MXPA06011106A - Novel diazine derivatives, their manufacture and use as pharmaceutical agents - Google Patents

Abstract

Objects of the present invention are the compounds of formula (I), their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the useof the above-mentioned compounds in the control or prevention of illnesses such as cancer.

Description

NEW DERIVATIVES OF DIAZINE, ITS MANUFACTURE AND ITS USE AS PHARMACEUTICAL AGENTS DESCRIPTION OF THE INVENTION The present invention relates to new diazine derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to the use of these compounds as active pharmaceutical agents. Protein tyrosine kinases (PTK) catalyze the phosphorylation of tyrosyl residues of several proteins involved in the regulation of cell growth and differentiation (IL et al., Progress in Growth Factor Research 91 (1990) 2; AC, and Shaw, AS, Curr Opin. Immunol., 8 (1996) 394-401). These PTKs can be divided into receptor tyrosine kinases (eg EGFR / HER-1, c-erB2 / HER-2, c-met, PDGFr, FGFr) and non-receptor tyrosine kinases (eg src, lck). It is known that many oncogenes encode proteins that are aberrant tyrosine kinases, capable of causing cell transformation (Yarden, Y., and Ullrich, A., Annu, Rev. Biochem., 57 (1988) 443-478; Larsen et al. ., Ann., Reports in Med. Chem., 1989, chapter 13). Also the overexpression of a normal proto-oncogenic tyrosine kinase can lead to proliferative disorders. It is known that the receptor tyrosine kinases of Ref. 175311 HER group, such as HER-2 and EGFR (HER-1), are often aberrantly expressed in the most frequent types of human cancer, for example cancer. of breast, gastrointestinal cancer, for example colon, rectal or stool cancer, leukemia and cancer of the ovaries, bronchi or pancreas. The elevated levels of these receptors are related to a prognosis and a low response to treatment (Wright, C. et al., Br. J. Cancer 65 (1992) 118-121). It has been recognized, therefore, that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of cancer cells in mammals. Therefore, various small molecule compounds and also monoclonal antibodies are in the clinical trial phase for the treatment of various types of cancer (Baselga, J., and Hammond, LA, Oncology 63 (Suppl 1) (2002) 6 -16; Ranson, M., and Sliwkowski, MX, Oncology 63 (Suppl 1) (2002) 17-24). Some substituted oxazoles are already known in the art. In WO 98/03505, EP 1 270 571, WO 01/77107, WO 03/031442 and WO 03/059907 heterocyclic compounds of this type are described as tyrosine kinase inhibitors. However, there is still a need for new compounds that have better therapeutic properties, for example higher activity, lower toxicity, better solubility and better pharmacokinetic profile, just to name a few. The present invention relates to novel compounds of the general formula I, formula (I), wherein R1 is halogen; -O-alkyl; -S ~ alkyl; -S (O) -alkyl; -S (O) 2-alkyl, -SF 5, -NH-alkyl; or alkyl, all alkyl groups are optionally substituted one or more times by halogen; and R2 is hydrogen; or halogen; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the carbon atoms of the phenyl ring to which they are attached form a 5- or 6-membered heterocyclic ring; and A is W is -CH2-CH2-; -CH = CH- or -C = C-; and pharmaceutically acceptable salts thereof. The compounds of the present invention show activity as inhibitors of the HER signaling pathway and, therefore, possess an anti-proliferative activity. The present invention relates to compounds of the formula I and their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the aforementioned compounds, the medicaments containing them and their manufacture, and the use of the aforementioned compounds. for control o. prevention of diseases, especially diseases and disorders such as the ones just mentioned or for the manufacture of the corresponding medicines. As used in the present description, the term "alkyl" means a saturated straight-chain or branched-chain hydrocarbon containing from 1 to 4 carbon atoms, preferably from 1 to 2, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, t-butyl. Said alkyl group is optionally substituted by one or more halogen atoms, preferably fluorine. Examples are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and the like. The term "halogen" used herein denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. As used in this description, the heterocyclic ring formed by R1 and R3 means a saturated or unsaturated hydrocarbon ring having 5 or 6 ring atoms, of which 1 or 2 atoms have been substituted by heteroatoms chosen from S, N and 0, preferably between N and 0, and the remaining carbon atoms, where possible, are substituted once or several times by halogen, preferably fluorine. Said "5- or 6-membered heterocyclic ring" is preferably formed by R1 and R3 located on two adjacent carbon atoms of the phenyl ring to which they are attached. Examples of a "5- or 6-membered heterocyclic ring", including the phenyl ring to which it is attached, are benzo [1,3] dioxol, 2,2-difluoro-benzo [1,3] dioxole, iH -benzimidazole, 2,3-dihydro-benzo [1,4] dioxin, 3,4-dihydro-2H-benzo [1,4] oxazine and the like. When used here, when reference is made to the receptor tyrosine kinases of the HER family similar to HER-2 and EGFR (HER-1), the abbreviations "HER" refer to a human epidermal receptor and the initials "EGFR" are refer to an epidermal growth factor receptor.

When used here, in relation to mass spectroscopy (MS), the term "ESI +" refers to the positive electrorotiated ionization mode. The compounds according to the present invention can exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid addition salts which preserve the efficacy and biological properties of the compounds of formula I and are formed from suitable, non-toxic organic or inorganic acids. Examples of acid addition salts include those derived from inorganic acids, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and organic acid derivatives, for example p-acid. toluenesulfonic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Chemical modification of a pharmaceutical compound (ie, a drug) to obtain a salt is a well-known technique of pharmaceutical chemists to obtain better physical and chemical stability, hygroscopy, fluidity and solubility of the compounds. See, for example, Bastin, R.J., et al., Organic Proc. Res. Dev. 4 (2000) 427- Preferred are pharmaceutically acceptable salts, which are formed with p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, methanesulfonic acid and hydrochloric acid. Preferred substituents of R 1 are trifluoromethyl, pentafluorosulfanyl, trifluoromethanesulfinyl, trifluoromethanesulfonyl, trifluoromethylsulphanyl, methoxy, difluoromethoxy, trifluoromethoxy, chlorine and fluorine, especially trifluoromethyl, trifluoromethoxy and chlorine. When "R1 and R3 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic ring", the resulting bicyclic system, including the phenyl ring to which R1 and R3 are attached, is preferably 2, 2-difluoro-benzo [1,3] dioxolyl. A preferred embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen; -O-alkyl; -S-alkyl; -S (0) -alkyl; -S (0) 2-alkyl, -SF 5, -NH-alkyl; or alkyl, all alkyl groups are optionally substituted one or more times by halogen; and R2 is hydrogen; or halogen; and R3 is hydrogen; and A is W is -CH2-CH2-; -CH = CH- or -C = C-; and pharmaceutically acceptable salts thereof. Another preferred embodiment is the compounds of the formula I, wherein R 1 is fluorine or chlorine; -SF5; -0-CF3; -OCHF2; -S (0) -CF3; -S (0) 2-CF3; -S-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the phenyl ring to which they are attached form a portion of 2,2-difluorobenzo [1,3] dioxolyl, and R2 is hydrogen; Y A is W is -CH2-CH2-; -CH = CH- or -C = C-; and and its pharmaceutically acceptable salts. Another preferred form are the compounds of the formula I, wherein R 1 is chloro; -0-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; or alternatively A is W is -CH2-CH2-; -CH = CH- or -C = C-; and their pharmaceutically acceptable salts. Still another preferred embodiment are the compounds of the formula I, wherein -R 1 is fluorine or chlorine; -SF5; -0-CF3; -OCHF2; -S (0) -CF3; -S (0) 2-CF3; -S-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the phenyl ring to which they are attached form a portion of 2,2-difluorobenzo [1,3] dioxolyl, and R2 is hydrogen; Y A is N = N; Y W is -CH2-CH2-; -CH = CH- or -C = C-; and the pharmaceutically acceptable salts thereof. Such compounds are, for example: 3- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine; 3- (4- [1, 2, 3] triazol-1-yl-butyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine, -3- (4- [1,2,3] triazol-1-yl-butyl) -6-. { 2- [(E) -2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine; 3- . { 2- [(E) -2- (2-fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine; and 3-. { 2- [(E) -2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-ylmetho-xi} -6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine. Another preferred embodiment are the compounds of the formula I, wherein R 1 is chloro; -0-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; Y A is N = N Still another embodiment of the present invention are the compounds of the formula I, wherein R 1 is fluorine or chlorine; -SF5; -0-CF3; -OCHF2; -S (0) -CF3; -S (0) 2-CF3; -S-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the phenyl ring to which they are attached form a portion of 2,2-difluorobenzo [1,3] dioxolyl, and R2 is hydrogen; and A is = \ .¿ 7 W is -CH2-CH2-; -CH = CH- or -C = C-; and pharmaceutically acceptable salts thereof. Such compounds are, for example: 2- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxyApyrazine; 2- (4- [1,2,3] Triazol-1-yl-butyl) -5-. { 2- [2- (4-trifluoromethyl-phe nyl) -vinyl] -oxazol-4-ylmethoxy} -pyrazine; and 2- (4- [1, 2, 3] triazol-1-yl-butyl) -5-. { 2- [(E) -2- (4-trifluorometho-xi-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pirazine. Another preferred embodiment is the compounds of formula I, wherein R 1 is chloro; -0-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; Already-. Still another embodiment of the present invention are the compounds of the formula I, wherein R 1 is fluorine or chlorine; -SF5; -0-CF3; -OCHF2; -S (0) -CF3; -S (0) 2-CF3; -S-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the phenyl ring to which they are attached form a 2,2-difluorobenzo [1, 3] dioxolyl portion, and R2 is hydrogen; and A is W is -CH2-CH2-; -CH = CH- or -C = C-; and the pharmaceutically acceptable salts thereof. Such compounds are for example: 5- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy) -pyrimidine; 5- (4- [1, 2, 3] triazol-1-yl-butyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine; 5- (4- [1,2,3] Triazol-1-yl-butyl) -2-. { 2- [(E) -2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine; 2- . { 2- [(E) -2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -5- (4- [1,2,3] triazol-1-yl-butyl) -pyrimidine; and 2-. { 2- [(E) -2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-ylmetho-xi} -5- (4- [1,2,3] triazol-1-yl-butyl) -pyrimidine. Another preferred modality are the compounds of the formula I, wherein R1 is chloro; -0-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; and A is ~ 0 ~ Another embodiment of the present invention are the compounds of the formula I, wherein R 1 is fluorine or chlorine; -SF5; -0-CF3; -OCHF2; -S (0) -CF3; -S (0) 2-CF3; -S-CF3; O -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the phenyl ring to which they are attached form a 2,2-difluorobenzo [1, 3] dioxolyl portion, and R2 is hydrogen; and A is ".}." - Y W is -CH2-CH2-; -CH = CH- or -C = C-; and pharmaceutically acceptable salts thereof. Such a compound is for example: 2- (4- [1,2,3] triazol-l-yl-butyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine. Another preferred embodiment are the compounds of the formula I, wherein R 1 is chloro; -0-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; and A is -OR- Still another embodiment of the invention is a process for obtaining the compounds of the formula (I), in which (a) the compound of the formula (XII) is reacted formula (XII), where A is X is bromine or iodine; with but-3-inyl-lH- [1, 2,3] triazole, (b) if desired, the compound of the formula (I) (in which W is -C = C-), obtained in section (a), is then reacted in a reduction step to obtain the corresponding compound of the formula (I), wherein W is -CH2-CH2- or -CH = CH- or; (c) said compound of the formula (I) is isolated from the reaction mixture, and (d) if desired, it is converted into a pharmaceutically acceptable salt. The diazine derivatives of the general formula (I), or a pharmaceutically acceptable salt thereof, can be obtained by any process known to those skilled in the art that can be applied to obtain chemically related compounds. Such processes, when used to obtain the diazine derivatives of the formula (I), or a pharmaceutically acceptable salt thereof, are provided as an additional feature of the invention and are illustrated by the following representative examples of the reaction scheme. 1 to reaction scheme 4, in which, unless otherwise indicated, R1, R2, R3", A and W have the meanings defined above.The necessary starting materials are commercial products or can be obtained by standard procedures of organic chemistry Obtaining such starting materials are described in the accompanying and non-limiting examples, in US 03/069419 or WO 03/091247. Alternatively, the necessary starting materials can be obtained by procedures similar to those illustrated, which are part of the ordinary knowledge of the organic chemistry specialist. The preparation of the compounds of the formula (i) varies according to the nature of "A" of the formula (i). The compounds of the present invention, in which "A" is pyridazine, can be obtained according to reaction scheme 1, and are referred to as "la". b) Optional reduction f Reaction Scheme 1 A preferred method for the synthesis of the compounds of the formula (Ia) is part of the corresponding benzaldehydes of the formula (II), wherein R 1, R 2 and R 3 have the meanings defined above for formula 1. Stage 1 of the reaction sequence (reaction scheme 1) is a condensation of Knoevenagel with malonic acid and subsequent decarboxylation, obtaining the acrylic acid derivatives of the formula (III). The reaction is typically carried out in solvent of the pyridine type, N-methylpyrrolidinone, acetonitrile, N, -dimethylformamide and mixtures thereof, at temperatures up to 140 ° C or reflux. The bases used typically are piperidine, triethylamine and diisopropylamine. In step 2, reaction scheme 1, the obtained compounds of the formula (III) are converted into their corresponding amides of the formula (IV), using methods well known to those skilled in the art, for example by activating the carboxyl group of said compounds of the formula (III) with oxalyl chloride in solvents of the tetrahydrofuran, dichloromethane, N, N-dimethylformamide type and mixtures thereof, at temperatures ranging from -30 ° C to 40 ° C. The addition of ammonia gives rise to the amides of the formula (IV). In step 3, reaction scheme 1, the chlorides of the formula (V) are synthesized using generally known methods. The amides of the formula (IV) and the 1,3-dichloroacetone are subjected to a condensation / dehydration sequence, obtaining the compounds of the formula (V). Typical solvents for these types are toluene, benzene, acetone and chloroform. If desired, the reaction can be carried out under solvent-free conditions. The reaction temperatures can vary between 50 ° C and 150 ° C. In step 4, reaction line 1, the hydroxymethyl oxazole derivatives of the formula (VI) are obtained. This reaction is typically carried out in a two-stage process, starting with the reaction of the chlorides of the formula (V) with sodium or potassium acetate which is typically carried out in solvents of the N, N- type. dimethylformamide, N-methylpyrrolidinone, acetonitrile, dimethyl sulfoxide and mixtures thereof, at temperatures between 50 ° C and 140 ° C or at reflux. In the second step, a hydrolysis of the resulting acetates is carried out by standard methods for any expert in the field. Bases which are typically used are for example sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH) in solvents of the water type, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol or mixtures thereof, at temperatures between 0 ° C and 150 ° C, obtaining the hydroxymethyl derivatives of the formula (VI).

Step 5 of reaction scheme 1 is an addition-elimination reaction of the hydroxymethyl derivatives of the formula (VI) and 3-chloro-6-iodopyridazine which is typically carried out in solvents of the tetrahydrofuran, acetonitrile type , N, N-dimethylformamide and mixtures thereof at temperatures between -20 ° C and 50 ° C, obtaining the iodo-pyridazines of the formula (VII). The reaction is carried out in the presence of a non-nucleophilic base, for example sodium tert-butoxide, potassium tert-butoxide, N-ethyl-N, N-diisopropyl-amine, triethylamine or the like. Alternatively, the reaction can be carried out with 3,6-diiodo-pyridazine in place of 3-chloro-6-iodopyridazine under similar reaction conditions. In step 6, reaction scheme 1, the obtained iodo-pyridazines of formula (VII) are reacted with l-but-3-inyl-lH- [1, 2, 3] triazole in a crosslinking reaction of Sonogashira in the presence of catalytic amounts of copper iodide and a palladium complex, for example Pd (PPh3) 4, Pd (PPh3) 2Cl2 or the like. The reaction is carried out in the presence of a base of the type of triethylamine, diisopropyl-amine, isopropyl-amine, piperidine, morpholine or pyrrolidine and in solvents of the tetrahydrofuran, N, N-dimethylformamide type or mixtures thereof at temperatures which they vary from 20 ° C to 100 ° C, obtaining derivatives of the formula (la) in which W is -C = C- (reaction a), step 6). When the synthesis is further carried out with the step of reduction b) in step 6, the compounds of the formula (la) are obtained, in which W is -HC = CH- or -CH 2 -CH 2 -. As the reduction reaction, catalytic hydrogenation is preferably carried out using different catalytic species, for example Lindiar catalysts or certain nickel borides (to obtain compounds, in which W is -HC = CH-), palladium on activated carbon, nickel or platinum (to obtain compounds, wherein W is -CH2-CH-). The reaction is typically carried out at temperatures between 0 ° C and 50 ° C, with hydrogen pressures between 1 to 4 atm, in solvents of the methanol, ethanol, tetrahydrofuran, acetone, ethyl acetate or mixtures thereof type. same. As an alternative, metallic sodium is used in liquid ammonia to hydrogenate an alkyne group (W is -C = C-) to an alkene group (W is -HC = CH-). As an alternative, steps 5 and 6 of reaction scheme 1 can be carried out in reverse order, obtaining the products of formula (la). In the reaction scheme 2, a preferred method for the synthesis of the derivatives of the formula (I) is described, wherein A is a pyrimidine which is linked via the oxygen atom to the 2-position and the W-group to the position 5. Derivatives of the formula (I), in which A represents a pyrimidine of this type are called Ib in reaction enzyme 2. b) Optional reduction Ib Reaction scheme ~ The starting materials are the corresponding hydroxymethyl derivatives of the formula (VI), reaction scheme 1, in which R1, R2 and R3 have the meanings defined above. Step 1 of reaction scheme 2 of the reaction sequence is an addition-elimination reaction of the hydroxymethyl derivatives (VI) and the 5-bromo-2-chloro-pyrimidine which is typically carried out in solvents of the tetrahydrofuran type , acetonitrile, N, N-dimethylformamide or mixtures thereof at temperatures between 0 ° C and 50 ° C, obtaining the bromo-pyrimidines of the formula (VIII). The reaction is carried out in the presence of a base or nucleophile, for example sodium tert-butoxide, potassium tert-butoxide, N-ethyl-N, N-diisopropylamine, triethylamine or the like. In step 2, reaction scheme 2, the bromo-pyrimidines of the formula (VIII) are reacted with l-but-3-inyl-lH- [1, 2, 3] triazole in a cross-coupling reaction of Sonogashira in the presence of catalytic amounts of copper iodide and a complex or palladium, for example Pd (PPh3), Pd (PPh3) 2Cl2 or the like. The reaction is carried out in the presence of a base, for example triethylamine, diisopropylamine, isopropylamine, piperidine, morpholine or pyrrolidine and in solvents of the tetrahydrofuran, N, N-dimethyl formamide type or mixtures thereof. the same at temperatures ranging from 20 ° C to 100 ° C, obtaining derivatives of the formula (Ib) in which W is -C = c- (reaction a), step 2). The subsequent continuation of the reaction by the reduction reaction b) in step 2 provides the compounds of the formula (Ib) wherein W is -HC = CH- or -CH2-CH-. A preferred reaction of reduction b) in step 2 is a catalytic hydrogenation which is carried out using different catalytic species, for example Lindiar catalysts or certain nickel borides (to obtain compounds, in which W is -HC = CH- ), palladium on activated carbon, nickel or platinum (to obtain compounds, in which W is -CH2-CH2-). The reaction is typically carried out at temperatures between 0 ° C and 50 ° C, with hydrogen pressures between 1 and 4 atm, in solvents of the methanol, ethanol, tetrahydrofuran, acetone, ethyl acetate or mixtures thereof type. As an alternative, metallic sodium is used in liquid ammonia to hydrogenate an alkyne group (W is -C = C-) to an alkene group (W is -HC = CH-). Alternatively, steps 1 and 2 of the reaction scheme 2 can be carried out in the reverse order, obtaining the products of the formula (Ib). The synthesis of the derivatives of the formula (I), in which A is a pyrimidine, which is linked via the oxygen atom to position 5 and group W to position 2, is described in reaction scheme 3. The derivatives of the formula (I), in which A represents a pyrimidine of this type, are referred to in the reaction scheme 3.

Stage 2 b) Optional reduction Reaction Scheme 3 In step 1 of reaction scheme 3 of the reaction sequence, 5-bromo-2-iodo-pyrimidine is reacted with l-but-3-inyl-lH- [1, 2, 3] triazole in a cross-linked reaction of Sonogashira in the presence of catalytic amounts of copper iodide and a palladium complex, for example Pd (PPh3), Pd (PPh3) 2Cl2 or the like. The reaction is carried out in the presence of a base of the triethylamine or diisopropylamine type and in solvents of the tetrahydrofuran, N, N-dimethylformamide type or mixtures thereof at temperatures varying from 20 ° C. at 80 ° C, obtaining the compounds of the formula (IX) wherein W is -C = C- (reaction a), step 1). The subsequent continuation of the reaction by a reduction reaction b) in step 1 of reaction scheme 3 provides the compounds of the formula (IX), wherein W is -HC = CH- or -CH 2 -CH 2 -. A preferred reaction of reduction b) in stage 1 is catalytic hydrogenation using different catalytic species, for example Lindiar catalysts or certain nickel borides (to obtain compounds, in which W is -HC = CH-), palladium on activated carbon, nickel or platinum (to obtain compounds, in which W is -CH2-CH2 -). The reaction is typically carried out at temperatures between 0 ° C and 50 ° C and with hydrogen pressures between 1 and 4 atm, in solvents of the methanol, ethanol, tetrahydrofuran, acetone, ethyl acetate or mixtures thereof type. As an alternative, metallic sodium is used in liquefied ammonia to hydrogenate an alkyne group (W is -C = C-) to an alkene group (W is -HC = CH-). In step 2 of reaction scheme 3, the pyrimidin-5-ol derivatives of the formula (X) are obtained. This reaction is carried out typically in a two-step process, starting with the reaction of the compounds of the formula (IX) with the bis (pinacolato) diboro in the presence of catalytic amounts of a palladium complex, for example dichloro [ 1, 1'-bis- (diphenylphosphino) ferrocene] aladium (II) (PdCl2 (dppf)), bis (dibenzylidene-acetone) -palladium (Pd (dba) 2), tris (dibenzylideneacetone) -dipaladium (Pd2 (dba) 3) or palladium acetate (Pd (0Ac) 2) and optionally various phosphine or imidazolium ligands, for example tricyclohexylphosphine, 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl, l-butyl tetrafluoroborate 3-methyl-lH-imidazolium, 1,3-bis (2,6-diisopropylphenyl) -1H-imidazolium chloride. The reaction is typically carried out in solvents of the type of dimethyl sulfoxide, dioxane, tetrahydrofuran, N, N-dimethyl-amide, acetonitrile, 1,2-dimethoxyethane or mixtures thereof at temperatures between 50 ° C and 140 °. C or reflux in the presence of bases of the type of potassium acetate, potassium phosphate or potassium carbonate. Alternatively, the resulting boronic acid derivatives are obtained using n-butyl lithium and various organic borates, such as triisopropyl borate or trimethyl borate or the like, at temperatures between -100 ° C and 30 ° C, in solvents of the type of toluene, hexane and tetrahydrofuran or mixtures thereof. In the second step, the oxidation of the resulting boronic acid derivatives is carried out by standard methods for any person skilled in the art. The reagents typically used for oxidation are, for example, hydrogen peroxide or potassium peroxymonosulfate (2KHS05 KHS04 K2S04), in solvents of the water type, tetrahydrofuran, acetone or mixtures thereof, at temperatures between 0 ° C and 80 °. C, obtaining the pyrimidin-5-ol derivatives of the formula (X). The derivatives of the formula (le) can be obtained by reactions well known to those skilled in the art, for example by alkylation of pyrimidin-5-ol derivatives of the formula (X) with the chlorides of the formula (V), in the that R1, R2 and R3 have the meanings defined above for formula I, according to a reaction step 3 of reaction scheme 3. The alkylation is carried out typically in solvents of the N, N-dimethyl- formamide or acetonitrile. Typical bases for this reaction are sodium carbonate, potassium carbonate, cesium carbonate, sodium methylate, sodium hydride, lithium diisopropyl-amide. The reaction temperatures can vary from 50 ° C to 150 ° C. The compounds of the present invention, in which "A" is pyrazine, can be obtained in accordance with reaction scheme 4 and are referred to as (Id) b Opc ona re Reaction Scheme 4 The starting materials are the corresponding chlorides of the formula (V) of reaction scheme 1, in which R1, R2 and R3 have the meanings defined above. The oxazole derivatives of the formula (XI) can be obtained by reactions well known to one skilled in the art, for example by O-alkylation of 5-bromo-pyrazin-2-ol with said chlorides of the formula (V), in the that R1, R2 and R3 have the meanings defined above for formula I, according to reaction step 1 of reaction scheme 4. The alkylation is carried out typically in solvents of the N, N-dimethyl type -formamide or acetonitrile. Typical bases for this reaction are sodium carbonate, potassium carbonate, cesium carbonate, sodium methylate, sodium hydride, lithium diisopropylamide. The reaction temperatures can vary from 50 ° C to 150 ° C. In step 2 of reaction scheme 4 the bromo-pyrazines of the formula (VIII) are reacted with the 1-but-3-inyl-lH- [1, 2, 3] triazole in a cross-coupling reaction of Sonogashira in presence of catalytic amounts of copper iodide and a palladium complex, for example Pd (PPh3) 4, Pd (PPh3) 2Cl2 or the like. The reaction is carried out in the presence of a base of the type of triethylamine, diisopropyl-amine, isopropyl-amine, piperidine, morpholine or pyrrolidine and in solvents of the tetrahydrofuran, N, N-dimethylformamide type or mixtures thereof at temperatures ranging from 20 ° C to 120 ° C, obtaining the derivatives of the formula (Id) in which w is -C = C- (reaction a), step 2). The subsequent continuation of the reaction with a reduction reaction b) in step 2 provides the compounds of the formula (Id), wherein W is -HC = CH- or -CH2-CH2-. A preferred reaction of reduction b) in step 2 is a catalytic hydrogenation which is carried out using different catalytic species, for example Lindiar catalysts or certain nickel borides (to obtain compounds, in which W is -HC = CH- ), palladium on activated carbon, nickel or platinum (to obtain compounds, in which W is -CH-CH2-). The reaction is typically carried out at temperatures between 0 ° C and 50 ° C, with hydrogen pressures between 1 and 4 atm, in solvents of the methanol, ethanol, tetrahydrofuran, acetone, ethyl acetate or mixtures thereof type. As an alternative, metallic sodium in liquid ammonia is used to hydrogenate an alkyne group (W is -C = C-) to an alkene group (W is -HC = CH-). Alternatively, the pyrazine derivatives of the formula (Id) can be prepared according to reaction scheme 5. b) optional reduction • VI Reaction Scheme 5 In the reaction scheme 5, W, R1, R2 and R have the meaning given above in the synthesis of the compounds of the formula Id in the reaction scheme 5 starting from the corresponding 5-bromo-2-iodo-pyrazine , which can be prepared from 5-amino-2-iodo-pyrazole according to WO 2004/000811. In step 1, of reaction scheme 5, 5-bromo-2-iodo-pyrazine is reacted with l-but-3-inyl-lH- [1,2,3] -triazole in a crosslinked reaction of Sonogashira in the presence of catalytic amounts of copper iodide and a palladium complex, for example Pd (PPh3), Pd (PPh3) Cl2 or the like. The reaction is carried out in the presence of a base of the type of triethylamine, diisopropyl-amine, isopropyl-amine, piperidine, morpholine or pyrrolidine and in solvents similar to tetrahydrofuran, N, -dimethylformamide or mixtures thereof at temperatures which vary from 20 ° C to 120 ° C, obtaining the bromo-pyrazine derivatives of the formula (XII) in which W is -C = C- (reaction a), step 1). The subsequent continuation of the reaction with a reduction reaction b) in step 1 provides the compounds of the formula (XII), wherein W is -HC = CH- or -CH2-CH2-. "A preferred reaction of reduction b) in step 2 is a catalytic hydrogenation which is carried out using different catalytic species, for example Lindiar catalysts or certain nickel borides (to obtain compounds, in which W is -HC = CH-), palladium on activated carbon, nickel, platinum or platinum (IV) oxide (to obtain compounds, in which that W is -CH2-CH2-). The reaction is typically carried out at temperatures between 0 ° C and 50 ° C, at hydrogen pressures between 1 and 4 atm, in solvents of the methanol, ethanol, tetrahydrofuran, acetone, ethyl acetate or mixtures thereof type. As an alternative, metallic sodium in liquid ammonia is used to hydrogenate the alkyne group (W is -C = C-) to an alkene group (W is -HC = CH-). Step 2 of reaction scheme 5 is an addition-elimination reaction of the hydroxymethyl derivatives of the formula (VI) and the bromo-pyrazine derivatives of the Formula (XII), which is typically carried out in solvents of the type of tetrahydrofuran, acetonitrile, N, N-dimethylformamide and mixtures thereof at temperatures between 0 ° C and 50 ° C, obtaining the compounds of the formula (Id). The reaction is carried out in the presence of a non-nucleophilic base, similar to sodium tert-butoxide, potassium tert-butoxide, N-ethyl-N, N-diisopropylamine, triethylamine or the like. The compounds of the formulas VII, VIII, IX, X, XI and XII are new and are also the subject of this invention. The compounds of the formula I may contain one or more chiral centers and may then be present in racemic form or in an optically active form. The racemates can be separated by known methods to obtain the enantiomers. For example, diastereomeric salts which can be separated by crystallization are formed from racemic mixtures by reaction with an optically active acid, for example D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphor orsulfonic acid. Alternatively, the separation of the enantiomers can also be carried out by HPLC chromatography through chiral phases, which are commercial products. The compounds of the formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties. It has been found that said compounds inhibit the pathway of the HER signals and display antiproliferative activity. Accordingly, the compounds of the present invention are useful for the therapy and / or prevention of diseases due to overexpression of receptor tyrosine kinases from the HER group, for example HER-2 and EGFR (HER-1), especially for the therapy and / or prevention of the diseases mentioned above. The activity of the compounds present as inhibitors of the HER signaling pathway is demonstrated by the following biological assay.

Inhibition of phosphorylation of HER2 in the Calu3 tumor cell line In a 12-cavity plate, Calu3 cells are deposited in each cavity 2x1O5. After 4 days the cells were fasted for 16 h in DMEM / 0.5% FCS / 1% glutamine. During this time the cells are incubated with 1 μM of a compound of the present invention. The cells are then subjected to a lysate with a lysis buffer containing 1% Triton, 10% glycerol, 1 M ethylene glycol bis (2-aminoethyl ether) -N, N, N, N-tetracetic acid (EGTA). ), 1.5 mM MgCl2, 150 mM NaCl, 50 M 4- (2-hydroxyethyl) -1-piperazineethane sulfonic acid buffer (HEPES), pH 7.5, 1 mM phenylmethylsulfonyl fluoride (PMSF), μg / ml of aprotinin dprotein that is naturally present, which is obtained and purified from the lungs of the cow) and 0.4 mm orthovanadate (Na3V04). The cell lysates are analyzed in Polyacrylamide Gel Electrophoresis in Dodecyl Sulfate and Sodium (SDS PAGE) and after transferring them to a nitrocellulose membrane they are detected with an antibody that specifically recognizes pY 1248 of HER2 (residue 1248 of tyrosine phosphorylated human epidermal receptor 2). After incubation with an anti-rabbit antibody bound to POD (Peroxidase available from Biorad, Munich, Germany) the signals were detected by chemiluminescence (ECL, Amersham). The inhibition of HER-2 phosphorylation is calculated as a percentage of the control, which is treated only with DMSO. The percentage of inhibition is calculated according to the following formula:% inhibition = 100 - (phosphorylated HER2 signal from Test Sample * 100 / DMSO control from the phosphorylated HER2 signal). With all the compounds, a significant inhibition of the HER2 phosphorylation is observed, which is exemplified by the compounds shown in table 1. For this, the reference compound is l- [4- (4- { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy] -phenyl) -butyl] -lH- [1,2,3] triazole (Example 4, p.88, del WO 01/77107). Table 1: Live win tumor inhibition assay ": Non-Small Lung Cancer (NSCLC) cells (for example Calu-3 (ATTC HTB-55) or A549 (ATCC CCL-185)) are injected subcutaneously to generate the primary tumors. (4-5 x 10 6 in a volume of 100 μl) to the left flank of beige SCID female mice (beige mice / Severe Combined Immunodeficient available from Charles River, Sulzfeld, Germany) or bare BALB / c (Nude Spontaneous Moves Mice BALB / c (homozygous) available from Taconic Europe, Ry, Denmark.) The cells are thawed and expanded "in vitro" before use in the assay.The mice used in the assay are divided into treatment groups between 14 and 21 days After injection of the cells, for allocation to the various groups (n = 10-15 mice per group), the animals are randomly selected to have a similar mean primary tumor volume of about 100-150 mm3 per The compounds a are administered in orally administered once a day in the form of 7.5% gelatin suspension in NaCl of 0.22% with an administered volume of 10 ml / kg of the actual body weights. The treatment is started one day after fasting, and it is carried out until day 20-50, the final day of the study. Subcutaneous primary tumors are measured twice a week, beginning before division into groups at random, in two dimensions (length and width) using an electronic gauge. The volume of the primary tumor is calculated by the following formula: V [mm3] = (length [mm] x width [mm] x width [mm]) / 2. The body weight of all animals is also recorded at least twice a week. Finally, at the end of the study, the tumors are removed and weighed. The compounds of this invention and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of a pharmaceutical composition. The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories or parenterally, for example in the form of injectable solutions. The pharmaceutical compositions mentioned above can be obtained by processing the compounds of the invention together with pharmaceutically inert organic or inorganic excipients. As excipients of tablets, coated tablets, dragees and hard gelatine capsules, lactose, corn starch or its derivatives, talc, stearic acids or their salts, and the like can be used. For soft gelatin capsules suitable excipients are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient, it is usually possible to dispense with the use of excipients in soft gelatine capsules. The suitable excipients for the manufacture of solutions and syrups are, for example, water, polyols, glycerin, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hydrogenated oils, waxes, fats, polyols, illiquids or liquids, and the like. The pharmaceutical compositions may additionally contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffer solutions, masking agents or antioxidants. They may also contain other therapeutically valuable substances. Preferred pharmaceutical compositions contain the following: a) Tablet formulation (wet granulation): Manufacturing process: 1. Mix elements 1, 2, 3 and 4 and granulate with purified water. 2. The granules are dried at 50 ° C. 3. The granulates are passed through an appropriate grinding machine. 4. Element 5 is added and mixed for three minutes; It is compressed in a suitable press. b) Capsule formulation: Manufacturing process: 1. Mix elements 1, 2 and 3 in an appropriate mixer for 30 minutes. 2. Add elements 4 and 5 and mix for 3 minutes. 3. They are packed in a suitable capsule. c) Microsuspension 1. 4.0 g of glass pellets are weighed in a GL 25, 4 cm tube (the pellets fill half of the tube). 2. 50 mg of the compound is added, dispersed with spatula and swirled. 3. Add 2 ml of gelatin solution (weight of the pellets / weight of gelatin solution = 2/1) and stir in a swirl. 4. Cover and wrap with an aluminum foil to protect the tube from light. 5. A counterweight is prepared for the mill. 6. It is milled for 4 hours, in a Retsch mill that rotates at 20 / s (for some compounds: 24 hours at 30 / s). 7. The suspension of the pellets is extracted with two filter layers (100 μm) in a filter holder, coupled with a vial type vessel for centrifugation at 400 rpm for 2 min. 8. Transfer the extract to the calibrated specimen. 9. Repeat washing with small volumes (here 1 ml steps) until the final volume is reached or the extract becomes clear. 10. Complete with gelatin until the final volume and it is homogenized. The manufacturing method just described provides microsuspensions of the compounds of the formula I-A with particle sizes between 1 and 10 μm. The suspensions are suitable for oral applications and can be used for the "in vivo" assay just described.

Medicaments containing a compound of the formula loa pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also the object of the present invention, as well as the process for its manufacture, which consists of incorporating one or several compounds of the present invention and / or pharmaceutically acceptable salts and, if desired, one or more additional therapeutically valuable substances to a galenic administration form together with one or more therapeutically inert excipients. 1. According to the invention, the compounds of the present invention and their pharmaceutically acceptable salts are useful for the control or prevention of diseases. On the basis of their inhibition of the HER signaling pathway and their antiproliferative activity, said compounds are useful for the treatment of diseases such as cancer of humans and animals and for the manufacture of the corresponding medicaments. The dose administered will depend on several factors, for example the mode of administration, the species, the age and / or the state of health or of the individual. The following examples and references are given to assist in understanding the present invention, the true scope of which is defined in the appended claims. It is understood that modifications to the described procedures can be made without departing from the spirit of the invention. Examples: A: starting materials Obtaining 3-chloro-6-iodo-pyridazine To a suspension of 3,6-dichloro-pyridazine (1.0 g, 6. 71 mmoles) and Nal (1.35 g, 9.0 mmoles) in chloroform (2.5 ml) is added to hydroiodic acid (57% by weight) (2.85 g, . 6 mmole) at 0 ° C. The mixture is stirred for 20 hours (h) at room temperature (T.A.) and then poured into a mixture of 100 ml of ice-water and 20 ml of sodium hydroxide.

(NaOH) ION. Chloroform (50 ml) is added and the mixture is stirred for 10 minutes (min). The organic phase is separated, the aqueous phase is extracted with chloroform (1 x 50 ml), the organic phases are combined, dried with magnesium sulfate (MgSO4) and concentrated in vacuo to obtain 3-chloro-6-iodo- piri-dazina in the form of a matt white solid. Performance: 1. 16 g (72%). MS: M = 340.6 (ESI +). NMR-H1 (300 MHz, CDC13): 7.22 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H). Obtaining 5-bromo-2-chloro-pyrimidine Dissolve 2-pyrimidinol hydrochloride (13.26 g, 100 mmol) in 2N NaOH (50 ml) and for 15 min. Bromine (17.98 g, 112.5 mmol) is added. The mixture is stirred for 45 min at T.A. and then concentrated in vacuo, obtaining a brownish solid. The solid is suspended in phosphorus oxychloride (125 ml), N, N-dimethylaniline (9.35 g, 77 mmol) is added and the mixture is heated at reflux for 3 h. The reaction mixture was cooled, poured slowly with stirring over 1 liter of ice water and the resulting mixture was extracted with diethyl ether (3 x 200 ml). The extract is washed with brine, dried with MgSO 4 and concentrated in vacuo to give 5-bromo-2-chloro-pyrimidine as a pale yellow solid. Yield: 10.85 g (56%). NMR-H1 (300 MHz, CDC13): 8.70 (s, 2H). Obtaining 5-bromo-2-iodo-pyrimidine To a suspension of 5-bromo-2-chloro-pyrimidine (5.80 g, 30 mmol) and sodium iodide (7.5 g, 50 mmol) in chloroform (20 ml) a hydroiodic acid (57% by weight) (2.85 g, 25.6 mmol) is added to 0aC. The cooling is removed, the reaction mixture is stirred at T.A. for 20 h and then poured into a mixture of 200 ml of ice-water and 30 ml of ION NaOH. Chloroform (150 ml) is added and the mixture is stirred for 10 min. The organic phase is separated, the aqueous phase is extracted with chloroform (2 x 100 ml), the organic phases are combined, dried over MgSO and concentrated in vacuo to obtain 5-bromo-2-iodo-pyrimidine in solid form pale yellow. Rendition: 6.29 g (84%).

MS: M = 284.8 (ESI +). NMR-H1 (300 MHz, CDC13): 8.54 (s, 2H), 7.56 (d, J = 16.4 Hz, 1H), 7.59-7.66 (m, 4H). Obtaining l-but-3-inyl-lH- [1, 2,3] triazole Under nitrogen, but-3-in-l-ol (49.57 g, 707.2 mmol) and triethylamine (107.7 ml, 777) are dissolved. mmoles, dried with KOH) in dry dichloromethane (500 ml) and cooled to 0 ° C. In 90 min, methanesulfonyl chloride (54.8 ml, 708 mmol), dissolved in 500 ml of dry dichloromethane, is added, while maintaining the temperature below 5 ° C. The mixture is stirred for 3.5 hours at room temperature and then poured onto 2.5 liter of ice-water. The organic phase is separated and washed with 2 x 500 ml of water and 1 x 250 ml of brine and dried with sodium sulfate. The volatiles are removed, obtaining 94.18 g of the methanesulfonate (631.2 mmoles, 89.2%) as a yellow liquid. Under inert atmosphere, a suspension of NaOH (37.86 g, 946.5 mmol), sodium iodide (94.65 g, 631.5 mmol) and H H- [1,2,3] triazole (61.03 g, 883.6 g) were kept under boiling under reflux for 3 h. mmoles) in 2-methyl-2-butanol (750 ml). After cooling to room temperature the methanesulfonate (94.18 g, 631.2 mmoles) is added in 5 minutes. "The suspension is then heated at reflux for 3 h, cooled to room temperature and concentrated in vacuo at 45 ° C.

Water (500 ml) and dichloromethane (11) are added and the organic phase is separated, dried with sodium sulfate and the volatiles are removed at 30 ° C. The residue is distilled at a pressure of 1 mm Hg. A first distillate is collected at 20-70 ° C. The main fraction distils at 123-129 ° C as a colorless and turbid liquid. After filtration through Celite, the l-but-3-ynyl-lH- [1, 2, 3] triazole was obtained as a colorless liquid (29.77 g, 38.9%). NMR-H1 (400 MHz, CDCl3) d: 2.05 (t, 1H), 2.75 (dt, 2H), 4.5 (t, 2H), 7.65 (s, ÍH), 7.7 (s, 1H). Obtaining the. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-yl} -methanol A solution of 4-chloromethyl-2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazole (0.300 g, 0.99 mmol) and sodium acetate (0.162 g, 1.976 mmol) is refluxed for 48 h. ) in acetic acid (5 ml). The reaction mixture was cooled to T.A., concentrated in vacuo and the resulting residue was dissolved in ethanol (2 ml) and 5M potassium hydroxide.

(KOH) (5 ml). The solution is refluxed for 5 h and cooled to T.A. A saturated solution of ammonium chloride (NH4C1) is added and the mixture is extracted with ethyl acetate (3x) The extract is washed with brine, dried with Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate / hexanes 1: 1) to obtain the. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-yl} -methanol in the form of a colorless solid. Yield: 200 mg (71%). NMR-H1 (400 MHz, CDCl3): d = 4.64 (s, 2H, CH2-0), 6.85 (d, 1H, = CH), 7.21 (d, 2H, Ph), 7.49-7.57 (m, 4H) . Obtaining the. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-yl} -methanol A solution of 4-chloromethyl-2- [2- (2-fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazole (1,000 g, 3.27 mmol) and sodium acetate (0.536) is refluxed for 55 h. g, 6.54 mmole) in acetic acid (10 ml). The reaction mixture was cooled to T.A., concentrated in vacuo and the resulting residue was dissolved in ethanol (5 ml) and 7M potassium hydroxide (KOH) (12 ml). The solution is refluxed for 5 h and cooled to T.A. A saturated solution of ammonium chloride (NH4C1) is added and the mixture is extracted with ethyl acetate (3x) The extract is washed with brine, dried with Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate / hexanes 1: 1) to obtain the. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-yl} -methanol in the form of a colorless solid. Yield: 0.791 g (84%). NMR-H1 (400 MHz, CDC13): d = 4.65 (s, 2H, CH2-0), 7.09 (d, ÍH, = CH), 7.36 (d, ÍH, Ph), 7.42 (d, 1H, Ph) , 7.61 (s, ÍH, oxazole), 7.63 (d, lH, = CH), 7.66 (dd, 1H, Ph).

Obtaining the. { 2- [2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-yl} -methanol A solution of 2- [2- (4-chloro-2-fluoro-phenyl) -vinyl] -4-chloromethyl-oxazole (0.800 g, 2.94 mmol) and sodium acetate (0.482) is maintained under reflux for 55 h. g, 5.88 mmol) in acetic acid (10 ml). The reaction mixture is cooled to T.A., concentrate in vacuo and dissolve the resulting residue in ethanol (4 ml) and 5M potassium hydroxide (KOH). (15 ml). The solution is refluxed for 5 h and cooled to T.A. A saturated solution of ammonium chloride (NHC1) is added and the mixture is extracted with ethyl acetate (3x) The extract is washed with brine, dried with Na 2 SO 4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate / hexanes 1: 1) to obtain the. { 2- [2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-yl} -methanol in the form of a colorless solid. Yield: 0.582 g (78%). NMR-H1 (400 MHz, CDCl3): d = 4.63 (s, 2H, CH2-0), 6.95 (d, 1H, = CH), 7.11-7.15 (m, 2H, Ph), 7.47 (t, 1H, Ph), 7.57 (d, ÍH, = CH), 7.58 (s, 1H, oxazole). B. Products Example 1: 3- (4- [1,2,3] triazol-l-yl-but-l-ynyl) -6-. { 2- [2- (4 ~ tri-fluorome il-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine 4-Hydroxymethyl-2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazole (0.090 g, 0.33 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) and then the tert-amine is added. sodium butoxide (NaOtBu) (0.048 g, 0.5 mmol). After shaking at T.A. for 10 min the mixture is cooled to 0 ° C, 3-chloro-6-iodo-pyridazine (0.060 g, 0.33 mmol) in THF (3 ml) is added slowly over a period of 15 min, and the mixture is stirred at 02 ° C. for another 30 min. Ethyl acetate (30 ml) is added; the mixture is washed with a saturated solution of ammonium chloride (NH4CI), dried with MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate / hexanes 1: 2 → 2: 3), 3-iodo-6- can be isolated. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine in the form of a pale yellow solid. Yield: 0.12 g (77%). MS: M = 382.0 (ESI +). NMR-H1 (300 MHz, CDC13): 5.50 (s, 2H), 6.76 (d, J = 9.1 Hz, ÍH), 7, .1 (d, J = 16.4 Hz, ÍH), 7.56 (d, J = 16.4 Hz, 1H), 7.60-7.63 (m, 4H), 7.68 (d, J = 9.1 Hz, 1H), 7.85 (s, ÍH). The 3-iodo-6 is dissolved. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine (0.114 g, 0.25 mmol), l-but-3-inyl-lH- [1, 2,3] triazole (0.040 g, 0.30 mmol) and triethylamine (NEt3) (0.125 ml) in THF (1 ml) and copper iodide (Cul) (0.0048 g, 0.025 mmol) is added with stirring. After passing a stream of argon through the mixture for 10 min, the bis (triphenylphosphine) palladium (II) dichloride (0.088 g, 0.0125 mmol) is added and stirring is continued for 3 h at T.A. Ethyl acetate (30 ml) is added; the mixture is washed with a saturated solution of ammonium chloride (NH4CI) and brine, dried with MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate / hexanes 1: 3 -> ethyl acetate (100%)), yielding 3- (4- [1,2,3] triazole- 1-il-but-l-inyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine in the form of a colorless solid. Yield: 93 mg (64%). MS: M = 467.1 (ESI +). Example 2: 3- (4- [1,2,3] triazol-1-yl-butyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} pyridazine 3- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -6- is dissolved. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} pyridazine (0.047 g, 0.1 mmol) in ethyl acetate (3 ml) and hydrogenated for 3 h at T.A. in the presence of palladium on charcoal (10%, 20 mg). After filtration and concentration in vacuo, the residue was purified by flash column chromatography (ethyl acetate / methanol 19: 1) to obtain 3- (4- [1,2,3] triazole-1-yl- butyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine in the form of a matt white solid.

Yield: 30 mg (63%) MS: M = 471.2 (ESI +). NMR-H1 (300 MHz, CDCl3): 1.76-1.87 (m, 2H), 1.89-1.97 (m, 2H), 2.93 (t, J = 7.4 Hz, 2H), 4.45 (t, J = 7.2 Hz, 2H), 5.52 (s, 2H), 6.99 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 16.4 Hz, ÍH), 7.23 (d, J = 9.0 Hz, ÍH), 7.54 (s, ÍH), 7.56 (d, J = 16. 4 Hz, ÍH), 7.63 (m, 4H), 7.70 (s, lH), 7.87 (s, ÍH). Example 2a: 3- (4- £ l, 2,3] triazol-l-yl-but-l-enyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} pyridazine 3- (4- [1, 2,3] triazol-1-yl-but-l-ynyl) -6- is dissolved. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} pyridazine (0.047 g, 0.1 mmol) in ethyl acetate (3 ml) and hydrogenated for 1 h at T.A. in the presence of palladium on charcoal (10%, 5 mg). After filtration and concentration in vacuo the residue yielded 3- (4- [1, 2, 3] triazol-1-yl-but-1-enyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine in the form of a matt white solid. The raw material product contained 60% of the product and 40% of the product. The ratio was detected by CLAR-MS (High Resolution Liquid Chromatography-Mass Spectrometry, Eluent: H20 / CH3CN, Gradient: in 20 minutes from 0% (volume vs. volume (v / v)) up to 95% (v / v of CH3CN, UV detection at 226 nm) MS: M = 469.2 (ESI +).

Example 3: 5- (4- [1, 2,3] triazol-l-yl-but-l-ynyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine 4-hydroxymethyl-2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazole (0.538 g, 2.0 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (10 ml) and then NaOtBu is added. (0.231 g, 2.4 mmol). After shaking at T.A. for 15 min, 5-bromo-2-chloropyrimidine (0.426 g, 2.2 mmol) in THF (5 ml) is slowly added over a period of 10 min and stirred at RT. for 30 more minutes Chloroform (25 ml) is added; the mixture is washed with 0.5N hydrochloric acid (HCl) and water, dried over MgSO4 and concentrated in vacuo. After flash column chromatography (100% chloroform), 5-bromo-2- can be isolated. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-yl-methoxy} -pyrimidine in the form of a matt white solid. Yield: 0.60 g (71%). MS: M = 426.0 (ESI +). NMR-H1 (300 MHz, CDC13): 5.40 (s, 2H), 7.00 (d, J = 16.4 Hz, ÍH), 7.54 (d, J = 16.4 Hz, 1H), 7.60-7.66 (, 4H), 7.74 (s, ÍH), 8.57 (s, 2H). To a solution of 5-bromo-2-. { 2- [2- (4-trifluoromethyl-phe nyl) -vinyl] -oxazol-4-ylmethoxy} pyrimidine (0.213 g, 0.50 mmol), l-but-3-inyl-lH- [1, 2, 3] triazole (0.067 g, 0.55 mmol) and diisopropyl-amine (iPr2NH) (2 ml) in DMF (4 ml) and THF (2 ml) was added with stirring copper iodide (Cul) (0.0048 g, 0.025 mmol). After passing an argon stream through the mixture for 10 min, tetrakis (triphenylphosphine) palladium (0.029 g, 0.025 mmol) is added and the mixture is heated at 80 ° C for 3 h. Ethyl acetate (150 ml) is added, the resulting mixture is washed with ammonium chloride (NH4CI) and brine, dried with MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (chloroform (100%) - > ethyl acetate (100%)), yielding 5- (4- [1,2,3] triazol-1-yl) -but-l-inil) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine in the form of a pale yellow solid. Yield: 138 mg (59%). MS: M = 467.1 (ESI +). Example 4: 5- (4- [1,2,3] triazol-l-yl-butyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine 5- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -2- is dissolved. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} pyrimidine (0.047 g, 0.1 mmol) in ethyl acetate (3 ml) and hydrogenated for 1 h at T.A. in the presence of palladium on charcoal (10%, 20 mg). After filtration and concentration in vacuo, the crude product is purified by flash column chromatography (ethyl acetate / hexanes 1: 3 - >; ethyl acetate (100%)), yielding 5- (4- [1, 2, 3] triazol-1-yl-butyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine in the form of a white solid. Yield: 35 mg (74%) MS: M = 471.0 (API +). NMR-H1 (300 MHz, CDC13): 1.60-1.70 (m, 2H), 1.98-2.11 (m, 2H), 2.62 (t, J = 7.4 Hz, 2H), 4.46 (t, J = 7.2 Hz, 2H ), 5.43 (s, 2H), 7.04 (d, J = 16.4 Hz, ÍH), 7.52-7.58 (m, 2H), 7.61-7.67 (, 4H), 7.76 (s, ÍH), 7.79 (s, lH ), 8.39 (s, 2H). Example 5: 2- (4- [1,2,3] triazol-1-yl-butyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine 5-bromo-2-iodo-pyrimidine (1.14 g, 4.0 mmol), l-but-3-inyl-lH- [1, 2, 3] triazole (0.533 g, 4.4 mmol) are dissolved and the triethylamine (NEt3) (2 ml) in DMF (1 ml) and copper iodide (Cul) (0.38 g, 0.2 mmol) is added with stirring. After passing an argon stream through the mixture for 10 min, bis (triphenylphosphine) palladium (II) dichloride (0.140 g, 0.2 mmol) is added and stirring is continued at T.A. for 3 h. Chloroform (300 ml) is added; the mixture is washed with IN HCl and water, dried with MgSO 4 and concentrated in vacuo. The residue was purified by flash column chromatography (chloroform (100%) -> ethyl acetate (100%)), yielding 5-bromo-2- (4- [1, 2, 3] triazole-1 -yl-but-l-inyl) -pyrimidine in the form of a beige solid. Yield: 0.96 g (86%).

MS: M = 277.9 (ESI +). The 5-bromo-2- (4- [1, 2, 3] triazol-1-yl-but-1-ynyl) -pyrimidine (0.350 g, 1.26 mmol) is dissolved in ethyl acetate (3 ml) and hydrogenated to TA for 2 h in the presence of palladium on charcoal (10%, 175 mg). The reaction mixture was filtered and concentrated in vacuo to give 5-bromo-2- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrimidine as a beige solid. Yield: 290 mg (82%) MS: M = 281.8 (ESI +). To a solution of tris (dibenzylideneacetone) dipalladium (0) (0.027 g, 0.03 mmol in dioxane (6 ml) is added tricyclohexylphosphine (0.084 g, 0.30 mmol) and the mixture is stirred under an argon atmosphere for 30 min. add a solution of 5-bromo-2- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridine (0.282 g, 1.0 mmol), bis (pinacolato) diboro (0.279 g, 1.1 mmol) and potassium acetate (0.147 g, 1.5 mmol) and the mixture is heated at 80 ° C for 5 h.The mixture is cooled, concentrated in vacuo and the crude product is purified by column chromatography. flash desorption (ethyl acetate (100%) -> ethyl acetate / tetrahydrofuran 1: 1), yielding 2- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrimidine-5 acid -boronic in the form of beige solid Yield: 140 mg (57%) MS: M = 248.2 (ESI +) 2- (4- [1,2,3] triazol-1-yl-butyl acid is dissolved) -pyrimidine-5-boronic acid (0.099 g, 0.40 mmol) in THF (0.5 ml) and water (0.5 ml) and the peroxide is added of hydrogen (30% by weight) (0.054 g, 0.48 mmole). After stirring the solution at T.A. for 2 h brine (3 ml) is added and the mixture is extracted with THF (2 x 10 ml). The organic phases are combined, dried over MgSO4 and concentrated in vacuo to give 2- (4- [1,2,3] triazol-1-yl-butyl) -pyrimidin-5-ol as a solid in color. matte white. Yield: 85 mg (97%). MS: M = 219.9 (ESI +). A mixture of 4-chloromethyl-2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazole (0.144 g, 0.50 mmol), 2- (4- [1, 2, 3] is maintained at 80 ° C for 2 h. ] triazol-1-yl-butyl) -pyrimidin-5-ol (0.078 g, 0.357 mmol) and cesium carbonate (CS2CO3) (0.175 g, 0.536 mmol) in DMF (10 mL). After cooling, ethyl acetate (25 ml) is added, the mixture is washed with a sat. NH4CI and brine, dried with MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate (100%) -> ethyl acetate / methanol 9: 1) and the 2- (4- [1, 2, 3] triazole can be isolated -1-yl-butyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine in the form of a white solid. Yield: 40 mg (24%). MS: M = 471.1 (ESI +). NMR-H1 (300 MHz, CDC13): 1.82-1.92 (m, 2H), 1.97-2.06 (m, 2H), 2.99 (t, J = 7.2 Hz, 2H), 4.45 (t, J = 7.2 Hz, 2H ), 5.12 (s, 2H), 7.02 (d, J = 16.4 Hz, 1H), 7.56-7.62 (m, 2H), 7.65-7.69 (m, 4H), 7.71 (s, ÍH), 7.76 (s, 1H), 8.47 (s, 2H). Example 6: 2- (4- [1, 2,3] triazol-l-yl-but-l-ynyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrazine A mixture of 4-chloromethyl-2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazole (0.345 g, 1.2 mmol), 5-bromo-pyrazin-2-ol is maintained at 80 aC for 1 h. (0.175 g, 1.0 mmol) and cesium carbonate (CS2CO3) (0.489 g, 1.5 mmol) in DMF (4 mL). After cooling, ethyl acetate (40 ml) is added, the mixture is washed with a saturated solution of NH 4 Cl and brine, dried with MgSO 4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate / hexane 1: 9 -> ethyl acetate / hexane 1: 2) to obtain 2-bromo-5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-yl-methoxy} -pyrazine in the form of a white solid. Yield: 122 mg (29%). MS: M = 425.9 (ESI +). NMR-H1 (300 MHz, CDCl3): 5.34 (s, 2H), 7.01 (d, J = 16.4 Hz, HH), 7.57 (d, J = 16.4 Hz, HH), 7.60-7.63 (m, 4H), 7.73 (s, ÍH), 8.09 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, lH). The 2-bromo-5- is dissolved. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrazine (0.128 g, 0.30 mmol), l-but-3-inyl-lH- [1, 2, 3] triazole (0.044 g, 0.36 mmol) and triethylamine (Et3) (0.60 mL) in THF (1, 5 ml) and DMF (1.5 ml) and copper iodide (Cul) (0.006 g, 0.03 mmol) is added with stirring. After passing an argon stream through the mixture for 10 min, tetrakis (triphenylphosphine) aladium (0.017 g, 0.015 mmol) is added and the mixture is heated at 80 ° C for 1.5 h. After cooling, ethyl acetate (40 ml) is added, the mixture is washed with a saturated solution of HCl and with brine, dried with gSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate / hexanes 1: 1 - >; ethyl acetate (100%)), yielding 2- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrazine in the form of a pale yellow solid. Yield: 134 mg (96%). MS: M = 467.1 (ESI +). NMR-H1 (300 MHz, CDCl3): 3.09 (t, J = 7.2 Hz, 2H), 4.47 (t, J = 7.2 Hz, 2H), 5.36 (s, 2H), 7.01 (d, J = 16.4 Hz, ÍH), 7.57 (d, J = 16.4 Hz, 1H), 7.63-7.68 (m, 4H), 7.74-7.77 (m, 3H), 8.16 (s, ÍH), 8.23 (s, 1H). Example 7: 2- (4- [1,2,3] riazol-1-yl-butyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrazine The 2- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -5- is dissolved. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pirazine (0.060 g, 0.129 mmol) in ethyl acetate (30 ml) and hydrogenated for 30 min at T.A. in the presence of palladium on charcoal (10%, 30 mg). After filtration and concentration in vacuo, the residue was purified by preparative HPLC, yielding 3- (4- [1,2,3] triazol-1-yl-butyl) -6. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} - pyridazine in the form of a matt white solid. Yield: 38 mg (63%). MS: M = 471.1 (ESI +). NMR-H1 (300 MHz, CDCl3): 1.71-1.81 (m, 2H), 1.98-2.06 (, 2H), 2.80 (t, J = 7.2 Hz, 2H), 4.45 (t, J = 7.2 Hz, 2H) , . 36 (S, 2H), 7.05 (d, J = 16.4 Hz, lH), 7.54 -7.60 (m, 2H), 7. 64-7.67 (, 4H), 7.73 (s, 1H), 7.80 (s, ÍH), 7.98 (d, J = 1. 1 Hz, ÍH), 8.23 (d, J = 1.1 Hz, ÍH). Example 8: 5- (4- [1, 2,3] triazol-1-yl-butyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine 5-bromo-2-chloro-pyrimidine (0.500 g, 2.53 mmol), l-but-3-inyl-lH- [1, 2, 3] triazole (0.368 g, 3.03 mmol) are dissolved and the triethylamine (NEt3) (5.0 ml) in DMF (10 ml) and copper iodide (Cul) (0.052 g, 0.27 mmol) is added with stirring. After passing a stream of argon through the mixture for 10 min, tetra uis (triphenylphosphine) palladium (0) (0.149 g, 0.13 mmol) is added and stirring is continued at 802C for 4 h. Dichloromethane (125 ml) is added, the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried with NaS04 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate / hexanes 4: 1), yielding 2-chloro-5- (4- [1,2,3] triazol-1-yl-but- l-inyl) -pyrimidine as a colorless solid. Yield: 373 mg (63%). MS: M = 234 (API +). NMR-H1 (400 MHz, CDCl3): d = 3.10 (t, 2H, CH2-C =), 4.63 (t, 2H, CH2-N), 7.64 (s, 1H, triazole), 7.72 (s, 1H, triazole) 8.54 (s, 2H, pyrimidine). Dissolve 2-chloro-5- (4- [1, 2, 3] triazol-1-yl-but-1-ynyl) -pyrimidine (2.52 g, 10.8 mmol) in ethyl acetate (210 ml) and hydrogenated to T.A. for 2.5 h in the presence of palladium on calcium carbonate (10%, 2.55 g). The reaction mixture was filtered and concentrated in vacuo, obtaining the 2-Chloro-5- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrimidine as a colorless solid. Yield: 2.15 g (84%) MS: M = 236.2, 238.2 (ESI +). NMR-H1 (400 MHz, CDCl3): d = 1.60-1.68 (m, 2H, CiT2-CH2-C =), 1.94-2.02 (m, 2H, CH2-CH2-N), 2.62 (t, 2H, CH2 -C =), 4.42 (t, 2H, CH2-N), 7.50 (s, ÍH, triazole), 7.70 (s, 1H, triazole), 8.41 (s, 2H, pyrimidine). It dissolves. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-yl} -methanol (0.097 g, 0.34 mmol) in anhydrous tetrahydrofuran (THF) (4 ml) and then adding sodium terebutoxide (NaOtBu) (0.040 g, 0.41 mmol). After shaking at T.A. for 15 min 2-chloro-5- (4- [1,2,3] triazol-1-yl-butyl) -pyrimidine (0.090 g, 0.38 mmol) is added slowly and stirred at RT. for 1.5 h more. Ethyl acetate (20 ml) is added; the mixture is washed with a saturated solution of ammonium chloride (NH4CI), dried with MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate), 5- (4- [1, 2, 3] triazol-1-yl-butyl) -2- is obtained. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine in the form of a colorless solid. Yield: 0.104 g (63%). MS: M = 487.5 (ESI +). NMR-H1 (400 MHz, CDCl3): d = 1.58-1.65 (m, 2H, Cff2-CH2- C =), 1.93-2.00 (, 2H, CH2-CH2-N), 2.57 (t, 2H, CH2- Cír2-C =), 4.41 (t, 2H, CH2-N), 5.37 (s, 2H, CH2-0), 6.88 (d, 1H, = CH), 7. 21 (d, 2H, Ph), 7.48 (d, ÍH, = CH), 7.50-7.53 (m, 3H), 7.69-7.71 (m, 2H), 8.32 (s, 2H, pyrimidine). Example 9: 2-. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -5- (4- [1,2,3] triazol-1-yl-butyl) -pyrimidine It dissolves. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-yl} -methanol (0.100 g, 0.35 mmol) in anhydrous tetrahydrofuran (THF) (3 ml) and then sodium tert-butoxide (NaOtBu) (0.041 g, 0.42 mmol) is added. After shaking at T.A. for 15 min 2-chloro-5- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrimidine (0.075 g, 0.32 mmol) is added slowly and stirred at RT. for 3 more hours Ethyl acetate (20 ml) is added, the mixture is washed with a saturated solution of ammonium chloride (NH 4 Cl), dried with MgSO 4 and concentrated in vacuo. After column chromatography by flash desorption (ethyl acetate / methanol 97: 3), 2- is obtained. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -5- (4- [1, 2,3] triazol-1-yl-butyl) -pyrimidine as a colorless solid. Yield: 0.104 g (75%). MS: M = 489.2 (ESI +). NMR-H1 (400 MHz, CDC13): d = 1.58-1.65 (m, 2H, CH2-CH2-C =), 1.93-2.02 (m, 2H, CH2-CH2-N), 2.58 (t, 2H, CH2 -Cyf2-C =), 4.42 (t, 2H, CH2-N), 5.39 (s, 2H, CH2-0), 7.07 (d, lH, = CH), 7.35 (d, ÍH, Ph), 7.41 ( d, HH, Ph), 7.51 (s, HH, triazole), 7.61 (d, HH, = CH), 7.65 (d, 1H, Ph), 7.71 (s, HH), 7.74 (s, 1H), 8.33 (s, 2H, pyrimidine). Example 10: 2- { 2- [2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-ylme-toxy} -5- (4- [1,2, 3] triazol-1-yl-butyl) -pyrimidine The is dissolved. { 2- [2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-yl} -methanol (0.100 g, 0.39 mmol) in anhydrous tetrahydrofuran (THF) (3 ml) and then the sodium tert-butoxide (NaOtBu) (0.046 g, 0.47 mmol) is added. After shaking at T.A. for 15 min 2-chloro-5- (4- [1,2,3] triazol-1-yl-butyl) -pyrimidine (0.085 g, 0.36 mmol) is added slowly and stirred at RT. for 3 more hours Ethyl acetate (20 ml) is added, the mixture is washed with a saturated solution of ammonium chloride (NH 4 Cl), dried with MgSO 4 and concentrated in vacuo. After flash column chromatography (ethyl acetate / methanol 98: 2), 2- is obtained. { 2- [2- (4-Chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-ylmethoxy} -5- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrimidine as a colorless solid. Yield: 0.125 g (77%). MS: M = 455.2, 457.2 (ESI +). NMR-H1 (400 MHz, CDCl3): d = 1.60-1.66 (m, 2H, CIT2-CH2-C =), 1.95-2.02 (m, 2H, CH2-CH2-N), 2.59 (t, 2H, CH2 -CH2-C =), 4.44 (t, 2H, CH2-N), 5.40 (s, 2H, CH2-0), 7.02 (d, 1H, = CH), 7.12-7.18 (m, 2H, Ph), 7.46 (t, 1H, Ph), 7.53 (s, 1H, triazole), 7.57 (d, 1H, = CH), 7.72-7.74 (m, 2H, triazole, oxazole), 8.35 (s, 2H, pyrimidine). Example 11: 3- (4- [1,2,3] triazol-l-yl-butyl) -6-. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrxdazine 3-chloro-6-iodo-pyridazine (11.56 g, 48.1 mmol), l-but-3-inyl-lH- [1, 2, 3] triazole (6.99 g, 57.7 mmol) are dissolved and the triethylamine (NEt3) (94 ml) in DMF (188 ml) and copper iodide (Cul) (0.981 g, . 15 mmoles). After passing a stream of argon through the mixture for 10 min, tetrakis (triphenylphosphine) palladium (0) (2, 836 g, 2.43 mmol) is added and stirring is continued at T.A. for 6 h. Dichloromethane (300 ml) is added, the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried with a2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate), yielding 3-chloro-6- (4- [1, 2, 3] triazol-1-yl-but-1-ynyl) - pyridazine as a colorless solid. Yield: 9.52 g (85%). NMR-H1 (400 MHz, CDCl3): d = 3.12 (t, 2H, CH2-C =), 4.67 (t, 2H, CH2-N), 7.39 (d, ÍH, pyridazine), 7.45 (d, 1H, pyridazine), 7.70 (s, 1H, triazole), 7.73 (s, 1H, triazole). The 3-chloro-6- (4- [1, 2, 3] triazol-1-yl-but-1-ynyl) -pyridazine (2.50 g, 10.7 mmol) is dissolved in ethyl acetate (450 ml) and hydrogenated to TA for 3.5 h in the presence of palladium on charcoal (10%, 2.50 g). The reaction mixture was filtered and concentrated in vacuo. The residue is dissolved in THF (10 ml) and added to a benzyl alcohol solution. (0.94 ml, 9.0 mmol) and sodium tert-butoxide (NaOtBu) (0.842 g, 8.76 mmol) in THF (80 ml). After stirring for 2 h, ethyl acetate (100 ml) is added, the mixture is washed with a saturated solution of ammonium chloride (NH 4 Cl), dried with a 2 SO 4 and concentrated in vacuo. After flash column chromatography (ethyl acetate), 3-chloro-6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine is obtained as a colorless solid. Yield: 1.14 g (45%). NMR-H1 (400 MHz, CDCl3): d = 1.76-1.84 (m, 2H, Cí2-CH2- C =), 1.97-2.05 (m, 2H, CH2-CH2-N), 2.98 (t, 2H, CH2 -C =), 4.43 (t, 2H, CH2-N), 7.25 (, lH, pyridazine), 7.40 (d, lH, pyridazine), 7.52 (s, 1H, triazole), 7.68 (s, lH, triazole). It dissolves. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-yl} -methanol (0.050 g, 0.17 mmol) in anhydrous tetrahydrofuran (THF) (2 ml) and then sodium tert-butoxide (NaOtBu) (0.019 g, 0.19 mmol) is added. After shaking at T.A. for 15 min 3-chloro-6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine (0.035 g, 0.15 mmol) is slowly added and stirred at 60 aC for a further 4 h. Ethyl acetate (20 ml) is added, the mixture is washed with a saturated solution of ammonium chloride (NH 4 Cl), dried with Na 2 SO and concentrated in vacuo. After flash column chromatography (ethyl acetate / methanol 97: 3), 3- (4- [1,2,3] triazol-1-yl-butyl) -6- is isolated. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine in the form of a colorless solid. Yield: 0.049 g (69%). MS: M = 487.5 (ESI +). RMM-H1 (400 MHz, CDCl3): d = 1.76-1.84 (, 2H, CH2-CH2- C =), 1.98-2.05 (m, 2H, CH2-CH2 ~ N), 2.96 (t, 2H, CH2- CH2-C =), 4. 44 (t, 2H, CH2-N), 5.49 (s, 2H, CH2-0), 6.89 (d, ÍH, = CH), 7.02 (d, 1H, pyridazine), 7.20-7.26 (m, 3H), 7.48-7.54 (m, 4H), 7.68 (s, ÍH), 7.76 (s, ÍH). Example 12: 3-. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1,2,3] riazol-1-yl-butyl) -pyridazine The is dissolved. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-yl} -methanol (0.114 g, 0.40 mmol) in anhydrous tetrahydrofuran (THF) (3 ml) and then sodium tert-butoxide (NaOtBu) (0.043 g, 0.43 mmol) is added. After shaking at T.A. for 15 min 3-chloro-6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine (0.075 g, 0.32 mmol) is slowly added and stirred at 60 ° C. for a further 4 h. Ethyl acetate (20 ml) is added; The mixture is washed with a saturated solution of ammonium chloride (NH4CI), dried with MgSO4 and concentrated in vacuo. After column chromatography by flash desorption (ethyl acetate / methanol 98: 2), the 3- is obtained. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine as a colorless solid. Yield: 0.115 g (75%). MS: M = 489.1 (ESI +). NMR-H1 (400 MHz, CDC13): 8 = 1.76-1.84 (m, 2H, CH2-CH2-C =), 1.98-2.08 (m, 2H, CJT2-CH2-N), 2.95 (t, 2H, CH2-CH2-C =) , 4.44 (t, 2H, CH2-N), 5.50 (s, 2H, CH2-0), 6.99 (d, lH, pyridazine), 7.11 (d, lH, = CH), 7.24 (d, lH, pyridazine) , 7.36 (d, 1H, Ph), 7.42 (d, ÍH, Ph), 7.53 (s, ÍH, triazole), 7.63 (d, 1H, = CH), 7.64 (dd, ÍH, Ph), 7.68 (s , ÍH), 7.80 (s, 1H). Example 13: 3-. { 2- [2- (4-Chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1,2,3] triazol-1-yl-butyl) -pyridazine The is dissolved. { 2- [2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-yl} -methanol (0.100 g, 0.40 mmol) in anhydrous tetrahydrofuran (THF) (3 ml) and then the sodium tert-butoxide (NaOtBu) (0.043 g, 0.43 mmol) is added. After shaking at T.A. for 15 min 3-chloro-6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine (0.075 g, 0.32 mmol) is slowly added and stirred at 60 aC for a further 4 h. Ethyl acetate (20 ml) is added, the mixture is washed with a saturated solution of ammonium chloride (NH 4 Cl), dried with MgSO 4 and concentrated in vacuo. After flash chromatography by flash desorption (ethyl acetate / methanol 98: 2), the 3- is isolated. { 2- [2- (4-chloro-2-fluorophenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1, 2, 3] triazol-1-yl-butyl) -pyridazine as a colorless solid. Yield: 0.105 g (73%). MS: M = 455.02, 457.01 (ESI +). NMR-H1 (400 MHz, CDCl3): d = 1.76-1.84 (, 2H, CH2-CH2-C =), 1.97-2.04 (m, 2H, CH2-CH2-N), 2.93 (t, 2H, CH- CH2-C =), 4.43 (t, 2H, CH2-N), 5.49 (s, 2H, CH2-0), 6.98 (d, 1H, pyridazine), 7.00 (d, ÍH, = CH), 7.11-7.15 (m, 2H, Ph), 7.21 (d, HH, pyridazine), 7.43 (t, HH, Ph), 7.53 (s, 1H, triazole), 7.56 (d, HH, = CH), 7.68 (s, ÍH ), 7.77 (s, ÍH). Example 14: 2- (4- [1, 2,3] triazol-1-yl-butyl) -5-. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrazine The 2-bromo-5-iodo-pyrazine (13.69 g, 48.0 mmol), the l-but-3-inyl-lH- [1, 2, 3] triazole (7.01 g, 57.9 mmol) are dissolved and the triethylamine (Et3) (94 ml) in DMF (188 ml) and copper iodide (Cul) (0.984 g, 5.17 mmol) is added with stirring. After passing a stream of argon through the mixture for 10 min, tetrakis (3-phenylphosphine) aladin (0) (2.844 g, 2.46 mmol) is added and stirring is continued at T.A. for 5 h. Dichloromethane (300 ml) is added; the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried with Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (7: 3 ethyl acetate / hexanes), yielding 2-bromo-5- (4- [1, 2, 3] triazol-1-yl-but- 1-ynyl) -pyrazine as a colorless solid. Yield: 9.99 g (75%). NMR-H1 (400 MHz, CDC13): d = 3.10 (t, 2H, CH2-C =), 4.66 (t, 2H, CH2-N), 7.70 (s, 1H, triazole), 7.72 (s, 1H, triazole), 8.31 (d, 1H, pyrazine), 8.60 (d, 1H, pyrazine). Dissolve 2-bromo-5- (4- [1, 2, 3] triazol-1-yl-but-1-ynyl) -pyrazine (2.50 g, 9.0 mmol) in methanol (700 mL) and hydrogenate. to TA for 2 h in the presence of platinum (IV) oxide x H0 (0.840 g, 3.40 mmol). The reaction mixture was filtered and concentrated in vacuo to give 2-bromo-5- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrazine as a colorless solid. Yield: 1.63 g (64%) MS: M = 282.1, 284.2 (ESI +). NMR-H1 (400 MHz, CDC13): d = 1.72-1.80 (m, 2H, CH2-CH2-C =), 1.94-2.01 (m, 2H, CiT2-CH2-N), 2.79 (t, 2H, CH2-C =), 4.42 (t, 2H, CH2-N), 7.51 (s, ÍH, triazole), 7. 69 (s, 1H, triazole), 8.17 (d, 1H, pyrazine), 8.57 (d, 1H, pyrazine). It dissolves. { 2- [2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-yl} -methanol (0.067 g, 0.23 mmol) in anhydrous tetrahydrofuran (THF) (3 ml) and then the sodium tert-butoxide (NaOtBu) (0.025 g, 0.25 mmol) is added. After shaking at T.A. for 15 min, 2-bromo-5- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrazine (0.055 g, 0.19 mmol) is slowly added and stirred at 60 aC for a further 4 h. Ethyl acetate (20 ml) is added; the mixture is washed with a saturated solution of ammonium chloride (NH 4 Cl), dried with MgSO 4 and concentrated in vacuo. After column chromatography by flash desorption (ethyl acetate / methanol 98: 2), the 3- is obtained. { 2- [2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1, 2,3] triazol-1-yl-butyl) -pyridazine as a colorless solid. Yield: 0.079 g (83%). MS: M = 487.4 (ESI +).

NMR-H1 (400 MHz, CDCl3): d = 1.71-1.78 (m, 2H, CiJ2-CH2-C =), 1.93-2.01 (m, 2H, Cir2-CH2-N), 2.76 (t, 2H, CH2 -CfT2-C =), 4.41 (t, 2H, CH2-N), 5.31 (s, 2H, CH2-0), 6.89 (d, 1H, = CH), 7.21 (d, 2H, Ph), 7.50 ( d, 1H, = CH), 7.51-7.53 (m, 3H), 7.68-7.70 (m, 2H), 7.92 (s, 1H), 8.20 (s, ÍH, pyrazine). List of references Baselga, J., and Hammond, L.A., Oncology 63 (Suppl 1) (2002) 6 16 Bastin, R.J., et al., Organic Proc. Res. Dev. 4 (2000) 427-435 Chan, A.C., and Shaw, A.S., Curr. Opin. Immunol. 8 (1996) 394-401 EP 1 270 571 Larsen et al., Ann. Reports in Med. Chem., 1989, chap. 13 Ranson, M., and Sliwkowski, MX, Oncology 63 (Suppl 1) (2002) 17-24 US 03/069419 Wilks et al., Progress in Growth Factor Research 97 (1990) 2 WO 01/77107 WO 03/031442 WO 03/059907 WO 03/091247 OR 2004/000811 O 98/03505 Wright, C, et al., Br. J. Cancer 65 (1992) 118-121 Yarden, Y., and Ullrich, A., Annu. Rev. Biochem. 57 (1988) 443-478 It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (15)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula (I)
2. Formula (I), characterized in that: R1 is halogen; -O-alkyl; -S-alkyl; -S (O) -alkyl; -S (O) 2-alkyl, -SF 5, -NH-alkyl; or alkyl, all alkyl groups are optionally substituted one or more times by halogen; and R2 is hydrogenated; or halogen; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the carbon atoms of the phenyl ring to which they are attached form a 5- or 6-membered heterocyclic ring; and A is
3. W is -CH2-CH2-; -CH = CH- or -C = C-; and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, characterized in that: R1 is fluorine or chlorine; -SF5; -0-CF3; -OCHF2; -S (0) -CF3; -S (0) 2-CF3; -S-CF3; or -CF3; and R2 is hydrogen; or fluorine or chlorine; and R3 is hydrogen; or alternatively R1 and R3 are adjacent and together with the phenyl ring to which they are attached form a portion of 2,2-difluorobenzo [1,3] dioxolyl, and R2 is hydrogen; Y
4. A and W have the meaning in accordance with claim 1; and their pharmaceutically acceptable salts. 3. A compound according to any of claims 1 to 2, characterized in that A is
5. N = N; Y pharmaceutically acceptable salts thereof. 4. The compounds according to claim 3, characterized in that they are: 3- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -6-. { 2- [2- (4-trifluoromethyl-10-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine; 3- (4- [1,2,3] triazol-l-yl-butyl) -6-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine; 3- (4- [1, 2,3] triazol-1-yl-butyl) -6-. { 2- [(E) -2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyridazine; 15 3-. { 2- [(E) -2- (2-Fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1,2,3] triazol-1-yl-butyl) -pyridazine; and 3-. { 2- [(E) -2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-ylmethoxy} -6- (4- [1,2,3] triazol-1-yl-butyl) -pyridazine. 5. A compound according to any of the claims 1 to 2, characterized in that: A is pharmaceutically acceptable salts thereof.
6. 6. The compounds according to claim 5, characterized in that they are: 2- (4- [1, 2, 3] triazol-1-yl-but-l-ynyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrazine; 2- (4- [1,2,3] triazol-l-yl-butyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy) -pyrazine; and 2- (4- [1,2,3] triazol-1-yl-butyl) -5-. { 2- [(E) -2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pirazine.
7. 7. A compound according to any of claims 1 to 2, characterized in that A is pharmaceutically acceptable salts thereof.
8. 8. The compounds according to claim 7, characterized in that they are: 5- (4- [1,2,3] triazol-l-yl-but-l-ynyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine; 5- (4- [1, 2, 3] triazol-1-yl-butyl) -2-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine; 5- (4- [1, 2,3] triazol-1-yl-butyl) -2-. { 2- [(E) -2- (4-trifluoromethoxy-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine; 2- . { 2- [(E) -2- (2-fluoro-4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -5- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrimidine; and 2-. { 2- [(E) -2- (4-chloro-2-fluoro-phenyl) -vinyl] -oxazol-4-ylmetho-xi} -5- (4- [1, 2, 3] triazol-1-yl-butyl) -pyrimidine.
9. 9. A compound of conformity with any of claims 1 to 2, characterized in that: A is pharmaceutically acceptable salts thereof.
10. 10. The compound according to claim 9, characterized in that it is 2- (4- [1, 2, 3] triazol-1-yl-butyl) -5-. { 2- [2- (4-trifluoromethyl-phenyl) -vinyl] -oxazol-4-ylmethoxy} -pyrimidine.
11. 11. The process for obtaining the compounds according to claim 1, characterized in that: (a) the compound of the formula (XII) formula (XII), in which A is X is, bromine or iodine; and R1, R2 and R3 have the meaning given in the claim 1; it is reacted with the but-3-inyl-lH- [1, 2, 3] triazole, to give the corresponding compound of the formula (I), wherein W is -C = C-; (b) if desired, the compound of the formula (I) (in which W is -C = C-), obtained in section (a), is then reacted in a reduction step to obtain the corresponding compound of the formula (I), wherein W is -CH2-CH2- or -CH = CH- or; (c) said compound of the formula (I) is isolated from the reaction mixture, and (d) if desired, it is converted into a pharmaceutically acceptable salt.
12. 12. A pharmaceutical composition, characterized in that it contains one or more compounds according to any of claims 1 to 6 together with pharmaceutically acceptable excipients.
13. 13. A pharmaceutical composition according to claim 8, characterized in that it is used for the inhibition of tumor growth.
14. 14. The use of a compound according to any of claims 1 to 6 for the treatment of cancer.
15. 15. The use of a compound according to any of claims 1 to 6 for the manufacture of the corresponding medicaments for the inhibition of tumor growth.