, TLC: Rf = 0.22 (ethyl acetate / methanol 95: 5), HPLC: tR = 7.77 min (purity: 95.2%, gradient C), ESI-MS: 376/378 [MH] +.

Example 91: 1- {6 - [(trans) -4- (tert-Butyl-dimethyl-silanyloxy) -cyclohexylamino] -pyrimidin-4-yl} -3- (2,6-dichloro-phenyl) -urea

Colorless powder, m.p. 211-212 ° C, HPLC: t R = 2.63 min (purity: 97.9%, gradient D), ESIMS: 510/512 [MH] +. Example 92: 1- (2,6-Dichloro-phenyl) -3- [6 - ((trans) -4-hydroxy-cyclohexylamino) -pyrimidin-4-yl) -urea

10 Amorphous material, TLC: Rf = 0.28 (ethyl acetate / methanol 95: 5), HPLC: tR = 13.54 min (purity: 100%, gradient C), ESI-MS: 396/398 [MH] +.

Example 93: 1- (2-Chloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Beige powder, HPLC: t R = 4.17 min (purity: 100%, (gradient B), ESI-MS: 438/440 [MH] +. Example 94: 1- (2-Bromo-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 4.23 min (purity: 100%, gradient B), ESI-MS: 482/484 [MH] +. Example 95: 1- {6-Amino-pyrimidin-4-yl} -3- (2-chloro-phenyl) -1- [4- (3-diethylamino-propoxy) -phenyl] -urea

Colorless powder, HPLC: t R = 4.42 min (purity: 100%, gradient B), ESI-MS: 469/471 [MH] +. Example 96: 1- (2,6-Dichloro-phenyl) -3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Beige powder, HPLC: t R = 3.93 min (purity: 100%, gradient B), ESI-MS: 503/505 [MH] +. Example 97: 1- (2-Bromo-phenyl) -3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

White powder, HPLC: t R = 4.29 min (purity: 100%, gradient B), ESI-MS: 513/515 [MH] +. Example 98: 1- (2,6-Dichloro-phenyl) -3- {6- [4- (3-morpholin-4-yl-propoxy) -phenylamino] -pyrimidin-4-yl} -urea Colorless powder, HPLC : tR = 4.05 min (purity: 100%, gradient B), ESI-MS: 517/519 [MH] +. Example 99: 1- (2-Bromo-phenyl) -3- {6- [4- (3-morpholin-4-yl-propoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 4.42 min (purity: 100%, gradient B), ESI-MS: 527/529 [MH] +. Example 100: 1- (2,6-Dichloro-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 4.12 min (purity: 100%, gradient B), ESI-MS: 489/491 [MH] +. Example 101: 1- (2-Bromo-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

10 Colorless powder, HPLC: t R = 4.55 min (purity: 100%, gradient B), ESI-MS: 489/501 [MH] +. Example 102: 1- (2-Chloro-phenyl) -3- {6- [4- (3-diethylamino-propoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC: t R = 4.58 min (purity: 100%, gradient B), ESI-MS: 469/471 [MH] +. Example 103: 1- (2,6-Dichloro-phenyl) -3- {6- [4- (3-diethylamino-propoxy) -phenylamino] -pyrimidin-4-yl} -urea

Colorless powder, HPLC; tR = 4.26 min (purity: 100%, gradient B), ESI-MS: 503/505 [MH] +. Example 104: 1- (2-Bromo-phenyl) -3- {6- [4- (3-diethylamino-propoxy) -phenylamino] -pyridin-4-yl} -urea

Colorless powder, HPLC: t R = 4.62 min (purity: 100%, gradient B), ESI-MS: 513/515 [MH] +. Example 105: 1- [6- (4-Diethylamino-phenylamino) -pyrimidin-4-yl] -3- (2,6-difluoro-phenyl) -urea

A. N- (4-Diethylamino-phenyl) -pyrimidine-4,6-diamine

A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 4-amino-N, N-diethylaniline, (0.82 mL, 5 mmol), 2-propanol (5 mL) and concentrated HCl (0.225 mL, -2.5 mmol) is stirred for 36 hours at 90 ° C. After cooling to room temperature, the reaction mixture is distributed between semisaturated K2CO3 solution and ethyl acetate. He

The precipitate thus formed is filtered, washed with H2O and ethyl acetate and dried in vacuo to yield the title compound. Gray solid, HPLC: t R = 2.37 min (gradient F), ESI-MS: 258.3 [MH] +.

B. 1- [6- (4-Diethylamino-phenylamino) -pyrimidin-4-yl] -3- (2,6-difluoro-phenyl) -urea

A mixture of N- (4-diethylamino-phenyl) -pyrimidine-4,6-diamine (257.4 mg, 1 mmol), 2,6-difluorophenyl isocyanate

(170.6 mg, 1.1 mmol) in dry dioxane (4 mL) is stirred for 1.5 hours at 80 ° C. After evaporation of

In solvent in vacuo, the residue is distributed between CH2Cl2 and semi-saturated solution of K2CO3. The organic layer is dried over Na2SO4, evaporated and the residue is purified by flash chromatography (CH2Cl2 / CH3OH). The combined pure fractions are evaporated, the residue is triturated with CH2Cl2 and the solid is filtered and dried in vacuo to yield the title compound. White solid, HPLC: t R = 3.35 min (purity: 100%, gradient F), ESI-MS: 413.4 [MH] +.

Example 106: 1- (2,6-Dichloro-phenyl) -3- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -urea

A. N- (3-Dimethylamino-phenyl) -pyrimidine-4,6-diamine

A mixture of N, N-dimethyl-m-phenylenediamine (1.36 g, 10 mmol), 6-chloro-pyrimidin-4-ylamine (1.30 g, 10 mmol) 2propanol (10 mL) and concentrated HCl (0.45 mL, -5 mmol) is stirred for 16 hours at 90 ° C. After cooling until

At room temperature, the reaction mixture is distributed between semi-concentrated Na2CO3 solution and ethyl acetate. The organic layer is dried over Na2SO4, evaporated and the residue is purified by flash chromatography (ethyl acetate / CH3OH). The combined pure fractions are evaporated to give the title compound.

Solid beige. HPLC: t R = 1.53 min (gradient F), ESI-MS: 230.3 [MH] +.

B. 1- (2,6-Difluoro-phenyl) -3- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -urea

A mixture of N- (3-dimethylamino-phenyl) -pyrimidine-4,6-diamine (458.6 mg, 2 mmol) 2,6-difluorophenyl isocyanate

(341.2 mg, 2.2 mmol) in dry dioxane (5 mL) is stirred for 2.5 hours at 80 ° C. After cooling, the mixture

The reaction is treated with ethyl acetate. The precipitate is filtered and dried in vacuo to produce the compound of the Title. White solid, HPLC: t R = 3.39 min (purity: 100%, gradient F), ESI-MS: 385.4 [MH] +. Example 107: 1- (2,6-Dichloro-phenyl) -3- [6- (4-diethylamino-phenylamino) -pyrimidin-yl] -urea

The title compound the title compound is prepared analogously as described in Example 105A from N- (4-diethylamino-phenyl) -pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate. White solid, HPLC: t R = 3.61 min (purity: 100%, gradient F), ESI-MS: 445.3 / 447.3 [MH] +. Example 108: 1 (2,6-Dichloro-phenyl) -3- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea

A. N- (4-Morpholin-4-yl-phenyl) -pyrimidine-4,6-diamine

The title compound is prepared analogously as described in example 105A from 6-chloropyrimidin-4-ylamine and 4-morpholinoaniline. The semi-solid reaction mixture obtained after cooling to room temperature is dissolved in warm methanol, basified with concentrated aqueous ammonia solution, and the

The mixture is concentrated to half its volume. The precipitate obtained after the addition of H2O is filtered, washed with H2O and dried in vacuo to yield the title compound. Slightly violet solid, ESI-MS: 272.3 [MH] +.

B. 1- (2,6-Dichloro-phenyl) -3- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea

The title compound the title compound is prepared analogously as described in Example 105B 20 from N- (4-morpholin-4-yl-phenyl) -pyrimidine-4,6-diamine and 2,6 -dichlorophenyl isocyanate.

Solid with violet dyes, HPLC: t R = 3.74 min (purity: 100%, gradient F), ESI-MS: 459.3 / 461.3 [MH] +.

Example 109: 1- (2,6-Difluoro-phenyl) -3- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea

The title compound the title compound is prepared analogously as described in Example 105B 25 from N- (4-morpholin-4-yl-phenyl) -pyrimidine-4,6-diamine and 2,6 -difluorophenyl isocyanate. Slightly pink solid, HPLC: t R = 3.53 min (purity: 100%, gradient F), ESIMS: 427.4 [MH] +.

Example 110: 3- (2,6-Dichloro-phenyl) -1- [6- (4-diethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

A. N- (4-Diethylamino-phenyl) -N’-methyl-pyrimidine-4,6-diamine

The title compound is prepared analogously to that described in Example 105A from (6-chloropyrimidin-4-yl) -methyl amine and 4-amino-N, N-diethylaniline. The ethyl acetate layer is dried over Na2SO4 and evaporated in vacuo. The residue is suspended in CH2Cl2, filtered and dried to produce the title compound.

White solid, HPLC: t R = 2.48 min (gradient F), ESI-MS: 272.3 [MH] +.

B. 3- (2,6-Dichloro-phenyl) -1- [6- (4-diethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

The title compound the title compound is prepared analogously to that described in Example 105B from N- (4-diethylamino-phenyl) -N'-methyl-pyrimidine-4,6-diamine and 2.6- dichlorophenyl isocyanate. White solid, HPLC: t R = 2.46 min (purity: 95.6%, gradient H), ESI-MS: 459.2 / 461.2 [MH] +.

Example 111: 3- (2,6-Dichloro-phenyl) -1- {6- [4- (1-hydroxy-1-methyl-ethyl) -phenylamino] -pyrimidin-4-yl} -1-methyl-urea

15 A. 1- [4- (6-Methylamino-pyrimidin-4-ylamino) -phenyl] -ethanone

A mixture of (6-chloro-pyrimidin-4-yl) -methylamine (5.76 g, 40.1mmol), 4-amino-acetophenone (5.40 g, 40 mmol), 2propanol (40 mL) and concentrated HCl (1.8 mL, ~ 20 mmol) is stirred for 40 hours at 90 ° C. Concentrated HCl (0.9 mL, ~ 10mmol) is added and stirring is continued for 56 hours. After the addition of CH3OH the reaction mixture is basified with concentrated aqueous ammonia solution. H2O is added and the precipitate is

Filter, wash with H3O and dry in vacuo to yield the title compound. Yellow solid, ESI-MS: 243.4 [MH] +

B. 1- [6- (4-Acetyl-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -1-methyl-urea

A mixture of 1- [4- (6-methylamino-pyrimidin-4-ylamino) -phenyl] -ethanone (3.77 g, 15.56 mmol), 2,6-dichlorophenyl isocyanate (3.22 g, 17.12 mmol) in dry dioxane (30 mL ) stir for 16 hours at 80 ° C. After the

Evaporation of the solvent in vacuo the residue is distributed between ethyl acetate and semi-saturated K2CO3 solution. The precipitate is filtered and washed with H2O and ethyl acetate. The solid residue is suspended in methanol, heated to reflux for several hours and the yellow hot suspension is filtered. This procedure is repeated once. The residue obtained after the second filtration is washed with CH3OH and dried in vacuo to yield the title compound.

30 Yellowish solid, HPLC: t R = 4.81 min (gradient G), ESI-MS / 430.3 / 432.3 [MH] +.

C. 3- (2,6-Dichloro-phenyl) -1- {6- [4- (1-hydroxy-1-methyl-ethyl) -phenylamino] -pyrimidin-4-yl} -1-methyl-urea

To a freshly prepared solution of methylmagnesium iodide in diethyl ether (8 mL, ~ 7 mmol) is added 1- [6- (4-acetylphenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl ) -1-methyl-urea (0.5 g, 1.16 mmol) in several portions. After stirring for 5 hours, THF (4 mL) is added. After 16 hours the reaction is stopped by the addition of H2O and CH3OH and evaporated in vacuo. The residue is coevaporated twice with toluene and purified by flash chromatography (CH2Cl2 / CH3OH). The combined pure fractions evaporate to produce the title compound.

White solid, HPLC: t R = 4.39 min (purity: 100%, gradient G), ESI-MS: 448.4 / 448.4 [MH] +.

Example 112: 1- (2,6-Dichloro-phenyl) -3- [6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-y] -urea

A. N- (6-Methoxy-pyridin-3-yl) -pyrimidine-4,6-diamine

A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 5-amino-2-methoxypyridine (0.62 g, 5 mmol) and 2-propanol (5 mL) is stirred for 36 hours at 90 ° C. After cooling to room temperature, the reaction mixture is distributed between semisaturated Na2CO3 solution and ethyl acetate. The organic layer is dried over Na2SO4 and evaporated. The solid residue is washed consecutively with CH3OH, ethyl acetate and CH2C2 and dried in vacuo. Rosacea solid, HPLC: t R = 2.68 min (gradient F), ESI-MS: 218.3 [MH] +.

B. 1- (2,6-Dichloro-phenyl) -3- [6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-yl] -urea

The title compound the title compound is prepared analogously as described in Example 105B from N- (6-methoxy-pyridin-3-yl) -pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate. Slightly beige solid, HPLC: tR = 4.01 min (purity: 100%, gradient F), ESI-MS: 405.2 / 407.2 [MH] +. Example 113: 3- (2,6-Dichloro-phenyl) -1-methyl-1- [6- (3-trifluoromethyl-phenylamino) -pyrimidin-4-yl] -urea

A. (6-Chloro-pyrimidin-4-yl) - (3-trifluoromethyl-phenyl) -amine

A mixture of 4,6-dichloropyrimidine (18.6 g, 125 mmol) 3-aminobenzotrifluoride (16.5 mL, 133 mmol), acetone (60 mL) and H2O (90 mL) is refluxed for 3 hours. Acetone is removed in vacuo, the remaining aqueous layer is basified with concentrated aqueous ammonia solution and extracted with ethyl acetate. The organic extract is dried over Na2SO4 and evaporated. The residue is suspended in a small amount of acetone, filtered and the filter cake dried in vacuo to produce the title compound.

White solid, HPLC: tH = 4.82 min (gradient G). ESI-MS: 274.2 / 276.1 [MH] +.

B. N-Methyl-N ’- (3-trifluoromethyl-phenyl) -pyrimidine-4,6-diamine

A solution of methylamine in ethanol (32 mL, 256 mmol) is added to (6-chloro-pyrimidin-4-yl) - (3-trifluoromethylphenyl) amine (3.49 g, 12.8 mmol) and the mixture is stirred for 5 hours at 100 ° C in a pressure bottle. The reaction mixture is concentrated in vacuo, the residue is diluted with CH3OH and basified using concentrated aqueous ammonia solution. The product is filtered, washed with H2O and CH3OH and dried in vacuo.

Gray solid, HPLC: t R = 3.51 min (gradient G), ESI-MS: 269.2 [MH] +.

C. 3- (2,6-Dichloro-phenyl) -1-methyl-1- [6- (3-trifluoromethyl-phenylamino) -pyrimidin-4-yl] -urea

A mixture of N-methyl-N '- (3-trifluoromethyl-phenyl) -pyrimidine-4,6-diamine (536.5 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is stirred for 1 hour at 80 ° C. After evaporation of the solvent in vacuo, the residue is distributed between ethyl acetate and semi-saturated solution of K2CO3. The organic layer is dried over Na2SO4, evaporated, and the residue is recrystallized from CH2Cl2 / CH3OH. The solid residue is dried in vacuo to produce the title compound.

White solid, HPLC: t R = 5.08 min (purity: 100%, gradient H), ESI-MS: 456.3 / 458.3 [MH] +.

Example 114: 1- [6- (3-Cyano-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -1-methyl-urea

A. 3- (6-Methylamino-pyrimidin-4-ylamino) -benzonitrile

A mixture of (6-chloro-pyrimidin-4-yl) -methylamine (1.44 g, 10 mmol), 3-amino-benzonitrile (1.18 g, 10 mmol), 2propanol (10 mL) and concentrated HCl (0.45 mL, � 5 mmol) is stirred for 36 hours at 90 ° C. After cooling to room temperature, CH3OH is added and the reaction mixture is basified with concentrated aqueous ammonia solution. The precipitate that is formed by the addition of H2O is filtered, washed with H2O and dried in vacuo to yield the title compound.

Beige solid, HPLC: t R = 2.67 min (gradient G), ESI-MS: 226.2 [MH] +.

B. 1- [6- (3-Cyano-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -1-3- {2,6-dichloro-phenyl} -1- methyl urea

A mixture of 3- (6-methylamino-pyrimidin-4-ylamino) -benzonitrile (450.5 mg, 2 mmol), 2,6-dichlorophenyl isocyanate

(413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is stirred for 1.5 hours at 80 ° C and then evaporated in vacuo. The residue is suspended in a semi-concentrated aqueous solution of K2CO3, filtered, washed with H2O and acetone and dried in vacuo to yield the title compound.

Beige solid, HPLC: t R = 4.34 min (purity: 100%, gradient H), ESI-MS: 413.3 / 415.3 [MH] +.

Example 115: 1- (2,6-Dichloro-phenyl) -3- [6- (4-fluoro-phenylamino) -pyrimidin-4-yl] -urea

A. N- (4-Fluoro-phenyl) -pyrimidine-4,6-diamine

The title compound the title compound is prepared analogously as described in Example 114A from 6-chloro-pyrimidin-4-ylamine and 4-fluoroaniline. Brown tone solid, HPLC: tR = 3.09 min (gradient F), ESI-MS: 205.2 [MH] +.

B. 1- (2,6-Dichloro-phenyl) -3- [6- (4-fluoro-phenylamino) pyrimidin-4-yl] -urea

A suspension of N- (4-fluoro-phenyl) pyrimidine-4,6-diamine (408.4 mg, 2 mmol), 2,6-dichlorophenyl isocyanate (413.6 mg, 2.2 mmol) in dry dioxane (5 mL) is stirred for 14 hours at 80 ° C. After cooling to 5 ° C the suspension is filtered, the residue is washed with semi-saturated solution of K2CO3, H2O and acetone and dried in vacuo.

Gray solid, HPLC: t R = 4.11 min (purity: 100%, gradient G), ESI-MS: 392.3 / 394.3 [MH] +.

Example 116: 1- [6- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3- (4-methoxy-phenyl) -1-methyl-urea

A mixture of N- (4-fluoro-phenyl) -N'-methyl-pyrimidine-4,6-diamine (2.18 g, 10 mmol), 4-methoxyphenyl isocyanate

(1.29 mL, 10 mmol) and dibutyltin diacetate (0.54 mL, 2 mmol) in dry dioxane (20 mL) is stirred for 6 hours

5 to 100 ° C. After the addition of a second portion of 4-methoxyphenyl isocyanate (0.9 mL, 7 mmol) stirring is continued at 100 ° C for 9 hours. The reaction mixture is treated with ethyl acetate and semi-saturated Na2CO3 solution. The organic layer is filtered, dried over Na2SO4, evaporated and the residue is purified by flash chromatography (hexane / ethyl acetate). The combined pure fractions are evaporated, the residue is suspended in hot CH3OH and the hot mixture is filtered. This procedure is repeated several times. Solid like that

10 obtained is dried in vacuo to produce the title compound.

White powder, HPLC: t R = 4.54 min (purity: 100%, gradient G). ESI-MS: 368.3 [MH] +.

Example 117: 3- (2,6-Dichlorophenyl) -1-methyl-1- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea

A. N-Methyl-N ’- (4-morpholin-4-yl-phenyl) -pyrimidine-4,6-diamine

The title compound the title compound is prepared analogously as described in Example 114A from (6-chloro-pyrimidin-4-yl) -methylamine and 4-morpholinoaniline.

Slightly violet solid, HPLC: t R = 1.37 min (gradient G), ESI-MS: 286.3 [MH] +.

B. 3- (2,6-Dichloro-phenyl) -1-methyl-1- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea

A mixture of N-methyl-N '- (4-morpholin-4-yl-phenyl) -pyrimidine-4,6-diamine (428.0 mg, 1.5 mmol), 2,6-dichlorophenyl isocyanate (310.2 mg, 1.65 mmol) in dry dioxane (5 mL) it is stirred for 1.5 hours at 80 ° C. After evaporation of the solvent in vacuo, the residue is purified by flash chromatography (CH2Cl2 / CH3OH). The combined pure fractions are evaporated, the residue is triturated with CH2Cl2 and the solid is filtered and dried in vacuo to yield the title compound.

25 White solid, HPLC: t R = 2.79 min (purity: 100%, gradient H), ESI-MS: 473.3 / 475.3 [MH] +

Example 118: 3- (2,6-Dichloro-phenyl) -1- [6- (2,4-difluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-urea A. N- (2,4 -Difluoro-phenyl) -N'-methyl-pyrimidine-4,6-diamine

The title compound the title compound is prepared analogously as described in Example 114A from (6-chloro-pyrimidin-4-yl) -methylamine and 2,4-difluoroaniline. Rosacea solid, HPLC: tR = 3.21 min (gradient F), ESI-MS: 237.2 [MH] +.

B. 3- (2,6-Dichlorophenyl) -1- [6- (2,4-difluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

The title compound the title compound is prepared analogously as described in Example 1058 from N- (2,4-difluoro-phenyl) -N'-methyl-pyrimidine-4,6-diamine and 2 , 6-dichlorophenyl isocyanate. White solid, HPLC: t R = 4.41 min (purity: 100%, gradient H), ESI-MS: 424.2 / 426.2 [MH] +.

Example 119: 1- (2,6-Dichloro-phenyl) -3- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -urea

The title compound the title compound is prepared analogously as described in Example 105B from N- (3-dimethylamino-phenyl) -pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate using acetate of ethyl instead of CH2Cl2 for the handling procedure.

White solid, HPLC: t R = 3.61 min (purity: 100%, gradient F). ESI-MS: 417.3 / 419.2 [MH] +.

Example 120: 3- (2,6-Dichloro-phenyl) -1- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

A. N- (3-Dimethylamino-phenyl) -N’-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in example 105A from (6-chloro-pyrimidin-4-yl) methylamine and N, N-dimethyl-in-phenylenediamine. The crude product obtained after evaporation of the layer of

Ethyl acetate is purified by flash chromatography (CH2Cl2 / CH3OH).

Beige solid, HPLC: t R = 2.45 min (gradient F), ESI-MS: 244.3 [MH] +.

B. 3- (2,6-Dichloro-phenyl) -1- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

A mixture of N- (3-dimethylamino-phenyl) -N'-methyl-pyrimidine-4,6-diamine (243.3 mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) in dry dimethyl formamide ( 2.5 mL) is stirred for 14 hours at 90 ° C. Two are added

An additional 25 portions (188 mg, 1 mmol each) of 2,6-dichlorophenyl isocyanate are added after 14 hours and 26 hours. After 38 hours the reaction mixture is evaporated in vacuo and the residue is distributed between ethyl acetate and semi-saturated solution of K2CO3. The organic layer is dried over Na2SO4, evaporated and the residue is purified by flash chromatography (hexane / ethyl acetate). The combined pure fractions are evaporated, the residue is triturated with CH2Cl2 and the solid is filtered and dried in vacuo to yield the title compound.

30 White solid, HPLC: t R = 3.79 min (purity: 100%, gradient G), ESI.MS: 431.1 / 433.1 [MH] +.

Example 121: 1- [6- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-3- (3-trifluoro-methylphenyl) -urea

A mixture of N- (4-fluoro-phenyl) -N'-methyl-pyrimidine-4,6-diamine, 3-trifluoromethyl) phenyl isocyanate (218.2 mg, 1 mmol) and dibutyltin diacetate (165.2 DL, 1.2 mmol ) in dry dioxane (2.5 mL) is stirred for 14 hours at 5 100 ° C. 2 additional portions (82.6 μL, 0.6 mmol each) of 3-trifluoromethylphenyl isocyanate are added after 14 hours and 20 hours. After 26 hours the reaction mixture is distributed between ethyl acetate and semi-saturated Na2CO3 solution. The organic layer is dried over Na2SO4, evaporated and the residue is triturated with CH2Cl2. The solid is filtered and the filtrate is purified by flash chromatography (hexane / ethyl acetate). The combined pure fractions are evaporated, the residue is recrystallized from CH3OH / CH2Cl2 to produce the

10 title compound.

White solid, HPLC: tR, = 5.31 min (purity: 100%, gradient G), ESI-MS: 406.3 [MH] +,

Example 122: 3- (3-Chloro-phenyl) -1- [6- (4-fluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

The title compound the title compound is prepared analogously as described in Example 121 to 15 from N- (4-fluorophenyl) -N'-methyl-pyrimidine-4,6-diamine and 3-chlorophenyl isocyanate .

White solid, HPLC: t R = 5.25 min ((purity: 100%, gradient G), ESI-MS: 372.2 [MH] +,

Example 123: 3- (2,6-Dichloro-phenyl) -1- [6 (4-fluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

A mixture of N- (4-fluoro-phenyl) -N'-methyl-pyrimidine-4,6-diamine (218.2 mg, 1 mmol), 2,6-dichlorophenyl isocyanate

20 (188 mg, 1 mmol) and methylamine (1.11 mL, 8 mmol) in dimethylformamide (2.5 mL) is stirred for 14 hours at 90 ° C. The mixture is evaporated in vacuo and the residue is distributed between ethyl acetate and semi-saturated Na2CO3 solution. The organic layer is dried over Na2SO4, evaporated and the residue is purified by flash chromatography (CH2Cl2 / CH3OH). The combined pure fractions are evaporated, the residue is triturated with CH2Cl2 and the solid is filtered and dried in vacuo to yield the title compound.

25 White solid, HPLC: t R = 4.33 min (purity: 100%, gradient H), ESI-MS: 406.1 / 408.1 [MH] +.

Example 124: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -1-methyl-urea.

A. N- (3-Chloro-phenyl) -N’-methyl-pyrimidine-4,6-diamine

The title compound the title compound is prepared analogously as described in Example 105A from (6-chloro-pyrimidin-4-yl) -methyl-amine and 3-chloroaniline. The ethyl acetate layer is dried over Na2SO4 and evaporated. The solid residue is suspended in CH2Cl2, filtered and dried in vacuo to yield the title compound.

White solid, HPLC: t R = 3.23 min (gradient G). ESI-MS: 235.2 [MH] +. 5 B. 1- [6- (3-Chloro-phenylamino) pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -1-methyl-urea The title compound The title compound is prepared from analogously as described in Example 105B from N- (3-chlorophenyl) -N'-methylpyrimidine-4,6-diamine and 2,6-dichloroaniline. The oily residue received after evaporation of the CH2Cl2 layer is triturated with CH2Cl2 and the crystals thus obtained are filtered and dried in vacuo to give the title compound. 10 White solid, HPLC: t R = 4.97 min (purity: 100%, gradient H), ESI-MS: 422.3 / 424.3 [MH] +. Example 125: 1- (2-Chloro-phenyl) -3- {6- [4- (3-morpholin-4-yl-propoxy) -phenylamino] -pyrimidin-4-yl} -urea bis-hydrochloride salt

A. 1- (2-Chloro-phenyl) -3- (6-chloro-pyrimidin-4-yl) -urea

A solution of 6-chloro-pyrimidin-4-ylaminar (997 mg, 7.7 mmol) and 2-chlorophenyl isocyanate (0.46 mL, 3.85 mmol) in THF (20 mL) is refluxed for 4 hours. An additional amount of 2-chlorophenyl isocyanate is added

(0.46 mL, 3.85 mmol) and the reaction mixture is refluxed for 28 hours. The reaction mixture is cooled At room temperature, the precipitate is filtered to yield the title compound (1.9 g, 86%). White powder, HPLC: t R = 8.01 min (gradient 1), ESI-MS: 281.1 / 283.1 [M-H] -.

B 1- (2-Chloro-phenyl) -3- {6- [4- (3-morpholin-4-yl-propoxy) -phenylamino] -pyrimidin-4-yl} -urea Example 126: 1- (2 -Chloro-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

The title compound the title compound is prepared analogously to that described in Example 125B using 4- (2-diethylamino-ethoxy) -phenylamine, crystallization from DCM produces the title compound. White powder, HPLC: t R = 6.03 min (gradient 1), ESI-MS: 455 [MH] + 25 Example 127: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- ( 2,6-dimethyl-phenyl) -1-methyl-urea

A solution of N- (3-chloro-phenyl) -N'-methyl-pyrimidine-4,6-diamine (Example 124A, 94 mg, 0.4 mmol) and 2,6-dimethylphenyl isocyanate (74 mg, 0.52 mmol) in diglyme it was stirred at 80 ° C for 18 hours. The solvent evaporates in vacuo and

The residue is purified by flash column chromatography on silica gel (ethyl acetate / hexane 1: 2) to produce the title compound (29 mg, 19%). White powder, HPLC: tR = 9.60 min (gradient I), ESI-MS: 382.3 [MH] + Example 128: 3- (2-Chloro-phenyl) -1- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] -urea.

A. N- (3-Chloro-phenyl) -pyrimidine-4,6-diamine

The title compound the title compound is prepared analogously as described in Example 105A from 6-chloro-pyrimidin-4-ylamine and 3-chloroaniline. White powder, m.p. 171-172 ° C. HPLC: t R = 5.11 min (gradient I), ESI-MS: 221 [MH] +

10 B. 3- (2-Chloro-phenyl) -1- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] -urea A solution of N- (3-chloro-phenyl) -pyrimidine-4 , 6-diamine (110 mg, 0.5 mmol) and 2-chlorophenyl isocyanate (60 μL, 0.5

mmol) in diglyme (1.5 mL) is stirred at 80 ° C for 18 hours. The precipitate that deforms over time is filtered and wash with hexane / ethyl acetate to produce the pure title compound (98 mg, 52%). White powder, HPLC: t R = 8.95 min (gradient I), ESI-MS: 374.1 / 376.1 [MH] +.

Example 129: 1- (2-Bromo-phenyl) -3- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] urea

The title compound the title compound is prepared analogously as described in Example 128 using 2-bromophenyl isocyanate. White powder HPLC: t R = 9.03 min (gradient I), ESI-MS: 418.0 / 420.0 [MH] + 20 Example 130: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2 -fluoro-phenyl) -urea

The title compound the title compound is prepared analogously to that described in Example 128 using 2-fluorophenyl isocyanate.

White powder HPLC: t R = 8.24 min (gradient I), ESI-MS: 258.2 [MH] +

Example 131: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (3-methoxy-phenyl) -urea1

The title compound the title compound is prepared analogously as described in Example 128 using 3-methoxyphenyl isocyanate. White powder HPLC: tR = 7.90 min (gradient I), ESI-MS: 370.2 [MH] + Example 132: 1: [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,5-dimethoxy-phenyl) -urea

The title compound the title compound is prepared analogously to that described in Example 127 from N- (3-chlorophenyl) -pyrimidine-4,6-diamine and 2,5-dimethoxyphenyl isocyanate. 10 white powder HPLC: t R = 8.18 min (gradient I), ESI-MS: 400.2 [MH] + Example 133: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2-trifluoromethyl- phenyl) -urea

The title compound the title compound is prepared analogously to that described in Example 128 using 3-trifluoromethylphenyl isocyanate. 15 White powder HPLC: t R = 8.94 min (gradient I), ESI-MS: 408.1 [MH] + Example 134: - [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (5-methoxy-2 -methyl-phenyl) -urea

The title compound the title compound is prepared analogously as described in Example 2 from 5-methoxy-2-methylaniline and N- (3-chlorophenyl) -pyrimidine-4,6-diamine.

20 White powder, HPLC: tR = 8.38 min (gradient I), ESI-MS: 384.2 [MH] +

Example 135: 1- (3-Chloro-phenyl) -3- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] -urea

The title compound the title compound is prepared analogously as described in Example 128 using 3-chlorophenyl isocyanate. White powder HPLC: tR = 8.75 min (Gradient I), ESI-MS: 374.1 / 376.1 [MH] + Example 136: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (3,4,5-trimethoxy-phenyl) -urea

The title compound the title compound is prepared analogously to that described in Example 127 from N- (3-chlorophenyl) -pyrimidine-4,6-diamine and 3,4,5-trimethoxyphenyl isocyanate. White powder HPLC: tR = 7.60 min 10 (gradient I), ESI-MS: 430.2 [MH] +

Example 137: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -urea

The title compound the title compound is prepared analogously to that described in Example 127 from N- (3-chlorophenyl) -pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate. 15 White powder HPLC: t R = 8.30 min (gradient I), ESI-MS: 410 [MH] + Example 138: 1- (4-Chloro-phenyl) -3- [6- (3-chloro-phenylamino) -pyrimidin-4- il] -urea

The title compound the title compound is prepared analogously to that described in Example 128 using 4-chlorophenyl isocyanate.

20 white powder. HPLC: t R = 8.63 min (gradient I), ESI-MS: 374.1 / 376.1 [MH] +

Example 139: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (3,5-dimethoxy-phenyl) -urea

The title compound the title compound is prepared analogously as described in Example 128 using 3,5-dimethoxyphenyl isocyanate. White powder HPLC: tR = 8.06 min (gradient I), ESI-MS: 400.2 [MH] + Example 140: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,6-dimethyl-phenyl) -urea

The title compound the title compound is prepared analogously to that described in Example 127 from N- (3-chlorophenyl) -pyrimidine-4,6-diamine and 2,6-dimethylphenyl isocyanate. 10 white powder HPLC: t R = 7.97 min (gradient I), ESI-MS: 368.2 [MH] + Example 141: 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3-phenyl-urea

The title compound the title compound is prepared analogously to that described in Example 128 using phenyl isocyanate.

White powder HPLC: t R = 7.83 min (gradient I), ESI-MS: 338 [MH] +

Example 142: 1- (2-Chloro-phenyl) -3- (6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl) -urea

The title compound is prepared analogously to that described in Example 125B using 4- (2-morpholin-420 il-otoxy) -phenylamine, crystallization from DCM produces the title compound.

White powder HPLC: t R = 5.82 min (gradient I), ESI-MS: 469 [MH] + Example 143: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-ethyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin- 4-il} -urea

To a solution of 2,6-dichloro-3-methoxyphenylisocyanate (1.25 eq.) In toluene (1.9 ml) is added N-ethyl-N '- [4- (4-methylpiperazin-1-yl) -phenyl] -pyrimidine- 4,6-diamine (113 mg, 0.36 mmol), under an argon atmosphere. The resulting mixture is stirred at 70 ° C for 18 hours, allowed to cool to room temperature and filtered. The recovered solid is washed with diethyl ether, dried and further purified by MPLC (silica gel) (DCM / MeOH) to yield 10mg of the title compound as a white solid; ESI-MS: 559.9 / 561.9 [MH] +; tR = 3.53 min (purity: 100%,

10 gradient J); TLC: Rf = 0.28 (DCM / MeOH, 9: 1).

A. N- [3- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

A mixture of (6-chloro-pyrimidin-4-yl) -ethyl-amine (363 mg, 2.30 mmol, 1.1 equivalent) and 4- (4-methylpiperazin-1-yl) aniline (400 mg, 2.09 mmol) in water (0.8 ml) and glacial acetic acid (3.2 ml) is heated at 100 ° C for 3 hours. After evaporation of the solvent, the residue is taken in methanol, made alkaline by the addition of 25% NH3 in water and concentrated. The residue is purified by MPLC (silica gel) (DCM / MeOH) to yield 395 mg of the title compound as a white solid: ESI-MS: 313.2 [MH] +; tR = 1.25 min (purity: -90%, gradient J); TLC: R1 =

0.12 (DCM / MeOH, 9: 1).

B. (6-Chloro-pyrimidin-4-yl) -ethyl-amine

Ethyl amine (70% in water, 16 ml, 45.08 mmol, 2.5 equivalent) is added dropwise (for 15 minutes) to a suspension of 4,6-dichloro pyrimidine (12 g, 80.5 mmol) in EtOH (36 ml ) at room temperature. The resulting yellowish solution is left under stirring for 1 hour at room temperature and then cooled to 0 ° C. The resulting white precipitate is collected by vacuum filtration, washed with water and dried in vacuo to produce

12.4 g of the title compound: ESI-MS: 157.9 [MH] +; single peak at t R = 2.02 min (purity: 100%, gradient J).

Example 144: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (3-dimethylaminomethyl-phenylamino) -pyrimidin-4-yl] -1-methyl-urea.

2,6-Dichloro-3,5-dimethoxyphenyl isocyanate (1.25 equivalent) is added to a solution of N- (3-dimethylaminomethyl-phenyl) N'-methyl-pyrimidine-4,6-diamine (93 mg, 0.36 mmol, 1 equivalent) in toluene (3ml), at 70 ° C and under an argon atmosphere. The resulting mixture is stirred at 70 ° C for 18 hours, allowed to cool to room temperature, and eluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3eq, 9: 1) produces 121mg of

title compound in the form of a white solid: ESI-MS: 504.9 / 506.9 [MH] +: t R = 3.64 min (purity: 100%, gradient J); TLC: R1 = 0.12 (DCM / MeOH + 1% NH3eq, 9: 1).).

A. N- (3-Dimethylaminomethyl-phenyl) -N’-methyl-pyrimidine-4,6-diamine

A mixture of (6-chloro-pyrimidin-4-yl) -methyl-amine (Example 1) (750 mg, 5.2 mmol) 3-dimethylaminomethylphenylamine (787 mg, 5.2 mmol) and 4 N HCL in dioxane (15 ml) is heat in a sealed tube up to 150 ° C for 5 hours. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. 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% NH3eq 9: 1) yields 800 mg of the title compound as a white solid: ESI-MS: 258.1 [MH] +; tR = 1.00 min (purity: 100%, gradient J); TLC: Rf = 0.14 (DCM / MeOH + 1% NH3eq, 9: 1)

Example 145: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -1-methyl urea

The title compound is prepared as described in example 144 but using N- [4- (4-ethyl-piperazin-1-yl) phenyl] -N'-methylpyrimidine-4,6-diamine (2.39 mg, 7.7 mmol , 1 equivalent) and stirring the reaction mixture for 1.5 hours at reflux. Purification of the crude product by silica gel column chromatography (DCM / MrOH + 1% NH3eq, 95: 5), yields the title compound as a white solid: ESI-MS: 560.0 / 561.9 [MH] +; tR = 3.54 min (purity: 100%, gradient J); TLC: R1 = 0.28 (DCM / MeOH + 1% NH3eq, 95: 5).

A. N- [4- (4-ethyl-piperazin-1-yl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using 4- (4-ethylpiperazin-1-yl) -aniline (1 g, 4.88 mmol) and (6-chloro-pyrimidin-4-yl) -methyl- amine (Example 1) (771 1.81 g, 12.68 mmol, 1.3 eq.). Purification of the residue by silica gel column chromatography (DCM / MeOH, 93: 7) followed by trituration in diethyl ether yields the title compound as a white solid: ESI-MS: 313.2 [MH] +; tR = 1.10 min (gradient J); TLC: Rf = (0.21 (DCM / MeOH, 93: 7).

B. 4- (4-Ethylpiperidin-1-yl) -aniline

A suspension of 1-ethyl-4- (4-nitro-phenyl) -piperazine (6.2 g, 26.35 mmol) and Raney nickel (2 g) in MeOH (120 mL) is stirred for 7 h at RT, under a hydrogen atmosphere . The reaction mixture is filtered through a celite cloth and concentrated to yield 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [MH] +; TLC: Rf = 0.15 (DCM / MeOH + 1% NH3eq, 9: 1).

C. 1-Ethyl-4- (4-nitro-phenyl) -piperazine

A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 equivalent) is 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 / MrOH + 1% NH3eq, 9: 1) yields 6.2 g of the title compound as a yellow solid: ESI-MS: 236.0 [MH] +; tR = 2.35 min (purity: 100%, gradient J); TLC: Rf = 0.50 (DCM / MeOH + 1% NH3eq, 9: 1).

Example 146: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- (6- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenylamino} pyrimidin-4-yl) -urea

The title compound is prepared as described in Example 144 but using N-methyl-N '- {4- [3- (4-methylpiperazin-1-yl) -propoxy] -phenyl} -pyrimidine-4,6- diamine (93 mg, 0.26 mmol, 1 eq.). Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3eq, 95: 5) yields 86 mg of the title compound as a white solid: ESI-MS: 603.9 / 605.9 [MH] + ; tR = 3.21 min (purity: 100%, gradient J); TLC: Rf = 0.19 (DCM / MeOH + 1% NH3eq, 95: 5).

A. N-Methyl-N ’- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenyl} -pyrimidine-4,6-diamine

The title compound is prepared as described in example 143A but using 4- [3- (4-methylpiperazin-1-yl) propoxy] -phenylamine (383 mg, 1.50 mmol, 1.1 equivalent) and stirring the reaction mixture for 18 hours at 100 ° C. The reaction mixture is allowed to cool to room temperature, poured onto a saturated aqueous solution of sodium bicarbonate, and extracted with EE and DCM. The organic phase is dried (sodium sulfate), filtered and concentrated.

The residue is triturated with diethyl ether to provide 115 mg of the title compound as a white solid: ESI-MS: 357.1 [MH] +; tR = 1.10 min (gradient J); purity: 100%, gradient J); TLC: R1 = 0.08 (DCM / MeOH, 9: 1).

B. 4- [3- (4-Methylpiperazin-1-yl) -propoxy] -phenylamine

1- (3-Chloro-propyl) -4-methyl-piperazine hydrochloride (1.7 mg, 9.6 mmol, 1.2 equivalent) is added in one portion to a mixture of 4-aminophenol (893 mg, 8.0 mmol) and finely sodium hydroxide sprayed (808 mg, 20 mmol, 2.5 equivalent) in DMF (27 ml). The reaction mixture is stirred for 17 hours at room temperature. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2x50 ml). The aqueous layer back extracted with DCM. The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM / MeOH 7: 3) provides 1.86 g of the title compound as a yellow-brown oil: ESI-MS: 250.2 [MH] +; TLC: Rf = 0.31 (DCM / MeOH, 7: 3).

Example 147: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (3-dimethylamino-propyl) -phenylamino] -pyrimidin-4-yl} -1-methylurea

The title compound is prepared as described in Example 144 but using N- [4- (3-dimethylamino-propyl) phenyl] -N'-pyrimidine-4,6-diamine (206 mg, 0.72 mmol, 1 eq. ). Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3eq, 93: 7) yields 84 mg of the title compound as a white solid: ESI-MS: 532.9 / 534.9 [MH] + ; tR = 3.70 min (purity: 100%, gradient J); TLC: Rf = 0.15 (DCM / MeOH + 1% NH3eq, 93: 7).

A. N- [4- (3-Dimethylamino-propyl) -phenyl] -N'-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using 4- (3-dimethylaminopropylphenylamine (311 mg, 1.7 mmol). Purification of the residue by column chromatography using silica gel (DCM / MeOH + 1% NH3eq, 9 : 1), followed by trituration of the resulting solid in diethyl ether, yields 213 mg of the title compound as a white solid: ESIMS: 286.1 [MH] +; t R = 1.20 min (gradient J); purity: 100%, gradient J); TLC: Rf = 0.08 (DCM / MeOH + 1% NH3eq, 9: 1).

B. 4- (3-Dimethylamino-propyl-phenylamine

A mixture of dimethyl dimethyl- [3- (4-nitro-phenyl) -prop-2-inyl] -amine (1.35g, 6.6mmol), 10% palladium on carbon (140 mg) and EtOH (25 ml) is stir for 22 hours at room temperature, under an atmosphere of nitrogen. The reaction mixture is filtered through a celite cloth and concentrated. Purification of the residue by silica gel column chromatography (DCM / MeOH + 1% NH3eq, 95: 5) yields 797 mg of the title compound as a brown oil: ESI-MS: 179.0 [MH] +; TLC: Rf = 0.14 (DCM / MeOH + 1% NH3eq, 95: 5).

C. Dimethy- [3- (4-nitro-phenyl) -prop-2-ynyl] -amine

Tri-t-butylphosphine (0.25 M in dioxane, 11.9 ml, 3.0 mmol, 0.2 equivalent), 3-dimethylamino-1-propyne (2.2 ml, 20.8 mmol, 1.4 equivalent) and diisopropylamine (2.7 ml, 19.3 mmol, 1.3 equivalent) are sequentially added to a mixture of 4-bromonitrobenzene (3 g, 14.9 mmol), copper (I) iodide (198 mg, 1.0 mmol, 0.07 equivalent), and Pd (PhCN) 2Cl2 (570 mg, 1.5 mmol, 0.1 equivalent ) in dioxane (20ml), under an argon atmosphere. The resulting mixture is stirred for 22 hours at room temperature and concentrated. The residue is dissolved in EE and water and filtered through a celite cloth. The aqueous layer is separated and extracted with EE. 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% NH3eq, 95: 5) yields 2.72 g of the title compound as a brown oil: ESI-MS: 205.0 [MH] +; tR = 2.51 min (purity: 100%, gradient J); TLC: Rf = 0.41 (DCM / MeOH + 1% NH3eq, 95: 5).

Example 148: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino] -pyrimidin- 4-il} -urea

The title compound is prepared as described in Example 144 but using N-methyl-N '- [4- (2-pyrrolidin-1-ylethoxy) -phenyl] -pyrimidine-4,6-diamine (227 mg, 0.72 mmol, 1 eq.). Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3eq, 92: 8) yields 156 mg of the title compound as a white solid: ESI-MS: 560.9 / 562.9 [MH] + ; tR = 3.64 min (purity: 100%, gradient J); TLC: Rf = 0.42 (DCM / MeOH + 1% NH3eq, 92: 8).

A. N-Methyl-N ’- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] - pyrimidine-4,6-diamine

The title compound is prepared as described in example 143A but using 4- (2-pyrrolidin-1-yl-ethoxy) phenylamine (360 mg, 1.70 mmol, 1 equivalent) and stirring the reaction mixture for 18 hours at 150 ° C . The reaction mixture is allowed to cool to room temperature and the upper phase is discarded. The gummy bottom residue is diluted with a saturated aqueous solution of sodium bicarbonate and DCM-The aqueous layer is separated and extracted with DCM. The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3eq, 9: 1), followed by trituration of the resulting solid in diethyl ether, yields 402 mg of the title compound as a gray solid ESI- MS: 314.1 [MH] +; tR =

1.15 min (gradient J); purity: 100%, gradient J); TLC: Rf = 0.15 (DCM / MeOH + 1% NH3eq, 9: 1).

B. 4- (2-Pyrrolidin-1-yl-ethoxy) -phenylamine.

The title compound is prepared as described in Example 146B but using 1- (2-chloroethyl) -pyrrolidine hydrochloride (7.6 g, 44.9 mmol, 1.2 eq.) And stirring the reaction mixture for 2h at 75 ° C . Purification of the residue by silica gel column chromatography (DCM / MeOH, 1: 1) yields 7.7 g of the title compound as a brown oil; ESI-MS: 207.1 [MH] +; TLC: Rf = 0.22 (DCM / MeOH, 1: 1).

Example 149: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1-methylurea

The title compound is prepared as described in Example 144 but using N- [4- (4-ethyl-piperazin-1-ylmethyl) phenyl] -N'-methyl-pyrimidine-4,6-diamine (140 mg, 0.43 mmol, 1 eq.). Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH3eq, 95: 5) yields 24 mg of the title compound: ESI-MS: 573.9 / 575.9 [MH] +; tR = 3.25 min (purity: 90%, gradient J); TLC: Rf = 0.09 (DCM / MeOH + 1% NH3eq, 9: 1).

A. N- [4- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using 4- (4-ethyl-piperazin-1-ylmethyl) phenylamine (500 mg, 2.28 mmol, 1 eq.) And stirring the reaction mixture for 18h at 150 ° C. Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH3eq, 9: 1) produces 140 mg of impure product which is used without further purification.

B. 4- (4-Ethyl-piperazin-1-ylmethyl) -phenylamine

A suspension of 1-ethyl-4- (4-nitro-benzyl) -piperazine (7.2 g, 29.14 mmol) and Raney nickel (1.5 g) in MeOH (100 ml) is stirred for 6 hours at room temperature, under an atmosphere of hydrogen. The reaction mixture is filtered through a celite cloth and concentrated to yield 6.3 g of the title compound as a yellow solid ESI-MS: 220.1 [MH] +; TLC: Rf = 0.08 (DCM / MeOH + 1% NH3eq, 9: 1).

C. 1-Ethyl-4- (4-nitro-benzyl) -piperazine.

A mixture of 4-nitrobenylchloride (5 g, 29.14 mmol), N-ethylpiperazine (4.4 ml, 34.97 mmol, 1.2 equivalent) potassium carbonate (8 g, 58.28 mmol, 2 equivalent) and acetone (100 ml) is stirred for 15 hours at reflux. The reaction mixture is allowed to cool to room temperature, filtered and concentrated to yield 7.2 g of the title compound as a brown oil: ESI-MS: 250.1 [MH] +; TLC: Rf = 0.31 (DCM / MeOH + 1% NH3eq, 9: 1).

Example 150: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [3- [4-ethyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1-methylurea

The title compound is prepared as described in Example 144 but using N- [3- (4-ethyl-piperazin-1-ylmethyl) phenyl] -N'-methyl-pyrimidine-4,6-diamine (306 mg, 0.94 mmol, 1 eq.). Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH3eq, 95: 5) yields 207 mg of the title compound: ESI-MS: 573.9 / 575.9 [MH] +; tR =

3.28 min (purity: 100%, gradient J); TLC: Rf = 0.24 (DCM / MeOH + 1% NH3 eq, 95: 5).

A. N- [3- (4-Ethyl-piperazin-1-ylmethyl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using 3- (4-ethyl-piperazin-1-ylmethyl) phenylamine (500 mg, 2.28 mmol, 1 eq.) And stirring the reaction mixture for 15h at 150 " ;C. Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH3 eq, 9: 1) yields 306 mg of the title compound as a beige solid: ESI-MS: 327.2 [MH] +; TLC: Rf = 0.05 (DCM / MeOH + 1% NH3 eq, 9: 1).

B. 3- (4-Ethyl-piperazin-1-ylmethyl) -phenylamine

The title compound is prepared as described in Example 149B: ESI-MS: 220.1 [MH] +; tR = 0.79 min (purity: 100%, gradient J).

C. 1-Ethyl-4- (3-nitro-benzyl) -piperazine

The title compound is prepared as described in Example 149C; ESI-MS: 250.1 [MH] +; tR = 1.50 min (purity: 100%, gradient J); TLC: Rf = 0.32 (DCM / MeOH + 1% NH3, 9: 1). Example 151: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (3-dimethylaminomethyl-phenylamino) -pyrimidin-4-yl] -1-ethyl-urea

A suspension of 2,6-dichloro-3-methoxyphenyl isocyanate (2 equivalent) in toluene (3 ml) is added to a reflux solution of N- (3-dimethylaminomethyl-phenyl) -N'-methyl-pyrimidine-4,6 -diamine (216 mg, 0.80 mmol, 1 equivalent) in toluene (3 ml), under an argon atmosphere. The resulting mixture is stirred at reflux for 2 hours and allowed to cool to room temperature. The reaction mixture is diluted with EE and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with EE. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM / eOH + 1% NH, 95: 5), followed by purification by reverse phase MPLC (AcCN / H2O / TFA) of the resulting product, produces 161 mg of the compound of the title in the form of a white solid: ESI-MS: 518.9 / 520.9 [MH] +; tR =

3.76 m / n (purity: 100%, gradient J); TLC: Rf = 0.21 (DCM / MeOH + 1% NH3, 95: 5).

A. N- (3-Dimethylaminomethyl-phenyl) -N'-ethyl-pyrimidine-4,6-diamine.

The title compound is prepared as described in example 143A but using 3-dimethylaminomethylphenylamine (3.34 mg, 2.20 mmol, 1 equivalent), (6-chloro-pyrimidin-4-yl) -ethyl-amine (Example 1438), and stirring the reaction mixture for 3 hours at 160 ° C. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3, 9: 1) followed by trituration of the resulting solid in diethyl ether, produces 335 mg of the title compound as a beige solid: ESIMS: 272.1 [MH] +; tR = 1.18 min (purity: 100%, gradient J); TLC: Rf = 0.16 (DCM / MeOH + 1% NH2, 9: 1).

Example 152: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -1-methyl -urea

The title compound is prepared as described in Example 151 but using N- [4- (2-diethylamino-ethoxy) -phenyl] N'-methylpyrimidine-4,6-diamine (255 mg, 0.81 mmol, 1 eq. ). Purification of the crude product by column chromatography (silica gel) (DCM / MeOH + 1% NH3, 95: 5), followed by trituration of the resulting solid in MeOH, yields 220 mg of the title compound as a white solid: ESI-MS: 562.9 / 564.9 [MH] +; tR = 3.70 min (purity: 93%, gradient J): TLC: Rf = 0.21 (DCM / MeOH + 1% NH3, 95: 5).

A. N- [4- (2-Diethylamino-ethoxy) -phenyl] -N'-methyl-pyrimidine-4,6-diamine.

The title compound is prepared as described in example 143A but using 4- (2-diethylamino-ethoxy) phenylamine (271 mg, 1.3 mmol, 1 equivalent) and stirring the reaction mixture for 18 hours at 150 ° C. The reaction mixture is allowed to cool to room temperature and the upper phase is discarded. The gummy bottom residue is diluted with a saturated aqueous solution of sodium bicarbonate and DCM. The aqueous layer is separated and extracted with DCM. The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3, 92: 8) provides 261 mg of the title compound as a gray solid ESI-MS: 316.1 [MH] +: tR = 1.25 min (purity: 100%, gradient J); TLC: Rf = 0.19 (DCM / MeOH + 1% NH3, 92: 8).

B. 4- (2-Diethylamino-ethoxy) -phenylamine.

The title compound is prepared as described in Example 146B but using 1- (2-chloroethyl) diethylamine hydrochloride (1.8 g, 11 mmol. 1.2 eq.) And stirring the reaction mixture for 1 h at RT. Purification of the residue by silica gel column chromatography (DCM / MeOH, 4: 1 - 7: 3) yields 1.52 g of the title compound as a brown oil: ESI.MS: 209.1 [MH] +; TLC: Rf = 0.12 (DCM / MeOH, 7: 3).

Example 153: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (2,6-dimethyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1-methylurea

The title compound is prepared as described in Example 151 but using N- (2,6-dimethyl-pyridin-3-yl) -N'methyl-pyrimidine-4,6-diamine.

ESI-MS: 476.9 / 478.9 [MH] +; tR = 3.44 min (purity: 100%, gradient J); TLC: Rf = 0.40 (DCM / MeOH + 1% NH3aq, 9: 1).

A. N- (2,6-Dimethyl-pyridin-3-yl) -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using 3-amino-2,6-dimethylpyrimidine and stirring the reaction mixture for 24h at 150 ° C.

ESI-MS: 230.1 [MH] +; TLC: Rf = 0.22 (DCM / MeOH, 9: 1). Example 154: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- [6- (6-trifluoromethyl-pyridin-3-ylamino) -pyrimidin-4-yl] -urea

The title compound is prepared as described in Example 151 but using N-methyl-N '- (6-triftuoromethylpyridin-3-yl) -pyrimidine-4,6-diamine.

ESI-MS: 514.8 / 516.8 [MH] +; tR = 5.27 min (purity: 100%, gradient J); TLC: Rf = 0.49 (DCM / MeOH, 9: 1).

A. N-Methyl-N '- (6-trifluoromethyl-pyridin-3-yl) -pyrimidin-4,6-diamine The title compound is prepared as described in Example 152A but using 3-amino-6- ( trifluomethyl) pyridine

25 and stirring the reaction mixture for 24h at 150 ° C. ESI-MS: 270.0 [MH] +: t R = 2.63 min (purity: 100%, gradient J); TLC: Rf = 0.32 (DCM / MeOH, 9: 1).

Example 155: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea

The title compound is prepared as described in Example 151 but using N- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl]

- pyrimidine-4,6-diamine.

5 ESI-MS: 546.9 / 548.8 [MH] +; tR = 3.15 min (purity: 100%, gradient J); TLC: Rf = 0.49 (OCM / MeOH + 1% NH3aq, 95: 5).

A. N- [4- (2-Pyrrolidin-1-yl-ethoxy) -phenyl] -pyrimidine-4,6-diamine The title compound is prepared as described in Example 152A but using 6-chloro-pyrimidine- 4-ylamine, 4 (2-pyrrolidin-1-yl-ethoxy) -phenylamine (Example 148B), and stirring the reaction mixture for 2h at 150 ° C.

10 ESI.MS: 300.1 [MH] +; tR = 1.10 min (purity: 100%, gradient J). Example 156: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-ethyl-1- {6- [4- (2-pyrrolidin-1-yl ethoxy) -phenylamino] -pyrimidin-4 -il} -urea

The title compound is prepared as described in Example 151 but using N-ethyl-N '- [4- (2-pyrrolidin-1-ylethoxy) -phenyl] -pyrimidin-4,6-diamine.

ESI-MS: 575.2 / 577.2 [MH] +; tR = 3.74 min (purity: 100%, gradient J); TLC; Rf = 0.42 (DCM / MeOH + 1% NH3aq, 95: 5).

A. N-Ethyl-N ’- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] - pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using 6-chloro-pyrimidin-4-yl) -ethylamine, 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (Example 148B), and stirring the reaction mixture for 6h at 150 ° C. The crude product is purified by trituration in diethyl ether. ESI-MS: 326.1 [MH] +; tR = 1.45 min (purity: 95%, gradient J).

Example 157: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- [6- (3-dimethylaminomethyl-phenylamino) -pyrimidin-4-yl] -urea

The title compound is prepared as described in Example 151 but using N- (3-dimethylaminomethyl-phenyl) 25 pyrimidine-4,6-diamine.

ESI-MS: 491.0 / 493.0 [MH] +; tR = 3.17 min (purity: 97%, gradient J): TLC: Rf = 0.25 (DCM / MeOH + 1% NH3aq, 92: 8).

A. N- (3-Dimethylaminomethyl-phenyl) -pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using 3-dimethylaminomethylphenylamine, 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 2 hours at 150 ° C. The crude product is purified by trituration with diethyl ether followed by silica gel column chromatography (DCM / MeOH + 1% NH3 27, 92: 8) of the resulting beige solid to yield the title compound as a white solid: ESI-MS: 242.1 [MH] +; tR = 0.95 min (purity: 100%, gradient J); TLC: Rf = 0.11 (DCM / MeOH + 1% NH3aq, 92: 8).

Example 158: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- (6- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenylamino} - pyrimidin-4-yl) urea

The title compound is prepared as described in Example 151 but using N- (3-dimethylaminomethyl-phenyl) pyrimidine-4,6-diamine.

ESI-MS: 575.9 / 577.9 [MH] +; tR = 2.83 min (purity: 100%, gradient J): TLC: Rf = 0.03 (DCM / MeOH + 1% NH3aq, 95: 5).

A. N- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenyl} -pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using 4- [2- (4-methyl-piperazin-1-yl) ethoxy] -phenylamine (300 mg, 1.28 mmol. 1 eq.), 6-chloro -pyrimidin-4-ylamine, water (0.5 ml), and stirring the reaction mixture for 2h at 150 ° C. The crude product is purified by trituration in diethyl ether to produce the title compound as a white solid. ESI-MS: 329.1 [MH] +; tR = 0.98 min (purity: 100%, gradient J).

Example 159: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- [6- (4-dimethylaminomethyl-3-trifluoromethyl-phenylamino) -pyrimidin-4-yl] urea

The title compound is prepared as described in Example 151 but using N- (4-dimethylaminomethyl-3-trifluoromethyl-phenyl) -pyrimidine-4,6-diamine.

ESI-MS: 558.9 / 560.9 [MH] +; tR = 3.69 min (purity: 100%, gradient J); TLC: Rf = 0.21 (DCM / MeOH + 1% NH3aq, 95: 5).

A. N- (4-Dimethylaminomethyl-3-trifluoromethyl-phenyl) -pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (218 mg, 1.46 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 5h at 150 ° C. The crude product is purified by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 92: 8) to yield the title compound as a white solid. ESI-MS: 312.1 [MH] +; tR = 1.20 min (purity: 100%, gradient J); TLC: Rf = 0.16 (DCM / MeOH + 1% NH3aq, 92: 8).

B. 4- (4- (N, N-Dimethylamino-methyl) -3-trifluoromethyl-phenyl-amine

N- (4-Dimethylaminomethyl-3-trifluoromethyl-phenyl) -pyrimidine-4,6-diamine (359 mg, 1.2 mmol) is dissolved in MeOH (12 ml) and treated with K2CO3 (6 mL of a 1N aqueous solution) at room temperature. The reaction is heated at reflux for 1.5 hours until termination, cooled again to room temperature and concentrated. Oil

Residual is taken in EtOAc and washed with brine. The organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. Drying under high vacuum gives the title compound as a yellow ESI-MS oil: 219 [MH] +.

C. N- (4-Dimethylaminomethyl-3-trifluoromethyl-phenyl) -pyrimidine-4,6-diamine.

501 mg of (1.5 mmol) N- (4-bromomethyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoro-acetamide (step 14.2) is added to 5 ml of a solution of dimethylamine in EtOH (33%) at room temperature. The reaction is stirred at room temperature for 0.5 hours until its termination. It is concentrated and the residual crude product is purified by flash chromatography (SiO2, CH2Cl2 / MeOH gradient 0-5% MeOH) to give the title compound as a yellow ESI-MS oil: 315 [MH] +.

D. -N (4-Bromomethyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide.

To a solution of 60.9 g (224.6 mmol) of N- (4-methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide in 830 ml of N-butyl acetate under a nitrogen atmosphere, 44 are added g (247 mmol) of N-bromosuccinimide and 830 mg (5 mmol) of azo-iso-butyronitrile. The suspension is heated to 60 ° C and then illuminated for 30 minutes with a Philips low-voltage lamp (500 w; 10500 lm), whereby the temperature rises to 70-75 ° C and a light brown solution is formed. There is still detectable remnant educt, so another 22 g of Nbromosuccinimide are added in three portions. After illumination for a total of 6 hours, the resulting solid is filtered and discarded and the filtrate is concentrated. The residue is distributed between 2L of CH2Cl2 and 1L of H2O and the aqueous layer is extracted with 1L of CH2Cl2. The organic phases are washed four times with 1 L of H2O, 0.5 L of brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2, hexane / CH2Cl2, 2: 1 -1: 1) and crystallization from CH2Cl2 / hexane yields the title compound: m.p .: 119-120 ° C.

E. N- (4-Methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoro-acetamide

To an ice-cold solution of 320 g (1,827 mol) of 5-amino-2-methylbenzotrifluoruroe and 1.47 l (18.27 mol) of pyridine in 4.5 l of CH2Cl2 under N2 atmosphere, 284 ml (2.01mol) of anhydride are added of trifluoroacetic acid drop by drop. After 50 minutes, the mixture is diluted with 5 L of ice cold 2N HCl. The organic phases are separated and washed twice with 2 liters of cold 2N HCl, then with 1 l of 2N HCl and finally with 2 l of brine. The aqueous layers are extracted twice with CH2Cl2, the organic phases are dried (Na2SO4), and partially concentrated. Crystallization by the addition of hexane yields the title compound m.p .: 72-73 ° C.

Example 160: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

2,6-Dichloro-3,5-dimethoxyphenyl isocyanate (1.2 equivalent) is added to a solution of N- [4- (4-ethyl-piperazin-1-yl) -phenyl]

-

 pyrimidine-4,6-diamine (350 mg, 1.18 mmol) in NPM (2 ml) at 70 ° C and under an argon atmosphere. The resulting mixture is stirred at 70 ° C for 2 hours, allowed to cool to room temperature and concentrated. The residue is diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the crude product by trituration in MeOH followed by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 97: 3) yields the title compound as a white solid: ESI-MS: 545.9 / 547.9 [ MH] +; tR = 3.10 min (purity: 100%, gradient J); TLC: Rf = 0.18 (DCM / MeOH + 1% NH3aq, 95: 5).

TO.

 N- [4- (4-Ethyl-piperazin-1-yl) -phenyl] pyrimidine-4,6-diamine.

A mixture of 6-chloro-pyrimidin-4-yl) -amine ((500 mg, 3.87 mmol, 1.3 equivalent) and 4- (4-ethylpiperazin-1-yl) -aniline (611 mg, 2.98 mmol) in water ( 3.0 ml) and glacial acetic acid (10 ml) is heated at 100 ° C. for 15 hours.The reaction mixture is diluted with DCM and brine.The aqueous layer is basified by the addition of sodium bicarbonate.The aqueous layer is separated and separated. Extract with DCM The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated Purification of the crude product by trituration in the US produces the title compound: ESI-MS: 299.2 [MH] +; tR = 1.05 min (gradient J).

Example 161: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [3- (4-isopropyl-piperzin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1 methyl urea.

The title compound is prepared as described in Example 151 but using N- [3- (4-isopropyl-piperazin-1-methylmethyl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine. Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH3aq, 95: 5) yields the title compound as a white solid. ESI-MS: 587.9 / 589.9 [MH] +; tR =

3.35 min (purity: 100%, gradient J); TLC: Rf = 0.17 (DCM / MeOH + 1% NH3aq, 9: 1).

A. N- [3- (4-Isopropyl-piperazin-1-ylmethyl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using 3- (4-isopropyl-piperazin-1-methylmethyl) -phenylamine and stirring the reaction mixture for 17.5h at 150 ° C. The crude product is purified by MPLC (silica gel) (DCM / MeOH + 1% NH3aq, 95: 5) to produce the title compound as a light yellow solid. ESI-MS: 341.2 [MH] +; tR = 1.05 min (purity: 100%, gradient J); TLC: Rf = 0.10 (DCM / MeOH + 1% NH3aq, 9: 1).

B. 3- (4-Isopropyl-piperazin-1-ylmethyl) -phenylamine

The title compound is prepared as described in Example 149B: ESI-MS: 234.2 [MH] +.

C. 1-Isopropyl-4- (3-nitro-benzyl) -piperazine

The title compound is prepared as described in Example 149C. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 9: 1) yields the title compound as a yellow solid: ESI-MS: 264.1 [MH] +; tR = 1.64 min (purity: 96.5%, gradient J); TLC: Rf = 0.35 (DCM / MeOH + 1% NH3aq, 9: 1).

Example 162: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- {3 - {[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -phenylamino) pyrimidine -4-il] -1-methyl-urea

The title compound is prepared as described in Example 151 but using N- (3 - ([(2-dimethylamino-ethyl) methyl-amino] -methyl) -phenyl) -N'-methyl-pyrimidine-4,6 -diamine. Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH3aq, 95: 5) yields the title compound as a white solid: ESI-MS: 561.9 / 563.9 [MH] +; tR = 3.24 min (purity: 100%, gradient J); TLC: TA = 0.10 (DCM / MeOH + 1% NH3aq, 9: 1).

A. N- (3 - {[(2-Dimethylamino-ethyl) -methyl-amino] -methyl} -phenyl) -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using N- (3-amino-benzyl) -N, N’.N’trimethylethane-1,2-diamine and stirring the reaction mixture for 17.5h at 150 ° C. The crude product is purified by MPLC (silica gel) (DCM / MeOH +% NH3aq, 95: 5) to produce the title compound as a beige solid. ESI-MS: 315.2 [MH] +; TLC: Rf = 0.05 (DCM / MeOH + 1% NH3aq, 9: 1).

B. N- (3-Amino-benzyl) -N, N ’, N’-trimethyl-ethane-1,2-diamine

The title compound is prepared as described in Example 149B: ESI-MS: 208.2 [MH] +.

C. N, N ’, N’-Trimethyl-N’ - (3-nitro-benzyl) -ethane-1,2-diamine

The title compound is prepared as described in Example 149C. Purification of the crude product by silica gel column chromatography (DCM-DCM / MeOH + 1% NH3aq, 9: 1) yields the title compound as a brown oil: ESI-MS: 238.1 [MH] +; tR = 1.15 min (purity: 96.5%, gradient J); TLC: TA = 0.10 (DCM / MeOH, 9: 1).

Example 163: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-isopropyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -1-methylurea

The title compound is prepared as described in Example 151 but using N- [4- (4-isopropyl-piperazin-1-yl) 10 phenyl] -N'-methyl-pyrimidine-4,6-diamine.

ESI-MS: 573.9 / 575.9 [MH] +; tR = 3.65 min (purity: 97%, gradient J): TLC: Rf = 0.10 (DCM / MeOH + 1% NH3aq, 97: 3).

A. N- [4- (4-Isopropyl-piperazin-1-yl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 152A but using N- (3-amino-benzyl) -N, N ’, N’

15 trimethylethane-1,2-diamine and stirring the reaction mixture for 4h at 150 ° C. The crude product is purified by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 92: 8) to yield the title compound as a white solid. ESI-MS: 327.2 [MH] +; TLC: Rf = 0.26 (DCM / MeOH + 1% NH3aq, 92: 8).

B. 4- (4-Isopropyl-piperazin-1-yl) -phenylamine The title compound is prepared as described in Example 149B: ESI-MS: 220.1 [MH] +. C. 1-Isopropyl-4- (4-nitro-phenyl) -piperazine The title compound is prepared as described in Example 149C. Purification of the crude product by

silica gel column chromatography (DCM / MeOH, 95: 5) produces the title compound as a yellow solid: ESI-MS; 238.1 [MH] +: tR = 2.57 min (purity: 100%, (gradient J); TLC: Rf = 0.16 (DCM / MeOH, 95: 5) Example 164: 1- (2,6-Dichloro-3, 5-dimethoxy-phenyl) -3- {6- [4- (1-methyl-piperidin-4-yloxy): phenylamino] -pyrimidin-4-yl} -urea

Example 165: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl- {6- [4- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4- il} -urea Example 166: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-ethyl- (6- [4- (1-methyl-piperidin-4-yloxy) -phenylamino] - pyrimidin-4-yl) -urea

Example 167: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (4-dimethylaminomethyl-3-trifluoromethylamino) -pyrimidin-4-yl] -1-methyl-urea

Example 168: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl-3- {6- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenylamino] -pyrimidin4-yl }-urea

Example 169: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenylamino] 10 pyrimidine- 4-yl} -1-methyl-urea

Example 170: Enzymatic data in vitro

The compounds of Examples 1 to 169 were tested under the protocols as described herein for their inhibitory activity against KDR, FGFR3 and TEK. The measurements were made as described in the methods before

15 mentioned in the general description. For KDR a 10 μM inhibition of 67-100% was observed, for FGFR3 (K650E) a 27-100% inhibition at 10 μM and for TEK a 12-100% inhibition at 10 μM.

Method A: Examples 171-193

Example 171: N- [4-Methyl-3- (3-methyl-3 {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -ureido) -phenyl] -3trifluoromethyl-benzamide

To a solution of N- (3-Amino-4-methyl-phenyl) -3-trifluoromethyl-benzamide (preparation 3.62 mg, 0.21 mmol, 1.25 equivalent) in dioxane is added 20% phosgene solution in toluene (110 μL , 0.21 mmol, 1.25 equivalent) under argon. The reaction mixture is stirred for an additional 22 hours at room temperature under argon. Then, the solvent is evaporated and the residue is taken in dry toluene (2 ml). After the addition of N-Methyl N '- [4- (4-methylpiperazin-1-yl) -phenyl] -pyrimidine-4,6-diamine (50 mg, 0.168 mmol, 1.0 equivalent) the suspension is

25 refluxed for 24 hours under argon. After cooling ether (2 ml) is added and the mixture is stirred for

30 minutes. The precipitated product is filtered, washed (1x toluene / ether 1: 1, 1 x ether) and dried in vacuo at 60 ° C overnight to yield the title compound as colorless crystals: M.p. 189.5-191 ° C, HPLC: t R = 6.02 min (purity:> 99%, gradient A), ESI-MS: 619.6 [MH] +.

N-Methyl-N ’- [4- (4-methyl-piperazin-1-yl) -phenyl] -4,6-diamine

A solution of (6-chloro-pyrimidin-4-yl) -methyl-amine (1.65 g, 11.5 mmol, 1.1 equivalent) and 4- (4-methylpiperazin-1-yl) aniline (2.0 g, 10.5 mmol, 1.0 equivalent ) commercially available in a mixture of water (4 ml) and glacial acetic acid (16 ml) is heated at 100 ° C internal temperature for 16 hours. After cooling, the solvent evaporates.

The residue is taken in methanol (50 ml) and is achieved by the addition of 25% NH3 in water. To this silica gel (11 g) is added and the solvent evaporates. The crude product adsorbed on the silica is purified by medium pressure liquid chromatography (A: TBME; B: MeOH-NH3 99: 1; gradient: 5% B -> 25% B in 180 min). Fractions containing the product are combined and evaporated to dryness. The residue is triturated with ether. The product is filtered, washed with ether, and dried in vacuo at 50 ° C overnight to give the title compound as a pale yellow powder: t R = 3.04 min (purity: 97%. Gradient A), ESI- MS: 299.3 [MH] +.

(6-Chloro-pyrimidin-4-yl) -methyl-amine

This material was prepared using a modified procedure published in the literature (J. Appl. Chem. 1955, 5, 358): to a suspension of 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0 equivalent) commercially available in isopropanol ( 60 ml) 33% methylamine in ethanol (40.1 ml, 328.9 mmol, 2.5 equivalent) is added at such a rate that the internal temperature does not rise above 50 ° C. After finishing the addition the reaction mixture was stirred for 1 hour at room temperature. Water (50 ml) was then added and the suspension formed is cooled in a water bath at 5 ° C. The precipitated product is filtered, washed with 2: 1 isopropanol / cold water (45 ml) and water. The collected material is dried under vacuum overnight at 45 ° C to produce the title compound as colorless crystals: tR = 3.57 min (purity:> 99%, gradient A), ESI-MS: 144.3 /146.2 [MH] + .

Following the procedure of example 171 but using the appropriate starting materials, examples 172 to 193 can be prepared.

Example 172: N- (4-Methyl-3- [3- (6-methylamino-pyrimidin-4-yl) -ureido] -phenyl) -3-trifluoromethyl-benzamide

Colorless crystals, TLC: Rf = 0.40 (TBME / MeOH / NH3 90: 9: 1), HPLC: is = 5.88 min (purity: 85%, gradient A), ESI-MS: 445.4 [MH] +.

Example 173: N- (4-Methyl-3- [3- (6-phenylamino-pyrimidin-4-yl) -ureid] -phenyl) -3-trifluoromethyl-benzamide

Colorless crystals, HPLC: t R = 6.94 min (purity:> 99%, gradient A), ESI-MS: 507.4 [MH] +.

Example 174: N- [4-Methyl-3- (3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -_ ureido) -phenyl] - 3-trifluoromethylbenzamide

Colorless crystals, TLC: Rf = 0.53 (TBME / MeOH / NH3 80: 18: 2), HPLC; tR = 5.79 min (purity:> 99%, gradient A), ESI-MS: 605.5 [MH] +.

Example 175: N- [4-Methyl-3- (3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} ureido) -phenyl] -3- trifluoromethylbenzamide

Colorless crystals, TLC: Rf = 0.34 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.72 min (purity:> 99%, gradient A), ESIMS: 605.5 [MH] +.

Example 176: N- [3- (3- {6- [4- (2-Diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl) -ureido} -4-methyl-phenyl] -3-trifluoromethylbenzamide

Colorless crystals, TLC: Rf = 0.63 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 5.84 min (purity:> 99%, gradient A), ESIMS: 622.4 [MH] +

Example 177: N- [3- (3- {6- [4- (3-Dimethylamino-propoxy) -phenylamino] -pyrimidin-4-yl} -ureido) -4-methyl-phenyl] -3-trifluoromethylbenzamide

Colorless crystals, HPLC: t R = 5.75 min (purity:> 99%, gradient A), ESI-MS: 608.4 [MH] +.

Example 178: N- [3- (3- {6- [3- (2-Dimethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -ureido); 4-methyl-phenyl] -3-trifluoromethylbenzamide

Colorless crystals, TLC: Rf = 0.17 (TBME / MeOH 30:70). HPLC: t R = 5.72 min (purity: 95%, gradient A), ESI-MS:

594.5 [MH] +.

Example 179: N- [4-Methyl-3 (3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl) -ureido) -phenyl-3- trifluoromethylbenzamide

Colorless crystals, TLC: Rf = 0.31 (TBME / MeOH 80:20), HPLC: tR = 5.66 min (purity:> 99%. Gradient A), ESI-MS:

636.5.4 [MH] +.

Example 180: N- [4-Methyl-3- {6- [3- (2-morpholin-4-yl-ethoxy) -phenylamino} -pyrimidin-4-yl} -ureido) -phenyl] -3-trifluoromethylbenzamide

Colorless crystals, TLC: Rf = 0.42 (TBME / MeOH 75:25), HPLC: tR = 5.36 min (purity:> 99%, gradient A), ESI-MS:

636.6 [MH] +.

Example 181: N- {4-Methyl-3- [3-methyl-3- (6-phenylamino-pyrimidin-4-yl) -ureido] -phenyl} -3-trifluoromethyl-benzamide

Colorless crystals, TLC: Rf = 0.69 (TBME / MeOH90: 10), HPLC: tR = 7.67 min (purity:> 99%, gradient A), ESI-MS:

521.4 [MH] +.

Example 182: N- [3- (3- {6- [3- (2-Dimethylamino-ethoxy-phenylamino] -pyrimidin-4-yl) -3-methyl-ureido) -4-methyl-phenyl] -3trifluoromethyl- benzamide

Colorless crystals, TLC: Rf = 0.51 (TBME / MeOH / NH3 80: 18: 2). HPLC: t R = 6.02 min (purity:> 99%, gradient A), ESIMS: 608.4 [MH] +.

Example 183: N- [3- (3- {6- [4- (2-Diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -3-methyl-ureido) -4-methyl-phenyl] - 3trifluoromethyl-benzamide

Colorless crystals, TLC: Rf = 0.24 (TBME / MeOH 75:25), HPLC: tR = 6.23 min (purity: 94%, Gradient A), ESI-MS:

636.5 [MH] +.

Example 184: N- {4-Methyl-3- [3-methyl-3- (6- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenylamino-pyrimidin-4- il) -ureido] -phenyl} -3trifluoromethyl-benzamide

Colorless crystals, TLC: Rf = 0.21 (DCM / MeOH 80:20), HPLC: tR = 6.07 min (purity: 88%, gradient A), ESI-MS:

633.2 [MH] +.

Example 185: N-4-Methyl-3- [3-methyl-3- (6- {3- [2- (4-methyl-piperazin-1yl) -ethoxy] -phenylamino} -pyrimidin-4-yl) -ureido] -phenyl} -3trifluoromethyl-benzamide

Colorless crystals, HPLC: t R = 6.15 min (purity: 92%, gradient A), ESI-MS: 633.3 [MH] +.

Example 186: 4-Methyl-3- (3-methyl-3- {6- [4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -ureido) -N- (3-trifluoromethyl -phenyl) -benzamide

Colorless powder, HPLC: t R = 6.19 min (purity: 96%, gradient A), ESI-MS: 619.3 [MH] +.

5 Example 187: N- [4-Methyl-3- (3-methyl-3- {6- [4-methyl-piperazin-1-carbonyl-phenylamino] -pyrimidin-4-yl} -ureido) -phenyl] - 3trifluoromethyl-benzamide

Colorless crystals TLC: Rf = 0.50 (DCM / MeOH 80:20), HPLC: tR = 5.82 min (purity: 88%, gradient A), ESI-MS:

647.6 [MH] +.

Example 188: N- [4-Methyl-3- (3-methyl-3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -ureido) -phenyl] -3trifluoromethyl-benzamide

Pale yellow crystals, TLC: Rf = 0.50 (TBME / MeOH / NH3 80: 18: 2), HPLC: tR = 6.14 min (purity: 95%, gradient A), ESIMS: 619.5 [MH] +.

Example 189: N- (4-Methyl-3- {3- [2- (4-methyl-piperazin-1-yl) -ethyl] -3- (6-phenylamino-pyrimidin-4-yl) -ureido] -phenyl} -3trifluoromethyl-benzamide

Colorless crystals, TLC: Rf = 0.04 (TBME / MeOH 90:10), HPLC: tR = 6.26 min (purity:> 100%, gradient A), ESI-MS: 633.5 [MH] +.

Example 190: N- {4-Methyl-3- [3- (6-phenylamino-pyrimidin-4-yl) -3- (2-pyridin-2-yl-ethyl) -ureido] -phenyl} -3- trifluoromethylbenzamide

Colorless crystals, HPLC: t R = 7.58 min (purity:> 100%, gradient A), ESI-MS: 612.4 [MH] +.

Example 191: N- {4-Methyl-3- [3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimid-in-4-yl} -3- (2- pyridin-2-ylethyl) -ureido] phenyl} -3-trifluoromethyl-benzamide

Pink crystals, TLC: Rf = 0.54 (DCM / MeOH 80:20), HPLC: tR = 5.87 min (purity: 92%, gradient A), ESI-MS:

710.6 [MH] +.

Example 192: N- [3- (3-Ethyl-3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -ureido) -4-methyl- phenyl] -3trifluoromethyl-benzamide

Colorless crystals, TLC: Rf = 0.45 (DCM / MeOH 60:20), HPLC: tR = 6.18 min (purity:> 100%, gradient A), ESI-MS: 10 633.6 [MH] +.

Example 193: N- [4-Methyl-3- (3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-in-4-yl} -3-thiophene-2 -ylmethyl-ureido) -phenyl] -3-trifluoromethyl-benzamide

Colorless crystals, TLC: Rf = 0.26 (DCM / MeOH 90:10), HPLC: tR = 6.51 min (purity:> 100%, gradient A), ESI-MS: 15 701.5 [MH] +.

Method B: Examples 194-201

Example 194: N- {3- [3- (6-Amino-pyrimidin-4-yl) -3-methyl-ureido] -4-methyl-phenyl} -4- (4-methyl-piperazin-1-ylmethyl) -3trifluoromethyl-benzamide

A tert-Butyl [6- (1-Methyl-3- {2-methyl-5- [4- (4-methyl-piperazin-1-ylmethyl-3-trifluoro-methyl-benzoylamino] -phenyl} -ureido) -pyrimidin-4-yl] -carbamate (50 mg, 0.076 mmol) trifluoroacetic acid / DCM 2: 3 (2ml) is added.The clear reaction mixture is stirred for 1 hour at room temperature, then methanol / DCM 1: 9 is added (20 ml) The solution is washed with 50% aqueous K2CO3, dried over MgSO4 and evaporated to give the title compound as a beige powder: Mp 191.5-193 ° C, HPLC: t R = 5.27 min ( purity:> 99%, gradient A), ESI-MS: 557.3 [MH] +, 400 MHz 1H

25 NMR (DMSO-d4) 5: 2.19 (s, 3H, NMe), 2.30 (s, 3H, ArMe), 2.24-2.62 (br m, 8H, piperazine), 3.32 (s, 3H, urea-NMe),

3.69 (s, 2H, ArCH2N), 6.09 (s, 1H, pyrimidine-H5), 7.02 (s, 2H, NH2), 7.19 (d, 1H, Ar-H5), 7.50 (dd, 1H, Ar-H4) , 7.91 (d, 1H, Ar'-H5), 8.23 (dd, 1H, Ar'-H6), 8.26 (d, 1H, Ar-H2), 8.30 (s, 1H, pyrimidine-H2), 8.41 (d , 1H, Ar'-H2), 10.41 (s, 1H, amide-NH).

tert-Butyl [6- (1-Methyl-3- {2-methyl-5- [4 - (- 4-methyl-piperazin-1-ylmethyl) -3-trifluoro-methyl-benzoylamino] -phenyl} -ureido) 30 pyrimidin-4-yl] -carbamate.

To a solution of 4- (4-Methyl-piperazin-1-ylmethyl) -2-trifluoromethyl-benzoic acid (preparation 2.80 mg, 0.27 mmol, 1.1 equivalent) in DMA is added HATU (138 mg, 0.36 mmol, 1.5 equivalent) and diisopropylethylamine (83 μl, 0.48 mmol,

2.0 equivalent) after stirring 10 minutes at room temperature, tert-butyl {6- [3- (5-Amino-2-methylphenyl) -1-methyl-ureido] -pyrimidin-4-yl} -carbamate is added. The reaction mixture is sonicated for 5 minutes. After stirring at room temperature overnight a gray suspension is formed. The precipitate is filtered, washed with DMA and ether. Drying under vacuum at 60 ° C overnight produces a gray powder: HPLC: t R = 6.30 min (purity:> 99%, gradient A), ESI-MS: 657.4 [MH] +

tert-Butyl {6- [3- (5-Amino-2-methyl-phenyl) -1-methyl-ureido] - pyrimidin-4-yl} -carbamate

A solution of tert-butyl {6- [3- (2-methyl-5-nitro-phenyl) -1-methyl-ureido] -pyrimidin-4-yl} -carbamate (330 mg, 0.82 mmol) in a mixture of Methanol (20 ml) and DMF (50 ml) are hydrogenated in the presence of 10% palladium on carbon (500 mg) at atmospheric pressure. After 20 hours the hydrogenation is terminated and the catalyst is filtered off. The filtrate is evaporated to dryness. The residue obtained is triturated with ether, filtered and dried under vacuum to yield a gray powder: HPLC: t R = 5.38 min (purity: 97%, gradient A), ESI-MS: 373.4 [MH] +.

tert-Butyl {6- [3- (2-methyl-5-nitro-phenyl) -1-methyl-ureido] - pyrimidin-4-yl} -carbamate

A solution of commercially available tert-butyl (6-Methylamino-pyrimidin-4-yl) -carbamate (240 mg, 1.07 mmol, 1.0 equivalent), 2-methyl-5-nitrophenyl isocyanate (210 mg, 1.18 mmol, 1.1 equivalent) and DMAP ( 26 mg, 0.21 mmol,

0.2 equivalent) in toluene (10 ml) is stirred at 80 ° C for 24 hours. After cooling to room temperature, methanol (10 ml) is added and the suspension formed is stirred for 10 minutes at 50 ° C. The precipitate is filtered and washed with methanol (2 x 10 ml). After drying in vacuo an extremely insoluble colorless powder is obtained: HPLC:% tR = 8.09 min (purity: 85%, gradient A). ESI-MS: 403.5 [MH] +.

tert-Butyl (6-Methylamino-pyrimidin-4-yl) -carbamate.

A solution of bis (tert-butyl) - (6-chloro-4-pyrimidinyl) -imidodicarboxylate (1 g, 3.03 mmol, 1.0 equivalent) in 33% methylamine in ethanol (5.63 ml, 45.5 mmol, 15 equivalent) is heated at 80 ° C in a sealed tube for 2 hours and then allowed to reach room temperature. The precipitated product is filtered, washed with cold ethanol and dried under vacuum at 60 ° C overnight. The title compound is obtained in the form of colorless crystals: HPLC: tR =

3.82 min (purity: 99%, gradient A), ESI-MS: 225.1 [MH] + (weak), 169.1 [MH-tBu] +. Bis (tert-butyl) - (6-chloro-4-pyrimidinyl) -imidodicarboxylate can be prepared according to a procedure published in the literature; J. M. Lehn et al. Eur. J. Chem. 2001, 1515-1521.

Following the procedure of example 194 but using the starting materials, examples 195-201 can be prepared:

Example 195: N- {4-Methyl-3- [3-methyl-3- (6-phenylamino-pyrimidin-4-yl) -ureido] -phenyl} -4- (4-methyl-piperazin-1-ylmethyl) -3trifluoromethyl-benzamide

Beige crystals, HPLC: t R = 6.33 min (purity. 96%, gradient A), ESI-MS; 633.8 [MH] + Example 196: 3- (5-Amino-2-methoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

Beige crystals, TLC: Rf = 0.19 (DCM / MeOH85: 15) .HPLC: tR = 3.72 min (purity:> 100%, gradient A), ESI-MS:

463.6 [MH] +.

Example 197: N- [4-Methoxy-3- (3-methyl-3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -ureido) phenyl ] -3trifluoromethyl-benzamide

Pale yellow crystals, TLC: Rf = 0.21 (TBME / MeOH 60:40), HPLC; tR = 5.94 min (purity: 97%, gradient A), ESI-MS: 635.2 [MH] +.

Example 198: N- [4Methoxy-3- (3-methyl-3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -ureido) - phenyl] -4- (4methyl-piperazin-1-ylmethyl) -3-trifluoro-methyl-benzamide

Pale yellow crystals, TLC: Rf = 0.19 (TBME / MeOH / NEt3 50: 50: 1.5), HPLC: tR = 5.07 min (purity: 96%, 10 gradient A), ESIMS: 747.4 [MH] +.

Example 199: N- {3- [3- (6-Amino-pyrimidin-4-yl) -3-methyl-ureido] -5-methox-phenyl} -4- (4-methyl-piperazin-1-ylmethyl) -3trifluoromethyl-benzamide

Colorless crystals, HPLC: t R = 5.12 min (purity: 97%, gradient A), ESI-MS: 573.2 [MH] +.

Example 200: N- {3-Methoxy-5- [3-methyl-3- (6-phenylamino-pyrimidin-4-yl) -ureido] -phenyl} -4- (4-methyl-piperazin-1-ylmethyl ) -3trifluoromethyl-benzamide

Yellow resin, HPLC: t R = 6.20 min (purity: 99%, gradient A), ESI-MS: 649.4 [MH] +.

Example 201: N- [3-Methoxy-5- (3-methyl-3- {6- [4- (4-melyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -ureido ) -phenyl] -4-methyl3-trifluoromethyl-benzamide

Beige crystals, TLC: Rf = 0.39 (DCM / MeOH85: 15), HPLC: tR = 6.17 min (purity:> 100%, gradient A), ESI-MS. 649.7 [MH] +.

Example 202: N- [3- (3- (6-Acetylaminopyrimidin4-yl) -3-methylureido] -4-methylphenyl] -4- (4-methylpiperazin-1-ylmethyl) -3trifluoromethylbenzamide

colorless crystalline solid, TLC: TA = 0.24 (DCM / EtOH / NH3 90: 9: 1), HPLC: tR = 10.57 min (purity: 100%, gradient: 10 B), ESI-MS: 599 [MH] +.

Example 203: [6- (1-Methyl-3- {2-methyl-5- [4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-benzoylamino] -phenyl} ureido) -pyrimidine- 4-yl] -carbamic methyl ester

Colorless powder, TLC: Rf = 0.20 (DCM / EtOH / NH3 90: 9: 1). HPLC: t R = 11.25 min (purity: 100%, gradient B), ESI-MS: 15 615 [MH] +.

Example 204: [6- (1-Methyl-3- {2-methyl-5- [4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenylcarbamoyl] -phenyl} ureido) -pyrimidine- 4-yl] -carbamic methyl ester

Colorless powder, TLC: Rf = 0.33 (DCM / EtOH / NH3 90: 9: 1), HPLC: tR = 10.97 min (purity: 100%, gradient B). ESIMS: 20 615 [MH] +.

Example 205: 3- [3- (6-Acetylamino-pyrimidin-4-yl) -3-methyl-ureido] -4-methyl-N- [4- (4-methyl-piperazin-1-ylmethyl) -3trifluoromethyl- phenyl] -benzamide

Example 206: 3- [3- (6-Amino-pyrimidin-4-yl) -3-methyl-ureido] -4methyl-N [4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethylphenyl] - benzamide

Example 207: Inhibition data in vitro The compounds of Examples 171 to 206 were tested under the protocols described herein for their inhibitory activity against c-Abl, KDR and FGFR3.

For c-Abl an inhibition of 79-100% at 10 μM was observed, for KDR of 87-100% inhibition at 10 μM and for FGFR3 of 56-98% inhibition at 10 μM Example 208: N- [4 -Methyl-3- (3-methyl-3- {6 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4-yl} -ureido) -phenyl] -3-trifluoromethylbenzamide

A Pal resin carrying C- (Tetrahydro-furan-2-yl) -methylamine (1g, 1mmol), DIEA (0.52 mL, 3 mmol) and 4,6-dichloropyrimidine (300 mg, 2 mmol) are mixed in n-BuOH (15 ml). The reaction vial is placed on a heated stirrer and heated to 80 ° C for 16 hours. The resulting mixture is filtered and the resin is washed with DMF (3x20mL), MeOH (3x20mL), CH2Cl2 (3x20mL), and dried under vacuum. 10mgs of the resin are treated with TFA / CH2Cl2) H2O (45/50/5) (20μL) for 1 hour. LC-MS revealed only one major peak: observed MS (M +

20 H +) is 214.2;

Pal resin bearing (6-Chloro-pyrimidin-4-yl) - (tetrahydro-furan-2-ylmethyl) -amine (1 mmol), 40% solution in methylamine water (1.95 mL, 25 mmol), 15 ml of a-BaOH are mixed together in a sealed tube. The reaction vial is placed on a heated stirrer and heated to 100 ° C for 12 hours. After cooling, another 1.95 mL of a 40% solution of methylamine water is added to the reaction vial. The reaction is heated at 100 ° C for 12 hours. The resulting mixture is filtered and the resin is washed with DMF (3x20mL), MeOH (3x20mL), CH2Cl2 (3x20mL), and dried under vacuum. 10mgs of the resin are treated with TFA / CH2Cl2 / H2O (45/50/5) (200 μl) for 1 hour. LC-MS revealed only one major peak: observed MS (M + H +) is 209.2.

Pal resin carrying N-Methyl-N '- (tetrahydro-furan-2-ylmethyl) -pyrimidine-4,6-diamine (1mmol), 2-methyl-5nitrophenylisocyanate (540mg, 3mmol), DIEA (0.52mL, 3mmol ), 15mL of anhydrous DMF are mixed together. The reaction vial is heated with stirring at 60 ° C for 14 hours. The resulting mixture is filtered and the resin is washed with DMF (3x20mL), MeOH (3x20mL), CH2Cl2 (3x20mL), and dried under vacuum. 10mgs of resin are treated with

10 TFA / CH2Cl2 / H2O (45/50/5) (200μL) for 1 hour. LC-MS revealed only one major peak: observed MS (M + H +) is 387.2.

Pal resin carrying 1-Methyl-3- (2-methyl-5-nitro-phenyl) -1- {6 - [(tetrahydro-furan-2-ylmethyl) -amino] - pyrimidin-4-yl} -urea ( 1mmol), tin (II) chloride (1.55g, 8mmol), 15mL NMP are mixed together. The reaction vial is stirred at

15 room temperature 16 hours. The resulting mixture is filtered and the resin is washed with DMF (3x20mL), MeOH (3x20) mL), CH2Cl2 (3x20mL), and dried under vacuum. 10mgs of the resin are treated with TFA / CH2Cl2 / H2O (45/50/5) (200μL) for 1 hour. LC-MS revealed only one major peak: observed MS (M + H ’) is 357.3.

Pal resin bearing 3- (5-Amino-2-methyl-phenyl) -1-methyl-1- {6 - [(tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4-yl}

20 urea (1mmol), 3-trifluoromethyl-benzoyl chloride (630mg, 3mmol), DIEA (0.52mL, 3mmol) and 15mL of anhydrous DMF are mixed together. The reaction vial is stirred at room temperature for 6 hours. The resulting mixture is filtered and the resin is washed with DMF (3x20mL), MeOH (3x20mL). CH2Cl2 (3x20mL), and dried under vacuum. 10mgs of the resin are treated with TFA / CH2Cl2 / H2 (45/50/5) (200μL) for 1 hour. LC-MS revealed only one major peak: observed MS (M + H ’) is 529.3.

25 All psl resin is treated with TFA / CH2Cl2 / H2O (45/50/5) (10 ml) for 2 hours. After removing the solvent under vacuum, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product N- [4-Methyl-3- (3-methyl-3- {6 - [( tetrahydro-furan-2-ylmethyl) -amino] -pyrimidin-4-yl} -ureido) -phenyl] -3triflyoromethyl-benzamide as white solid, 241 mg. A procedure summary is described in the flow chart below. Solid spheres indicate a solid support (Pal resin); 1H NMR (600 MHz, DMSO-d6) 5 12.84 (s,

30 1H), 10.44 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.60 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.16 (s, 1H), 3.92-3.79 (m, 3H), 3.64: 3.62 (m, 2H), 3.34 (s, 3H), 2.31 (s, 3H), 1.85-1.82 (m, 4H); ESIMS m / z 529.3 (M + +1).

Example 209

N- (3- {3- [6- (Benzo [1,3] dioxo-5-ylamino) -pyrimidin-4-yl] -3-methyl-ureido} -4-methyl-phenyl) -3-trifluoromethyl- benzamide

The general procedure is the same as example 208, except that the Pal resin is bonded to benzo [1,3] dioxol-5-amine. All pal resin is treated TFA / CH2Cl2 / H2O (45/50/5) (10 ml) for 2 hours. After removing the solvent under vacuum, the crude product is dissolved in DMSO and purified by preparative HPLC in reserve phase to give the final product N- (3- {3- [6- (Benzo [1,3] dioxol-5 -lamino) -pyrimidin-4-yl] -3-methyl-ureido} -4-methyl-phenyl) -3trifluoromethylbenzamide as a white solid; 1H NMR (400 MHz, DMSO-d6) 5 12.70 (s, 1H), 10.44 (s, 1H), 9.58 (s,

10 1H), 8.49 (s, 1H), 8.40 (d, J = 11.8 Hz, 2H), 8.30 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 7.6 Hz , 1H), 7.78 (t, J =

7.8 Hz, 1H), 7.51 (d, J = 8.4Hz, 1H), 7.37 (t, J = 8.1Hz, 1H), 7.25 (d, J = 8.8Hz, 1H), 6.88 (d, J = 8, 3 Hz, 1H), 6.35 (s, 1H), 6.00 (s, 2H), 3.33 (s, 3H), 2.32 (s, 3H); ESIMS m / z 565.3 (M + + 1).

wherein R represents a substituent R7 as defined in the summary of the invention

Example 210

N- (3- {3- [6- (3-Dimethylamino-phenylamino) -pyrimidin-4-yl] -3-methyl-ureido} -4-methyl-phenyl) -3-trifluoromethyl-benzamide

A reaction scheme for this protocol is shown above. 4,6-Dichloropyrimidine (1.0g, 6.75mmol), 2.0M methylamine are dissolved in MeOH (3.38mL, 6.75mmol) and DIEA (1.76mL, 10.13mmol) in 30mL of ethanol. The reaction is heated at 70 ° C for 4 hours. After removing the solvent, the crude product is purified by flash chromatography using EA / Hexane (3: 7) to obtain the final product (6-Chloro-pyrimidin-4-yl) -methylamine as a white solid.

(6-Chloro-pyrimidin-4-yl) -methyl-amine (940mg, 6.57mmol), 2-methyl-5-nitrophenyl-isocyanate (1.23g, 6.90mmol), DIEA (2.30mL, 13. 15mmol) dissolve in 30mL DMF anhydrous. The reaction is stirred at room temperature for 14 hours. After removing the solvent, the crude product is purified by flash chromatography using EA / Hexane (4: 6) to obtain the final products 1- (6-Chloro-pyrimidin-4-yl) -1-methyl-3- (2 -methyl-5-nitro-phenyl) -urea as a white solid. 1- (6-Chloro-pyrimidin-4-yl) -1-methyl-3- (2-methyl-5-nitro-phenyl) -urea (100mg, 0.31 mmol), N, N-Dimethylbenzene-1,3- diamine HCl salt (82 mg, 0.47 mmol) that is dissolved in 6 mL of n-BuOH. The reaction is heated to 90 ° C for 16 hours. After removing the solvent, the crude product is purified by flash chromatography using EA / Hexane (1: 1) to obtain the final product 1- [6- (3-dimethylamino-phenylamino) -pyrmidin-4-yl] 1-methyl -3- (2-methyl-5-nitro-phenyl) -urea as a white solid. 1- [6- (3-Dimethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-3- (2-methyl-5-nitro-phenyl) -urea (110 mg, 0.26 mmol) and 10 mg of powder 10% palladium on carbon are mixed in 20ml of EtOH under hydrogen. The reaction is stirred at 50 ° C for 4 hours. The reaction mixture is passed through a plug of celite and washed with methanol. After removing the solvent under vacuum, the crude product 3- (5Amino-2-methyl-phenyl) -1- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea is used for the next reaction stage without purification.

3- (5-Amino-2-methyl-phenyl) -1- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea (0.26mmol), 3-trifluoromethylbenzoyl chloride (57mg , 0.27mmol) and DIEA (68uL. 0.39mmol) are dissolved in 10 ml of anhydrous DMF. The reaction is stirred at room temperature for 4 hours. After removing the solvent, the crude product is dissolved in DMSO and purified by reverse phase preparative HPLC to give the final product N- (3- {3- [6- (3-Dimethylaminophenylamino) -pyrimidin-4-yl] -3-methyl-ureido} -4-methyl-phenyl) -3-trifluoromethyl-benzamide as a white solid; 1H NMR (600 MHz, DMSO-d6) 5 12.67 (s, 1H), 10.44 (s, 1H), 9.84 (s, 1H), 8.56 (s, 1H), 8.40 (d, J = 11.8 Hz, 2H) , 8.28 (s, 1 H),

8.24 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.35 ( t, J = 8.1Hz, 1H), 7.22 (d, J = 8.8Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.64 (s, 1H), 6.59 (d, J = 8.2Hz, 1H), 3.35 (s, 3H), 2.92 (s, 6H),

2.35 (s, 3 H); ESIMS m / z 565.3 (M + + 1).

Example 211

N- (3- {3- [6- (3-Acetylamino-phenylamino) -pyrimidin-4-yl] -3-methyl-ureido} -4-methyl-phenyl) -3-trifluoromethyl-benzamide

The general procedure is as in Example 3, except that N- (3-Amino-phenyl) -acetamide (71mg, 0.47mmol) and 0.12mL 4M HCl are added to the reaction in dioxane solutions. The final product N- (3- {3- [6- (3-Acetylaminophenylamino) -pyrimidin-4-yl] -3-methyl-ureido} -4-methyl-phenyl) -3-trifluoromethyl-benzamide is purified by HPLC reverse phase preparation to give the white solid; 1H NMR (600 MHz, DMSO-d6) 5 12.67 (s, 1H), 10.44 (s, 1H), 9.84 (s, 1H),

8.56 (s, 1H), 8.40-8.36 (m, 2H), 8.31 (s, 1H), 8.28 (d, J = 7.8 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J = 7.7 Hz , 1H), 7.84 (d, J

= 6.6 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 6.6Hz, 1H), 7.47 (d, J = 7.8Hz, 1H), 7.41 (t, J = 7.8Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 6.48 (s, 1H), 3.37 (s, 3H), 2.79 (d, J = 4.2, 3H), 2.34 (s, 3H) ; ESIMS m / z 578.3 (M + + 1).

Example 212

N- (4-Methyl-3- {3-methyl-3- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -ureido} -phenyl) -3-trifluoromethyl-benzamide

4-methyl-3-nitroaniline (3.0 g, 20 mmol) is dissolved in 100 ml of methylene chloride, and 3 ml of triethylamine (22 mmol) are added, the solution is cooled to 0 ° C and acid chloride 3 is slowly added -trifluorobenzoic acid (4.1 g, 20 mmol) to the above mixture while stirring. The reaction mixture was allowed to rise to room temperature and the reaction was terminated in 1 hour. The reaction mixture was washed with 10% NaHCO3 solution, brine and dried over Na2SO4. The final product (3) N- (4-Methyl-3-nitro-phenyl) -3-trifluoromethyl-benzamide is a yellow solid, 6.28g.

N- (4-Methyl-3-nitro-phenyl) -3-trifluoromethyl-benzamide (6.2 g, 19 mmol) was dissolved in 80 ml of ethanol and 600 mg of Pd / C was added to the solution. The mixture was stirred under hydrogen at room temperature for 4 hours. The Pd / C was removed by filtration. The crude product was recrystallized from ethyl acetate. The final product (4) N- (3-Amino-4-methylphenyl) -3-trifluoromethyl-benzamide is a dark solid, 5.5 g.

4,6-Dichloropyrimidine (10 g, 67 mmol) was dissolved in 50 ml of methanol. Then 37 ml of a 2M methylamine solution in THF was added. The reaction was stirred for 10 hours at room temperature. The solvent was removed by rotary evaporation and the crude product was recrystallized from methanol. The final product (5) (6-Chloro-pyrimidin-4-yl) methylamine was a pale yellow solid, 8.2 g.

(6-Chloro-pyrimidin-4-yl) -methyl-amine (1.43 g 10 mmol) was dissolved in 20 ml of dioxane and mixed with 1.7 ml of DIEA (15 mmol), and then 1.2 g of triphosgene was added to the solution. The reaction mixture was stirred at 85 ° C for 3 hours. The reaction mixture was cooled to room temperature. To this reaction mixture, 1.7 ml of DIEA and 2.94 g of N- (3-Amino 4-methyl-phenyl) -3-trifluoromethyl-benzamide (4) were added. The reaction was stirred at room temperature for 3 hours. The crude product was recrystallized from ethyl acetate. The final product

(8) N- {3- [3- (6-Chloro-pyrimidin-4-yl) -3-methylureido] -4-methyl-phenyl} -3-trifluoromethyl-benzamide is a light yellow solid,

3.9 g

N- {3- [3- (6-Chloro-pyrimidin-4-yl) -3-methyl-ureido] -4-methyl-phenyl} -3-trifluoromethyl-benzamide (50 mg, 0.107 mmol) and ptoluenesulfonic acid ( 20 mg, 0.105 mmol) were mixed and dissolved in one ml of DMF. Then 4-Morpholin-4-ylphenylamine (22 mg, (0.11 mmol) was added. The reaction was stirred at 80 ° C. for 10 hours. The crude product was purified by reverse phase HPLC to give the final product N- (4-Methyl) -3- {3-methyl-3- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] ureido} -phenyl) -3-trifluoromethyl-benzamide as a gray solid, 48 mg; 1H NMR 600 MHz (DMSO) 5 12-74 (s, 1H),

10.46 (s, 1H), 9.53 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H), 8.31 (s, 1H), 8.28 (d, 1H, J = 7.8 Hz), 7.97 (d , 1H, J = 7.2 Hz), 7.79 (t, 1H, J = 4.2 Hz), 7.52 (d, 1H, J = 7.8 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.22 (d , 1H, J = 8.4 Hz), 6.99 (s, 1H), 6.98 (s, 1H), 6.34 (s, 1H), 4.15 (m, 4H), 3.76 (m, 4H), 3.10 (m, 3H) , 2.32 (s, 3H); MS m / z 606.2 (M + 1).

Example 213

N- [4-Methyl-3- (3-methyl-3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -ureido) -phenyl] - 3-trifluoromethylbenzamide

This compound was made using the same procedure above, except 4- (4-Methyl-piperazin-1-yl) phenylamine was used instead of 4-Morpholin-4-yl-phenylamine. The final compound N- [4-Methyl-3- (3-methyl-3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -ureido) - phenyl] -3-trifluoromethyl-benzamide as a white solid, 43 mg; 1H NMR 600 MHz 10 (DMSO) 5 12.75 (s, 1H), 10.47 (s, 1H), 9.64 (s, 1H), 9.55 (s, 1H), 8.47 (s, 1H), 8.41 (m, 1H) , 8.31 (s, 1H), 8.28 (d, 1H, J = 7.8 Hz), 7.97 (d, 1H, J = 7.2 Hz), 7.79 (t, 1H, J = 4.2 Hz), 7.52 (d, 1H, J = 7.8 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.22 (d, 1H, J = 8.4 Hz), 6.99 (s, 1H), 6.98 (s, 1H), 6.34 (s, 1H) , 3.79 (m, 2H), 3.56 (m, 4H), 3.18 (m, 3H), 2.95 (m, 2H),

2.87 (s, 3H), 2.33 (s, 3H); MS m / z 620.2 (M + 1).

15 Example 214

N- {3- [3- (6-Amino-pyrimidin-4-yl) -3- (2-morpholin-4-yl-ethyl) -ureido] -4-methyl-phenyl} -3-trifluoromethyl-benzamide

Rink resin with free amino group (50 g, 53 mmol) is mixed with 4,6-dichloropyrimidine (23g, 159 mmol) in 60 ml of butanol and 28 ml DIEA. The reaction mixture is stirred on a heating block at 50 ° C for 10 hours. The resin was washed with DMF, methanol and ethylene chloride. Then to 1 g of resin 3 equivalents of amine and 3 ml of butanol were added, the reaction was stirred at 90 ° C for 10 hours. The resin was washed with DMF, methanol and methylene chloride. N- (3-Amino-4-methyl-phenyl) -3-trifluoromethyl-benzamide (880 mg, 3 mmol) was dissolved in 8 ml of dioxane with

0.52 ml of DIEA. Then triphosgene (357 mg, 1.2 mmol) was added to this solution. The reaction was stirred at room temperature for 1 hour. This reaction mixture was then added to the previous resin. The reaction was stirred at 60 ° C for 10 hours. The resin was washed with DMF, methanol and methylene chloride. The resin was cleaved with TFA at room temperature for 1 hour. The crude product was purified by RP-HPLC.

Example 214 is prepared using 2-morpholin-4-yl-ethylamine as an amine in the above procedure. The final product N- {3- [3- (6-Amino-pyrimidin-4-yl) -3- (2-morpholin-4-yl) -ethyl) -ureido] -4-methyl-phenyl} -3- Trifluoromethyl-benzamide is a white solid, 63 mg; 1H NMR 600 MHz (DMSO) 5 12.95 (s, 1H), 10.46 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.95 (d, 1H, J = 7.7 Hz), 7.77 (t, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 6.8 Hz), 7.20 (d, 2H, J = 8.3 Hz),

7.03 (s, 2H), 6.99 (s, 1H), 6.17 (s, 1H), 3.98 (s, 2H), 3.59 (s, 4H), 3.35 (m, 2H), 2.50 (m, 4H), 2.30 (s, 3H); MS m / z 544.2 (M + 1).

Example 215

10 N- (3- {3- (6-Amino-pyrimidin-4-yl) -3- [3- (2-oxo-pyrrolidin-1-yl) -propyl] -ureido} -4-methylphenyl) -3 -trifluoromethyl-benzamide

The compound was prepared using 1- (3-Amino-propyl) -pyrrolidin-2-one as an amine in the above procedure. The final product N- (3- {3- (6-Amino-pyrimidin-4-yl) -3- [3- (2-oxopyrrolidin-1-yl) -propyl] -ureido} -4-methyl-phenyl) -3trifluoromethylbenzamide in the form of a white solid, 14 mg; 1H NMR 600 MHz (DMSO) 5 12.51 (s, 1H), 10.40 (s,

15 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.95 (d, 1H, J = 7.7 Hz), 7.77 (t, 1H, J = 7.8 Hz), 7.54 (d, 1H, J = 6.8 Hz), 7.20 (d, 2H, J = 8.3 Hz), 7.03 (s, 2H), 6.99 (s, 1H), 6.17 (s, 1H) , 3.70 (m, 2H), 3.31 (t, 2H, J = 7.2 Hz), 3.24 (t, 2H, J = 7.2 Hz), 2.23 (s, 3H), 2.16 (t, 2H, J = 8.4 Hz) , 1.87 (m, 2H), 1.74 (m, 2H); MS m / z 556.2 (M + 1).

Example 216

Repeating the procedures described in the previous examples 208 to 215, using appropriate starting materials, the following compounds of Formula I are obtained, as identified in Table 1.

Table 1 (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued) (continued)

Compound number

Structure Physical data

one

1H NMR (400 MHz, CD3OH-d4) 5 9.92 (d, J = 5.1 Hz, 1H), 9.80 (s, 1H), 9.20 (d, J = 8.1 Hz, 2H), 8.93 (d, J = 8.5 Hz , 2H), 8.85 (d, J = 8.6 Hz, 2H), 8.79 (d, J = 5.0 Hz, 2H), 8.76 (d, J = 8.0 Hz, 2H), 8.75 (s, 1H), 8.46 (t , J = 9.0 Hz, 1H), 8.08 (s, 1H), 4.92 (s, 2H), 4.71 (s, 2H), 3.66 (m, 6H); ESIMS m / z623.20 (M ++ 1).

2

1H NMR (600 MHz, DMSO-d6) 512.82 (s, 1H), 10.44 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.9Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.78 (t, 7.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1Hz. 1H), 6.21 (s, 1H), 4.57 (s. 2H), 3.18 (s, 3H), 2.39 (s, 3H); ESIMS m / z 569.10 (M ++ 1).

Compound number

Structure Physical data

3

1H NMR (600 MHz, DMSO-d6) 512.85 (s, 1H), 10.44 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H). 7.62 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 7.31 (d, J = 7.1 Hz, 1H), 7.28 (8.1H), 7.27 (s, 1H) , 7.22 (d, J = 9.2 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.15 (s, 1H), 3.30 (m, 2H), 3.18 (s, 3H), 2.80 (t, J = 6.7 Hz, 2H), 2.24 (s, 3H); ESIMS m / z549.20 (M ++ 1).

4

1H NMR (600 MHz, DMSO-d6) 512.83 (s, 1H), 10.44 (s, 1H), 8.40 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 7.99 (s, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.27 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 6.90 (s, 1H), 6.15 (s, 1H), 4.50 (s , 2H), 3.73 (s, 3H), 3.29 (s, 3H), 2.20 (3H); ESIMS m / z 565.20 (M ++ 1).

Compound number

Structure Physical data

5

1H NMR (600 MHz, DMSO-d6) 512.86 (s, 1H), 10.44 (s, 1H), 8.41 (s, 1H), 8.35 (br, 1H), 8.31 (s, 1H), 8.28 (d , J = 7.8 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.51 (4, J = 8.2 Hz, 1H ), 7.20 (d, J = 8.3 Hz, 2H), 6.12 (s.1H), 3.24 (s, 3H), 3.31 (t, J = 7.0 Hz, 2H), 3.25 (t, J = 7.0 Hz, 4H ), 2.31 (s, 3H), 2.22 (t, J = 8.1 Hz, 2H), 1.93 (dt, J = 7.6, 14.1 Hz, 2H), 1.73 (m, 2H); ESIMS m / z 570.20 (M ++ 1).

6

ESIMS m / z559.10 (M ++ 1).

7

ESIMS m / z 549.20 (M + + 1).

8

ESIMS m / z 572.30 (M + + 1).

9

ESIMS m / z 513.20 (M ++ 1).

Compound number

Structure Physical data

10

ESIMS m / z 572.30 (M ++ 1).

eleven

ESIMS m / z487.20 (M ++ 1).

12

ESIMS m / z487.20 (M ++ 1).

13

ESIMS m / z525.20 (M ++ 1).

14

1HNMR (400 MHz, DMSO-d6) 510.47 (s, 1H). 8.40 (d. J = 2.1 Hz, 1H), 8.33 (s, 1H), 8.318.25 (m, 2H),), 7.98 (t, J = 7.8 Hz. 1H), 7.78 (t, J = 7.8 Hz. 1H), 7.54 (d, J = 6.0, 1H). 7.52 (d, J = 8.2Hz, 1H), 7.21 (d, J = 8.3Hz, 2H) 6.13 (s, 1H), 3.31 (s, 3H), 2.31 (s, 3H), 2.17 (s, 2H) ;

fifteen

ESIMS m / z 445.10 (M + + 1).

Compound number

Structure Physical data

16

ESIMS m / z 567.10 (M + + 1).

17

ESIMS m / z 553.10 (M + + 1).

18

ESIMS m / z 517.10 (M + + 1)

19

ESIMS m / z 502.20 (M + + 1)

twenty

ESIMS m / z 579.20 (M + + 1).

twenty-one

ESIMS m / z 552.10 (M + + 1)

Compound number

Structure Physical data

22

ESIMS m / z 803.10 (M + + 1).

2. 3

ESIMS m / z 579.15 (M + + 1)

24

ESIMS m / z 578.30 (M + + 1)

25

ESIMS m / z-515.20 (M + + 1)

26

ESIMS m / z 558.30 (M + + 1).

27

ESIMS m / z 485.20 (M + + 1).

Compound number

Structure Physical data

28

ESIMS m / z 564.20 (M + + 1).

29

ESIMS m / z 578.20 (M + + 1).

30

ESIMS m / z 633.30 (M + + 1).

31

ESIMS m / z 620.30 (M + + 1).

32

ESIMS m / z 670.30 (M + + 1).

Compound number

Structure Physical data

33

ESIMS m / z 499.2 (M + + 1).

3. 4

ESIMS m / z 515.2 (M + + 1).

35

ESIMS m / z 528.3 (M + + 1).

36

ESIMS m / z 537.2 (M + + 1).

37

ESIMS m / z 503.2 (M + + 1).

Compound number

Structure Physical data

38

ESIMS m / z 522.2 (M + + 1).

39

ESIMS m / z 536.2 (M + + 1).

40

ESIMS m / z 516.2 (M + + 1).

41

ESIMS m / z 542.30 (M + + 1).

Compound number

Structure Physical data

42

ESIMS m / z 614.30 (M + + 1).

43

ESIMS m / z 558.30 (M + + 1).

44

ESIMS m / z 553.30 (M + + 1).

Four. Five

ESIMS m / z 649.30 (M + + 1).

46

ESIMS m / z 649.30 (M + + 1).

Compound number

Structure Physical data

47

ESIMS m / z 558.30 (M + + 1).

48

ESIMS m / z 558.30 (M + + 1).

49

ESMIS m / z 403.30 (M + + 1).

fifty

ESIMS m / z 403.30 (M + + 1).

Compound number

Structure Physical data

51

ESIMS m / z 403.30 (M + + 1).

52

ESIMS m / z 403.30 (M + + 1).

53

ESIMS m / z 495.3 (M + + 1).

54

ESIMS m / z 479.30 (M + + 1).

1. Essays

The compounds of Examples 208 to 216 are tested to measure their ability to selectively inhibit cell proliferation of 32D cells expressing BCR-ABL (32D-p210) compared to original 32D cells. Compounds that selectively inhibit the proliferation of these BCR-ABL transformed cells are tested for antiproliferative activity on Ba / F3 cells expressing the wild or mutant forms of Ber-abl. In addition, the compounds are tested to measure their ability to inhibit FGFR35 kinases (in an enzymatic and cellular assay), FLT3, PDGFR�, trkB, c-SRC, BMX, SGK, Tie2, Lck, JNK2a2, MKK4, c-RAF , MKK6, SAPK2a and SAPK2�.

Inhibition of cell-dependent Bcr-Abl proliferation (high performance method)

The murine cell line used is the 32D hemopoietic progenitor cell line transformed with BCR-ABL cDNA (32Dp210). These cells are maintained in RPMI / 10% fetal calf serum (RPMI / FCS) supplemented with 50 μg / ml penicillin, 50 μg / ml streptomycin and 200 mM L-glutamine. Non-transformed 32D cells are maintained in the same manner with the addition of 15% conditioned WEHI medium as a source of IL-3. 50 μl of a suspension of 32D or 32D-p210 cells are seeded in 384 well Greiner microplates (black) at a density of 5000 cells per well. 50 NL of test compound (1 mM in stock solutions in DMSO) are added to each well (ST1571 is included as a positive control). The cells are incubated for 72 hours at 37 ° C, 5% CO2, 10 µl of a 60% Alamar Blue solution (Tek diagnostic) that is added to each well and the cells are incubated for an additional 24 hours. The fluorescence intensity (excitation at 530 nm, emission at 580 nm) is quantified using the Acquest ™ (Molecular Devices) system.

Inhibition of cell-dependent Bcr-Abl proliferation.

32D-p210 cells are seeded in 96-well CT plates at a density of 15,000 cells per well. 50 μl of serial dilutions twice of the test compound (Cmax is 40 μM) is added to each well (STI-571 is included as a positive control). After incubating the cells for 48 hours at 37 ° C, 5% CO2, 15 µl of MTT (Promega) is added to each well and the cells are incubated for an additional 5 hours. The optical density at 570 nm is quantified spectrophotometrically and the IC30 values, the concentration of the compound required for 50% inhibition is determined from a dose response curve.

Effect on cell cycle distribution

32D and 32D-p210 cells are seeded in 6-well TC plates at 2.5x106 cells per well in 5 ml of medium and test compound is added at 1 or 10 μM (STI-571 is included as a control). The cells are then incubated for 24 to 48 hours at 37 ° C, 5% CO2. 2 ml of cell suspension are washed with PBS, fixed in 70% EtOH for 1 hour and treated with PBS / EDTA / RNase for 30 minutes. Propidium iodide (Cf = 10 μg / ml) is added and the fluorescence intensity is quantified by flow cytometry in the FACScalibur ™ system (BD Biosciences). The test compounds of the present invention demonstrated an apoptotic effect on 32D-p210 cells, but do not induce apoptosis in the original 32D cells.

Effect on autophosphorylation by cellular Bcr-Abl

Autophosphorylation of BCR-Ab1 is quantified with capture ELISA using a c-abl specific capture antibody and an antiphosphotyrosine antibody. 32D-p210 cells are plated in 96-well TC plates at 2x105 cells per well in 50 ml of medium. 50 μl of two serial dilutions of test compounds (Cmax is 10 mM) are added twice to each well (STI-571 is included as a positive control). The cells are incubated for 90 minutes at 37 ° C, 5% CO2. The cells are then treated for 1 hour on ice with 150 ml of lysis regulator (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mM EGTA and 1% NP-40) containing protease and inhibitors Phosphatase 50 μl of cell lysate are added to the 96-well optiplates previously coated with the specific anti-Abl antibody and blocked. The plates are incubated for 4 hours at 4 ° C. After washing with TBS-Tween 20 as a regulator, 50 µL of alkaline phosphatase conjugated antiphosphotyrosine antibody is added and the plate is further incubated overnight at 4 ° C. After washing with TBS-Tween 20 regulator, 90 μL of a luminescent substrate is added and the luminescence is quantified using the Acquest ™ (Molecular Devices) system. Test compounds of the invention that inhibit the proliferation of cells expressing BCR-ABL, inhibit cell autophosphorylation by BCR-Abl in a dose-dependent manner.

Effect on the proliferation of expressed cells

The compounds of the invention are tested for their antiproliferation effect on cells expressing in Ba / F3 either wild type or mutant forms of BCR-ABL (G250E, E255V, T315I, F317L, M351T) which confers resistance or decreased sensitivity to ST1571. The antiproliferative effects of these compounds on the cells expressing the mutant BCR-ABI and on the non-transformed cells was checked at 10, 3.3, 1.1 and 0.37 μM as described above (in media lacking IL3). The IC30 values of compounds that lacked toxicity in the non-transformed cells were determined from the dose response curves obtained as described above.

FGFR35 (enzymatic test)

The kinase activity test with purified FGFR35 (Upstate) is carried out in a final volume of 10 μl containing 0.25 μg / mL enzyme in kinase regulator (30 mM Tris-HCl pH7.5.15 mM MgCl2, 4.5 mM MnCl2, 15 mMNa3 VO4 and 50 μg / mL BSA), and substrates (5 mg / mL biotin-poly-EY (Glu, Tyr) (CIS-US, Inc.) and 3μM ATP). Two solutions are made: the first 5 μl solution containing the enzyme FGFR35 in kinase regulator was first dispensed in a ProxiPlate 384® (Perkin-Elmer), of format 384 followed by the addition of 50 nL of the compounds dissolved in DMSO, then 5 μl of the second solution contains the substrate (poly-EY) and ATP in kinase regulator that was added to each well. The reactions are incubated at room temperature for one hour, stopped by the addition of 10 μl of HTRF detection mixture, containing 30 mM Tris-HCl pH 7.5, 0.5 M KF, 50 mM ETDA, 0.2 mg / ml BSA, streptavidin -XL665 15 μg / ml (CIS-US. Inc.) and 150 ng / mL of crypto-conjugated antiphosphotyrosine antibody (CIS USA, Inc.). One hour after incubation at room temperature to allow streptavidin-biotin interaction, the fluorescent signals resolved over time on an Analyst GT (Molecular Devices Corp.) are read. IC30 values are calculated by linear regression analysis of the percentage of inhibition of each compound at 12 concentrations (1: 3 dilution from 50 μm to 0.28 nM). In this test, the compounds of the invention have an IC50 in the range of 10 μM to 2 μM.

FGFR35 (Cellular Assay)

The compounds of the invention are tested for their ability to inhibit the proliferation of transformed Ba / F3 TEL-FGFR35 cells, which depends on the activity of the FGFR35 cell kinase. Ba / F3-TEL-FGFR35 are grown up to 800,000 cells / ml in suspension, with RPMI 1640 supplemented with 10% fetal bovine serum as culture medium. The cells are dispensed in 384 well format plates to 5000 cells / wells in 50 μl of culture medium. The compounds of the invention are dissolved and diluted in dimethylsulfoxide (DMSO). Serial dilutions 1:03 of twelve points are made in DMSO to create concentration gradients that typically range from 10 mm to 0.05 μm. Cells with 50 nL of diluted compounds are added and incubated for 48 hours in a cell culture incubator, AlamarBlue® (TREK Diagnostic Systems), which can be used to monitor the reducing environment caused by proliferating cells, and added to the cells at a final concentration of 10%. After an additional four hours of incubation in a cell culture incubator at 37 ° C, the reduced AlamarBlue® fluorescence signals (excitation at 530 nm, emission at 580 nm) on an Analyst GT (Molecular Devices Corp.) are quantified. The IC50 values are calculated by linear regression analysis of the percentage of inhibition of each compound at 12 concentrations.

KinstaProfileTAM Upstate Binding Test with Radio-Enzymatic Filter

The compounds of the invention are established as to their ability to inhibit individual members of a kinase group (a partial, non-limiting kinase list that includes; Abl, H3CR-Abl, BMX, FGFR35, Lck, JNK1, JNK2, CSK , RAF, MKK6 and P38). The compounds are tested in duplicates at a final concentration of 10 μM following this generic protocol. Note that the composition of the kinase regulator and the substrates varies for the different kinases included in the "Upstate Kinase-ProfileTAM" panel. The compounds are tested in duplicates at a final concentration of 10 μM following this generic protocol. Kinase regulator (2.5 µl, 10x containing MnCl3 when required), active kinase (0.001-0.01 units, 2.5 µl) specific peptide or poly (Glu4-Tyr) (5-500 µm or 01 mg / ml) are mixed in kinase regulator and kinase regulator (50 μM, 5 μl) in an eppendorf on ice. Mg / ATP mix (10μL; 67.5 (or 33.75) mM MgCl2, 450 (or 225)% mM ATP and 1 µCl / µL [l-32P] -ATP (3000Ci / mmol) are added and the reaction is incubated at approximately 30 ° C for about 10 minutes The reaction mixture is seeded (20 μl) on a P81 of 2cm x 2cm (phosphocellulose, for positively charged peptide substrates) or Whatman No. 1 (for poly (Glu4-Tyr) peptide substrate) The test squares they are washed four times, for 5 minutes each, with 0.75% phosphoric acid and washed once with acetone for 5 minutes.The test squares are transferred to a scintillation vial, 5 ml of scintillation cocktail is added and the Incorporation of 32P (cpm) into the peptide substrate is quantified with a Beckman scintillation counter.The percentage inhibition is calculated for each reaction.

N- (3- {3- [6- (3-Acetylamino-phenylamino) -pyrimidin-4-yl] -3-methyl-ureido} -4-methyl-phenyl) -3-trifluoromethyl-benzamide (Example 211) It has an IC50 of <0.5 nM, 38 nM, 44 nM, 41 nM.

<0.5 nM and <0.5 nM for wild type, G250E, E255V, T3151, F317L and M351T Bcr-abl, respectively;

b). N- {3- [3- (6-Amino-pyrimidin-4-yl) -3- (2-morpholin-4-yl-ethyl) -ureido] -4-methylphenyl} -3-trifluoromethyl-benzamide (Example 214 ) has an IC50 of 65nM and 49nM for the FGFR35 enzyme and cellular tests, respectively, and 14.9nM and 0.4nM for wild type Bcr-abl and PDGFR�, respectively,

C). N- (3- {3- (6-Amino-pyrimidin-4-yl) -3- [3- (2-oxo-pyrrolidin-1-yl) -propyl] -ureido} -4-methyl-phenyl) - 3-trifluoromethylbenzamide (Example 215) has an IC50 of 16nM and 15nM, for the enzyme FGFR35 and cellular tests, respectively, and 10nM, and 2nM for wild type Bcr-ably PDGFR, respectively;

d). N- (3- {3- (6-Amino-pyrimidin-4-yl) -3- [3- (2-oxo-pyrrolidin-1-yl) -propyl] -ureido} -4-methyl-phenyl) - 3-trifluoromethylbenzamide (Example 215), at a concentration of 10μM. inhibits the following kinases with the percentage shown in parentheses (for example, 100% means complete inhibition, 0% indicates no inhibition): Abl (99%) wild type, c-RAF (99%), CSK (97%) , c-SRC (100%), FGFR35 (99%), JNK2a2 (93%), Ick (100%), MKK6 (88%), pa70S6K (81%), ROS (95%), SAPK2a (99%) , SAPK2� (99%), Tie2 (100%) and TrkB (99%).

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in the light thereof will be suggested to persons skilled in the art and will be included within the spirit and purpose of this application.

Example 217: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (4-isopropyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea

The title compound is prepared as described in Example 160 but using N- [4- (4-isopropyl-piperazin-1-yl) phenyl] -pyrimidine-4,6-diamine (385 mg, 1.23 mmol, 1 eq .), and stirring the reaction mixture for 0.5 h at 70 ° C. The title compound: ESI-MS: 560.0 / 562.0 [MH] +; tR = 3.17 min (purity: 98%, gradient J); TLC: TA = 0.31 (DCM / MeOH + 1% NH3 aq, 95: 5).

A. N- [4 - (- 4-Isopropyl-piperazin-1-yl) -phenyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using 4- (4-isopropylpiperazin-1-yl) phenylamine (400 mg, 1.83 mmol, 1 eq.), 6-chloro-pyrimidin-4-yl) - amine (1.3 eq.), and stirring the reaction mixture at 150 ° C for 18h. Purification of the crude product by trituration in diethyl ether yields the title compound as a white solid: ESIMS: 313.2 [MH] +: t R = 1.00 min (gradient J).

B. 4- (4-Isopropylpiperazin-1-yl) -aniline

A suspension of 1-isopropyl-4- (4-nitro-phenyl) -piperazine (5.18 g, 20.80 mmol) and Palladium (5%) on carbon (0.5 g) in MeOH (100 mL) is stirred for 2.7 h at RT, under An atmosphere of hydrogen. The reaction mixture is filtered through a celite cloth and concentrated to produce the title compound as a violet solid: ESI-MS: 220.1 [MH] +; tR = 0.95 min (gradient J).

C. 1-Isopropyl-4- (4-nitro-phenyl) -piperazine

A mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) Is heated at 80 ° C for 15h. After cooling to RT, the reaction mixture is subjected to concentration. Purification of the residue by silica gel column chromatography (DCM / MeOH, 95: 5) yields 5.18 g of the title compound as a yellow solid: ESI-MS: 250.1 [MH] +; tR = 2.57 min (purity: 100%, gradient J); TLC: TA = 0.16 (DCM / MeOH, 95: 5).

Example 218: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- (6- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenylamino} -pyrimidin4-yl) -urea

The title compound is prepared as in Example 144, but using N- {4- [2- {4-methyl-piperazin-1-yl) -ethoxy]

5 phenyl} -pyrimidine-4,6-diamine (227 mg, 1.23 mmol, 1 eq.), And stirring the reaction mixture for 18 hours at 70 ° C. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3aq1, 95: 5) yields the title compound as a white solid: ESI-MS: 589.9 /591.9 [MH] +: tR = 3.11 min (purity: 100%, gradient J); TLC: Rf = 0.12 (DCM / MeOH + 1% NH3aq 95: 5).

A. N-Methyl-N ’- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenyl} -pyrimidine-4,6-diamine

The title compound is prepared as described in Example 180A but using 4- [2- (4-methyl-piperazin-1-yl) ethoxy] -phenylamine (500 mg, 2.13 mmol, 1 eq.), (6 -chloro-pyrimidin-4-yl) -ethyl-amine and stirring the reaction mixture at 150 ° C for 20h. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 9: 1) followed by trituration in diethyl ether yields 250 mg of the title compound as a white solid: ESI-MS: 343.2 [MH] +: t R = 1.00 min (gradient J); TLC: Rf = 0.23 (DCM / MeOH + 1% NH3aq, 9: 1).

Example 219: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-isopropyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl } -1-methylurea

The title compound is prepared as described in Example 144 but using N- [4- (4-isopropyl-piperazin-1-yl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine (1.71 g, 5.25 mmol, 1 eq.) and carrying out the reaction mixture during

20 45 minutes at reflux. Purification of the crude product by trituration in MeOH followed by silica gel column chromatography (DCM / MeOH + 1% NH3aq 97: 3) yields the title compound as a white solid: ESI-MS: 573.9 / 575.9 [MH ] +; tR = 3.65 min (purity: 100%; gradient J); TLC: TA = 0.10 (DCM / MeOH + 1% NH3aq, 97: 3).

A. N- [4- (4-Isopropyl-piperazin-1-yl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using 4- (4-isopropylpiperazin-1-yl) aniline (Example 217B) (2.6 g, 11.9 mmol). Purification of the residue by silica gel column chromatography (DCM / MeOH, 93.7) yields 1.71 g of the title compound as a white solid: ESI-MS: 327.2 [MH] +; tR =

1.30 min (gradient J); TLC: TA = 0.26 (DCM / MeOH, 93: 7).

Example 220: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- [6- (4-dimethylaminomethyl-3-trifluoromethyl-phenylamino) -pyrimidin-4-yl] 30 urea

The title compound is prepared as described in Example 144, but using N- (4-dimethylaminomethyl-3-trifluoromethylphenyl) -pyrimidine-4,6-diamine (250 mg, 0.80 mmol, 1 eq.), 2 equivalents of isocyanate, and bringing the reaction mixture for 30 minutes to reflux. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 95: 5) yields the title compound as a white solid: ESI-MS:

558.9 / 560.9 [MH] +; tR = 3.69 min (purity: 100%, gradient J); TLC: Rf = 0.21 (DCM / MeOH + 1% NH3aq, 95: 5).

A. N- (4-Dimethylaminomethyl-3-trifluoromethyl-phenyl) -pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (300 mg, 1.46 mmol) and 6-chloro-pyrimidin-4-yl) -amine (1.3 eq.). Purification of the crude product by silica gel column chromatography (DCM / MeOH, 93: 7) yields the title compound as a white solid: ESI-MS: 312.1 [MH] +: TLC: TA = 0.16 (DCM / MeOH, 93: 7).

Example 221: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (4-dimethylaminomethyl-3-trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

The title compound is prepared as described in Example 144 but using N- (4-dimethylaminomethyl-3-trifluoromethylphenyl-N'-methyl-pyrimidine-4,6-diamine (200 mg, 0.62 mmol, 1 eq.), And subjecting the reaction mixture at reflux for 1h. Purification of the crude product by trituration in MeOH followed by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 95: 5) yields the title compound as a white solid. : ESI-MS:

572.8 / 574.8 [MH] +; tR = 4.14 min (purity: 100%, gradient J); TLC: TA = 0.24 (DCM / MeOH + 1% NH3aq, 95: 5).

A. N- (4-Dimethylaminomethyl-3-trifluoromethyl-phenyl) -N’-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (300 mg, 1.46 mmol) and 1.3 eq. of 6-chloro-pyrimidin-4-yl) -methyl-amine. Purification of the crude product by silica gel column chromatography (DCM / MeOH, 93: 7) yields the title compound as a white solid: ESt-MS: 326.1 [MH] +; TLC: Rf = 0.27 (DCM / MeOH, 93: 7).

Example 222: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (3 - {[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -phenylamino) pyrimidine -4-il] -1-methyl-urea

The title compound is prepared as described in Example 144 but using N- (3 - {[(2-dimethylamino-ethyl) methyl-amino] -methyl} -phenyl) -pyrimidine-4,6-diamine (250 mg , 0.80 mmol, 1 eq.), 1.5 eq. of isocinazo, and bringing the reaction mixture to reflux for 6 hours. Purification of the crude product by MPLC (by silica gel) (DCM / MeOH + 1% NH3aq, 95: 5) followed by trituration in diethyl ether yields the title compound as a white solid: ESI-MS: 561.9 / 563.9 [MH] +; tR = 3.24 min (purity: 100%, gradient J); TLC: TA = 0.10 (DCM / MeOH

+

 1% NH3aq, 9: 1).

TO.

 N- (3 - {[(2-Dimethylamino-ethyl) -methyl-amino] -methyl} -phenyl) -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using N- (3-amino-benzyl) -N, N ’, N’trimethylethane-1,2-diamine (500 mg, 2.41 mmol), 1.1 eq. of 6-chloro-pyrimidin-4-yl) -methyl-amine, and stirring the mixture

reaction for 17.5h. Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3aq, 95:

5) produces the title compound as a beige solid: ESI-MS: 315.2 [MH] +; TLC: Rf = 0.05 (DCM / MeOH + 1% NH3aq, 9: 1).

B. N- (3-Amino-benzyl) -N, N ’, N’-trimethyl-ethane-1,2-diamine

A suspension of N, N ', N'-trimethyl-N' - (3-nitro-benzyl) -ethane-1,2-diamine (4.5 g. 18.96 mmol) and Raney Nickel (1.2 g) in MeOH (100 mL ) stir for 2 hours at room temperature, under an atmosphere of hydrogen. The reaction mixture is filtered through a celite cloth and concentrated to produce the title compound as a yellow oil; ESI-MS: 208.2.

C. N, N ’, N’-Trimethyl-N’ - (3-nitro-benzyl) -ethane-1,2-diamine

A mixture of 3-nitrobenzyl chloride (4.5 g, 26.23 mmol), N, N, N-trimethylenediamine (4.1 ml, 31.47 mmol, 1.2 eq.), Potassium carbonate (7.3 g, 52.46, 2 eq.), And Acetone (90 ml) is stirred for 19 hours at 80 ° C. The reaction mixture is allowed to cool to room temperature, filtered and concentrated. Purification of crude product by silica gel column chromatography DCM / MaOH + 1% NH3eq, 9: 1) yields the title compound as a brown oil: ESI-MS: 238.1 [MH] +: t R = 1.10 min (gradient J); TLC: Rf = 0.10 (DCM / MeOH + 1% NH3eq, 9: 1).

Example 223: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [3- (4-isopropyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1methyl urea

The title compound is prepared as described in Example 144 but using M- [3- (4-isopropyl-piperazin-1-methylmethyl) -phenyl] -N'-methyl-pyrimidine-4,8-diamine (250 mg, 0 , 73 mmol, 1 eq.), Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH3 eq. 95: 5) followed by trituration in diethyl ether yields the title compound as a solid. White: ESIMS: 587.9 / 589.9 [MH] +; tR = 3.35 min (purity: 100%, gradient J); TLC: TA =

0.17 (DCM / MeOH + 1% NH3eq, 9: 1).

A. N- [3- (4-Isopropyl-piperazin-1-ylmethyl) -phenyl] -N'-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 143A but using 3- (4-isopropyl-piperzin-1-methyl) -phenylamine (500 mg, 2.14 mmol, 1 eq.) And stirring the reaction mixture for 17.5ha 150 ° C Purification of the crude product by MPLC (silica gel) (DCM / MeOH + 1% NH33q, 95: 5) yields the title compound as a light yellow solid: TLC: Rf = 0.10 (DCM / MeOH + 1% NH3eq , 9: 1).

B. 3- (4-Isopropyl-piperazin-1-ylmethyl) -phenylamine

The title compound is prepared as described in Example 149B: ESI-MS: 234.1 [MH] +; tR = 0.95 min (gradient J).

C. 1-Isopropyl-4- (3-nitro-benzyl) -piperazine

The title compound is prepared as described in Example 222C: ESI-MS: 264.1 [MH] +; TLC: Rf = 0.35 (DCM / MeOH + 1% NH3eq, 9: 1).

Example 224: 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [3- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4-yl} -urea

The title compound is prepared as described in Example 160 but using N- [3- (1-methyl-piperidin-4-yloxy) phenyl] -pyrimidine-4,6-diamine (205 mg, 0.69 mmol, 1 eq .). Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3 eq, 95: 5) followed by trituration in MeOH yields the title compound as a white solid: ESI-MS: 546.9 / 548.9 [MM] +: t R = 3.14 min (purity: 100%, gradient J); TLC: Rf = 0.13 (DCM / MeOH + 1% NH3eq, 95: 5).

A. N- [3- (1-Methyl-piperidin-4-yloxy) -phenyl] -pyrimidine-4,6-diamine

The title compound is prepared as described in Example 160A but using 3- (1-methyl-piperidin-4-yloxy) phenylamine (500 mg, 2.43 mmol, 1 eq.) And stirring the reaction mixture for 20h to 100 ° C. Trituration of the crude product in EE produces the title compound as a red solid: ESI-MS: 300.2 [MH] +; tR = 0.85 min (gradient J).

B. 3- (1-Methyl-piperidin-4-yloxy) -phenylamine

The title compound is prepared as described in Example 217B: ESI-MS: 207.1 [MH] +.

C. 1-Methyl-4- (3-nitro-phenoxy) -piperidine

A mixture of 4-fluoro-nitrobenzene (10 g, 71.0 mmol), 4-hydroxy-1-methyl-piperidine (16.6 ml, 141.8 mmol, 2 eq.), Tetrabutylammonium bromide (4.6 g, 14.2 mmol, 0.2 eq. ), toluene (50 ml) and a 25% aqueous solution of potassium hydroxide (50 ml) are stirred for 15 hours at 60 ° C. The reaction mixture is cooled to room temperature and poured onto ice / water. The resulting suspension is filtered and the filtrate is extracted with EE. The organic phase is washed with 0.5 N HCl, brine, then dried (sodium sulfate), filtered and concentrated to yield 6 g of the title compound. The aqueous layer is neutralized by the addition of sodium bicarbonate and extracted with EE. The organic phase is washed with brine, dried (sodium sulfate), filtered. and concentrated to produce an additional 10 g of the title compound: ESI-MS: 237.0 [MH] +: t R = 2.61 min (purity: 90%, gradient J)

Example 225: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl- (6- [3- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4- il) -urea

The title compound is prepared as described in Example 144 but using N-methyl-N '- [3- (1-methyl-piperidin4-yloxy) -phenyl] -pyrimidine-4,6-diamine (130 mg, 0.41 mmol, 1 eq.). Purification of the crude product by silica gel column chromatography (DCM / MeOH + 1% NH3 eq, 95: 5) followed by trituration in MeOH yields the title compound as a white solid: ESI-MS; 561.0 / 563.0 [MH] +; tR = 3.66 min (purity: 97%, gradient J).

A. N-Methyl-N ’- [3- (1-methyl-piperidin-4-yloxy) -phenyl] - pyrimidine-4,6-diamine

The title compound is prepared as described in Example 160A but using 3- (1-methyl-piperidin-4-yloxy) phenylamine (Example 224B). The title compound as a red solid: ESI.MS: 314.2 [MH] +: TLC: Rf = 0.16 (DCM / MeOH + 1% NH3 eq, 9: 1).

Example 226: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (3-diethylaminomethyl-phenylamino) -pyrimidin-4-yl] -1-methyl-urea

The title compound is prepared as described in Example 144 but using N- (3-diethylaminomethyl-phenyl) -N'methylpyrimidine-4,6-diamine (128 mg, 0.45 mmol, 1 eq.). The title compound: ESI-MS: 533.0 / 535.0 [MH] +; tR =

3.94 min (purity: 100%, gradient J); TLC: Rf = 0.37 (DCM / MeOH + 1% NH3eq, 92: 8).

A. N- (3-Dietylaminomethyl-phenyl) -N’-methyl-pyrimidine-4,6-diamine

The title compound is prepared as described in Example 144A but using 3-diethylaminomethyl-phenylamine. The title compound: ESI-MS: 286.1 [MH] +: TLC: TA = 0.05 (DCM / MeOH + 1% NH3eq, 9: 1).

B. 3-Diethylaminomethyl-phenylamine

The title compound is prepared as described in Example 149B but using diethyl- (3-nitrobenzyl) -amine. The title compound contains 30% 3-methyl-aniline and is used as crude impure material.

C. Diethyl- (3-nitrobenzyl) -amine

The title compound is prepared as described in Example 149C but using diethylamine. The title compound: t R = 1.83 min (purity: 100%, gradient J); TLC: Rf = 0.38 (DCM / MeOH, 9: 1).

Example 227: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {4- [4- (4-methyl-piperazin-1-yl) -phenylamino] - [1 , 3,5] triazin-2-yl} urea

To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg, 0.56 mmol; Preparation 2) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.52 ml 20% in toluene, 0.98 mmol). The mixture is stirred for 70 minutes at 100 ° C, cooled to room temperature and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenyl isocyanate.

The resulting solid is added portion by portion to a boiling solution of N-methyl-N '- [4- (4-methyl-piperazin-1-yl) phenyl] - [1,3,5] triazine-2,4 -diamine (141 mg, 0.47 mmol) in 8 ml of toluene for 20 minutes. After 3 hours, another 2 equivalents of 2,6-dichloro-3,5-dimethoxyphenyl isocyanate are added and stirring is continued for a total of 5 hours. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM / MeOH / NH3eq 97: 3: 0.2) gives the title compound: ESI-MS: 547/549 [MH] +; tR = 3.5 min (purity: 100%, gradient J); TLC: Rf = 0.40 (DCM / MeOH + 1% NH3eq, 95: 5).

A. N-Methyl-N ’- [4- (4-methyl-piperazin-1-yl) -phenyl] - [1,3,5] triazine-2,4-diamine

To a solution of (4-chloro- [1,3,5] triazin-2-yl) -methyl-amine (290 mg, 2.00 mmol) and 4- (4-methylpiperazin-1-yl) -aniline (570 mg , 3.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (530 ml, 3.1 mmol) is heated at 80 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture is concentrated and the residue is dissolved in EE and water. The separated aqueous phase is extracted twice with EE, the organic layer is washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM / MeOH / NH3eq 95: 5: 0.2) gives the title compound: TLC: TA = 0.07 (DCM / MeOH NH3eq + 1% 95: 5.).

B. (4-Chloro- [1,3,5] triazin-2-yl) -methyl-amine

To an ice-cold solution of 2,4-dichlor- [1,3,5] triazine (2.25 g, 15 mmol; WO 2004/072063, Expl. 9) in 20 ml of THF, MeNH2 (15 ml of 2M solution in THF). After 1 hour the mixture is diluted with 15 ml of water and partially concentrated in vacuo. The precipitated title compound can be filtered, washed with ice water and dried: ESI-MS: [143 MH.

Example 228: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {4- [4- (4-ethyl-piperazin-1-yl) -phenylamino] - [1 , 3,5] triazin-2-yl} urea

To a solution of 2,5-dichloro-3,5-dimethoxy-aniline (133 mg, 0.60 mmol, Preparation 2) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.54 ml of 20% in toluene, 1.0 mmol). The mixture is stirred for 60 minutes at 100 ° C, cooled to room temperature and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenyl isocyanate.

The resulting solid is added portion by portion to a boiling solution of N-methyl-N '- [4- (4-ethyl-plperazin-1-yl) phenyl] - [1,3,5] triazine-2,4 -diamine (156 mg, 0.50 mmol) in 7 ml of toluene for 15 minutes. After 5 hours, the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM / MeOH / NH3 95: 5: 0.2) gives the title compound: ESI-MS: 561/563 [MH] +, t R = 3.6 min (gradient J); TLC: Rf = 0.4 (DCM / MeOH + 1% NH3aq, 95: 5).

A. N-Methyl-N ’- [4- (4-ethyl-piperazin-1-yl) -phenyl] - [1,3,5] trizane-2,4-diamine

A mixture of (4-chloro- [1,3,5] triazin-2-yl) -methyl-amine (290 mg, 2.00 mmol), Nal (28 mg) and 4- (4-ethylpiperazin-1-yl) Aniline (410 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350m 2.0 mmol) is heated at 80 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture is cooled to room temperature, partially concentrated in vacuo and diluted with hexane at 0 ° C. The precipitate is filtered, washed with Et2O and redissolved in EE and water. The separated aqueous phase is extracted twice with EE, the organic layer is washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: ESI-MS: 314 [MH] +; TLC: R1 = 0.10 (DCM / MeOH 9: 1).

Example 229: 3- (4-Fluoro-3-trifluoromethyl-phenyl) -1-methyl-1- {4- [4- (4-ethyl-piperaxin-1-yl) -phenylamino] - [1,3,5 ] triazin-2-yl} urea

To a solution of N-methyl-N '- [4- (4-ethyl-piperazin-1-yl) -phenyl] - [1,3,5] triazine-2,4-diamine (24 mg, 0.077 mmol) in 1.5 ml of THF and 2.5 ml of toluene, 4-fluoro-3-trifluoromethyl-phenylisocyanate (25 ml, 0.17 mmol) is added and the mixture is stirred for 5 hours at 100 ° C. Manipulation analogous to that described in Example 171 gives the title compound: ESI-MS: 519 [MH] +; tR = 4.3 min (purity: 100%, gradient J); TLC: Rf = 0.43 (DCM / MeOH 9).

Example 230: 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-melthyl-1- {4- [4- (4-isopropyl-piperazin-1-yl) -phenylamino] - [1 , 3,5] triazin2-yl} -urea

As described in Example 230, 2,6-dichloro-3,5-dimethoxy-aniline (133 mg, 0.60 mmol; Preparation 2) and N-methyl

5 N '- [4- (4-isopropyl-piperazin-1-yl) -phenyl] - [1,3,5] triazine-2,4-diamine (163 mg, 0.50 mmol) becomes the title compound : ESI-MS, 575/577 [MH] +; tR = 3.7 min (gradient J); TLC: Rf = 0.32 (DCM / MeOH + 1% NH3eq, 95: 5).

A. N-Methyl-N ’- [4- (4-isopropyl-piperazin-1-yl) -phenyl] - [1,3,5] triazine-2,4-diamine

A mixture of (4-chloro- [1,3.5] triazin-2-yl) -methyl-amine (290 mg, 2.00 mmol), Nal (28 mg) and 4- (4-propylpiperazin-1

10 il) aniline (500 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl diisopropyl amine (350 ml, 2.0 mmol) is heated at 80 ° C for 3 hours under a nitrogen atmosphere. Manipulation as described in Example 228A gives the title compound: ESI-MS: 328 [MH] +; TLC: Rf = 0.14 (DCM / MeOH, 9: 1).

Example 231: 3- (2,6-Dichloro-3-trifluoromethyl-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -1 -methyl urea

To a solution of 2,6-dichloro-3-trifluoromethyl-aniline (138 mg, 0.60 mmol) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.54 ml 20% in toluene, 1.0 mmol) is added. The mixture is stirred for 2 hours at 100 ° C, cooled to room temperature and concentrated in vacuo yielding 2,6-dichloro-3-tritluoromethyl-phenylisocyanate.

This oil is redissolved in 2 ml of toluene and added portion by portion to a boiling solution of N- [4- (4-ethyl-piperazin-1-yl) -phenyl] -N'-methyl-pyrimidine-4,6- diamine (156 mg, 0.50 mmol; Examples 145A) in 6 ml of toluene 20 for 10 minutes. After 1.5 hours, another 2 equivalents of 2,6-dichloro-3-trifluoromethylphenyl isocyanate are added and stirring continues for a total of 2 hours. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2 / MeOH / NH3eq 95: 5: 0.5) gives the title compound: ESI-MS; 568/570 [MH] +; tR = 4.1 min (gradient J); TLC: Rf

25 = 0.3 (DCM / MeOH + 1% NH3eq, 95: 5).

A. 2,6-Dichloro-3-trifluoromethyl-anilin

Hydrogenation of 2,4-dichloro-3-nitro-benzotrifluoride (5.0 g, 19.2 mmol; ABCR, Karlsruhe / Germany) in 100 ml of MeOH in the presence of 1 g of Raney nickel, filtration and filtrate concentration gives the compound of title: TLC: Rf =

0.67 (EE).

Claims (36)

1. A compound of Formula (I): where the following fragments hereinafter referred to as "left ring" and "right ring", respectively: The left hand ring the right hand ring where X is C-R5, and Y and Z are both N, so the ring on the left has the structure of the Fragment (A): n is 0, 1, 2, 3, 4 or 5; X1 is oxygen. where R1 is of the formula R2-NRa- where Ra is hydrogen, hydroxy, hydrocarbyloxy or hydrocarbyl, where hydrocarbyl has 1 to 15 carbon atoms, is optionally interrupted by an -O- or -NH- bond and is unsubstituted or it is substituted by hydroxy, halo, amino or mono- or di- (C1-C4) alkylamino, alkanoyl having 4 chain atoms, trifluoromethyl, cyano, azo or nitro; and R2 is selected from

(i)

 linear or branched alkyl having 1, 2, 3 or 4 carbon atoms,

(ii)

 linear or branched alkyl having 1, 2, 3 or 4 carbon atoms substituted by one or more halogens and / or one or

Two functional groups selected from hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, lower acyl, lower acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups which are optionally substituted in at least one heteroatom by one or, when possible, more groups linear or branched alkyl having 1, 2, 3 or 4 carbon atoms, (iii) a group of the formula where: Ring A represents a 6-membered carbocyclic or heterocyclic ring; m is 0, 1 or 2; the or each Rb is independently selected from -L2-NRcRd; -L2-RING where RING is a substituted mono or bicyclic ring as defined below; halogen; hydroxy; protected hydroxyl; Not me; amidino; guanidino; hydroxyguanidino; formamidine; isothioureido; ureido; mercapto; acyl having 4 chain atoms; acyloxy having 4 chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; or nitro; and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isotioureido , ureido, mercapto, acyl having 4 chain atoms, acyloxy having 4 chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of which hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups are optionally substituted on at least one heteroatom by one or, when possible, more C1-C7 aliphatic groups, where L2 is a direct link; a link selected from -O-; -S-; -CO)-; -OC (O) -; -NRaC (O) -; -C (O) -NRa -; -OC (O) -NRa -; cyclopropyl and -NRa-; or is a linear or branched group having 1, 2, 3 or 4 carbon atoms optionally interrupted and / or terminated at a single end or at both ends by a said link; and where Rc and Rd are each independently selected from hydrogen, and linear or branched alkyl having 1, 2, 3 or 4 carbon atoms optionally substituted by one or more halogens, by a 5- or 6-membered heterocyclic or carbocyclic ring optionally substituted, and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, acyl having 4 chain atoms, acyloxy having 4 chain atoms, carboxy , sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro, hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl, carbamoyl and cyano groups which are optionally substituted on at least one heteroatom for one or more C1-C7 aliphatic groups, or Rc and Rd together with their attached nitrogen form an optionally substituted 5 or 6 member ring as described below, said rings being optionally substituted independently of one another by 0, 1, 2, 3, 4 or 5 halogen selected substituents; hydroxy; protected hydroxy; Not me; amidino; guanidino; hydroxyguanidino; formamidine; isothioureido; ureido; mercapto; acyl having 4 chain atoms; acyloxy having 4 chain atoms; carboxy; sulfo; sulfamoyl; carbamoyl; cyano; azo; nitro; C1-C7 aliphatic optionally substituted by one or more halogens and / or one or two functional groups selected from hydroxy, protected hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isotioureido, ureido, mercapto, acyl that has 4 chain atoms, acyloxy having 4 chain atoms, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, or nitro; all of the above being hydroxy, amino, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, carboxy, sulfo, sulfamoyl and carbamoyl groups in turn optionally substituted on at least one heteroatom by one or, when possible , more aliphatic C1-C7 groups; R2 is H, halo, alkyl, alkyl interrupted by an -O- or -NH- bond and / or linked to the left ring by a said bond, trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl structural unit (interrupted or not) having 1, 2, 3 or 4 carbon atoms; R3 is H, a straight or branched C1-C4 alkyl or a straight or branched C1-C4 alkyl substituted by a saturated or unsaturated 5 or 6 membered carbocyclic or heterocyclic ring; R4 is selected from hydroxy, protected hydroxy, alkoxy, alkyl, trifluoromethyl and halo, where alkyl and the alkyl part of the alkoxy is a straight or branched chain and has 1, 2, 3, or 4 carbon atoms; R5 is H, halo, alkyl, alkyl interrupted by an -O- or -NH- bond and / or linked to the left ring by a said bond, trifluoromethyl, hydroxy, amino, mono- or dialkylamino; any alkyl structural unit (interrupted or not) having 1, 2, 3 or 4 carbon atoms, or salts, hydrates, solvates, esters, N-oxides, protected derivatives, individual stereoisomers and mixtures of pharmaceutically acceptable stereoisomers thereof. 2. The compound of claim 1 wherein R5 is H or halo. The compound of claim 2 wherein R5 is H.

Four.

 The compound of a previous claim wherein, regardless of the identity of R5, R2 is a structural unit cited in relation to R5 in any of claims 2 or 3.

5.

 The compound of claim 1 wherein the ring on the left has the structure of the Fragment (B):

Fragment (B)

6.

 The compound of any preceding claim wherein R2 is of the formula

7.

 The compound of claim 6 comprising at least one Rb which is -L2-NRcRd or -L2-RING, wherein L2 is a

direct bond, linear alkyl, adjacent A ring terminated in linear alkyl by a said link of claim 1, 20 or is a said link.

8.

 The compound of claim 7 wherein said bond is -O-.

9.

 The compound of any one of claims 6 to 8 wherein ring A is phenyl, cyclohexenyl or cyclohexyl.

10.

 The compound of any one of claims 6 to 9 wherein there is a simple Rb group which is selected

of -L2-NRcRd and -L2-RING and there are 0, 1 or 2 additional substituents that are selected from halogen, alkyl, alkoxy, hydroxy, amino and trifluoromethyl, where alkyl and the alkoxy alkyl part, has 1, 2, 3 or 4 carbon atoms.

eleven.

 The compound of any one of claims 1 to 10 wherein m is 1.

12.

 The compound of claim 11 wherein ring A is phenyl or cyclohexyl and Rb is selected from -L2-NRcR and -L2-RING.

13.

 The compound of claim 12 wherein the substituent is in position 3 or position 4 of ring A.

14. The compound of claim 1, the ring on the left having a structure corresponding to the Fragments (D1), (D2), (E1) or (E2):

fifteen.

 The compound of claim 14 wherein Ra is H.

16.

 The compound of claim 14 or claim 15 wherein the phenyl ring of said Fragments has 1, 2, 3

or 4 additional substituents, selected from halogen, methyl, methoxy and trifluoromethyl. The compound of any one of claims 14 to 16 wherein RING is a saturated heterocycle containing a ring nitrogen. 18. The compound of any of claims 14 to 16 which contains an NRcRd structural unit and wherein Rc and Rd are the same or different and are selected from straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms . The compound of any one of claims 14 to 16 which contains an NRcRd structural unit and wherein Rc and Rd together with the adjacent atom form a 5- or 6-membered heterocyclic ring, optionally substituted by 0, 1, 2, 3 , 4 or 5 substituents selected from C1, C2, C3 or C4 straight or branched chain alkyl, halogen and C1, C2, C3 or C4 alkoxy, where alkyl and the alkoxy alkyl part are unsubstituted or substituted by halogen. 20. The compound of claim 19 wherein the heterocycle is saturated. 21. The compound of claim 20 wherein L2NRcRd is selected from -Pip, -Morf, -OCH2Pip, -OCH2Morf, -OCH2CH2Pip, -OCH2CH2Morf, -OCH2CH2CH2Pip, -OCH2CH2CH2Morf, -CH2Pip, -CH2M2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2M2 CH2CH2CH2Pip, -CH2CH2CH2Morf, -C (O) Pip and -C (O) Morf, where &quot; Pip &quot; means piperazine and &quot; Morf &quot; means morpholine, piperazine that is optionally substituted in N by C1, C2, C3 or C4 straight chain alkyl or 20 branched. 22. The compound of any of claims 14 to 21 wherein the ring on the left has the structure of the following Fragment (F): Fragment (F) 25 23. The compound of any preceding claim wherein n is 1, 2, 3 or 4.

24.

 The compound of any preceding claim wherein R4 is selected from hydroxy, protected hydroxy, alkoxy, alkyl, trifluoromethyl and halo, wherein alkyl and the alkyl part of the alkoxy is a straight or branched chain and has 1, 2, 3, or 4 atoms of carbon.

25.

 The compound of claim 24 wherein R4 is selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl.

26.

 The compound of any one of claims 1 to 22 wherein the ring on the right corresponds to Fragment (G):

Fragment (G) where: Q is selected from F and Cl; U is selected from H, F, Cl, methyl, trifluoromethyl and methoxy; T and V are the same or different and are selected from H, methyl, trifluoromethyl and methoxy. The compound of claim 26 wherein the ring on the right is Fragment (H): 28. The compound of any one of claims 1 to 22 wherein the ring on the right corresponds to Fragment (I): Fragment (I) where: Q is selected from F and Cl; Ua and Ub are each independently selected from H, F, Cl, methyl, trifluoromethyl and methoxy. 29. The compound of claim 1 which is selected from the following formulas (IV), (V), (VI) and (VII): wherein L2NRcRd is -Pip, -Morf, -OCH2Pip, -OCH2Morf, -OCH2CH2Pip, -OCH2CH2Morf, -OCH2CH2CH2Pip, -OCH2CH2CH2Morf, -CH2Pip, -CH2Morf, -CH2CH2CH2P2, P2CH2P2, P2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2P, 5 C (O) Pip or -C (O) Morf, where &quot; Morf &quot; means morpholine optionally substituted by C1-C4 alkyl and &quot; Pip &quot; means piperazine optionally substituted by C1-C4 alkyl; L2RING is -RING, -OCH2RING, -OCH2CH2RING, -OCH2CH2CH2RING, -CH2RING, -CH2CH2RING, -CH2CH2CH2RING, and, or is -C (O) RING, where RING is a heterocycle optionally substituted by C1-C4 alkyl or C1-C4 haloalkyl and selected from pyrrolidine, piperidine, piperazine or morpholine; R3 is H; R4 is selected from Cl, F, hydroxy, methyl, methoxy and trifluoromethyl; n is 0, 1, 2, 3, 4 or 5. 30. A compound selected from: 3- (2,6- Dichloro- 3- methoxyphenyl) -1- methyl- 1- {6- [4- (4- methyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl} - urea; 3- 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4- il} -urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl }-urea; 1- (2,6-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-6-methyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-6-methyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3-Methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (3-Methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (3,5-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (3,5-Dichloro-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,5-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2,5-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- {6- [4- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (3,4,5-trimethoxy-phenyl) -urea; 1- {6- [3- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (3,4,5-trimethoxy-phenyl) -urea; 1- (2,4-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2,4-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3,5-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3,5-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3,5-Bis-trifluoromethyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (3,5-Bis-trifluoromethyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (3,5-Dimethyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3,5-Dimethyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] - piritnidin-4-yl} -urea, 1- (3 -Cloro-4-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3-Chloro-4-methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (5-Methoxy-2-methyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (5-Methoxy-2-methyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-5-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-5-methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3,4-Dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (3,4-Dimethoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (4-Fluoro-3-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (4-Fluoro-3-methoxy-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (4,5-Dimethoxy-2-methyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (4,5-Dimethoxy-2-methyl-phenyl) -3- {6- [3- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-3-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-3-methoxy-phenyl) -3- {6- [3- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- (6-methylamino-pyrimidin-4-yl) -urea; 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- (6-phenylamino-pyrimidin-4-yl) -urea; 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenyl-amino] -pyrimidin-4-yl} -urea; 1- (2- Chloro-3,5-dimethoxy-2- methyl-phenyl) -3- {6- [3- (4- methyl-piperazin-1- yl) -phenyl-amino] -pyrimidin-4-yl }-urea; 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [3- (2-dimethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-3,5-dimethoxy-phenyl) -3- {6- [3- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 3- (2,3-Dimethoxy-phenyl) -1-ethyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 3- (3,5-Dimethoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 3- (3,5-Dimethoxy-phenyl) -1-methyl-1- {6- [3- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 3- (2-Chloro-3,5-dimethoxy-phenyl) -1-methyl-1- (6-phenylamino-pyrimidin-4-yl) -urea; 3- (2- Chloro-3,5-dimethoxyphenyl) -1- methyl- 1- {6- [4- (4- methyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2- Chloro-3,5-dimethoxyphenyl) -1- methyl- 1- {6- {3- (4- methyl-piperazin- 1- yl) -phenylamino} -pyrimidin-4-yl} - urea; 3- (2-Chloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazine-1-carbonyl) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2- Chloro-3,5-dimethoxy-phenyl) -1- {6- [4- (2- diethylamino-ethoxy) -phenylamino] -pyrimidin-4- yl} -1-methylurea; 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- {6- [3- (2-dimethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -1-methylurea; 3- (2- Chloro-3,5-dimethoxyphenyl) -1- ethyl- 1- {6- [4- (4- methyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -1-thiophene- 2-ylmethyl urea; 3- (2- Chloro-3,5-dimethoxyphenyl) -1- [2- (4- methyl-piperazin-1- yl) -ethyl] -1- (6- phenylamino-pyrimidin-4-yl) - urea; 3- (2-Chloro-3,5-dimethoxy-phenyl) -1- (6-phenylamino-pyrimidin-4-yl) -1- (2-pyridin-2-yl-ethyl) -urea; 3- (2,6- Dichloro- 3- methoxyphenyl) -1- ethyl- 1- {6- [4- (4- methyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2,6- Dichloro- 3- methoxyphenyl) -1- methyl- 1- {6- [3- (4- methyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2,6-Dichloro-3-methoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazine-1-carbonyl) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2,6-Dichloro-3-methoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2,6-Dichloro-3-methoxy-phenyl) -1- (6-methoxy-pyridin-3-ylmethyl) -1- {6- [4- (4-methyl-piperazin-1-yl) - phenylamino] - pyrimidin-4-yl} urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-ethyl-1- {6- [4- (4-methyl-piperazine-1-carbonyl) -phenylamino] -pyrimidin-4-yl }-urea; 1- (2-Chloro-6-methyl-phenyl) -3- (6-isopropylamino-pyrimidin-4-yl) -urea; (2,6-Dichloro-phenyl) -carbamic acid 4- {6- [3- (2,6-dichloro-phenyl) -ureido] -pyrimidin-4-ylamino} -cyclohexyl ester; 1- (6-Isoprooylamino-pyrimidin-4-yl) -3- (2,4,6-trichloro-phenyl) -urea; 1- (2,6-Dichloro-phenyl) -3- (6-isopropylamino-pyrimidin-4-yl) -urea; 1- {6- [4- (1-Methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichlorophenyl) -urea; 1- (2-Chloro-6-methyl-phenyl) -3- {6- [4- (1-methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [4- (1-methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,5-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- {6- [4- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea; 1- {6- [4- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,5-trichloro-phenyl) -urea; 1- (3,4-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,3-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (5-Chloro-2-methoxy-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-6-methyl-phenyl) -3- {6- [3- (1-methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [3- (methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- {6- [3- (1-Methyl-piperidin-4-ylmethoxy) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichlorophenyl) -urea; 1- (2-Chloro-6-methyl-phenyl) -3- {6- [4- (4-methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -urea; 1- {6- [4- (4-Methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichlorophenyl) -urea; 1- {6- [4- (4-Methyl-piperazin-1-carbonyl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichlorophenyl) -urea; 1- {6- [3- (4-Methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -3- (2,4,6-trichloro-phenyl) -urea; 1- {6 - [(trans) -4- (tert-Butyl-dimethylsilanyloxy) -cyclohexylamino] -pyrimidin-4- yl} -3- (2,4,6-trichloro-phenyl) -urea; 1- [6 - ((trans) -4-Hydroxy-cyclohexylamino) -pyrimidin-4-yl] -3- (2,4,6-trichloro-phenyl) -urea; 1- {6 - [(trans) -4- (tert-Butyl-dimethylsilanyloxy) -cyclohexylamino] -pyrimidin-4- yl} -3- (2- chloro-6- methyl-phenyl) -urea; 1- (2-Chloro-6-methyl-phenyl) -3- [6 - ((trans) -4-hydroxy-cyclohexylamino) -pyrimidin-4-yl] -urea; 1- {6 - [(trans) -4- (tert-Butyl-dimethyl-silanyloxy) -cyclohexylamino] -pyrimidin-4-yl} -3- (2,6-dichloro-phenyl) -urea; 1- (2,6-Dichloro-phenyl) -3- [6 - ((trans) -4-hydroxy-cyclohexylamino) -pyrimidin-4-yl] -urea; 1- (2-Chloro-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Bromo-phenyl) -3- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Bromo-phenyl) -3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [4- (3-morpholin-4-yl-propoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Bromo-phenyl) -3- {6- [4- (3-morpholin-4-yl-propoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Bromo-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Chloro-phenyl) -3- {6- [4- (3-diethylamino-propoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2,6-Dichloro-phenyl) -3- {6- [4- (3-diethylamino-propoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- (2-Bromo-phenyl) -3- {6- [4- (3-diethylamino-propoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- [6- (4-Diethylamino-phenylamino) -pyrimidin-4-yl] -3- (2,6-difluoro-phenyl) -urea; 1- (2,6-Difluoro-phenyl) -3- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -urea; 1- (2,6-Dichloro-phenyl) -3- [6- (4-diethylamino-phenylamino) -pyrimidin-4-yl] -urea; 1- (2,6-Dichloro-phenyl) -3- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea; 1- (2,6-Difluoro-phenyl) -3- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea; 3- (2,6-Dichloro-phenyl) -1- [6- (4-diethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea; 3- (2,6-Dichloro-phenyl) -1- {6- [4- (1-hydroxy-1-methyl-ethyl) -phenylamino] -pyrimidin-4-yl} -1-methyl-urea; 1- (2,6-Dichloro-phenyl) -3- [6- (6-methoxy-pyridin-3-ylamino) -pyrimidin-4-yl] -urea; 3- (2,6-Dichloro-phenyl) -1-methyl-1- [6- (3-trifluoromethyl-phenylamino) -pyrimidin-4-yl] -urea; 1- [6- (3-Cyano-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -1-methyl-urea; 1- (2,6-Dichloro-phenyl) -3- [6- (4-fluoro-phenylamino) -pyrimidin-4-yl] -urea; 1- [6- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -3- (4-methoxy-phenyl) -1-methyl-urea; 3- (2,6-Dichloro-phenyl) -1-methyl-1- [6- (4-morpholin-4-yl-phenylamino) -pyrimidin-4-yl] -urea; 3- (2,6-Dichloro-phenyl) -1- [6- (2,4-difluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-urea; 1- (2,6-Dichloro-phenyl) -3- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -urea; 3- (2,6-Dichloro-phenyl) -1- [6- (3-dimethylamino-phenylamino) -pyrimidin-4-yl] -1-methyl-urea; 1- [6- (4-Fluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-3- (3-trifluoro-methyl-phenyl) -urea; 3- (3-Chloro-phenyl) -1- [6- (4-fluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-urea; 3- (2,6-Dichloro-phenyl) -1- [6- (4-fluoro-phenylamino) -pyrimidin-4-yl] -1-methyl-urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -1-methyl-urea; 1- (2-Chloro-phenyl) -3- {6- [4- (3-morpholin-4-yl-propoxy) -phenylamino] -pyrimidin-4-yl} -urea bis-hydrochloride salt; 1- (2-Chloro-phenyl) -3- {6- [4- (2-diethylamino-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,6-dimethyl-phenyl) -1-methyl-urea; 3- (2-Chloro-phenyl) -1- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] -urea; 1- (2-Bromo-phenyl) -3- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2-fluoro-phenyl) -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (3-methoxy-phenyl) -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,5-dimethoxy-phenyl) -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2-trifluoromethyl-phenyl) -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (5-methoxy-2-methyl-phenyl) -urea; 1- (3-Chloro-phenyl) -3- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (3,4,5-trimethoxy-phenyl) -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,6-dichloro-phenyl) -urea; 1- (4-Chloro-phenyl) -3- [6- (3-chloro-phenylamino) -pyrimidin-4-yl] -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (3,5-dimethoxy-phenyl) -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3- (2,6-dimethyl-phenyl) -urea; 1- [6- (3-Chloro-phenylamino) -pyrimidin-4-yl] -3-phenyl-urea; 1- (2-Chloro-phenyl) -3- {6- [4- (2-morpholin-4-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- ethyl- 1- {6- [4- (4- methyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl }-urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (3-dimethylaminomethyl-phenylamino) -pyrimidin-4-yl] -1-methylurea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -methylurea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- (6- {4- [3- (4-methyl-piperazin-1-yl) -propoxy] -phenylamino} -pyrimidin-4-yl) -urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (3-dimethylamino-propyl) -phenylamino] -pyrimidin-4-yl} -1-methyl-urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- {6- [4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino] -pyrimidin-4-yl }-urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1- methyl urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [3- (4-ethyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1- methyl urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- [6- (3- dimethylaminomethyl-phenylamino) -pyrimidin-4- yl] -1-ethylurea; 3- (2,6- Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (2- diethylamino-ethoxy) -phenylamino] -pyrimidin-4- yl} -1-methyl-urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (2,6-dimethyl-pyridin-3-ylamino) -pyrimidin-4-yl] -1-methyl-urea; 3- (2,6-Dichloro-3,5-dimethoxyphenyl) -1-methyl-1- [6- (6- trifluoromethyl-pyridin-3--ylamino) -pyrimidin-4-yl] -urea; 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino] -pyrimidin-4-yl} -urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- ethyl- 1- {6- [4- (2- pyrrolidin- 1- yl-ethoxy) -phenylamino] -pyrimidin-4-yl }-urea; 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- [6- (3-dimethylaminomethyl-phenylamino) -pyrimidin-4-yl] -urea; 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- (6- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenylamino} -pyrimidin-4 -il) -urea; 1- (2,6- Dichloro-3,5-dimethoxyphenyl) -3- [6- (4- dimethylaminomethyl-3- trifluoromethyl-phenylamino) -pyrimidin-4-yl] -urea; 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [3- (4-isopropyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1- methyl urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (3- {[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -phenylamino) -pyrimidin-4 -il] -1 methyl urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- {6- [4- (4- isopropyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl} -1- methyl urea; 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4-yl} -urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl- {6- [4- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-ethyl- {6- [4- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4-yl} - urea; 3- (2,6- Dichloro-3.5-dimethoxyphenyl) -1- [6- (4- dimethylaminomethyl- 3- trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1-methyl urea; 5 1- (2,6- Dichloro-3,5-dimethoxyphenyl) -3- {6- [4- (4- ethyl-piperazin-1- ylmethyl) -3-trifluoromethyl-phenylamino] -pyrimidin-4- il} urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- {6- [4- (4- ethyl-piperazin-1- ylmethyl) -3- trifluoromethyl-phenylamino] -pyrimidin-4-yl } 1-methyl urea; 3- (5-Amino-2-methoxy-phenyl) -1-methyl-1- {6- [4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea; 1- 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (4-isopropyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -urea ; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl-1- (6- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -phenylamino} -pyrimidin-4-yl) -urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- {6- [4- (4- isopropyl-piperazin- 1- yl) -phenylamino] -pyrimidin-4-yl} -1- methyl urea; 1- (2,6- Dichloro-3,5-dimethoxyphenyl) -3- [6- (4- dimethylaminomethyl-3- trifluoromethyl-phenylamino) -pyrimidin-4-yl] -urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- [6- (4- dimethylaminomethyl- 3- trifluoromethyl-phenylamino) -pyrimidin-4-yl] -1-methyl 15 urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- [6- (3- {[(2-dimethylamino-ethyl) -methyl-amino] -methyl} -phenylamino) -pyrimidin-4 -il] -1methyl-urea; 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [3- (4-isopropyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-yl} -1- methyl urea; 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [3- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4-yl} -urea; 20 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1-methyl- {6- [3- (1-methyl-piperidin-4-yloxy) -phenylamino] -pyrimidin-4-yl} -urea; 3- (2,6- Dichloro-3,5-dimethoxyphenyl) -1- [6- (3- diethylaminomethyl-phenylamino) -pyrimidin-4- yl] -1-methylurea; and 3- (2,6-Dichloro-3-trifluoromethyl-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} -1-methyl -urea.

31.

 The compound 3- (2,6-Dichloro-3,5-dimethoxy-phenyl) -1- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} - 1-methylurea, which has the following structure:

32

 The compound 1- (2,6-Dichloro-3,5-dimethoxy-phenyl) -3- {6- [4- (4-ethyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-yl} - urea, which has the following structure:

33.

 A pharmaceutically acceptable salt or N-oxide of the compound of claim 31 or claim 32.

3. 4.

 A pharmaceutically acceptable compound or salt or N-oxide thereof of any preceding claim, for use as a pharmaceutical agent.

35

 The use of a compound or a pharmaceutically acceptable salt or N-oxide according to any preceding claim for the manufacture of a medicament for use in the treatment of a protein kinase dependent disease.

36.

 The use according to claim 35, wherein the protein kinase dependent disease is a tyrosine kinase dependent disease.

37.

 The use according to claim 36 wherein the tyrosine kinase dependent disease is a proliferative disease that depends on any one or more of the following tyrosine protein kinases: FGFR1, FGFR2, FRF3 and / or FGFR4.

38.

 The use according to claim 36 wherein the tyrosine kinase dependent disease is a proliferative disease that depends on any one or more of the following tyrosine protein kinases: KDR, HER1, HER2, Bcr-Abl, Tie2 and / or Ret.

39.

 The use according to claim 35 wherein the protein kinase dependent disease is selected from bladder cancer, breast cancer and multiple myeloma.

40

 A combination of the compound or pharmaceutically acceptable salt or N-oxide thereof of any one of claims 1 to 33 with one or more other therapeutic agents.

41.

 A combination of the compound or pharmaceutically acceptable salt or N-oxide thereof of any one of claims 1 to 32 with one or more cytostatic or cytotoxic compounds.

42

 The combination of claim 41, wherein the combination comprises (N- {5- [4- (4-methyl-piperazino-methyl) benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidine-amine .

43

 A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable compound or salt or N-oxide thereof of any one of claims 1-32 in combination with a pharmaceutically acceptable excipient.