MXPA06006036A - Diaryl urea derivatives in the treatment of protein kinase dependent diseases - Google Patents

Abstract

The invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for the treatment of RET dependent disorders, especially RET dependent tumor diseases. The invention further relates to novel N-[4-(pyrimidin-4-yloxy)-phenyl]-NâÇÖ-phenyl-urea derivatives and their use in the treatment of the animal or human body, especially in the treatment of a protein kinase dependent disease, to pharmaceutical compositions comprising such novel N-[4-pyrimidin-4-yloxy)-phenyl]-NâÇÖ-phenyl-urea derivatives and to the use of such novel N-[4-(pyrimidin-4-yloxy)-phenyl]-NâÇÖ-phenyl-urea derivatives for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as tumour diseases.

Description

DIARIL-UREA DERIVATIVES IN THE TREATMENT OF - DEPRIVED DISEASES OF PROTEIN KINASE SUMMARY OF THE INVENTION The invention relates to the use of diarylurea derivatives for the manufacture of pharmaceutical compositions for the treatment of RET-dependent disorders, especially tumor diseases dependent on RET. The invention also relates to novel N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivatives and their use in the treatment of the animal or human body, especially in the treatment of a protein kinase dependent disease, to pharmaceutical compositions comprising these novel N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivatives, and to the use of these novel N-derivatives [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea for the preparation of pharmaceutical compositions for use in the treatment of protein kinase-dependent diseases, especially of proliferative diseases, such as tumor diseases .

BACKGROUND OF THE INVENTION Protein kinases (PKs) are enzymes that catalyze the phosphorylation of specific serine, threonine or tyrosine residues in cellular proteins. These post-translational modifications of the substrate proteins act as a molecular change that regulates cell proliferation, activation and / or differentiation. Abnormal or excessive activity of the wild-type or mutated protein kinase has been observed in many disease states, including benign and malignant proliferative disorders. In many cases, it has been possible to treat diseases, such as proliferative disorders, by making use of the protein kinase inhibitors. In view of the large number of protein kinases and the multitude of proliferative diseases and other diseases related to protein kinase, there is an ever-existing need to provide compounds that are useful as inhibitors of protein kinase and, therefore, in the treatment of these diseases related to protein kinase.

General Description of the Invention The reconfigured proto-oncogene during transfection (RET) was identified as the susceptibility gene for multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC) ( reviewed in Eng. J. Clin Oncol., 17, 380-93, 1999; Takahashi, Cytokine and Growth Factor Rev., 12, 361-73, 2001). The RET / MEN2A subtype is characterized by mutations in the extra-cellular domain (eg, C634R), which lead to a dimerization and constitutive activation of the kinase. The less prevalent RET / MEN2B subtype is characterized by a mutation in the activation cycle (M918T), which leads to constitutive activation and altered substrate specificity. RET / MEN2B continues to respond to its ligands and, consequently, the temporal and spatial expression of the neurotropic factors of the GDNF family may have an additional influence on the clinical phenotypes of MEN2B patients (reviewed in Jhiang, Oncogene, 19, 5590 -7, 2000). Papillary thyroid carcinoma (PTC) is the most common type (85 percent) of thyroid malignancy (Lorentz, World Journal of Surgery, 18, 547-50, 1994). The tumor is associated with somatic mutations of the RET proto-oncogene, which is activated by genetic reconfigurations (Pacini, J. Endocrin, Invest., 23, 328-38, 2000; T al M ni and Asa, Adv. Anat. Pathol ., 8, 345-54, 2001). The reconfigured proto-oncogene, the PTC oncogene (RET / PTC), is the fusion product of the tyrosine kinase domain of proto-RET for other genes. The three most common variants are RET / PTC1, RET / PTC2, and RET / PTC3 (Pacini, J. Endocrin, Invest., 23, 328-38, 2000; Talllni and Asa, Adv. Anat. Pathol., 8, 345 -54, 2001). In RET / PTC1, RET / PTC2, and RET / PTC3, the tyrosine kinase domain is fused with the H4 genes, R1s, and ELE1, respectively (Tallini and Asa, Adv. Anat. Pathol., 8, 345-54, 2001). Therefore, the different mutated forms of the receptor tyrosine kinase of RET are attractive targets for the development of drugs that are directed towards cancer, especially thyroid cancer. It has also been found that RET and the different mutated forms thereof are expressed at the level of the protein and / or the mRNA in many different tumor cell lines and tissues. Accordingly, wild-type and mutated RET inhibitors are also especially suitable in the treatment of other RET-dependent cancers, such as RET-dependent cancers of the colon, lung, breast, and pancreas, as well as other solid tumors and leukemias dependent on RET. It has now been found that the compounds of the formula I are inhibitors of wild type and / or mutated RET. Accordingly, these compounds are useful in the treatment of RET-dependent diseases, especially RET-dependent proliferative diseases, in particular tumor diseases dependent on RET, such as RET-dependent cancers of the colon, lung, breast, and pancreas, as well as other solid tumors and RET-dependent leukemias, and especially RET-dependent thyroid cancer.

Detailed Description of the Invention The invention relates to the use of diarylurea derivatives which are the compounds of formula I: wherein G is not present, or is lower alkylene or cycloalkylene of 3 to 5 carbon atoms, and Z is a radical of the formula la: or G is not present, and Z is a radical of formula b: A is CH, N or N? O and A 'is N or N- O, with the proviso that no more than one of A and A' can be N- »0; n is 1 or 2; m is 0, 1, or 2; p is 0, 2, or 3; r is from 0 to 5; X is NR if p is O, where R is hydrogen or an organic fraction, or if p is 2 or 3, X is nitrogen that, together with (CH2) P and the bonds represented in dotted (interrupted) lines (including atoms with which they are linked), forms a ring, or X is CHK, wherein K is lower alkyl or hydrogen, and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y2 is O, S, or NH; with the proviso that (Y 1) n - (Y 2) m does not include groups O-O, S-S, NH-O, NH-S, or S-O; each of R (, R2, R3, and R5, independently of the others, is hydrogen or an inorganic or organic fraction, or any two of them together form a lower alkylene bridge-di oxy which is bonded via the oxygen, and the remainder of these fractions is hydrogen or an inorganic or organic fraction, and R (if present, that is, if r is not zero) is an inorganic or organic fraction, or a tautomer thereof, or a salt pharmaceutically acceptable thereof, for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases.

The present invention also relates to novel N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivatives of the formula I, as disclosed in the Examples below. in the present (Examples 1-70), which are hereinafter referred to as "NOVEDOUS COMPOUNDS OF THE INVENTION"). The novel compounds of the invention show in particular an inhibition of one or more of the following tyrosine protein kinases: c-Abl, Bcr-Abl, the receptor tyrosine kinases Flt-3, RET, the vascular endothelial growth factor receptor (VEGF-R) and Tek (Tie2), especially Flt-3, as well as combinations of two or more of these; The NOVEL COMPOUNDS OF the INVENTION are furthermore also suitable for the inhibition of the non-receptor tyrosine kinase Raf, and / or for the inhibition of mutants of these enzymes, especially Bcr-Abl, for example the mutant Glu255? Lysine In view of these activities, the NOVEL COMPOUNDS OF the INVENTION can be used for the treatment of diseases related to a particularly aberrant or excessive activity of these types of kinases, especially those mentioned. The general terms used hereinbefore and hereinafter, preferably have, within this disclosure, the following meanings, unless otherwise indicated. When "the use of diarylurea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases" is mentioned, this means that the use of these diarylurea derivatives in the treatment of diseases is also included. RET-dependent, methods of using these diaryl-urea derivatives in the treatment of RET-dependent diseases, and pharmaceutical compositions comprising these diaryl-urea derivatives for the treatment of RET-dependent diseases. In addition it also means that the diaryl urea derivatives are included for use in the treatment of RET-dependent diseases. The prefix "lower" denotes a radical that has from 1 up to and including a maximum of 7, especially from 1 up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching . For examplelower alkyl is methyl, ethyl, normal propyl, secondary propyl, normal butyl, isobutyl, secondary butyl, tertiary butyl, normal pentyl, normal hexyl, or normal heptyl. When the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, it is also intended to mean a single compound, salt, or the like. Halo (geno) is preferably iodo, bromo, chloro, or fluoro, especially fluorine, chlorine, or bromine. In view of the close relationship between the diaryl urea derivatives in free form and in the form of their salts, including the salts that can be used as intermediates, for example in the purification or identification of the compounds of the formula I, tautomers , or tautomeric mixtures, and their salts, any reference hereinbefore and hereinafter to these compounds, especially the NOVEDOUS COMPOUNDS OF THE INVENTION, should be understood as a reference also to the corresponding tautomers of these compounds, mixtures tautomerics of these compounds, N -oxides of these compounds, or salts of any of them, as appropriate and convenient, and if not mentioned otherwise. For example, tautomers may be present in cases where amino or hydroxyl, each with at least one bound hydrogen, are bonded to carbon atoms that are linked to adjacent atoms by double bonds (eg, ketone tautomerism). enol or mine-enamine). Preferred tautomers are the pyridin-on-yl or pyrimidin-on-yl forms of the compounds wherein R is hydroxyl and the other fractions are as defined for the compounds of the formula I. When you mention "a compound ..., a tautomer of it; or a salt thereof, or the like, this means "a compound ..., a tautomer thereof, or a salt of the compound or the tautomer." The asymmetric carbon atoms of a compound of the formula I which are optionally present , they can exist in the configuration (R), (S), or (R, S), preferably in the configuration (R) or (S). Substituents in a double bond or in a ring, can be present in the Accordingly, the compounds may be present as mixtures of isomers, or preferably as the pure Isomers The salts are preferably the pharmaceutically acceptable salts of the diaryl derivatives. -urea of the present invention, in particular of the NOVEDOUS COMPOUNDS OF THE INVENTION The salt-forming groups are groups or radicals having basic or acidic properties Compounds having at least one basic group or at least one basic radical, amino example, a amino group sec which 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 a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or dicarboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, or acid oxalic; or with amino acids, such as arginine or lysine; with aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-amino-salicylic acid; with aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid; with hetero-aromatic carboxylic acids, such as nicotinic acid or isonicotinic acid; with aliphatic sulfonic acids, such as methan-, ethane-, or 2-hydroxyethane-sulphonic acid; or with aromatic sulfonic acids, for example benzene-, p-toluene-, or naphthalene-2-sulfonic acid. When several basic groups are present, salts of mono- or poly-acid addition can be formed. The compounds having acidic groups, a carboxyl group, or a phenolic hydroxyl group, can form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium, or calcium salts, or ammonium salts with ammonia or with suitable organic amines, such as tertiary monoamines, for example triethylamine or tri- (2-hydroxyethyl) -amine, or heterocyclic bases, for example N-ethyl-piperidine or N, N '-dimethylpiperazine. Mixtures of salts 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 the compounds which are used additionally as intermediates, it is also possible to use pharmaceutically unacceptable salts, for example the picrates. However, for therapeutic purposes, only pharmaceutically acceptable non-toxic salts can be used, and therefore, those salts are preferred. An organic fraction R is preferably unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted cycloalkenyl; unsubstituted alkyl is preferred. "Substituted", whenever used for a fraction, means that one or more hydrogen atoms in the respective fraction, especially up to 5, more especially up to 3, of the hydrogen atoms, are replaced independently of each other by the number of substituents which are preferably independently selected from the group consisting of lower alkyl, for example methyl, ethyl, or propyl, lower haloalkyl, for example trifluoromethyl, aryl of 6 to 16 carbon atoms, especially phenyl or naphthyl (wherein aryl of 6 to 16 carbon atoms, especially phenyl or naphthyl) is unsubstituted or substituted by one or more, especially by up to three fractions selected from halogen, carboxyl, lower alkoxy-carbonyl, hydroxyl, lower alkoxy, lower phenyl-lower alkoxy, lower alkanoyloxy, lower alkanoyl, N-lower alkyl amino, N, N-lower-dialkyl amino, N-phenyl-lower alkyl-amino, N, N-bis (phenyl-lower alkyl) -amino, lower alkanoyl-amino, halogen, halo-lower alkyl, for example trifluoro -methyl, sulfo, sulfamoyl, carbamoyl, N-lower alkyl-carbamoyl, N- (hydroxy-lower alkyl) -carbamoyl, such as N- (2-hydroxy-ethyl) -carbamoyl, cyano, cyano-lower alkyl, and nitro ), cycloalkyl of 3 to 10 carbon atoms, especially cyclopropyl or cyclohexyl, hydroxyl i-cycloalkyl of 3 to 8 carbon atoms, such as hydroxy-cyclohexyl, heterocyclyl with 5 or 6 ring atoms and with 1 to 3 ring heteroatoms selected from O, N, and S, especially piperidinyl, especially piperidin -1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl, in particular morpholin-1-yl, hydroxyl, lower alkoxy, for example methoxy, halo-lower alkoxy, especially 2,2,2-trifluoro-ethoxy , phenyl-lower alkoxy, amino-lower alkoxy, such as 2-amino-ethoxy; lower alkanoyloxy, lower hydroxyalkyl, such as hydroxymethyl or 2-hydroxyethyl, amino, N-lower alkyl-amino, N, N-lower dialkyl-amino, N-phenyl-lower alkyl-a, N, N-bis (f-lower alkyl) -amino, lower-amino alkanoyl, especially acetylamino, benzoyl-amino, carbamoyl-lower alkoxy, N-lower alkyl-carbamoyl-lower alkoxy, or N, N- lower dialkyl-carbamoyl-lower alkoxy, amidino, N-hydroxy-amidino, guanidino, lower amino-alkyl, such as amino-methyl or 2-amino-ethyl, lower amidino-alkyl, such as 2-amidino-ethyl, N-hydroxy-amidino-lower alkyl, such as N-hydroxy-amide and non-methyl or -2-ethyl, halogen, for example fluorine, chlorine, bromine, or iodine, carboxyl, lower alkoxyl-carbonyl, phenyl-, naphthyl -, or fluorenyl-lower alkoxy-carbonyl, such as benzyloxycarbonyl, lower alkanoyl, sulfo, lower alkane-sulfonyl, for example methansulfonyl (CH3-S (0) 2-), phosphono (-P (= 0) (0H) 2), hldroxy-alkoxy inf erior, phosphoryl or di-lower alkoxyl-phosphoryl, carbamoyl, mono- or di-lower alkyl-carbamoyl, mono- or di- (hydroxy-lower alkoyl) -carbamoyl, sulfamoyl, mono- or di-lower alkyl-amino -sulfonyl, nitro, cyano-lower alkyl, such as cyano-methyl, and cyano. It remains without saying that the substituents are only in the positions where they are chemically possible, and the person skilled in the art is able to decide (either experimentally or theoretically), without an inappropriate effort, which substitutions are possible and which are not. . For example, amino or hydroxyl groups with free hydrogen may be unstable if they are bonded to carbon atoms with unsaturated (eg, olefinic) bonds. Alkyl preferably has up to 20, more preferably up to 12 carbon atoms, and is linear or branched one or more times; lower alkyl is preferred, especially alkyl of 1 to 4 carbon atoms, in particular methyl, ethyl, or normal propyl. Alkyl is unsubstituted or substituted, preferably by one or more substituents independently selected from those mentioned above under "Substituted". As an organic fraction R, unsubstituted alkyl, preferably lower alkyl, is particularly preferred. Among the fractions corresponding to substituted alkyl, hydroxy-lower alkyl, in particular 2-hydroxy-ethyl, and / or halo-lower alkyl, especially trifluoro-methyl or 2,2,2-trifluoro-etiol, are especially preferred. Alkenyl is preferably a moiety with one or more double 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 far as possible in view of the number of carbon atoms). Preference is given to alkenyl of 2 to 7 carbon atoms, especially alkenyl of 3 to 4 carbon atoms, such as allyl or crotyl. Alkenyl can be unsubstituted or substituted, in particular by one or more, more especially by up to three, of the substituents mentioned above under "Substituted". Substituents, such as amino or hydroxyl (with free dissociable hydrogen), are preferably not bonded to carbon atoms participating in a double bond, and other substituents that are not sufficiently stable are also preferably excluded. Unsubstituted alkenyl, in particular alkenyl having 2 to 7 carbon atoms, is preferred. Alkynyl is preferably a moiety 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 far as possible in view of the number of carbon atoms). Preference is given to alkynyl of 2 to 7 carbon atoms, especially alkynyl of 3 to 4 carbon atoms, such as ethynyl or propyne-2-yl. Alkynyl can be unsubstituted or substituted, in particular by one or more, more especially up to three, of the substituents mentioned above under "Substituted". Substituents such as amino or hydroxyl (with free dissociable hydrogen)they preferably do not bind to the carbon atoms participating in a triple bond, and other substituents that are not sufficiently stable are also preferably excluded. Unsubstituted alkynyl, in particular alkynyl of 2 to 7 carbon atoms is preferred. Aryl preferably has a ring system of not more than 16 carbon atoms, is preferably mono-, bi-, or tri-cyclic, and is unsubstituted or preferably substituted as defined above under "Substituted". Preferably, aryl is selected from phenyl, naphtyl, indenyl, azulenyl, and anthryl, and is preferably in each case unsubstituted or lower alkyl, especially methyl, ethyl, or normal propyl, halogen (especially fluorine, chlorine, bromine, or iodine), halo-lower alkyl (especially trifluoromethyl), hydroxyl, lower alkoxy (especially methoxy), lower haloalkoxy (especially 2,2,2-trifluoro-ethoxy), amino-lower alkoxy (in special 2-amino-ethoxy), lower alkyl (especially methyl or ethyl), carbamoyl, N- (hydroxy-lower alkyl) -carbamoyl (especially N- (2-hydroxy-ethyl) -carbamoyl), and / or sulfamoll -substituted aryl, especially a corresponding substituted or unsubstituted phenyl. Heterocyclyl is preferably a heterocyclic radical that is unsaturated, saturated, or partially saturated in the linking ring, and is preferably a monocyclic ring, or in a broader aspect of the invention, a bicyclic or tricyclic ring; has from 3 to 24, more preferably from 4 to 16 ring atoms; wherein at least in the ring that is linked to the radical of the molecule of formula I, one or more, preferably one to four, especially one or two ring carbon atoms, are replaced by a heteroatom selected from from the group consisting of nitrogen, oxygen, and sulfur, preferably having the linking ring from 4 to 12, especially from 5 to 7 ring atoms; the heteroaryl being unsubstituted or substituted by one or more, especially 1 to 3 substituents independently selected from the group consisting of the substituents defined above under "Substituted"; in particular a heteroaryl radical selected from the group consisting of oxirane, azirinyl, 1,2-oxathiolanyl, midazolyl, thienyl, furyl, tetrahydro-furyl, pyranyl, thiopyranyl, thiantrenyl, isobenzo-furanyl, benzo -f uranyl, chromenyl, 2H-pirroIilo, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, piraniol, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, especially piperidin-1-yl, piperazinyl, especially piperazin-1-yl, pyridazinyl, morpholinyl, in particular morpholino, thiomorpholinyl, especially thiomorpholino, indoliznyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, coumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizlnyl, iso-quinolyl, quinolyl, tetrahydro-quinolyl, tetrahydro-isoquinolyl, decahydro-quinolyl, octahydro-1-isoquinol, benzo-furanyl, dibenzo-furanyl, benz otio-phenyl, d-benzo-thiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl and chromanyl, each one of these radicals unsubstituted or substituted by one to two radicals selected from the group consisting of lower alkyl, especially methyl or tertiary butyl, lower alkoxy, especially methoxy, and halogen, especially bromine or chlorine. Preferred is unsubstituted heterocyclyl, especially piperidyl, piperazinyl, thiomorpholino, or morpholino. Cycloalkyl is preferably cycloalkyl of 3 to 10 carbon atoms, especially cyclopropyl, dimethylcyclopropella, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, the cycloalkyl being unsubstituted or substituted by one or more, in particular 1 to 3 substituents independently selected from from the group consisting of the substituents defined above under "Substituted". Cycloalkenyl is preferably cycloalkenyl of 5 to 10 carbon atoms, especially cyclopentenyl, cyclohexenyl, or cycloheptenyl, the cycloalkenyl being unsubstituted or substituted by one or more, in particular 1 to 3 substituents independently selected from the group consisting of substituents previously defined under "Substituted". An inorganic fraction is preferably halogen, hydroxyl, amino, or nitro. The links represented by dotted lines (interrupted) and linking (CH2) P, are present if p is 2 or 3, or absent if p is zero. An organic fraction is preferably unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted cycloalkenyl, unsubstituted or substituted alkoxy, unsubstituted or substituted alkenyloxy , unsubstituted or substituted alkynyloxy, unsubstituted or substituted aryloxy, unsubstituted or substituted heterocyclyloxy, unsubstituted or substituted cycloalkoxy or unsubstituted or substituted cycloalkenyloxy, or unsubstituted or substituted alkylamino, unsubstituted or substituted alkenylamino;, unsubstituted or substituted alkynylamino, unsubstituted or substituted arylamino, unsubstituted or substituted heterocyclic-amino, unsubstituted or substituted cycloalkylamino, or unsubstituted or substituted cycloalkenylamino. An organic fraction is preferably alkyl, especially lower alkyl, such as methyl, ethyl, or propyl, halo-lower alkyl, such as trifluoromethyl, lower alkoxy, such as methoxy, halo-lower alkoxy, such as 2, 2,2-trifluoro-ethoxy, halogen, such as chlorine or bromine, phenyl, phenyl-amino, hydroxy-phenyl-amino, such as 4-hydroxy-phenyl-amino, amino-lower alkyl-oxyphenyl-amino, such as [ 4- (2-amino-ethyl) -oxi] -phenyl-amino, carbamoyl-phenyl-amino, such as 4-sulfamoyl-phenylamino, [N- (hydroxy-lower alkyl) -carbamoyl-phenyl-amino, such as . { N- [4- (2-hydroxy-ethyl) -carbamoyl] -phenyl} -amino, saturated 5- or 6-membered heterocyclyl with 1 or 2 heteroatoms selected from the group consisting of N, O, and S, especially piperidyl, such as piperidin-1-yl, piperazinyl, such as piperazin-1 - ilo, morpholinyl, such as morpholino, or in addition thiomorpholinyl, such as thiomorpholino. A basic organic fraction is a fraction selected from the definition of an organic fraction as given herein, and which has basic (alkaline) properties. Preferably, a basic organic fraction is piperidyl, especially piperidin-1-yl, piperidyl-lower alkyl, especially piperidin-1-methylmethyl, lower alkyl-piperazinyl, especially 4-methyl-piperazin-1-yl or 4- ethyl-piperazin-1-yl, or lower alkyl-piperazinyl-lower alkyl, especially 4-methyl-piperazin-1-methylmethyl or 4-ethyl-piperazin-1-ylmethyl. If any two of R1 (R2, and R3 together form a lower alkylene-dioxyl bridge bonded via the oxygen atoms, this bridge is preferably methylene-dioxyl (O-CH2-O) or ethylene-dioxyl (O- CH2-CH2-O) linked by means of the oxygen atoms to the vicinal carbon atoms, and the remainder of these fractions is hydrogen or an inorganic or organic fraction, as described above. protein tyrosine kinase "refers to the prophylactic, or preferably therapeutic (including palliative and / or curative) treatment of these diseases, especially the diseases mentioned herein.The compounds of the formula I have valuable pharmacological properties and are useful in the treatment of RET-dependent diseases, especially RET-dependent proliferative diseases, in particular tumor diseases dependent on RET, such as cancers of RET-dependent colon, lung, breast, and pancreas, as well as other solid tumors and RET-dependent leukemias, and especially thyroid cancer dependent on RET.

Inhibition of the RET kinase is determined as follows: Cloning and expression: The baculovirus donor vector pFB-GSTX3 is used to generate a recombinant baculovirus expressing the amino acid region 658-1072 (Swiss protein number Q9BTB0) of the kinase domain cytoplasmic of human RET-Men2A corresponding to the wild-type kinase domain of RET (wtRET) and RET-Men2B, which differs from wtRET by the activating mutation in the M918T activation cycle. The coding sequence for the cytoplasmic domain of wtRET is amplified by polymerase chain reaction from a cDNA library using specific primers. RET-Men2B is generated through site-directed mutagenesis, which results in the M918T mutation. The amplified DNA fragments and the pFB-GSTX3 vector are made compatible for ligation by digestion with Sali and Kpnl. Ligation of these DNA fragments results in the baculovirus donor plasmids pFB-GX3-RET-Men2A and pFB-GX3-RET-Men2B, respectively. Virus production: The baculovirus donor plasmids containing the kinase domains are transfected into the DHIOBac cell line (GIBCO), and the transfected cells are applied to selective agar dishes. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. Individual white colonies are collected, and viral DNA (bacmid) is isolated from the bacteria by conventional plasmid purification procedures. The Sf9 or Sf21 (American Type Culture Collection) cells are then transfected into 25-centimeter-volume flasks with the viral DNA using the Cellfectin reagent. Protein expression in Sf9 cells: The virus-containing medium is harvested from the transfected cell culture, and used for infection, in order to increase its titration. The virus-containing medium obtained after two rounds of infection is used for large-scale expression of the protein. For large-scale protein expression, round tissue culture dishes of 100 square centimeters, with 5 x 10 7 cells / dish, are seeded and infected with 1 milliliter of virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the dish and centrifuged at 500 revolutions per minute for 5 minutes. The cell granules from 10 to 20 plates of 100 square centimeters are resuspended in 50 milliliters of ice cold lysis buffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 percent NP-40, 1 mM DTT , 1 mM PMSF). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes.

Purification of GST-labeled proteins: The centrifuged cell lysate is loaded onto a 2 milliliter column of glutathione-Sepharose (Pharmacia), and washed 3 times with 10 milliliters of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. Then the GST-labeled proteins are eluted by 10 applications (1 milliliter each) of 25 mM Tris-HCl, pH 7.5, reduced glutathione 10 mM, 100 mM NaCl, 1 mM DTT, 10 percent glycerol, and Store at -70 ° C. Measurement of enzyme activity: Tyrosine protein kinase assays are carried out with either purified GST-wtRET protein, or with GST-RET-Men2B protein, in a final volume of 30 microliters containing 15 nanograms of GST-wtRET protein or GST-RET-Men2B, 20 mM Tris-HCl, pH 7.5, 1 mM MnCl 2, 10 mM MgCl 2, 1 mM DTT, 3 micrograms / milliliter of poly (Glu, Tyr) 4: 1, dimethyl sulfoxide 1 percent, ATP 2.0 μM ((- [33P] -ATP 0.1 μCi) Activity is assayed in the presence or absence of inhibitors, by measuring the Incorporation of 33P from [(33P) ATP into poly ( Glu, Tyr) 4: 1. The assay is carried out in 96-well plates at room temperature for 15 minutes under the conditions described above., and is terminated by the addition of 20 microliters of 125 mM EDTA. Subsequently, 40 icrolitres of the reaction mixture are transferred onto an Immobilon-PVDF (Miilipore) membrane previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5% H3PO4, and mounted on a vacuum manifold with the vacuum source disconnected. After placing all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of 0.5% H3PO4. The membranes are removed and washed 4 times on a shaker with 1.0 percent H3PO4, and once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96-well Packard TopCount frame, and with the addition of 10 micro-liters / well of Microscint ™ (Packard). The IC 50 values are calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, in 4 concentrations (usually 0.01, 0.1, 1, and 10 μM). One unit of protein kinase activity is defined as 1 nanomole of 33P transferred from the [(33P) ATP to the protein substrate / min / milligram protein at 37 ° C. The compounds of the formula I show IC50 values here the interval between 0.005 and 5 μM, especially between 0.01 and 1 μM, when the term "USE" is subsequently mentioned in relation to the NOVEL COMPOUNDS OF the INVENTION, this includes any one or more of the following embodiments of the invention, respectively: the use in the treatment of protein kinase-dependent diseases (especially tyrosine), the use for the preparation of pharmaceutical compositions to be used in the treatment of such diseases, the methods of use of the NOVEDOUS COMPOUNDS OF the INVENTION in the treatment of These diseases, pharmaceutical compositions comprising the NOVEL COMPOUNDS OF THE INVENTION for use in the treatment of these diseases, and CO NOVELTIES OF THE INVENTION for use in the treatment of such diseases, as appropriate and convenient, if not otherwise reported. In particular, the diseases to be treated, and therefore, those preferred for the USE of a NOVEDOUS COMPOUND OF THE INVENTION, are selected from the dependent diseases (meaning "dependent" as well). "supported", not only "exclusively dependent") of the protein kinase (especially tyrosine) mentioned below, especially the corresponding proliferative diseases, more especially diseases that depend on the activity of c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R, and / or Tek, especially Flt-3, especially the diseases mentioned below under these specific tyrosine protein kinases. Other kinases that can be inhibited by the NOVEDOUS COMPOUNDS OF THE INVENTION Include the platelet-derived growth factor receptor (PDGF-R), the fibroblast growth factor receptor (FGF-R), the growth factor receptor type. insulin I (IGF-IR), to Eph receptors such as especially the EphB4 receptor, c-Kit, Met, c-Src, and ras. The NOVEL COMPOUNDS OF THE INVENTION have valuable pharmacological properties and are useful in the treatment of protein kinase-dependent diseases, especially of tyrosine protein kinase-dependent diseases, for example as drugs for treating proliferative diseases. The efficacy of the NOVEL COMPOUNDS OF the INVENTION as inhibitors of the protein tyrosine c-Abl protein kinase activity can be demonstrated as follows: An in vitro enzymatic assay is carried out in 96-well plates as a protein binding assay. filter, as described by Geissier et al. in Cancer Res. 1992; 52: 4492-4498, with the following modifications. The His-tagged kinase domain of c-Abl is cloned and expressed in the baculovirus / Sf9 system, as described by Bhat et al in J. Biol. Chem. 1997; 272: 16170-16175. A 37 kD protein (c-Abl kinase) is purified by a two step procedure on a cobalt metal chelate column, followed by an anion exchange column, with a yield of 1 to 2 milligrams / liter of cells Sf9 (Bhat et al., Cited reference). The purity of the c-Abl kinase is > 90 percent, judged by SDS-PAGE after staining with Coomassie blue. The assay contains (total volume of 30 micro-liters): c-Abl kinase (50 nanograms), 20 mM Tris? CI, pH 7.5, 10 mM MgCl 2, 10 μM Na3VO 4, 1 mM DTT, and 0.06 μCi / assay [ (33P) ATP (5 μM ATP) using 30 micrograms / milliliter of poly-Ala, Glu, Lys, Tyr-6: 2: 5: 1 (Poly-AEKY, Sigma P1152) in the presence of 1-dimethyl sulfoxide The reactions are terminated by the addition of 10 microliters of 250 mM EDTA and 30 microliters of the reaction mixture are transferred onto an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol. Rinse with water, then soak for 5 minutes with 0.5 percent H3PO4, and mount it on a vacuum manifold with the vacuum source disconnected.After putting all the samples, the vacuum is connected and each well is rinsed with 200 microliters of 0.5 percent H3PO4 The membranes are removed and washed on a shaker with 0.5 percent H3PO4 (4 times), and a once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96-well Packard TopCount frame, and with the addition of 10 microliters / well of Microscint ™ (Packard). Using this test system, the NOVEL COMPOUNDS OF the INVENTION show ICSo inhibition values in the range of 0.001 to 100 μM, usually between 0.05 and 5 μM. The inhibition of the autophosphorylation of the VEGF-induced receptor can be confirmed with additional experiments in vitro in cells such as transfected CHO cells, which permanently express the human receptor VEGF-R2 (KDR), are seeded in a complete culture medium (with fetal calf serum = 10 percent FCS) in 6-well cell culture plates, and incubated at 37 ° C under 5 percent C02, until they show a confluence of approximately 80 percent. The compounds to be tested are then diluted in the culture medium (without fetal calf serum, with 0.1 percent bovine serum albumin), and added to the cells. (The controls comprise a medium without test compounds). After two hours of incubation at 37 ° C, recombinant VEGF is added; The final VEGF concentration is 20 nanograms / milliliter. After an additional five minutes of incubation at 37 ° C, the cells are washed twice with ice cold PBS (phosphate buffered serum), and immediately lysed in 100 microliters of lysis buffer per well. The used ones are then centrifuged to remove the cell nuclei, and the protein concentrations of the supernatants are determined using a commercial protein assay (BIORAD). Then the Used ones can be used immediately or, if necessary, they can be stored at -20 ° C- A sandwich ELISA is carried out to measure the phosphorylation of VEGF-R2: A monoclonal antibody to VEGF-R2 (for example, Mab 1495.12.14, prepared by H. Towbin, Novartis, or a comparable monoclonal antibody) is immobilized on black ELISA plates (OptiPlate R HTRF-96 from Packard). The plates are then washed, and the remaining free protein binding sites are saturated with 3 percent TopBlock® (Juro, Cat. # TB232010) in phosphate buffered serum with Tween 20® (polyoxyethylene sorbitan monolaurate (20) , IC l / U nlq uema) (PBST). Cells (20 micrograms of protein per well) are then incubated in these plates overnight at 4 ° C, together with an anti-phosphotyrosine antibody, coupled with alkaline phosphatase (PY20: AP from Zymed). The (plates are washed again, and the) binding of the anti-phosphotyrosine antibody to the captured phosphorylated receptor is then demonstrated using a luminescent AP substrate (CDP-Star, ready for use, with Emerald II, Applied Biosystems). The luminescence is measured on a Packard TopCount Microplate Cintilation Counter. The difference between the signal of the positive control (stimulated with VEGF) and that of the negative control (not stimulated with VEGF) corresponds to the VEGF-R2 phosphorylation induced by VEGF (= 100 percent). The activity of the test substances is calculated as the percentage inhibition of VEGF-induced phosphorylation of VEGF-R2, where the concentration of the substance that induces half of the maximum inhibition is defined as the IC5o (inhibitory dose for an inhibition). 50 percent). The NOVEL COMPOUNDS OF the INVENTION here show an IC 50 in the range of 0.0003 to 20 μM, preferably between 0.001 and 10 μM. In analogy, the inhibition of VEGF-R1 can be shown as follows: The test is conducted using the receptor tyrosine kinase of VEGF Flt-1. The detailed procedure is as follows: 30 microliters of kinase solution (10 nanograms of the kinase domain of Flt-1, Shibuya et al., Oncogene 5_, 519-24 (1990)) in 20 mM Tris-HCl, pH 7.5, 3 mM manganese dichloride (MnCl 2), 3 mM magnesium chloride (MgCl 2), 10 mM sodium vanadate, 0.25 milligrams / milliliter of polyethylene glycol (PEG) 20,000, 1 mM dithioerythritol, and 3 micrograms / poly milliliter (Glu, Tyr) 4: 1 (Sigma, Buchs, Switzerland), [(33P) ATP 8 μM (0.2 μCi), dimethyl sulfoxide at 1 percent, and 0 to 100 μM of the NOVEDOUS COMPOUND OF THE INVENTION to be tested , they are incubated together for 10 minutes at room temperature, then the reaction is terminated by the addition of 10 microliters of ethylene diamine acetate (EDTA) 0.25 M, pH 7. Using a multi-channel dispenser (LAB SYSTEMS, USA) , a 20 microliter aliquot is applied to an Immobilon P PVDF membrane (= polyvinyl difluoride) (Millipore, USA), a through a Millipore microtiter filter manifold, and connected to a vacuum. Following the complete elimination of the liquid, the membrane is washed 4 times successively in a bath containing phosphoric acid (H3PO4) at 0.5 percent and once with ethanol, incubated for 10 minutes with stirring, then mounted on a Hewlett Multiple Packard TopCount, and radioactivity is measured after the addition of 10 microlitres of Microscint® (liquid scintillation counter-β). IC50 values are determined by linear regression analysis of the percentages of inhibition of each compound under three conditions (as a rule, 0.01, 0.1, and 1 micromoles). The IC50 values that can be found with the NOVEL COMPOUNDS OF the INVENTION are in the range of 0.01 to 100 μM, preferably in the range of 0.01 to 50 μM. The inhibition of Flt-3 kinase is determined as follows: The baculovirus donor vector pFbacGOl (GIBCO) is used to generate a recombinant baculovirus expressing the amino acid region 563-993 of the cytoplasmic kinase domain of human Flt-3. The coding sequence for the cytoplasmic domain of Flt-3 is amplified by polymerase chain reaction from human cDNA libraries (Clontech). The amplified DNA fragments and the pFbacGOl vector are made compatible for ligation by digestion with BamH1 and HindIII. Ligation of these DNA fragments results in the baculovirus donor plasmid pFbacG01 -Flt-3. The production of the viruses, the expression of proteins in Sf9 cells, and the purification of the proteins fused with GST, are carried out as follows: Virus production: The baculovirus donor plasmid (pFbacGOl -Flt-3) containing the Flt-3 kinase domain is transfected into the DHIOBac cell line (GIBCO), and the transfected cells are applied to selective agar dishes. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. Individual white colonies are collected, and viral DNA (bacmid) is isolated from the bacteria by conventional plasmid purification procedures. The Sf9 or Sf21 (American Type Culture Collection) cells are then transfected in flasks with the viral DNA using the Cellfectin reagent. Protein expression in Sf9 cells: The virus-containing medium is harvested from the transfected cell culture, and used for infection, in order to increase its titration. The virus-containing medium obtained after two rounds of infection is used for large-scale expression of the protein. For large-scale protein expression, round tissue culture dishes of 100 square centimeters, with 5 x 10 7 cells / dish, are seeded and Infected with 1 milliliter of virus-containing medium (approximately 5 MOls). After 3 days, the cells are scraped off the dish and centrifuged at 500 revolutions per minute for 5 minutes. The cell granules from 10 to 20 plates of 100 square centimeters are resuspended in 50 milliliters of ice cold lysis buffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 percent NP-40, DTT 1 mM, 1 mM PMSF). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. Purification of the GST-labeled protein: The used centrifuged cell is loaded onto a 2 milliliter column of glutathione-Sepharose (Pharmacia), and washed 3 times with 10 milliliters of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA , 1 mM DTT, 200 mM NaCl. Then the GST-labeled protein is eluted by 10 applications (1 milliliter each) of 25 mM Tris-HCl, pH 7.5, reduced glutathione 10 M, 100 mM NaCl, 1 mM DTT, 10 percent glycerol, and Store at -70 ° C. Measurement of enzymatic activity: Tyrosine protein kinase assays are carried out with purified GST-Flt-3 protein, in a final volume of 30 microliters containing from 200 to 1,800 nanograms of enzyme protein (depending on the specific activity), Tris -HCl mM, pH 7.6, 3 mM MnCl 2, 3 mM MgCl 2, 1 mM DTT, Na3VO4 10 μM, 3 μm crossthome / m i I liter of poll (Glu, Tyr) 4: 1, dimethyl sulfoxide at 1 percent, ATP 8.0 μM, and 0.1 μCi ((33P) -ATP) Activity is assayed in the presence or absence of inhibitors, by measuring the incorporation of 33P from [(33P) ATP into the poly (Glu, Tyr) substrate. (30 microliters) is carried out in 96-well plates at room temperature for 20 minutes, and is terminated by the addition of 20 microliters of 125 mM EDTA Subsequently, 40 microliters of the reaction mixture is transferred onto a membrane Immobilon-PVDF (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5% H3P04, and mounted on a vacuum manifold with the source of empty disconnected. After putting all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of H3P04 at 0.5 percent. The membranes are removed and washed 4 times on a shaker with H3P0 at 1. 0 percent, and once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96-well Packard TopCount frame, and with the addition of 10 microliters / well of Microscint ™ (Packard). The IC5o values are calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, in four concentrations (usually 0.01, 0.1, 1, and 10 μM). One unit of protein kinase activity is defined as 1 nM of 33P transferred from [(33P) ATP to the substrate protein per minute per milligram of protein at 37 [deg.] C. The NOVECOUS COMPOUNDS OF the INVENTION show IC50 values here the interval between 0.005 and 20 μM, preferably between 0.01 and 10 μM Inhibition of proliferation in Ba / F3 cells dependent on Flt-3: The potential of the compound to penetrate the cell membranes and exert anti-proliferative effects is determined in Ba / F3 cells depending on the mutated Flt-3 receptor kinases [ITD or D835Y, Gilliland and Griffin, Blood, Volume 100, Number 5, 1532-42 (2002)]. A modified protocol of the YO-PRO-1 assay in a 96-well format is based on the use of the wild-type IL-3 dependent hematopoietic cell line Ba / F3 (DSMZ, Braunschweig, Germany), and the mutant sub-lines ITD-Ba / F3 or D835Y-Ba / F3 [Weisberg et al., Cancer Cell 1 (5): 433-43 (2002)] qu and express constitutively activating Flt-3 kinases.

The ITD-FLT3- or D835Y-FLT3-BaF3 cells are diluted in a fresh medium to a final concentration of 3 x 10 5 cells per milliliter, and 50 microliter aliquots are seeded into 96-well plates (1.5 x 10 4 cells per well) . Subsequently, 50 microliters of compound solutions are added 2 times, and the cells are incubated for 48 hours. The anti-proliferative and apoptotic activity of a compound is initially tested in triplicate at a concentration of 10 μM, 1 μM, and 0.1 μM in both cell lines. Cells treated with dimethyl sulfoxide alone (added to a final concentration of 0.1 percent) always serve as a control. In addition, a plate control value in a well containing only 100 microliters of the medium and no cells is routinely determined. To further profile a compound, an ED5o determination is made starting at 10 μM or 3 μM of the compound of interest. From these concentrations, nine dilutions are prepared in steps, reaching the final concentrations of 2 nM and 0.5 nM, respectively. The activity of the inhibitors is evaluated by the YO-PRO-1 assay, as described previously in [Idziorek et al., J. Immunol. Methods; 185: 249-58 (1995)]. Briefly stated, after the 48 hour treatment period, an aliquot of 25 microliters of a solution containing 100 mM sodium citrate, pH 4.0, 134 mM sodium chloride, and YO-PRO-1 dye is added. 12. 5 μM (iodide of YO-PRO-1, # Y3603, Molecular Probes) directly to the 100 microliters of the medium in the wells of the 96-well plate. This results in a final dye concentration of 2.5 μM. Then the plate is incubated for 10 minutes at room temperature in the dark. The recovery of YO-PRO-1 dye in the cells is evaluated by a first measurement using a Cytofluor II 96-well plate reader (PerSeptive Biosystems) with the following positions: Excitation (nanometer) 485/20 and Emission (nanometers) 530/25, Gain 75. After this first reading, 25 microliters of lysis buffer consisting of 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, are added to each well, NP40 at 0. 4 percent, 20 mM EDTA and 20 mM. The cell lysis is terminated within 60 minutes at room temperature, and the total amount of YO-PRO-1 bound to the DNA is determined by a secmeasurement using the 96-well Cytofluor II reader with identical positions to those described above. Using this test, the COMPOUNDS NOVELTS OF THE INVENTION exhibit ED50 values for both mutant sub-lines in the range of 0.1 nM to 1 μM, especially 0.1 nM to 100 nM. Inhibition of Tek kinase can be carried out as follows: The baculovirus donor vector pFbacGOl is used to generate a recombinant baculovirus expressing the region of amino acids 773-1124 of the cytoplasmic kinase domain of human Tek, N-terminally merged with GST. The Tek is cloned back into the pFbacGOl transfer vector by EcoRI cleavage and ligating in pFbacGOl digested with EcoRI (FBG-Tie2 / Tek). The production of the viruses, the expression of the proteins in Sf9 cells, and the purification of the proteins fused with GST, are carried out as follows: Virus production: The transfer vectors containing the kinase domain are transfected into the DHIOBac cell line (GIBCO), and the transfected cells are applied to selective agar dishes. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. Individual white colonies are collected, and viral DNA (bacmid) is isolated from the bacteria by conventional plasmid purification procedures. The Sf9 or Sf21 (American Type Culture Collection) cells are then transfected into 25-centimeter-volume flasks with the viral DNA using the Cellfectin reagent. Protein expression in Sf9 cells: The virus-containing medium is harvested from the transfected cell culture, and used for infection, in order to increase its titration. The virus-containing medium obtained after two rounds of infection is used for large-scale expression of the protein. For large-scale protein expression, round tissue culture dishes of 100 square centimeters, with 5 x 10 7 cells / dish, are seeded and infected with 1 milliliter of virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the dish and centrifuged at 500 revolutions per minute for 5 minutes. The cell granules from 10 to 20 plates of 100 square centimeters are resuspended in 50 milliliters of ice cold regulator (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 percent NP-40, DTT 1 mM, 1 mM PMSF). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. Purification of the GST-labeled protein: The centrifuged cell lysate is loaded onto a 2 milliliter column of glutathione-Sepharose (Pharmacia), and washed three times with 10 milliliters of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA , 1 mM DTT, 200 mM NaCl. Tek labeled with GST is eluted by 10 applications (1 milliliter each) of 25 mM Tris-HCl, pH 7.5, reduced glutathione 10 mM, 100 mM NaCl, 1 mM DTT, 10 percent glycerol, and stored at -70 ° C.

Kinase assay: Tyrosine protein kinase assays are carried out with purified GST-Tek protein, in a final volume of 30 microliters containing 15 milligrams / milliliter of GST-Tek, 20 mM Tris-HCl, pH of 7.5, 3 mM MnCl 2, 3 mM MgCl 2, 1 mM DTT, 10 μM Na3VO 4, 3.0 micrograms / milliliter of poly (Glu, Tyr) 4: 1, PEG 0.25 mM, dimethyl sulfoxide at 1 percent, ATP 8.0 μM, and ([(33P) -ATP 0.1 μCi) The activity is tested in the presence or absence of inhibitors, by measuring the incorporation of 33P from [(33P) ATP in poly (Glu, Tyr) 4: 1. The assay (30 microliters) is carried out in 96-well plates at room temperature for 10 minutes, and is terminated by the addition of 20 microliters of 125 mM EDTA Subsequently, 40 microliters of the reaction mixture is transferred onto an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5 percent H3PO4, and mounted on a vacuum manifold with the vacuum source disconnected. After putting all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of 0.5% H3PO4. The membranes are removed and washed 4 times on a shaker with 1.0 percent H3PO4, and once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96-well Packard TopCount frame, and with the addition of 10 microliters / well of Microscint ™ (Packard). The IC 50 values are calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, in four concentrations (usually 0.01, 0.1, 1, and 10 μM). One unit of protein kinase activity is defined as 1 nanomole of 33P transferred from [(33P) ATP to the substrate protein per minute per milligram of protein at 37 [deg.] C. The NOVECTIOUS COMPOUNDS OF the INVENTION show IC50 values here the interval between 0.001 and 5 μM, especially between 0.01 and 0.2 μM The inhibition of Bcr-Abl can be determined by a capture ELISA as follows: The murine myeloid progenitor cell line 32Dcl3 transfected with the expression vector of p210 Bcr -Abl, pGDp21 OBcr / Abl (32D-bcr / abl) is obtained from J. Griffin (Bazzoni et al., J. Clin. Invest. 9_8, 521-8 (1996); Zhao et al., Blood 90, 4687-9 (1997)). The cells express the bcr-abl fusion protein with a constitutively active abl kinase, and proliferate independently of the growth factor. The cells are expanded in RPMI 1640 (AMIMED; Cat. # 1-41F01), 10 percent fetal calf serum, 2 mM glutamine (Gibco) ("complete medium"), and a processing supply is prepared by freezing of aliquots of 2 x 106 cells per bottle in a freezing medium (95 percent calf fetal serum, 5 percent dimethyl sulfoxide (SIGMA, D-2650) .Following thawing, the cells are used for a maximum 10 to 12 steps for the experiments For the ELISA, the SH3 domain of the anti-abl antibody, Cat. # 06-466 of Upstate Biotechnoiogy is used For the detection of bcr-abl phosphorylation, the Ab antibody is used. PY20 anti-phosphotyrosine, labeled with alkaline phosphatase (PY10 (AP)) from ZYMED (Cat. # 03-7722) As a comparison and reference compound, the (N- { 5- [4- ( 4-methyl-piperazino-methyl) -benzoyl-amydo] -2-methyl-phenyl] -4- (3-pyridyl) -2-pyrimidine, in the form of the salt of methanesulfonate (mon omesylate) (STI571) (traded as Gleevec® or Glivec®, Novartis). A 10 mM supply solution in dimethyl sulfoxide is prepared and stored at -20 ° C. For cell assays, the delivery solution is diluted in a complete medium in two steps (1: 100 and 1:10) to give a starting concentration of 10 μM, followed by the preparation of triple dilutions in series in the complete medium . Solubility problems are not found using this procedure. The COMPOUNDS NOVELTIES OF THE INVENTION test are treated in an analogous manner. For the assay, 200,000 32D-bcr / abl cells are seeded in 50 microliters per well in 96-well round-bottom tissue culture plates. 50 microliters per well of the triple serial dilutions of the test compound are added to the cells in triplicate. The final concentration of the test compound is in the range, for example, of 5 μM down to 0.01 μM. The untreated cells are used as a control. The compound is incubated together with the cells for 90 minutes at 37 ° C, with 5 percent CO 2, followed by centrifugation of the tissue culture plates at 1,300 revolutions per minute.

(Centrifugal Beckman GPR), and the removal of the supernatants by careful aspiration, taking care not to remove clustered cells. The cell granules are used by the addition of 150 microliters of lysis buffer (50 mM Tris / HCl, pH 7.4, 150 mM sodium chloride, 5 mM EDTA, 1 mM EGTA, 1 percent NP-40 (non-detergent Ionic, Roche Diagnostics GmbH, Mannheim, Germany), 2 mM sodium ortho-vanadate, 1 mM phenyl-methyl-sulfonyl fluoride, 50 micrograms / milliliter of aprotinin, and 80 micrograms / milliliter of leupeptin), and are used immediately for the ELISA, or Store frozen at -20 ° C until use. The domain antibody Anti-abl SH3 is coated at 200 nanograms in 50 microliters of phosphate-buffered serum per well in black ELISA plates (Packard HTRF-96 black plates; 6005207) overnight at 4 ° C. After washing 3 times with 200 microliters / well of phosphate-buffered serum containing 0.05 percent Tween 20 (PBST) and 0.5 percent TopBlock (Juro, Cat. # TB 232010), the residual protein binding sites are blocked with 200 microliters / well of PBST, 3 percent TopBlock, for 4 hours at room temperature, followed by incubation with 50 microliters of untreated cells or treated with the test compound (20 micrograms of total protein per well) during 3 to 4 hours at 4 ° C. After washing 3 times, 50 microliters / well of PY20 (AP) (Zymed) diluted to 0.5 micrograms / milliliter in blocking buffer is added and incubated overnight (4 ° C). For all incubation steps, the plates are covered with plate sealers (Costar, Cat. # 3095). Finally, the plates are washed three more times with a washing regulator, and once with deionized water, before the addition of 90 microliters / well of the AP substrate, CPDStar RTU, with Emerald II. The plates now sealed with Packard Top Seal ™ A-plate sealers (Cat. # 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 counter. of Packard Top Count Microplates (Top Count). For the final optimized version of the ELISA, 50 microliters of the used ones are transferred from the cultured, treated and used cells in the 96-well tissue culture plates, directly from these plates to the ELISA plates, which are pre-coated with 50 μl. nanograms / well of the SH3 rabbit polyclonal anti-abl domain AB 06-466 from Upstate. The concentration of AB PY20 anti-phosphotyrosine (AP) can be reduced up to 0.2 micrograms / milliUtro. Washing, blocking and incubation with the luminescent substrate are as before. The quantification is achieved as follows: The difference between the ELISA reading (counts per second) obtained with the used of the untreated 32D-bcr / abl cells, and the reading for the assay background (all components, but without the used cellular), and it is taken as 100 percent reflecting the constitutively phosphorylated bcr-abl protein present in these cells. The activity of the compound in the bcr-abl kinase activity is expressed as the percentage reduction of bcr-abl phosphorylation. The values for the ICSo are determined from the response curves to the dose by means of inter- or extrapolation graph. The NOVECOUS COMPOUNDS OF the INVENTION preferably show IC50 values in the range of 20 nM to 200 μM here. The NOVEL COMPOUNDS OF the INVENTION also inhibit tyrosine protein kinases that are involved in signal transmission mediated by trophic factors, for example kinases of the src kinase family, such as in particular the c-Src kinase, the members of the tyrosine kinase family receiving the platelet-derived growth factor (PDGF), for example PDGF-R, c -Kit, VEGF-R, and / or FGF-R; all of which are part of the regulation of growth and transformation in the cells of animals, especially mammals, including human cells. An appropriate trial is described in Andrejauskas-Buchdunger et al., Cancer Res. 5_2_, 5353-8 (1992). Accordingly, the NOVEL COMPOUNDS OF the INVENTION can be used in the treatment of protein kinase dependent diseases. Protein kinase dependent diseases are especially proliferative diseases, preferably benign or especially malignant tumors (eg carcinoma of the kidneys, liver, adrenal glands, bladder, breast, stomach, ovaries, colon, rectum, prostate, pancreas, lungs, vagina or thyroid, sarcoma, glioblastomas, and numerous neck and head tumors, as well as leukemias). They are capable of causing the regression of tumors and preventing the formation of tumor metastasis and the growth of (also micro) metastasis. In addition, they can be used in epidermal hyperproliferation (for example, psoriasis), in prostate hyperplasia, and in the treatment of neoplasms, especially of epithelial character, for example mammary carcinoma. It is also possible to use the NOVEDOUS COMPOUNDS OF THE INVENTION in the treatment of diseases of the immune system, up to where several are involved, or in particular, the individual tyrosine protein kinases; In addition, the NOVEDOUS COMPOUNDS OF the INVENTION can also be used in the treatment of diseases of the central or peripheral nervous system, where signal transmission is involved by at least one tyrosine protein kinase, especially selected from the aforementioned ones. specific way. The p21ras oncogene is a major contributor to the development and progress of human solid cancers, and is mutated in 30 percent of all human cancers. The endogenous GTPase activity, if relieved in the mutated ras cancer cells, mediates the constitutive growth signals towards the downstream effectors, such as the raf kinase. Accordingly, inhibition of the signaling pathway of the raf kinase can be used to inhibit the effect of active ras. The INNOVATIVE COMPOUNDS OF THE INVENTION useful as ras inhibitors, therefore, are especially suitable for the therapy of diseases related to overexpression or overexertion of ras. Vascular endothelial growth factor receptor-2 (VEGF-R2; KDR) is selectively expressed in the primary vascular endothelium, and is essential for normal vascular development. In order to grow beyond the minimum size. the tumors must generate new vascular supply. Angiogenesis, or the sprouting of new blood vessels, is a central process in the growth of solid tumors. For many cancers, the spread of a tumor's vascularity is a negative prognostic indicator that signifies aggressive disease and a greater potential for metastasis. Recent efforts to understand the molecular basis of tumor-associated angiogenesis have identified several potential therapeutic targets, including receptor tyrosine kinases for vascular endothelial growth factor (VEGF) of the angiogenic factor (see Zeng et al., J. Biol. Chem. 276 (35), 32714-32719 (2001)). Accordingly, the INNOVATIVE COMPOUNDS OF THE INVENTION useful as KDR inhibitors are especially suitable for the therapy of diseases related to overexpression of the tyrosine kinase receptor of vascular endothelial growth factor. Among these diseases, especially retinopathies, age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory diseases such as rheumatoid or rheumatic inflammatory diseases are especially important., especially arthritis, such as rheumatoid arthritis, or other chronic inflammatory disorders, 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, of the pancreas, breast, stomach, cervix, bladder, kidney, prostate, ovaries, endometrium, lung, brain, melanoma, Kaposi's sarcoma, squamous cell carcinoma of the head and neck, malignant pleural mesothelioma, lymphoma or multiple myeloma), and tumors liquids (for example, leukemia). Flt-3 (tyrosine kinase type FMD) is expressed especially in hematopoietic progenitor cells, and in the progenitors of the lymphoid and myeloid series. Aberrant expression of the Flt-3 gene has been documented in adult and childhood leukemias, including AML (acute myelogenous leukemia), acute myeloid leukemia with myelodysplasia of three lineages (AML / TMDS), ALL (acute lymphoblastic leukemia) , CML (chronic myelogenous leukemia), and myelodysplastic syndrome (MDS), which, consequently, are the preferred diseases to be treated with the NOVEDOUS COMPOUNDS OF THE INVENTION. Activating mutations have been found in Flt-3 in approximately 25 to 30 percent of patients with acute myelogenous leukemia. Therefore, there is accumulating evidence of the role of Flt-3 in human leukemias, and the NOVEDOUS COMPOUNDS OF THE INVENTION useful as Flt-3 inhibitors are especially useful in the therapy of this type of diseases (see Tse et al., Leukemia 1_5_ (7), 1001-1010 (2001); Tomoki et al., Cancer Chemother. Pharmacol. 48_ (Supplement 1), S27-S30 (2001); Birkenkamp et al., Leukemia ± 5 (12), 1923-1921 (2001); Kelly et al., Neoplasia 9_9_ (1), 310-318 (2002)). In chronic myelogenous leukemia (CML), a reciprocally balanced chromosomal translocation in totipotent hematopoietic cells (HSCs), produces the hybrid BCR-ABL gene. The latter encodes the oncogenic Bcr-Abl fusion protein. Although ABL encodes a tightly regulated tyrosine protein kinase, which has a fundamental role in the regulation of cell proliferation, adhesion and apoptosis, the BCR-ABL fusion gene is encoded as a constitutively activated kinase, which transforms hematopoietic totipotent cells to produce a phenotype that exhibits a dysregulated clonal proliferation, a reduced capacity to adhere to the stroma of the bone marrow, and a reduced apoptotic response to mutagenic stimuli, which make it possible to progressively accumulate more malignant transformations. 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. Bcr-Abl inhibitors that compete for ATP have been described, which prevent the kinase from activating the mitogenic and anti-apoptotic pathways (e.g., P-3 kinase, and STAT 5), leading to cell death. BCR-ABL phenotype, and thus providing an effective therapy against chronic myelogenous leukemia. The novel compounds of the invention useful as inhibitors of Bcr-Abl, therefore, are especially suitable for the therapy of diseases related to their overexpression, especially leukemias, such as leukemias, for example chronic myelogenous leukemia or lymphoblastic leukemia acute The NOVEL COMPOUNDS OF the INVENTION, in view of their activity as inhibitors of platelet-derived growth factor receptor, are also especially suitable in the treatment of proliferative diseases, especially small cell lung cancer, atherosclerosis, thrombosis, psoriasis, scleroderma , or fibrosis. There are also experiments to demonstrate the anti-tumor activity of the compounds of the present invention in vivo: The anti-tumor activity in vivo is tested, for example, using breast carcinoma cell lines, such as estrogen-dependent human breast carcinoma MCF-7 (ATCC: HTB22) or ZR-75-1 (ATCC: CRL 1500), or estrogen-independent breast carcinomas MDA-MB468 (ATCC: HTB132) or MDA-MB231 (ATCC: HTB26); colon carcinoma cell lines, such as colon carcinoma 205 (ATCC: CCL222); glioblastoma cell lines, such as glioblastomas U-87MG (ATCC: HTB14) or U-373MG (ATCC: HTB17); lung carcinoma cell lines, such as "small cell lung carcinomas" N C I -H69 (ATCC: HTB119) or NCI-H209 (ATCC: HTB172), or lung carcinoma NCI-H596 (ATCC: HTB178); the tumor cell lines of the skin, such as melanomas Hs294T (ATCC: HTB140) or A375 (ATCC: CRL1619); the tumor cell lines of the genitourinary systems, such as NIH-Ovcar3 ovarian carcinoma (ATCC: HTB161), as well as the prostate carcinomas DU145 (ATCC: HTB81) or PC-3 (ATCC: CRL1435), or the carcinoma of bladder T24 (ATCC: HTB4); epithelial carcinomas, such as epithelial carcinoma KB31; or (especially with respect to leukemias) K562 cells (American Type Culture Collection, Mannassas, VA) or human CFU-G cells (CFU-G stands for granulocolous colony-forming unit, and represents an early granulocyte-forming precursor cell but compromised that circulates in the bloodstream or in the bone marrow), each of which is transplanted in female Balb / c hairless mice or males. 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 2 x 10 6 cells in 100 milliliters of phosphate-regulated physiological saline) in the carrier mice (e.g., 4 to 8 mice per cell line). The resulting tumors are passed in series through at least three subsequent transplants before starting treatment. Tumor fragments (approximately 25 milligrams each) were injected subcutaneously into the left flank of the animals using a 13-gauge Trocar needle under narcosis with Forene (Abbott, Switzerland) for the implant. Mice transplanted with estrogen-dependent tumor are supplied in addition with an estrogen granule (1.0 cm of a tube of appropriate quality for medical purposes, Dow Chemicals, with 5 milligrams of estradiol, Sigma). The treatment is started routinely (ie, with a low or intermediate tumor load), as soon as the tumor has reached an average size of 100 cubic millimeters. Tumor growth is determined once, twice, or three times a week (depending on the tumor cell growth), and 24 hours after the last treatment by measuring the perpendicular diameter. In the case of tumors, the tumor volumes are determined according to the formula L x D xp / 6 (see Evans, BD, Smith, IE, Shorthouse, AJ and Millar, JJ, Brit. J. Cancer, 45: 466 -468, 1982). The antitumor activity is expressed as T / C% (average increase in tumor volume of treated animals divided by the average increase in tumor volume of the control animals multiplied by 100). Tumor regression (%) represents the smallest mean tumor volume compared to the mean tumor volume at the beginning of treatment. Each animal in which the tumor reaches a diameter of more than 1.5 to 2 cubic centimeters is sacrificed. The burden of leukemia is assessed by examining both the peripheral white blood cell count and the weight of the spleen and thymus in animals with tumors of leukemia cell lines. An example program (although not limiting) for the administration of a compound of the present invention, or a salt thereof, is daily administration, preferably with 1 to 3 daily dosages for a longer time, possibly until it is cured. the disease, or, if only palliative treatment is achieved, for as long as required; in an alternative way, treatment is possible, for example, for 5 days, and / or administration on days 1, 4, and 9, with eventual repetition after some time without treatment. Alternatively, treatment is 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, the administration is oral or parenteral, preferably oral. The test compounds are preferably diluted in water or in sterile 0.9 percent serum. All human tumor cell lines are obtained from the American Type Culture Collection (ATCC, Rockville, MD., USA) if not otherwise indicated, and cultured in the suggested medium with the corresponding additives (ATCC culture conditions). ), if not mentioned otherwise. BALB / c e-sis- and v-s / s-transformed 3T3 cells are obtained from Dr. C. S ti 11 es (Dana Farber Cancer Institute, Boston, MA, E.U.A.). They are grown in a "Dulbecco modified Eagle's medium" (DMEM), which is supplemented with 10 percent calf serum and Hygromycin B in a concentration of 0.2 milligram / milliliter, or G418 in a concentration of 0.5 milligram / milliliter. BALB / c AMuLV A.6R.1 (ATCC) cells are maintained in Dulbecco's modified Eagle's medium, supplemented with 10 percent fetal calf serum. The pharmacological activity of a compound of the present invention, for example, can be demonstrated in a clinical study, or in a test procedure as essentially described hereinafter. Suitable clinical studies are, for example, open-label dose scale studies without random selection in patients with one of the above-mentioned tumor diseases. The beneficial effects on proliferative diseases can be determined directly through the results of these studies, or through changes in the design of the study, which are known as such by a person skilled in the art. In these studies the effectiveness of the treatment can be determined, for example, in the case of tumors, after 18 or 24 weeks, by means of a radiological evaluation of the tumors every 6 weeks, in the case of a leukemia, for example, by means of the determination of the count of aberrant white blood cells, and by staining the mononuclear cells, and / or by determining the minimum residual disease (MRD), for example, by means of FACS-LPC MRD or chain reaction of the polymerase Alternatively, a double-blind, placebo-controlled study can be used to test the benefits of the compounds of the present invention. The diaryl urea derivatives of the formula I can be prepared as described in International Publication Number WO 03/099771. The NOVECOUS COMPOUNDS OF the INVENTION are preferably prepared as described hereinafter, under "Examples".

Preferred embodiments according to the invention: In the following preferred embodiments, the general expression may be replaced by the corresponding more specific definitions provided above and below, thereby producing stronger preferred embodiments of the invention. In a preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diaryl urea derivative is a compound of the formula I : wherein A, A ', n, m, p, r, X, Y ,, Y2, and R1-R5, have the meanings defined above for a compound of the formula I; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In another preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I, where A is CH, N or N? O and A 'is N or N? O, with the proviso that no more than one of A and A' can be N- O; n is 1 or 2; m is 0, 1, or 2; p is 0, 2, or 3; r is from 1 to 5; X is NR if p is 0, where R is hydrogen or an organic fraction, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dashed lines (interrupted) (including atoms with which they are linked) forms a ring, with the proviso that if X is NH, each of R4, independently of the others if r > 1, is a fraction as defined above under formula I, but is not linked to the remainder of formula I by means of a bridge of -C (= O) -, -C (NR) -, or -S ( O2) -, X is CHK, wherein K is lower alkyl or hydrogen, and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; And i is O, S, or CH2; Y2 is O, S, or NH; with the proviso that (Y?) n- (Y2) m does not include groups O-O, S-S, NH-O, NH-S, or S-O; each of R (, R2, R3, and R5, independently of the others, is hydrogen or an inorganic or organic fraction, or any two of R-., R2, and R3, together form a lower alkylene-dioxyl bridge bonded by means of the oxygen atoms, and the remainder of these fractions is hydrogen or an inorganic or organic fraction, with the proviso that if G is not present and Z is a radical of the formula la, Ri, R2, and R3 do not they can all be hydrogen, and with the additional proviso that if one of R -., R2, and R3 is halogen or lower alkyl sulfonyl, the other two can not both be hydrogen, R is an inorganic or organic fraction, with the condition that if n is 1, m is 0, p is 0, r is 1, X is NH, Yi is O, G is not present, and Z is a radical of the formula la, R4, together with the ring of benzene containing A and A ', does not form methyl pyridinyl, 2-hydroxy-pyridin-4-yl, or 1H-2-oxo-1,2-dihydro-pyridin-4-yl, and G and Z have the meanings given to previously under formula I; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In a further preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I *, where A is CH, N or N- »0 and A 'is N or N? O, with the proviso that not more than one of A and A' can be N? O; n is 1; m is 0; p is 0, 2, or 3; r is 1; X is NR if p is 0, where R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dashed lines (interrupted) (including atoms) with which they are linked) forms a ring, or X is CH2 and p is zero, with the proviso that the links represented in dotted lines, if p is zero, are absent; Y! is O or CH2; each of Ri, R2, and R3, independently of the others, is hydrogen, lower alkyl, halogen, especially bromine or chlorine, halo-lower alkyl, especially trifluoromethyl, lower alkoxy, especially methoxy, halo-lower alkoxy , in particular 2,2,2-trifluoro-ethoxy, phenyl, piperidyl, especially piperidin-1-yl, piperazinyl, in particular piperazin-1-yl, morpholinyl, in particular morpholine, thio-morpholinyl, especially thiomorpholine, or any two of them together form a lower alkylene-dioxyl bridge bonded via the oxygen atoms, and the remainder of these fractions is hydrogen or one of the mentioned fractions, with the proviso that R-, R2, and R3 they can not all be hydrogen, and with the additional condition that if one of Ri, R2, and R3 is halogen, the other two can not be both hydrogen; R 4 is lower alkoxy, especially methoxy, lower-amino alkanoyl, especially acetyl-amino, hydroxy-phenyl-amino, especially p-hydroxy-phenyl-amino, amino-lower alkyl-oxyphenyl-amino, especially [(2-amino-ethyl) -oxyphenyl] -amino, sulfamoyl-phenyl-amino, especially 4-sulfamoyl-phenylamino, carbamoyl-phenyl-amino, especially 4-carbamoyl-phenyl-amino, [N- ( hydroxy-lower alkyl) -carbamoyl] -phenyl-amino, in particular [N- (2-hydroxyethyl) -carbamoyl] -phenyl-amino, or halogen, especially chloro; and R5 is hydrogen, lower alkyl or halogen, especially hydrogen; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In a further especially preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I, wherein: G is not present or is lower alkylene, especially methylene or ethylene, or cyclopalkylene of 3 to 5 carbon atoms, especially cyclopropylene, and Z is a radical of the formula la, or G is not present and Z is a radical of the formula Ib; A is CH or N and A 'is N or N? O; n is 1; m is 0 or 1; p is 0, 2, or 3; r e s 0 or 1; X is NR if p is 0, where R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dashed lines (interrupted) (including atoms) with which they are linked) forms a ring, or X is CHK, where K is hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; And «is O, S, or CH2; Y2 is O; with the proviso that (Y?) n- (Y2) m does not include O-O, or S-O groups; each of Ri, R2, and R3, independently of the others, is hydrogen, lower alkyl, especially methyl, ethyl, normal propyl, isopropyl or tertiary butyl, lower alkenyl, especially isopropenyl, hydroxy-lower alkyl, especially hydroxy-propyl, lower alkoxy, especially methoxy, halogen, in particular chlorine or bromine, halo-lower alkyl, especially trifluoromethyl, halo-lower alkoxy, especially trifluoromethoxy or trifluoromethoxy, lower aminoalkyl, in particular amino-methyl, amino-lower alkoxy, especially amino-ethoxy, di-lower alkyl-amino, especially diethylamine, hydroxy-lower alkyl-amino, especially hydroxypropyl ammonium, (lower alkoxy-lower alkyl) -amino, especially bis- (2-methoxy-etyl) -amino, lower dialkyl-amino-lower alkyl, especially dimethyl-amino-methyl, phenyl, morpholinyl, especially morpholin-4- ilo, piperidyl, especially piperidin-1-yl, piperidyl-lower alkyl, especially pipe Ridin-1-methylmethyl, lower alkyl-piperazinyl, in particular 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, lower-alkyl-piperazinyl-lower alkyl, in particular 4-methyl-piperazin-1 -methylmethyl or 4-ethyl-piperazin-1-ylmethyl, pyridyl, especially pyridin-2-yl, or lower alkyl-imidazolyl, in particular 2- or 4-methyl-imidazol-1-yl; if r is 1, R is lower alkyl, especially methyl, ethyl or isopropyl, hydroxyl, aminocarbonyl, lower alkylcarbonyl, especially methylcarbonyl, cyclohexyl, halogen, especially chlorine or fluorine, halo-lower alkyl, in particular trifluoro-methyl, lower alkoxy, especially methoxy, amino, lower alkyl-amino, especially methyl-amino, ethyl-amino, isopropyl-amino or terbutyl-amino, di-lower alkyl-amino, especially dimethyl-amino , lower alkenyl-amino, especially prop-2-enyl-amino or but-3-enyl-amino, lower alkylcarbonyl amine, especially methyl-carbonyl-amino, cyano, azido, hydroxy-phenyl- amino, especially 3- or 4-hydroxy-phenyl-amino, mono- or tri-lower alkoxy-phenyl-amino, especially methoxy-phenyl-amine or trimethoxy-phenyl-amino, lower alkoxy-halo-phenyl-amino , especially methoxy-fluoro-phenyl-amino, phenyl-lower alkyl-amino, especially benzylamino, (mono- or di-lower alkoxy) -phenyl-lower alkyl-amino, especially methoxy-benzyl -amino or dimethoxy-benzyl-amino, amino-sulfonyl-phenyl-lower-alkyl-amino, especially amino-sulfonyl-benzyl-amino, amino-lower alkoxy-phenyl-amino, especially amino-ethoxy-phenyl-amino, lower alkyl-amino-sulfonyl-lower alkyl-phenyl-amino, especially methyl-amino-sulfonyl-methyl-phenyl-amino, lower alkyl-piperazinyl-lower alkyl-amino, especially 4-methyl-plperazin-1 -I- propyl-amino, morpholinyl-lower alkyl-amino, especially morpholin-4-yl-propyl-amino, lower alkyl-piperidyl-amino, especially 1-methyl-piperidin-4-ylamino, tetrazolyl, especially 1H-tetrazole- 5-yl, lower alkyl-tetrazolyl, especially lower alkyl-tetrazol-5-yl such as 1-methyl-1 H-tetrazoI-5-yl or 2-methyl-2H-tetrazole-5-yl, or lower alkyl) -amino-lower alkyl-tetrazolyl, especially (di-lower alkyl) -amino-lower alkyl-tetrazole-5-ylo such as 2- (3-dimethyl-amino-propyl) -2H-tetrazole -5-ilo; and R5 is more preferably hydrogen, or lower alkyl, especially methyl, or halogen, especially chlorine; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In another especially preferred embodiment, the invention relates to the use of diaryurea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I , where: A and A 'are both N, n is 1, m is 0, p is 0 or 2, r is 1, X is NH if p is 0, or if p is 2, X is nitrogen that, together with (CH2) 2 and the bonds represented in dashed lines (interrupted) (including the atoms with which they are bound) forms a ring, Yj is O, G is not present, Z is a radical of the formula la, at least one of R (, R2, and R3 is a basic organic fraction, R4 is amino or lower alkyl-amino, and R5 is hydrogen, or a tautomer thereof, or pharmaceutically acceptable salts thereof.

In another preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I , where: A is CH, N or N? 0 and A 'is N or N- »O, with the proviso that not more than one of A and A' can be N? O; n is 1; m is 0; p is 0, 2, or 3; r is 0, 1, or 2; X is NR if p is 0, where R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dotted (interrupted) lines (including atoms with which they are linked) forms a ring, or X is CH2 and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; each of R ^ R2, and R3, independently of the others, is hydrogen, lower alkyl, halogen, especially bromine or chlorine, halo-lower alkyl, especially trifluoromethyl, lower alkoxy, especially methoxy, halo-lower alkoxy, in particular 2,2,2-trifluoro-ethoxy, phenyl, piperidyl, especially piperidin-1-yl, piperazinyl, especially piperazin-1-yl, morpholinyl, especially morpholine, thio-morpholinyl, especially thiomorpholino, or any two of them form together a bridge of alkylene inferlor-dioxyl linked by means of the oxygen atoms, and the remainder of these fractions is hydrogen or one of the mentioned fractions; if r is not zero, R 4 is lower alkyl, especially methyl or ethyl, lower alkoxy, especially methoxy, lower alkanoyl-amino, especially acetylamino, hydroxy-phenylamino, especially p-hydroxy-phenyl-amine , amino-lower alkyl-oxyphenyl-amino, in particular 4 - [(2-amino-ethyl) -oxyphenyl] -amino, sulf-amyl-phenyl-amino, especially 4-sulfamoll-phenyl-amino, carbamoyl-phenyl-amine , in particular 4-carbamoyl-phenyl-amino, [N- (hydroxy-lower alkyl) -carbamoyl] -phenyl-amino, in particular [N- (2-hydroxy-ethyl) -carbamoyl] -phenyl-amino, halogen, in particular chlorine, or hydroxyl; and R5 is hydrogen, lower alkyl or halogen, especially hydrogen; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In another especially preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I , wherein: G is not present, or is lower alkylene, especially methylene or ethylene, or cycloalkylene of 3 to 5 carbon atoms, especially cyclopropylene, and Z is a radical of the formula la, or G is not present and Z is a radical of the formula Ib; A is CH or N and A 'is N or N? O; n is 1; m is 0 or 1; p is 0, 2, or 3; r is 1; X is NR if p is 0, where R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dashed lines (interrupted) (including atoms) with which they are linked) forms a ring, or X is CHK where K is hydrogen and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y-, is O, S, or CH2; Y2 is O; with the proviso that (Y -?) n- (Y2) m does not include O-O, or S-O groups; each of R ,, R2, and R3, independently of the others, is hydrogen, lower alkyl, especially methyl, ethyl, normal propyl, isopropyl, or tertiary butyl, lower alkenyl, especially isopropenyl, hydroxy-lower alkyl, in particular hydroxy-propyl, lower alkoxy, especially methoxy, halogen, in particular chlorine or bromine, halo-lower alkyl, especially trifluoromethyl, halo-lower alkoxy, especially trifluoro-methoxy or trifluoro-ethoxy, lower aminoalkyl , especially amino-methyl, lower amino-alkoxy, especially amino-ethoxy, di-lower alkyl-amino, especially diethylamino, hydroxy-lower alkyl-amino, especially hydroxy-propyl-amino, bis- ( lower alkoxy-lower alkyl) -amino, in particular bis- (2-methoxy-etl) -amino, lower dialkyl-amino-lower alkyl, especially dimethyl-amino-methyl, phenyl, morpholinyl, especially morpholin-4 -yl, piperidyl, especially plperidine n-1-yl, piperidyl-lower alkyl, especially pip eridin-1-methylmethyl, lower alkyl-piperazinyl, in particular 4-methyl-piperazin-1-yl or 4-ethyl-piperazin-1-yl, lower alkyl-piperazinyl-lower yolk, especially 4-methyl-piperazin-1 -methylmethyl or 4-ethyl-piperazin-1-ylmethyl, pyridyl, especially pyridin-2-yl, or lower alkyl-imidazolyl, especially 2- or 4-methyl-imidazol-1-yl, with the proviso that G is not present and Z is a radical of the formula la, R ,, R2, and R3 can not all be hydrogen, and with the additional proviso that if one of Rn, R2, and R3 is halogen, the other two do not they can both be hydrogen; R 4 is lower alkyl, especially methyl, ethyl or isopropyl, idroxyl, aminocarbonyl, lower alkylcarbonyl, especially methylcarbonyl, cyclohexyl, halogen, especially chlorine or fluorine, halo-lower alkyl, especially trifluoromethyl , lower alkoxy, especially methoxy, amino, lower alkyl amino, especially methyl amino, ethyl amino, isopropyl amino or terbutyl amino, di-lower alkyl amino, especially dimethyl amino, lower alkenyl amino, especially prop-2-enyl-amino or but-3-enylamino, lower alkyl-carbonyl-amino, especially methyl-carbonyl-amino, cyano, azido, hydroxy-phenyl-amine, especially 3- or 4-hydroxy-phenyl-amino, mono- or tri-lower alkoxy-phenyl-amino, especially methoxy-phenyl-amino or trimethoxy-phenyl-amino, lower alkoxy-halo-phenyl-amino, especially methoxy-fluoro-phenyl -amino, phenyl-lower alkyl-amino, especially benzyl-amino, (mono- or di-lower alkoxy) -phenyl-lower alkyl-amino, especially methoxy-benzyl-amino or dime toxi-benzyl-amino, amino-sulfonyl-phenyl-lower alkyl-amino, especially amino-sulfonyl-benzyl-amino, amino-lower alkoxy-phenyl-amino, especially amino-ethoxy-phenyl-amino, lower-amino-alkyl -sulfonyl-lower alkyl-phenyl-amino, especially methyl-amino-sulfonyl-methyl-phenyl-amino, lower alkyl-piperazinyl-lower alkyl-amino, especially 4-methyl-piperazin-1-yl-propyl-amino, morpholinyl-lower alkyl-amino, in particular morpholin-4-yl-propyl-amino, lower alkyl-piperidyl-amino, in particular 1-methyl-piperidin-4-ylamino, tetrazolyl, in particular 1H-tetrazol-5-yl, lower alkyl tetrazolyl, especially lower alkyl-tetrazol-5-yl such as 1-methyl-1 H-tetrazol-5-yl or 2-methyl-2H-tetrazol-5-yl, or (di-lower alkyl) - amine-lower alkyl-tetrazolyl, especially (di-lower alkyl) -amino-lower alkyl-tetrazol-5-yl such as 2- (3-dimethyl-amino-propyl) -2H-tetrazol-5-yl, with the condition that if X is NH, R4 is not amino-carbonyl or lower alkyl or -carbonyl, and with the additional proviso that if n is 1, p is 0, r is 1, X is NH, Y - [is O, G is not present, and Z is a radical of the formula la, R4 , together with the benzene ring containing A and A ', does not form methyl-pyridinyl, 2-hydroxy-pyridin-4-yl, or 1-H-2-oxo-1,2-dihydro-pyridin-4-yl; R5 is more preferably hydrogen, or lower alkyl, especially methyl, or halogen, especially chloro; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In a further very preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I, where: A and A 'are both N, n is 1, m is 0, p is 0 or 2, r is 1, X is NH if p is 0, or if p is 2, X is nitrogen which, together with (CH2) 2 and the bonds represented in dotted (interrupted) lines (including the atoms to which they are linked) forms a ring , Y * is O, G is not present, Z is a radical of the formula la, at least one of R ,, R2, and R3 is a basic organic fraction, R4 is amino or lower-amino alkyl, and R5 is hydrogen, or a tautomer thereof, or pharmaceutically acceptable salts thereof.

In another especially preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I *, where: A, A ', n, m, p, and Y2, R-, R2, R3, and R have the meanings given in formula I * above, and r is from 1 to 5, X is NR if p is 0, where R is hydrogen or an organic fraction, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dotted (interrupted) lines (including the atoms to which they are bound) form a ring, or X is CH2 and p is zero, and, if p is zero, the links represented in dotted lines are absent; with the proviso that if X is NH, each of R4, independently of the others, if present, is a fraction as defined under the formula I * above, but is not linked to the rest of the formula I * by middle of a bridge of -C (= O) -, -C (NR) -, or -S (Q2) -, and the substituents R- ,, R2 > and R3 are selected from the following fractions, where positions are indicated (o = ortho, m = meta, p = para) with respect to the position where the ring is linked to the rest of the molecule in the formula I * (by means of the fraction NH-C (= 0) -X); if only R1 is different from hydrogen: R1 = p-lower alkyl, especially p-methyl, p-ethyl, normal p-propyl; m-halo-lower alkyl, especially m-trifluoromethyl; or phenyl, p-piperidin-1-yl, or p-piperazin-1-yl; if both R1 and R2 are different from hydrogen: R-i = lower m-haloalkyl, especially m-trifluoromethyl, and R2 = p-halogen, especially p-bromo; R-i = m-halo-lower alkyl, especially m-trifluoromethyl, and R2 = p-halo-lower alkoxy, especially p- (2,2,2-trifluoro-ethoxy); Ri = lower m-haloalkyl, in particular m-trifluoromethyl, and R2 = lower m-alkoxy, especially m-methoxy; R i = m-halo-lower alkyl, especially m-trifluoro-methyl, and R 2 = p-phenyl; Ri = m-halo-lower alkyl, especially m-trifluoromethyl, and R2 = p-piperidin-1-yl or p-piperazin-1-yl; R-i = m-halo-lower alkyl, especially m-trifluoromethyl, and R 2 = p-N-morpholino or p-N-thiomorpholino; R-i = lower m-alkoxy, especially m-methoxy, and R2 = p-halogen, especially p-bromine (less preferred); R-i = lower m-alkoxy, especially m-methoxy, and R2 = p-halo-lower alkoxy, especially p-2,2,2-trifluoro-ethoxy; R-= = lower m-alkoxy, especially m-methoxy, and R 2 = p-phenyl; or R1 = m-lower alkoxy, especially m-methoxy, and R2 = p-piperidin-1-yl or p-piperazin-1-yl; or, if R ^ R2, and R3 are different from hydrogen: R < = m-lower alkoxy, especially m-methoxy; R2 = m-lower alkoxy, especially m-methoxy; and R3 = p-lower alkoxy, especially p-methoxy; or R-i = lower alkoxy, especially methoxy, and R2 and R3 together form a lower alkylene-dioxyl bridge, especially of -O-CH2-CH2-O-; and R5 is hydrogen, lower alkyl or halogen, especially hydrogen; with the proviso that if n is 1, m is 0, p is 0, r is 1, X is NH, and Y-¡is O, R4, together with the benzene ring containing A and A ', does not form methyl-pyridinyl, 2-hydroxy-pyridin-4-yl, or 1-H-2-oxo-1,2-dihydro-pyridin-4-yl; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In a further especially preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I *, where: A is CH, N or N- »0 and A 'is N or N? O, with the proviso that no more than one of A and A' can be N? O; n is 1; m is 0; p is 0, 2, or 3; r is 1 or 2; X is NR if p is 0, where R is hydrogen or lower alkyl, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dashed lines (interrupted) (including atoms) with which they are linked), forms a ring, or X is CH2 and p is zero, with the proviso that the links represented in dotted lines, if p is zero, are absent; And, it is O or CH2; Ri, R2, and R3 are selected from the following fractions, where the positions are indicated (o = ortho, m = meta, p = para) with respect to the position where the ring is linked to the rest of the molecule in the formula I * (by means of the fraction NH-C (= 0) -X): if only R1 is different from hydrogen: R1 = p-lower alkyl, especially p-methyl, p-ethyl, p- normal propyl; m-halo-lower alkyl, especially m-trifluoromethyl; or phenyl, p-piperidin-1-yl, or p-piperazin-1-yl; if both R, and R2 are different from hydrogen: R-i = m-halo-lower alkyl, especially m-trifluoromethyl, and R2 = p-halogen, especially p-bromine; RT = lower m-haloalkyl, in particular m-trifluoro-methyl, and R 2 = p-halo-lower alkoxy, especially p- (2,2,2-trifluoro-ethoxy); R1 = m-halo-lower alkyl, especially m-trifluoro-methyl, and R2 = lower m-alkoxy, especially m-methoxy; Ri = m-halo-lower alkyl, especially m-trifluoro-methyl, and R2 = p-phenyl; RT = m-halo-lower alkyl, especially m-trifluoromethyl, and R2 = p-piperidin-1-yl or p-piperazin-1-yl; R-i = lower m-haloalkyl, in particular m-trifluoromethyl, and R 2 = p-N-morpholino or p-N-thiomorpholino; R-i = lower m-alkoxy, especially m-methoxy, and R2 = p-halogen, especially p-bromine (less preferred); R-i = lower m-alkoxy, especially m-methoxy, and R2 = p-halo-lower alkoxy, especially p-2,2,2-trifluoro-ethoxy; R i = m-lower alkoxy, especially m-methoxy, and R 2 = p-phenyl; or Ri = m-lower alkoxy, especially m-methoxy, and R2 = p-piperidin-1-yl or p-piperazin-1-yl; or, if R 1, R 2, and R 3 are different from hydrogen: R j = lower m-alkoxy, especially m-methoxy; R2 = m-lower alkoxy, especially m-methoxy; and R3 = p-lower alkoxy, especially p-methoxy; or R-i = lower alkoxy, especially methoxy, and R2 and R3 together form a lower alkylene-dioxyl bridge, especially -0-CH2-CH2-0-; if r is not zero, R 4 is lower alkoxy, especially methoxy, lower alkanoyl-amino, especially acetylamino, hydroxy-phenyl-amino, especially p-hydroxy-phenyl-amino, lower-alkyl-oxyphenyl-amino, special 4 - [(2-amino-ethyl) -oxyphenyl] -amino, sulfamoll-phenyl-amino, especially 4-sulfamoyl-phenyl-amino, carbamoyl-phenyl-amino, especially 4-carbamoyl-phenyl-amino, [ N- (hydroxy-lower alkyl) -carbamoyl] -phenyl-amino, especially [N- (2-hydroxy-ethyl) -carbamoyl] -phenyl-amino, or halogen, especially chloro; and R5 is halogen, especially chloro, lower alkyl, especially methyl, or preferably hydrogen; or a tautomer thereof; or pharmaceutically acceptable salts thereof.

In another highly preferred embodiment, the invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for use in the treatment of RET-dependent diseases, wherein the diarylurea derivative is a compound of the formula I , selected from Examples of International Publication Number WO 03/099771, or a pharmaceutically acceptable salt thereof.

More preferably, the invention relates to the NOVELTY COMPOUNDS OF THE INVENTION, or pharmaceutically acceptable salts thereof. Also preferred is the USE of the NOVEL COMPOUNDS OF the INVENTION, or pharmaceutically acceptable salts thereof, wherein the protein kinase dependent disease to be treated is a tyrosine protein kinase dependent disease, and especially a disease proliferative (preferably benign or especially malignant tumors), especially a disease that depends on any one or more of the following protein kinases: c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R, Tek, PDGF- R, FGF-R, IGF-IR, Eph receptors such as in particular the EphB4 receptor, cKit, Met, c-Src, Raf and / or ras, especially c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R, and / or Tek, more especially Flt-3.

Pharmaceutical Compositions: The invention also relates in particular to pharmaceutical compositions comprising a NOVEL COMPOSITE OF THE INVENTION, to the use of a NOVEDOUS COMPOUND OF the INVENTION in the therapeutic treatment (in a broader aspect of the invention, also prophylactic), or to a method of treatment of a protein kinase-dependent disease (especially tyrosine ), especially the preferred diseases mentioned above, to the COMPOUNDS NOVEDOSOS OF THE INVENTION for said use, and the preparation of pharmaceutical compositions, especially for the mentioned uses. The present invention also relates to prodrugs of a NOVEDOUS COMPOUND OF THE INVENTION, which are converted in vivo into the NOVEDOUS COMPOUND OF the INVENTION as such. Accordingly, it should be understood that any reference to a NOVEL COMPOUND OF THE INVENTION also refers to the corresponding pro-drugs of the NOVEDOUS COMPOUND OF the INVENTION, as appropriate and convenient. The 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 a pharmaceutically acceptable salt thereof, as an active ingredient, together or mixed with a significant amount of one or more inorganic or organic, solid or liquid, pharmaceutically acceptable vehicles. The invention also relates to a pharmaceutical composition which is suitable for administration to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human being, for example lymphocytes) , for the treatment or, in a broader aspect of the invention, the prevention of (= prophylaxis against) a disease that responds to the inhibition of protein kinase activity, especially the tyrosine protein kinase activity, especially one of the diseases mentioned above as preferred for the USE of a NOVEDOUS COMPOUND OF THE INVENTION, which comprises an amount of a NOVEDOUS COMPOUND OF THE INVENTION, or a pharmaceutically acceptable salt thereof, which is effective for said inhibition, together with at least one pharmaceutically acceptable vehicle. The pharmaceutical compositions according to the invention are those for enteral administration, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, to warm-blooded animals (especially a human being), which comprise an effective dose of the pharmacologically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual condition, the individual pharmacokinetic data, the disease to be treated, and the mode of administration. The invention also relates to a method of treatment for a disease that responds to the inhibition of a protein kinase (especially tyrosine), especially one of the diseases mentioned above as being preferred for the USE of a NOVEDOUS COMPOUND OF THE INVENTION, which comprises administering a prophylactically, or especially therapeutically effective (against the aforementioned disease) amount of a NOVEL COMPOUND of the INVENTION, in particular to an animal of stray blood, for example a human being, which, taking into account one of the mentioned diseases, requires such treatment. The dose of a compound of the formula I, or a pharmaceutically acceptable salt thereof, to be administered to warm-blooded animals, for example humans of a body weight of about 70 kilograms, is preferably about 3 milligrams a about 30 grams, more preferably from about 10 milligrams to about 1.5 grams, and most preferably from about 100 milligrams to about 1,000 milligrams per person per day, preferably divided into 1 to 3 individual doses, which, for example, may be of the same size. Normally, children receive half the dose for adults. The pharmaceutical compositions comprise from about 1 percent to about 95 percent, preferably from about 20 percent to about 90 percent active ingredient. The pharmaceutical compositions according to the invention can be, for example, in a unit dosage form, such as in the form of ampoules, flasks, suppositories, dragees, tablets, or capsules. The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional processes of dissolution, lyophilization, mixing, granulation, or confectionery. Solutions of the active ingredient, and also suspensions, and especially isotonic aqueous solutions or suspensions, are a preferred form used, being possible, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a vehicle, for example mannitol, that these solutions or suspensions occur before use. The pharmaceutical compositions can be sterilized and / or can comprise excipients, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or pH regulators, and are prepared in a manner known per se same, for example by means of conventional dissolution or lyophilization processes. These solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, or gelatin. Suspensions in oil comprise, as the oil component, the vegetable, synthetic, or semi-synthetic oils customary for injection purposes. As such, esters of liquid fatty acids containing, as the acid component, a long-chain fatty acid having from 8 to 22, in particular from 12 to 22, carbon atoms, for example lauric acid, can be mentioned as such. tridecylic acid, myristic acid, pentadecyl acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or the corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid, or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, β-carotene, or 3,5-diterbutyl-4-hydroxy-toluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms, and is a mono- or polyhydroxy alcohol, for example mono-, di-, or tri-hydroxylic, for example methanol, ethanol, propanol , butanol, or pentanol, or the isomers thereof, but especially glycol and glycerol. Accordingly, the following examples of fatty acid esters are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefossé, Paris), "Miglyol 812" ( triglyceride of saturated fatty acids with a chain length of 8 to 12 carbon atoms, Hüls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, and more especially peanut oil. The compositions for injection are prepared in the customary manner under sterile conditions; the same applies also to the introduction of the compositions in ampoules or flasks and to the sealing of the containers. Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired the resulting mixture is granulated, and the mixture is processed, if desired or necessary, after the addition of appropriate excipients, until form tablets, dragee cores, or capsules. It is also possible that they are incorporated in plastic vehicles that allow the active ingredients to be diffused or released in measured quantities. Suitable carriers are in particular fillers, such as sugars, for example lactose, sucrose, mannitol, or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium triphosphate or calcium acid phosphate, and binders, such as pastes starch using, for example, corn starch, wheat starch, rice starch, or potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, such as the starches mentioned above, and / or carboxymethyl starch, crosslinked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. The excipients are in particular flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric coatings, using, inter alia, concentrated sugar solutions, which may comprise gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and / or titanium dioxide, or solutions of coating in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxy-propyl methyl cellulose phthalate. The capsules are dry filled capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and / or skimmers, such as talc or magnesium stearate, and if desired, with stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil, or liquid polyethylene glycols, it also being possible for stabilizers and / or antibacterial agents to be added. Dyes or pigments may be added to the tablets or dragee coatings or to the capsule housings, for example for identification purposes or to indicate different doses of the active ingredient. A compound of the formula I, especially a NOVEDOUS COMPOUND OF THE INVENTION, can also be used with advantage in combination with other anti-proliferative agents. These anti-proliferative agents include, but are not limited to, aromatase inhibitors, anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active agents, alkylating agents, histone deacetylase inhibitors, farnesyl inhibitors. transferase, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic anti-metabolites, platinum compounds, compounds that decrease the activity of protein kinase and other anti-angiogenic compounds, gonadorelin agonists, anti- androgens, bengamides, bisphosphonates, steroids, anti-proliferative antibodies, 17- (aul-amino) -17-demethoxy-geldanamlcin (17-AAG) and temozolomide (TEMODAL®). The term "aromatase inhibitors", as used herein, refers to compounds that inhibit the production of estrogen, that is, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially exemestane and formestane, and, in particular, non-steroids, especially amino-glutethimide, vorozole, fadrozole, anastrozole, and most especially, letrozole. Exemestane can be administered, for example, in the form as it is traded, for example under the registered trademark AROMASINMR. Formestane can be administered, for example, in the form as it is traded, for example under the registered trademark LENTARON ™. Fadrozole can be administered, for example, in the form as it is traded, for example under the registered trademark AFEMAMR. Anastrozole can be administered, for example, in the form as it is traded, for example under the registered trademark ARIMIDEXMR. Letrozole can be administered, for example, in the form as it is traded, for example under the registered trademark FEMARAMR or FEMARMR. The amino-glutethimide can be administered, for example, in the form as it is traded, for example under the registered trademark ORIMETEN R. A combination of the invention comprising an antineoplastic agent which is an aromatase inhibitor, is particularly useful for the treatment of breast tumors positive for the hormone receptor. The term "anti-estrogens", as used herein, refers to compounds that antagonize the effect of estrogens at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form as it is traded, for example under the registered trademark NOLVADEX ™. Raloxifene hydrochloride can be administered, for example, in the form as it is traded, for example under the registered trademark EV1STAMR. The fulvestrant can be formulated as disclosed in US Pat. No. 4,659,516, or it can be administered, for example, in the form as it is traded, for example under the registered trademark FASLODEXMR. The term "topoisomerase I inhibitors", as used herein, includes, but is not limited to, topotecan, irinotecan, 9-nitro-camptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in International Publication Number WO 99/17804). The irinotecan can be administered, for example, in the form as it is traded, for example under the registered trademark CAMPTOSAR MR. The topotecan can be administered, for example, in the form as it is traded, for example under the registered trademark HYCAMTINMR. The term "topoisomerase M inhibitors", as used herein, includes, but is not limited to, the anthracyclines doxorubicin (including the liposomal formulation, eg CAELYXMR), epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone , and the podophyllotoxins etoposide and teniposide. The etoposide can be administered, for example, in the form as it is traded, for example under the registered trademark ETOPOPHOS MR The teniposide can be administered, for example, in the form as it is traded, for example under the registered trademark VM 26 -BRISTOLMR. Doxorubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ADRI BLASTI N R. Epirubicin can be administered, for example, in the form as it is traded, for example under the trademark Registered FARM ORU BIC I NMR. Idarubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ZAVEDOS ™. The mitoxantrone can be administered, for example, in the form as it is traded, for example under the registered trademark NOVANTRONMR. The term "microtubule-active agents" refers to microtubule stabilizing and microtubule destabilizing agents, including, but not limited to, taxanes paclitaxel and docetaxel, vinca alkaloids, for example vinblastine, especially vinblastine sulfate, vincristine, especially vincristine sulfate, and vinorelbine, discodermolide and epothilones, such as epothilones B and D. Docetaxel can be administered, for example, in the form as it is traded, for example under the registered trademark TAXOTEREMR. Vlnblastine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark VINBLASTIN R.P.MR. The vincristine sulfate can be administered, for example, in the form as it is traded, for example under the registered trademark FARMISTIN ™. The discodermolide can be obtained, for example, as disclosed in U.S. Patent No. 5,010,099. The term "alkylating agents", as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, and melphalan. Cyclophosphamide can be administered, for example, in the form as it is traded, for example under the registered trademark CYCLOSTIN ™. Ifosfamide can be administered, for example, in the form as it is traded, for example under the registered trademark HOLOXAN R. The term "inhibitors of histone deacetylase" refers to the compounds that inhibit histone deacetylase and which possess anti-proliferative activity. This includes the compounds disclosed in International Publication Number WO 02/22577, especially N-hydroxy-3- [4 - [[(2-hydroxy-ethyl) [2- (1H-indol-3-yl) - ethyl] -amino] -methyl] -phenyl] -2E-2-propenamide, N-hydroxy-3- [4 - [[2- (2-methyl-1H-indol-3-yl) -ethyl] -amino] ] -methyl] -fenu] -2E-2-propenam ida and the pharmaceutically acceptable salts thereof. It also includes in particular suberoylanilide hydroxamic acid (SAHA). The term "farnesyl transferase inhibitors" refers to compounds that inhibit farnesyl transferase and that possess anti-proliferative activity. The term "COX-2 inhibitors" refers to compounds that inhibit the enzyme cyclo-oxygenase type 2 (COX-2) and that possess anti-proliferative activity, such as celecoxib (Celebrex®), rofecoxib (Vioxx®), and lumiracoxib (COX189). The term "MMP inhibitors" refers to compounds that inhibit matrix metalloproteinase (MMP) and that possess anti-proliferative activity.

The term "mTOR inhibitors" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and that possess anti-proliferative activity, such as sirolimus (Rapamune®), everolimus (Certican ™), CCI-779 and ABT578 . The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gemcitabine, 6-mercapto-purine, hydroxyurea, methotrexate, edatrexate, and salts of these compounds, and in addition ZD 1694 (RALTITREXEDMR), LY231514 (ALIMTAMR), LY264618 (LOMOTREXOLMR), and OGT719. The term "platinum compounds", as used herein, includes, but is not limited to, carboplatin, cis-platin, and oxaliplatin. Carboplatin can be administered, for example, in the form as it is traded, for example under the registered trademark CARBOPLAT ™. Oxaliplatin can be administered, for example, in the form as it is traded, for example under the registered trademark ELOXATIN ™. The term "compounds that decrease the activity of the protein kinase and other anti-angiogenic compounds", as used herein, includes, but is not limited to, compounds that decrease the activity of, for example, the Vascular Endothelial Growth (VEGF), Epidermal Growth Factor (EGF), c-Src, Protein Kinase C, Platelet Derived Growth Factor (PDGF), Bcr-Abl, c-Kit, Flt-3, Receptor I of Insulin-like Growth Factor (IGF-IR), and cyclin-dependent kinases (CDKs), and anti-angiogenic compounds that have another mechanism of action different from the decrease in protein kinase activity. The compounds that decrease the activity of vascular endothelial growth factor are in particular the compounds that inhibit the vascular endothelial growth factor receptor, especially the activity of the vascular endothelial growth factor receptor tyrosine kinase, and the compounds that they are linked to the vascular endothelial growth factor, and are in particular the compounds, proteins, and monoclonal antibodies generically and specifically disclosed in International Publication Number 98/35958 (which describes the compounds of the formula I), in the Publications International Numbers WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899, and European Patent Number EP 0,769,947; those described by M. Prewett et al. in Cancer Research 59. (1999) 5209-5218, by F. Yuan et al in Proc. Nati Acad. Sci. USA, Volume 93, pages 14765-14770, December 1996, by Z. Zhu and collaborators in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al. In Toxicologic Pathology, Volume 27, Number 1 , pages 14-21, 1999; in International Publications Nos. WO 00/37502 and WO 94/10202; Ang iostati nMR, 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; the compounds that decrease the epidermal growth factor activity are in particular the compounds that inhibit the epidermal growth factor receptor, especially the tyrosine kinase activity of the epidermal growth factor receptor, and the compounds that bind to the epidermal growth factor receptor. the epidermal growth factor, and are in particular those compounds generically and specifically disclosed in Patent Numbers WO 97/02266 (which discloses compounds of formula IV), EP 0,564,409, WO 99/03854, EP 0,520,722, EP 0,566,226, EP 0 787,722, EP 0,837,063, WQ 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, in particular, WO 96/33980; Compounds that decrease the activity of c-Src include, but are not limited to, compounds that inhibit the kinase activity of the tyrosine protein c-Src as defined below, and the inhibitors of the interaction with SH2, such such as those disclosed in International Publications Nos. WO 97/07131 and WO 97/08193; Compounds that inhibit the tyrosine c-Src protein kinase activity include, but are not limited to, the compounds belonging to the pyrrolo-pyrimidine structure classes, especially pyrrolo [2,3-d] pyrimidines, purines , pyrazo-pyrimidines, especially pyrazo- [3,4-d] -pyrimidines, and pyrido-pyrimidines, especially pyrido- [2,3-d] -pyrimidines. Preferably, the term refers to the compounds disclosed in International Publications Nos. WO 96/10028, WO 97/28161, WO 97/32879, and WO 97/49706; the compounds that decrease the activity of protein kinase C are in particular the staurosporine derivatives disclosed in European Patent Number EP 0,296,110 (the pharmaceutical preparation described in International Publication Number WO 00/48571), which compounds are inhibitors of protein kinase C; the compounds that decrease IGF-IR activity are in particular the compounds disclosed in International Publication Number WO 02/92599; other specific compounds that decrease the activity of the protein kinase and which can also be used in combination with the compounds of the present invention are Imatinib (Gleevec® / Glivec®), PCK412, lressa ™ (ZD1839),. { 6- [4- (4-ethyl-piperazin-1-ylmethyl) -phenyl] -7H-pyrrolo- [2,3-d] -pyrimidin-4-yl} - ((R) -1-phenyl-ethyl) -amine (AEE 788) and pharmaceutically acceptable salts thereof (see also International Publication Number WO 03/13541), 1- (4-chloroanilino) -4- (4-pyridyl-methyl) -phthalazine (PTK787) and pharmaceutically acceptable salts thereof (see also International Publication Number WO 98/35958), ZD6474, GW2016, CHIR-200131, CE P-7055 / CE P-5214, CP-547632, KRN-633, and SU5416; Anti-angiogenic compounds that have another mechanism of action other than decreasing protein kinase activity include, but are not limited to, for example, thalidomide (THALOMID), celecoxib (Celebrex), and ZD6126. The term "gonadorelin agonist", as used herein, includes, but is not limited to, abarelix, goserelin, and goserellna acetate. Goserelin is disclosed in US Pat. No. 4,100,274, and may be administered, for example, in the form as it is traded, for example under the registered trademark ZOLADEX ™. Abarelix can be formulated, for example as disclosed in U.S. Patent No. 5,843,901. The term "anti-androgens", as used herein, includes, but is not limited to, bicalutamide (CASODEX ™), which may be formulated, for example, as disclosed in the United States Patent. US number 4,636,505. The term "bengamides" refers to the bengamides and derivatives thereof which have anti-proliferative properties. The term "bisphosphonates", as used herein, includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. The "etridonic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark DIDRONEL MR "clodronic acid" can be administered, for example, in the form as it is traded, for example under the Registered trademark BONEFOSMR. The "tiludronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark SKELIDMR. The "pamidronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark AREDIAMR. The "alendronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark FOSAMAX R. The "ibandronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONDRANATMR. The "risedronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ACTONELMR. The "zoledronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ZOMETAMR. The term "steroids" includes hydrocortisone, dexamethasone (Decadron®), methylprednisolone, and prednisolone.

The term "anti-proliferative antibodies", as used herein, includes, but is not limited to, trastuzumab (Herceptin ™), Trastuzumab-DM 1, erlotinib (Tarceva ™), bevacizumab (Avastin ™), rituximab (Rituxan®), PRO64553 (anti-CD40) and Antibody 2C4. For the treatment of acute myeloid leukemia (AML), the compounds of the formula I, especially the NOVEDOUS COMPOUNDS OF the INVENTION, can be used in combination with conventional leukemia therapies, especially in combination with the therapies used for the treatment of acute myeloid leukemia. In particular, the compounds of the present invention can be administered in combination, for example, with farnesyl transferase inhibitors and / or other drugs useful for the treatment of acute myeloid leukemia, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatin, and PKC412. The structure of the active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index" or from the databases, for example Patents International (for example, IMS World Publications ).

The above-mentioned compounds, which can be used in combination with a compound of the present invention, can be prepared and administered as described in the art, such as in the documents cited above.

Examples ("NOVEDOUS COMPOUNDS OF THE INVENTION"): The following Examples serve to illustrate the invention without limiting its scope. Temperatures are measured in degrees Celsius. Unless indicated otherwise, the reactions take place at room temperature. The Rf values that indicate the proportion of the distance moved by each substrate at the distance moved by the eluent front, are determined on silica gel thin-film plates (Merck, Darmstadt, Germany), by means of thin-layer chromatography using the respective mentioned solvent systems.

Abbreviations: Anal. Elemental analysis (for the indicated atoms, the difference between the calculated and measured value £. 0.4 percent). aq Aqueous. brine Saturated NaCl solution in water. Boc Terbutoxi-carbonilo. Bu Butilo. conc. Concentrated. d Day (s). DIPE Di-isopropyl-ether. DIPEA Di-isopropyl-ethyl-amine. DMAP Dimethyl-amino-pyridine. DME 1,2-dimethoxy-ethane. DMF Dimetll-formamide. DMSO-d6 Per-deuterated dimethyl sulfoxide. equiv. Equivalent (s) Ether Diethyl ether. EtOAc Ethyl acetate. EtOH Ethanol. Example. h Time (s). HPLC High pressure liquid chromatography. I Liter (s). I Metilo. MeOH Methanol. min M inuto (s). p.f. Melting point. MPLC Medium pressure liquid chromatography. -System Combi Flash: SiO2 in normal phase. - Gilson system: Nucleosil C18 in reverse phase (H2O / CH3CH + TFA), product obtained in general as the free base after neutralization with NaHCO3. MS Mass spectrum. NEt3 Triethyl-amine. NMR Nuclear magnetic resonance. Rf Proportion of fronts (thin layer chromatography). rt Ambient temperature. TBDMS Te rbu ti l-dimethyl-silyl. tBu Terbutyl. THF Tetrahydrofuran (distilled from Na / benzophenone). TFA Trifluoroacetic acid. TLC Thin layer chromatography. Ret Retention time (high pressure liquid chromatography). Triphosgene Bis- (trichloro-methyl) carbonate.

Conditions of High Pressure Liquid Chromatography (HPLC) ^ XR ^. Retention time [minutes] for System A: Linear gradient from 20 to 100 percent CH3CN (0.1 percent trifluoroacetic acid) and H20 (0.1 percent trifluoroacetic acid) in 13 minutes + 5 minutes at 100 percent of CH3CN (0.1 percent trifluoroacetic acid); detection at 215 nanometers; Flow rate of 1 milliliter / minute at 25 ° C or 30 ° C. Column: Nucleosil 120-3 C18 (125 x 3.0 millimeters). L J LL. Retention time [minutes] for System B_: Linear gradient from 20 to 100 percent CH3CN (0.1 percent trifluoroacetic acid) and H2O (0.1 percent trifluoroacetic acid) in 7 minutes; detection at 215 nanometers; Flow rate of 1 milliliter / minute at 25 ° C or 30 ° C. Column: Nucleosil 100-3 C18 HD (125 x 4.0 millimeters). ctRet: Retention time [minutes] for System C_: Linear gradient from 20 to 100 percent of CH3CN (0.1 percent trifluoroacetic acid) and H2O (0.1 percent trifluoroacetic acid) in 7 minutes + 2 minutes with 100 percent of CH3CN (0.1 percent trifluoroacetic acid); detection at 215 nanometers; flow rate of 1 milliliter / minute at 30 ° C. Column: Nucleosil 100-3 C18 HD (125 x 4.0 millimeters). ^ ÍR Retention time [minutes] for System D .: Linear graph of 20 to 100 percent CH3CN (0.1 percent trifluoroacetic acid) and H2O (0.1 percent trifluoroacetic acid) in 5 minutes + 1.5 minutes with 100 percent CH3CN (0.1 percent trifluoroacetic acid); detection at 215 nanometers; flow rate of 1 milliliter / minute at 30 ° C. Column: Nucleosil 100-3 C18 HD (70 x 4 millimeters).

Example 1: N-r4- (6-chloro-pyrim idin-4-yloxy) -phenyl] -N'-f3 (azetidin-1-ylmethyl) -5-trifluoromethyl-phenan-urea.

To a solution of 935 milligrams (3.78 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) in 3 milliliters of tetrahydrofuran under an atmosphere of N2, 870 milligrams (3.78 millimoles) are added. of 3- (azetidin-1-ylmethyl) -5-trifluoro-methyl-aniline (Step 1.6) dissolved in 20 milliliters of ether. After stirring for 3 hours at room temperature, the reaction mixture is partially concentrated in vacuo, diluted with ether, whereby the title compound is crystallized and can be filtered and washed with ether: MS: [M + 1] + = 478; 1 H-NMR (CDCl 3): 8.58 (s, 1 H), 7.61 (s, 1 H), 7.46 (s, 1 H), 7.44 (d, 8.6 Hz, 2 H), 7.24 (s, 1 H), 7.12 (d, 8.6 Hz, 2H), 6.93 (s, 1H), 6.89 (s, 1H), 6.81 (s, 1H), 3.59 (s, 2H), 3.24 (t, 7.0 Hz, 2 x 2H), 2.11 (q, 7.0 Hz, 2H).

The starting material is prepared as follows: Step 1.1: 4-chloro-6- (4-nitro-phenoxy) -pyrimidine. To an ice-cold solution of 214 grams (5.35 moles) of NaOH dissolved in 6.5 liters of H2O, 744 grams (5.35 moles) of 4-nitrophenol are added. Then a solution of 797 grams (5.35 moles) of 4,6-dichloro-pyrimidine in 6.5 liters of acetone is added dropwise over 60 minutes, and the mixture is stirred for 18 hours at 65 ° C. The reaction mixture is cooled to 10 ° C, the crude product precipitated is filtered and washed with 400 milliliters of H20 / acetone, 1: 1. P.f .: 127-128 ° C; Analysis C10H6CIN3O3: C, H, N.CI, 0; MS: [M] + = 251; 1 H-NMR (DMSO-d 6): 8.70 (s, 1 H, pyrimidinyl), 8.34 (d, 9 Hz, 2 H, phenyl), 7.59 (s, 1 H, pyrimidinyl), 7.57 (d, 9 Hz, 2 H, phenyl) .

Step 1.2: 4- (6-chloro-irimidin-4-yl-oxy) -aniline. 1.095 grams (4.3 moles) of 4-chloro-6- (4-nitro-phenoxy) -pyrimidine dissolved in 10 liters of methanol / tetrahydrofuran, 2: 1, are hydrogenated in the presence of 33 grams of Raney nickel room temperature for 4 hours. The reaction solution is filtered and concentrated. Crystallization from EtOAc gives the title compound: Analysis C? 0H8CIN3O: C, H, N, CI, O; MS: [M + 1] + = 222; 1 H-NMR (D SO-ds): 8.60 (s, 1 H), 7.12 (s, 1 H), 6.86 (d, 9 Hz, 2 H, phenyl), 6.57 (d, 9 Hz, 2 H, phenyl), 5.13 ( s, 2H, NH2).

Step 1.3: 4-chloro-6- (4-isocyanate-f-enoxy) -pyrimidine. Apparatus: 18 liter reaction vessel, drip funnel, and condenser. A solution of phosgene (20 percent in toluene, 1.43 liters, 2.9 moles) diluted with 10 liters of toluene under an N2 atmosphere is cooled to about -20 ° C. Then a solution of 250 grams (1.12 moles) of 4- (6-chloro-pyrimidin-4-yl-oxy) -aniline in 4.4 liters of CH2Cl2 is added over 30 minutes. The resulting suspension is heated to distill approximately 4.5 liters of solvent. The distillation is Continue (boiling point: 110 ° C) to give a clear solution (about 3 liters) in the reaction vessel, which is cooled to room temperature and concentrated in vacuo. Distillation of the resulting waxy crude product at 0.2 mbar gives the title compound as a solid 0: m.p. : 103 ° C.

Step 1.4: (3-Nitro-5-trifluoro-methyl-phenyl) - (azetidin-1-yl) -methanone. In an ice bath under an N2 atmosphere, they mix 9.77 grams (41.6 millimoles) of 3-nitro-5-trifluoromethyl-benzoic acid (Lancaster), 150 milliliters of CH2CI2, a few drops of dimethyl formamide, and 5.8 milliliters (67 millimoles) of oxalyl chloride, and then they are stirred for 17 hours at room temperature. The resulting solution is concentrated in vacuo. The residue is dissolved in 50 milliliters of CH 2 Cl 2, and added dropwise to an ice-cold solution of 5.9 milliliters (87 millimoles) of azetidine in 50 milliliters of CH 2 Cl 2. After stirring for 15 minutes, the mixture is washed with 1 N HCl, a dilute solution of Na 2 CO 3, water, and brine. The aqueous layers are re-extracted twice with EtOAc, the combined organic phases are dried (Na2SO4), and concentrated. Crystallization from hexane gives the title compound. P.f .: 91 ° C; MS: [M + 1] + = 275.

Step 1.5: (3-Amino-5-trifluoromethyl-phenyl) - (azetldin-1-yl) -methanone. The hydrogenation of 10.39 grams (37.9 millimoles) of (3-nitro-5-trifluoromethyl-phenyl) - (azetidin-1-yl) -methanone in 200 milliliters of ethanol in the presence of 2 grams of Raney nickel, the filtration through Celite, partial concentration of the filtrate, and dilution with hexane, give the crystalline title compound; p.f .: 154 ° C; MS: [M + 1] + = 245.

Step 1.6: 3- (Azetidin-1-ylmethyl) -5-trifluoromethyl-aniline. To 8.62 grams (35.3 millimoles) of (3-amino-5-trifluoromethyl-phenyl) - (azetidin-1-yl) -methanone in 75 milliliters of tetrahydrofuran under an N 2 atmosphere cooled in an ice bath, drip 10.6 milliliters (95 percent; 106 millimoles) of BH3 * Me2S in 15 milliliters of tetrahydrofuran. The resulting solution is stirred for 2 days at room temperature, and then for 4 hours at 65 ° C. After cooling to room temperature, 50 milliliters of concentrated HCl / H 2 O, 1: 1 are added, and the mixture is stirred for 15 hours at room temperature, and for 7 hours at 65 ° C. The mixture is poured into ethyl acetate and a 10 percent solution of Na 2 CO 3, and the aqueous phase is separated and extracted twice with ethyl acetate. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Column chromatography (S02; EtOAc / EtOH, 95: 5? EtOAc / EtOH / Et3N, 95: 5: 1) produces the title compound; p.f. 60-61 ° C; MS: [M + 1] + = 231.

Eiem pío 2: N-r4- (6-metíl-amíno-pyrimidin-4-xlox) -phenp N '- (3-azetidin-1-ylmethyl-5-trifluoromethyl-phenyl) -urea.

Under an N2 atmosphere, 250 milligrams (0.52 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- (3-azetidin-1-methylmethyl-5-trifluoro-methyl) phenyl) -urea in 3 milliliters of a 33 percent solution of MeNH2 in EtOH are stirred in an ice bath for 4 hours. Then about 1 gram of SiO2 is added to the solution, and the mixture is concentrated in vacuo. The resulting powder is placed on top of a medium pressure liquid chromatography column (SiOz), and eluted with MeOH (+1 percent N N3qq) / CH2Cl2, 3:97? 1: 9 - »1: 4, yielding the title compound: MS: [M + 1] + = 473; 1 H-NMR (CD 3 OD + CDCl 3): 8.11 (s, 1 H), 7.95 (m, 1 H), 7.46 (s, 1 H), 7.45 (d, 7.4 Hz, 2 H), 7.17 (s, 1 H), 7.03 (d , 7.4 Hz, 2H), 5.59 (s, 1H), 3.90 (s, 2H), 3.63 (m, 2 x 2H), 2.81 (s, H3C), 2.30 (m, 2H).

Eiem pio 3: N-r4- (6-azido-pyrimidin-4-yloxy) -phenin-N '- (3 azetidin-1-ylmethyl-5-trifluoromethyl-phenyl) -urea.

A mixture of 300 milligrams (0.63 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- (3-azetidin-1-Umethyl-5-trifluoro-methyl- phenyl) -urea and 82 milligrams (1.26 mmol) of NaN3 in 5 milliliters of dimethyl formamide, is stirred for 16 hours at 40 ° C, and for 5 hours at 60 ° C. The reaction mixture is poured into water and extracted with 3 portions of EtOAc. The organic layers are washed with water and brine, dried (Na2SO), and concentrated. The residue is redissolved in 20 milliliters of tetrahydrofuran, filtered, and the filtrate is used directly in the hydrogenation step of Example 4. The title compound can be obtained by concentrating the filtrate in vacuo: MS: [M + 1] + = 485; 1 H-NMR (CDCl 3): 8.53 (s, 1 H), 7.96 (s, 1 H), 7.94 (s, 1 H), 7.57 (s, 1 H), 7.53 (s, 1 H), 7.45 (d, 8.6 Hz, 2 H ), 7.17 (s, 1H), 7.04 (d, 8.6 Hz, 2H), 6.25 (s, 1H), 3.58 (s, 2H), 3.27 (t, 7.0 Hz, 2 x 2H), 2.11 (q, 7.0) Hz, 2H).

Example 4: N-r 4 - (6-amino-pyrimidip 4-yloxy) -phenyl-N'-. { 3-Azetidin-1-ylmethyl-5-trifluoromethyl-phen-p-urea.

A solution of N- [4- (6-azido-pyrim idin-4-yloxy) -phenyl] -N '- (3-azetidin-1-ylmethyl-5-trifluoromethyl-phenyl) -urea (0.63 milli- moles) in 20 milliliters of tetrahydrofuran, hydrogenated in the presence of 60 milligrams of 10% Pd / C.

After filtering the catalyst, about 1 gram of SiO2 is added to the filtrate, and the mixture is concentrated in vacuo. The resulting powder is placed on top of a medium pressure liquid chromatography column (SiO2), and eluted with EtOH (+1 percent NEt3) / EtOAc, 1:49? 4:46? 1: 4, yielding the title compound: MS: [M + 1] + = 459; 1 H-NMR (CD 3 OD): 8.08 (s, 1 H), 7.82 (s, 1 H), 7.54 (s, 1 H), 7.52 (d, 9.0 Hz, 2 H), 7.24 (s, 1 H), 7.09 (d, 9.0) Hz, 2H), 5.75 (s, 1H), 3.68 (s, 2H), 3.35 (t, 7.2 Hz, 2 x 2H), 2.16 (q, 7.2 Hz, 2H).

Example 5: N -r4- (6-chloro-pyrim id in -4-i loxi) -f in il1-N'-r3- (4-isopropyl-piperazin-1-ylmethyl) -5-trifluoro-methyl -fenip-u rea, A solution of 1.00 grams (4.0 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 3 milliliters of tetrahydrofuran is added dropwise to a solution of 1.31 grams (4.3 millimoles) 3- (4-isopropylpiperazin-1-ylmethyl) -5-trifluoromethyl-aniline (Step . 3) in 33 milliliters of ether under an atmosphere of N2.

After stirring for 4 hours at room temperature, the reaction mixture is concentrated in vacuo. Column chromatography (SIO2; CH2Cl2 / MeOH, 9: 1 → 88:12 → 85:15) gives the title compound: mp: 101 ° C; MS: [M + 1] + = 549; 1 H-NMR (CDCl 3): 8.47 (s, 1 H), 7.64 (s, 1 H), 7.48 (s, 1 H), 7.47 (d, 9 Hz, 2 H), 7.28 (s, 1 H), 7.19 (m, 1 H) ), 7.13 (s, 1H), 7.12 (d, 9 Hz, 2H), 6.92 (s, 1H), 3.49 (s, 2H), 2.69 (sept., 6.3 Hz, 1H), 2.58 (m, 4H) , 2.52 (m, 4H), 1.08 (d, 6.3 Hz, 6H).

The starting material is prepared as follows: Step 5.1: (3-Nitro-5-trifluoromethyl-phenyl) - (4-isopropyl-p-piperazin-1-yl) -methanone. In an ice bath under an N2 atmosphere, 9.00 grams (38.3 mmol) of 3-nitro-5-trifluoro-methyl-benzoic acid (Lancaster), 150 milliliters of CH2Cl2, a few drops of dimethylformamide are mixed, and 5.3 milliliters (61 millimoles) of oxalyl chloride, and then stirred for 4.5 hours at room temperature. The resulting solution is concentrated in vacuo. The residue is dissolved in 50 milliliters of CH 2 Cl 2, and added dropwise to a frozen solution of 10.3 grams (80 millimoles) of 1-isopropyl-piperazine in 50 milliliters of CH 2 Cl 2. After stirring for 140 minutes, the mixture is washed with a dilute solution of Na 2 CO 3, water, and brine. The aqueous layers are re-extracted twice with EtOAc, the combined organic phases are dried (Na2SO4), and concentrated. Crystallization from diisopropyl ether / hexane gives the title compound: mp: 70-71 ° C; MS: [M + 1] + = 346.

Step 5.2: (3-am ino-5-trif I uoro-methyl-f-enyl) - (4-isopropyl-piperazin-1-yl) -methanone. The hydrogenation of 9.2 grams (27 millimoles) of (3-nitro-5-trifluoromethyl-phenyl) - (4-isopropylpiperazin-1-yl) -methanone in 200 milliliters of ethanol in the presence of 2 grams of Raney nickel, as described in Step 1.5, gives the title compound: mp: 89-90 ° C: MS: [M + 1] + = 316.

Step 5.3: 3- (4-Isopropylpiperazin-1-ylmethyl) -5-trifluoromethyl-aniline. To 7.0 grams (22 millimoles) of (3-am ino-5-trifluoro-methyl-phenyl) - (4-isopropyl-piperazin-1-yl) -methanone in 70 milliliters of tetrahydrofuran under an atmosphere of N2, they are added drip 67 milliliters (1M in tetrahydrofuran, 67 millimoles) of BH3 * THF. The resulting solution is stirred for 18 hours at room temperature, then 100 milliliters of concentrated HCl / H20, 1: 1 is added, and the mixture is stirred for 5 hours at room temperature. The reaction mixture is extracted with EtOAc, the organic phase is washed with 0.1 N HCl and discarded. To the acidic aqueous layers are then added 250 milliliters of a saturated solution of Na 2 CO 3, followed by extraction with 3 portions of EtOAc. The organic layers are washed with brine, dried (Na2SO4), and concentrated, yielding the title compound as an oil: MS: [M + 1] + = 302; 1 H-NMR (CDCl 3): 6.93 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 3.82 (s, H2N), 3.45 (s, 2H), 2.67 (Sept., 6.3 Hz, 1H), 2.57 (m, 4H), 2.51 (m, 4H), 1.07 (d, 6.3 Hz, 6H).

Example 6: N-r4- (6-methyl-amino-pyrimidin-4-yloxy) -fenin N'-r3- (4-isopropyl-piperazin-1-ylmethyl) -5-trifluoro-methyl-f-enyl-u-rea Under an N2 atmosphere, 368 milligrams (0.67 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- [3- (4-isopropylpiperazine-1-methyl) -5-trifluoromethyl-phenyl] -urea in 3 milliliters of a 33 percent solution of MeNH2 in EtOH, are stirred in an ice bath for 4.5 hours. The mixture is poured into EtOAc and an aqueous solution of NaHCO 3, the aqueous phase is separated and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4), and concentrated. Reverse phase chromatography gives the title compound: MS: [M + 1] + = 544; 1 H-NMR (CD 3 OD): 8.15 (s, 1 H), 7.84 (s, 1 H), 7.66 (s, 1 H), 7.56 (d, 9 Hz, 2 H), 7.34 (s, 1 H), 7.13 (d, 9 Hz, 2H), 5.72 (s, 1H), 3.63 (s, 2H), 2.87 (s, H3C), 2.9-2.5 (m, 9H), 1.15 (d, 6.7 Hz, 6H).

Example 7: N-r4- (6-azido-pyrim id in-4-yloxy) -f-enyl1-N'-r3- (4-isopropyl-piperazin-1-ylmethyl) -5-trifluoro-methyl-phein-urea .

A mixture of 470 milligrams (0.86 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- [3- (4-isopropyl-piperazin-1 -i Im eti) -5-trifluoro-methyl-phenyl] -urea and 111 milligrams (1.7 mmol) of NaN3 in 7 milliliters of dimethylformamide, is stirred for 2 hours at 80 ° C. The solution is then cooled in an ice bath and poured into 80 milliliters of water with vigorous stirring. Filtration of the resulting suspension and washing with water gives the title compound: MS: [M + 1] + = 556; HPLC AtRet = 11.2.

Eiem pio 8: N-r4- (6-amino-pyrimidin-4-yloxy) -phen-P-N, -r3 (4-isopropyl-piperazin-1-ylmethyl) -5-trifluoro-methyl-pheno-urea, A solution of 0.39 grams (0.70 millimoles) of N- [4- (6-azido-pyrimidin-4-yloxy) -phenyl] -N '- [3- (4-isopropyl-piperazin-1-methylmethyl) -5- trifluoromethyl-phenyl] -urea in 20 milliliters of tetrahydrofuran, is hydrogenated in the presence of 100 milligrams of 5% Pd / C. The catalyst is filtered, the filtrate is concentrated in vacuo, the residue is redissolved in CH2Cl2 / MeOH, and after adding about 1 gram of SiO2, it is again concentrated. The resulting powder is placed on top of a medium pressure liquid chromatography column (SiO2), and eluted with EtOAc / EtOH (+1 percent NEt3) 19: 1? 9: 1? 7: 3, yielding the title compound after crystallization from hexane: Analysis C26H30N7F3O2 • 0.8 H2O • 0.2 EtOAc: C, H.N.H20; MS: [M + 1] + = 530; 1 H-NMR (CD 3 OD): 8.12 (s, 1 H), 7.86 (s, 1 H), 7.63 (s, 1 H), 7.57 (d, 8.6 Hz, 2 H), 7.34 (s, 1 H), 7.13 (d, 8.6 Hz, 2H), 5.79 (s, 1H), 3.62 (s, 2H), 2.8-2.5 (m, 9H), 1.13 (d, 6.7 Hz, 6H).

Eiem pío 9: N-r4- (6-chloro-pyrimidin-4-yloxy) -fenip-N'-r3 (4-methyl-piperazin-1-ylmethyl) -5-trifluoromethyl-pheep-urea. 1. 00 grams (4.0 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 3 milliliters of tetrahydrofuran and 1.1 grams (4.0 millimoles) of 3- (4-methyl-piperazin-1) -ylmethyl) -5-trifluoro-methyl I-aniline (Step 9.3) in 30 milliliters of ether, converted analogously to Example 5, into the title compound: mp: 292-292 ° C; Analysis C24H24N6CLF302 • 0.5 H20: C, H, N, CI, F; MS: [M + 1] + = 521.

The starting material is prepared as follows: Step 9.1: (3-Nitro-5-trifluoromethyl-phenyl) - (4-methyl-piperazin-1-yl) -methanone. In a manner analogous to Step 5.1, 9.00 grams (38.3 millimoles) of 3-nitro-5-trifluoromethyl-benzoic acid are activated with 5.3 milliliters (61 millimoles) of oxalyl chloride, and reacted with 8.9 milliliters (80 millimoles) of 1-methyl-piperazine, yielding the title compound as an oil; MS: [M + 1] + = 318; HPLC AtRet = 8.7.

Step 9.2: (3-Amino-5-trifluoro-methyl-phenyl) - (4-methyl-piperazin-1-yl) -methanone. The hydrogenation of 11.8 grams (37 millimoles) of (3-nitro-5-trifluoromethyl-phenyl) - (4-methyl-piperazin-1-yl) -methanone in 200 milliliters of ethanol in the presence of 2 grams of nickel of Raney, as described in Step 1.5, gives the title compound; p.f .: 114-115 ° C; MS: [M + 1] + = 288.

Step 9.3: 3- (4-Methyl-piperazin-1-ylmethyl) -5-trifluoromethyl-aniline. In a manner analogous to Step 1.6, 9.91 grams (34.5 millimoles) of (3-amino-5-trif-I uoro-methyl-fenu) - (4-methyl-plperazin-1-yl) -methanone in 90 milliliters of tetrahydrofuran, they are reduced by BH3 »Me2S to the title compound; p.f .: 98-99 ° C; MS: [M + 1] + = 274; 1 H-NMR (CDCl 3): 6.94 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 3.82 (s, H2N), 3.45 (s, 2H), 2.48 (m, 8H), 2.30 (s, H3C).

The compounds of Examples 10 to 13 can be prepared in a manner analogous to the methods described herein: Example 10: N-r4- (6-Chloro-pyrimidin-4-Moxy) -fenM1-N '- (3-diethyl-amine-methyl-5-trifluoro-methyl-phenyl) - urea. 171 milligrams (0.69 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 2 milliliters of tetrahydrofuran and 170 milligrams (0.69 millimoles of 3-diethyl-amino-methyl) -5- trifluoromethyl-aniline (Step 10.3) in 6 milliliters of ether, converted in a manner analogous to Example 5, into the title compound. MS: [M + 1] + = 493.9.

The starting material is prepared as follows: Step 10.1: (3-Nitro-5-trifluoromethyl-phenyl) - (diethylamino) -methanone. In a manner analogous to Step 5.1, 2.40 grams (10.0 mmol) of 3-nitro-5-trifluoromethyl-benzoic acid are activated with 1.7 milliliters (20.0 mmol) of oxalyl chloride, and are reacted with 7.3 grams ( 100 millimoles) of diethylamine, yielding the title compound as an oil; MS: [M-1] = 290; 1 H-NMR (DMSO-d 6): 8.79 (s, 1 H), 8.41 (s, 1 H), 8.21 (s, 1 H), 3.50 (q, 2 H), 3.21 (q, 2 H), 1.19 (t, 3 H) , 1.01 (t, 3H).

Step 10.2: (3-Amino-5-trifluoromethyl-phenyl) - (4-methyl-piperazin-1-yl) -methanone. The hydrogenation of 2.8 grams (9.6 millimoles) of (3-nitro-5-trifluoromethyl-phenyl) - (diethylamino) -methanone in 50 milliliters of ethanol in the presence of 140 milligrams of Pd-C, described in Step 1.5, give the title compound as a yellow solid; MS: [M + 1] + = 261; 1 H-NMR (DMSO-d 6): 6.89 (s, 1 H), 6.78 (s, 1 H), 6.60 (s, 1 H), 5.79 (s, 2 H, NH 2), 3.50 - 3.39 (m, 2 H), 3.25 - 3.02 (m, 2H), 1.21-0.99 (m, 6H).

Step 10.3: 3- (Diethylamino-methyl) -5-trifluoromethyl-aniline. In a manner analogous to Step 1.6, 1.04 grams (4.0 mmol) of (3-amlno-5-trifluoro-methyl-phenyl) - (4-methyl-piperazin-1-yl) -methanone in 15 milliliters of tetrahydrofuran are reduced by BH3 * Me2S, to the title compound: MS: [M + 1] + = 247; 1 H-NMR (DMSO-d 6): 6.87 (s, 1 H), 6.84 (s, 1 H), 6.81 (s, 1 H), 5.60 (s, 2 H, NH 2), 2.75 - 2.65 (m, 4 H), 1.28 - 1.08 (m, 6H).

Example 11: N -r4- (6-methy1-am in o-pi rim d1 -in-4-yloxy) -f in MT-N '- (3-diethyl-amino-methyl-5-trifluoromethyl) phenyl) -urea.

Under an N2 atmosphere, 250 milligrams (0.52 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- (3-diethyl-amino-methyl-5-trifluoromethyl) phenyl) -urea in 3 milliliters of a 33 percent solution of MeNH2 in EtOH, are stirred at 5 ° C for 2 hours. After aqueous workup, the crude product is purified by flash chromatography (Si02, gradient of CH 2 Cl 2 / MeOH, from 0 to 40 percent), yielding the title compound: mp: 68-70 ° C; MS: [M + 1] + = 489; 1 H NMR (DMSO-d 6): 9.21 (s, 1 H, NH), 8.83 (s, 1 H, NH), 8.09 (s, 1 H), 7.85 (s, 1 H), 7.45 (d, 2 H), 7.20 (s) s, 1H), 7.05 (d, 2H), 5.71 (s, 1H), 3.56 (s, 2H), 2.74 (s, 3H), 2.50 - 2.32 (m, 4H), 1.01 - 0.95 (m, 6H) . Example 12: N -r4- (6-azido-pi rim id i n-4-yloxl) -f in il1-N '- (3-diethyl-amine-methyl-5-trifluoromethyl-phenyl) - urea.

A mixture of 218 milligrams (0.44 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- (3-diethyl-amino-methyl-5-trifluoromethyl-phen) -urea and 50 milligrams (0.7 mmol) of NaN3 in 6 milliliters of dimethyl formamide, is stirred for 2 hours at 80 ° C. The reaction mixture is then diluted with ethyl acetate and washed with brine. The organic layer is separated, dried, and concentrated, to give the crude product, which is purified by flash chromatography (Si02, gradient of CH2Cl2 / MeOH, from 0 to 40 percent). MS: [M + 1] + = 501.

Example 13: N -T4- (6-am ino-pyrim id in -4-i loxi) -f in M-N'-O diethyl-amine-methyl-5-trifluoromethyl-phenyl) -urea.

A solution of 98 milligrams (0.17 millimoles) of N- [4- (6-azido-pyrimidin-4-yloxy) -phenyl] -N '- (3-diethyl-amino-methyl-5-trifluoromethyl-phenyl) -urea in 10 milliliters of 1,2-dimethoxy-ethane is hydrogenated in the presence of 20 milligrams of 5% Pd / C. The catalyst is filtered, the filtrate is concentrated in vacuo, the residue is purified by preparative thin layer chromatography (SiO 2, CH 2 Cl 2 / MeOH, 9: 1), yielding the title compound; p.f. 63-65 ° C. MS: [M + 1] + = 475.

Example 14: N-r4- (6-chloro-pyrimidin-4-yloxy) -phenyl? -N'-r4- (4-methyl-piperazin-1-ylmethyl-3-trifluoromethyl-phenin- urea.

To a freeze-dried solution of 687 milligrams (2.77 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 3 milliliters of tetrahydrofuran under an N2 atmosphere, a solution of 758 milligrams (2.77 millimoles) of 4- (4-methyl-piperazin-1-methylmethyl) -3-trifluoromethyl-aniline (Step 14.4) in 20 milliliters of ether. After stirring for 3 hours at room temperature, the resulting suspension is filtered, and the residue is washed with ether, yielding the title compound: MS: [M + 1] + = 521; 1 H-NMR (CDCl 3): 8.55 (s, 1 H), 7.67 (d, 8.6 Hz, 1 H), 7.56 (d, 8.6 Hz, 1 H), 7.54 (s, 1 H), 7.41 (d, 9 Hz, 2 H) , 7.21 (s, 1H), 7.15 (s, 1H), 7.08 (d, 9 Hz, 2H), 6.91 (s, 1H), 3.58 (s, 2H), 2.48 (m, 8H), 2.30 (s, H3C).

The starting material is prepared as follows: Step 14.1: N- (4-methyl-3-trif luoro-m ethyl-phenyl) -2,2,2-trifluoroacetamide. To an iced solution of 320 grams (1,827 moles) of benzotrif 5-amino-2-methyl luoride and 1.47 liters (18.27 moles) of pyridine in 4.5 liters of CH2Cl2 under an N2 atmosphere, 284 milliliters are added dropwise ( 2.01 moles) of trifluoroacetic acid anhydride. After 50 minutes, the mixture is diluted with 5 liters of ice cold 2N HCl. The organic phases are separated and washed twice with 2 liters of cold 2N HCl, then with 1 liter of 2N HCl, and finally with 2 liters of brine. The aqueous layers are extracted twice with CH 2 Cl 2, the organic phases are dried (Na 2 SO 4) and partially concentrated. Crystallization by the addition of hexane produces the title compound; p.f .: 72-73 ° C.

Step 14.2: N- (4-bromo-methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide. To a solution of 60.9 grams (224.6 millimoles) of N- (4-methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide in 830 milliliters of normal butyl acetate under an N 2 atmosphere, 44 grams (247 millimoles) of N-bromosuccinimide and 830 milligrams (5 millimoles) of azo-iso-butyronitrile are added. The suspension is heated up to 60 ° C, and then illuminated for 30 minutes with a low-voltage Philips head (500 W; 10500 Im), whereby the temperature rises to 70-75 ° C, and a transparent chestnut solution. A remaining residue is still detectable, and therefore, another 22 grams of N-bromosuccinimide are added in 3 portions. After a total of 6 hours of illumination, the resulting solid is filtered and discarded, and the filtrate is concentrated. The residue is distributed between 2 liters of CH 2 Cl 2 and 1 liter of H 2 O, and the aqueous layer is extracted with 1 liter of CH 2 Cl 2. The organic phases are washed 4 times with 1 liter of H2O, 0.5 liters of brine, dried (Na2SO4), and concentrated. Column chromatography (SiO 2, hexane / CH 2 Cl 2, 2: 1 → 1: 1) and crystallization from C H 2 Cl 2 / hexane yield the title compound; p.f. 119-120 ° C.

Step 14.3: 2, 2, 2-trifluoro-N-r4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phen-p-acetamide. To a frozen solution of 1.9 milliliters (17.1 millimoles) of N-methyl-piperazine in 50 milliliters of acetonitrile under an atmosphere of N2, a solution of 2.00 grams (5.71 millimoles) of N- (4-bromo) is added dropwise. methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide in 50 milliliters of acetonitrile, for 30 minutes. After an additional 20 minutes, the reaction mixture is concentrated in vacuo. The resulting oil is diluted with EtOAc and a saturated solution of NaHCO3 / H2O, 1: 1. The aqueous layer is separated and extracted twice with EtOAc. The organic layers are washed with a saturated solution of NaHCO3 / H20, 1: 1, water and brine, dried (Na2SO4), concentrated, and used directly in Step 14.4; MS: [M + 1] + = 370; HPLC AtRet = 9.5.

Step 14.4: 4- (4-methyl-piperazin-1-Umethyl) -3-trifluoromethyl-aniline. To a solution of 1.102 grams (2.98 mmol) of 2,2,2-trifluoro-N- [4- (4-methyl-piperazin-1-ylmethyl) -3-tri-fluoro-methyl-phenyl] -acetamide in 26 milliliters of boiling methanol, 14 milliliters of a 1 M solution of K2C03 in water are added dropwise. After 1 hour of stirring, the reaction mixture is cooled to room temperature and diluted with EtOAc and water. The aqueous layer is separated and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4), and concentrated to give the title compound, which is used directly in Example 14; MS: [M + 1] + = 274; HPLC? TRet = 5.4. Alternative synthesis for 4- (4-methyl-piperazin-1-methylmethyl) -3-trifluoromethyl-aniline: Step 14.4.1: 4-Nitro-2-trifluoro-methyl-benzoic acid [see: J. Gen. Che. USSR (English translation) 33 (1963), 2957]. Under an N2 atmosphere, a mechanically stirred mixture of 50 grams (263 millimoles) of o-trifluoromethyl-benzoic acid and 307 milliliters of 96% H2SO4, it cools in an ice bath. Then 105 milliliters of 100% HN03 are added dropwise at 5-7 ° C for 75 minutes. The ice bath is removed and stirring is continued for 2 hours at room temperature. The reaction mixture is poured into 1.9 kilograms of ice and stirred for 20 minutes. Filtration of the suspension, washing with 100 milliliters of cold water, and drying (0.2 mbar, 50 ° C) give the crude title compound, which contains 20 percent of a regio-isomer. This material is partially dissolved in 0.4 liter of boiling toluene and filtered. The filtrate is concentrated to half its volume, and then 0.1 liters of hexane are added. After cooling to room temperature, the title compound crystallizes and can be filtered; m.p .: 138-141 ° C; 1 H-NMR (CDCl 3): 8.71 (d, 2.3 Hz, 1 H), 8.56 (dd, 2.3 Hz, 8.2 Hz, 1 H), 8.18 (d, 8.2 Hz, 1 HOUR).

Step 14.4.2: (4-n-tro-2-trif l or oro-m eti-l in f) - (4-m eti I-piperazin-1-yl) -methanone. To an ice-cold solution of 17.99 grams (76.5 millimoles) of 4-nitro-2-trifluoromethyl-benzoic acid, 300 milliliters of CH2Cl2, and 3 milliliters of dimethylformamide under an atmosphere of N2, 12.3 milliliters (145 millimoles) are added dropwise. of oxalyl chloride. After 4.5 hours, the resulting solution is concentrated in vacuo. The residue is dissolved in 300 milliliters of CH 2 Cl 2, and added dropwise to an ice solution of 17.8 milliliters (160 millimoles) of 1-methylpiperazine in 120 milliliters of CH 2 Cl 2. After stirring for 3 hours, the mixture is diluted with 0.5 liters of CH 2 Cl 2, washed with 3 portions of a 10 percent solution of Na 2 CO 3, water and brine. The organic phase is dried (Na2SO4) and concentrated to give the title compound as an oil; MS: [M + 1] + = 318: 1 H-NMR (CDCl 3): 8.62 (d, 2.3 Hz, 1 H), 8.50 (dd, 2.3 Hz, 8.2 Hz, 1 H), 7.60 (d, 8.2 Hz, 1 H) , 3.90 (m, 1H), 3.84 (m, 1H), 3.21 (t, 5.1 Hz, 2H), 2.53 (t, 5.1 Hz, 2H), 2.36 (s, 3H), 2.36 (m, 2H).

Step 14.4.3: (4-am ino-2-trif I uoro-methyl-phenyl) - (4-methyl-p-piperazin-1-yl) -methanone. A solution of 24 grams (76 millimoles) of (4-nitro-2-trifluoromethyl-phenyl) - (4-methyl-piperazin-1-yl) -m-ethanone in 400 milliliters of ethanol is hydrogenated for 14 hours in the presence of 4 grams of Raney nickel. The catalyst is filtered, and the filtrate is concentrated in vacuo. The residue is filtered in 500 milliliters of boiling toluene, the filtrate is partially concentrated until the product begins to crystallize. Cooling to room temperature and filtration provide the title compound; p.f .: 154-156 ° C; MS: [M + 1] + = 288.

Step 14.4.4: 4- (4-methyl-piperazin-1-ylmethyl) -3-trif luoro-methyl-aniline. To 17.2 grams (60 millimoles) of (4-amino-2-trifluoromethyl-phen) - (4-methylpiperazin-1-yl) -methanone in 160 milliliters of tetrahydrofuran under an atmosphere of N2, 180 milliliters are added ( 1 M in tetrahydrofuran, 180 mmol) of BH3 * THF for 75 minutes. The resulting solution is stirred for 18 hours at room temperature, then 180 milliliters of concentrated HCl / H20, 1: 1 is added, with cooling, and the mixture is stirred for 18 hours at room temperature. The reaction mixture is partially concentrated, the residue is extracted with EtOAc, the separated organic phase is washed with 0.1 N HCl, and discarded. Then 0.7 liters of a saturated solution of Na2CO3 is added to the aqueous acidic layers (pH of 9-10), followed by extraction with 3 portions of EtOAc. The organic phases are washed with brine, dried (Na2SO4), and concentrated. Crystallization from boiling toluene gives the title compound; p.f .: 119-121 ° C.

Example 15: N -r4- (6-chloro-pyrim id in-4-i loxi) -f in ill-N '-T4- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoro-methyl-phenin - urea, To a cooled solution of 1.251 grams (5.05 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 4 milliliters of tetrahydrofuran under an N2 atmosphere, a solution is added dropwise. of 1.522 grams (5.05 millimoles of 4- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoro-methyl-aniline (Step 15.2) in 25 milliliters of ether After stirring for 2.5 hours, the mixture of The reaction is diluted with ether, the solid is filtered and washed with ether, the crude product is redissolved in CH2Cl2 / MeOH, absorbed on S02, which is then placed on top of an SiO2 chromatography column. with CH2Cl2 / MeOH / NH3aq, 95: 5: 1, produces the title compound; Analysis C26H28N6CLF302 • 0.5H2O: C, H, N, F; MS: [M + 1] + = 549; 1H-NMR (CDCl3) : 8.56 (s, 1H), 7.68 (d, 8 Hz, 1H), 7.57 (d, 8 Hz, 1H), 7.56 (s, 1H), 7.43 (d, 9 Hz, 2H), 7.11 (s, 1H) ), 7.10 (d, 9 Hz, 2H), 7.05 (s, 1H), 6.92 (s, 1H), 3.58 (s, 2H), 2.67 (Sept., 6.3 Hz, 1H), 2.56 (m, 4H) , 2.5 1 (m, 4H), 1.08 (d, 6.3 Hz, 6H).

The starting material is prepared as follows: Step 15.1: 2,2,2-Trifluoro-N- [4- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoromethyl-pheyp-acetamide. To an ice cold solution of 3.46 grams (27 millimoles) of N-isopropyl-piperazine in 70 milliliters of acetonitrile under an atmosphere of N2, a solution of 3.15 grams (9.0 mmol) of N- (4-bromo-methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) in 70 milliliters is added dropwise. of acetonitrile for 35 minutes. After an additional 5 minutes, a work procedure as described in Step 14.3 gives the title compound as an oil; MS: [M + 1] + = 398; HPLC AtRet = 10.1.

Step 15.2: 4- (4-isopropyl-piperazin-1-ylmethyl) -3-tri-fluoro-methyl-aniline. To a solution of 3.58 grams (9.0 millimoles) of 2,2,2-trifluoro-N- [4- (4-lsopropyl-piperazin-1-ylmethyl) -3-tri-fluoro-methyl-phenyl] -acetamide in 90 milliliters of boiling methanol, 45 milliliters of a 1 M solution of K2C03 in water are added dropwise. After 110 minutes of stirring, the reaction mixture is cooled to room temperature and partially concentrated in vacuo. The residue is diluted with EtOAc and water, the aqueous layer is separated and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4), and partially concentrated. After dilution with hexane, the title compound is crystallized, and can be isolated by filtration; p.f .: 117-119 ° C; MS: [M + 1] + = 302.

Example 16: N-R4- (6-Methyl-amino-pyrimidin-4-yloxy) -phenn-N'-r4- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoro-methyl trifluoroacetate fenip-urea Under an N2 atmosphere, 450 milligrams (0.82 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- [4- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea in 4 milliliters of a 33 percent solution of MeNH2 in EtOH, are stirred in an ice bath for 3 hours. The mixture is poured into EtOAc and a 10 percent solution of NaHCO 3, the aqueous phase is separated and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na SO4), and concentrated. Reverse phase chromatography gives the title compound; MS: [M + 1] + = 544; 1 H-NMR (DMSO-d 6): 9.16 (s, HN), 9.04 (m, HN +), 8.93 (s, HN), 8.12 (m, 1H), 7.95 (s, 1H), 7.62 (2s, 2H ), 7.48 (d, 9 Hz, 2H), 7.33 (m, HNMe), 7.05 (d, 9 Hz, 2H), 5.73 (s, 1H), 3.65 (s, 2H), 3.47 (m, 1H), 3.39 (m, 2H), 3.00 (m, 2H), 2.95 (m, 2H), 2.76 (m, H3C), 2.39 (m, 2H), 1.26 (d, 7 Hz, 6H).

Example 17: N-R4- (6-Methyl-amino'-pyrimidin-4-yloxy) -phenyl] -N'-r4- (4-isopropyl-4-oxy-piperazin-1-ylmethyl-3-trifluoroacetate -trifluoro-methyl-fenip-urea.

The title compound can be isolated as the slower-moving by-product during reverse phase chromatography of the reaction mixture of Example 16; MS: [M + 1] + = 560; 1 H-NMR (DMSO-d 6): 11.48 (s, HN), 9.14 (s, HN), 8.92 (s, HN), 8.11 (m, 1H), 7.95 (s, 1H), 7.63 (m, 2H) , 7.47 (d, 8 Hz, 2H), 7.30 (m, HNMe), 7.05 (d, 8 Hz, 2H), 5.73 (s, 1H), 3.95 (sept., 7 Hz, 1H), 3.69 (s, 2H), 3.60 (m, 4H), 2.87 (m, 2H), 2.76 (m, H3C), 2.7 (m, 2H), 1.35 (d, 7 Hz, 6H).

Example 18: N -r4- (6-azido-pi rim id in-4-yloxy) -f in ill-N '- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenol p-urea. The title compound is prepared from 647 milligrams (1.18 millimoles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- [4- (4-isopropyl-piperazine-1 -ylmethyl) -3-tri-fluoro-methyl-phenyl] -urea as described in Example 7; MS: [M + 1] + = 556; HPLC AtRet = 11.4.

Example 19: N -T4- (6-am ino-pi rim id in -4-i loxi) -f in ill-N'- - (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoro-methyl- feniH-urea The hydrogenation of 0.66 grams (1.18 millimoles) of N- [4- (6-azido-pyrimidin-4-yloxy) -phenyl] -N '- [4- (4-isopropyl-piperazin-1-methylmethyl) -3- trifluoromethyl-phenol] -urea, in 25 milliliters of tetrahydrofuran, in the presence of 0.12 grams of 10% Pd / C ("Engelhard 4505"), filtration, concentration of the filtrate, and chromatography [MPLC: CH2Cl2 / MeOH (+1 percent aqueous NH3), 199: 1 - > 93: 7 - > 82:18], give the title compound. Analysis C26H30N7F3O2 • 0.8 H2O: C.H.N.F; MS: [M + 1] + = 530; 1 H-NMR (CDCl 3): 8.25 (s, 1H), 7.86 (s, 1H), 7.65 (d, 8.2 Hz, 1H), 7.56 (m, 3H), 7.25 (d, 8 Hz, 2H), 6.97 ( d, 8 Hz, 2H), 5.64 (s, 1H), 5.26 (s, H2N), 3.57 (s, 2H), 2.64 (sept., 6.7 Hz, 1H), 2.53 (m, 4H), 2.49 (m , 4H), 1.06 (d, 6.7 Hz, 6H).

The compounds of Examples 19-1 and 19-1 can be prepared in a manner analogous to the methods described herein: Example 19-1: N -f4- (6-am ino-pi rim id in-4-i loxi) -f in ill-N '-T4- (4-H-piperazin-1-ylmethyl) -5-trifluoro -m eti l-fen Mi-urea.

Hydrogenation of 0.33 grams (0.68 mMoles) of N- [4- (6-azido-pyrimidin-4-yloxy) -phenyl] -N '- [4- (4-benzoyloxycarbonyl-piperazin-1- ümethyl) -3-trifluoro-methyl-phenyl] -urea in 10 milliliters of 1,2-dimethoxyethane in the presence of 0.05 grams of 10 percent Pd / C ("Engelhard 4505"), filtration, filtrate concentration , and chromatography [C18: CH3CN / H20 (+ 0.1 percent trifluoroacetic acid)], give the title compound; p.f .: 153-155 ° C. MS: [M + 1] + = 488; 1 H-NMR (DMSO-d 6): 9.39 (s, 1 H), 9.17 (s, 1 H), 8.59 (s, 2 H, NH), 8.18 (s, 1 H), 7.98 (s, 1 H), 7.59 (s, 1H), 7.42 (d, 2H), 7.01 (d, 2H); 5.62 (s, 2H), 3.17 - 3.08 (m, 4H), 2.62-2.52 (m, 4H).

The starting material is prepared as follows: Step 19.1.1: 2.2.2-trif I uoro-N-4 (4-benzo-loxi-carbon and I-piperazin-1-ylmethyl) -3-trifluoro-methyl-phenyl-1-acetamide. To a solution of 1.57 grams (7.1 mmol) of N-benzyl-1-piperazine carboxylate in 10 milliliters of EtOH under an atmosphere of N2, a solution of 1.0 grams (2.8 mmol) of N- (4) is added dropwise. -bromo-methyl-3-trifluoromethyl-phenyl) -2,2,2-fluoro-acetamide (Step 14.2) in 5 milliliters of EtOH for 35 minutes. After an additional 30 minutes of stirring and working procedure as described in Step 14.3, the title compound is obtained as an oil: MS: [M + 1] + = 491; 1 H-NMR (CDCl 3): 8.15 (s, 1 H, NH), 7.81 - 6.99 (m, 3 H), 7.39 - 7.28 (m, 5 H), 5.15 (s, 2 H), 3.59 (s, 2 H), 3.52 - 3.43 (m, 4H), 2.44-2.39 (m, 4H).

Step 19.1.2: 4- (4-benzoyloxy-carbonyl-pi-ezin-1-ylmethyl) -3-trifluoromethyl-aniline. To a solution of 1.31 grams (2.67 millimoles) of 2,2,2-trifluoro-N- [4- (4-benzyloxy-carbonyl-piperazin-1-yl-methyl) -3-trifluoromethyl-phenyl] -acetamide in 20 milliliters of boiling methanol, 13 milliliters of a 1 M solution of K2C03 in water are added dropwise. After 1 hour of stirring, the reaction mixture is cooled to room temperature and diluted with EtOAc and water. The aqueous layer is separated and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to yield the title compound, which is used directly in Step 19.1.3: [M + 1] + = 394; 1 H-NMR (DMSO-d 6): 7.39 - 7.21 (m, 6H), 6.82 (s, 1H), 6.75 (d, 1H), 5.41 (s, 2H), 5.01 (s, 2H), 3.40 - 3.29 ( m, 6H), 2.31 -2.24 (m, 4H).

Step 19.1.3: N-r4- (6-Chloro-pyrimidin-4-yloxy) -phenyl-1-N'-r4- (4-benzoyloxy-carbonyl-piperazin-1-ylmethyl) -3-trifluoro-methyl -phenill-urea. To a freezing solution of 0.38 grams (1.52 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 5 milliliters of tetrahydrofuran under an N2 atmosphere, a solution is added dropwise. of 0.60 grams (1.52 millimoles) of 4- (4-benzoyloxy-carbonyl-piperazin-1-ylmethyl) -3-trifluoromethyl-aniline (Step 15.2) in 15 milliliters of ether. After stirring for 1.5 hours, the reaction mixture is diluted with ether, the solid is filtered and washed with ether. The crude product is redissolved in CH2Cl2 / MeOH, absorbed on Si02, which is then placed on top of an Si02 chromatography column. Elution with CH2Cl2 / MeOH, in a gradient of 0 to 3 percent MeOH, yields the title compound: MS: [M + 1] + = 642.7; 1 H-NMR (CDCl 3): 8.59 (s, 1 H), 7.62 (d, 1 H), 7.59 - 7.51 (m, 2 H), 7.41 (d, 2 H), 7.35 - 7.30 (m, 3 H), 7.18 (s, 1H), 7.15 (d, 2H), 7.05 (s, 1H), 6.90 (s, 1H), 5.19 (s, 2H), 3.62 (s, 2H), 3.59 - 3.40 (m, 4H), 2.51 - 2.38 (m, 4H).

Step 19.1.4: N-r4- (6-azido-pyrim idin-4-yloxy) -fenin-N'-r4- (4-benzoyloxycarbonyl-piperazin-1-ylmethyl) -3-trifluoro-methyl- phenyl-urea. The title compound is prepared from 300 milligrams (0.46 millimoles) of N- [4- (6-chloro-pyrimidin-4-yl-oxy) -phenyl] -N '- [4- (4-benzyloxycarbonyl -piperazin-1-ylmethyl) -3-trifluoro-methyl-phenyl] -urea, as described in Example 7: MS: [M + 1] + = 648; 1 H-NMR (CDCl 3): 8.58 (s, 1 H), 8.01 (s, 1 H), 7.69 - 7.59 (m, 3 H), 7.41 (d, 1 H), 7.39 - 7.35 (m, 5 H), 7.20 (s, 1H), 7.09 (d, 2H), 6.25 (s, 1H), 5.17 (s, 2H), 3.61 (s, 2H), 3.59-3.42 (m, 4H), 2.43-2.38 (m, 4H).

Example 19.2: N -r4- (6-m eti l-am i no-pirim id i n-4-i loxl) -f in iH-N'-r4- (4-H-pi erazin-1-ylmethyl) -5-trifluoro-methyl-phen-p-urea, The hydrogenation of 88.0 milligrams (0.14 millimoles) of N- [4- (6-methyl-ami no-pyrim idin-4-i loxi) -phenyl] -N '- [4- (4-benzoyloxy-carbonyl-piperazine- 1-ylmethyl) -3-trifluoromethyl-phenyl] -urea in 5 milliliters of MeOH in the presence of 15 milligrams of 10 percent Pd / C ("Engelhard 4505"), filtration, filtrate concentration, and Chromatography [C18: CH3CN / H20 (+ 0.1 percent trifluoroacetic acid) gives the title compound: mp: 197-198 ° C; MS: [M + 1] + = 502; 1 H-NMR (DMSO-d 6): 8.80 (s, 1 H, NH), 8.52 (s, 1 H, NH), 8.06 (s, 1 H), 7.89 (s, 1 H), 7.63 (d, 1 H), 7.58 ( d, 1 H), 7.49 (d, 2 H), 7.05 (d, 2 H), 5.79 (s, 1 H), 3.18 - 3.09 (m, 4 H), 2.80 (s, 3 H), 2.69 - 2.59 (m, 4 H) .

The starting material is prepared as follows: Step 19.2.1: N-r4- (6-Methyl-amino-pyrimidin-4-yloxy) -phenyl N 'f4- (4-benzoyloxy-carbonyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl- urea. Under an N2 atmosphere, 122 milligrams (0.19 milli-moles) of N- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -N '- [4- (4-benzoyloxy-carbonyl-piperaz n-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea (Example 20.1) in 4 milliliters of a 33 percent solution of MeNH2 in EtOH, is stirred in an ice bath for 2 hours. The mixture is poured into EtOAc and a 10 percent solution of NaHCO3, the aqueous phase is separated and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4), and concentrated. Flash chromatography (SiO2, CH2Cl2 / MeOH, gradient from 0 to 5 percent MeOH) gives the title compound: MS: [M + 1] + = 636; 1 H-NMR (CDCl 3): 8.21 (s, 1H), 7.61-7.44 (m, 3H), 7.39-7.31 (m, 5H), 7.17-6.99 (m, 3H), 6.51 (d, 1H), 5.75 ( s, 1 H), 5.12 (s, 2 H), 3.59 (s, 3 H), 3.48 - 3.41 (m, 4 H), 2.91 (s, 2 H), 2.41 - 2.35 (m, 4 H).

Example 20: N-r4- (6-chloro-pyrim id in -4-i loxi) -f in 11-N'-T4- (4-tert-butyl-piperazin-1-ylmethyl) -3-trifluoro -methyl-phenyl-urea.

It is prepared in analogy with Example 14. The crude product is purified by flash chromatography (SiO2, CH2Cl2 / MeOH, gradient of 0 to 10 percent MeOH), to give the title compound 10 as a yellow foam. C27H3oCLF3 6? 2; MS (ES +), M + H = 563.6; 1 H-NMR (300 MHz, CDCl 3): 8.59 (s, 1 H), 7.62 (d, 1 H), 7.60 - 7.56 (m, 2 H), 7.42 (d, 2 H), 7.18 - 7.11 (m, 3 H). 7.02 (s, 1H), 3.79 (s, 2H), 2.78 - 2.54 (m, 4H), 2.51 - 2.40 (m, 4H), 1.04 (s, 9H). The starting material is prepared as follows: Step 20.1: Bis- (2-chloroethyl) -carbamic acid ethyl ester. The title compound is prepared from bis- (2-chloro-ethyl) -amine according to the procedure of the literature [J. Pharmaceutical Sci. 61 (1972), 1316].

C7H13Cl2NO2; MS (ES +), M + H = 216.4; 1 H-NMR (300 MHz, CDCI3): 4.19 (q, 2H), 3.75 - 3.58 (m, 8H), 1.14 (t, 3H).

Step 20.2: Ethyl ester of 4-tert-butyl-piperazine-1-carboxylic acid. The compound of Step 20.1 (10 grams, 46 mmol) is dissolved in terbutanol and subsequently Nal (280 milligrams, 1.8 mmol), and terbuthylamine (5.12 grams, 70 mmol) is added at room temperature. Then the yellow reaction mixture is heated to 130 ° C in an oil bath, and stirred for 13 hours. Allow to cool to room temperature again, and add K2C03 (6.9 grams, 50 mmol). Then the reaction is exposed to microwave irradiation (130 ° C / 6 minutes). The product is collected by filtration, recovered in EtOAc, and purified by acid / base washing, to give the title compound as a yellow oil. (2.54 grams, 32 millimoles, 26 percent). C11H22N202; MS (ES +), M + H = 215.5; 1 H-NMR (300 MHz, CDCl 3): 4.15 (q, 2 H), 3.51 - 3.40 (m, 4 H), 2.58 - 2.41 (m, 4 H), 1.12 (t, 3 H), 1.02 (s, 9 H).

Step 20.3: 1-tert-butyl-piperazine. The compound from Step 20.2 (1 gram, 4.6 mmol) is dissolved in ethanol (15 milliliters). KOH (1.2 grams, 201 mmol) is added, and the reaction is refluxed for 12 hours. Allow to cool to room temperature, and concentrate under reduced pressure. The residue is taken up in EtOAc and washed with brine. The organic layers are dried over Na 2 SO 4, concentrated, and dried under a high vacuum, to give the title compound as a yellow oil. (546 milligrams, 3.7 millimoles, 82 percent). C8H18N2; MS (ES +), M + H = 143.5; 1 H-NMR (300 MHz, CDCl 3): 2.91-2.84 (m, 4 H), 2.59-2.48 (m, 4 H), 1.02 (s, 9 H).

Step 20.4: N-4 - (4-tert-butyl-piperazin-1-ylmethyl) -3-tri-fluoro-methyl-phenyl-2,2,2-trifluoro-acetamide. The compound from Step 20.3 (540 milligrams, 3.8 mmol) is dissolved in EtOH (3 milliliters) and 532 milligrams (1.5 millimoles) of N- (4-bromo-methyl-3-trifluoromethyl-phenyl) -2 are added, 2,2-trifluoroacetamide (Step 14.2) at room temperature. The reaction is stirred at room temperature for 1.5 hours until complete. Concentrate, and the residual crude product is purified by flash chromatography (Si02; CH2Cl2 / MeOH, gradient from 0 to 8 percent MeOH), to give the title compound as a yellow oil (654 milligrams, 1.5 mmol, 42 percent). C18H23F6N30; MS (ES +), M + H = 412.0.

Step 20.5: 4- (4-tert-butyl-piperazin-1-ylmethyl) -3-tri-fluro-methyl-f-enyl-amine. The compound from Step 20.4 (650 milligrams, 1.5 mmol) is dissolved in MeOH (15 milliliters), and treated with K2CO3 (7.9 milliliters of a 1N aqueous solution) at room temperature. The reaction is refluxed for 1 hour until complete, cooled back to room temperature, and concentrated. The residual oil is recovered in EtOAc and washed with brine. The organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. Drying under a high vacuum gives the title compound as a yellow oil (496 milligrams, 1.5 millimoles). C16H24F3N3; MS (ES +), M + H = 316.1; 1 H-NMR (300 MHz, CDCl 3): 7.44 (d, 1 H), 6.91 (d, 1 H), 6.79 (d, d, 1 H), 3.79 (bs, 2 H), 3.51 (s, 2 H), 2.67 - 2.59 (m, 4H), 2.58-2.40 (m, 4H), 1.01 (s, 9H).

The compounds of Examples 20-1 to 20-8 can be prepared in a manner analogous to the methods described herein: Example 20-1: N-r4- (6-chloro-pyrimidin-4-yloxy) -phen Ml-N'-H- (4-benzoyloxy-carbonyl-piperazin-1-ylmethyl) -3-trifluoro -methyl-feni ll-u rea.

Prepared in analogy to Example 14, from 600 milligrams (1.5 millimoles) of 4- (4-amino-2-trifluoromethyl-benzyl) -piperazine-1-carboxylic acid benzyl ester. The crude product is purified by flash chromatography (SiO 2, CH 2 Cl 2 / MeOH, gradient from 0 to 10 percent MeOH), MS (ES +), M + H = 643, 1 H-NMR (300 MHz , CDCI3): 8.57 (s, 1H), 7.64 (d, 1H, J = 8.2 Hz), 7.59 - 7.55 (m, 2H), 7.43 (d, J = 8.7 Hz), 7.36 - 7.32 (m, 3H) , 7.17 (s, 1H), 7.08 (d, J = 8.7 Hz), 7.04 (s, 1H), 6.91 (s, 1H), 5.17 (s, 2H), 3.60 (s, 2H), 3.57 - 3.45 ( m, 4H), 2.49-2.33 (m, 4H).

The starting material is prepared as follows: Step 20-1.1: Benzyl ester of 4-r4- (2.2.2-trifluoro-acetylamino) -2-trifluoro-meth i-benzyl-piperazine-1-carboxylic acid. A solution of 1.0 grams (2.8 millimoles) of N- (4-bromo-methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) in 15 milliliters of EtOH is treat with 1.57 grams (7.1 mmol) of benzyl-1-piperazine-carboxylate at room temperature. The reaction is stirred for 1 hour at room temperature. After completion, it is concentrated and the residual crude product is purified by flash chromatography (SiO2, CH 2 Cl 2 / MeOH, gradient from 0 to 10 percent MeOH), to give the title compound as a yellow solid. MS (ES +), M + H = 491; 1 H NMR (300 MHz, CDCl 3): 8.19 (s, 1 H, NH), 7.92 - 7.89 (m, 3 H), 7.40 - 7.38 (m, 5 H), 5.18 (s, 2 H), 3.60 (s, 2 H) , 3.58 - 3.52 (m, 4H), 2.49 - 2.38 (m, 4H).

Step 20-1.2: 4- (4-Amino-2-trifluoro-methyl-benzyl) -pi-erazin-1-carboxylic acid benzyl ester. A solution of 1.3 grams (2.6 millimoles) of 4- [4- (2,2,2-trifluoro-acetyl-amino) -2-trifluoro-methyl-benzyl] -piperazine-1-carboxylic acid benzyl ester in 20 milliliters of MeOH, treated with 13.4 milliliters of a 1 M aqueous solution of K2CO3 at room temperature. The reaction is then heated to reflux and stirred for 2 hours. After completion, the MeOH is distilled off, and the residual aqueous suspension is extracted with EtOAc (3 times). The combined organic extracts are dried over Na2SO4, and after filtration and concentration in vacuo, the title compound is obtained as a yellow solid. MS (ES +), M + H = 394; 1 H-NMR (300 MHz, DMSO-d 6): 7.39-2.29 (m, 6H), 6.82 (s, 1H), 6.74 (d, 1H); 5.41 (s, 2H; NH2), 5.02 (s, 2H), 3.42 (s, 2H), 3.40-3.31 (m, 4H), 2.31-2.24 (m, 4H).

Example 20-2: N-r4- (6-Chloro-pyrimidin-4-yloxy) -phenn-N'-r4 (N, N-dimethylammonium) -3-trifluoro-methyl-phen Mi-urea.

It is prepared in analogy to Example 14, starting from 110 milligrams (0.5 millimoles) of 4- (4- (N, N-dimethylamino-methyl) -3-trifluoro-methyl-phenyl-amine and 125 milligrams (0.5 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) The crude product is purified by flash chromatography (Si02, CH 2 Cl 2 / MeOH, gradient from 0 to 10 percent MeOH), to give the title compound as a yellow foam. P.f .: 98-105 ° C. MS (ES +), M + H = 466. 1 H-NMR (300 MHz, DMSO-de): 9.02 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H), 7.97 (s, 1H ), 7.59-7.54 (m, 2H), 7.49 (d, 2H), 7.38 (s, 1H), 7.12 (d, 2H), 3.41 (s, 2H). 2.19 (s, 6H).

The starting material is prepared as follows: Step 20-2.1: 4- (4- (N, N-dimethyl-am i non-methyl) -3-trif luoro-methyl-phenyl-2,2,2-trifluoro-acetamide 501 milligrams (1.5 mmol) are added ) of N- (4-bromo-methyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) to 5 milliliters of a solution of dimethylamine in EtOH (33 percent) At room temperature, the reaction is stirred at room temperature for 0.5 hour until complete, concentrated, and the residual crude product is purified by flash chromatography (S02; CH2Cl2 / MeOH, gradient from 0 to 5 percent of MeOH), to give the title compound as a yellow oil, MS (ES +), M + H = 315.

Step 20-2.2: 4- (4- (N, N-dimethyl-am i non-methyl) -3-trifluoromethyl-phenyl-amine The compound of Step 20-1.1 (359 milligrams, 1.2 mmol) is dissolved in MeOH (12 milliliters), and treated with K2CO3 (6 milliliters of a 1N aqueous solution) at room temperature, the reaction is heated to reflux for 1.5 hours until complete, cooled back to room temperature, and concentrated. The residual oil is taken up in EtOAc and washed with brine, the organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure.Drying under a high vacuum gives the title compound as a yellow oil.M + H = 219 .

Example 20-3: -r4- (6-chloro-pyrim id in -4-i loxi) -f in i I1-N '-T4 (N, N-dietM-amino-methyl) -3-trifluoro-methyl -fenp-urea.

Cl H is prepared in analogy to Example 14, starting from 370 milligrams (1.5 millimoles) of 4- (4- (N, N-diethyl-amino-methyl) -3-trifluoromethyl-phenyl-amine and 371 milligrams (1.5 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) The crude product is purified by flash chromatography (Si02, CH2C.I2 / MeOH, gradient from 0 to 10 percent MeOH), to give the title compound: MS (ES +), M + H = 494.

Example 20-4: N -r4- (6-chloro-rim id in -4-yloxy) -f in i II -N'-T4-r (3-dimethyl-amino-yl) -methyl-amino -metl) 1-3-trifluoro-methyl-f in M1-u rea.

It is prepared in analogy to Example 14, starting from 600 milligrams (2.2 millimoles) of 4- [(3-dim eti I-amino-propyI) -methyl-amino-methyl)] - 3-trifluoromethyl-phenyl-amine and 539 milligrams (2.2 mmol) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3), to give the title compound: MS (ES +), M + H = 523.

Example 20-5: N -r4- (6-chloro-pi rim id in -4-i loxi) -f in i I1-N '-f4-r (4-cyan o-be n cil) -am in om etin-3-trifluoro-methyl-phenyl-u-rea, prepared in analogy to Example 14, starting from 440 milligrams (1.4 mmol) of 4 - [(4-cyano-benzyl) -amino-methyl)] - 3-trifluoro-methyl-phenyl-amine and 375 milligrams (1.4 mmol) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3), to give the title compound: MS (ES +) , M + H = 553.

Example 20-6: N -r4- (6-chloro-pi rim id i n -4-i loxi) -f in ill-N '-T4 (1-morpholinyl) -3-trifluoromethyl-phenyl-urea.

It is prepared in analogy to Example 14, starting from 260 milligrams (1.0 millimoles) of 4- (morpholin-4-methylmethyl) -3-trifluoro-methyl-phenyl-amine and 248 milligrams (1.0 millimoles) of 4-Chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3), to give the title compound: MS (ES +), M + H = 508. 1 H-NMR (300 MHz, DMSO-d 6) : 8.82 (s, 1H, NH), 8.79 (s, 1H, N?), 8.69 (s, 1H), 7.91 (s, 1H), 7.75 - 7.65 (2xd, 2H), 7.50 (d, 2H), 7.15 (d, 2H), 7.12 (s, 1H), 3.74 (s, 2H), 3.71 3.61 (m, 4H), 2.62-2.52 (m, 4H).

Example 20-7: N-r4- (6-Chloro-pyrimidin-4-Moxy) -fenM1-N'-r4- (pyrrolidin-1-yl-amino-methyl) -3-trifluoro-methyl-phenyl p-urea.

Prepared in analogy to Example 14. MS (ES +), M + H = 493. 1 H-NMR (300 MHz, CDCl 3): 8.59 (s, 1 H), 7.71 (d, 2 H), 7.51 - 7.39 (m, 3H), 7.17 (s, 1H), 7.02 (d, 2H), 6.93 (s, 1H), 3.79 (s, 2H), 2.62-2.58 (m, 4H), 2.93-2.72 (m, 4H).

Example 20-8: N -r4- (6-chloro-pi rim id in-4-yloxy) -f in M1-N '-f4- (4- (4-methoxy-benzyl) -piperazin-1-ylmethyl) -3-trifluoro-methyl-f in Mu rea.

It is prepared in analogy to Example 14, starting from 878 milligrams (2.3 millimoles) of 4- [4- (4-methoxy-benzyl) -piperazinyl] -3-3-trifluoromethyl-phenyl-amine and 573 milligrams of (2.3 mmol) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3), to give the title compound: MS (ES +), M + H = 628. 1 H-NMR (300 MHz, CDCl 3): 8.59 (s, 1H), 7.75 (d, 1H), 7.41 (d, 2H), 7.20 (d, 2H), 7.17 (d, 2H), 6.98 (s, 1 H), 6.83 (d, d, 3H), 6.79 (s, 1H), 3.80 (s, 3H), 3.59 (s, 2H), 3.42 (s, 2H), 2.58-2.37 (m, 8H).

Example 21: N -r4- (6-chloro-pyrim id in-4-loxi) -f in M1-N '-T4- (methyl-tert-butyl-amino-methyl) -3-trifluoro-methyl-phen P-urea In a manner analogous to Example 14, 1.0 grams (4.0 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 3 milliliters of tetrahydrofuran, and a solution of 1.1 grams (4.2 millimoles) ) of 4- (methyl-tert-butyl-amino-methyl) -3-trifluoromethyl-aniline (Step 21.2) in 30 milliliters of ether, are reacted to obtain the title compound: Analysis C24H25N5CLF3O2: C, H, N, CI, F; MS: [M + 1] + = 508; 1 H-NMR (CDCl 3): 8.61 (s, 1 H), 7.94 (d, 8.2 Hz, 1 H), 7.63 (d, 2 Hz, 1 H), 7.54 (dd, 8 Hz, 2 Hz, 1 H), 7.47 (d , 9 Hz, 2H), 7.14 (d, 9 Hz, 2H), 6.95 (s, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 3.69 (s, 2H), 2.13 (s. ), 1.17 (s, terbutyl).

The starting material is prepared as follows: Step 21.1: 2.2, 2-trifluoro-N-r4- (m ethyl-tert-butyl-am-ino-methyl) -3-trifluoromethyl-pheyp-acetamide. To a freeze-dried solution of 2.05 milliliters (17 millimoles) of methyl-terbutyl-amine in 80 milliliters of acetonitrile under an N 2 atmosphere, a solution of 2.0 grams (5.7 millimoles) of N- (4-bromo-methyl) is added dropwise. -3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide (Step 14. 2) in 80 milliliters of acetonitrile, for 30 minutes.

After an additional 30 minutes, a working procedure as described in Step 14.3, gives the title compound as an oil: MS: [M + 1] + = 357; HPLC AtRet = . 0 Step 21.2: 4- (methyl-tert-butyl-amino-methyl-3-trifluoromethyl-aniline) The saponification of 2.55 grams (7.2 mmol) of 2,2,2-trifluoro-N- [4- (methyl- terbutil-amino-methyl) -3-tri-fluoro-methyl-phenol] -acetamide, as described in Step 15.2, gives the title compound as an oil: MS: [M + 1] + = 261; HPLC AtRet = 8.3.

Example 22: N-T4-α6-chloro-pyrimidin-4-yloxy) -fenin-N'-r4- (azetidin-1-methyl) -3-trifluoromethyl-pheep-urea.

In a manner analogous to Example 14, 431 milligrams (1.7 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 2 milliliters of tetrahydrofuran, and a solution of 400 milligrams (1.7 millimoles) ) of 4- (azetidin-1-ylmethyl) -3-trifluoro-methyl-aniline (Step 22.2) in 10 milliliters of ether, are reacted to obtain the title compound: MS: [M + 1] + = 478; HPLC AtRet = 11.3.

The starting material is prepared as follows: Step 22.1: 2.2.2-trifluoro-N-r4- (azetidin-1-Umethyl) -3-trifluoromethyl-phenyl-acetamide. To a freezing solution of 1.74 milliliters (25.7 millimoles) of azetidine in 100 milliliters of acetonitrile under an atmosphere of N2, a solution of 3.0 grams (8.5 millimoles) of N- (4-bromo-metll-3-) is added dropwise. trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) in 100 milliliters of acetonitrile, for 65 minutes. After an additional 75 minutes, a working procedure as described in Step 14.3 gives the title compound as an oil: MS: [M + 1] + = 327; HPLC AtRet = 9.1.

Step 22.2: 4- (Azetidin-1-ylmethyl) -3-trifluoromethyl-aniline. The saponification of 2.67 grams (8.2 millimoles) of 2,2,2-trifluoro-N- [4- (azetidin-1-ylmethyl) -3-trifluoromethyl-phenyl] -acetamide, as described in Step 15.2, gives the title compound as an oil: MS: [M + 1] + = 231; 1 H-NMR (CDCl 3): 7.37 (d, 8.2 Hz, 1 H), 6.90 (d, 2 Hz, 1 H), 6.79 (dd, 8 Hz, 2 Hz, 1 H), 3.75 (s, H 2 N), 3.64 (s) , 2H), 3.25 (t, 6.8 Hz, 4H), 2.10 (quint., 6.8 Hz, 2H).

Example 23: N -r4- (6-chloro-pyrim id in -4-i loxi) -f in M1-N '-T4- (4,5-dimethyl-imidazol-1-ylmethyl) -3-trifluoro-methyl l-phenin-urea. 238 milligrams (0.96 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 246 milligrams (0.91 millimoles) of 4- (4,5-dimethyl-imidazol-1-ylmethyl) ) -3-trifluoro-methyl-aniline (Step 23.2), are dissolved in 5 milliliters of tetrahydrofuran under an atmosphere of N2.

After 15 minutes, 10 milliliters of di-isopropyl ether (formed by precipitation) are added, and stirring is continued for 2 hours. Filtration and washing with di-iso-propyl ether give the title compound: m.p .: 195-196 ° C; Analysis C24H2oN6CIF3? 2 • 0.4 d i-iso-propi I-ether • 0.1 tetrahydrofuran: C, H, N.CI, F; MS: [M + 1] + = 517; 1 H-NMR (CDCl 3): 9.23 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.46 (d, 2 Hz, 1H), 7.55 (d, 9.0 Hz, 2H), 7.45 ( s, 1H), 7.03 (d, 9 Hz, 2H), 6.83 (s, 1H), 6.34 (dd, 8.6 Hz, 2 Hz, 1H), 6.12 (d, 8.6 Hz, 1H), 5.15 (s, 2H) ), 2.20 (s, H3C), 2.02 (S, H3C).

The starting material is prepared as follows: Step 23.1: 2, 2, 2-trifluoro-N-r4- (4, 5-d imeti I-i m azole-1-methylmethyl) -3-trifluoromethyl-phenyl-1-acetamide. To a freezing solution of 1.81 grams (18.8 millimoles) of 4,5-dimethyl-imidazole in 70 milliliters of acetonitrile under an N 2 atmosphere, a solution of 2.2 grams (6.3 millimoles) of N- (4-bromine) is added dropwise. -methyl-3-trifluoro-methyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) in 70 milliliters of acetonitrile, for 30 minutes. After 5 hours, the suspension is filtered, and the residue is washed with CH3CN, yielding the title compound (more product can be isolated from the filtrate by concentration and extraction, as described in Step 14.3): mp: 238 -239 ° C; MS: [M + 1] + = 366.

Step 23.2: 4- (4,5-d-imethyl-imid-azol-1-ylmethyl) -3-trifluoro-methyl-aniline. The saponification of 2.67 grams (7.3 millimoles) of 2,2,2-trifluoro-N- [4- (4,5-dimethyl-imidazol-1-ylmethyl) -3-tri-fluoro-methyl-phenyl] - acetamide, as described in Step 15.2, gives, after chromatography (SiO2: EtOAc / Et3N, 99: 1? EtOAc / EtOH / Et3N, 97: 2: 1) and crystallization from EtOAc, the title: mp: 185-186 ° C; MS: [M + 1] + = 270.

Example 24: N-r 4 - (6-Chloro-pyrimidin-4-yloxy) -phen M 1 -N'-r 4 - (2-metM-imidazol-1-ylmethyl) -3-trifluoromethyl- Mi-urea phenomenon. 1. 00 grams (4.04 mmol) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 1.03 grams (4.04 mmol) of 4- (2-methyl-imidazol-1-methyl) - 3-trifluoro-methyl-aniline (Step 24.2), dissolved in 40 milliliters of tetrahydrofuran under an N2 atmosphere. During stirring at room temperature for 4 hours, a suspension is formed, and the title compound can be filtered: m.p. 228 ° C; Analysis C23H •, 8N6CI F302: C.H.N.CI; MS: [M + 1] + = 503; 1 H-NMR (DMSO-d 6): 9.15 (s, 1 H), 8.93 (s, 1 H), 8.67 (s, 1 H), 8.14 (d, 2 Hz, 1 H), 7.55 (d, 9.0 Hz, 2 H), 7.54 (m, 1H), 7.36 (s, 1H), 7.19 (d, 9 Hz, 2H), 7.08 (s, 1H), 6.84 (s, 1H), 6.66 (d, 8.6 Hz, 1H), 5.27 ( s, 2H), 2.20 (s, H3C).

The starting material is prepared as follows: Step 24.1: 2, 2, 2-trif luoro-N-r4- (2-methyl-imidazol-1-methyl-methyl) -3-trifluoromethyl-phenyl-1-acetamide. To a frozen suspension of 1.85 grams (22.5 millimoles) of 2-methyl-imidazole in 80 milliliters of acetonitrile under an N2 atmosphere, a solution of 2.64 grams (7.5 millimoles) of N- (4-bromomethyl) is added dropwise. 3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) in 80 milliliters of acetonitrile, for 30 minutes. After stirring for 5 hours at room temperature, a solution is formed, which is then concentrated in vacuo. The residue is diluted with EtOAc and a saturated solution of NaHCO3 / H2O, 1: 1. The aqueous layer is separated and extracted twice with EtOAc. The organic layers are washed with a saturated solution of NaHCO3 / H20, 1: 1, water and brine, dried (Na2SO4), and concentrated. Column chromatography (Si02: EtOAc / EtOH, 19: 1 - »9: 1) gives the title compound: mp: 229-230 ° C; MS: [M + 1] + = 352.

Step 24.2: 4- (2-Methyl-imidazol-1-ylmethyl) -3-trifluoro-methyl aniline. Saponification of 2.0 grams (5.69 millimoles) of 2,2,2-trifluoro-N- [4- (2-methyl-imidazol-1-ylmethyl) -3-trifluoromethyl-phenyl] -acetamide, as described in Step 15.2 gives, after crystallization from EtOAc, the title compound: mp: 146-147 ° C; MS: [M + 1] + = 256.

Example 25: N -r4- (6-chloro-p irim id in -4-i loxi) -f in 11-N '-T4- (2,4-dimethyl-imidazol-1-ylmetM) -3-trifluoro- methyl-fenip-urea.

It can be prepared in a manner analogous to Example 23 or 24.

Example 26: N -r4- (6-chloro-pyrim id in-4-loxi) -f in ill-N'-H- (4-ethyl-pi-erazin-1-ylmethyl) -3-methyl-phenyl n-urea Cl ° H In a manner analogous to Example 14, 467 milligrams (1.88 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 2 milliliters of tetrahydrofuran, and a suspension are reacted. of 440 milligrams (1.88 millimoles) of 4- (4-ethyl-piperazin-1-ylmethyl) -3-methyl-aniline (Step 26.4) in 8 milliliters of ether, to obtain the title compound: MS: [M + 1 ] + = 481; 1 H-NMR (DMSO-de): 8.77 (s, 1 H), 8.67 (s, 1 H), 8.60 (s, 1 H), 7.53 (d, 9.0 Hz, 2 H), 7.35 (d, 0.8 Hz, 1 H), 7.21 - 7.27 (m, 2H), 7.17 (d, 9.0 Hz, 2H), 7.10 (d, 8.2 Hz, 1H), 3.34 (S, 2H), 2.36 (m, 10H), 2.30 (s, H3C), 0.98 (t, 7.2 Hz, H3C).

The starting material is prepared as follows: Step 26.1: 4-Nitro-2-methyl-benzoic acid. A mixture of 3.04 grams (18.7 millimoles) of 2-methyl-4-nltro-benzonitrile [for the preparation, see: J. Med.

Chem. 44 (2001), 3856], 26 milliliters of concentrated HCl, and 26 milliliters of acetic acid, is placed in a sealed tube for 8 hours at 150 ° C. Filtration of the cold reaction mixture and washing with water give the title compound: m.p .: 151-155 ° C; MS: [M + 1] + = 180.

Step 26.2: (4-Nitro-2-methyl-phenyl) - (4-ethyl-piperazin-1-yl) -methanone.

In a manner analogous to Step 5.1, 8.72 grams (48.1 millimoles) of 4-nitro-2-methyl-benzoic acid are activated with 6.52 milliliters (77 millimoles) of oxalyl chloride, and are reacted with 13.45 milliliters (106 millimoles) of 1-ethylpiperazine, yielding the title compound: mp: 96-99 ° C; MS: [M + 1] + = 278.

Step 26.3: (4-Amino-2-methyl-phenyl) - (4-ethyl-piperazin-1-yl) -methanone. The hydrogenation of 12.6 grams (45.5 millimoles) of (4-nitro-2-methyl-phenyl) - (4-ethyl-piperazin-1-yl) -methanone in 200 milliliters of ethanol in the presence of 2 grams of Raney nickel , as described in Step 1.5, gives the title compound as an oil: MS: [M + 1] + = 248.

Step 26.4: 4- (4-ethyl-piperazin-1-ylmethyl) -3-methylaniline. In a manner analogous to Step 5.3, 11.12 grams (45 mmol) of (4-am i non-2-methyl-phenyl) - (4-ethyl-piperazin-1-yl) -methanone in 100 milliliters of tetrahydrofuran, reduce by 135 milliliters of BH3 (1M in tetrahydrofuran). Chromatography (SiO2; CH2Cl2 / MeOH / NH3aq, 97: 3: 1) gives the oily title compound: MS: [M + 1] + = 234; 1 H-NMR (CDCl 3): 7.04 (d, 8.2 Hz, 1H), 6.54 (d, 2.4 Hz, 1H), 6.51 (dd, 8 Hz, 2.4 Hz, 1H), 3.59 (s, H2N), 3.39 (s) , 2H), 2.5 (m, 8H), 2.43 (q, 7.2 Hz, 2H), 2.31 (s, H3C), 1.11 (t, 7.2 Hz, H3C).

Example 27: N-r4- (6-chloro-pi rim id in -4-loxi) -f in i 11-N'-T4- (4-ethyl-piperazin-1-ylmethyl) -phen Mi-urea.

A solution of 230 milligrams (0.93 millimoles) of 4-cioro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 200 milligrams (0.91 millimoles) of 4- (4-ethylpiperazin-1-methylmethyl) -anillna in 8 milliliters of tetrahydrofuran, stir during 40 minutes at room temperature. Crystallization by the addition of about 15 milliliters of di-iso-propyl ether, filtration and washing with di-iso-propyl ether, gives the title compound: mp: 203-204 ° C; MS: [M + 1] + = 467; 1 H-NMR (CDCl 3): 8.62 (s, 1 H), 7.48 (d, 9.0 Hz, 2 H), 7.33 (m, 4H), 7.13 (d, 9.0 Hz, 2H), 6.95 (s, 1 H), 6.88 (s, 1H), 6.75 (s, 1H), 3.52 (s, 2H), 2.53 (m, 8H), 2.45 (q, 7.0 Hz, 2H), 1.12 (t, 7.0 Hz, H3C).

The starting material is prepared as follows: Step 27.1: 4- (4-eti-pi-erazin-1-ylmethyl) -aniline. In a manner analogous to Step 5.3, 7.8 grams (33.4 millimoles) of (4-amino-phenyl) - (4-ethyl-piperazin-1-yl) -methanone [the synthesis is as described above, or in an alternative manner in J. Pharmaceutical Sci. 57 (1968), 2073] in 105 milliliters of tetrahydrofuran, are reduced by 100 milliliters of BH3 (1 M in tetrahydrofuran) at 65 ° C: MS: [M + 1] + = 220; 1 H-NMR (CDCl 3): 7.13 (d, 8.2 Hz, 2 H), 6.68 (d, 8.2 Hz, 2 H), 3.67 (s, H 2 N), 3.47 (s, 2 H), 2.6 (m, 8 H), 2.53 ( q, 7.3 Hz, 2H), 1.16 (t, 7.3 Hz, H3C).

Example 28: 1- (4-M, 4'1-dipperidinyl-1 '-yl-3-trif luoro-methyl-pMM) -3-r4- (6-chloro-pi rim id in-4-yloxy) -phenyl- urea.

A solution of 248 milligrams (1.0 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 327 milligrams (1.0 millimoles) of 4- [1,4 '] bi piperldinyl-1' -U-3-trifluoro-methyl-fenll-amine (Step 28.2) in 8 milliliters of tetrahydrofuran, is stirred for 30 minutes at room temperature. Crystallization by the addition of about 15 milliliters of di-iso-propyl ether, filtration and washing with di-iso-propyl ether gives the title compound: MS: [M + 1] + = 575; HPLC BtRet = 2.06.

/ The starting material is prepared as follows: Step 28.1: 1 '- (4-nitro-2-trifluoro-m et i I -f e n i I) - f 1, 4'1-bipiperidinyl. A solution of 1.0 milliliter (7.27 millimoles) of 1-fluoro-4-nitro-2-trifluoromethyl-benzene, 1.47 grams (8.73 millimoles) of [1, 4 '] bipiperidinyl, and 1.51 grams (10.9 milli-moles) of K2C03 in 15 milliliters of dimethylformamide, is stirred at room temperature for 17 hours. After evaporation of the dimethylformamide under reduced pressure, the reaction mixture is diluted with 80 milliliters of H20, and extracted 3 times with 60 milliliters of EtOAc. The combined organic phases are washed with 30 milliliters of H20 and 30 milliliters of brine, dried (MgSO4), concentrated under reduced pressure, and passed by flash chromatography (Si02, 4.0 x 24 centimeters, MeOH / CH2Cl2, 1 : 19), to give the title compound as an oil: 1 H-NMR (400 MHz, CDCl 3): 8.45 (dd, 1H), 8.25 (dd, 1H), 7.20 (dd, 1H), 3.45 (m, 2H ), 2.88 (m, 2H), 2.58 (m, 4H), 2.40 (m, 1H), 1.60 (m, 10H).

Step 28.2: 4-Ri, 4'-lipypiperidinyl-1'-yl-3-trifluoromethyl-phenyl-amine. The hydrogenation of 2.14 grams (5.99 millimoles) of 1 '- (4-nitro-2-trifluoromethyl-phenyl) - [1,4'] bipiperidinyl in 25 milliliters of ethanol in the presence of 220 milligrams of Pd / C at 10 percent, as described in Step 1.5, gives the title compound as an oil: MS: [M + 1] + = 328.

Example 29: 1-r4- (6-chloro-pi rim id in -4-i loxl) -f in M1-3- (4-r4- (2,2-dimetM-propyl) -piperazin-1-ylmetip- 3-trifluoro-metM-f-enyl) -urea.

A solution of 112 milligrams (0.45 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 150 milligrams (0.45 millimoles) of 4- [4- (2,2-dimethyl-propyl ) -piperazin-l-methylmethyl] -3-trifluoro-methyl-phenyl-amine (Step 29.4) in 8 milliliters of tetrahydrofuran, is stirred for 30 minutes at room temperature. Crystallization by addition of about 15 milliliters of di-iso-propyl ether, filtration and washing with di-iso-propyl ether give the title compound: MS: [M + 1] + = 578; HPLC BtRet = 2.18; 1 H-NMR (d 6 -DMSO): 9.00 (bs, 1H), 8.82 (bs, 1H), 8.60 (s, 1H), 7.94 (s, 1H), 7.5 (m, 4H), 7.30 (s, 1H) , 7.10 (m, 2H), 3.46 (bs, 2H), 2.45 (m, 4H), 2.35 (m, 4H), 2.00 (s, 2H), 0.80 (s, 9H).

The starting material is prepared as follows: Step 29.1: 3-f2- (2,2-djmethyl-propyl-amino) -etip-oxazolidin-2-one. A solution of 5 grams (17.5 millimoles) of 2- (2-oxo-oxazolidin-3-yl) -ethyl ester of toluene-4-sulfonic acid, 1.68 grams (19.2 millimoles) of 2, 2-d imethyl-propyl -amine, and 3.63 grams (26.3 millimoles) of K2CO3 in 35 milliliters of MeCN, is stirred at 40 ° C for 12 hours. After evaporating the MeOH under reduced pressure, the reaction mixture is diluted with 80 milliliters of H20, and extracted 3 times with 60 milliliters of EtOAc. The combined organic phases are washed with 30 milliliters of H 2 O and 30 milliliters of brine, dried (MgSO 4), and concentrated under reduced pressure, to give the crude title compound as an oil. MS: [M + 1] + = 201; 1 H-NMR (CDCl 3): 4.30 (dd, 2H), 3.65 (dd, 2H), 3.35 (t, 2H), 2.80 (t, 2H), 2.35 (s, 2H), 0.90 (s, 9H).

Step 29.2: Salt of 1- (2,2-dimethyl-propyl) -piperazine dibromhydrate. The 1- (2,2-dimethyl-propyl) -piperazine dibromhydrate salt is prepared using 3- [2- (2,2-dithnethyl-propyl-amino) -ethyl] -oxazolidin-2-one according to a literature procedure (Tetrahedron Letters, 40, 7331, 1994): MS: [M + 1] + = 157, Step 29.3: N- (4-f4 -? / 2,2-dimethyl-propyl) -piperazin-1-ylmethyl-H-3-trifluoromethyl-phenyl > -2,2.2-trifluoroacetamide. 1.0 grams (3.14 millimoles) of 1- (2,2-dimethyl-propyl) -piperazine dibromhydrate salt, 440 milligrams (1.25 millimoles) of N- (4-bromo-methyl-3-trifluoro-methyl-phenyl) - 2,2,2-trifluoroacetamide (Step 14.2), and 0.53 milliliters (3.77 millimoles) of triethylamine, dissolved in 10 milliliters of dimethyl formamide, are stirred for 3 hours at room temperature. After evaporating the acetonitrile under reduced pressure, the reaction mixture is diluted with 80 milliliters of H20 and extracted 3 times with 70 milliliters of EtOAc. The combined organic phases are washed twice with a solution of 30 milliliters of NaHCO 3 and 30 milliliters of brine, dried (MgSO 4), concentrated under reduced pressure, and passed by flash chromatography (MeOH / CH 2 Cl 2, 1:19 ), to give a yellow solid: MS: [M + 1] + = 426; HPLC BtRet = 2.13.

Step 29.4: 4-f4- (2,2-Dimethyl-propyl) -piperazin-1-yl-methyl-3-trifluoromethyl-phenyl-amine. To a solution of 445 milligrams (1.04 miUmoles) of N-. { 4- [4- (2,2-dimethyl-propyl) -piperazin-1-ylmethyl] -3-tri-f-uo-methyl-phenyl} -2,2,2-trifluoroacetamide in 18 milliliters of boiling methanol, 5.2 milliliters of a 1M solution of K2C03 in water are added dropwise. After 1 hour of stirring, the reaction mixture is cooled to room temperature, and diluted with EtOAc and water. The aqueous layer is separated and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4), and concentrated, to yield the title compound, which is used directly in Example 29: MS: [M + 1] + = 330; HPLC DtRet = 1 -73.

Example 30: 1-r4- (6-chloro-pyrim id in -4-loxi) -f in i1-3- (4-T4- (2,2-dimethyl-propyl) -piperazin-1-yl1-3- trifluoro-methyl-phenyl) -urea.

A solution of 141 milligrams (0.57 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 180 milligrams (0.57 millimoles) of 4- [4- (2,2-dimethyl-propyl ) -piperazin-1-yl] -3-trifluoromethyl-phenyl-amine (Step 30.2) in 8 milliliters of tetrahydrofuran, is stirred for 30 minutes at room temperature. Crystallization by addition of about 15 milliliters of di-iso-propyl ether, filtration and washing with di-iso-propyl ether give the title compound: MS: [M + 1] + = 563; HPLC DtRet = 2.28.

The starting material is prepared as follows: Step 30.1 1- (2,2-Dimethyl-propyl) -4- (4-nitro-2-trifluoromethyl-phenyl-piperazine) A solution of 0.36 milliliters (2.62 millimoles) of 1-fluoro-4-nitro-2 -trifluoro-methyl-benzene, 1.0 grams (3.14 millimoles) of 1- (2,2-dimethyl-propyl) -piperazine dibromhydrate salt, and 1.08 grams (7.86 millimoles) of K2C03 in 8 milliliters of dimethylformamide, is stirred at room temperature for 17 hours After evaporating the dimethylformamide under reduced pressure, the reaction mixture is diluted with 80 milliliters of H20 and extracted 3 times with 60 milliliters of EtOAc The combined organic phases are washed with 30 milliliters of H20 and 30 milliliters of brine, dried (MgSO 4), concentrated under reduced pressure, and passed by flash chromatography (SiO 2, MeOH / CH 2 Cl 2, 1:19), to give the title compound as an oil: MS: [M + 1] + = 346; HPLC DtRet = 2.39; H-NMR (300 MHz, CDCl 3): 8.50 (dd, 1H), 8.30 (dd, 1H), 7.25 (dd, 1H), 3.15 (m, 4H), 2.70 (m, 4H), 2.10 (s) , 2H), 0.90 (s, 9H).

Step 30.2: 4-í4- (2,2-Dimeti-l-propyl) -pi perazin-1-l-3-trifluoromethyl-phenyl-amine. The hydrogenation of 210 milligrams (0.63 millimoles) of 1- (2,2-dimethyl-propyl) -4- (4-nitro-2-trifluoromethyl-phenyl) -piperazine in 10 milliliters of ethanol in the presence of 40 milligrams of Pd / C at 10 percent, as described in Step 1.5, gives the title compound as an oil: MS: [M + 1] + = 316.

Example 31: 1-r4- (6-chloro-pyrim idin-4-yloxy) -f in i p-3-T4-f 1 methyl-piperid i n-4-ylmethoxy) -3-trifluoro-methyl-phen Mi -urea.

A solution of 248 milligrams (1.00 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 288 milligrams (1.00 millimoles) of 4- (1-methyl-piperidin-4-yl- methoxy) -3-trifluoromethyl-phenyl-amine (Step 31.2) in 8 milliliters of tetrahydrofuran, is stirred for 30 minutes at room temperature. Crystallization by the addition of about 15 milliliters of di-iso-propyl ether, filtration and washing with di-iso-propyl ether gives the title compound: MS: [M + 1] + = 535; HPLC AtRet = 1.98.

The starting material is prepared as follows: Step 31.1: 1-methyl-4- (4-nitro-2-trifluoro-methyl-phenoxy) -di-piperidine.

A solution of 1.00 milliliters (7.27 millimoles) of 1- fluoro-4-nitro-2-trifluoromethyl-benzene, 1.88 grams (14.5 millimoles) of (1-methyl-piperidin-4-yl) -methanol, and 470 milligrams (1.45 mMol) of tetrabutyl ammonium bromide in 6 milliliters of toluene and 6 milliliters of 25% KOHaq is stirred at 60 ° C for 17 hours. After cooling the solution, the reaction mixture is diluted with 80 milliliters of H20 and extracted 3 times with 60 milliliters of EtOAc. The combined organic phases are washed twice with 30 milliliters of a solution of NaHCO 3 and 30 milliliters of brine, dried (MgSO 4), concentrated under reduced pressure, and passed by flash chromatography (MeOH / CH 2 Cl 2, 1:19 ), to give the title compound: MS: [M + 1] + = 319.

Step 31.2: 4- (1-methyl-pi-eridin-4-ylmethoxy) -3-trifluoromethyl-phenyl-amine. Hydrogenation of 1.86 grams (5.84 miUmols) of 1-methyl-4- (4-nitro-2-trifluoromethyl-phenoxymethyl) -piperidine in 20 milliliters of ethanol in the presence of 190 milligrams of 10% Pd / C , as described in Step 1.5, gives the title compound as an oil: MS: [M + 1] + = 289.

Example 32: 1-r4- (6-chloro-pyrim id in-4-yloxy) -fen i II -3-f4- (1-methyl-piperidin-4-yloxy) -3-trifluoromethyl-phenyl-1 urea.

A solution of 248 milligrams (1.00 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) and 274 milligrams (1.00 millimoles) of 4- (1-methyl-piperidin-4-yloxy) -3-trifluoro-methy-phen-amine (Step 32.2) in 8 milliliters of tetrahydrofuran, is stirred for 30 minutes at room temperature. Crystallization by the addition of about 15 milliliters of di-iso-propyl ether, filtration and washing with di-iso-propyl ether give the title compound: MS: [M + 1] + = 522; HPLC AtRet = 1-96.

The starting material is prepared as follows: Step 32.1: 1-methyl-4- (4-nitro-2-trifluoromethyl-phenoxy) -piperidine. A solution of 1.00 milliliters (7.27 millimoles) of 1-fluoro-4-nitro-2-trifluoro-methyl-benzene, 1.71 milliliters (14.5 millimoles) of 1-methyl-piperidin-4-ol and 470 milligrams (1.45 millimoles) of tetrabutyl ammonium bromide in 6 milliliters of toluene and 6 milliliters of 25% KOHaq, is stirred at 60 ° C for 17 hours. After cooling the solution, the reaction mixture is diluted with 80 milliliters of H20, and extracted 3 times with 60 milliliters of EtOAc. The combined organic phases are washed twice with 30 milliliters of a solution of NaHCO 3 and 30 milliliters of brine, dried (MgSO 4), concentrated under reduced pressure, and passed by flash chromatography (MeOH / CH 2 Cl 2, 1:19 ), to give the title compound: MS: [M + 1] + = 305.

Step 32.2: 4- (1-methyl-piperidin-4-yloxy) -3-trifluoromethyl-phenyl-amine. The hydrogenation of 1.74 grams (5.72 millimoles) of 1-methyl-4- (4-nitro-2-trifluoromethyl-phenoxy) -piperidine in 20 milliliters of ethanol in the presence of 180 milligrams of 10% Pd / C , as described in Step 1.5, gives the title compound as an oil: MS: [M + 1] + = 275.

Example 33: -r4- (6-chloro-pyrim id in-4-i loxi) -f in M1-N '-f 4-r2- (4-eti-piperazin-1-yl) -etip-3 -trifluoro-methyl-phenyl-urea, 370 milligrams (1.49 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine are dissolved (Step 1.3) and 450 milligrams (1.49 millimoles) of 4- [2- (4-ethyl-piperazine-1 - il) -ethyl] -3-trifluoromethyl-phenylamine (Step 33.3), in 1.4 milliliters of tetrahydrofuran and 7.4 milliliters of ether under an N 2 atmosphere, and stirred for 1 hour. Concentration and reverse phase chromatography (Gilson System) give the title compound: HPLC AtRet = 11.1; MS: [M + 1] + = 549; 1 H-NMR (CDCl 3): 8.60 (s, 1H), 7.58 (d, 1H), 7.57 (s, 1H), 7.46 (d, 9.0 Hz, 2H), 7.30 (m, 1H), 7.12 (m, 4H ), 6.95 (s, 1H), 2.94 (m, 2H), 2.6 (m, 12H), 1.13 (t, 7.2 Hz, H3C).

The starting material is prepared as follows: Step 33.1: 2- (4-Nitro-2-trifluoromethyl-phenyl) -1- (4-ethyl-pi-ezin-1-yl) -ethanone. To an ice-cold solution of 11.4 grams (45.9 milli-moles) of (4-nitro-2-trifluoro-methyl-phenyl) -acetic acid in 200 milliliters of CH2Cl2 and 2 milliliters of dimethyl formamide, 7.36 milliliters are added dropwise. (87.2 mmol) of oxalyl chloride. After 20 minutes, the reaction mixture is concentrated in vacuo. The residue is redissolved in 200 milliliters of CH 2 Cl 2 and a solution of 12.2 milliliters (96 millimoles) of N-ethyl-piperazine in 80 milliliters of CH 2 Cl 2 is added dropwise. After 1 hour, the mixture is diluted with 0.4 liters of a 10 percent solution of Na 2 CO 3 and 0.4 liters of CH 2 Cl 2, the aqueous layer is separated and extracted twice with CH 2 Cl 2. Washing of the organic phases twice with a 10 percent solution of Na2CO3, water and brine, drying (Na2SO4), and concentration, give the title compound: HPLC AtRet = 9.2; MS: [M + 1] + = 346.

Step 33.2: 2- (4-am ino-2-trif luoro-methyl-f-enyl) -1 - (4-ethyl-piperazin-1-yl) -ethanone. 15.35 grams (44.5 mmol) of 2- (4- nit ro-2-tr i-fluoro-methyl-phenyl) -1 - (4-ethyl-piperazin-1-yl) -ethanone in 245 milliliters of ethanol, are hydrogenated in the presence of 2.46 grams of Raney nickel (B113W Degussa). Filtration, filtrate concentration, and column chromatography (Si02; EtOAc / EtOH + 1% NH3aq, 4: 1) give the title compound: MS: [M + 1] + = 316; R, (EtOAc / EtOH + 1% NH3aq, 4: 1): 0.11.

Step 33.3: 4-f2- (4-ethyl-piperazin-1-yl) -etin-3-tri-fluoro-methyl-phenyl-amine. To a solution of 3.47 grams (11.0 mmol) of 2- (4-amino-2-trifluoromethyl-phenyl) -1- (4-ethyl-piperazin-1-yl) -ethanone in 35 milliliters of tetrahydrofuran, it is drip 46.8 milliliters of a 1 M solution of BH3 in tetrahydrofuran for 30 minutes. After stirring for 20 hours, 60 milliliters of a 1: 1 mixture of concentrated HCl and water are added dropwise over 20 minutes at about 30 ° C. The mixture is stirred for 16 hours at room temperature, and then partially concentrated in vacuo. The residue is extracted 3 times with EtOAc, and the organic layers are washed with 0.1 N HCl, and then discarded. The acidic aqueous phases are made basic by the addition of a saturated solution of Na 2 CO 3, and extracted 3 times with EtOAc. The organic layers are washed with brine, dried (Na2SO4), and concentrated. Flash Combi flash chromatography (CH2CI2 / Me0H + 1% NH3aq, 99: 1 -> 95: 5), gives the title compound: MS: [M + 1] + = 302.

Example 34: The following compounds can be prepared in a manner analogous to that of the described procedures: *) Synthesis of the product A, see Example 65. **) It is prepared from MeNH2 and EtNH2, respectively, in tetrahydrofuran at room temperature for 4 to 10 days, in a manner analogous to the 16th Axis. ***) Step Educt 69.1.

The compounds of Examples 35 to 44 can be prepared in a manner analogous to the methods described herein.

Example 35: 3-f 3-r4- (6-chloro-pi rim id i n-4-yloxy) -f in i II ureidr-5-trifluoromethyl-benzamide.

In a manner analogous to Example 14, 250 milligrams (1.0 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 2 milliliters of tetrahydrofuran and a solution of 204 milligrams are reacted. (1.0 mmol) of 3-amino-5-trifluoro-methyl) -benzamide (Step 35.2) in 6 milliliters of ether, to give the title compound: MS: [M + 1] + = 452; 1 H NMR (DMSO-d 6): 9.41 (s, 1 H, NH), 9.05 (s, 1 H, NH), 8.62 (s, 1 H), 8.16 (s, 2 H, NH 2), 8.14 (s, 1 H), 8.02 (s, 1H), 7.81 (s, 1H), 7.55-7.52 (m, 3H), 7.32 (s, 1H), 7.17 (d, 2H).

The starting material is prepared as follows: Step 35.1: (3-Nitro-5-trifluoromethyl) -benzamide. It is prepared in analogy to Step 1.4 from 2.35 grams (10.0 mmol) of 3-nitro-5-trifluoromethyl-benzoic acid (Lancaster), and 20 milliliters of NH3 (25 percent aqueous solution), to give the title compound. MS: [M + 1] + = 233. Step 35.2: (3-Amino-5-trifluoromethyl) -benzamide. It is prepared in analogy to Step 1.5 from 2.34 grams (10 millimoles) of 3-nitro-5-trifluoromethyl) -benzamide by hydrogenation over 250 milligrams of Pd-C (10 per cent, Engelhardt 4505). MS: [M + 1] + = 205. 1 H-NMR (400 MHz, DMSO-d 6): 7.99 (s, 1 H), 7.31 (s, 1 H), 7.19 (s, 2 H, NH 2), 6.89 (s, 1H), 5.78 (s, 2H, NH2). P.f .: 94-98 ° C.

Example 36: 3-f 3-r4- (6-methyl-am ino-pyrim id in-4-yloxy) fenin-ureid? F-5-trifluoromethyl-benzamide.

It is prepared in analogy to Example 16 from 45 milligrams (0.1 millimoles) of 3-. { 3- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -ureido} -5-trifluoro-methyl-benzamide and 0.8 milliliters of methyl-amine (33 percent in EtOH). MS: [M + 1] + = 447. HPLC BtRet = 2.31.

Example 37: 3-f 3-r 4 - (6-azido-pi rim id i n-4-i loxy) -f in 11-ureidr-5-trifluoromethyl-benzamide.

The ticompound is prepared from 150 milligrams (0.33 millimoles) of 3-. { 3- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -ureido} -5-trifluoro-methyl-benzamide, as described in Example 7, to produce the ticompound, which is used directly as the starting material in Example 38. MS: [M + 1] + = 459.

Example 38: 3-f 3-T4- (6-am i n o-p i r i m i d i n -4-loxi) -f in i 11 ureidr-5-trifluoro-methyl-benzamide.

The hydrogenation of 0.15 grams (0.33 millimoles) of 3-. { 3- [4- (6-Azido-pyrimidin-4-yloxy) -phenyl] -ureido} -5-tri-fluoro-methyl-benzamide in 10 milliliters of 1,2-dimethoxy-ethane in the presence of 20 milligrams of 10% Pd / C ("Engelhard 4505"), filtration, filtrate concentration, and chromatography (Thin Layer Chromatography of Preparation: CH2Cl2 / MeOH, 9: 1), give the ticompound. MS: [M + 1] + = 433; 1 H-NMR (DMSO-d 6): 9.72 (s, 1 H, NH), 9.43 (s, 1 H, NH), 8.18 (s, 1 H), 8.16 (s, 1 H), 8.06 (s, 2 H), 7.78 ( s, 1H), 7.52 (d, 2H), 7.05 (d, 2H), 6.82 (s, 2H, NH2).

Example 39: N -T4- (6-m eti-am i no-pi rim id in -4-yloxy) -f in 11 N '- (3-amino-methyl-5-trifluoromethyl-phenyl) -urea.

Example 40: 3-f 3-r 4 - (6-chloro-pi rim id i n -4-I oxy) -f in i 11 -ureidr-N-methyl-5-trifluoromethyl-benzamide.

In a manner analogous to Example 14, 250 milligrams (1.5 millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3) dissolved in 3 milliliters of tetrahydrofuran, and a solution of 218 milligrams are reacted (1.5 mmol) of 3-amino-N-methyl-5- (trifluoromethyl) -benzamide (Step 35.2) in 6 milliliters of ether, to obtain the ticompound. MS: [M + 1] + = 466; HPLC BtRet = 2.31.

The starting material is prepared as follows: Step 40.1: N-methyl- (3-nitro-5-trifluoromethyl) -benzamide. It is prepared in analogy to Step 1.4 from 2.35 grams (10.0 mmol) of 3-nitro-5-trifluoromethylbenzoic acid (Lancaster), and 40 milliliters of NH3 (40 percent aqueous solution), to give the composed of the ti MS: [M-1] = 247. 1 H-NMR (400 MHz, DMSO-d 6): 9.09 (q, 1 H, NH), 8.89 (s, 1 H), 8.39 (s, 1 H), 8.38 (s, 1 H) ), 2.81 (d, 3H).

Step 40.2: 3-amino-N-methyl-5- (trifluoromethyl) -benzamide. It is prepared in analogy to Step 1.5 from 2.34 grams (10 millimoles) of N-methyl- (3-nitro-5-trifluoromethyl) -benzamide, by hydrogenation on 240 milligrams of Pd-C (at 10 percent, Engelhardt 4505). MS: [M + 1] + = 219. 1 H-NMR (400 MHz, DMSO-d 6); 8.41 (q, 1H, NH), 7.24 (s, 1H), 7.19 (s, 1H), 6.98 (s, 1H), 3.41 (s, 2H, NH2), 2.78 (d, 3H).

Example 41: 3-f 3-r 4 - (6-methyl-am i no-pi rim id in-4-i loxy) phene-ureido) -N-methyl-5-trifluoromethyl-benzamide.

It is prepared in analogy to Example 16 from 83 milligrams (0.18 millimoles) of 3-. { 3- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -ureido} -N-methyl-5-trifluoromethyl-benzamide and 1.5 milliliters of methyl-amine (33 percent in EtOH). MS: [M + 1] + = 461. 1 H-NMR (400 MHz, DMSO-d 6): 9.19 (s, 1 H, NH), 8.87 (s, 1 H, NH), 8.65 (q, 1 H, NH), 8.13 (s, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.5 (s, 1H), 7.26 (s, 1H), 7.07 (d, 2H), 5.72 (s, 1H), 3.59 (s, 3H), 2.82 (d, 3H).

Example 42: 3-f 3-r 4 - (6-azido-pi rim id in-4-i loxy) -f in the II-u-one) -N-methyl-5-trifluoromethyl-benzam ida.

The ticompound is prepared from 300 milligrams (0.64 millimoles) of 3-. { 3- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -ureido} -N-methyl-5-trifluoromethyl-benzamide, as described in Example 7, to produce the ticompound, which is used directly as the starting material in Example 43. MS: [M + 1] + = 473.

Example 43: 3-f3-r4-6-amino-pyrimidin-4-yloxy) -phenepyridyl-N-methyl-5-trifluoromethyl-benzamide.

The hydrogenation of 0.3 grams (0.64 millimoles) of 3-. { 3- [4- (6-Azido-pyrimidin-4-yloxy) -phenyl] -ureido} -N-methyl-5-trifluoromethyl-benzamide in 10 milliliters of 1,2-dimethoxy-ethane in the presence of 60 milligrams of 10 percent Pd / C ("Engelhard 4505"), filtration, and concentration of the filtrate give the title compound: MS: [M + 1] + = 447. 1 H-NMR (DMSO-d 6): 9.17 (s, 1 H, NH), 8.82 (s, 1 H, NH), 8.60 (q , 1H, NH), 8.12 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.50 (d, 2H), 7.05 (d, 2H), 6.80 (s, s, 1H), 5.68 (s, 1H), 3.57 (s, 3H), 2.80 (d, 3H). HPLC BtRet = 1-82. Example 44: N-r 4 - (6-methylamino-pyrimidin-4-yloxy) -phenyl-N '- (3-methyl-amino-methyl-5-trifluoromethyl-phenyl) -urea.

It can be synthesized in a manner analogous to the compounds described herein.

Example 45: N-T4- (2-amin-pyrim id in-4-i loxyl-phen M1-N'-r4- (4-isoprop-pi-erazin-1-ylmethyl) -3-trifluoro-metM -fenin-urea, To a solution of 98 milligrams (0.33 millimoles) of triphosgene in 11 milliliters of CH 2 Cl 2 under an N 2 atmosphere, cooled in an ice bath, 302 milligrams (1.00 millimoles) of 4- (4-isopropyl-piperazine) are added dropwise. 1-ylmethyl) -3-trifluoro-methylene-aniline (Step 15.2) and 0.14 milliliter (1.0 mmol) of NEt3 in 5 milliliters of CH2Cl2. After stirring for 10 minutes in the ice bath, and for 30 minutes at room temperature, a suspension of 202 milligrams (1.0 mmol) of 4- (4-amino-phenoxy) -pyrimidin-2-ylamine is added (Step 45.3) and 0.14 milliliters (1.0 millimoles) of NEt3 in 5 milliliters of CH2CI2 for 5 minutes. After 15 minutes of stirring at room temperature, the reaction mixture is concentrated in vacuo, the residue is redissolved in CH 2 Cl 2 / MeOH, and after the addition of SiO 2, it is again concentrated. The resulting powder is placed on top of a medium pressure liquid chromatography column, and the title compound is eluted with CH2Cl2 / methanol (+ 1 percent NH3aq), 19: 1 - > 9: 1, and finally it is freeze-dried from dioxane: Analysis C26H30N7F3O2 • 1.2 H20 • 0.1 C4H802: C, H, N, F; MS: [M + 1] + = 530. 1 H-NMR (DMSO-de): 9.06 (s, HN), 8.86 (s, HN), 8.10 (d, 5.5 Hz, 1H), 7.98 (d, 2.3 Hz , 1H), 7.65 (d, 8.6 Hz, 1H), 7.59 (dd, 8.6 Hz, 2.3 Hz, 1H), 7.50 (d, 9.0 Hz, 2H), 7.10 (d, 9.0 Hz, 2H), 6.62 (s) , H2N), 6.09 (d, 5.5, 1H), 3.54 (s, 2H), 2.67 (m, 1H), 2.50 (m, 4H), 2.41 (m, 4H), 0.99 (d, 6.7 Hz, 6H) .

The starting material is prepared as follows: Step 45.1: 2-chloro-4- (4-nitro-phenoxy) -pyrimidine. 18 grams (130 millimoles) of 2,4-dichloro-pyrimidine dissolved in 100 milliliters of acetone are added slowly to a solution of 5.32 grams (130 millimoles) of NaOH and 16.64 grams (118.4 millimoles) of 4-nitrophenol in 100 milliliters of H20 at 0 ° C. After stirring for 23 hours at 80 ° C, the reaction mixture is concentrated under reduced pressure, cooled, and the crude product precipitated is filtered, washed with H20, and dried under vacuum. Purification is carried out by flash chromatography (Si02; 4.5 x 46 centimeters, hexane / EtOAc, 2: 1): MS: [M + 1] + = 252. 1 H-NMR (400 MHz, DMSO-d6) : 8.67 (d, 4.5 Hz, 1H, pyrimidinyl), 8.33 (d, 8.5 Hz, 2H, phenyl), 7.56 (d, 8.5 Hz, 2H, phenyl), 7.31 (d, 4.5 Hz, 1H, pyrimidinyl), Rf (hexane / EtOAc = 1: 1): 0.38, HPLC BtRet = 5.97.

Step 45.2: 4- (4-nitro-phenoxy) -pyrimidin-2-ylamine. 4 grams (15.9 millimoles) of 2-chloro-4- (4-nitro-phenoxy) -pyrimidine dissolved in 100 milliliters of EtOH and 100 milliliters of aqueous NH3 (25 percent) are stirred in an autoclave (2 bar) at 100 ° C for 2 hours. After concentrating the reaction mixture under reduced pressure, the precipitated product is taken up in MeOH and passed through flash chromatography (Si02, 4.5 x 26 centimeters, EtOAc / hexane / N H3, 50: 50: 1.5? 100). : 50: 1.5), to give the title compound as a white solid: Rf (EtOAc / hexane / NH3: 100: 50: 1.5): 0.10; MS: [M + 1] + = 233.

Step 45.3: 4- (4-Amino-phenoxy) -pyrimidin-2-ylamine. 1.68 grams (6.7 millimoles of 4- (4-nitro-phenoxy) -pyrimidin-2-ylamine dissolved in 50 milliliters of MeOH, is hydrogenated in the presence of 500 milligrams of Raney nickel for 4 hours after filtering on Hyflo and After washing twice with 40 milliliters of EtOH, the reaction solution is concentrated under reduced pressure and passed through flash chromatography (Si02).; 4.5 x 26 centimeters, EtOAc / hexane / N H3, 100: 50: 1.5? 200: 50: 1.5), to give the title compound as a beige solid: Rf (EtOAc / hexane / NH3: 100: 50: 1.5): 0.10; MS: [M + 1] + = 203.

Example 46: N - | "4- (2-m ethyl-am i no-pi rim id in -4-i loxi) -f in II II N'-r4- (4-isopropyl-piperazin-1-ylmethyl) -3-trifluoro-methyl-f in ill-u rea.

To a solution of 60 milligrams (0.20 millimoles) of triphosgene in 7 milliliters (CH2Cl2 under an N2 atmosphere cooled in an ice bath), 181 milligrams (0.60 millimoles) of 4- (4-isopropyl-piperazine) are added dropwise. 1-methylmethyl) -3-trifluoro-methyl-aniline (Step 15.2) and 83 microliters (0.6 mmol) of NEt3 in 3 milliliters of CH2Cl2 After stirring for 10 minutes in the ice bath and for 30 minutes at room temperature At room temperature, a suspension of 130 milligrams (0.60 millimoles) of [4- (4-am ino-phenoxy) -pyrimidin-2-yl] -methyl-amine (Step 46.2) and 83 microliters (0.6 mmol) of NEt3 is added to 3 milliliters of CH2Cl2 for 5 minutes After 90 minutes of stirring at room temperature, the reaction mixture is concentrated in vacuo, the residue is redissolved in CH2Cl2 / MeOH, and after the addition of SiO2, it is again concentrated The resulting powder is placed on top of a medium pressure liquid chromatography column, and the compound is eluted. the title with CH2Cl2 / methanol (+ 1% NH3aq), 97: 3? 93: 7: MS: [M + 1] + = 544. 1 H-NMR (CD30D / CDCI3): 7.99 (d, 5 Hz, 1 H), 7.67 (d, 2 Hz, 1 H), 7.60 (dd, 8.6 Hz, 2 Hz, 1H), 7.55 (d, 8.6 Hz, 1H), 7.43 (d, 9.0 Hz, 2H), 7.03 (d, 9.0 Hz, 2H), 5.96 (d, 5 Hz, 1H), 3.59 (s, 2H), 2.99 (m, 1H), 2.83 (s, H3C), 2.70 (m, 4H), 2.58 (m, 4H), 1.12 (d, 6.3 Hz, 6H).

The starting material is prepared as follows: Step 46.1: Methyl-f4- (4-nitro-phenoxy) -pyrimidin-2-in-amine. 2 grams (7.95 millimoles) of 2-chloro-4- (4-nitro-phenoxy) -pyrimidine dissolved in 40 milliliters of MeNH2 (30 percent in EtOH) are stirred at room temperature for 50 minutes. After evaporation of the solvent, the crude product is passed by flash chromatography (SiO2, 4.5 x 30 centimeters, hexane / EtOAc, 1: 1) to give the title compound as a white solid: Rf (hexane / EtOAc, 2: 1): 0.18; MS: [M + 1] + = 247. 1 H-NMR (400 MHz, CDCl 3): 8.33 (d, 8.5 Hz, 2 H, phenyl), 8.24 (broad d, 1 H, pyrimidinyl), 7.35 (d, 8.5 Hz , 2H, phenyl), 6.22 (d, 6.0 Hz, 1H, pyrimidinyl), 2.90 (broad s, 3H, CH3).

Step 46.2: r4- (4-Amino-phenoxy) -pyrimidin-2-ill-methyl-amine. The title compound is prepared by hydrogenation in the presence of Raney nickel from methyl- [4- (4-nltro-phenoxy) -pyrimidin-2-yl] -amine: Rf (hexane / EtOAc, 1: 1): 0.13; MS: [M + 1] + = 217. 1 H-NMR (400 MHz, DMSO-d 6): 8.04 (broad s, 1 H, pyrimidinyl), 6.95 (broad s, 1 H, HN), 6.76 (d, 8.5 Hz, 2H, phenyl), 6.54 (d, 8.5 Hz, 2H, phenyl), 5.90 (broad s, 1H, pyrimidinyl), 5.00 (s, 2H, NH2), 2.70 (broad s, 3H, CH3).

Example 47: N -r4- (2-chloro-pyrim id in-4-loxi) -f in Ml-N '-T4- (dimethyl-am i no-m eti l) -3-trifluoro-m ethi l-phen Mi-urea.

The title compound is prepared from 2-chloro-4- (4-isocyanato-phenoxy) -pyrimidine and 4- (dimethylaminomethyl) -3-trifluoromethyl-phenyl-amine.

The compounds of Examples 48 to 50 can be prepared in a manner analogous to the methods described herein: Example 48: N-r4- (2-Methyl-amino-pyrimidin-4-yloxy) -f -nill-N'-r4- (4-dimethyl-amyl-non-methyl) -3-trifluoro-methyl -fen Mi-urea.

Preparation according to Example 45 from 101 milligrams (0.43 mmol) of 4- (N, N-dimethyl-amino-methyl) -3-trifluoromethyl-aniline (Step 20.1-2) and 100 milligrams ( 0.43 mmol) of [4- (4-am ino-f-enoxy) -pyrimidin-2-yl] -methyl-amine (Step 46.2). After 3 hours of stirring at room temperature, the reaction mixture is concentrated in vacuo, the residue is redissolved in CH2Cl2 / MeOH, and the crude product is purified by thin layer chromatography of preparation (CH2Cl2 / MeOH, 9: 1), to give the title compound. MS: [M + 1] + = 461; HPLC BtRet = 2.03, Rf CH2Cl2 / MeOH, 9: 1): 0.65.

Example 49: N -f4- (2-m ethyl-am.no-pyrim id in -4-yloxy) -f -nyl-N, -r4- (4-tert-butyl-p-piperazinyl-met.p-3-trifluoro -methyl-phenan-urea.

Prepared according to Example 45 from 146 milligrams (0.43 millimoles) of 4- (4-tert-butyl-piperazin-1-methylmethyl) -3-trifluoromethyl-phenyl-amine (Step 20.5) and 100 milligrams (0.43 mmol) of [4- (4-am ino-phenoxy) -pyrim idin-2-yl] -methyl-amine (Step 46.2) and 83 microliters (0.6 mmol) of NEt3 in 3 milliliters of CH2Cl2 are added. for 5 minutes. After 0.5 hours of stirring at room temperature, the precipitated product is isolated by filtration. MS: [M + 1] + = 558; p.f. 257-258 ° C, 1 H-NMR (400 MHz, DMSO-d 6): 9.60 (bs, 1H, NH), 9.09 (s, 1H, NH), 8.78 (s, 1H, NH), 8.10 (d, 1H ), 7.86 (s, 1H), 7.69-7.55 (m, 2H), 7.48 (d, 2H), 7.08 (d, 2H), 6.50 (bs, 1H, NH), 6.04 (d, 1H), 3.70 ( s, 2H), 3.49 - 3.37 (m, 4H), 3.10 - 2.87 (m, 4H), 2.85 (s, 3H), 1.37 (s, 9H).

Example 50: N-T4- (2-aminopyrim id in-4-yloxy) -f in M1-N '-T4- (4-tert-butyl-piperazinyl-methyl) -3-trifluoro- methyl-fenip-urea.

Prepared according to Example 45 from 312 milligrams (0.98 mmol) of 4- (4-tert-butyl-piperazin-1-methylmethyl) -3-trifluoromethyl-phenylallamine (Step 20.5), and 200 milligrams (0.98 mmol) of 4- (4-amino-phenoxy) -pyrimidin-2-ylamine (Step 45.3). After 30 minutes of stirring at room temperature, the precipitated product is isolated by filtration, and washed with cold tetrahydrofuran, and dried under vacuum to give the title compound as a white solid. MS: [M + 1] + = 548. 1 H-NMR (DMSO-d 6): 9.41 (s, 1 H, HN), 9.17 (s, 1 H, NH), 8.03 (d, 1 H), 7.97 (s, 1 H) ), 7.62 - 7.58 (m, 2H), 7.43 (d, 2H), 7.02 (d, 2H), 6.59 (bs, 2H), 6.01 (d, 1H), 3.62 (s, 2H), 3.49 - 3.39 ( m, 2H), 2.99-2.82 (m, 4H), 2.61-2.48 (m, 2H), 1.17 (s, 9H).

The starting material (amine component) is prepared as described in Example 20, Steps 1 to 5. Example 51: The following compounds can be prepared in an analogous manner: 1) Prepare in a manner analogous to Example 45. 2) Prepare in a manner analogous to Example 46.

Eiem pio 52: In a manner analogous to Example 45, the following compounds are prepared: Step 52c.1: N-r4- (4-Ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl-2,2,2-trifluoroacetamide. 2 grams (5.71 mmol) of N- (4-bromomethyl-3-trifluoromethyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) and 2.22 milliliters (17.14 mmol) of N-ethylpiperazine, dissolved in 55 milliliters of acetonitrile are stirred for 45 minutes at room temperature. After evaporating the acetonitrile under reduced pressure, the reaction mixture is diluted with 80 milliliters of H20 and extracted 3 times with 70 milliliters of EtOAc. The combined organic phases are washed twice with 30 milliliters of a solution of NaHCO 3 and 30 milliliters of brine, dried (MgSO 4), concentrated under reduced pressure, and passed by flash chromatography (SiO 2, 4.0 x 24 centimeters, Me0H / CH2Cl2, 1:19), to give a yellow solid: Rf (Me0H / CH2Cl2, 1: 4): 0.42; MS: [M + 1] + = 384. 1 H-NMR (400 MHz, DMSO-d 6): 11.40 (broad s, 1H, NH), 8.02 (s, 1H), 7.90 (d, 7.5 Hz, 1H) , 7.74 (d, 7.5 Hz, 1H), 3.56 (s, 2H, CH2-aryl), 2.30 (m, 10H), 2.51 (t, 7.5 Hz, 3H, CH3).

Step 52c.2: 4- (4-ethyl-pi-perazin-1-ylmethyl) -3-trifluoromethyl-phenyl-amine. A solution of 1.59 grams (4.1 mmol) of N- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -2,2,2-tri-f-luoroacetamide in 41 milliliters of MeOH and 20.5 milliliters of a 1 M solution of K2C03 in H20, is stirred under Ar at 70 ° C for 1.5 hours. After evaporating the MeOH under reduced pressure, the reaction mixture is diluted with 80 milliliters of H20 and extracted 3 times with 60 milliliters of EtOAc. The combined organic phases are washed with 30 milliliters of H20 and 30 milliliters of brine, dried (MgSO4), concentrated under reduced pressure, and passed by flash chromatography (Si02, 4.0 x 24 centimeters, MeOH / CH2Cl2, 1). : 19), to give the title compound as a yellow solid: Rf (Me0H / CH2Cl2, 1: 4): 0.42; MS: [M + 1] + = 288. 1 H-NMR (400 MHz, DMSO-d 6): 7.24 (d, 7.5 Hz, 1H), 6.81 (s, 1H), 6.73 (d, 7.5 Hz, 1H), 5.41 (s, 2H, CH2-aryl), 3.35 (m, 2H, CH2-CH3), 2.30 (m, 8H, piperazinyl), 2.51 (t, 6.5 Hz, 3H, CH3).

Step 52d.1 3-pyridin-2-yl-5-trifluoromethyl-phenyl-amine.

The title compound is synthesized according to the procedure of [Lam F., Chan K.S. (1995), Synthesis of acyclic dinucleating Schiff base-pyridine and Schiff base-phosphine ligands. Tetrahedron Lett; 36 (6): 919-922], by stirring 600 milligrams (2.44 millimoles) of 3-amino-5-bromo-benzo-trifluoride, 1 gram (2.69 millimoles) of 2- (tributylstannyl) -pyridine, and 285 milligrams of tetrakis-triphenyl-phosphine Pd, dissolved in 10 milliliters of tetrahydrofuran for 7 days under Ar at 90 ° C. Chromatographic separation (Si02, 4.5 x 19 centimeters, EtOAc / hexane, 1: 2 → 2: 3) gives the title compound as a slightly brown solid: Rf (hexane / EtOAc, 2: 1): 0.17; MS: [M + 1] + = 239. 1 H-NMR (400 MHz, DMSO-d 6): 8.81 (d, 4.5 Hz, 1H, pyridinyl), 7.88 (m, 2H, pyridinyl), 7.53 (s, 1H, phenyl-CF3), 7.43 (s, 1H, phenyl-CF3), 7.37 (m, 1H, pyridinyl), 6.89 (s, 1H, phenyl-CF3), 5.73 (s, 2H, NH2).

Eiem pio 53: In a manner analogous to Example 46, the following compounds are prepared: XX? H H > R2 * The synthesis of the corresponding trifluoromethyl-phenyl-amine building blocks are described in Steps 53b.3 and 53d.1, respectively.

Step 53b.1: (3-brom or-5-trifluoro-methyl-phenyl-carbamic acid) tertiary butyl ester A solution of 25 grams (104 millimoles) of 3-bromo-5-trifluoromethyl-aniline, 24 grams (110 millimoles) of (Boc) 2O, and 1.2 grams (10 millimoles) of dimethylaminopyridine in 200 milliliters of MeCN, is stirred at 60 ° C for 10 hours.After evaporating the solvent under reduced pressure, the residue pass through flash chromatography (Si02; hexane / EtOAc, 10: 1), and crystallize from hexane to give the title compound as white crystals: Rf (hexane / EtOAc, 1: 5): 0.23; : [M + 1] + = 341.

Step 53b.2: R3- (4-Methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl-carbamic acid terbutil- ester. 6.8 grams (20 millimoles) of (3-bromo-5-trifluoromethyl-phenyl) -carbamic acid tertiary butyl ester, 2.6 milliliters (24 millimoles) of 1-methyl-piperazine, 2.7 grams (28 millimoles) of NaOtBu, 6 milliliters of tri-tert-butyl-phosphine (10 percent in hexane, 3 mmol), and 0.5 grams (1 millimole) of tris- (dibenzylidene-acetone) -di-palladium dissolved in 100 milliliters of toluene, are stirred under Ar at 70 ° C for 6 hours. The reaction solution is diluted with 200 milliliters of EtOAc, and filtered over Hyflo. After washing with 50 milliliters of brine, the filtrate is dried (MgSO4), concentrated under reduced pressure, and reprecipitated from EtOAc / hexane, to give the title compound as a brown oil: Rf (MeOH / CH2Cl2, 1: 5): 0.45; MS: [M + 1] + = 360. Step 53b.3: 3- (4-methyl-pi-perazin-1-yl) -5-trifluoromethyl-phenyl-amine. A solution of 3.2 grams (8.9 millimoles) of [3- (4-methyl-piperazin-1-yl) -5-tri-fluoro-methyl-phenol] -carbamic acid terbutil ester dissolved in 60 milliliters of 2.5 N HCl in 2 -propanol, is stirred at 60 ° C for 5.5 hours. After evaporating the solvent under reduced pressure, the residue is divided between 200 milliliters of EtOAc and 100 milliliters of a solution of NaHCO 3. The organic phase is washed with 50 milliliters of brine, dried (MgSO4), and the solvent is evaporated to give the title compound as a brown oil: MS: [M + 1] + = 260; R f (M eOH / C H 2 Cl 2, 1: 5): 0.18; 1 H-NMR (400 MHz, DMSO-d 6): 6.31 (s, 1 H), 6.27 (s, 1 H), 5.34 (s, 1 H), 3.32 (broad s, 2 H, NH 2), 3.70 / 2.42 (m / m, 4H / 4H, CH2-piperazinyl), 2.20 (s, 3H, CH3).

Step 53d.1: 4- (4-methyl-piperazin-1-yl) -3-trifluoro-methyl-phenyl-amine. The title compound is synthesized by a nucleophilic substitution reaction from 1-bromo-4-nitro-2-trifluoromethyl-benzene with 1-methyl-piperazine (140 ° C, 4 hours), and also a reduction hydrogenolytic nitro function for the amine by means of Raney nickel; p.f .: 121-123 ° C; R f (MeOH / CH 2 Cl 2 = 1: 5): 0.17; MS: [M + 1] + = 260. 1 H-NMR (400 MHz, DMSO-d 6): 7.21 (d, 9 Hz, 1 H), 6.74 (m, 2 H), 5.35 (broad s, 2 H, NH 2) , 2.70 (broad m, 4H, CH2), 2.36 (s, broad, 4H, CH2), 2.18 (s, 3H, CH3).

Example 54: 1 -f4- (6-am-no-pyrim id in-4-yloxy) -f-enyl] -3-r3- (6-methyl-pyridin-2-yl) -5-trifluoro-methyl-phenyl -urea.

A solution of 252 milligrams (1 millmol) of 3- (6-methyl-pyridin-2-yl) -5-trif luoro-methyl-phenyl-amine (Step 54.2), and 0.I2 milliliters of NEt3 in 4.5 milliliters of CH2Cl2 is added to 99 milligrams (0.33 millimoles) of triphosgene dissolved in 9 milliliters of CH2CI2 at 0 ° C. After stirring at room temperature for 15 minutes, a solution of 202 milligrams (1 millimole) of 4- (4-am-no-phenoxy) -pipmidin-6-ylamine (Step 54.3) and 0.12 milliliter of NEt3 in 4.5 is added. milliliters of CH2CI2 and 0.5 milliliters of dimethylformamide. After stirring the brown reaction solution at room temperature for 3.5 hours, the solvent is evaporated under reduced pressure and passed through flash chromatography (Si02, 2.5 x 18 centimeters, MeOH / CH2Cl2 / NH3, 5: 95: 0.5). , to give the title compound as a beige solid: Rf (MeOH / CH 2 Cl 2 / N H 3, 5: 95: 0.5): 0.06; MS: [M + 1] + = 481. H-NMR (DMSO-d 6): 9.21 / 8.83 (s / s, 1H / 1H, urea), 8.29 (s, 1H, pyrimidinyl), 8.06 (m, 2H, pyridinyl), 7.93 (s, 1H, phenyl-CF3), 7.80 (s, 1H, phenyl-CF3), 7.79 (s, 1H, phenyl-CF3), 7.51 (d, 9.0 Hz, 2H, phenyl), 7.26 ( m, 1H, pyridinyl), 7.06 (d, 9.0 Hz, 2H, phenyl), 6.77 (s, 2H, NH2), 5.66 (s, 1H, pyrimidinyl), 2.51 (s, 3H, CH3).

Step 54.1: 6-methyl-2- (tributyl-stanyl) -pyridine. The title compound is synthesized in a manner analogous to the procedure of Zhang et al. (Synthetic Communications 31 (2001), 1129). To a solution of 3.83 grams (22.2 millimoles) of 2-bromo-6-methyl-pyridine in 7 milliliters of tetrahydrofuran, 13.9 milliliters of nBuLi (1.6 N in hexane, 22.2 mmol) are added slowly at -5 78 ° C under Ar. After stirring at -78 ° C for 1.5 hours, 6 milliliters (22.2 mmol) of tributyltinyl chloride are added slowly, and the reaction solution is stirred for an additional 30 minutes at -78 ° C. After filtration of the reaction mixture, the title compound is isolated by flash chromatography (Si02; 5 x 16 centimeters, EtOAc / hexane, 1: 9): colorless oil: Rf (hexane / EtOAc, 3: 2): 0.42; MS: [M + 1] + = 380.

Step 54.2: 3- (6-Methyl-pyridin-2-yl) -5-trifluoromethyl-phenyl-amine. 1 gram (4.19 millimoles) of 3-amino-5-bromo-benzo-trifluoride, 1 gram (2.60 millimoles) of 6-methyl-2- (tributyl-stanyl) -pyridine, and 30 milligrams of tetrakis-triphenyl-phosphine Pd dissolved in 1.5 milliliters of tetrahydrofuran, are stirred in a sealed tube in a microwave oven (Emrys Optimizer, Personal Chemistry, Sweden) under Ar at 140 ° C for 1,000 seconds. Chromatographic separation (S02; 5 x 18 centimeters, EtOAc / Hexane, 1: 9 → 2: 3) gives the title compound as a colorless oil: Rf (hexane / EtOAc, 3: 2): 0.42; MS: [M + 1] + = 253. 1 H-NMR (400 MHz, DMSO-d 6): 7.62 (t, 6.5 Hz, 1H, pyridinyl), 7.74 / 7.70 (s / s, 1H / 1H, phenyl-CF3 ), 7.69 (d, 6.5 Hz, 1H, pyridinyl), 7.12 (d, 6.5 Hz, 1H, pyridinyl), 6.91 (s, 1H, phenyl-CF3), 3.95 (broad s, 2H, NH2), 2.63 ( s, 3H, CH 3).

Step 54.3: 4- (4-Amino-phenoxy) -pyrimidin-6-ylamine. 2.0 grams (9.725 millimoles) of 4- (6-chloro-pyrimidin-4-i-oxy) -annoline (Step 1.2) dissolved in 80 milliliters of aqueous NH3 (25 percent) and 60 milliliters of EtOH, they are stirred in a sealed tube at 80 ° C for 23 hours. After evaporation of the solvent under reduced pressure on a water bath at 40 ° C, the residue is passed by flash chromatography (Si02, 5.5 x 65 centimeters; CH 2 Cl 2 / MeOH, 9: 1), to give the title as a white solid: Rf (CH2Cl2 / MeOH = 9: 1): 0.37; MS: [M + 1] + = 203. 1 H-NMR (400 MHz, DMSO-d 6): 8.01 (s, 1H, pyrimidinyl), 6.74 (d, 9 Hz, 2H, phenyl), 6.70 (s, 2H , NH2), 6.57 (d, 9 Hz, 2H, phenyl), 5.51 (s, 1H, pyrimidinyl), 5.03 (s, 2H, NH2).

Example 55: Additional compounds are synthesized by urea formation in a manner analogous to the preparation of the compound of Example 54: * The OH group of the phenolic amine is protected by tert-butyl-dimethyl-silyl. After urea formation, the tert-butyl-dimethylsilyl protecting group of the phenolic oxygen is divided by means of HF in pyridine (30 percent).

Step 55a.1a: 4-f 6- (4-n.tro-phenoxy) -pyrimidin-4-ylamolol-phenol. 3 grams (11.9 mmol) of 4-chloro-6- (4-nitro-phenoxy) -pyrimidine (Step 1.1), 1.95 grams (17.9 mmol) of 4-amino-phenol, and 3.04 milliliters (17.9 mmol) of di- isopropyl-ethyl-amine dissolved in 50 milliliters of 2-propanol, are stirred at 85 ° C for 18 hours. After concentrating the reaction mixture under reduced pressure, the product is precipitated as a colorless fine solid: Rf (EtOAc / hexane, 2: 1): 0.48; MS: [M + 1] + = 245. 1 H-NMR (400 MHz, DMSO-d 6): 9.40 / 9.25 (s / s, 2H, NH / OH), 8.28 (d, 7.5 Hz, 2H, fenll-N02 ), 8. 26 (s, 1H, pyrimidinyl), 7.40 (d, 7.5 Hz, 2H, phenyl-N02), 7.24 (d, 8.0 Hz, 2H, phenyl-OH), 6.77 (d, 8.0 Hz, 2H, phenyl-OH) 6.15 (s, 1H, pyrimidinyl).

Step 55a.1b: f4- (tert-butyl-dimethylsilyloxy) -phenyl-r6- (4-nitro-phenoxy) -pyridin-4-yn-amine. 1.5 grams (4.63 millimoles) of 4- [6- (4-nitro-phenoxy) -pyrimidin-4-ylammon] -phenol, 1.39 grams (9.26 miUmols) of tert-butyl-l-dimethylsilyl chloride, 1.29 milliliters (9.26 milli-moles) of NEt3, dissolved in 20 milliliters of dimethylformamide, are stirred for 3.5 hours. After concentrating the reaction mixture under reduced pressure and dissolving in a phosphate buffer (50 milliliters, pH = 7), extract the product by 10 milliliters of EtOAc, and purify by flash chromatography (S02). 3.0 x 17 centimeters, EtOAc / hexane, 1: 1 → 4: 1), to give the title compound as a colorless solid: MS: [M + 1] + = 439. 1 H-NMR (400 MHz, DMSO- d6): 9.56 (s, 1H, NH), 8.28 (m, 3H, pyrimidinyl, phenyl-N02), 7.40 (m, 4H, phenyl-OTBS, phenyl-N02), 6.81 (d, 8.8 Hz, 2H, phenyl -OTBS, 6.20 (s, 1H, pyrimidinyl), 0.93 (s, 9H, TBS), 0.18 (s, 6H, TBS).

Step 55a.1c: T6- (4-am ino-phenoxy) -pyrimidin-4-yl-1-r4- (tert-butyl-dimethyl-silanyloxy) -phenyl-amine. 1.8 grams (4.1 mmol) of [4- (tert-butyl-dimethylsilyloxy) -phenyl] - [6- (4-nitro-phenoxy) -pyrimidin-4-yl] -amine are hydrogenated in the presence of 0.4 grams of Raney nickel in 50 milliliters of EtOH / THF (35/15) for 3 hours, and purified by flash chromatography (Si02, 3.0 x 18 centimeters, EtOAc / hexane, 1: 1 → 4: 1 ), to give the title compound as a colorless solid: Rf (EtOAc / hexane = 2: 1): 0.22; MS: [M + 1] + = 409. 1 H-NMR (400 MHz, DMSO-d 6): 9.22 (s, 1 H, NH), 8.20 (s, 1 H, pyrimidinyl), 7.37 (d, 8.8 Hz, 2 H, phenyl-OTBS), 6.77 (d, 8.8 Hz, 2H, phenyl-NH2), 6.70 (d, 8.8 Hz, 2H, phenyl-OTBS), 6.55 (8.8 Hz, 2H, phenyl-N H2), 5.79 (s, 1H, pyrimidinyl), 5.02 (s, 2H, NH2), 0.90 (s, 9H, TBS), 0.12 (s, 6H, TBS).

Step 55b.2: 4-Dimethyl-amino-methyl-3-trif luoro-methyl-phenyl-amine. 1.8 grams (5.14 millimoles) of N- (4-bromo-methyl-3-trifluoro-methyl-phenyl) -2,2,2-trifluoroacetamide (Step 14.2) dissolved in 25 milliliters of HNMe2 (30 percent by weight) EtOH), is stirred at room temperature for 1 hour, and then (for the saponification of the function of 2,2,2-trifluoroacetamide) further at 50 ° C for 3 hours. After evaporating the solvent under reduced pressure, the residue is purified by flash chromatography (S02, 5.5 x 17 centimeters, acetone / CH2Cl2 / N H3, 5: 94: 1 → 50: 49: 1), to give a yellow oil: Rf (acetone / CH2Cl2 / NH3, 50: 49: 1): 0.73; MS: [M + 1] + = 219. 1 H-NMR (400 MHz, DMSO-d 6): 7.32 (d, 8.5 Hz, 1H), 6.88 (d, 4.5 Hz, 1H), 6.76 (d, 8.5 Hz, 1H), 5.44 (s, 2H, CH2), 3.33 (s, 2H, NH2), 2.12 (s, 6H, CH3).

Step 55c.1a: (3-methoxy-phenyl) -r6- (4-nitro-phenoxy) -pyrimidin-4-yn-amine. 5 grams (19.9 millimoles) of 4-chloro-6- (4-nitro-phenoxy) -pyrimidine (Step 1.1) and 4.88 milliliters (43.8 millimoles) of M-anisidine dissolved in 7.5 milliliters of di-iso-propyl-ethyl- amine and 85 milliliters of 2-propanol are refluxed for 162 hours. During the concentration of the reaction mixture under reduced pressure, the residue is precipitated to give the title compound as white crystals, which are washed with cold MeOH: MS: [M + 1] + = 339. 1 H-NMR (400 MHz, DMSO-de): 9.69 (s, 1H, NH), 8.40 (s, 1H, pyrimidinyl), 8.31 (d, 9.5 Hz, 2H, phenyl), 7.44 (d, 9.5 Hz, 2H, phenyl), 7.29 (s / broad, 1H, MeO-phenyl), 7.23 (t, 8.5 Hz, 1H, MeO-phenyl), 7.16 (d, 8.5 Hz, 1H, MeO-phenol), 6.62 (d / amp, 8.5 Hz, 1H , MeO-phenyl), 7.97 (broad s, 1H, pyrimidinyl), 5.11 (s, 2H, NH2), 3.74 (s, 3H, CH3).

Step 55c.1b: í6- (4-ami no-phenoxy) -pyrimidin-4-ill- (3-methoxy-phenyl) -amine. 5.4 grams (16 mMol) of (3-methoxy-phenyl) - [6- (4-nitro-phenoxy) -pyrimidin-4-yl] -amine dissolved in 160 milliliters of MeOH / THF, 2: 1, are hydrogenated in the presence of Raney nickel for 16 hours. After filtering the suspension of the reaction on Hyflo, and concentrating the reaction mixture, the title compound is precipitated as white crystals: MS: [M + 1] + = 309. H-NMR (400 MHz, DMSO-d6 ): 9.47 (s, 1H, NH), 8.36 (s, 1H, pyrimidinyl), 7.31 (s / broad, 1H, MeO-phenyl), 7.19 (t, 8.5 Hz, 1H, MeO-phenyl), 7.14 (d , 8.5 Hz, 1H, MeO-phenyl), 6.88 (d, 9.5 Hz, 2H, phenyl), 6.63 (d, 9.8 Hz, 2H, phenyl), 6.58 (broad d, 8.5 Hz, 1H, MeO-phenyl) , 7.97 (broad s, 1H, pyrimidinyl), 5.06 (broad s, 2H, NH2) 5.11 (s, 2H, NH2), 3.73 (s, 3H, CH3); HPLC BtRet: 3.82.

Step 55c.2: 4-morph olin-4-yl-3-trif luoro-methyl-phenyl-amine. The title compound is synthesized by a nucleophilic substitution reaction from 1-bromo-4-nitro-2-trifluoromethyl-benzene with morpholine (140 ° C, 4 hours), and also hydrogenolytic reduction of the nitro function to the amine by means of Raney nickel: mp: 149-151 ° C; Rf (hexane / EtOAc, 1: 1). 0.30; MS: [M + 1] + = 247. 1 H-NMR (400 MHz, DMSO-d 6): 7.22 (d, 9 Hz, 1 H), 6.77 (m, 2 H), 5.37 (broad s, 2 H, NH 2) , 3.62 (m / broad, 4H, CH2), 2.67 (m, broad 4H, CH2).

Step 55d.1a: 4-r6- (4 ^ nitro-phenoxy) -pyrimidin-4-ylamino-cyclohexanol. 300 milligrams (1.19 miUmols) of 4-chloro-6- (4-nitro-phenoxy) -pyrimidine (Step 1.1) and 184 milligrams (1.60 milli-moles) of 4-amino-cyclohexanol, dissolved in 0.5 milliliters of di-iso -propyl ethyl amine and 30 milliliters of 2-propanol are refluxed for 3 hours. After evaporating the solvent, the residue is passed through flash chromatography twice (SiO2, 2.5 x 12 centimeters, hexane / EtOAc, 1: 1? MeOH / EtOAc, 5:95, Si02, 2 x 15 centimeters, 5? 10 percent MeOH in CH 2 Cl 2), to give a colorless oil: Rf (MeOH / CH 2 Cl 2, 1: 9): 0.50; MS: [M + 1] + = 331. 1 H-NMR (400 MHz, DMSO-d 6): 8.30 (d, 10.5 Hz, 2H, phenyl), 8.14 (broad s, 1H, pyrimidinyl), 7.43 (d, 8.5 Hz, 1H, NH), 7.38 (d, 10.5 Hz, 2H, phenyl), 5.95 (broad s, 1H, pyrimidinyl), 5.06 (broad s, 2H, NH2), 4.55 (d, 4.5 Hz, 1H , OH), 3.76 (broad s, 1H, CH), 3.41 (broad m, 1H, CH), 1.92-1.80 (m, 4H, CH2), 1.25 (m, 4H, CH2).

Step 55d.1b: 4-y6- (4-am ino-f enoxi) -pi rim idin-4-ylam inol-cyclohexanol. 100 milligrams (0.30 millimoles) of 4- [6- (4-nitro-phenoxy) -pyrimidin-4-ylammon] -cyclohexanol, dissolved in 15 milliliters of MeOH, are hydrogenated in the presence of Raney nickel for 3 hours . After filtering the suspension of the reaction on Hyflo and evaporating the solvent, the crude product is purified by flash chromatography (SiO 2, 2 x 20 centimeters, acetone / CH 2 Cl 2 / NH 3, 5: 94: 1 → 50:49: 1), to give the title compound as a yellowish oil: Rf (MeOH / CH 2 Cl 2 / NEt 3, 15: 84: 1): 0.12; MS: [M + 1] + = 301. 1 H-NMR (400 MHz, DMSO-d 6): 8.09 (s, 1H, pyrimidinyl), 7.13 (d, 8.5 Hz, 1H, NH), 6.76 (d, 9.5 Hz , 2H, phenyl), 6.56 (d, 9.5 Hz, 2H, phenyl), 5.55 (broad s, 1H, pyrimidinyl), 5.06 (broad s, 2H, NH2), 4.56 (d, 4.0 Hz, 1H, OH ), 3.64 (broad s, 1H, CH), 3.38 (broad m, 1H, CH), 1.79 (m, 4H, CH2), 1.23 (m, 4H, CH2).

Eiem pio 56 The following compounds can be prepared in an analogous way: Example 57: 1 -T4- (6-am i no-pirim id in-4-i loxi) -f in M1-3- (4-pyridin-2-M-3-trifluoromethyl-phenyl) - urea. In a sealed tube, 150 milligrams (0.320 millimoles) of 1- [4- (6-amino-pyrimidin-4-yloxy) -phenyl] -3- (4-brothno-3-tri-fluoro-methyl-phen) - urea (Step 57.3), 590 milligrams (1,603 miUmols) of 2- (tributyl-stanyl) -pyridine and 97 milligrams (0.084 mmol) of tetrakis- (triphenyl-phosphine) -palladium, are suspended in 1,4-dioxane under a argon atmosphere. After stirring for 2.5 hours at 150 ° C, the solvent is removed under reduced pressure. Column chromatography (Si02; CH2Cl2 / MeOH, 95: 5) and crystallization from ether give the title compound as a white powder: m.p .: 188-192 ° C; R, (CH2Cl2 / MeOH, 9: 1): 0.19; MS: [M + 1] + = 470; HPLC ctRet = 5.49.

The starting material is prepared as follows: Step 57.1: 2- (4-brom or-3-trifluoromethyl-phenyl) -3-F4- (6-chloro-pyrimidin-4-yloxy) -phenyl-urea. To a solution of 4.0 grams (16.15 mmol) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Example 1, Step 1.3) in 13 milliliters of tetrahydrofuran under an atmosphere of N2, 3.88 grams are added (16.15). millimoles) of 4-bromo-3-trifluoro-methyl-aluminum dissolved in 85 milliliters of ether. After stirring for 27 hours at room temperature, the product is filtered and washed with ether. After drying, the title compound is obtained as white crystals: mp .: 179-182 ° C; Rf (EtOAc): 0.55; MS: [M + 1] + = 489; HPLC ctRet = 7.46.

Step 57.2: 1- [4- (6-azido-pyrimidin-4-yloxy) -phenn-3- (4-bromo-3-trifluoro-methyl-phenyl) -urea. A mixture of 4.13 grams (8.47 millimoles) of 1- (4-bromo-3-trifluoro-methyl-phenyl) -3- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] - urea and 1.1 grams (16.94 millimoles) of NaN3 in 65 milliliters of dimethyl formamide, is stirred for 19 hours at 50 ° C, and for 6 hours at 60 ° C. The reaction mixture is poured into 150 milliliters of water and extracted with EtOAc (3 x 350 milliliters). The organic layers are washed with water and brine, dried (Na2SO4), and concentrated. The crude product is used directly in the next hydrogenation step (Step 47.3). Rf (EtOAc): 0.58; MS: [M + 1] + = 494; HPLC ctRet = 7.58.

Step 57.3: 1-r4- (6-Amino-pyrimidin-4-yloxy) -phenyl-3- (4-bromo-3-trifluoro-methyl-phenyl) -urea. 4.1 grams (8.3 mMol) of 1 - [4- (6-azido-pyrimidin-4-yloxy) -phenyl] -3- (4-bromo-3-tpfluoromethyl-phenyl) -urea dissolved in 80 milliliters of EtOH , are hydrogenated in the presence of 1 gram of Raney nickel at room temperature for 15 hours. The reaction solution is filtered and concentrated. Column chromatography (Si02, EtOAc) and crystallization from ether give the title compound: m.p .: 186-188 ° C; Rf (EtOAc): 0.18; MS: [M + 1] + = 469; HPLC ctRet = 5.49.

Example 58: 1-r4- (6-amino-pyrim id in-4-i loxi) -f inM1-3- (4-pyridin-3-yl-3-trifluoro-methyl-phenyl) -urea. The title compound is prepared as described in Example 57, using 3- (1,1,1-tributyl-stanyl) -pyridine: mp: 132-135 ° C; MS: [M + 1] + = 467; HPLC ctReí = 3.54.

Example 59: 1 -T4- (6-am i no-pirim id i n-4-i loxi) -f in M1-3- (4-pyridin-4-M-3-trifluoromethyl-phenyl) -urea . The title compound is prepared as described in Example 57, using 4- (1,1,1-tributyl-stanyl) -pyridine: m.p .: 131-135 ° C; MS: [M + 1] + = 467; HPLC ctRet = 3.51.

Example 60: 1- (4- (6-am ino-pyrim id in-4-yloxy) -f in M1-3-r4- (6-methyl-p i ridin-2-yl) -3-trifluoro-methyl- The Mi-urea The title compound is prepared as described in Example 57 using 2-methyl-6-tributyl-stanyl-pyridine (Step 54.1): mp: 130-133 ° C; MS: [M + 1] + = 481; HPLC ctRet = 3.66.

Example 61: 1-r4- (6-Methyl-amino-pyrimidin-4-yloxy) -phenyl-3- (4-pyridin-2-yl-3-trifluoromethyl-phenyl) -urea. In a sealed tube, 136 milligrams (0.282 millimoles) of 1- (4-bromo-3-trifluoromethyl-phenyl) -3- [4- (6-methyl-pyrimidin-4-yloxy) -phenyl] - urea (Step 61.1), 129 milligrams (0.35 millimoles) of 2- (tributyl-stanyl) -pyridine, and 36 milligrams (0.031 millimoles) of tetrakis- (triphenyl-phosphine) -palladium, are suspended in 0.5 milliliters of tetrahydrofuran under a argon atmosphere. The reaction mixture is heated in a microwave oven (Emrys Optimizer) for 85 minutes at 140 ° C. After filtration, the mother liquor is evaporated and passed through chromatography (S02; CH2Cl2 / MeOH, 95: 5). By means of thin layer chromatography (Si02; CH2Cl2 / MeOH, 9: 1), the title compound is obtained as a white powder; p.f .: 114-118 ° C; R f (CH 2 Cl 2 / MeOH, 9: 1): 0.32; MS: [M + 1] + = 481; HPLC ctRet = 3.78.

The starting material is prepared as follows: Step 61.1: 1- (4-Bromo-3-trifluoromethyl-phenyl) -3-r4- (6-methyl-amino-pyrimidin-4-yloxy) -phen-p-urea. 3 grams (6.15 mllimoles) of 1- (4-bromo-3-trifluoromethyl-phenyl) 3- [4- (6-chloro-pyrimidin-4-yloxy) -phenyl] -urea (Step 57.1), dissolve in 35.5 milliliters of a 33 percent solution of MeNH2 in EtOH, and stirred in an ice bath for 4 hours. After removing the solvent under reduced pressure, the residue is passed through chromatography (Si02, EtOAc), and crystallized from ether, to give the title compound as white crystals: mp: 161-164 ° C; Rf (EtOAc): 0.26; MS: [M + 1] + = 482; HPLC ctRet = 5.64.

Example 62: 1-r4- (6-methyl-amino-p rim id in-4-Moxy) -f in 11-3- (4-pyridin-3-M-3-trifluoromethyl-phenyl) - urea. The title compound is prepared as described in Example 61 using 3- (1,1,1-tributyl-stanyl) -pyridine: mp .: 118-123 ° C; MS: [M + 1] + = 481; HPLC ctRet = 3.67.

Example 63: 1 -T4- (6-m eti-l-am i no-pic rim id in -4-yloxy) -f in II-3- (4-pyridin-4-yl-3-trifluoro- methyl-phenyl) -urea. The title compound is prepared as described in Example 61 using 4- (1,1,1-tributyl-stanyl) -pyridine: mp .: 127-130 ° C; MS: [M + 1] + = 481; HPLC ctRet = 3.64.

Example 64: 1 -T4- (6-m et i l-am in op i ri midin -4-i I oxy) -f in i II -3-r4- (6-methyl-pyrid i n-2-il ) -3-trifluoro-m eti l-fen Mi-urea. The title compound is prepared as described in Example 61 using 2-methyl-6-tri-butylstannyl-pyridine (Step 54.1): mp: 106-109 ° C; MS: [M + 1] + = 495; HPLC ctRet = 3.80.

Example 65: N -r4- (6-chloro-pi rim id in -4-i loxi -f in i II -N t-T4 • (4-ethyl-piperazin-1-ylmetM) -3-chloro-phen Mi -urea.

To a solution of 720 milligrams (2.8 millimoles) of 4- (4-ethylpiperazin-1-ylmethyl) -3-chloroaniline (Step 65.3) in 30 milliliters of tetrahydrofuran under an atmosphere of N2, 710 milligrams are added (2.86). millimoles) of 4-chloro-6- (4-isocyanato-phenoxy) -pyrimidine (Step 1.3). After stirring for 18 hours, the reaction mixture is filtered, the filtrate is partially concentrated, and the title compound is crystallized by the addition of di-iso-propyl ether: MS: [M + 1] + = 501; 1 H-NMR (DMSO-d 6): 8.91 (s, 1 H), 8.88 (s, 1 H), 8.66 (s, 1 H), 7.72 (d, 2 Hz, 1 H), 7.54 (d, 9 Hz, 2 H) , 7.36 (d, 8 Hz, 1 H), 7.35 (s, 1 H), 7.28 (dd, 8 Hz, 2 Hz, 1 H), 7.18 (d, 9 Hz, 2 H), 3.49 (s, 2 H), 2.43 (m, 8H), 2.32 (q, 7.1 Hz, 2H), 0.99 (t, 7.1 Hz, H3C).

The starting material is prepared as follows: Step 65.1: (4-Nitro-2-chloro-phenyl) - (4-ethyl-piperazin-1-yl) -methanone.

In a manner analogous to Step 5.1, 5.0 grams (24.8 millimoles) of 4-nitro-2-chloro-benzoic acid are activated with 6.0 milliliters (71 millimoles) of oxalyl chloride, and reacted with 6.6 milliliters (52 millimoles) of 1-ethyl-piperazine, yielding the title compound: MS: [M + 1] + = 298; HPLC AtRet = 7.3.

Step 65.2: (4-Amino-2-chloro-phenyl) - (4-ethyl-plperazin-1-yl) -methanone. The hydrogenation of 7.29 grams (24.5 miUmols) of (4-nitro-2-chloro-phenyl) - (4-eti piperazin-1-yl) -methanone in 130 milliliters of ethanol in the presence of 1.3 grams of Raney nickel, as described in Step 1.5, and crystallization from toluene, give the title compound: mp: 123-124 ° C; MS: [M + 1] + = 268.

Step 65.3: 4- (4-ethyl-piperazin-1-ylmethyl) -3-chloroaniline. In a manner analogous to Step 5.3, 5.06 grams (18.9 mMol) of (4-amino-2-chloro-phenyl) - (4-ethyl-piperazin-1-yl) -methanone in 60 milliliters of tetrahydrofuran are reduced by milliliters of BH3 (1 M in tetrahydrofuran). Chromatography (S02; CH2Cl2 / MeOH / NH3aq, 95: 5: 1 → 80: 20: 1) gives the title compound: MS: [M + 1] + = 254; 1 H-NMR (CDCl 3): 7.21 (d, 8 Hz, 1 H), 6.72 (d, 2.3 Hz, 1 H), 6.58 (dd, 8 Hz, 2.3 Hz, 1 H), 3.70 (s, H2N), 3.57 (s, 2H), 2.6 (m, 8H), 2.47 (q, 7.2 Hz, 2H), 1.13 (t, 7.2 Hz, H3C).

Example 66: 1 -T4- (2-am ino-pyrim id i n-4-yloxy-f in i I-3-C4-piperazin-1-ylmetM-3-trifluoromethyl-phenyl) -urea.

The hydrogenation of 107 milligrams (0.172 millimoles) of 4- (4. {3- [4- (2-amino-pyrimidin-4-yloxy) -phenyl] -ureido} -2-trifluoro- benzyl ester methyl-benzyl) -piperazine-1-carboxylic acid (Example 51. h. 1) in 6 milliliters of methanol in the presence of 20 milligrams of Pd / C (10 percent; Engelhard 4505), filtration, and chromatography flash evaporation Combi Flash (CH2Cl2 / MeOH + 1% NH3aq, 95: 5 → 4: 1), give the title compound: Rf (CH2Cl2 / MeOH / NH3aq, 80: 20: 1): 0.10; HPLC AtRet = 7.6; MS: [M + 1] + = 488; 1 H-NMR (CD 3 OD): 8.09 (d, 5.9 Hz, 1 H), 7.90 (m, 1 H), 7.74 (d, 8.2 Hz, 1 H), 7.64 (d, 8.2 Hz, 1 H), 7.53 (d, 9.0 Hz). , 2H), 7.12 (d, 9.0 Hz, 2H), 6.18 (d, 5.9 Hz, 1H), 3.63 (s, 2H), 2.88 (m, 4H), 2.48 (m, 4H).

Example 67: 1-r4- (2-Methyl-amino-pyrimidin-4-yloxy-pheyp-3 (4-p-piperazin-1-ylmethyl-3-trifluoro-methyl-phenyl) -urea.

It can be prepared in a manner analogous to the methods described herein.

Example 68: N - (6-f 4-f3-f3-trif I uoro-methyl-f in i l) -u laughed! phenoxy > -pyrimidin-4-yl) -acetamide.

-A fl cp N- (4- (4-chloropyrimidin-6-yl) -oxyphenyl) -N '- (3-trifluoromethyl-phenyl) -urea (Step 68.1) (100 milligrams, 0.245 milli-moles) , acetamide (40 milligrams, 0.68 millimoles), Pd2 (dba) 3 [tris- (dibenzyl-diketone) -dipaladium (0)] (6 milligrams), 4,5-bis- (diphenyl-phosphino) -9.9 Dimethylxanthrene (9 milligrams), and Cs2CO3 (160 milligrams), are stirred in tetrahydrofuran (3 milliliters) at 55 ° C for 8 hours under argon. After filtration and evaporation of the solvent, the product is isolated by preparative thin layer chromatography (4 plates 20 x 20 centimeters, acetone / CH 2 Cl 2 = 3: 7): white solid, M + H = 431.9. 1 H-NMR (400 MHz, DMSO-d 6): 10.85 (s, 1H, pyrimidinyl), 9.03 / 8.84 (s / s, 1H / 1H, urea), 8.45 (s, 1H, NH), 7.98 (s, 1H , piri idinilo), 7.56 (d, 8. 5 Hz, 1H), 7.56 (d / s, 9.0 Hz, 2H / 1H), 7.29 (d, 8.5 Hz, 1H), 7. 06 (d, 9.0 Hz, 2H), 2.09 (s, 3H, CH3), Rf (acetone / CH2Cl2 = 3: 7): 0.34.

Step 68.1: N- (4- (4-chloro-pyrimidn-6-yl) -oxyphenyl) -N '- (3-trifluoro-methyl-phenyl-urea.

After stirring 3-tri-fluoro-methyl-phenyl isocyanate (412 milligrams, 2.2 mmol), (4- (6-chloro-pyrimidin-4-yl-oxp-aniline) (Step 68.2, 0.25 grams, 1.1 mmol) , and pyridine (0.18 milliliters), dissolved in tetrahydrofuran (3 milliliters) overnight, the reaction solution is concentrated under reduced pressure and passed through flash chromatography (silica gel, 2.5 x 17 centimeters; acetone / CH2CI2 = 5:95 - 1: 9), to give the title compound as a colorless solid: M + H = 408.9 / 410.9, 1 H-NMR (400 MHz, DMSO-d 6): 9.07 (s, 1H, NH), 8.89 (s, 1H, NH), 8.63 (d, 2.0 Hz, 1H, pyridinyl), 8.01 (s, 1H, 3-CF3-phenyl), 7.57 (broad d, 8.0 Hz, 1H, CF3-phenyl), 7.52 (d, 9.5 Hz, 2H, oxo-phenyl-amine), 7.50 (m, 1H, 3-CF3-phenyl), 7.32 (d, 2.0 Hz, 1H, pyridinyl), 7.29 (broad d, 8.0 Hz, 1H, -CFs-phenyl), 7.15 (d, 9.5 Hz, 2H, oxo-phenyl-amine), (d, 6.5 Hz, 2H, pyridinyl); Rf (acetone / CH2Cl2 = 1: 9): 0.54; pf = 187.4- 189.7 ° C.

The starting materials are prepared as follows: Step 68.2: (4- (6-chloro-pyrimidin-4-yl-oxy) -aniline) 4-Chloro-6- (4-nitro-phenoxy) -pyrimidine (Step 68.3, 3.6 grams, 14.3 mmol) dissolved in MeOH (250 milliliters), hydrogenated in the presence of Raney nickel (3 grams) at 40 ° C. for 3 days.The reaction solution is filtered, concentrated under reduced pressure, and crystallized from EtOAc hexane to give 4-chloro-6- (4-amino-phenoxypyrimidine: M + H = 222/224; 1 H-NMR (400 MHz, DMSO-d 6): 8.62 (s, 1H, piperidinyl), 7.13 (s, 1 H, piperidinyl), 6.83 (d, 9 Hz, 2 H, phenyl), 6.56 (d, 9 Hz, 2 H, phenyl), 5.12 (s, 2 H, NH 2); mp = 135.5-138.1 ° C.

Step 68.3: 4-chloro-6- (4-nitro-phenoxypyrimidine) 4-nitrophenol (2.8 grams, 20.1 mmol), 2,4-dichloro-pyrimidine (3 grams, 20.1 mmol), NaOH (0.8 grams) , 20.1 mmol) dissolved in H20 / acetone (80 milliliters, 1: 1), stirred at 60-65 ° C for 1 hour.The reaction solution is concentrated under reduced pressure and passed through flash chromatography (gel silica, 4.5 x 22 centimeters, EtOAc / hexane = 1: 4), to give the title compound as a colorless solid: M + H = 252/254; 1 H-NMR (400 MHz, DMSO-d 6): 8.67 ( s, 1H, pyrimidinyl), 8.34 (d, 9 Hz, 2H, phenyl), 7.58 (d, 9 Hz, 2H, phenyl), 7.53 (s, 1H, pyrimidinyl); Rf (EtOAc / hexane = 1: 1) : 0.16; pf = 125.4-126.6 ° C.

Example 69: N - (6-f 4-r3- (4-morpholin-4-l-3-trif) luoro-methyl-phein-ureido-phenoxy-pyrimidin-4-in-acetamide.

The title compound is prepared in a manner analogous to the synthesis of the compound of Example 68 from 1- [4- (6-chloro-pyrimidin-4-yloxyl) -phenyl] -3- (4-morpholine- 4-yl-3-trifluoro-methyl-phenyl) -urea (Step 69.1): beige solid, M + H = 516.9, HPLC [20? 100 percent CH3CN (0.1 percent trifiuoroacetic acid) and H20 (0.1 percent trifluoroacetic acid) in 7 minutes, and remaining in 100 percent CH3CN (0.1 percent trifluoroacetic acid) for 2 minutes] : t Ret = 7.72 minutes, Rf (MeOH / CH2Cl2 = 1: 9): 0.42.

Step 69.1: 1- [4- (6-chloro-pyrimidin-4-yloxy) -fenin-3- (4-morpholin-4-yl-3-trifluoro-methyl-phenyl) -urea. The title compound is prepared in a manner analogous to the synthesis of the compound of Example 1, starting from the compound of Step 55c.2: white solid, M-H = 491.9, HPLC [20? 100 percent CH3CN (0.1 percent trifluoroacetic acid) and H20 (0.1 percent trifluoroacetic acid) in 7 minutes and remaining at 100 percent CH3CN (0.1 percent trifluoroacetic acid) for two minutes]: tRet = 7.52 minutes, Rf (Me0H / CH2CI2 = 3:97): 0.17.

Example 70: 6- (4-f 3-T4-F 4-ethyl-piperazin-1-ylmethyl) -3-trifluoro-methyl-phenyl-1-ureido-r-phenoxy) -pyrimidin-4-methyl ester ill-carbámico. 787 microliters (10.2 mMol) of methyl chloroformate dissolved in 10 milliliters of CH2Cl2 are slowly added to a solution of 160 milligrams (0.31 mMol) of 1- [4- (6-aminopyrimidin-4-yloxy) -phenyl] - 3- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea (Step 70.1), 5.6 milliliters of pyridine, and 20 milligrams of dimethylaminopyridine in 16 milliliters of CH2Cl2 at room temperature. After stirring for 2 hours, the resulting suspension is filtered, the filtrate is diluted with 100 milliliters of EtOAc, washed twice with H20 and brine. The aqueous layers are extracted twice with EtOAc, the organic phases are dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography Combi Flash (CH2Cl2 / NH3aq / MeOH, 96: 1: 3 → 90: 1: 9) gives white crystals: m.p .: 191-193 ° C; Analysis C27H30N7F3O4: C.H.N; MS: [M + 1] + = 574.

Step 70.1: 1-r4- (6-Amino-pyrimidin-4-yloxp-pheny1-3-r4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl-urea. of the title is prepared in a manner analogous to the synthesis of the compound of Example 19: Analysis C25H28N7F3O2 • 0.86 H20: C, H, N, F, H20; MS: [M + 1] + = 516; HPLC AtRet = 8.0.

Example 71: 1-r4- (2-Acetyl-amino-pyrimidin-4-Moxp-phenM1-3-r4- (4-methyl-piperazin-1-Mmethyl) -3-trifluoromethyl-phenol-u-reactane. 119 microliters (1.67 millimoles) of acetyl chloride dissolved in 7 milliliters of CH2Cl2 for 2.5 hours are added to a solution of 250 milligrams (0.50 millimoles) of 1- [4- (2-amino-pyrimidin-4-yloxyl) -fen L] -3- [4- (4-methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea (Example 52a) and 10 milligrams of dimethylaminopyridine in 6.5 milliliters of pyridine. After stirring for another hour, the mixture is diluted with 200 milliliters of water and 250 milliliters of EtOAc. The separated aqueous layer is re-extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4), and concentrated in vacuo. Reverse phase chromatography (Gilson System) gives the title compound: acetone / EtOH + Et3N 1 percent, 95: 5? 4: 1; MS: [M + 1] + = 544; R f (aceton a / EtO H / Et 3 N, 80: 20: 1): 0.11; HPLC AtRe = 7.8.

Eiem pio 72: The following compounds can be prepared in a manner analogous to the procedures described: Example 73: 3-f3- (4-f6-r4-terbutil-d im ethyl-silan-iloxp-phenyl-amino-1-pyrimidin-4-yloxy > -phenyl) -ureido-1-5-trifluoro-methyl-benzamide .

The title compound is prepared by the formation of urea from [6- (4-amino-phenoxy) -pyrimidin-4-yl] - [4- (tert-butyl-dimethyl-silanyloxy) -phenyl] -amine and -amino-5-trifluoromethyl-benzamide (Step 73.1) in a manner analogous to the preparation of the compound of Example 54: MS: [M + 1] + = 639; Rf (MeOH / CH2Cl2) = 1: 9): 0.49.

Step 73.1: [6- (4-Amino-phenoxypyrimidin-4-in- [4-tert-butyl-dimethyl-silanyloxp-phenyl-amine] The title compound is prepared as described in International Publication Number WO 2003/099771.

Example 74: 1 - (3'-chloro-2-trif luoro-methyl-biphenyl-4-yl) -3 f4-r2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy -2-m ethyl-f in i I) -u rea.

A solution of 3'-chloro-2-trif I uoro-methyl-biphenyl-4-amine (48 milligrams, 0.18 mmol) and di-isopropyl-ethyl-amine (67 microliters, 0.38 mmol, 2.2 equivalents) in CH2Cl2 (0.6 milliliters), it is added dropwise to a cold solution (0 ° C) of tri-phosgene (19 milligrams, 0.07 millimoles) in CH2CI2 (0.6 milliliters). Then a solution of N- [4- (4-amino-3-methyl-phenoxy) -pyrimidin-2-yl-N ', N'-dimethyl-butane-1,4-diam is added to the reaction mixture. ina (56 milligrams, 0.18 millimoles) and di-isopropyl-ethyl-amine (66 microliters, 0.38 millimoles, 2.2 equivalents) in CH2Cl2 (1.1 milliliters). The mixture is allowed to warm to room temperature, stirred for 10 minutes, and concentrated in vacuo. Purification by medium pressure liquid chromatography (CH3CN / H20 / TFA) of the crude material gives the title compound as a yellow solid: MS: 613.9 [M] +; HPLC DtRet = 4.2.

Step 74.1 N-í4- (4-amino-3-methyl-phenoxy) -pyrimidin-2-yN'.N'-dimethyl-butan-1,4-diamine.

A mixture of [4- (2-chloro-pyrimidin-4-yloxy) -2-methyl-phenyl] -amine (808 milligrams, 3.43 mmol), 4-di-methyl-amino-butyl-amine (438 milligrams, 3.77 millimoles, 1.1 equivalents), and K2CO3 (1.3 grams, 9.26 mmol, 2.7 equivalents) in dimethyl formamide (8 milliliters) is stirred for 1 hour at 100 ° C. The reaction mixture is allowed to cool to room temperature, and is filtered through a sintered glass funnel. The filtrate is concentrated in vacuo. Purification of the crude material by silica gel column chromatography (CH2Cl2 / MeOH, 9: 1? CH2Cl2 / MeOH + 1 percent NH3aq, 9: 1) gives the title compound as a yellow oil: MS: 316.1 [ M] +; Rf = 0.23 (CH2Cl2 / MeOH + 1% NH3aq, 4: 1).

Step 74.2: r4- (2-Chloro-pyrimidin-4-yloxy) -2-methyl-phenyl-11-amine.

A mixture of 2-chloro-4- (3-methyl-4-nitro-phenoxypyrimidine (992 milligrams, 3.73 mmol) and Raney nickel (700 milligrams) in MeOH / THF (3: 1, 40 milliliters) is stirred for 7 hours at room temperature under a hydrogen atmosphere.The reaction mixture is filtered through a pad of Celite, and the filtrate is concentrated in vacuo, to give the title compound as a yellow solid: MS: 236.0 [M + 1] +; HPLC DtRet = 2.2.

Step 74.3: 2-Chloro-4- (3-methyl-4-nitro-phenoxypyrimidine. 2,4-Dichloro-pyrimidine (3.7 grams, 25.17 millimoles, 2 equivalents) is added in one portion, to a mixture of 4-nitro-m-cresol (1.9 grams, 12.59 millimoles) and NaOH powder (0.605 grams, 15.11 millimoles, 1.2 equivalents) in dimethyl formamide (25 milliliters). The reaction mixture is stirred for 1 hour at room temperature, diluted with H20 (300 milliliters), and extracted with EtOAc (600 milliliters).

The aqueous layer is saturated with NaCl and extracted with CH2Cl2 / MeOH (9: 1, 300 milliliters twice). The combined organic phase is dried (Na 2 SO), filtered, and concentrated. The resulting yellow crystalline material is purified by silica gel column chromatography (hexane? Hexane / EtOAc, 6: 1 - »4: 1), to give the title compound as white crystals: HPLC DtRet = 4.7; Rf = 0.17 (hexane / EtOAc, 3: 1).

Step 74.4: 3'-clo r 0-2 -trif luoro-m eti -bifeni l-4-amine, A mixture of 5-amino-2-bromobenzotrifluoride (500 milligrams, 2.1 micromoles), 3-chloro-phenyl-boronic acid (970 milligrams, 6.2 millimoles, 3 equivalents), Pd (PPh3) 4 (70 milligrams, 0.018 millimoles, 0.03 equivalents), Na 2 CO 3 (2 M solution in H 2 O, 5 milliliters, 10 mmol, 4.76 equivalents), and toluene (14 milliliters), is stirred at reflux for 1 hour. The reaction mixture is allowed to cool to room temperature and is filtered through a pad of Celite, washing the filter cake with CH2Cl2 and H20. The layers are separated, and the aqueous phase is extracted with CH2Cl2 (60 milliliters, 2 times). The combined organic phase is washed with brine, dried (Na2SO), filtered, and concentrated in vacuo. Purification by medium pressure liquid chromatography (CH3CN / H20 / TFA) of the crude material gives the title compound: MS: 270.0 [M-2] "; HPLC DtRet = 4.9.

Example 75: 2- (3'-bromo-2-trifluo-ro-methyl-bifenyl-4-P-3 f4-r2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-lox 1-2-m eti lf in i 1 - u rea.

The title compound is prepared as described in Example 74 for 1- (3'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using 3'-bromo-2-trifluoromethyl-biphenyl-4-amine. The title compound: MS: 658.8; [M + 1] +; HPLC DtRet = 4.3; Rf = 0.47 CH2Cl2 / Me0H, 99: 1).

Step 75.1: 3'bromo -2-trif I or oro-m e til-bife n il-4-a mine, The title compound is prepared as described in Example 74 (Step 74.4) for 1- (3'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using 3-bromo-phenyl-boronic acid. The title compound: MS: 315.9 [M + 1] +; HPLC DtRet = 4.9; Rf = 0.16 (hexane / EtO Ac, 4: 1).

Example 76: 1 - (4'-chloro-2-trif luoro-methyl-b if in i I -4 - i I) - 3 f4-r2- (4-d-methyl-amino-butyl-amino) - pyridin-4-xloxy-1-2-methyl-f-yl) -urea.

The title compound is prepared as described in Example 74 for 1- (3'-chloro-2-trifluoro-methyl-b-phenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using 4'-chloro-2-trifluoro-methyl-biphenyl-4-amine. The title compound: MS: 612.9 [M] +; HPLC DtRet = 4.3; Rf = 0.13 (CH2Cl2 / Me0H + 1% aqueous NH3, 9: 1).

Step 76.1: 4'-chloro-2-triflu or ro-methyl-biphenyl-4-amine.

The title compound is prepared as described in Example 74 (Step 74.4) for 1- (3'-chloro-2-trifluoro-methyl-biphenyl-4-yl) -3-. { 4- [2- (4-dlmethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using 4-chloro-phenyl-boronic acid. The title compound: MS: 270.0 [M -2] -; HPLC DtRet = 4.9.

Example 77: 1- (4'-b rom or-2-trif luoro-m eti-l-bif in l-4-yl) -3 f4-r2- (4-dimethyl-amino-butl-amino) -pyrimidin-4-yloxy-1-2-methyl-phenyl-urea.

The title compound is prepared as described in Example 74 for 1- (3'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using 4'-bromo-2-trifluoro-methyl-biphenyl-4-amine. The title compound: MS: 658.8 [M + 1] +; HPLC DtRet = 4.4; Rf = 0.07 (CH2Cl2 / Me0H + 1% aqueous NH3, 9: 1).

Step 77.1: 4'-bromo-2-trifluoro-methy! -biphenl-4-amine, The title compound is prepared as described in Example 74 (Step 74.4) for 1- (3'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-buty-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using 4-bromo-phenyl-boronic acid. The title compound: MS: 315.9 [M -1] "; HPLC DtRet = 4.9; Rf = 0.14 (Hexane / EtOAc, 4: 1).

Example 78: 1 - (3'-chloro-2-trif I uoro-methyl-bif in M-4-ÍP-3-f4-r2- (4-dimethyl-amino-butyl-amino) -pyrimidin 4-yloxy-1-2-tr, fluoro-methyl-phenyl-urea.

The title compound is prepared as described in Example 74 for 1- (3'-chloro-2-trif luoro-methyl-biphen-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyridin-4-yloxy] -2-methyl-phenyl} -urea, but using N- [4- (4-amino-3-trifluoro-methyl-phenoxy) -pyrimidin-2-yl] -N ', N'-dimethyl-butan-1,4-d-amines. The title compound: MS: 668.8 [M + 1] +; HPLC DtRet = 4.4; Rf = 0.01 (CH2Cl2 / MeOH + aqueous NH3 at 1 percent, 9: 1).

Step 78.1: N-4 (4-amino-3-trifluoro-methyl-phenoxypyrimidin-2-y-N ', N'-dimethyl-butane-1,4-diamine).

The title compound is prepared as described in Example 74 (Step 74.1) for N- [4- (4-amino-3-methyl-phenoxy) -pyrimidin-2-yl] -N ', N'-dimethyl- butan-1,4-diamine, but using [4- (2-chloro-pyrimidin-4-yloxy) -2-trifluoromethyl-phenylline. The title compound: MS: 370.1 [M] +; HPLC DtRet = 2.6; Rf = 0.14 (CH2Cl2 / Me0H + 1% aqueous NH3, 4: 1).

Step 78.2: f4- (2-Chloro-pyrimidin-4-yloxp-2-trifluoromethyl-phenyl-amine.

The title compound is prepared as described in Example 74 (Step 74.2) for [4- (2-chloro-pyrimidin-4-yloxy) -2-methyl-phenyl-amine, but using 2-chloro-4- ( 4-nitro-3-trifluoro-methyl-phenoxy) -pyrimidine. The title compound: MS: 288.0 [M-1] "; HPLC DtRet = 4.6.

Step 78.3: 2-chloro-4- (4-nitro-3-trifluoro-methyl-phenoxp-pyrimidine.

The title compound is prepared as described in Example 74 (Step 74.3) for 2-chloro-4- (3-methyl-4-nitro-phenoxypyrimidine, but using 4-nitro-3- (trifluoromethyl)) The reaction mixture is stirred for 3 hours at room temperature The title compound: MS: 317.9 [M-1] "; HPLC DtRet = 4.8.

Example 79: 1 - (3'-brom or-2-trifluo-ro-methyl-bif in M-4-ÍP-3-f4-r2- (4-dimethyl-amino-butyl-amine) -pyrimidin- 4-Iloxy1-2-tri-fluoro-methyl-phenyl-urea.

The title compound is prepared as described in Example 75 for 1- (3'-bromo-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using N- [4- (4-amino-3-tpfluoromethyl-phenoxy) -pyrimidin-2-yl} -N ', N'-d-methyl-butan-1,4-diamine (Example 78, Step 78.1). The title compound: MS: 712.7 [M + 1] +; HPLC DtRet = 4.5; Rf = 0.04 (CH2Cl2 / MeOH + aqueous NH3 at 1 percent, 9: 1).

Example 80: 2- (4'-chloro-2-trifluoro-m ethyl-bifenyl-4-iP-3-f4-r2- (4-dimethylamino-butyl-amino) -pyrimidin- 4-yloxy-1-2-tri-fluoro-methyl-phenyl-urea.

The title compound is prepared as described in Example 76 for 1- (4'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using N- [4- (4-amino-3-trifluoromethyl-phenoxy) -pyrimidin-2-yl] -N ', N, -dimethyl-butan-1,4-diamine (Example 78, Step 78.1). The title compound: MS: 668.8 [M + 1] +; HPLC DtRet = 4.5; Rf = 0.08 (CH2Cl2 / Me0H + 1% aqueous NH3, 9: 1).

Example 81: 1 - (4'-bromo-2-trif luoro-methyl-bifen M-4-ÍP-3-f4-r2- (4-dimethylamino-butylamino) -pyrimidin-4-yloxy-1-2-tri -fluoromethyl-phenyl-urea.

The title compound is prepared as described in Example 77 for 1- (4'-bromo-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using N- [4- (4-amino-3-trifluoromethyl-phenoxy) -pyrimidin-2-yl] -N ', N'-dimethyl-butan-1,4-diamine (Example 78, Step 78.1). The title compound: MS: 712.7 [M + 1] +; HPLC DtRet = 4.5; Rf = 0.07 (CH2Cl2 / Me0H + 1% aqueous NH3, 9: 1).

Example 82: 1 - (3'-chloro-2-trif I uoro-methyl-b if in i I-4-11) - 3 • f4-r2- (4-dimethyl-amino-butyl-amino) ) -pyrimidin-4-yloxy-f in iP-u rea.

The title compound is prepared as described in Example 74 for 1- (3'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amine-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using N- [4- (4-amino-phenoxy) -pyrimidin-2-yl] -N ', N'-dimethyl-butan-1,4-diamine. The title compound: MS: 600.9 [M + 1] +; HPLC DtRet = 4.3; Rf = 0.02 (CH2Cl2 / Me0H + 1% aqueous NH3, 9: 1).

Step 82.1: N-f4- (4-amino-phenoxy) -pyrimidn-2-1-N ', N; dimethyl-butan-1,4-diamine.

The title compound is prepared as described in Example 74 (Step 74.1) for N- [4- (4-amino-3-methyl-phenoxy) -pyrimidin-2-yl] -N ', N'-dimethyl. -butan-1,4-diamine, but using 4- (2-chloro-pyrimidin-4-yloxy) -phenyl-amine. The title compound: MS: 302.2 [M] +; Rf = 0.27 (CH2Cl2 / MeOH + 1% aqueous NH3, 4: 1). Step 82.2: 4- (2-Chloro-pyrimidin-4-yloxp-phenylamino).

The title compound is prepared as described in Example 74 (Step 74.2) for [4- (2-chloro-pyrimidin-4-yl) -2-methyl-phenyl] -amine, but using 2-chloro- 4- (4-nitro-phenoxypyrimidine (Example 45, Step 45.1) The title compound: MS: 223.9 [M + 1] +; HPLC DtRet = 1.6; R, = 0.62 (CH2Cl2 / MeOH, 95: 5 ).

Example 83: 1- (4'-chloro-2-trifluo-ro-methyl-bifenyl-4-iP-3-f4-r2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy1- f enil.}. -u rea.

The title compound is prepared as described in Example 76 for 1- (4'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using N- [4- (4-amino-phenop-pyrim idin-2-yl] -N ', N' -d-imethyl-butan-1,4-diamine (Example 82, Step 82.1). Title compound: MS: 598.9 [M] +; HPLC DtRet = 4.3; Rf = 0.10 (CH2Cl2 / MeOH + 1% aqueous NH3, 9: 1).

Example 84: 1 - (4'-bromo-2-trif luoro-methyl-bifenyl-4-yl) -3- f4-r2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-lox 1 f in i I > - u rea.

The title compound is prepared as described in Example 77 for 1 - (4'-brom or-2-trif I uoro-methyl-biphenyl-4-yl) -3-. { 4- [2- (4-Dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using N- [4- (4-amino-phenoxy) -pyrimidin-2-yl] -N ', N'-dimethyl-butan-1,4-diamine (Example 82, Step 82.1). The title compound: MS: 644.8 [M-1] +; HPLC DtRet = 4.3; Rf = 0.10 (CH2Cl2 / MeOH + 1% aqueous NH3, 9: 1).

Example 85: 1-f 4-T2-f 3-methoxy-f in il-am i no) -pyrim id in-4-yloxy-1-phenyl-3-r4- (4-methyl-piperazin-1-methyl) - 3-trifluoro methyl-f in ill-u rea.

The title compound is prepared as described in Example 74 for 1- (3'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using [4- (4-amino-3-methyl-phenoxypyrimidin-2-yl] - (3-methoxy-phenyl) -amine and 4- (4-methyl-piperazin-1-ylmethyl) ) -3-trifluoro-methyl-amino (Example 14, Step 14.4) The title compound: MS: 622.0 [M + 1] +; HPLC DtRet = 3.5; Rf = 0.33 (CH2Cl2 / MeOH + aqueous NH3 at 1 percent, 9: 1).

Step 85.1: [4- (4-amino-3-methyl-phenoxp-pyrimidin-2-yl-1- (3-methoxy-phenyp-amine.

A mixture of (3-methoxy-phenyl) - [4- (3-methyl-4-nitro-phenoxy) -pyrimidin-2-yl] -amine (400 milligrams, 1.14 mmol) and Raney's nickel (200 milligrams) in MeOH / THF (3: 1, 40 milliliters) is stirred for 2 hours at room temperature under an atmosphere of hydrogen. The reaction mixture is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to provide the title compound as a yellow-brown solid: MS: 323.1 [M + 1] +; HPLC DtRet = 2.6.

Step 85.2: (3-methoxy-phenyp- [4- (3-methyl-4-nitro-phenoxypyrimidin-2-ill-amine A mixture of 2-chloro-4- (3-methyl-4-nitro-phenoxy) -pyrimidine (Example 74, Step 74.3) (700 milligrams, 2.63 mmol), m-anisidine (357 milligrams, 2.90 mmol, 1.1 equivalents) , and 2-propanol (10.5 milliliters), is stirred for 1 hour at 100 ° C. The reaction mixture is allowed to cool to room temperature, diluted with H20 (90 milliliters), and extracted with CH2Cl2 (350 milliliters). The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The title compound: MS: 353.3 [M + 1] +; HPLC DtRet = 4.6; Rf = 0.08 (hexane / EtOAc 3: 1).

Example 86: 1, 2-methyl-4-f 2-r4- (4-methyl-piperazin-1 -iP-phenM-amino-1-pyridin-4-Moxy) -phenyl-3- (3-trifluoromethyl) il) -urea.

The title compound is prepared as described in Example 74 for 1- (3'-chloro-2-trifluoromethyl-biphenyl-4-yl) -3-. { 4- [2- (4-dimethyl-amino-butyl-amino) -pyrimidin-4-yloxy] -2-methyl-phenyl} -urea, but using [4- (4-amino-3-methyl-phenoxy) -pyrimidin-2-yl] - [4- (4-methyl-p-eperazin-yl) -phenyl] -amine and 3-amino-benzotrifluoride. The title compound: MS: 577.9 [M] +; HPLC DtRet = 3.7; Rf = 0.29 (CH 2 Cl 2 / M eO H, 9: 1).

Step 86.1: r4- (4-amino-3-methyl-phenoxy) -pyrimidin-2-yl-r4- (4-methyl-piperazin-1-iP-phenylamine.

A mixture of [4- (3-methyl-4-nitro-phenoxy) -pyrimidin-2-yl] - [4- (4-methyl-piperazin-1-yl) -phenyl] -am ine (133 milligrams, 0.32 mmol) and Raney nickel (50 milligrams) in MeOH (10 milliliters), is stirred for 6 hours at room temperature, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite, and the filtrate is concentrated in vacuo, to give the title compound as a red-brown solid: MS: 391.1 [M] +; HPLC DtRet = 1-3.

Step 86.2: í4- (3-Methyl-4-nitro-phenoxy) -pyrimidin-2-ill-f4- (4-methyl-piperazin-1-yl) -phenyl] -amine A mixture of 2-chloro-4- (3-methyl-4-nitro-phenoxy) -pyrimidine (Example 74, Step 74.3) (400 milligrams, 1.51 mmol), 4- (4-methyl-piperazin-1-yl) ) -phenylamine (318 milligrams, 1.66 millimoles, 1.1 equivalents), 4N HCl (1.1 milliliters, 4.08 millimoles, 2.7 equivalents), and 2-propanol (6 milliliters), is stirred for 1 hour at 100 ° C. The reaction mixture is allowed to cool to room temperature, diluted with H20 (30 milliliters), and extracted with CH2Cl2 (120 milliliters). The organic phase is washed with brine, dried (Na2SO4), filtered, and concentrated. The title compound: MS: 421.1 [M + 1] +; HPLC DtRet = 3.1; Rf = 0.39 (CH2Cl2 / MeOH, 9: 1).

Example 87: 1-f 4-r6- (5-Chloro-2-methoxy-phen-yl-yl) -pyrimidin-4-Moxy-1-phenyl-3- (4-morpholin-4-M-3-trifluoromethyl) f eniP-u rea.

To a solution of 1- [4- (6-chloro-pyrimidin-4-yloxp-phenyl] -3- (4-morpholin-4-yl-3-trifluoro-methyl-phenyl) -urea (Step 69. 1) (34 milligrams, 68 micromoles) in 3 milliliters of isopropanohdioxane (1: 1, volume / volume), 5-chloro-2-methoxy-phenylamine (54 milligrams, 340 micromoles, Fluka, Buchs, Switzerland) was added. ) and concentrated HCl (5 microliters). The mixture is heated in a microwave oven (Emrys Optimizer, Personal Chemistry, Uppsala, Sweden) until the reaction is complete. The reaction mixture is diluted with EtOAc (50 milliliters), and extracted with 0.1 N NaOH (2 times) and water (2 times). The aqueous phases are discarded, and the organic is dried (Na2SO4), filtered, and concentrated to dryness. The title compound is obtained by chromatography on silica gel (CH2Cl2 / MeOH, 98: 2, volume / volume): MS: 615.2, 616.4, 617.4; HPLC tRetnuev ° = 8.67 (NEW GRADIENT: Linear gradient for 7 minutes of MeCN / 0.09% TFA and H20 / 0.1% TFA from 1:49 to 1: 0 and 3 minutes to 1: 0, detection at 215 nanometers, flow rate 2.0 milliliters / minute Column: Nucleosil C18 column (250 x 4.6 millimeters, 5 microns, 100 Angstroms).

The following compounds are prepared as described in Example 87, using the appropriate amine derivative: Example 96: Inhibition of the activity of the tyrosine protein kinase of RET. Inhibition tests are carried out as described above. The IC50 values for some of the compounds of the formula I are given in the following table: Name of Compound IC50 RET [μM] 1- [4- (6-amino-pyrimidin-4-yloxy) -phenyl] -3- (3- 0.083 azetidin-l-ylmethyl-5-trifluoromethyl-phenyl) -urea 1- (3-dimethylaminomethyl-5-trifluoromethyl) phenyl) -3- 0.11 [4- (6-methylamino-pyrimidin-4-yloxy) -phenyl] -urea 1- [4- (2-amino-pyrimidin-4-yloxy) -phenyl] -3- [4 - (4- 0.18 methyl-piperazin-1-ylmethyl) -3-trifluoromethyl-phenyl] -urea 1- [4- (6-amino-pyrimidin-4-yloxy) phenyl] -3- [3- (4- 0.26 methyl-piperazin-1-ylmethyl) -5-trifluoromethyl-phenyl] -urea l- [4- (2-amino-pyrimidin-4-yloxy) -phenyl] -3- [4- (4- | 0.31 ethyl-piperazine -1-ylmethyl) -3-trif luor omethyl-phenyl] -urea 1- [4- (4-ethyl-piperazin-1-ylmethyl) -3-trifluoro-I 0.35 methyl-f-enyl] -3- [4 - (2-methylamino-pyrimidin-4-yloxy) -phenyl] -urea 1- [4- (2-amino-pyrimidin-4-yloxy) -phenyl] -3- [4- (4- I 0. 4 isopropyl -piperazin-1-ylmethyl) -3-trif luoromethyl-phenyl] -urea 1- [4- (2-methylamino-pyrimidin-4-yloxy) -phenyl] -3- | 0.45 [4- (4-methyl-piperazin-1-yl) -3-trifluoromethyl-phenyl] -urea 1- [4- (2-methylamino-pyrimidin-4-yloxy) -phenyl] -3- Example 97: Inhibition of the activity of the tyrosine protein kinase of Flt-3 Inhibition tests are carried out as described above. The IC50 values for some of the compounds of the Examples are given in the following table: Example No. IC50 Flt-3 [μM] 1 0.905 2 1.2 4 0.153 5 0.54 6 0.4 8 0.51 9 0.32 11 0.23 13 0.34 14 0.36 15 0.6 16 0.36 17 0.94 19 0.25 19-1 0.038 19-2 0.08 21 1.8 23 1.3 24 0.17 34a.1 1.1 34a.3 0.83 34b.1 0.36 34b.3 0.37 34c.1 0.54 34c.3 0.35 34d.1 0.67 34d.3 0.29 34e.1 0.16 34e.3 0.079 34g.1 0.3 34g.3 0.378 34J.1 0.25 34J.3 0.283 34k.1 0.13 34k.3 0.1 341. 1 0.62 34m.1 0.4 34m.3 0.2 34n.1 0.31 34n.3 0.2 34p.1 0.59 34S.2 0.24 34t.2 0.29 34u.2 1.5 34W.2 0.14 38 0.354 41 0.42 43 0.16 48 0.58 50 0.12 51a.1 0.085 51a.2 0.12 51b.1 0.13 51b.2 0.17 51 d.1 0.091 51d.2 0.135 51e.1 0.25 51e.2 0.91 52a 0.12 52b 0.08 52c 0.029 52d 0.26 53b 0.12 53d 0.19 55c 0.37 55d 0.97 57 0.118 58 0.12 59 0.076 60 0.16 61 0.49 62 0.16 63 0.14 64 0.34 Example 98: Inhibition of Flt-3-dependent cell proliferation. The inhibition assay is carried out as described above, using the hematopoietic cell line Ba / F3 dependent on IL-3 and the mutant sub-lines ITD-Ba / F3 or D835Y-Ba / F3, which express the Flt kinases. -3 constitutively activating. The ED5o values for some of the compounds of the Examples are given in the following table: Inhibition of Flt-3 Dependent Proliferation (ED50 [nM]). Axis Pl or N o. ITD-Mutant D835-Mutant 53c 0.1 3.3 55a < 0.5 < 0.5 45 < 0.2 0.5 46 < 0.2 3.9 55b < 0.5 < 0.5 49 0.1 11.7 53a < 0.5 1.0 Example 99: Tablets comprising a compound of the Axis. Tablets are prepared which comprise, as an active ingredient, 100 milligrams of any of the compounds of Examples 1 to 95, with the following composition, following the conventional procedures: Composition Active ingredient 100 mg Crystalline lactose 240 mg Avicel 80 mg PVPPXL 20 mg Aerosil 2 mg Magnesium stearate 5 mg 447 mg Manufacturing: The active ingredient is mixed with the vehicle materials, and compressed by means of a tablet-forming machine (Korsch EKO, 10-millimeter die). Avicel is microcrystalline cellulose (FMC, Philadelphia, E.U.A.). PVPPXL is cross-linked polyvinyl-polypyrrolidone (BASF, Germany). Aerosil is silicon dioxide (Degussa, Germany).

Example 100: Capsules. Capsules are prepared which comprise, as active ingredient, 100 milligrams of any of the compounds of Examples 1 to 95, of the following composition, according to the conventional procedures: Com position Active ingredient 100 mg Avicel 200 mg PVPPXL 15 mg Aerosil 2 mg Magnesium stearate 1.5 mg 318. 5 mg Manufacturing is done by mixing the components and filling them in hard gelatin capsules, size 1.

Claims (12)

1. CLAIMS The use of a compound of the formula wherein G is not present, or it is lower alkylene or cycloalkylene of 3 to 5 carbon atoms, and Z is a radical of the formula la: or G is not present, and Z is a radical of the formula Ib: A is CH, N or N? O and A 'is N or N? Or, with the proviso that no more than one of A and A 'may be N ~ »O; n is 1 or 2; m is 0, 1, or 2; p is 0, 2, or 3; r is from 0 to 5; X is NR if p is 0, where R is hydrogen or an organic fraction, or if p is 2 or 3, X is nitrogen which, together with (CH2) P and the bonds represented in dotted (interrupted) lines (including atoms with which they are linked), forms a ring, or X is CHK, wherein K is lower alkyl or hydrogen, and p is zero, with the proviso that the bonds represented in dotted lines, if p is zero, are absent; Y-, is O, S, or CH2; Y2 is O, S, or NH; with the proviso that (Y?) p- (Y2) m does not include groups O-O, S-S, NH-O, NH-S, or S-O; each of R ,, R2, R3, and Rs, independently of the others, is hydrogen or an inorganic or organic fraction, or any two of them together form a lower alkylene-dioxyl bridge bonded via the oxygen atoms, and the remaining of these fractions is hydrogen or an inorganic or organic fraction; and R4 (if present, that is, if r is not zero) is an inorganic or organic fraction; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; for the manufacture of a pharmaceutical composition for the treatment of a RET-dependent disease.
2. 2. The use according to claim 1, wherein the RET-dependent disease is a tumor disease dependent on RET.
3. 3. The use according to claim 2, wherein the RET-dependent tumor disease is selected from colon cancer, lung cancer, breast cancer, pancreatic cancer, and thyroid cancer.
4. 4. The use according to claim 3, wherein the cancer is thyroid cancer.
5. 5. A N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivative selected from the group consisting of the compounds of Examples 1 to 67, 68 to 70, or 71 to 95, as described in the description, or a salt thereof.
6. 6. A pharmaceutical composition comprising a N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivative selected from the group consisting of the compounds of Examples 1 to 67, 68 to 70, or 71 to 95, as described in the description, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. 7. A N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivative selected from the group consisting of the compounds of Examples 1 to 67, 68 to 70, or 71 to 95, as described in the description, or a pharmaceutically acceptable salt thereof, for use in the treatment of the animal or human body, especially in the treatment of a protein kinase-dependent disease. A compound according to claim 7, wherein the protein kinase-dependent disease to be treated is a tyrosine protein kinase-dependent disease, especially a proliferative disease dependent on any one or more of the following protein tyrosine kinases: c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R, and / or Tek, especially Flt-3. 9. The use of a N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivative selected from the group consisting of the compounds of Examples 1 to 67, 68 a 70, or 71 to 95, as described in the description, or a pharmaceutically acceptable salt thereof, for use in the treatment of a protein kinase-dependent disease. 10. The use of an N- [4- (pyrimidin-4-yloxy) -phenyl] -N'-phenyl-urea derivative selected from the group consisting of the compounds of Examples 1 to 67, 68 to 70 , or 71 to 95, as described in the description, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for use in the treatment of a protein kinase dependent disease. The use according to claim 9 or 10, wherein the protein kinase-dependent disease is a tyrosine protein kinase dependent disease, especially a proliferative disease that depends on any one or more of the following protein kinases. tyrosine protein: c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R, and / or Tek, especially Flt-3. 12. A method of treatment for a disease that responds to the inhibition of a protein kinase (especially tyrosine), which comprises administering a prophylactically, or especially therapeutically effective amount of an N- [4- (pyrimidine- 4-yloxy) -phenyl] -N'-phenyl-urea selected from the group consisting of the compounds of Examples 1 to 67, 68 to 70, or 71 to 95, as described in the description, or a salt pharmaceutically acceptable thereof, to a warm-blooded animal, for example a human being, in need of such treatment.