MXPA06008683A - Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors - Google Patents

Abstract

The invention relates to processes for preparing compounds having the formula (I) and crystalline forms thereof, wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, which compounds are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase.

Description

PROCESS FOR PREPARING CARBOXAMIDAS 2-AMINOTIAZOL-5 -AROMÁTICAS AS INHIBITORS OF THE KINASE " FIELD OF THE INVENTION The present invention relates to processes for preparing 2-aminothiazole-5-aromatic carboxamides which are useful as inhibitors of the kinase, such as inhibitors of protein tyrosine kinase and p38 kinase, intermediates and crystalline forms thereof. BACKGROUND OF THE INVENTION The aminothiazole-aromatic amides of the formula I wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R 2, R 3, R 4 / and R 5 / are as defined in the specification herein, are useful as inhibitors of the kinase, in particular, inhibitors of protein tyrosine kinase and p38 kinase. They are expected to be useful in the treatment of disorders associated with protein tyrosine kinase such as immunological and oncological disorders [see, U.S. Pat. No. 6,596,746 (the "746 patent", assigned to the present assignee and incorporated herein by reference], and conditions associated with the p38 kinase such Ref: 174570 as inflammatory and immune conditions, as described in the patent application E.U.A. Serial No. 10 / 773,790 filed on February 6, 2004, which claims priority of the provisional application E.Ü.A Serial No. 60 / 445,410, filed on February 6, 2003 (hereinafter the application " 410), both of which are also assigned to the present assignee and are incorporated herein by reference The compound of the formula (IV), "N- (2-Chloro-6-methylphenyl) -2- [[6- [ 4- (2-hydroxyethyl) -1-piperazinyl] -2-methyl-4-pyrimidinyl] amino] -5-thiazolecarboxamide, is an inhibitor of SRC / ABL and is useful in the treatment of oncological diseases.

(IV).

Other approaches for preparing 2-aminothiazole-5-carboxamides are described in the "746 patent and in the application" 410. The patent "746 describes a process that involves the treatment of chlorothiazole with n-BuLi followed by the reaction with phenyl isocyanates to give chlorothiazole-benzamides, which are further elaborated for inotiazole-benzamide end products after protection, amino substitution to chlorine and deprotection, for example, Desprot. The application "410 describes a multistep process involving first converting the methyl or ethyl esters of the amino-aminothiazole carboxylic acid not substituted by N to esters of the bro-otiazole carboxylic acid by means of diazotization with tert-butyl nitrite and the treatment posterior with CuBr2, for example, then, hydrolyze the resulting bromothiazole esters to the corresponding carboxylic acids and convert the acids to the corresponding acyl chlorides, for example, then finally, coupling the acyl chlorides with anilines to provide the bromothiazole-benzamide intermediates which are further elaborated for end products of inotiazole-benzamide, for example, BG '~ * B' HPh and ^ y? HPh 0 O Other approaches for making 2-aminothiazole-5-carboxamides include the coupling of 2-aminothiazole-5-carboxylic acids with amines using various coupling conditions such as DCC [Roberts et al, J. Med. Chem. (1972), 75 , in P. 1310], and DPPA [Marsham et al., J. Med. Chem. (1991). 34, on p. 1594)]. The above methods have disadvantages with respect to the production of side products, the use of expensive coupling reagents, less desirable yields, and the need for multiple reaction steps to make the 2-aminothiazole-5-carboxamide compounds. New and efficient processes are desired to prepare 2-aminothiazole-5-carboxamides. The reaction of N, N-dimethyl-N '- (aminothiocarbonyl) -formamidines with a-haloketones and esters to give 5-carbonyl-2-aminotiazoles have been reported. See Lin, Y. et al, J Heterocycl. Chem. (1979), 16, in 1377; Hartmann, H. et al, J Chem. Soc. Perkin Trans. (2000), 7, at 4316; Noack, A. et al Tetrahedron (2002), 58, in 2137; Noack, A .; et al., Angew Chem. (2001), 113, in 3097; and Kantlehner, W. et al., J. Prakt Chem. / Chem. -Ztg. (1996), 338, at 403. The reaction of β-ethoxy acrylates and thioureas to prepare 2-aminothiazole-5-carboxylates has also been reported. See Zhao, R., et al., Tetrahedron Lett. (2001), 42, at 2101. However, the electrophilic bromination of acrylanilide and crotonanilide is known to undergo both aromatic bromination and the addition of carbon-carbon double bonds, ß-unsaturated. See Autenrieth, Chem. Ber. (1905), 38, at 2550; Eremeev et al., Chem. Heterocycl. Compd. Engl. Transí. (1984), 20, in 1102. SUMMARY OF THE INVENTION This invention relates to the process for the preparation of 2-aminothiazole-5-aromatic amides having the formula (I), wherein L, Ar,? 2,? 3,?,? 5, and are as defined below, which comprises reacting a compound having the formula (II), < p > . where Q is the group -OP *, where P * is selected so that, when considered together with the oxygen atom to which P * is linked, Q is a leaving group, and Ar, L, R2, R3 , and m are as defined below, with a halogenating reagent in the presence of water followed by a thiourea compound having the formula (III), wherein, R4 and R5, are as defined below, to provide the compound of the formula (I) wherein, Ar is the same in formulas (I) and (II) and is aryl or heteroaryl; L is the same in formulas (I) and ("II) and is optionally substituted alkylene, R2 is the same in formulas (I) and (II), and is selected from hydrogen, alkyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R3 is the same in formulas (I) and (II), and is selected from hydrogen, halogen, cyano, haloalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R4 is (i) the same in each of the formulas (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, or alternatively, R4 is taken together with R5 to form heteroaryl or heterocycle; R5 is (i) the same in each of formulas (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl-substituted, aryl, heteroaryl, cycloalkyl, and heterocycle, or alternatively, R5 is taken together with R4 to form heteroaryl or heterocycle; and m is 0 or 1. Applicants have surprisingly discovered the process for converting aromatic ß- (P *) oxy acryl-amides and thioureas to 2-aminothiazole derivatives, wherein the aromatic amides are not halogenated. The aromatic amides of aminothiazole, particularly 2-aminothiazole-5-benzamides, can thus be prepared efficiently with this process in high yield. In another aspect, the present invention is directed to crystalline forms of the compound of the formula (IV). BRIEF DESCRIPTION OF THE FIGURES The invention is illustrated by reference the accompanying drawings described below. Figure 1 shows simulated patterns (background) (calculated from the atomic coordinates generated at room temperature) and experimental (top) pXRD for crystalline monohydrate of the compound of the formula (IV). Figure 2 shows a DSC and TGA of the crystalline form of monohydrate of the compound of the formula (IV)). Figure 3 shows simulated (background) patterns (of refined atomic parameters at room temperature) and Experimental (upper) pXRD for crystalline butanol solvate of the compound of the formula (IV). Figure 4 shows simulated (background) patterns (of refined atomic parameters at -40 ° C) and experimental (top) pXRD for crystalline ethanol solvate for the compound of formula (IV). Figure 5 shows simulated patterns (background) (from atomic parameters refined at room temperature) and experimental (top) pXRD for the pure crystalline form (N-6) of the compound of formula (IV). Figure 6 shows simulated patterns (background) (of refined atomic parameters at room temperature) and experimental (top) pXRD for the pure crystalline form (T1H1-7) of the compound of formula (IV). DETAILED DESCRIPTION OF THE INVENTION Abbreviations For ease of reference, the following abbreviations may be used herein: Ph = phenyl Bz = benzyl t-Bu = tertiary butyl Me = methyl Et = ethyl Pr = propyl Iso-P = isopropyl MeOH = methanol EtOH = ethanol EtOAc = ethyl acetate Boc = tert-butyloxycarbonyl CBZ = carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl DMF = dimethyl formamide DMF-DMA = N, -dimethylformamide dimethyl acetal DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide DPPF = 1,1'-bis (diphenylphosphino) ferrocene HATU = O-benzotriazole-1-yl hexafluorophosphate N, N, N ', N' -tetramethyluronium LDA = lithium di-isopropyl amide TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran KOH = potassium hydroxide K2C03 = potassium carbonate POCl3 = phosphorus oxychloride EDC or EDCI = 3-ethyl -3 '- (dimethylamino) propyl-carbodiimide DIPEA = diisopropylethylamine HOBt = 1-hydroxybenzotriazole hydrate NBS = N-bromosuccinamide NMP = N-methyl-2-pyrrolidinone NaH = sodium hydride NaOH = sodium hydroxide Na2S203 = sodium thiosulfate Pd = palladium Pd-C or Pd / C = palladium min. = Minute (s) ". L = liter mL = milliliter μL = microliter g = gram (s) mg = milligram (s) mol = moles mmol = millimole (s) meq = milliequivalent TA or ta = room temperature RBF = round bottom flask t. ret. = retention time CLAR (minutes) sat or sat 'd = saturated ac. = aqueous CCD = thin layer chromatography HPLC = high performance liquid chromatography LC / MS = high performance liquid chromatography / mass spectrometry EM = mass spectrometry NMR = nuclear magnetic resonance pf = melting point Definitions The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term in the present applies to such group or term through the specification and claims, individually or as part of another group, unless otherwise indicated. The term "alkyl" as used herein by itself or as part of another group, refers to straight or branched chain hydrocarbons, containing 1 to 20 carbons, 1 to 10 carbons, or 1 to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl , the various branched chain isomers thereof, and the like. The lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms. The term "substituted alkyl" refers to an alkyl group substituted with one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents) at any available point of attachment. Exemplary substituents may be selected from one or more (or 1 to 3) of the following groups: (i) halogen (e.g., a single halo substituent or multiple halo substituent forms, in the latter case, groups such as a perfluoroalkyl group or an alkyl group carrying Cl3 or CF3), haloalkoxy, cyano, nitro, oxo (= 0), -0Ra, -SRa, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 3H, -P (= 0) 2-Re, -S (= 0) 20Re, -P (= 0) 20Re, -Ua-NRbRc, -Ux- ÍRdJ-Us-NRbRc, -Ui -NRd-Ua-Rb, -NRbP (= 0) 2Re, P (= 0) 2NRbRc, -C (= 0) 0Re, -C (= 0) Ra, -0C (= 0) Ra, -NRdP (= 0) 2NRbRc, - RbP (= 0) 2Re, -Ux-aryl, -Ui-heteroaryl, -Ui-cycloalkyl, ~ U? -heterocycle, -U? -arylene-Re, -Ui-heteroarylene-Re, -Ui - cycloalkylene-Re, and / or -U? -heterocycle-Re, wherein, in group (i), (ii) -Ui- and -U2 ~ are each independently a single bond, -U3-S (0 ) t-U4-, -U3-C (0) -U4-, -U3-C (S) -U4-, -U'-O-U4-, -U ^ S-U4-, -U3-0- C (0) -U4-, -U3-C (0) ~ 0 -U4-, or -U3-C (= NRg) -U4-; wherein, (iii) U3 and U4 are each independently a single bond, alkylene, alkenylene, or alkynylene; wherein, in group (i), (iv) Ra, Rb, RCi d / e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, each of which is substituted or not substituted with one to four Rf groups, except that Re is not hydrogen; or Rb and Re can be taken together to form a saturated or unsaturated ring of 3 to 8 members together with the atoms to which they are bonded, which ring is substituted or unsubstituted with one to four groups listed below by Rf; or R and Rc together with the The carbon atom to which they are linked can be combined to form a group -N = CRgRh where Rg and Rh are each independently hydrogen, alkyl or alkyl substituted with a group Rf; and wherein, (v) Rf each occurring is independently selected from alkyl, halogen, cyano, hydroxy, O (alkyl) _, SH, -S (alkyl), amino, alkylamino, haloalkyl, haloalkoxy, or a lower alkyl substituted with one to two of halogen, cyano, hydroxy, -O (alkyl), SH, -S (alkyl), amino, alkylamino, haloalkyl, and / or haloalkoxy, and wherein, (vi) t is 0, 1 or 2. The term "alkenyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, alternatively 2 to 12 carbons, and / or 1 to 8 carbons in the normal chain, which includes one up to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2 heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like. A "substituted alkenyl" refers to an alkenyl having one or more substituents (eg, 1 to 3 substituents, or 1 to 2) substituents), selected from those defined above by the substituted alkyl. The term "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms, 2 to 4 carbon atoms, and at least one carbon-to-carbon triple bond, such as ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octinyl, 3-noninyl, 4-decinyl, 3-undecinyl, 4-dodecinyl and the like. A "substituted alkynyl" refers to an alkynyl having one or more substituents (eg, 1 to 4 sustitiants, or 1 to 2 substituents), selected from those defined above by substituted alkyl. When the term "alkyl" is used as a suffix with another group, such as in (aryl) alkyl or arylalkyl, this conjunction is a means to refer to a substituted alkyl group wherein at least one of the substituents is the specifically named group in the conjunction. For example, (aryl) alkyl refers to a substituted alkyl group as defined above wherein at least one of the alkyl substituents is an aryl, such as benzyl. However, in the designated groups -O (alkyl) and -S (alkyl), it is to be understood that the linking points in this case are the oxygen and sulfur atoms, respectively.

Where the alkyl groups as defined are divalent, that is, with two single bonds for linking to two other groups, they are referred to as "alkylene" groups. Similarly, where the alkenyl groups as defined above and the alkynyl groups as defined above, respectively, are divalent radicals having single bonds to be placed in two other groups, they are referred to as "alkenylene groups" and "alkynylene groups" respectively. Examples of the alkylene, alkenylene and alkynylene groups include: - CH = CH CH2 - CH2CH = CH? - C ^ = C CH2, CH3 CH2 - CH2C = CCH2 -, - C I = CH - CH2 -, - < CH2) 2-? (CH2) 3, (CH2) 4 9 CH3 • (CH2> 2 C CH2CH2-, CH2CH-, CH2CHCH2, ^ CH3 C2H5 CH2 - CH - CH - CH2 '-' CH2 - CH - CH2 - CH -, CH3 CH3 CH3 CH3 CH3 - CH CH2CH2 and similar. The alkylene groups can be optionally substituted independently so as to allow the valence with one or more groups as defined by the substituted alkyl groups. So, for example, an alkylene group substituted may include OCH3 F - (CHzb-C- and forward, CH CH2CH2- and the term "cycloalkyl" as used herein by itself or as part of another group refers to optionally substituted saturated and partially unsaturated cyclic hydrocarbon groups (containing 1 or 2 double bonds) containing 1 to 3 rings, which include monocyclic alkyl, bicyclic alkyl and tricyclic alkyl, containing a total of 3 to 20 carbons forming the rings, or 3 to 7 carbons, which form the ring. Additional rings of multiple ring cycloalkyls can be either fused, bridged and / or linked through one or more spiro bonds. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl, cyclodecyl, cyclododecyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, Each of the references for a cycloalkyl is intended to include both substituted and unsubstituted cycloalguyl groups as defined immediately below, unless the reference is made for a particular selection of substituents made for the cycloalguyl (eg, wherein cycloalguyl is substituted with one or more Rf groups). When a particular selection is not recited, the optional substituents for the cycloalguyl groups can be selected from the following: (i) halogen (e.g., a single halo substituent or multiple halo substituent which, in the latter case, forms groups such as a perfluoroalkyl group or an alkyl group carrying Cl3 or CF3), haloalkoxy, cyano, nitro, oxo (= 0), -ORa, -SRa, -S (= 0) Re, -S (= 0) 2Re, -S ( = 0) 3H, -P (= 0) 2-Re, -S (= 0) 2ORe, -P (= 0) 2ORe, -Ux-NRbRc, -Ui-N (Rd) -U2-NRbRc, -U ! -NRd-U2-Rb, -NRbP (= 0) 2Re, -P (= 0) 2NRbRc, -C (= 0) ORe, -C (= 0) Ra, -OC (= 0) Ra, - (ii) -Ui-alkyl, -Ui-alkenyl, or -Ui-alkynyl wherein the alkyl, alkenyl, and alkynyl are substituted with one or more (or 1 to 3) groups recited in (i), wherein, in groups (i) and (ii), (iii) -Ui- and ~ U2- are each independently a single bond, -U3-S (O) t-U4-, -U3-C (0) -U4- , -U3-C (S) -U4-, -U3-0-U4-, -U ^ S-U4-, -O3-0 ~ C (0) -tf-, -O3-C (0) -0 -? -, or -U3-C (= NRg) -U4; where, in group (iii), (iv) U3 and U4 are each independently a single bond, alkylene, alkenylene, or alkynylene; wherein, (v) Ra, Rb, RC / Rd / e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl, each of which is substituted or unsubstituted with one or more Rf groups, except that Re is not hydrogen; or Rb and Rc can be taken together to form a saturated or unsaturated ring of 3 to 8 members together with the atoms which are bonded, which ring is substituted or unsubstituted with one or more groups listed below by Rf, or Rb and Re together with the nitrogen atom to which they are linked can be combined to form a group -N = C RgRh, where Rg and Rh are each independently hydrogen, alkyl, or alkyl substituted with a group Rf; and wherein, (vi) Rf is each occurring independently selected from alkyl, halogen, cyano, hydroxy, O (alkyl), SH, -S (alkyl), amino, alkylamino, haloalkyl, haloalkoxy, or substituted lower alkyl with one to of halogen, cyano, hydroxy, -O (alkyl), SH, -S (alkyl), amino, alkylamino, haloalkyl, and / or haloalkoxy, and wherein, (vii) t is 0, 1 or 2 When the full suffix is used in conjunction with a cyclic group, this is intended to mean the cyclic group as it is defined in the present that it has simple links as link points to other groups. Thus, for example, the term "cycloalkylene" as used herein, refers to a "cycloalkyl" group as defined above which is a linking group such as and similar. The term "alkoxy" refers to an alkyl or substituted alkyl group as defined above linked through an oxygen atom (-0-), that is, the group -ORi, wherein R is alkyl or substituted alkyl. The term "alkylthio" refers to an alkyl or substituted alkyl group as defined above linked through a sulfur atom (-S-), that is, the group -SRi, wherein Ri is alkyl or substituted alkyl. The term "acyl" refers to a carbonyl group bonded to an alkyl radical, more particularly, the group C (= 0) Rj, wherein Rj may be selected from alkyl, alkenyl, substituted alkyl, or substituted alkenyl, as defined herein. The term "alkoxycarbonyl" refers to an O II carboxy group linked to an alkyl radical (C02Rj, where Rj is as defined above by acyl. designation "C02" is used herein, is intended to be O II refers to the group -C-O- _ The term "alkylamino" refers to amino groups wherein one or both of the hydrogen atoms are replaced with an alkyl group, that is, NRkR ?, where one of Rk and Ri is hydrogen and the other is alkyl, or both Rk and Ri are alkyl. The term "halo" or "halogen" refers to chlorine, bromine, fluorine and iodine. The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono, bi, and trifluoromethyl. The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3. The terms "ar" or "aryl" as used herein by themselves or as part of another group, refer to monocyclic, bicyclic or aromatic tricyclic aromatic homocyclic (i.e., hydrocarbon) groups containing 6 to 14 carbons in the ring portion [such as phenyl, biphenyl, naphthyl (including 1-naphthyl and 2-naphthyl) and anthracenyl], and may optionally include one to three additional rings (either cycloalkyl, heterocycle or heteroaryl) fused. Examples include: co -.- o-. c? > . x < X3 and similar.

Each of the references to an aryl is intended to include both substituted and unsubstituted aryl groups as defined herein, unless reference is made to a particular selection of substituents to be made by the aryl (eg, as when aryl is replaced with one or more Rf groups, above). When the particular selection is not recited, the optional substituents for the aryl groups can be selected from those recited above, as valence allows, by the cycloalkyl groups. The term "heteroaryl" as used herein by itself or as part of another group refers to monocyclic and optionally substituted aromatic bicyclic rings containing from 5 to 10 atoms, which they include 1 to 4 heteroatoms such as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or heterocycle ring, where the sulfur and nitrogen heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazole, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, carbazolyl, benzidolyl, fenantrollinyl, acridinyl, phenanthridinyl, xanthenyl O XO XO and the like, Each of the references for a heteroaryl is intended to include both substituted and unsubstituted heteroaryl groups as defined herein, unless reference is made to a particular selection of substituents to make the heteroaryl (eg, as when the heteroaryl is substituted with one or more Rf groups, above). When the particular selection is not recited, the optional substituents of the heteroaryl groups can be selected from those recited above, as the valence allows, for the cycloalkyl groups. The terms "heterocyclic" or "heterocycle" as used herein by themselves or as part of other groups, refer to non-aromatic, optionally substituted, fully saturated or partially unsaturated cyclic groups (e.g., monocyclic ring systems of 3 to 13 members, bicyclic of 7 to 17 members, or tricyclic of 10 to 20 members, or containing a total of 3 to 10 atoms in the ring) which have at least one heteroatom in at least one ring containing carbon. Each of the rings of the heterocyclic group contains a heteroatom which may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.

The heterocyclic group can be linked to any heteroatom or carbon atom of the ring or ring system, where valence allows. Multiple ring heterocyclic rings can be fused, bridged and / or linked through one or more spiro junctions. Exemplary heterocyclic groups include oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, sulfoxide. of a orpholinyl aunt, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, which can optionally be replaced. Each of the references to a heterocycle is intended to include both substituted and unsubstituted heterocyclic groups as defined herein, unless reference is made to a particular selection of substituents to make the heterocycle (for example, as when the heterocycle is substituted with one or more Rf groups, above). When the particular selection is not recited, the optional substituents for the heterocyclic groups can be selected from those recited above, as the valence allows, for the cycloalkyl groups. The term "ring" embraces homocyclic (that is, as used herein, all atoms in the ring are carbon) or the "heterocyclic" (that is, as used herein, the atoms in the ring include carbon and one to four heteroatoms selected from N, 0 and / or S, also refers to heterocycle), where, as used herein, each of which (homocyclic or heterocyclic) may be saturated or partially or completely unsaturated. Unless otherwise indicated, when referring to an aryl (for example, phenyl), cycloalguyl (for example, cyclohexyl), heterocycle (for example, pyrrolidinyl) or heteroaryl (for example, imidazolyl) named specifically, a unless specifically stated otherwise, the reference is intended to include rings having 0 to 3, or 0 to 2, substituents selected from those recited above by the aryl, cycloalguyl, heterocycle and / or heteroaryl groups, as appropriate. The term "heteroatoms" will include oxygen, sulfur and nitrogen. The term "carbocyclic" means a saturated or unsaturated mincyclic or bicyclic ring in which all ring atoms are carbon. Thus, the term includes cycloalguyl and aryl rings. The carbocyclic ring may be substituted in which case the substituent is selected from those recited above by cycloalkyl and aryl groups. When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be completely unsaturated or partially unsaturated. "Base" when used herein includes hydroxide oxides or metal alkoxides, hydrides or compounds such as ammonia, which accept protons in water or solvents. Thus, exemplary bases include, but are not limited to, alkali metal hydroxides and alkoxides (ie, MOR, wherein M is an alkali metal such as potassium, lithium, or sodium, and R is hydrogen or alkenyl, as defined above, or where R is a C or straight or branched algayl chain, including, without limitation, potassium hydroxide, sodium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, tert-butoxide sodium, lithium hydroxide, etc.); other hydroxides such as magnesium hydroxide (Mg (OH)) or calcium hydroxide (Ca (OH) 2); alkali metal hydrides (ie, MH, wherein M is as defined above, thus including, without limitation, sodium hydride and lithium hydride); alkylated disilazides, such as, for example, potassium hexamethyldisilazide and lithium hexamethyldisilazide; carbonates such as potassium carbonate (K2C03), sodium carbonate (Na2C03), potassium bicarbonate (KHC03), and sodium bicarbonate (NaHC03), alkyl ammonium hydroxides such as n-tetrabutyl ammonium hydroxide (TBAH); and thereafter. The term "coupling reagent" as used herein refers to a reagent used to couple the carboxylic acid and an amine or an aniline to form an amide bond. A coupling additive, such as CD1, HOBt, HOAt, HODhbt, OSu or NEPIS, used in combination with another coupling reagent can be included to accelerate the coupling process and inhibit side reactions. Particular peptide coupling reagents can include CD1, DCC, EDC, BBC, BDMP, BOMI, HATU, HAPyU, HBTU, TAPipU, AOP, BOP, BOP, PyAOP, PyBOP, TDBTU, TNTU, TPTU, TSTU, BEMT, BOP -Cl, BroP, BTFFH, CIP, EDPBT, Dpp-Cl, EEDQ, FDPP, HOTT-PF6, TOTT-BF4, PyBrop, PyClop, and TFFH. See "Peptide Coupling Reagents: Yams, Acronyms and References," Albany Molecular Research, Inc., Technical Reports, Vol. 4, No. 1, incorporated herein reference. The terms "halogenating agent" or "halogenating reagent" means an agent or agents capable of halogenating compounds of formula (II) herein. Halogenating reagents include inorganic and organic halogenating reagents. Examples of inorganic halogenating reagents include chlorine, bromine, iodine, fluorine and sodium hypochlorite. Organic halogenated reagents include N-chlorosuccinamide (SNC), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS). 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin and 1,3-diiodo-5,5-dimethylhydantoin. "High performance" as used herein means a yield of more than 80%, more than 85%, more than 90% or more than 95%. "Leaving group" means groups that have the ability to move during the reaction with a nucleophile including I, Br, Cl, R? 0SO2O- (where Rxo is alkyl, substituted alkyl, aryl, or heteroaryl, as defined in the present), and weak bases, such as, for example, HS04-. Examples of leaving groups include I, Br, Cl, and methyl sulfate ions, mesylate (methane sulfonate), trifluoromethanesulfonate, and tosylate (p-toluenesulfonate). In the compounds of the formula (II) herein, the group Q is -O-P *, where P * is selected so that when considered together with the oxygen atom to which P * binds, Q is a leaving group, that is, Q has the ability to move during the reaction with a nucleophile. Accordingly, the P * group can be selected from alger, -S020 R? 0, -C (= 0) Rn and Si (R? 2) 3, where Rio is as defined above in the definition of "leaving group". Ra? is alkenyl, aryl or heteroaryl, and R12 is selected from alkenyl and aryl. "Appropriate solvent" as used herein is intended to refer to a simple solvent as well as mixtures of solvents. The solvents may be selected, as appropriate for a given reaction step, from, for example, aprotic polar solvents such as DMF, DMA, DMSO, dimethylpropyleneurea, N-methylpyrrolidone (NMP), and hexamethylphosphoric triamide; ether solvents such as diethyl ether, THF, 1,4-dioxane, methyl t-butyl ether, dimethoxymethane and ethylene glycol dimethyl ether; alcohol solvents such as MeOH, EtOH and isopropanol; and solvents which contain halogen such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Solvent mixtures may also include biphasic mixtures. The term "thickened mixture" as used herein is meant to mean a saturated solution of the compound of the formula (IV) and an additional amount of the compound of the formula (IV) to give a heterogeneous solution of the compound of the formula (IV) and the solvent. The present invention describes crystalline forms of the compound of the formula (IV) in a substantially pure form. As used herein, "substantially pure" means a compound having a purity greater than 90%, including 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and 100%. When they dissolve, the crystalline forms of the compound of the formula (IV) lose their crystalline structure, and are therefore referred to as a solution of the compound of the formula (IV). All forms of the present invention, however, can be used for the preparation of liquid formulations in which the drug is dissolved or suspended.

In addition, the crystalline forms of the compound of the formula (IV) can be incorporated in solid formulations. A therapeutically effective amount of the crystalline forms of the compound of the formula (IV) is combined with a pharmaceutically acceptable carrier to produce the pharmaceutical compositions of this invention. By "therapeutically effective amount" means that an amount which when administered alone or an amount when administered with an additional therapeutic agent, is effective to prevent, suppress or alleviate the disease or condition or the progress of the disease or condition. GENERAL METHODS This invention relates to a process for the preparation of 2-aminothiazolyl-5-aromatic amides which are useful as inhibitors of the kinase, particularly the protein tyrosine kinase and the p38 kinase. The process involves the halogenation of ß- (P *) oxy-, ß-unsaturated carboxyl aromatic amides (II) (wherein P * is as defined herein), such as the β-carboxyl benzamides (alguyl) oxy-a, ß-unsaturated, and the reaction with thioureas (III) to give 2-aminothiazole-5-aromatic amides of the formula (I). The desired substituents of the 2-amino group and / or the 5-aromatic group can be linked either before or after the formation of aminothiazole. For example, in one embodiment, the compound of the formula (I) is prepared by the reaction of a thiourea wherein R 4 is hydrogen, and the hydrogen atom R 4 is then processed to more functionalized groups such as, in a , substituted pralines In another embodiment, the compound of the formula (I) is prepared by means of the thiourea reaction wherein R is pyrimidinyl, and the pyrimidinyl is optionally further elaborated with additional substituents, as desired. The process provides an efficient route to prepare 2-aminothiazolyl-5-aromatic amides, essentially in one step and in high yield, without the use of expensive coupling reagents or catalysts. Surprisingly, with this process the halogenation after the reaction with thiourea to form the aminothiazole is carried out without a Undesired aromatic halogenation. One embodiment of the invention is represented in Reaction Escape 1. Reaction Scheme 1 In Reaction Scheme 1, Ar is aryl or heteroaryl, more preferably aryl, even more preferably optionally substituted phenyl. Even more preferred is the process involving compounds wherein Ar is phenyl substituted with one to three alkyl, halogen, -C (= 0) NR8, and / or NR8C (= 0), wherein R3 is alkyl, cycloalkyl, or heteroaryl, more preferably wherein R8 is cyclopropyl or methyl, and even more preferably wherein Ar is selected from 2-chloro 6-methylphenyl, N-cyclopropyl-1-methyl-benzamide, and N, 1-dimethyl-benzamide The inventive process can be carried out where the linking group L is present, as in the formula I, but advantageously the group Ar is bonded directly to the nitrogen atom carboxylamide, as in formula (la). As noted, the desired substituents can be linked to the Ar group either before or after the halogenation and cyclization process.

Thiourea (III) can be prepared, prior to cyclization, having desired R4 and R5 groups, corresponding to the groups in the desired final product, or alternatively, the desired groups can be linked to the amino-thiazolyl after cyclization. For example, the thiourea (III) compounds can be prepared and used in the reaction wherein R4 and Rs both are hydrogen, or R4 and R5, are other groups, different from those of the final desired product, and then, after the formation of aminothiazole (I) or (la), the groups R4 and R5 are prepared for the substituents of the final desired product. All of these modalities and alternative variations thereof are contemplated within the scope of the present invention. In the intermediates of formula (II) and (lia), herein, preferably the group P * can be selected from alkyl, -S020 R10, -S02R? 0, -C (= 0) Rüy -Si (RX2) 3 , as defined above, but preferably P * is an alkyl, more preferably a lower alkyl, that is, methyl, ethyl, n-propyl, isoP, or a straight or branched butyl.

Preferably the group R 2 is hydrogen or lower alkyl, more preferably hydrogen, and R 3 is preferably hydrogen. For the compounds (II), the β-alkyloxy-α, β-unsaturated carboxyl benzamides are preferred in this manner, including β-alkyloxy-α, β-substituted with benzamides and unsubstituted with β, with the latter more preferred, wherein the phenyl group of the benzamide is optionally substituted as recited above for Ar in the formula (la). Also preferred are β-alkyloxy-α, β-unsubstituted carboxy benzamides with β are β-ethoxy acryl benzamides, again, wherein the phenyl group of the benzamide is optionally substituted as recited above for Ar. Intermediates (II) and (lia) can be prepared during the reaction of the corresponding anilines, NHR2-Ar, with alkoxy acryloyl compound. The methods for making the β-ethoxy acryl benzamides are also described as for example in Ashwell, M.A. et al. , J. Bioorg. Med. Chem. Lett. (2001), 24, in 3123; and Yoshizaki, S., et al. Chem. Pharni. Bull. (1980), 28, at 3441, incorporated herein by reference. The halogenating agents used in the process can be any agent or agents as defined herein capable of halogenating compounds (II), as previously defined herein. Preferred agents include NBS and the N-halohydantoins. The thiourea (III) compounds include unsubstituted thioureas, N-monosubstituted thioureas, and N, N-disubstituted thioureas. The halogenation and cyclization steps are carried out in a suitable solvent which may include one or more solvents such as hydrocarbons, ethers, esters, amides and ketones with ethers, with dioxane being preferred. Another embodiment of the invention is illustrated in the Scheme of reaction 2. Reaction scheme 2 As can be seen, in Reaction Scheme 2, the β- (P *) oxy-acryl benzamides (Ilb), wherein R and R3 are hydrogen, and P * is as previously defined, preferably a lower alkyl, are halogenated with a halogenating agent, such as NBS, in an appropriate solvent, in the presence of water, then cyclized with unsubstituted thiourea (Illa). The resulting 2- (unsubstituted) amino-thiazole-5-aromatic amide (Ib) is reacted with a pyrimidine compound 4, wherein R and R 'are hydrogen or optional substituents, more preferably hydrogen or lower alkyl, and X e And both are outgoing groups, as defined herein, for produce the compounds you. The leaving groups X and Y are preferably I, Br, Cl, or R? 0SO2O- (wherein Rxo is alkyl, substituted alkyl, aryl, or heteroaryl, as defined herein), more preferably X and Y are selected from I, Br, Cl, methyl sulfate, mesylate, trifluoromethanesulfonate, and tosylate, even more preferably Cl and Br. Thus, the pyrimidines 4 include pyrimidines substituted by sulfonyloxy and bis-halogenated with the latter such as pyrimidines substituted by bis -I prefer favorite. Advantageously, this step is carried out in the presence of a base, wherein the base may include alkali hydride and alkoxides with the latter such as preferred sodium t-butoxide. Suitable solvents include solvents such as hydrocarbons, ethers, esters, amides, ketones and alcohols, or mixtures of the above solvents, with an ether such as preferred THF. The compound (le) can then be reacted with amine NHR20R2? (5), to provide compounds of the formula (Id). For example, R20 and R2? both can be hydrogen, or R20 and R2? can independently be selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, or R20 and R2? they can be taken together to form a heterocycle. Preferably, R20 and R2? Are they taken together so that NHR20R2? form an optionally substituted piperazine, more preferably a piperazine N'-substituted with substituted alkyl, more preferably hydroxyethyl. Advantageously, this step is carried out in the presence of a base, which includes organic and inorganic bases, with organic bases such as tertiary amines being preferred. Suitable solvents include solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, ketones, lactams and alcohols and samples of the above solvents, with alcohols such as n-butanol as a non-limiting example, and DMF (dimethylformamide), DMA (dimethylacetamide) and NMP (N-methylpyrrolidine) as other examples. The compounds of the formula (Id) formed in this way can optionally be further processed as desired and / or purified and crystallized. An alternative approach is illustrated in Reaction Scheme 3, wherein the thiourea compound substituted by mono (Illb) is used. Reaction scheme 3 As can be seen in Reaction Scheme 3, the • benzamides (ß (P *) oxy-acryl (Ilb), as in Reaction Scheme 2, are halogenated with a halogenating agent, then further reacted with a monosubstituted thiourea (Illb) having linked thereto a pyrimidine group functional group, wherein R, R 'and Y are as in Reaction Scheme 2, to provide the 2-substituted-aminothiazole aromatic aromatic amides of the formula (le) The compounds of the formula (le) can then optionally react with amines NHR 2 or R 2i (5), to provide the compounds of the formula (Id), and / or optionally further elaborated as desired, and / or purified and crystallized. ADDITIONAL MODALITIES In one embodiment, the process comprises preparing a compound of the formula (le), wherein Zi and Z5 is selected from hydrogen, alkyl, halogen, hydroxy, and alkoxy; Z2, Z3 and Z4 is selected from hydrogen, alkyl, halogen, hydroxy, alkoxy, C (= 0) NR8, and / or NR8C (= 0), wherein R8 is alkyl, cycloalkyl, or heteroaryl; which comprises reacting a compound having the formula, where Q is the group -OP *, where P * is selected such that, when considered together with the oxygen atom to which P * is linked Q is a leaving group, and Zi, Z2, Z3, Z and Z5 are as defined above, with a halogenating reagent followed in the presence of water by a thiourea compound having the formula, to provide the compound that has the formula (le) in the above process, in one embodiment, R4 is hydrogen, therefore the process provides a compound having the formula (If), tt2y? s _ (> - £ and Z3 * • df).

In another embodiment, R4 can be a group that has the formula, wherein R15 and Rig are as defined herein, therefore the process provides a compound having the formula (I), where R15, R16, Zi, Z2, Z3, Z4, Z5, R20 and R2? they are as defined in the present. Still in another modality, R is a group that has the formula, wherein Y, R15 and R6 are as defined herein, wherein the process provides a compound having the formula (Ii), Still in another modality, R4 is a group that has the formula, In another embodiment of the above process, for example, when R4 is hydrogen to provide the compounds of the formula (If), the process can further comprise reacting the compound of the formula with a pyrimidine compound that has the formula, 4a, where X and Y are outgoing groups, and R15 and i6 are independently selected from hydrogen, alkyl and substituted alkyl, to provide a compound having the formula, where Y, R? 5, R16, Zi, Z2, Z3, Z4 and Z5 are as defined above.

In another embodiment of the above process, for example, when R is hydrogen to provide the compounds (If), the. The process can also comprise reacting the compound of the formula with a pyrimidine compound that has the formula, 4a, for example, is reacted with a base or metal catalyst) wherein X and Y are leaving groups, and Ris and Rie are independently selected from hydrogen, alkyl and substituted alkyl, to provide a compound having the formula, where Y, R? 5, Laugh, Zi, Z2, Z3, Z4 and Z5 are as defined above. The compounds (Ig) can optionally also be made reacting with an amine having the formula NHR20 21 / wherein R2o and R2? are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, or R2o and R21 may be taken together to form a heterocycle, to provide a compound having the formula (Ih), where R15, Rie, Zi, Z2, Z3, Z4, Z5, R2o and R2? they are as defined above. In one embodiment, the amine NHR20R21 is piperazine in turn optionally substituted with hydroxy (alkyl), more preferably hydroxyethyl.

In one embodiment, the amine NHR20R2? is In another embodiment, when R is hydrogen to provide the compounds (If), the process may further comprise reacting the compound of the formula with a pyrimidine compound that has the formula, wherein R15, R6, R20 and R21 are as defined above, to provide a compound having the formula (Ih), Other variations of the processes above are also contemplated within the scope of the invention, including processes that further involve the preparation of the 2-amino-thiazole-5-aromatic amides. In one embodiment, the present invention provides a crystalline monohydrate of the compound of the formula (IV), (IV).

In another embodiment, the monohydrate form is in substantially pure form. In another embodiment, the monohydrate form is in the form substantially pure, wherein substantially pure is greater than 90% pure. In another embodiment, the monohydrate form of the compound of the formula (IV) is characterized by an X-ray powder diffraction pattern substantially in accordance with that shown in Figure 1. In another embodiment, the monohydrate form of the compound of (IV) is characterized by differential random calorimetric thermography and a thermogravimetric analysis substantially in accordance with that shown in Figure 2. In another embodiment, the monohydrate form of the compound of the formula ( IV) is characterized by an X-ray powder diffraction pattern (CuKa? = 1.5418A at a temperature of about 23 ° C) comprising four or more 2T values (alternatively comprises five or more, six or more, or includes 2T values) selected from the group consisting of: 18.0 ± 0.2, 18.4 ± 0.2, 19.2 + 0.2, 19.6 ± 0.2, 21.2 + 0.2, 24.5 ± 0.2, 25.9 ± 0.2 and 28.0 ± 0.2. In another embodiment, the monohydrate form of the compound of the formula (IV) is characterized by an X-ray powder diffraction pattern (CuK? = 1.5418Á at a temperature of about 23 ° C) comprising four or more 2T values (alternatively, it comprises five or more, six or more, or 'includes 2T values) selected from the group consisting of: 4. 6 ± 0.2, 11.210.2, 13.8 ± 0.2, 15.210.2, 17.910.2, 19.1 + 0.2, 19.6 + 0.2, 23.210.2, 23.610.2. In another embodiment, the monohydrate form of the compound of the formula (IV) is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a (A) = 13,862 (1); B (A) = 9.286 (1); C (A) = 38.143 (2); Volume = 4910 (l) Á3 Space group Pbca Molecules / unit cell 8 Density (calculated) (g / cm3) 1,300 where the compound is at a temperature of around -50 ° C. In another modality, the. The monohydrate form of the compound of the formula (IV) is a water molecule per molecule of the formula (IV). In another embodiment, the present invention provides a crystalline butanol solvate of the compound of the formula (IV). In another embodiment, the butanol solvate form of the compound of the formula (IV) is characterized by the unit cells approximately equal to the following: Cell dimensions a (A) = 22.8102 (6); b (A) = 8. 691 (3); c (A) = 15.1436 (5); volume = 2910.5 (2) Á3 Space group P2i / a Molecules / unit cell 4 Density (calculated) (g / cm3) 1.283. In another embodiment, the crystalline butanol solvate of the compound of the formula (IV) is characterized by an X-ray powder diffraction pattern (Cuka? = 1.5418Á at a temperature of about 23 ° C) comprising four or more 2T values (alternatively, comprises five or more, six or more, or comprises values 2?) selected from the group consisting of: 5.9 ± 0.2, 12.0 ± 0.2, 13.0 + 0.2, 17.7 ± 0.2, 24.1 ± 0.2 and 24.6 + 0 . In another embodiment, the present invention is. directed to the crystalline ethanol solvate of the compound of the formula (IV). In another embodiment, the crystalline ethanol solvate of the formula (IV) is characterized by an X-ray powder diffraction pattern (CuKa? -1.5418A at a temperature of about 23 ° C) comprising four or more 2T values (alternatively, it comprises five or more, six or more, or comprises 2T values) selected from the group consisting of: 5.8 + 0.2, 11.3 + 0.2, 15.8 ± 0.2, 17.2 + 0.2, 19.5 ± 0.2, 24.1 ± 0.2, . 3 ± 0.2 and 26.2 ± 0.2. In another embodiment, the present invention is directed to the pure crystalline form of the compounds of the formula (IV). In another embodiment, the pure crystalline form of the compounds of the formula (IV) is characterized by an X-ray powder diffraction pattern (CUKa? = 1.54181A at room temperature of about 23 ° C) comprising four or more values 2T (alternatively, comprises five or more, six or more, or comprises values 2?) Selected from the group consisting of: 6.8 ± 0.2, 11.1 + 0.2, 12.3 ± 0.2, 13.2 ± 0.2, 13.7 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 24.3 ± 0.2 and 24.8 ± 0.2. In another embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of at least one of the crystalline forms of the compound of the formula (IV) and a pharmaceutically acceptable carrier. In another embodiment, the present invention describes a method for the treatment of cancer comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the crystalline forms of the compound of the formula (IV). In another embodiment, the present invention describes a method for oncological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of the compound of the forms Crystallins of at least one of the compound of the formula (IV), wherein the disorders are selected from chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer, non-small cell lung cancer ( NSCLC), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, breast cancer, colorectal cancer, pancreatic cancer, and prostate cancer. When administered intravenously, the compounds of the present invention, including the crystalline forms of the compounds of formula IV, are administered using the formulations of the invention. In one embodiment, the compounds of the present invention are administered by IV infusion over a period of time from about 10 minutes to about 3 hours, preferably from about 30 minutes to about 2 hours, more preferably about 45 minutes. at 90 minutes, and most preferably about 1 hour. Typically, the compounds are administered intravenously in a dose of about 0.5 mg / m2 to 65 mg / m2, preferably from about 1 mg / m2 to 50 mg / m2, more preferably about 2.5 mg / m2 to 30 mg / m2, and even more preferably approximately 25 mg / m2. A person skilled in the art will easily know how to convert the doses of mg / kg to mg / m2 given the height or weight or both of the patient (see, for example, http: // www. fda.gov/cder/cancer/animalframe.htm). As discussed above, the compounds of the present invention, including the crystalline forms of the compounds of formula IV can be administered orally, intravenously, or both. In particular, the methods of the invention comprise dosage protocols such as once a day for 2 to 10 days, preferably every 3 to 9 days, more preferably every 4 to 8 days and "even more preferably every 5 days. there is a period of from 3 days to 5 weeks, alternatively 4 days to 4 weeks, or 5 days to 3 weeks, or 1 week to 2 weeks, between cycles where there is no treatment, in another embodiment the compounds of the present invention, including crystalline forms of the compounds of formula IV can be administered orally, intravenously, or both, once a day for 3 days, with a period of 1 week to 3 weeks between cycles where there is no treatment. of the present invention, the crystalline forms of the compounds of formula IV, can be administered orally, intravenously, or both, once a day for 5 days, with a period of 1 week to 3 weeks between cycles where there is no treatment . In another embodiment, the treatment cycle for the administration of the compounds of the present invention, the crystalline forms of the compounds of formula IV, is once a day for 5 consecutive days and the period between treatment cycles is 2 to 10 days, or alternatively one week. In one embodiment, a compound of the present invention, for example, a compound of formula IV, is administered once daily for 5 consecutive days, followed by 2 days when there is no treatment. The compounds of the present invention, the crystalline forms of the compounds of formula IV, can also be administered orally, intravenously, or both once every 1 to 10 weeks, every 2 to 8 weeks, every 3 to 6 weeks, alternatively every 3 weeks In another method of the invention, the compounds of the present invention, the crystalline forms of the compounds of formula IV, are administered in a 28-day cycle wherein the compounds are administered intravenously on days 1, 7 and 14 and are orally administered on day 21. Alternatively, the compounds of the present invention, the crystalline forms of the compounds of formula IV, are administered in a 28-day cycle wherein the compound of formula IV is administered orally on the day 1 and is administered intravenously on days 7, 14 and 28. According to the methods of the invention, the compounds of the present invention, including the compounds of formula IV, are administered until the patient shows a response, for example, a reduction in the size of the tumor, or until the dose limiting the toxicity is reached. Compounds within the scope of formula (I) can be tested for their activity as inhibitors of protein kinases using the assays described below, or variations thereof which are within the level of one skilled in the art. In another embodiment, the present invention relates to the use of at least one of the crystalline forms of the compound of Formula (IV), in the preparation of a medicament for the treatment of oncological disorders, such as those described herein. In another embodiment, the present invention relates to a method for treating oncological disorders, as described herein, which are resistant or tolerant to Gleevec® (STI-571), which comprises administering to a host in need thereof. treating a therapeutically effective amount of a compound of formula (IV) or at least one of the crystalline forms of a compound of formula (IV). The invention also encompasses all combinations of the alternative aspects mentioned herein. It will be understood that one and all of the embodiments of the present invention can be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. In addition, any of the elements of a modality means that it can be combined with one and all the elements of one of the modalities to describe additional modalities. Utility The compounds of the formula (I) prepared according to the inventive process of the present invention inhibit the protein tyrosine kinase, specifically the kinases of the Src family such as Lck, Fyn, Lyn, Src, Yes, Hck, Fgr and Blk, and thus are useful in the treatment, including prevention and therapy, of disorders associated with protein tyrosine kinase such as immunological and oncological disorders. The compounds of formula (I) also inhibit the receptor tyrosine kinases including HERI and HER2 and are therefore useful in the treatment of proliferative disorders such as psoriasis and cancer. The ability of these compounds to inhibit HERI and other kinase receptors also allows their use as anti-angiogenic agents to treat disorders such as cancer and diabetic retinopathy. The "disorders associated with protein tyrosine kinase" are those disorders that result from the aberrant activity of tyrosine kinase, and / or that are alleviated by the inhibition of one or more of these enzymes. For example, Lck inhibitors are of value in the treatment of a number of such disorders (for example, the treatment of autoimmune diseases), since the Lck inhibitor blocks the activation of the T cell. The treatment of T cell-mediated diseases, including the inhibition of T cell activation and proliferation , is a particularly preferred embodiment of the compounds of the formula (I) prepared according to the present process. The use of the compounds of the formula (I) in the treatment of disorders associated with the protein tyrosine kinase is exemplified by, but is not limited to, the treatment of a range of disorders such as: transplantation (such as organ transplantation, acute transplantation or rejection of the heterotransplant or homotransplant (such as that used in the treatment of burns)); protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; induction of transplant tolerance; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; chronic obstructive pulmonary disease (COPD); such as emphysema; inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosus); graft versus host disease; Hypersensitive diseases mediated by the T cell, including hypersensitivity to contact, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome; autoimmune hyperthyroidism, such as Graves' disease; Addison's disease (autoimmune disease of the adrenal glands); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain Barre syndrome; other autoimmune diseases; various types of cancer, including cancers where Lck kinases or others of the Src family such as Src are activated or overexpressed, such as colon carcinoma and thymoma, and cancers where the family kinase activity Src facilitates the growth or survival of a tumor; glomerulonephritis; serum sickness; urticaria; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; palmoplanteris pustulosis; gangrene Pyoderma; Sezary syndrome; atopic dermatitis; systemic sclerosis; and morphea. The compounds of the present invention are useful for the treatment of cancers such as chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer (SCLC). in English), non-small cell lung cancer (NSCLC for its acronym in English), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, cancer of breast, colorectal cancer, pancreatic cancer, cancer of the prostate and others known to be associated with the protein tyrosine kinase, such as, for example, SRC, BCR-ABL and c-KIT. The compounds of the present invention are also useful in the treatment of cancers that are sensitive to and resistant to chemotherapeutic agents that target BCR-ABL and c-KIT, such as, for example, Gleevec (STI-571). In another embodiment of the invention, the compound of formula I is administered in conjunction with at least one antineoplastic agent. As used herein, the phrase "antineoplastic agent" or "anti-cancer agent" is synonymous with "chemotherapeutic agent" and / or "anti-proliferative agent" and refers to compounds that prevent cancer, or that hyperproliferative cells multiply. The anti-aging agents proliferative cells prevent cancer cells from multiplying by: (1) interfering with cellular capacity to replicate DNA and (2) inducing cell death and / or apoptosis in cancer cells. The classes of compounds that can be used as cytotoxic-anti-proliferative agents and / or antiproliferative agents include the following: Alkylating agents (including, without limitation, nitrogen mustards, ethylene imine derivatives, alkylsulfonates, nitrosoureas and triazenes): uracil mustard , chloromethine, cyclophosphamide, (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. Antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogues, and adenosine deaminase inhibitors): Methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine. Natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins): vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (paclitaxel is commercially available as Taxol®), mithramycin, deoxy-formicin, mitomycin C, L-Asparaginase, interferons (especially IFN-a), Etoposide, and Teniposide. Other cytotoxic anti-poliferative agents and / or anti-proliferative agents are navelbena, CPT-11, anastrazole, letrazole, capecitabine, reloxaphine, cyclophosphamide, iophosamide, and droloxaphine. The phrase "radiation therapy" includes, but is not limited to, X-rays or gamma rays that are administered from either an externally applied source, such as a beam or by implanting radioactive sources. The radiation therapy may be useful in combination with the compound of the present invention. The following may also be useful when administered in combination with the compound of the present invention. Agents that affect microtubules that interfere in cellular mitosis and are well known in the art for their antiproliferative cytotoxic activity. The microtubule-affecting agents useful in the invention include, but are not limited to, alocolguicin (NSC 406042), halicondrine B (NSC 609395), colchicine (NSC 757), colchicine derivatives (for example, NSC 33410), dolastatin 10 (NSC 376128), aytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC 608832), thiocolquicin NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vicristin sulfate (NSC 67574), synthetic and natural epothilones including, but not limited to, epothilone A, epothilone B, epothilone C, epothilone D, deoxyepotilone A, deoxyepotilone B, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] -7-11-dihydroxy- 8, 8, 10, 12, 16-pentamethyl-3- [l-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17 oxabicyclo [1.1.0] heptadecan-5, 9-dione (described in US patent 6,262,094 , published July 17, 2001), [ÍS- [IR *, 3R *, (E), 7R *, IOS *, 11R *, 12R *, 16S *]] -3- [2- [2- (aminomethyl ) -4-thiazolyl] -1-methyletenyl] -7-11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo [14.1.0] -heptadecan-5,9-dione (described in USSN 09 / 506,481 filed on February 17, 2000, and examples 7 and 8 in the present), [1S- [1R *, 3R, (E), 7R *, 10S *, 11R *, 12R *, 16S *]] -7, 11-dihydroxy-8,8,10, 12,16-pentamethyl-3- [l-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyl [14.1 .0] -h eptadecan-5, 9-dione, [ÍS- [1R *, 3R * (E), 7R *, IOS *, 11R *, 12R *, 16S *]] -3- [2- [2- '(Aminomethyl) -4-thiazolyl] -1-methyletenyl] -7, 11-dihydroxy-8,8, 10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione, and derivatives of the same; and other agents that break the microtubule. Additional antineoplastic agents include, discodermolide (see Service, (1996) Science, 274: 2009) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in the scientific and patent literature, see, for example, Bulinski (1997) J. Cell Sci. 110: 3055-3064; Panda (1997) Proc. Nati Acad. Sci USA 94: 10560-10564; Muhlradt (1997) Cancer Res. 57: 3344-3346; Nicolaou (1997) Nature 387: 268-272; Vasquez (1997) Mol. Biol. Cell. 8: 973-985; Panda (1996) J. Biol. Chem 271: 29807-29812. In cases where it is desired to give quiescent aberrant proliferative cells in conjunction with or prior to treatment with the chemotherapeutic methods of the invention, the hormones and steroids (including synthetic analogues): 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Droesterolone Propionate, Testoiactone, Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Zoladex can also be administered to the patient. Also suitable for use in the combination chemotherapeutic methods of the invention are antiangiogenic agents such as metalloproteinase matrix inhibitors, and other VEGF inhibitors, such as anti-VEGF antibodies and small molecules such as ZD6474 and SU6668 are also included. Genetech anti-Her2 antibodies can also be used. An EGFR inhibitor appropriate is EKB-569 (an irreversible inhibitor). Also included are Imclone antibody C225 immunospecific for EGFR, and src inhibitors. Casodex ™, which reverts to non-proliferating androgen-dependent carcinomas. Yet another example of the cytostatic agent is the anti-estrogen Tamoxifen which inhibits the proliferation or growth of estrogen-dependent breast cancer. Inhibitors of cell proliferative signal transduction are cytostatic agents. Examples are inhibitors of epidermal growth factor, Her-2 inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3 inhibitors, Src kinase inhibitors and PDGF inhibitors. As mentioned, certain anti-proliferative agents are anti-angiogenic and anti-vascular agents and, by interrupting the blood flow to solid tumors, they return to the quiescent cancer cells by depriving them of their nutrients. Neutering, which also returns to non-proliferating androgen-dependent carcinomas, can also be used. Starvation by means other than interruption of blood flow is another example of a cytostatic agent. A particular class of antivascular cytostatic agents are combretastatins. Other exemplary cytostatic agents include MET kinase inhibitors, cintos inhibitors MAP, receptor and non-receptor tyrosine kinase inhibitors, inhibitors of integrin signaling and inhibitors of insulin-like growth factor receptors. Also suitable are anthracyclines (eg, daunorubicin, doxorubicin), cytarabine (ara-C, Cytosar-U); 6-thioguanine (Tabloid "), mitoxantrone (Novantrone" and etoposide (VePesid®), "amsacrine (AMSA), and all trans retinoic acids (ATRA)." - The compounds of the present invention may be useful in combination with BCR-ABL inhibitors such as, but not limited to, Gleevec® (imatinib, STI-571) or AM-107). The compounds of the present invention may be useful in combination with anti-cancer compounds such as fentanyl, doxorubicin, interferon alfa-n3, palonosetron dolasetron anastrozole, exemestane, bevacizumab, bicalutamide, cisplatin, dacarbazine, cytarabine, clonidine, epirubicin, levamisole, toremifene , fulvestrant, letrozole, tamsulosin, gallium nitrate, trastuzumab, altretamine, hydroxycarbamide, ifosfamide, interferon alfacon-1, gefitinib, granisetron, leuprorelin, dronabinol, megestrol, pethidine, promethazine, morphine, vinorelbine, pegfilgrastim, filgrastim, nilutamide, tietilperazine, leuprorelin, pegaspargase, muromonab-CD3, porfimer sodium, cisplatin, abarelix, capromab, samarium SM153 lexidronam, paclitaxel, docetaxel, etoposide, triptorelin, valrubicin, nofetumomab merpentan tecnetium 99m Te, vincristine, capecitabine, streptozocin and ondansetron. Thus, the present invention provides methods for the treatment of a variety of cancers, including, but not limited to: carcinoma including that of the bladder (including bladder and metastatic cancer), breast, colon (which includes cancer colorectal), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testis, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus , stomach, gall bladder, cervical, thyroid and skin (including squamous cell carcinoma). hemopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burketts lymphoma; hematopoietic tumors of the myeloid line including chronic and acute myelogenous leukemias, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia; tumors of the central and peripheral nervous system that include astrocytoma, neuroblastoma, glioma and schwannomas, - tumors of mesenchymal origin that include fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors that include melanoma, xenaderma pigmentosum, keratoactanoma, seminoma, follicular thyroid cancer, and teratocarcinoma. The present invention provides methods for the treatment of a variety of non-cancerous proliferative diseases. The invention is used to treat GIST, breast cancer, pancreatic cancer, colon cancer, NSCLC, CML and ALL, sarcoma and various pediatric cancers. The compounds of the present invention are inhibitors of the protein tyrosine kinase and as such are useful in the treatment of immunological disorders in addition to oncological disorders. U.S. Patent No. 6,596,746 describes the utility of the compound in immunological disorders and is incorporated herein by reference to the description of the compound in such immunological disorders. The present invention also encompasses a pharmaceutical composition used in the treatment of cancer, comprising administering a therapeutically effective amount of the combinations of this invention with or without pharmaceutically acceptable carriers or diluents. The pharmaceutical compositions of this invention comprise an anti-proliferative agent or agents, a compound of the formula I and a pharmaceutically acceptable carrier. The methods cover use of the neoplastic agent in combination with the compound of the formula I. The compositions of the present invention may further comprise one or more additional pharmaceutically acceptable ingredients such as alumina, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants and the like. The antineoplastic agents, compounds of the formula I and compositions of the present invention can be administered orally or parenterally including the routes of intravenous, intramuscular, intraperitonal, subcutaneous, rectal and topical administration. The present invention also provides the use of the compounds obtained with the inventive process to further prepare pharmaceutical compositions capable of treating conditions associated with the Src kinase, which include the conditions described above. The compositions may contain other therapeutic agents. The pharmaceutical compositions can be formulated by using conventional solid and liquid carriers or diluents, as well as pharmaceutical additives at the type appropriate to the type of administration desired (eg excipients, binders, preservatives, stabilizers, flavorings, etc.) in accordance with such techniques. as those well known in the art of pharmaceutical formulations. The pharmaceutical compositions can be administered by any means for the treated condition, which depends on the need for the specific site treatment or amount of drug to be administered. Topical administration is generally preferred for skin-related diseases and the preferred systematic treatment for cancerous or precancerous conditions, although other modes of administration are contemplated. For example, the compounds of the formula I can be delivered orally, such as in the form of tablets, capsules, granules, powders or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; buccally parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g. as suspensions or solutions, injectable, sterile, aqueous or non-aqueous); nasally such as by inhalation of dew; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Unit dosage formulations containing non-toxic pharmaceutically acceptable carriers or diluents can be administered. The compounds of formula I prepared according to the inventive process can be administered in an appropriate form for immediate release or prolonged release. The immediate release or prolonged release can be carried out with appropriate pharmaceutical compositions or, as in the case of prolonged release, with devices such as subcutaneous implants or osmotic pumps. Exemplary compositions for topical administration include a topical carrier such as PLASTIBASEß (mineral oil gelled with polyethylene). Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose to impart volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art. the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose and / or other excipients, binders, diluting agents, disintegrants, diluents and lubricants such as known in art. The compounds of the formula I can also be administered orally by sublingual and / or buccal administration, for example, with freeze-dried tablets, compressed or molded. Exemplary compositions can include rapidly dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrin. Also included in such formulations are high molecular weight excipients such as celluloses (AVICEL8) or polyethylene glycols (PEG); an auxiliary excipient to assist mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and / or maleic anhydride copolymer (eg, GANTREZ); and agents to control the release such as the polyacrylic copolymer (e.g., CARBOPOL 934). Lubricants, flow improvers, flavors, coloring agents and stabilizers can also be added for ease of manufacture and use. Exemplary compositions for nasal spray or administration by inhalation include solutions which may contain for example, benzyl alcohol or other suitable preservatives, absorption promoters to improve absorption and / or bioavailability and / or other solubilizing or dispersing agents such as those known in the art. the art. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain for example non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other agents Suitable dispersants, wetting agents and suspending agents, including synthetic mono or diglycerides including oleic acid. Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic diglyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and / or dissolve in the rectal cavity to release the drug. The effective amount of a compound of formula (I) can be determined by one of ordinary skill in the art and includes exemplary amounts of doses for a mammal from about 0.05 to 100 mg / kg body weight of active compound per day, which it can be administered in a single dose or in the form of simple divided doses, such as from 1 to 4 times a day. It will be understood that the specific dose level and dose frequency for any particular subject can be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability, and the duration action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination of drugs, and severity of the particular condition. Preferred subjects for treatment include animals more preferably mammalian species such as humans and domestic animals such as dogs, cats, horses and the like. Thus, when the term "patient" is used herein, this term is intended to include all subjects, more preferably mammalian species that are affected by the mediation of Src kinase levels. Compounds within the scope of formula I can be tested as activity as inhibitors of protein kinases using the assays described below or variations thereof which are within the level of ordinary skill in the art. Cell assays (1). Tyrosine .cellular phosphorylation Jurkat T cells are incubated with the test compound and then stimulated by the addition of the antibody to CD3 (monoclonal antibody G19-4). The cells are used after 4 minutes or at another desired time, by the addition of lysis buffer containing NP-40 detergent. Phosphorylation of the proteins is detected by immunostaining anti-phosphotyrosine. Detection of the phosphorylation of specific proteins of interest, such as ZAP-70, is detected by immunoprecipitation with anti-ZAP-70 antibody followed by anti-phosphotyrosine immunostaining. Such procedures are described in Schieven GL, Mittler, RS, Nadler, SG, Kirihara, JM, Bolen, JB, Kanner, SB, and Ledbetter, JA, "ZAP-70 tyrosine kinase, CD 5 and T cell receptor involvement a W and H202 induced T cell signal transduction ", J. Biol. Chem., 269, 20718-20726 (1994), and references incorporated herein. Lck inhibitors inhibit tyrosine phosphorylation of cellular proteins induced by the anti-CD3 antibodies. For the preparation of G19-4, see Hansen, JA, Martin, PJ, Beatty, PG, Clark, EA, and Ledbetter, JA, "Human T lymphocyte cell surface molecules defined by the monoclonal antibodies workshop", in Luekocyte Typing I, A. Bernard, J. Boumsell, J. Dausett, C. Milstein, and S. Schlossman, eds. (New York: Springer Verlag), pages 195-212 (1984); and Ledbetter, JA, June, CH, Rabinovitch, PS, Grossman, A., Tsu, TT, and Imboden, JB, "Signal transduction through CD4 receptors: stimulatory vs. inhibitory activity is regulated by CD4 proximity to the CD3 / T cell receptor ", Eur., J. Immunol. , 18, 525 (1988) '. (2) . Calcium assay Mobilization of Lck inhibitors that block calcium in T cells is stimulated with anti-CD3 antibodies. The cells are loaded with the indo-1 calcium indicator dye, treated with an anti-CD3 antibody such as the monoclonal antibody G19-4, and the calcium mobilization is measured using flow cytometry recording changes in the blue / violet ratio of the indo-1 as described in Schieven, GL, Mittler, RS, Nadler, SG, Kirihara, JM, Bolen, JB, Kanner, SB, and Ledbetter, JA, "ZAP-70 tyrosine kinase, CD45 and T cell receptor involvement in W and H202 induced T cell signal transduction ", J. Biol. Chem., 269, 20718-20726 (1994), and references incorporated herein. (3) . Proliferation assays Lck inhibitors inhibit the proliferation of T cells from normal human peripheral blood to grow with anti-CD3 antibody plus anti-CD28. A 96-well plate is coated with a monoclonal antibody to CD3 (such as G19-4), the antibody is allowed to bind, and then the plate is washed. The antibody bound to the plate serves to stimulate the cells. T cells from normal human peripheral blood are added to the wells together with the test compound plus anti-CD28 antibody to provide co-stimulation.

After a desired period of time (eg, 3 days), [3 H] -thymidine is added to the cells, and after further incubation to allow labeling into the newly synthesized DNA, the cells are harvested and they are counted in a scintillation counter to measure cell proliferation. The following examples illustrate the invention but will not be construed as a limitation thereof. EXAMPLES Example 1 Preparation of the intermediate: (S) -1-sec-Butylthiourea To a solution of S-sec-butyl-amine (7.31 g, 0.1 mol) in chloroform (80 mL) at 0 ° C was slowly added benzoyl isothiocyanate (13.44 mL, 0.1 mol). The mixture was allowed to warm to 10 ° C and was stirred for 10 minutes. The solvent was then removed under reduced pressure, and the residue was dissolved in MeOH (80 mL). An aqueous solution (10 mL) of NaOH (4 g, 0.1 mol) was added to this solution, and the mixture was stirred at 60 ° C for another 2 hours. The MeOH was then stirred under reduced pressure, and the residue was stirred in water (50 mL). The precipitate was collected by vacuum filtration and dried to give S-1-sec-butyl thiourea (12.2 g, 92% yield). Mp 133-134 ° C; XH NMR (500 MHz, DMSO-D6) d 7.40 (s, 1H), 7.20 (br s, 1H), 6.76 (s, 1H), 4.04 (s, 1H), 1.41 (, 2H), 1.03 (d, J = 6.1 Hz, 3H), 0.81 (d, J = 7.7 Hz, 3H); 13 C NMR (125 MHz, DMSO-D6) d 182.5, 50.8, 28.8, 19.9, 10.3; LRMS m / z 133.2 (M + H); Analysis calculated for C5H? 2N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.49; H, 8.88; N, 21.32; S, 24.27. Example 2 Preparation of the intermediate: (R) -1-sec-Butylthiourea (R) -1-sec-Butyl thiourea was prepared in 92% yield according to the general method summarized by Example 1. pf 133-134 ° C; X H NMR (500 MHz, DMSO) d 0.80 (m, 3 H, J = 7.7), 1.02 (d, 3 H, J = 6.1), 1.41 (, 2 H), (3.40, 4.04) (s, Í H), 6.76 ( s, ÍH), 7.20 (s, br, 1H), 7.39 (d, ÍH, J = 7.2); 13 C NMR (500 MHz, DMSO) d: 10.00, 19.56, 28.50, 50.20, 182.00; m / z 133.23 (M + H); Analysis calculated for C5H? 2N2S: C, 45.41, H, 9.14; N, 21.18; S, 24.25. Found: C, 45.32; H, 9.15; N, 21.14; S, 24.38. Example 3 Preparation of: To a solution of 3-amino-N-methyl-4-methylbenzamide hydrochloride (1.0 g, 5 mmol) in acetone (10 mL) at 0 ° C was added pyridine (1.2 mL, 15 mmol) dropwise by a syringe The 3-methoxyacryloyl chloride (0.72 mL, 6.5 mmol) was added and the reaction was stirred at room temperature for 1 h. The solution was cooled again to 0 ° C and IN HCl (1.5 mL) was added dropwise by means of a pipette. The reaction mixture was stirred for 5 minutes, then water (8.5 mL) was added by means of an addition funnel. The acetone was removed in vacuo and the resulting solution was stirred for 4 hours. hours. The callization started within 15 minutes. After stirring for 4 hours, the vessel was cooled in an ice bath for 30 minutes, filtered and rinsed with ice-cold water (2 x 3 L) to give compound 3A (0.99 g, 78% yield) as a white solid. - - - - H NMR (400 MHz, CDC13) d 8.95 (s, ÍH), 8.12 (br s, ÍH), 7.76 (s, 1H), 7.29 (, 2H), 7.05 (d, J = 7.9 Hz, 1H), 5.47 (d, J = 12.3 Hz, ÍH), 3.48 (s, 3H), 2.54 (d, J = 4.7 Hz, 3H), 2.03 (s, 3H), CLAR tr 2.28 minutes (Condition A). 3B Example 3 To a RBF 50 mL containing the above compound 3A (0.5 g, 2.0 mmol) was added THF (2.5 mL) and water (2 L), followed by NBS (0.40 g, 2.22 mmol), and the solution The mixture was stirred for 90 minutes, R-sec-butyl thiourea (Ex.2) (267 mg) was added, and the solution was heated at 75 ° C for 8 hours.The concentrated NH4OH was added to adjust the pH to 10 followed. by addition of EtOH (15 mL) Water (15 mL) was added and the slurry was stirred for 16 hours, filtered and washed with water to give Example 3 as a light brown solid (0.48 g, 69%). yield, 98% purity) EM 347.1; CLAR 2.59 Example 4 Preparation of: Example 4 was prepared following the methods of Example 3 but using the appropriate acryl benzamide and Example 1. Example 5 Preparation of: N- (2-chloro-6-methylphenyl) -2- (6- (4- (3 hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (The compound of the formula (IV)) (rv) 5A. 1- (6-Chloro-2-methylpyrimidin-4-yl) thiourea To a stirred slurry of 4-amino-5-chloro-2-methylpyrimidine (6.13 g, 42.7 mmol) in THF (24 mL) was added ethyl isothiocyanoformate (7.5 mL, 63.6 mmol), and the mixture was heated to reflux . After 5 hours, another portion of ethyl isothiocyanate formate (1.0 mL, 8.5 mmol) was added and after 10 hours, a final portion (1.5 mL, 12.7 mmol) was added and the mixture was stirred an additional 6 hours. The slurry was evaporated under vacuum to remove most of the solvent and heptane (6 mL) was added to the residue. The solid is Collect by vacuum filtration and wash with heptane (2 mL) to give 8.01 g (68% yield) of the ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate intermediate. A solution of ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (275 mg, 1.0 mmol) and IN sodium hydroxide (3.5 eq) was heated and stirred at 50 ° C for 2 hours. The resulting slurry was cooled to 20-22 ° C. The solid was collected by vacuum filtration, washed with water, and dried to give 185 mg of 1- (6-chloro-2-methylpyrimidin-4-yl) thiourea (91% yield). ^ -NMR (400 MHz, DMSO-d6): d 2.51 (S, 3H), 7.05 (s, ÍH), 9.35 (s, 1H), 10.07 (s, ÍH), 10.91 (s, 1H); 13 C NMR (125 MHz, DMSO-d 6) d: 25.25, 104.56, 159.19, 159.33, 167.36, 180.91. 5B. (E) -N- (2-Chloro-6-methylphenyl) -3-ethoxyacrylamide To a cold stirred solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 L) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly maintaining temperature at 0-5 ° C. The mixture was then warmed and stirred for 2 hours at 20 ° C. Hydrochloric acid (1N, 115 mL) was added at 0-10 ° C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick mixture. The slurry was diluted with toluene (275 L) and stirred for 15 minutes at 20-22 ° C then 1 hour at 0 ° C. The solid was collected by vacuum filtration, washed with water (2 x 75 mL) and dried to give 74.1 g (73.6% yield) of (E) -N- (2-chloro-6-methylphenyl) -3 - ethoxy acrylamide). XH NMR (400 Hz, DMS0-d6) d 1.26 (t, 3H, J = 7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J = 7 Hz), 5.58 (d, 1H, J = 12.4 Hz), 7.10-7.27 (m, 2H, J = 7.5 Hz), 7.27-7.37 (d, ÍH, J = 7.5 Hz), 7.45 (d, 1H, J = 12.4 Hz)., 9.28 (s, ÍH ); 13C NMR (100 MHz, CDC13) d: 14.57, 18.96, 67.17, 97.99, 126.80, 127.44, 129.07, 131.32, 132.89, 138.25, 161.09, - 165.36. 5C. 2-Amino-N- (2-chloro-6-methylphenyl) thiazoyl-5-carboxamide To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at -10 to 0 ° C. The slurry was warmed and stirred at 20-22 ° C for 3 hours. Thiourea (1.60 g, 21 mmol) was added and the mixture was heated to 80 ° C. After 2 hours, the resulting solution was cooled to 20-22 ° C and concentrated ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half the volume and cooled to 0-5 ° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide. XH NMR (400 MHz, DMSO-d6) dd 2.19 (s, 3H), 7.09-7.29 (m, 2H, J = 7.5), 7.29-7.43 (d, ÍH, J = 7.5), 7.61 (s, 2H) 7.85 (s, 1H), 9.63 (s, 1H); 13 C NMR (125 MHz, DMSO-d 6) d: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02. 5 D. 2- (6-Chloro-2-methylpyrimidin-4-ylamino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide To a stirred solution of compound 5C (5.00 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (3.65 g, 22.4 / mmol) in THF (65 L) was added a 30 wt.% Solution of t-butoxide of sodium in THF (21.1 g, 65.36 mmol) slowly with cooling until maintaining the temperature at 10-20 ° C. The mixture was stirred at room temperature for 1.5 hours and cooled to 0-5 ° C. The hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture was stirred 1.75 h at 0-5 ° C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4% yield) of compound 5D. XH NMR (400 MHz, DMSO-d6) d 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, ÍH), 7.18-7.34 (, 2H, J = 7.5), 7.34-7.46 (d, 1H, J = 7.5), 8.31 (s, ÍH), 10.02 (s, ÍH), 12.25 (s, 1H). 5E. Example 5 To a mixture of compound 5D (4.00 g, 10.14 mmol) and hydroxyethylpiperazine (6.60 g, 50.69 mmol) in n-butanol (40 mL) was added DIPEA (3.53 mL, 20.26 mmol). The slurry was heated at 118 ° C for 4.5 hours, then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with n-butanol (5 mL), and dried. The product (5.11 g) was dissolved in 80% hot EtOH-H20 (80 mL), and the solution was clarified by filtration. The hot solution was slowly diluted with water (15 mL) and cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with 50% ethanol-water (5 mL) and dried to provide 4.27 g (83.2% yield) of N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazi -1-il) -2 -methylpyrimidin-4-ylamino) thiazole-5-carboxamide as monohydrate. ^? NMR (400 MHz, DMSO-d6) d 2.23 (s, 3H), 2.40 (s, 3H), 2.42 (t, 2H, J = 6), 2.48 (t, 4H, J = 6.3), 3.50 (m, 4H), 3.53 (q, 2H, J = 6), 4.45 (t, ÍH, J = 5.3), 6.04 (s, 1H), 7.25 (t, ÍH, J = 7.6), 7.27 (dd, 1H , J = 7.6, 1.7) 7.40 (dd, ÍH, J = 7.6, 1.7), 8.21 (s, ÍH), 9.87 (s, ÍH), 11.47.

EXAMPLE 6 Preparation of: N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamic (IV) To a slurry of (E) -N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide 5B (120 mg, 0.50 mmol) in THF (0.75 ml) and water (0.5 L) was added NBS (98 mg, 0.55 mmol) at 0 ° C. The mixture was warmed "and-stirred at 20-22 ° C for 3 hours, to which was added 1- (6-chloro-2-methylpyrimidin-4-yl) thiourea 5A (100 mg, 0.49 mmol), and the suspension The thick slurry was heated and stirred at reflux for .2 hours.The slurry was cooled to 20-22 ° C and the solid was collected by vacuum filtration to give 140 mg (71% yield) of 2- (6-chloro-2). -methylpyrimidin-4-ylamino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide 5D. 1 H NMR (400 MHz, DMSO-d6) d 2.23 (s, 3H), 2.58 (s, 3H) , 6.94 (s, ÍH), 7.18-7.34 (, 2H, J = 7.5), 7.34-7.46 (d, ÍH, J = 7.5), 8.31 (s, 1H), 10.02 (s, ÍH), 12.25 (s) , 1H) Compound 5D was made for N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide, following Step 5E.

EXAMPLE 7 Preparation of: N- (2-Chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin--ylamino) thiazole-5-carboxamide 7A . 2- [4- (6-Chloro-2-methyl-pyrimidin-4-yl) -piperazin-1-yl] -ethanol (7A) (7B) (7C) 2-Piperazin-1-yl-ethanol (8.2 g, 63.1 mmol) was added to a solution of 4,6-dichloro-2-methylpyrimidine (5.2 g, 31.9 mmol) in dichloromethane (80 mL) at room temperature. The mixture was stirred for 2 hours and triethylamine (0.9 ml) was added. The mixture was stirred at room temperature for 20 hours. The resulting solid was filtered. The cake was washed with dichloromethane (20 ml). The filtrate was concentrated to give an oil. This oil was dried under high vacuum for 20 hours to give a solid. This solid was stirred with heptane (50 ml) at room temperature for 5 hours. Filtration gave 7C (8.13 g) as a white solid. 7B. Example 7 (5C) (IV) To a 250 ml round bottom flask was charged 5C (1.9 g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2C03 (16 g, 115.7 mmol), Pd (OAc) 2 (52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and cleaned with nitrogen. Toluene (60 ml) was added. The suspension was heated to 100-110 ° C and stirred at this temperature for 20 hours. After cooling to room temperature, the mixture was applied to a column of silica gel. The column was eluted first with EtOAc, and then with 10% MeOH in EtOAc. Finally, the column was washed with 10% 2M ammonia solution in MeOH / 90% EtOAc. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g). ANALYTICAL METHODS Solid state nuclear magnetic resonance (NMRHR) All measurements of C-13 NMR in the solid state are made with a 400 MHz NMR spectrometer, Bruker DSX-400. High resolution spectra are obtained using high power proton decoupling and the TPPM pulse sequence and cross polarization ramp amplitude (RAMP-CP) with magic angle rotation (MAS) at approximately 12 kHz (A.E. Bennett et al, J. Chem.

Phys., 1995, 103, 6951), (G. Metz, X. Wu and S.O. Smith, J.

Magn. Reson. A., 1994, 110, 219-227). Approximately 70 mg of the sample, packed in a zirconia rotor designed with a canister was used for each experiment. The chemical changes (S) are they make reference to an external adamantine with high frequency resonance placed at 38.56 ppm (W.L. Earl and D.L. VanderHart, J. Magn. Reson., 1982, 48, 35-54). Diffraction of X-ray powder A person skilled in the art will appreciate that an X-ray diffraction pattern can be obtained with a measurement error that depends on the measurement conditions employed. In particular, it is generally known that the intensities in an X-ray diffraction pattern may vary depending on the measurement conditions employed. It will be further understood that the relative intensities may also vary depending on the experimental conditions and, consequently, the exact order of the intensity should not be taken into account. Additionally, a measurement error of the diffraction angle for a conventional X-ray diffraction pattern is typically around 5% or less, and such a degree of measurement error should be taken into account as regards the aforementioned diffraction angles. Accordingly, it will be understood that the crystal forms of the present invention are not limited to the crystal forms that provide the X-ray diffraction patterns completely identical to the X-ray diffraction patterns described in the accompanying figures described herein. Any of the crystal shapes that provide X-ray diffraction patterns substantially identical to those described in the accompanying figures, fall within the scope of the present invention. The ability to find out substantial identities of X-ray diffraction patterns is within the eyes of someone of ordinary skill in the art. X-ray powder-diffraction data for the crystalline forms of Compound (IV) are obtained using the Bruker GADDS manual chi-platform goniometer (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, WL 53711 USA). Diffraction System English General Area Detector) Dust samples are placed in thin-walled glass capillaries of 1 mm or less in diameter; the capillary is rotated during the data collection. The sample-detector distance was 17 cm. The radiation was Cu Ka (45kV lllmA,? = 1.5418 A). The data was collected for 3 < 2? < 35 ° with a time of exposure to the sample of at least 300 seconds. Simple Crystal X-ray All single-crystal data were collected on a Kappa CCD 2000 Bruker-Nonius system (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wl 53711 USA) using Cu Ka radiation (? = 1.5418 Á) and were collected only for the Lorentz polarization factors. The index and the processing of the measurement of the intensity data were carried out with the software payer HKL2000 (Otwinowski, Z &Minor, W. (1997) in Macromolecular Crystallography, eds. Carter, W.C. Jr & Sweet, R.M. (Academic, NY), Vol. 276, pp. 307-326) in the collection program set (Data collection and processing user interface: Collect: Data collection softaware, R. Hoof t, Nonius B.V., 1998). The structures are solved by direct methods and refined based on the observed reflections using either the SDP software package (SDP), Structure Determination Package, Enraf .Nonius, Bohemia NY 11716. Dispersion factors, including fyf ", in the SDP softaware are taken from the" International Tables for Crystallography ", Kynoch Press, Bromingham, England, 1974; Vol IV, Tables 2.2A and 2.3.1) with minor local modifications or the crystallographic package, MAXUS (set of solution and refinement software maXus: S. Mackay, CJ Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland MaXus: a computer program for the solution and refinement of diffraction crystal structures The derived atomic parameters (coordinates and temperature factors) are refined through the complete least squared matrix.The function minimized in the refinements was? W (IF0I - ÍRCI) 2- R is defined as S | F0 I - I Fc | | / S | F0 | whereas Rw = [? w (I F0 | - I Fc I) 2 / Sw | F012] 1/2 where w is an appropriate weight function based on errors in the observed intensities. HE they examine the maps of differences in all the stages of refinement. Hydrogens are introduced in idealized positions with isotropic temperature factors, but the hydrogen parameters do not vary. The derived atomic parameters (coordinates- and temperature factors) are refined through the complete least squared matrix. The function minimized in the refinements was? W (I Role ~ | FC |) 2. R is defined as S | | F0 | - I Fc | | /? | F0 | whereas Rw = [? w (| F0 | - | FC |) 2 / Sw | F0 | 2] 12 where w is an appropriate weight function based on errors in the observed intensities. The difference maps are examined in all the stages of refinement. Hydrogens are introduced at idealized positions with isotropic temperature factors, but the hydrogen parameters do not vary. Differential Scanning Calorimetry The DSC instrument used to test the crystalline forms was a TA Instruments model Q1000. The DSC cell / sample chamber was purged with 100 ml / min of ultra high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the sample temperature measured with this method is within about +/- 1 ° C, and the heat of fusion can be measured with a relative error of about +/- 5%. The sample was placed in an open aluminum DSC receptacle and measured again against an empty reference receptacle. At least 2 mg of the powder of The sample was placed at the bottom of the receptacle and tilted slightly to ensure good contact with the receptacle. The weight of the sample was accurately measured and recorded to one hundredth of a milligram. The instrument was programmed to heat at 10 ° C per minute in a temperature range between 25 and 350 ° C. The heat flow, which was normalized by a heavy sample, was grouped against the measured sample temperature. The data is reported in units of watts / grams (W / g). The group is made with the endothermic peaks pointing downwards. The endothermic fusion peak was evaluated by extrapolating the start temperature, peak temperature, and heat of fusion in this analysis. Thermogravimetric Analysis (TGA for its acronym in English) The TGA instrument used to test the crystalline forms was a TAInstruments model Q500. Samples of at least 10 milligrams were analyzed at a heating ratio of 10 ° C per minute in the temperature range between 25 ° C and around 350 ° C. EXAMPLE 8 Preparation of: N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole crystalline monohydrate 5-carboxamide (IV) An example of the crystallization process for obtain the form of the crystalline monohydrate is shown: Load 48 g of the compound of the formula (IV). Charge approximately 1056 mL (22 mL / g) of ethyl alcohol, or other suitable alcohol. Load approximately 144 mL of water. Dissolve the suspension by heating to approximately 75 ° C. Optional: polish the filter by transferring the compound of the formula (IV) solution at 75 ° C through the pre-heated filter and into the receiver. Rinse the dissolution reactor and transfer lines with a mixture of 43 mL of ethanol and 5 mL of water. Heat the contents in the receiver to 75 - 80 ° C and keep at 75 - 80 ° C to reach complete dissolution. Load approximately 384 mL of water at a ratio such that the bath temperature is maintained between 75-80 ° C. Cool to 75 ° C, and optionally, load seed crystals of monohydrate. Seed crystals are not essential to obtain monohydrate, but provide better control of crystallization. Cool to 70 ° C and hold at 70 ° C for ca. 1 hour. Cool from 70 to 5 ° C for 2 hours and maintain the temperature between 0 to 5 ° C for at least 2 hours. Filter the glass slurry.

Wash the filter cake with a mixture of 96 mL of ethanol and 96 mL of water. Dry the material to < 50 ° C under reduced pressure until the water content is 3.4 to 4.1% per KF to provide 41 g- "(85 M%). Alternatively, the monohydrate can be obtained by: 1) An aqueous solution of the salt of Compound IV acetate was seeded with monohydrate and heated to 80 ° C to give bulky monohydrate 2) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate.On standing for several days at room temperature, voluminous monohydrate is formed 3) An aqueous suspension of compound IV was seeded with monohydrate and heated at 70 ° C for 4 hours to give bulky monohydrate In the absence of seeded, an aqueous thick solution of compound I was unchanged after 82 days at room temperature 4) A solution of compound IV in a solvent such as NMP or DMS was treated with water until the solution became cloudy and was maintained at 75-85 ° C for several hours.The monohydrate was isolated after cooling and filtering . 5) A solution of compound IV in ethanol, butanol, and water was heated. Sodium monohydrate was added to the hot solution and then cooled. The monohydrate was isolated during cooling and filtration.

One of ordinary skill in the art will appreciate that the monohydrate of the compound of formula (IV) can be represented by the XRPD as shown in Figure 1 or by a representative sampling of peaks as shown in Table 1. Representative peaks taken from XRPD of the monohydrate of the compound of formula (IV) are shown in Table 1. Table 1 2-Theta d (Á) Height 17,994 4.9257 915 18,440 4.8075"" 338 19,153 4,6301 644 19,599 4.5258 361 21,252 4.1774 148 24,462 3.6359 250 25.901 3.4371 133 28.052 3.1782 153 The XRPD is also characterized by the following list which comprises values 2? selected from the group consisting of: 4.6+ 0.2, 11.2+ 0.2, 13.8 ± 0.2, 15.2 ± 0.2, 17.9 ± 0.2, 19. ± 0.2, 19.6 ± 0.2, 23.2 + 0.2, 23.6 + 0.2. The XRPD is also characterized by the list of values 2? selected from the group consisting of: 18.0 + 0.2, 18.4 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.2 ± 0.2, 24.5 + 0.2, 25.9 ± 0.2, and 28. O ± 0.2.

Single-crystal X-ray data are obtained at room temperature (+ 25 ° C). The molecular structure is confirmed as a monohydrate form of the compound of the formula (IV). The following unit cell parameters are obtained by the monohydrate of the compound of the formula (IV) from the X-ray analysis at 25 ° C: a (A) = 13.8632 (7); b (A) = 9.3307 (3); c (A) = 38.390 (2); V (A3) 965.9 (4); Z '= 1; Vm = 621 Space group Pbca Molecules / unit cell 8 Density (calculated) (g / cm3) 1.354 where Z '= number of drug molecules per asymmetric unit. Vm = V (cell unit) / Z (drug molecules per cell). Single-crystal X-ray data is also obtained at -50 ° C. The monohydrate form of the compound of the formula (IV) is characterized by the unit cell parameters approximately equal to the following: Cell dimensions: a (A) = 13,862 (1); a (A) = 9.286 (1); c (A) = 38.143 (2); Volume = 4910 (1) A3 Space group Pbca Molecule / unit cell 8 Density (calculated) (g / cm3) 1300 where the compound is at a temperature of around -50 ° C. The simulated XRPD was calculated from refined atomic parameters at room temperature. The monohydrate of the compound of the formula (IV) is represented by the DSC as shown in Figure 2. The DSC is characterized by a broad peak between about 95 ° C and 130 ° C. This peak is broad and variable and corresponds to the loss of a water of hydration as seen in the TGA graph. The DSC also has a characteristic peak at about 287 ° C which corresponds to the mixing of the dehydrated form of the compound of the formula (IV). The monohydrate TGA of the compound of the formula (IV) is shown in Figure 2 together with the DSC. The TGA shows a weight loss of 3.48% from 50 ° C to 175 ° C. The weight loss corresponds to a loss of a water of hydration of the compound of the formula (IV). The monohydrate can also be prepared by crystallizing the alcohol solvents, such as methanol, ethanol, propanol, i-propanol, butanol, pentanol, and water. EXAMPLE 9 Preparation of: N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4- crystalline n-butanol solvate ilamino) thiazole-5-carboxamide (IV) The crystalline butanol solvate of the compound of the formula (IV) is prepared by dissolving the compound (IV) in 1-butanol at reflux (116-118 ° C) at a concentration of about 1 g / 25 mL of the solvent. During cooling, the butanol solvate crystallizes from the solution. It is filtered, washed with butanol, and dried. The following unit cell parameters are obtained from the X-ray analysis for the crystalline butanol solvate, obtained at room temperature: A (Á) = 22.8102 (6); b (A) = 8.4691 (3); C (A) = 15.1436 (5); V (Á3) 2910.5 (2); Z '= l; Vm = 728 Space group P2? / A Molecules / unit cell 4 Density (calculated) (g / cm3) 1.283 where Z '= number of drug molecules per asymmetric unit. Vm = V (cell unit) / (Z drug molecules per cell). One of ordinary skill in the art will appreciate that the butanol solvate of the compound of the formula (IV) can be represented by the XRPD as shown in Figure 3 or by a representative sample of peaks. The representative peaks for the crystalline butanol solvate are values of: 5.9 ± 0.2, 12.0 + 0.2, 13. O ± 0.2, 17.7 ± 0.2, 24. ± 0.2, and 24.6 ± 0.2.

Example 10 Preparation of: Crystalline ethanol solvate of N- (2-chloro-6-methylphenyl) 2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole -5-carboxamide (IV) To a 100 mL round bottom flask was charged 4.00 g (10.1 mmol) of 5D (containing 2.3% area of 5C) 6.60 g (50.7 mmol) of 7B, 80 mL of n-butanol and 2.61 g (20.2 mmol) of DIPEA. The resulting slurry was heated to 120 ° C and maintained at 120 ° C for 4.5 h whereby the HPLC analysis shows a% relative area of 0.19 of residual 5D for compound IV. The homogeneous mixture was cooled to 20 ° C and allowed to stir overnight. The resulting crystals were filtered. The wet cake was washed twice with 10 mL portions of n-butanol to provide a white crystalline product. The CLAR analysis showed this material to contain 99.7% area of compound IV and 0.3% area of 5C. The resulting wet cake was returned to the reactor of 100 mL, and was charged with 56 mL (12 mL / g) of ethanol grade 200. At 80 ° C, an additional 25 mL of ethanol was added. To this mixture was added 10 mL of water resulting in rapid dissolution.

Heat was removed and crystallization was observed at 75-77 ° C. The glass slurry was further cooled to 20 ° C and filtered. The wet cake was washed once with 10 mL of 1: 1 ethanol: water and once with 10 mL of n-heptane. The wet cake contains 1.0% water per KF and 8.10% volatiles per LOD. The material was dried at 60 ° C / 30 in Hg for 17 h to provide 3.55 g (70 M%) of the material containing only 0.19% water per KF, 99.87% area per HPLC. The XH NMR spectrum, however, revealed that the ethanol solvate was formed. The following unit cell parameters were obtained from X-ray analysis for the crystalline ethanol solvate (di-ethanolate), obtained at -40 ° C: A (Á) = 22,076 (1); b (A) = 8.9612 (2); C (A) = 16.8764 (3); V (Á3) 3031.1 (1); Z '= 1; Vm = 758 Space group P2a / a Molecules / unit cell 4 Density (calculated) (g / cm3) 1.271 where Z '= number of drug molecules per asymmetric unit Vm = (cell unit) / (Z drug molecules per cell). One of ordinary skill in the art will appreciate that the ethanol solvate of the compound of the formula (IV) can be represented by the XRPD as shown in Figure 4 or by a representative sample of peaks. The representative peaks "for the crystalline ethanol solvate are values 20 of: 5.8 ± 0. 2, 11.3 ± 0.2, 15.8 ± 0.2, 17.2 ± 0.2, 19.5 ± 0.2, 24.0 ± 0.2, 25.3 ± 0.2, and 26.2 ± 0.2. EXAMPLE 11 Preparation of .- N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5- crystalline carboxamide (IV) (pure form N-6) To a mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL) was added DIPEA (155 mL, 0.89 mol) . The suspension was heated to 110 ° C (obtained solution) for 25 minutes, then cooled to about 90 ° C. The resulting hot solution was added dropwise to hot water (80 ° C) (8010) mL, maintaining the temperature at about 80 ° C. The resulting suspension was stirred 15 minutes at 80 ° C then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with water (2x1600 mL) and dried in vacuo at 55-60 ° C providing 192.45 g (88.7% yield) of N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide. H NMR (400 MHz, DMSO-ds): d 2.24 (s, 3H), 2.41 (s, 3H), 2.43 (t, 2H, J = 6), 2.49 (t, 4H, J = 6.3), 3.51 ( m, 4H), 3. 54 (q, 2H, J = 6), 4.46 (t, ÍH, J = 5.3), 6.05 (s, ÍH), 7.26 (t, ÍH, J = 7.6), 7.28 (dd, 1H, J = 7.6, 1.7), 7.41 (dd, ÍH, J = 7.6, 1.7), 8.23 (s, ÍH), 9.89 (s, 1H), 11.48. KF0.84; DSC: 285.25 ° C (start), 286.28 ° C (max). The following cell unit parameters are obtained from the X-ray analysis for the pure crystalline compound IV, obtained at 23 ° C: a (Á) = 22,957 (1); b (A) = 8.5830 (5); c (A) = 13803 (3); V (Á3) = 2521.0 (5); Z '= 1; Vm = 630 Space group P2? / A Molecules / unit cell 4 Density (calculated) (g / cm3) 1286 where Z '= number of drug molecules per asymmetric unit. Vm = V (cell unit) / (Z drug molecules per cell). One of ordinary skill in the art will appreciate that the crystalline form of the compound of formula (IV) can be represented by the XRPD as shown in Figure 5, or by a representative sample of peaks. The representative peaks for the pure crystalline form (N-6) are values of: 6.8 ± 0.2, 11.1 ± 0.2, 12.3 ± 0.2, 13.2 ± 0.2, 13.7 ± 0.2, 16.7 ± 0.2, 21.0 ± 0.2, 24.3 ± 0.2, and 24.8 ± 0.2. Example 12 Preparation of: N- (2-chloro-6-methylphenyl) -2- (6- (4- (3-hydroxyethyl) piperazin-1- il) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (IV) (pure form T1H1-7) crystalline The pure form of the title can be prepared by heating the monohydrate form of the compound of the formula (IV) above of the dehydration temperature. The following unit cell parameters are obtained from the X-ray analysis by the pure crystalline compound IV (T1H1-7), obtained at 25 ° C: A (A) = 13.4916; b (Á) = 9.3992 (2); C (A) = 38,817 (1); V (Á3) = 4922.4 (3); Z '= 1; Vm = 615 Group of space Pbca Density (calculated) (g / cm3) 1.317 where Z '= number of drug molecules per asymmetric unit. Vm = V (cell unit) / (Z drug molecules per cell). One of ordinary skill in the art will appreciate that the pure crystalline form (T1H1-7) of the compound of formula (IV) can be represented by the XRPD as shown in Figure 6, or by a representative sample of peaks. The representative peaks for the pure crystalline form (T1H1-7)) are values 2? of: 8.0 ± 0.2, 9.7 ± 0.2, 11.2 ± 0.2, 13.3 ± 0.2, 17.5 ± 0.2, 18.9 ± 0.2, 21.0 ± 0.2, 22.0 ± 0.2. Obviously, numerous variations and modifications of the present invention are possible in light of the above teachings. Therefore, it will be understood that within the scope of of the appended claims, the invention can be practiced differently. to which is specifically described herein. 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 (32)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. Process for preparing a compound having the formula (I), wherein L, Ar, R2, R3, R4, R5, and m are as defined below, characterized in that it comprises reacting a compound having the formula (II), where Q is the group -OP *, where P * is selected so that, when considered together with the oxygen atom to which P * is linked, Q is a leaving group, and Ar, L, R, R3 , and m are as defined below, with a halogenating reagent followed by a thiourea compound having the formula (III), wherein, R 4 and R 5, are as defined below, to provide the compound of the formula (I), wherein, Ar is the same in formulas (I) and (II) and is aryl or heteroaryl; L is the same in formulas (I) and (II) and is optionally substituted alkylene; R2 is the same in formulas (I) and (II), and is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R3 is the same in formulas (I) and (II), and is selected from hydrogen, halogen, cyano, haloalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocycle; R4 is (i) the same in each of formulas (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, or alternatively, R 4 is taken together with R 5 to form heteroaryl or heterocycle; R5 is (i) the same in each of the formulas (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycle, or alternatively, R5 is taken together with R to form heteroaryl or heterocycle; and M is 0 or 1.
2. 2. Process according to claim 1, characterized in that it comprises preparing a compound of the formula (le), wherein Zi and Z5 are selected from hydrogen, alkyl, halogen, hydroxy, and alkoxy; Z2, Z3 and Z4 are selected from hydrogen, alkyl, halogen, hydroxy, alkoxy, C (= 0) NR8, and / or NR8C (= 0), wherein R8 is alkyl, cycloalkyl or heteroaryl; which comprises reacting a compound having the formula, wherein Q is as defined in claim 1, and i, Z2, Z3, Z4 and Z5 are as defined above, with a reagent halogenant followed by a thiourea compound having the formula, to provide the compound that has the formula,
3. 3. Process according to claim 2, characterized in that R4 is hydrogen, to provide the compound having the formula (If),
4. 4. Process according to claim 3, further characterized in that it comprises: reacting the compound of the formula with a pyrimidine compound that has the formula, 4a, wherein X and Y are leaving groups, and Ri5 and R16 are independently selected from hydrogen, alkyl and substituted alkyl, "to provide a compound" having the formula, wherein Y, R15, R16 / Zi, Z2, Z3, Z4 and Z5 are as defined in claim 2. Process according to claim 4, further characterized in that it comprises reacting the compound having the formula, with an amine having the formula NHR2oR2 ?, wherein R2o and R2? are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, or R20 and R2? they can be taken together to form a heterocycle, to provide a compound having the formula (Ih), where R15, Ri6, Zl r Z2, Z3, Z4, Z
5. 5, R20 and R2? they are as defined above.
6. 6. Process according to claim 5, characterized in that the amine NHR20R2? is piperazine again optionally substituted with hydroxy (alkyl).
7. Process according to claim 1, characterized in that it comprises preparing the compound having the formula,
8. 8. Process according to claim 3, further characterized in that it comprises: reacting the compound of the formula (If), where Zi, Z2, Z3, Z4 and Z5 are as defined in the Claim 2, with a pyrimidine compound having the formula, 4b, wherein R15 and Ri6 are independently selected from hydrogen, alkyl and substituted alkyl, and R20 and R2? are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, or R2o and R2? it can be taken together to form a heterocycle; to provide a compound having the formula (Ih). where Ra5, Ri6, Zi, Z2, Z3, Z4, Z5, R20 and R2? they are as defined above.
9. 9. Process according to claim 2, characterized in that R4 is a group having the formula, where R? 5 and Rie are independently selected from hydrogen, alkyl and substituted alkyl, and R20 and R2? are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, or R20 and R2? they can be taken together to form a heterocycle; therefore the process provides a compound having the formula (Ih), where R15, R16, Zi, Z2, Z3, Z4, Z5, R20 and R2? they are as defined above.
10. 10. Process according to claim 2, characterized in that R4 is a group having the formula, wherein Y is a leaving group and R15 and Rie are independently selected from hydrogen, alkyl and substituted alkyl, wherein the process provides a compound having the formula (Ii), where Y, R15, Ri6 / Zi, Z2, Z3, Z4 and Z5 are as defined above.
11. 11. Process according to claim 10, further characterized in that it comprises reacting the compound of the formula (Ii) with an amine having the formula NHR20R2 ?, to provide a compound having the formula (Ih), where R15, Rie, Zi, Z2, Z3, Z4, Z5, R20 and R2? they are as defined in claim 10.
12. Process according to claim 2, characterized in that R4 is a group having the formula,
13. 13. Process according to claim 1, characterized in that Ar is optionally substituted phenyl.
14. 14. Process according to claim 1, characterized in that Ar is selected from,
15. 15. Process according to claim 1, characterized in that L is optionally substituted alkylene and m is 1.
16. 16. Process according to claim 1, characterized in that m is 0.
17. Process according to claim 1, characterized in that, R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; and R5 is hydrogen.
18. 18. Process according to claim 1, characterized in that the halogenating reagent is selected from NBS, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin and 1,3-diiodo 5, 5-dimethylhydantoin.
19. 19. Useful intermediary for the preparation of compounds useful as inhibitors of the kinase, characterized in that it has the formula, where Lanes is C? -alkyl; Zi and Z5 is selected from hydrogen, lower alkyl, and halogen; and Z4 is hydrogen, or -C (= 0) NR8, wherein R8 is alkyl, cycloalkyl, or heteroaryl.
20. 20. Crystalline monohydrate characterized in that it is selected from the compound of the formula (IV) (IV).
21. 21. Compound according to claim 20, characterized in that it has an X-ray powder diffraction pattern substantially in accordance with that shown in figure 1.
22. 22. Compound according to claim 20, characterized in that it has calorimetric thermography. differential scanning and a thermogravimetric analysis substantially in accordance with that shown in figure 2.
23. 23. Compound according to claim 20, characterized in that it has an X-ray powder diffraction pattern (CuKa? = l .5418Á at a temperature of about 23 ° C) comprising four or more selected 2T values from the group consisting of: 18.0 ± 0.2, 18.4 + 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.2 ± 0.2, 24.5 ± 0.2, 25.9 ± 0.2 and 28.0 ± 0.2.
24. 24. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound according to claim 20 and a pharmaceutically acceptable carrier.
25. 25. Method for the treatment of cancer, characterized in that it comprises administering to a host in need of such treatment a therapeutically effective amount of a compound according to claim 20.
26. 26. Compound according to claim 20, characterized in that the parameters of Unitary cell approximately equals the following: Cell dimensions: a (Á) = 13.8632 (7); B (Á) = 9.3307 (3); C (A) = 38,390 (2); Volume = 4965.9 (4) Á3 Space group Pbca Molecules / unit cell 8 Density (calculated) (g / cm3) 1.354.
27. 27. Compound according to claim 20, characterized in that it is a water molecule per molecule of the formula (IV).
28. 28. Treatment method of oncological diseases, characterized in that it comprises administering to a host that such a treatment requires a therapeutically effective amount of a compound according to claim 20, wherein the diseases are selected from chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer (SCLC), cancer of non-small cell lung (NSCLC), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, breast cancer, colorectal cancer, pancreatic cancer, and prostate cancer.
29. 29. Crystalline butanol solvate of the compound of the formula (IV) (IV).
30. 30. Compound according to claim 29, characterized in that the unitary cell parameters approximately equal to the following: Cell dimensions a (Á) = 22.8102 (6); b (A) = 8.4691 (3); c (A) = 15.1436 (5); volume = 2910.5 (2) A3 Space group P2? / a Molecules / unit cell 4 Density (calculated) (g / cm3) 1.283.
31. 31. Process for preparing the crystalline monohydrate of the compound of the formula (IV) (IV) characterized in that it comprises heating and dissolving the compound of the formula (IV) in an ethanol / water mixture and crystallizing the monohydrate from the ethanol / water mixture while cooling.
32. 32. Process according to claim 31, characterized in that the butanol solvate of the compound of the formula (IV) is dissolved in the ethanol / water mixture.