MXPA06009532A - Polymorphic and amorphous forms of2, 5-dimethyl- 2h-pyrazole-3 -carboxylic acid {2-fluoro- 5-[3-((e)-2 -pyridin-2 -yl-vinyl)-1h -indasol-6 -ylamino]-phenyl} -amide - Google Patents

Abstract

The invention provides several polymorphic forms and an amorphous form of 2, 5--Dimethyl- 2H-pyrazole-3 -carboxylic acid {2-fluoro -5-[3-((E)- 2-pyridin-2 -yl-vinyl)- 1H-indazol-6 -ylamino]-phenyl}-amide, pharmaceutical compositions containing such polymorphic or amorphous forms, and methods of using such pharmaceutical compositions to treat disease states mediated by protein kinases, such as cancer and other disease states associated with unwanted angiogenesis and/or cellular proliferation.

Description

POLYMORPHIC AND AMORPHAS FORMS OF F 2-FLUORO-5-r3- ((E) -2- PIRIPIN-2-L-VIN »L) -1H-INDAZOL-6-ILAMINO1-FENl AMID OF 2,5-DIMETHYL ACID -2H-PIRAZOL-3-CARBOXYLIC FIELD PE INVENTION This invention relates to amorphous and polymorphic forms of the. { 2-fluoro-5- [3 - ((E) -2-pyridin-2-yl-vinyl) -1H-indazol-6-ylamino] -phenyl} 2,5-dimethyl-2H-pyrazole-3-carboxylic acid amide, and the therapeutic or prophylactic use of such compounds, and pharmaceutical compositions made therefrom, to treat cancer and other disease states associated with undesired angiogenesis and / or proliferation unwanted cell BACKGROUND OF THE INVENTION U.S. Patent No. No. 6,531,491, which is incorporated herein by reference in its entirety, refers to indazole compounds that modulate and / or inhibit the activity of certain protein kinases. Such compounds are useful for the treatment of cancer and other diseases associated with angiogenesis or cell proliferation mediated by protein kinases. A compound described in the patent of the United States N °. 6,531,491 is. { 2-fluoro-5- [3 - ((E) -2-pyridin-2-yl-vinyl) -1H-indazol-6-ylamino] -phenyl} 2,5-dimethyl-2H-pyrazole-3-carboxylic acid amide, the structure of which is shown below as formula I: Another name for the compound of formula I is 6- [N- (3 - ((1,3-dimethyl-1H-pyrazol-5-yl) carboxamido) -4-fluoro-phenyl) amino] -3-E- [ 2- (pyridin-2-yl) ethenyl] -1H-indazole. To prepare pharmaceutical compositions containing the compound of formula I for administration to mammals in accordance with the requirements of the United States and international health registration authorities (for example, FDA's Good Manufacturing Practices ("GMP")), there is a need to produce the compound of formula I in a stable form, such as a stable crystalline form, having constant physical properties. Additionally, there is a need in the art to provide improved forms of the compound of formula I that have enhanced properties, such as improved solubility or oral bioavailability. SUMMARY OF THE INVENTION In one aspect, the present invention provides fourteen polymorphic forms and an amorphous form of the compound of formula I. In one embodiment, the invention provides a substantially pure polymorphism of the compound shown in formula I, wherein the polymorphism is designated as form I and has a powder X-ray diffraction pattern (PXRD) comprising the peaks at the diffraction angles (2T) of 5.5 and 28.4. More particularly, the polymorph form I has a PXRD pattern comprising the peaks at diffraction angles (2T) of 5.5, 9.5, 10.7 and 28.4. Even more particularly, the polymorph form I has a PXRD pattern which comprises the peaks at diffraction angles (20) essentially the same as those shown in Figure 1 A. Even more particularly, the polymorph I form is characterized by a spectrum Raman essentially the same as that shown in Figure 1C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form II and has a PXRD pattern comprising the peaks at diffraction angles (20) of 12.1 and 16.7. More particularly, the polymorph form II has a PXRD pattern comprising the peaks at diffraction angles (20) of 12.1, 13.0, 16.7 and 18.3. Even more particularly, the polymorph form II has a PXRD pattern comprising the peaks at diffraction angles (2T) essentially the same as those shown in Figure 2A. Even more particularly, the polymorph II form is characterized by a Raman spectrum essentially the same as that shown in Figure 2C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form III and has a PXRD pattern comprising the peaks at diffraction angles (2T) of 6., 4 and 23.4. More particularly, the polymorph form III has a PXRD pattern comprising the peaks at diffraction angles (2T) of 6.4, 23.4, 25.0, and 27.3. Even more particularly the polymorph form III has a PXRD pattern comprising the peaks at diffraction angles (2T) essentially the same as those shown in Figure 3A. Even more particularly, the polymorph form III is characterized by a Raman spectrum essentially the same as that shown in Figure 3C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form IV and has a PXRD pattern comprising the peaks at diffraction angles (2T) of 24, 5 and 34.1. More particularly, polymorph IV has a pattern of PXRD comprising the peaks at diffraction angles (20) of 12.8, 15.8, 24.5, and 34.1. Even more particularly, the polymorph form IV has a PXRD pattern comprising the peaks at diffraction angles (20) essentially equal to those shown in Figure 4A. Even more particularly, the polymorph form IV is characterized by a Raman spectrum essentially the same as that shown in Figure 4C. Even more particularly, the polymorph IV form can be characterized by an appearance of a glass melting endotherm at about 118 ° C at a scanning speed of 10 ° C per minute.

Even more particularly, the polymorph form IV has a DSC thermogram essentially the same as that shown in Figure 4B. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form V and has a PXRD pattern comprising the peaks at diffraction angles (2T) of 8.4 and 26.0. More particularly, the polymorph form V has a PXRD pattern comprising the peaks at diffraction angles (20) of 8.4, 14.2, 22.2, and 26.0. Even more particularly, the polymorphic form V has a PXRD pattern comprising the peaks at diffraction angles (2T) essentially the same as those shown in Figure 5A.

Even more particularly, the polymorphic form V is characterized by a Raman spectrum essentially the same as that shown in Figure 5C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as the form and has a PXRD pattern comprising the peaks at diffraction angles (2T) of 5.5 and 25.2. More particularly, the polymorphic form has a PXRD pattern comprising the peaks at diffraction angles (2T) of 5.5, 10.6, 18.9, and 25.2. Even more particularly, the polymorphic form has a PXRD pattern which comprises the peaks at diffraction angles (2T) essentially the same as those shown in Figure 6A. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form Ib and has a pattern of PXRD comprising the peaks at diffraction angles (20) of 10, 2 and 13.8. More particularly, the polymorphic form Ib has a PXRD pattern comprising the peaks at diffraction angles (20) of 10.2, 13.8, 20.1, and 26.2. Even more particularly, the polymorphic form Ib has a PXRD pattern comprising the peaks at diffraction angles (2T) essentially the same as those shown in Figure 7A. Even more particularly, the polymorphic form Ib is characterized by a Raman spectrum essentially the same as that shown in Figure 7C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form lia and has a PXRD pattern comprising the peaks at diffraction angles (29) of 12.8. and 22.9. More particularly, the polymorphine form has a PXRD pattern comprising the peaks at diffraction angles (2T) of 12.8, 16.0, 22.9, and 31.2. Even more particularly, the polymorphic form Ha has a PXRD pattern comprising the peaks at diffraction angles (29) essentially the same as those shown in Figure 8A. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form llb and has a PXRD pattern comprising the peaks at diffraction angles (29) of 14.3 and 19.0. More particularly, the polymorph form llb has a PXRD pattern comprising the peaks at diffraction angles (29) of 7.9, 14.3, 19.0, and 27.0. Even more particularly, the polymorph form 11b has a PXRD pattern which comprises the peaks at diffraction angles (29) essentially the same as those shown in Figure 9A. Even more particularly, the polymorph form llb is characterized by a Raman spectrum essentially the same as that shown in Figure 9C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein it is designated polymorph as Illa form and has a PXRD pattern comprising the peaks at diffraction angles (20) of 24.9 and 36.2. More particularly, the polymorph Illa has a PXRD pattern comprising the peaks at diffraction angles (29) of 14.7, 21.0, 24.9, and 36.2. Even more particularly, the polymorph Illa has a PXRD pattern which comprises the peaks at diffraction angles (29) essentially the same as those shown in Figure 10A. In another embodiment, the invention provides a purely pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form lllb and has a PXRD pattern comprising the peaks at diffraction angles (29) of 6, 8 and 14.5. More particularly, the polymorph form 111b has a PXRD pattern comprising the peaks at diffraction angles (29) of 6.8, 14.5, 20.8, and 24.8. Even more particularly, the polymorph form 111b has a PXRD pattern comprising the peaks at diffraction angles (29) essentially the same as those shown in Fig. 11A. Even more particularly, the polymorph form IIIb is characterized by a Raman spectrum essentially the same as that shown in FIG. 11 C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph it is designated as form IVa and has a pattern of PXRD comprising the peaks at diffraction angles (29) of 13.5 and 32.5. More particularly, the polymorphic form Via has a PXRD pattern comprising the peaks at diffraction angles (29) of 13.5, 15.8, 27.0, and 32.5. Even more particularly, the polymorph form IVa has a PXRD pattern comprising the peaks at diffraction angles (29) essentially equal to those shown in Figure 12A. Even more particularly, the polymorph form IVa has an occurrence of dehydration endotherm at about 63 ° C and an occurrence of glass melting endotherm at about 123 ° C at a scanning rate of 10 ° C per minute. Still further, the polymorph form IVa has a DSC thermogram essentially the same as that shown in FIG. 12B. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as the Va form and has a PXRD pattern comprising the peaks at diffraction angles (29) of 19.2 and 33.9. More particularly, the polymorphic form Va has a pattern of PXRD comprising the peaks at diffraction angles (29) of 11.5, 19.2, 24.4 and 33.9. Even more particularly, the polymorphic form Va has a PXRD pattern which comprises the peaks at diffraction angles 29 essentially the same as those shown in FIG. 13A. Even more particularly, the polymorphic form Va is characterized by a Raman spectrum essentially the same as that shown in Figure 13C. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as form VI and has a PXRD pattern comprising the peaks at diffraction angles (29) of 7.7. and 26.8. More particularly, polymorph VI has a pattern of PXRD comprising the peaks at diffraction angles (29) of 7.7, 12.9, 18.5, and 26.8. Even more particularly, polymorph VI has a PXRD pattern which comprises the peaks at diffraction angles (29) essentially the same as those shown in Figure 14A. Even more particularly, polymorph VI is characterized by a Raman spectrum essentially the same as that shown in Figure 14C. In another embodiment, the invention provides an amorphous form of the compound shown in formula I, wherein the amorphous form has a PXRD pattern that shows a wide peak at diffraction angles (29) ranging from 4 to 40 ° without none of the sharp peaks characteristic of a crystalline form. More particularly, the amorphous form is characterized in that it has a PXRD pattern essentially the same as that shown in Figure 15A. Even more particularly, the amorphous form is characterized by a Raman spectrum comprising displacement peaks (cm "1) essentially the same as those shown in Figure 15B, In yet another embodiment, the invention provides a solid form of the compound shown in formula I, wherein the solid form is a mixture comprising at least two of the following solid forms: polymorphic forms I, II, III, IV, V, la, Ib , lia, llb, Illa, lllb, IVa, Va, VI, and an amorphous form. In another embodiment, the invention provides a substantially pure polymorph of the compound shown in formula I, wherein the polymorph is designated as the Ibm-2 form, which is a mixture of the Ib and VI forms, and has a PXRD standard comprising the peaks at diffraction angles (29) of 12.9 and 13.8. More particularly, the polymorph form lbm-2 has a PXRD pattern comprising the peaks at diffraction angles (29) of 12.9, 13.8, 20.1, and 26.8. Even more particularly, the polymorph form lbm-2 has a PXRD pattern which comprises the peaks at diffraction angles (29) essentially the same as those shown in Figure 16. In another aspect, the invention relates to pharmaceutical compositions, each comprising an amorphous or crystalline form of the compound of formula I. The invention also relates to a pharmaceutical composition comprising a mixture of at least two of any of the polymorphic and amorphous forms. In a further aspect, the invention provides methods of treating cancer as well as other disease states associated with undesired angiogenesis and / or unwanted cell proliferation, comprising administering a therapeutically effective amount of a polymorph / amorphous compound of the invention to a patient in need of such treatment. The invention also relates to a method of modulating and / or inhibiting the kinase activity of VEGF-R (vascular endothelial cell growth factor receptor), FGF-R (fibroblast growth factor receptor), a CDK complex. (cyclin-dependent kinase), CHK1, LCK (also known as lymphocyte-specific tyrosine kinase), TEK (also known as Tie-2), FAK (focal adhesion kinase), and / or phosphorylase kinase administering a compound of the invention. The preferred compounds of the present invention have a selective kinase activity - that is, they possess significant activity against one or more specific kinases while possessing less activity or minimal activity against one or more different kinases. In a preferred embodiment of the invention, the polymorph / amorphous compounds of the present invention are those that possess substantially greater potency against the VEGF receptor of tyrosine kinase than against the receptor FGF-R1 of tyrosine kinase. The invention also relates to methods for modulating the tyrosine kinase activity of the VEGF receptor without significantly modulating the tyrosine kinase activity of the FGF receptor. The compounds of the invention can be used advantageously in combination with other known therapeutic agents. For example, polymorphic / amorphous forms of the compound of formula I possessing anti-angiogenic activity can be co-administered with chemotherapeutic cytotoxic agents, such as taxol, taxotere, vinblastine, cisplatin, doxorubicin, adriamycin, and the like, to produce an enhanced antitumor effect. Additive or synergistic potentiation of the therapeutic effect can also be obtained by co-administration of a compound of the invention possessing anti-angiogenic activity with other anti-angiogenic agents, such as combretastatin A-4, endostatin, prinomastat, celecoxib, rofocoxib, EMD121974, IM862, monoclonal antibodies. anti-VEGF, and anti-KDR monoclonal antibodies. BRIEF DESCRIPTION OF THE FIGURES Having thus described the invention in general terms, reference will now be made to the appended figures, in which: FIG. 1 is a powder X-ray diffraction diagram of the polymorph form I of the invention; FIG. ÍA is a Differential Scanning Calorimetry (DSC) thermogram of the polymorph form I of the invention; FIG. IB. is a Raman spectral diagram of the polymorph form I of the invention; FIG. 2 is a powder X-ray diffraction diagram of the polymorph II form of the invention; FIG. 2A is a DSC thermogram of the polymorph form II of the invention; FIG. 2B is a Raman spectral diagram of the polymorph II form of the invention; FIG. 3 is a powder X-ray diffraction diagram of the polymorph form III of the invention; FIG. 3A is a DSC thermogram of the polymorph form III of the invention; FIG. 3B is a Raman spectral diagram of the polymorph form III of the invention; FIG. 4 is a powder X-ray diffraction diagram of the polymorph form IV of the invention; FIG. 4A is a DSC thermogram of the polymorph form IV of the invention; FIG. 4B. is a Raman spectral diagram of the polymorphic form IV of the invention; FIG. 5 is a powder X-ray diffraction diagram of the polymorph form V of the invention; FIG. 5 is a DSC thermogram of the polymorph form V of the invention; FIG. 5B is a Raman spectral diagram of the polymorphic form V of the invention; FIG. 6 is a powder X-ray diffraction diagram of the polymorph form of the invention; FIG. 6A is a DSC thermogram of the polymorph form of the invention; FIG. 7 is a powder X-ray diffraction diagram of the polymorphic form Ib of the invention; FIG. 7 A is a DSC thermogram of the polymorphic form Ib of the invention; FIG. 7B a Raman spectral diagram of the polymorphic form Ib of the invention; FIG. 8 is a powder X-ray diffraction diagram of the polymorphic form Ha of the invention; FIG. 8A is a DSC thermogram of the polymorphic form Ha of the invention; FIG. 9 is a powder X-ray diffraction diagram of the polymorph form IIb of the invention; FIG. 9A is a DSC thermogram of the polymorph form IIb of the invention; FIG. 9B is a Raman spectral diagram of the polymorph form llb of the invention; FIG. 10 is a powder X-ray diffraction diagram of the polymorph Illa shape of the invention; FIG. 10A is a powder X-ray diffraction diagram of the polymorph form IIIb of the invention; FIG. 11 is a DSC thermogram of the polymorph form IIIb of the invention; FIG.'TIA is a Raman spectral diagram of the polymorph form IIIb of the invention; FIG. 12 is a powder X-ray diffraction diagram of the polymorph form IVa of the invention; FIG. 12A is a DSC thermogram of the polymorph form IVa of the invention; FIG. 13 is a powder X-ray diffraction diagram of the polymorphic form Va of the invention; FIG. Í3A 'is a DSC thermogram of the polymorph form Va of the invention; FIG. 13B is a Raman spectral diagram of the polymorphic form Va of the invention; FIG. 14 is a powder X-ray diffraction diagram of the polymorphic form VI of the invention; FIG. 14A is a DSC thermogram of the polymorphic form VI of the invention; FIG. 4B is a Raman spectral diagram of the polymorphic form VI of the invention; FIG. 15 is a powder X-ray diffraction diagram of an amorphous form of the invention; FIG. Í5.ÁI is a Raman spectral diagram of an amorphous form of the invention; and FIG. 16 is a powder X-ray diffraction diagram of the polymorph form lbm-2 of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be described more fully in a subsequent part of this document. This invention can, however, be expressed in many different forms and should not be construed as being limited to the embodiments explained herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and fully inform the scope of the nvención those skilled in the art. I. Definitions. The following terms used as in this document have the indicated meanings. As used in the specification and in the appended claims, the singular forms "a," "an", "the / the" include plural referents unless the context clearly indicates otherwise.

The terms "comprising" and "including" are used in the open sense, not limited. The term "polymorph" refers to a crystalline form of a compound with a spatial arrangement in a different lattice compared to other crystalline forms of the same compound. The term "amorphous" refers to a non-crystalline form of a compound. A "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable way. A compound of the invention may possess a sufficiently acidic functional group, a sufficiently basic functional group, or both functional groups, and accordingly react with any of a number of organic or inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates , metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1, 4 -dioates, hexin-1, 6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, and -hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates , naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. II. Polymorphic and amorphous forms of the compound of formula I. The present invention provides various crystalline polymorphic forms and an amorphous form of the compound of Formula I. Each crystalline or amorphous form of the compound can be characterized by one or more of the following: diffraction pattern X-ray powder (ie, X-ray diffraction peaks at various diffraction angles (2T)), appearance of the melting point (and occurrence of dehydration of the hydrated forms) as illustrated by the endotherms of a thermogram of Differential Scanning Calorimetry (DSC), Raman spectral diagram pattern, aqueous solubility, stability against light under high intensity light conditions of the International Harmonization Conference (ICH), and stability of physical and chemical storage. The powder X-ray diffraction pattern for each amorphous or polymorphic form of the invention was measured on a Shimadzu X-ray diffractometer XRD-6000 equipped with a copper X-ray source operated at 40 kV and 50 mA. The samples were placed in a sample carrier and then compacted and smoothed with a glass slide. During the analysis, the samples were rotated at 60 rpm and analyzed from the angles of 4 to 40 ° (? -2T) to 57minute with a jump of 0.04 ° or to 27minute with a jump of 0.02 °. If limited material was available, the samples were placed on a silicon plate (zero background) and analyzed without rotation. One of skill in the art will appreciate that the positions of the peak (2T) will show some variability between apparatuses, typically as much as 0.1 °. Accordingly, where the solid forms of the present invention are described as having a powder X-ray diffraction pattern essentially the same as that shown in a given figure, the term "essentially equal" wishes to encompass such variability between devices in the positions of the diffraction peaks. The DSC thermographs were obtained using a Mettler Toledo DSC821e instrument at a scanning speed of 10 ° C / minute over a temperature range of 30-250 ° C. The samples were weighed into 40 μl aluminum crucibles that were sealed and punched with a single hole. The extrapolated appearance of. the melting temperature and, when applicable, the appearance of the dehydration temperature. Depending on several factors, the endotherms exhibited by the compounds of the invention can vary (by about 0.01 -5 ° C for the melting of the polymorph crystal and by about 0.01-20 ° C for the dehydration of the polymorph) above or below the endotherms represented in the attached figures. Factors responsible for such mismatching include the heating rate (ie, the scanning speed) at which the DSC analysis is directed, the way in which the DSC start temperature is defined and determined, the calibration pattern used. , the instrumental calibration, the relative humidity and the chemical purity of the sample. For any given sample, the observed endotherms may also differ from instrument to instrument; however, this will generally be within the ranges defined herein whenever the instruments are similarly calibrated. The Raman scattering spectra were obtained using a Raman spectrophotometer by Fourier transform from Kaiser Optical Instruments, Ramen RXN1-785. The excitation light source was an Invictus NIR laser operating at 785 nm wavelength. The detector was an Andor CCD. The resolution was 34 cm "1. The polymorphic or amorphous forms of the invention are preferably substantially pure, meaning that each polymorph or amorphous form of the compound of formula I includes less than 10%, preferably less than 5%, preferably less than 3%. %, preferably less than 1% by weight of impurities, including other polymorphous or amorphous forms of the compound The solid forms of the present invention can also exist together in a mixture The polymorph mixtures and / or the amorphous form of the present invention they will have X-ray diffraction peaks characteristic of each of the polymorphous and / or amorphous forms present in the mixture, for example, a mixture of two polymorphs will have a powder X-ray diffraction pattern that is a spiral of the patterns of X-ray diffraction corresponding to substantially pure polymorphs A. Polymorph Form I Polymorph Form I, an anhydrous form, can be prepared by suspending the Compound of formula I in ethanol and then heating at reflux for 30 minutes, followed by slow cooling to 23 ° C. Form I has an aqueous solubility of about 39 μg / ml at pH 2 and about 0.4 μg / ml at pH 7.4. Form I is stable to light under high intensity ICH light conditions and is chemically stable at 80 ° C and 40 ° C / 75% RH for at least 14 days. Form I is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T):, 80, 5.49, 7.06, 7.90, 9.52, 10.67, 12.33, 14.10, 15.08, 15.80, 18.12, 18.80, 19.72 , 20.40, 21.09, 21, 95, 23.00, 23.48, 24.52, 25.52, 26.16, 27.92, 28.36 ,. 29.08, 29.88, 30.32, 30.96, 31.68, 33.59, 34.32, 34.72, 35.20, 36.64, and 38.00. Figure 1A provides a powder X-ray diffraction pattern for form I. The DSC thermogram for form I, shown in Figure IB, indicates an appearance of glass melting endotherm at about 183 ° C, a a scanning speed of 10 ° C / minute. The Raman spectral diagram for Form I, shown in Figure 1C, includes Raman displacement peaks (cm "1) at approximately 993, 1265, 1323, 1377, 1394, 1432, 1465, 1482, 1563, 1589, and 1640. B. Polymorph Form II Polymorphous form II, an anhydrous form, can be prepared by direct crystallization of a solution of the compound of formula I in tetrahydrofuran at 60 ° C. by hexanes Form II has an aqueous solubility of about 19 μg. / ml at pH 2 and approximately 0.7 μg / ml at pH 7.4 Form II is stable to light under conditions of high intensity of ICH light.Form II is characterized by an X-ray diffraction pattern in powder with peaks at the following approximate diffraction angles (2T): 4.65, 6.9200, 7.36, 7.76, 9.81, 11.41, 12.08, 12.60, 13.03, 13.72, 14.24, 14.72, 16.06, 16.66, 17.80, 18.32, 18.80, 19.68, 20.32, 21.05, 21.89, 22, 64, 23.00, 23.60, 25.45, 26.30, 27.18, 28.34, 29.04, 30.21, 31.14, 32.24, 34.14, 34.91, 36.97 , 39.21, and 39.92. Figure 2A provides a powder X-ray diffraction pattern for form II. The DSC thermogram for form II, shown in Figure 2B, indicates an occurrence of melting endotherm of the crystal at about 195 ° C, at a scanning speed of 10 ° C / minute. The Raman spectral diagram for form II, shown in Figure 2C, includes Raman displacement peaks (cm "1) at approximately 993, 1265.1323, 1377, 1394, 1432, 1465, 1482, 1563, 1589, and 1640 C. Polymorph Form Hl Polymorph III, an anhydrous form, can be prepared by suspending the solids of Form I in mineral oil at 192 ° C for about 1.5 hours, followed by washing with hexane and filtration. it has an aqueous solubility of about 10 μg / ml at pH 2 and about 0.6 μg / ml at pH 7.4 The lll form is stable to light under conditions of high light intensity ICH. a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 6.40, 6.87, 7.36, 9.73, 10.43, 13.20, 13.72, 14.04, 14.65, 15.20, 15.80, 17.60, 18.56, 19.56, 20.16, 20.56, 21, 49, 21.96, 22.92, 23, 40, 24.08, 24.98, 25.64, 27.32, 27.72, 28.35, 29.08, 29.56, 30.12, 30.58, 31.53, 33, 58, 35.01, 36.84, 37.24, 37.60, and 39.51. Figure 3A provides a powder X-ray diffraction pattern for the shape III. The DSC thermogram for form III, shown in FIG. 3B, indicates an appearance of melting endotherm of the crystal at about 210 ° C, at a scanning rate of 10 ° C / minute. The Raman spectral diagram for the form III, shown in Figure 3C, includes Raman displacement peaks (cm "1) to approximately 991, 1261, 1379, 1431, 1589 and 1634. D. Polymorphic form IV Form IV, an anhydrous form, can be prepared by crystallization of the compound of formula I in ethyl acetate and ethanol by NaHCO3: water 1: 1. Form IV has an aqueous solubility of about 7 μg / ml at pH 2. Form IV is stable to light under conditions of high ICH light intensity. Form IV is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 4.85, 7.95, 9.85, 11.51, 12.80, 13, 53, 14.56, 14.92, 15.80, 16.32, 17.43, 18.08, 18.44, 19.31, 20.08, 21.08, 21.61, 22.64, 23.24, 23.84, 24.48, 25.08, 26.24, 27.02, 27.92, 28.76, 30.12, 30.72, 31.40, 32.52, 34, 07, 37.48, and 38.20. Figure 4A provides a powder X-ray diffraction pattern for form IV. The DSC thermogram for form IV, shown in Figure 4B, indicates an appearance of melting endotherm of the crystal at about 118 ° C, at a scanning rate of 10 ° C / minute. The Raman spectral diagram for form IV, shown in the figure 4C, includes Raman displacement peaks (cm "1) to approximately 998, 1269, 1314, 1340, 1371, 1436, 1463, 1483, 1562, 1592, and 1644. E. Polymorphic form V Form V, an anhydrous form , can be prepared by suspending IV solids in heavy mineral oil at 130 ° C, and then at 180 ° C for about 1.5 hours, followed by washing with hexane and filtration.V-form has an aqueous solubility of about 8 μg / ml at pH 2 and approximately 0.2 μg / ml at pH 7.4 Form V is stable to light under conditions of high intensity of ICH light.V form is characterized by an X-ray diffraction pattern in powder with peaks at the following approximate diffraction angles (2T): 4.23, 8.38, 11.74, 12.00, 12.47, 12.95, 13.58, 14.17, 15.15, 16.76, 16.96, 17.44, 17.92, 18.28, 18.70, 19.37, 20.26, 21.16, 21.62, 21.84, 22.16, 22, 54, 23.28, 23.64, 24.17, 24.84, 25.12, 25.58, 25.98, 26.48, 27.02, 28.16, 28.54, 29.14, 29.89, 31.40, 32.23, 32.66, and 39.68. Figure 5A provides a powder X-ray diffraction pattern for the V shape. The DSC thermogram for the V shape, shown in Figure 5B, indicates an occurrence of glass melting endotherm at about 210 ° C, at a rate of scan of 10 ° C / minute. The Raman spectral diagram for the form V, shown in the figure 5C, includes Raman displacement peaks (cm "1) to approximately 989, 1230, 1298, 1374, 1433, 1466, 1481, 1562, 1586, and 1642. F. Polymorphic form The form, which is a form hydrate can be prepared by suspending form I in water at room temperature for 7 days.The form is stable to light under conditions of high intensity of ICH light.The form is characterized by a powder X-ray diffraction pattern. with peaks at the following approximate diffraction angles (2T): 4.84, 5.49, 7.07, 7.90, 9.55, 10.60, 10.96, 11, 48, 12.20, 12 , 72, 13.48, 14.10, 14.56, 15.78, 17.54, 18.08, 18.52, 18.88, 19.44, 21.11, 21.93, 22.48 , 23.06, 23.72, 24.20, 24.48, 25.20, 25.56, 26.12, 26.72, 27.12, 27.78, 28.75, 30.36, 30 , 68, 31.20, 31.64, 32.04, 34.64, 34.97, 36.16, 36.60, 36.92, 37.24, 37.68, 38.12, 38.48 , and 39, 80. Figure 6A provides a powder X-ray diffraction pattern for the shape of the DSC thermogram for the shape, shown in Figure 6B. indicates an occurrence of dehydration endotherm at approximately 60 ° C and an appearance of melting endotherm of the crystal at approximately 185 ° C, at a scanning rate of 10 ° C / minute. G. Polymorph Form Ib Form Ib, which is a monohydrate, can be prepared by suspending Form I in water at 90 ° C for three days, or by crystallization in water-ethanol at more than 65 ° C. Form Ib is physically and chemically stable for at least three months at 60 ° C and 40 ° C / 75% RH and is also stable to light under conditions of high ICH light intensity. The Ib form is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 7.93, 10.23, 11.04, 13.12, 13.79, 14, 88, 15.24, 15.81, 16, 81, 17.40, 17.89, 18.64, 19.00, 20.11, 20.96, 21.53, 22.14, 22.87, 23.80, 24.16, 25.20 , 26.20, 26.64, 27.76, 28.38, 28.84, 29.52, 29.92, 30.28, 30.92, 31.87, 32.80, 33.24, 34 , 07, 34.68, 35.74, 36.54, and 37.96. Figure 7A provides a powder X-ray diffraction pattern for the Ib form. The DSC thermogram for form Ib, shown in Figure 7B, indicates an occurrence of dehydration endotherm at about 67 ° C and an occurrence of glass melting endotherm at about 179 ° C, at a scanning rate of 10 ° C. /minute. The Raman spectral diagram for form Ib, shown in Figure 7C, includes Raman shift peaks (cm "1) to approximately 964, 1002, 1239, 1266, 1372, 1470, 1558, and 1641. H. Polymorphic shape Ha The Ha form, a monohydrate, can be prepared by suspending Form II in water at room temperature for 7 days.The Ha form is stable to light under high intensity ICH light conditions.The Ha form is characterized by a pattern of powder X-ray diffraction with peaks at the following approximate diffraction angles (2T): 4.77, 7.64, 8.80, 9.82, 11, 41, 12.75, 13.48, 14.23 , 15.96, 16.64, 17.68, 18.76, 21.67, 22.85, 25.38, 27.16, 28.24, 30.12, 31.23, 32.16, 34 , 02, 34.80, 35.92, 36.92, 38.32, and 39.25.Figure 8A provides a powder X-ray diffraction pattern for the Ha form. The DSC thermogram for the Ha form, shown in Figure 8B, indicates an occurrence of dehydration endotherm at approximately 51 ° C, and an appearance of endotherm mia of glass melting at approximately 194 ° C, at a scanning speed of 10 ° C / minute. I. Polymorph Form IIb Form IIb, a dihydrate, can be prepared by suspending form II in water at 90 ° C for three days and then at room temperature for 17 days. The form llb is stable to light under conditions of high light intensity ICH. Form IIb is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 4.80, 7.86, 8.73, 11.44, 12.70, 13, 41, 14.33, 15.71, 16.60, 17.43, 18.32, 19.03, 20.08, 21.56, 21.88, 22.56, 23.10, 23.76, 24.40, 25.04, 25.56, 26.20, 26.64, 27.02, 27.80, 28.64, 30.63, 31.36, 31.80, 32.28, 33, 88, 35.95, 37.03, 37.80, 38.16, and 39.88. Figure 9A provides a powder X-ray diffraction pattern for the form llb. The DSC thermogram for form llb, shown in Figure 9B, indicates an occurrence of dehydration endotherm at about 64 ° C and an appearance of melting endotherm of the crystal at about 97 ° C, at a scanning rate of 10 ° C. /minute. The Raman spectral diagram for the form llb, shown in Figure 9C, includes Raman displacement peaks (cm "1) at approximately 993, 1265, 1362, 1431, 1464, 1561, 1589, and 1639. J. Polymorphic shape Illa The Illa form, a dihydrate, can be prepared by suspending form III in water at room temperature for seven days, or by placing the lll form at 93% relative humidity at room temperature for ten days.The Illa form is characterized by a pattern powder X-ray diffraction with peaks at the following approximate diffraction angles (2T): 6.81, 7.36, 8.71, 9.37, 9.80, 10.51, 13.31, 13, 72, 14.72, 15.28, 17.60, 18.20, 19.09, 19.92, 20.48, 21.03, 22.27, 22.68, 23.84, 24.36, 24.86, 25.60, 26.16, 26.66, 27.33, 28.22, 29.41, 30.29, 31, 48, 32.27, 33.60, 35.35, 36, 22, and 38, 21. Figure 10A provides a powder X-ray diffraction pattern for the Illa form K. Polymorph form lllb The form lllb, an anhydrous form, can be prepared by drying Illa form at 50 ° C vacuum. The lllb form is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 6.28, 6.84, 7.36, 8.66, 9.66, 13, 13, 13.80, 14.4718, 15.40, 17.21, 18.39, 19.46, 20.78, 21.56, 22.70, 24.81, 25.52, 26.79, 27.60, 28.80, 29.45, 30.32, 31, 22, 33.47, 34.69, 37, 16, 37.88, and 39.45. Figure 11A provides a powder X-ray diffraction pattern for the form lllb ».

The DSC thermogram for the form lllb, shown in Figure 11B, indicates an appearance of melting endotherm of the crystal at about 210 ° C, at a scanning rate of 10 ° C / minute. The Raman spectral diagram for the form lllb, shown in Figure 11C, includes Raman shift peaks (cm "1) at about 993, 1267, 1311, 1326, 1378, 1436, 1466, 1481, 1563, 1592, and 1636. L. Polymorph Form IVa Form IVa, a dihydrate, can be prepared by suspending form IV in water for seven days.The form IVa is stable to light under conditions of high intensity of ICH light.The form IVa is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 4.85, 7.95, 9.85, 11.51, 12.80, 13.53, 14.56, 14.92, 15.80, 16.32, 17.43, 18.08, 18.44, 19.31, 20.08, 21.08, 21.61, 22.64, 23.24, 23, 84, 24.48, 25.08, 26.24, 27.02, 27.92, 28.76, 30.12, 30.72, 31.40, 32.52, 34.07, 37.48, and 38, 20. Figure 12A provides a powder X-ray diffraction pattern for form IVa.The DSC thermogram for form IVa, shown in Figure 12B, indicates an occurrence of dehydrated endothermy. at about 63 ° C and an appearance of glass melting endotherm at about 123 ° C, at a scanning speed of 10 ° C / minute. M. Form polymorph Va The form Va, a dihydrate form, can be prepared by suspending form V in water for seven days. The Va form is stable to light under conditions of high ICH light intensity. The Va form is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 4.26, 4.82, 7.92, 8.42, 8.96, 11, 45, 12.70, 13.40, 14.21, 15.21, 15.70, 16.64, 16.96, 17.30, 18.28, 19.16, 20.24, 21.14, 21.60, 22.56, 23.20, 23.80, 24.44, 24.96, 26.60, 27.08, 27.96, 28.56, 29.04, 30.62, 31, 34, 32.27, 32.84, 33.92, 34.83, 35.90, 36.99, and 37.44. Figure 13A provides a powder X-ray diffraction pattern for the form Va. The DSC thermogram for the Va form, shown in Figure 13B, indicates an occurrence of dehydration endotherm at approximately 74 ° C and an occurrence of glass melting endotherm at approximately 211 ° C, at a scanning rate of 10 ° C. /minute. The Raman spectral diagram for the Va form, shown in Figure 13C, includes Raman displacement peaks (cm "1) at approximately 989, 1228, 1298, 1372, 1430, 1465, 1561, 1584, and 1641. N. Polymorph Form VI Form VI, an anhydrous form, can be prepared by dehydration of Form Ib, such as by heating Form Ib at 140 ° C for 10 minutes.V VI is very hygroscopic and can easily be converted back to the form Ib under ambient humidity Form VI is characterized by a powder X-ray diffraction pattern with peaks at the following approximate diffraction angles (2T): 7.74, .00, 11.56, 12.85, 15.56, 16.04, 17.80, 18.47, 19.20, 20.43, 21.72, 22.16, 23.28, 24.00, 25.83, 26.79, 28.23, 29.88, 30.36, 31.36, and 39.69. Figure 14A provides a powder X-ray diffraction pattern for form VI. The DSC thermogram for form VI, shown in Figure 14B, indicates an appearance of glass melting endotherm at about 179 ° C, at a scanning speed of 10 ° C / minute. The Raman spectral diagram for the VI form, shown in Figure 14C, includes Raman displacement peaks (cm "1) at about 965, 993, 1201, 1230, 1267, 1320, 1368, 1412, 1426, 1469, 1557 , 1587, and 1647. O. Amorphous form The amorphous form can be prepared by dropwise dissolving in water (about 1:10 ratio) of the compound of formula I in polyethylene glycol 400 solution, or rotary evaporation of the compound of formula I in methanol or in THF solution, or lyophilization of the compound of formula I in t-butanol solution The X-ray powder diffraction pattern of the amorphous form is characterized by a typical amorphous wide hump-shaped peak of 4 to 40 °, without any sharp peak characteristic of the crystalline forms Figure 15A provides a powder X-ray diffraction pattern for the amorphous form.

The Raman spectral diagram for the amorphous shape, shown in Figure 15B, includes Raman displacement peaks (cm "1) at approximately 995, 1265, 1366, 1435, 1468, 1562, 1589, and 1640. P. Mixtures The crystalline and amorphous forms discussed above may also exist in mixtures, in which the solid form exists as a mixture comprising at least two of the solid forms discussed above For example, the lbm-2 form is a metastable form which is a mixture of form Ib and VI.This metastable form can be prepared by dehydrating the Ib form in vacuum at temperatures of about 45 ° C or greater.The partial hydration of form VI will also result in the metastable form lbm-2. 2 will be converted to Ib form after complete hydration under ambient humidity.The lbm-2 form is characterized by a powder X-ray diffraction pattern with peaks as shown in Figure 16. This diffraction pattern fits with the pattern resulting from the addition of the diffraction patterns of form Ib and form VI. The DSC thermogram for the lbm-2 form indicates an occurrence of dehydration endotherm at about 73 ° C and an occurrence of glass melting endotherm at about 177 ° C, at a scanning speed of 10 ° C / minute. lll. Pharmaceutical Compositions of the Invention The active agents (ie, polymorphous or amorphous forms, or mixtures thereof, of the compound of formula I described herein) of the invention can be formulated into suitable pharmaceutical compositions for both veterinary and non-veterinary use. for human medical use. The pharmaceutical compositions of the invention comprise a therapeutically effective amount of the active agent and one or more inert, pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilizers or the like. The vehicle (s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly harmful to the recipient thereof. The compositions may additionally include diluents, buffers, binding agents, disintegrants, thickeners, lubricants, preservatives (including antioxidants), flavoring agents, taste masking agents, inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g. benzalkonium chloride), sweeteners, antistatic agents, surfactants (for example, polysorbates such as "TWEEN 20" and "TWEEN 80", and pluronics such as F68 and F88, available from BASF), sorbitan esters, lipids (eg example, phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty esters, steroids (eg cholesterol)), and chelating agents (eg, EDTA, zinc and other suitable cations such). Other pharmaceutical excipients and / or additives suitable for use in compositions according to the invention are listed in "Remington: The Science &Practice of Pharmacy", 19th edition, Williams & Williams, (1995), and in the "Physician's Desk Reference," 52nd edition, Medical Economics, Montvale, NJ (1998), and in "Handbook of Pharmaceutical Excipients," third edition, A.H. Kíbbe, Pharmaceutical Press, 2000. The active agents of the invention can be formulated into compositions including those suitable for oral, rectal, topical, nasal, ophthalmic, or parenteral administration (including intraperitoneal, intravenous, subcutaneous, or intramuscular injection). The amount of the active agent in the formulation will vary depending on a variety of factors, including dosage form, the condition to be treated, the patient population to which it is addressed, and other considerations, and will generally be readily determined by someone skilled in the art. technique. A therapeutically effective amount will be an amount necessary to modulate, regulate or inhibit a protein kinase. In practice, this will vary widely depending on the particular active agent, the severity of the condition to be treated, the patient population, the stability of the formulation, and the like. The compositions will generally contain between about 0.001% by weight to about 99% by weight of the active agent, preferably between about 0.01% to about 5% by weight of the active agent, and more preferably from about 0.01% to 2% by weight. weight of the active agent, and will also depend on the relative amounts of excipients / additives contained in the composition. A pharmaceutical composition of the invention is administered in conventional dosage form prepared by combining a therapeutically effective amount of an active agent as an active ingredient with one or more appropriate pharmaceutical carriers according to conventional procedures. These methods may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation. The pharmaceutical carrier employed can be either a solid or a liquid. Exemplary solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and the like. Exemplary liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the vehicle may include time-delay or time-release materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethyl cellulose, hydroxypropyl methyl cellulose, methyl methacrylate and the like. A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be compressed, placed in a hard gelatin capsule in the form of powder or pellet or in the form of a troche or pellet. The amount of solid carrier may vary, but will generally be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. To obtain a stable, water-soluble dosage form, a pharmaceutically acceptable salt of an active agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the active agent can be dissolved in a suitable cosolvent or in combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. The composition may also be in the form of a solution of a salt form of the active agent in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution. It will be appreciated that the actual dosages of the active agents used in the compositions of this invention will vary according to the particular complex that is used, the particular composition formulated, the mode of administration and the particular site, host and disease. Those skilled in the art using conventional dosing determination tests in view of the experimental data for an agent can establish optimal dosages for a given set of conditions. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg / kg of body weight, more preferably from about 0.001 to about 50 mg / kg of body weight, with repeated courses of treatment at appropriate intervals. Prodrug administration is typically dosed at weight levels that are chemically equivalent to the weight levels of the fully active form. The compositions of the invention can be made in generally known ways to prepare pharmaceutical compositions, for example, using conventional techniques such as mixing, dissolving, granulating, preparing dragees, levigating, emulsifying, encapsulating, trapping or lyophilizing. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, which can be selected from excipients and adjuvants that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The proper formulation is dependent on the chosen route of administration. For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, the appropriate penetration agents for the barrier to permeate are used in the formulation. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated easily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such vehicles allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, colloids, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliary compounds, if desired, to obtain tablets or dragee cores. Suitable excipients include; bulking agents such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents. Pharmaceutical preparations that can be used orally include snap-fit capsules made of gelatin, like soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Pressure-adjusting capsules may contain the active ingredients in admixture with bulking agents such as lactose, binding agents such as starches and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration would be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For intranasal or inhalation administration, the compounds for use according to the present invention are conveniently administered in the form of an aerosol spray presentation of pressurized containers or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and gelatin cartridges can be formulated for use in an inhaler or insufflator and the like containing a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, for example, by rapid intravenous injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, suspensions of the active agents can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. For administration to the eye, the active agent is administered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is kept in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the camera anterior, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary, crystalline, choroid / retina, and sclera. The pharmaceutically acceptable ophthalmic vehicle can be, for example, an ointment, vegetable oil, or an encapsulating material. A compound of the invention can also be injected directly into the vitreous and aqueous humor or subtenon. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, the compounds can also be formulated as a sustained release preparation. Such long acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt. A pharmaceutical vehicle for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system can be a VPD cosolvent system. VPD is a solution of benzylic alcohol at 3% w / v, 8% w / v of the non-polar surfactant polysorbate 80, and polyethylene glycol 300 at 65% w / v, brought to volume with absolute ethanol. The VPD co-solvent system (VPD.5W) contains VPD diluted 1: 1 with 5% dextrose in solution in water. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity after systemic administration. Naturally, the proportions of a cosolvent system can be varied considerably without destroying its solubility and toxicity characteristics.

In addition, the identity of the co-solvent components can be varied: for example, other non-polar low toxicity surfactants can be used in place of polysorbate 80; the size of polyethylene glycol fraction can be varied; other biocompatible polymers can replace polyethylene glycol, for example polyvinylpyrrolidone; and dextrose can be replaced by other sugars or polysaccharides. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of carriers or delivery vehicles for hydrophobic drugs. Certain organic solvents such as dimethisulfoxide can also be used, although usually at the cost of greater toxicity. Additionally, the compounds can be administered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are known to those skilled in the art. Sustained-release capsules may, depending on the chemical nature, release the compounds for a few weeks to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for the stabilization of the protein may be employed. The pharmaceutical compositions may also comprise suitable carriers or excipients in solid or gel phase. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

IV. Method of using the compounds of the invention The compounds of the invention are useful for mediating the activity of protein kinases. More particularly, the compounds are useful as anti-angiogenesis agents and as agents for modulating and / or inhibiting the protein kinase activity, such as the activity associated with VEGF, FGF, CDK complexes, TEK, CHK1, LCK, FAK and phosphorylase kinase among others. , thus providing treatments for cancer or other diseases associated with protein proliferation mediated cell proliferation in mammals, including humans. Therapeutically effective amounts of the agents of the The invention may be administered, typically in the form of a pharmaceutical composition, to treat diseases mediated by modulation or regulation of protein kinases. An "effective amount" is meant to mean that amount of agent that, when administered to a mammal in need of such treatment, is sufficient to effect treatment for a disease mediated by the activity of one or more protein kinases, such as tyrosine kinases . Thus, a therapeutically effective amount of a compound of the invention is an amount sufficient to modulate, regulate, or inhibit the activity of one or more protein kinases such that a condition that is mediated by that activity is reduced or alleviated. The effective amount of a given compound will vary depending on factors such as a condition and its severity and the identity and condition (eg, weighed) of the mammal in need of treatment, but can nevertheless be determined routinely by one skilled in the art. . "Treat" is intended to mean at least the mitigation of a condition in a mammal, such as a human, that is affected, at least in part, by the activity of one or more protein kinases, such as tyrosine kinases, and includes: preventing the condition occurs in a mammal, particularly when the mammal is predisposed to have the condition but has not yet been diagnosed as having it; modulate and / or inhibit the condition; and / or alleviate the condition. Exemplary conditions include diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis, age-related macular degeneration (AMD), and cancer (solid tumors). The activity of the compounds of the invention as modulators of protein kinase activity, such as the activity of kinases, can be measured by any of the methods available to those skilled in the art, including in vivo and / or in vitro assays. Examples of suitable assays for activity measurements include those described in Parast C. et al, BioChemistry, 37, 16788-16801 (1998); Jeffrey et al., Nature, 376, 313-320 (1995); document international publication WIPO N °. WO 97/34876; and document international publication WIPO N °. WO 96/14843. V. EXAMPLES The following examples are given to illustrate the invention, but should not be considered as limitations of the invention. Unless otherwise indicated, all temperatures are shown in degrees Celsius and all parts and percentages are by weight. The HPLC data were obtained using HP-1100 HPLC equipment from Hewlett Packard. Example 1 Polymorphous Form I The crude synthesis material (155 mg) of the compound of formula I was suspended in 5 ml of ethanol and then heated to reflux for 30 minutes. The sample was allowed to cool slowly to 23 ° C. The solids were collected by filtration and dried at 85 ° C under high vacuum conditions. Form I was confirmed by X-ray diffraction and purity by HPLC was > 98%. Example 2 Polymorph Form II Form I of Example 1 was dissolved in tetrahydrofuran at 60 ° C and then recrystallized by gradual addition of hexanes to obtain Form II. Form II was confirmed by X-ray diffraction (purity by HPLC> 98%). Example 3 Polymorph Form III Form I of Example 1 is suspended in a light mineral oil at 192 ° C for 1 hour and then cooled to ambient temperature. The solids were collected by filtration, washed with hexanes, and then dried at 50 ° C in vacuo. Form III was confirmed by X-ray diffraction (purity by HPLC> 97%). Example 4 Polymorph Form IV The crude synthesis material of the compound of formula I was dissolved in ethyl acetate and ethanol. The recrystallization was done by addition of NaHCO3: water 1: 1. Form IV was confirmed by X-ray diffraction (HPLC purity> 99%). Example 5 Polymorph Form V Form IV solids of Example 4 were suspended in heavy mineral oil at 130 ° C and then suspended at 180 ° C for one and a half hours.

The solids were collected by filtration, washed with hexanes, and then dried in vacuo. Form V was confirmed by X-ray diffraction (purity by HPLC> 99%). Example 6 Polymorph Form I Form I of Example 1 was suspended in water (approximately 20-40 mg / ml) at room temperature for 7 days to obtain the la form. The form was confirmed by X-ray diffraction (purity by HPLC> 99%). Example 7 Polymorph Form Ib Form I of Example 1 was suspended in water (approximately 20-40 mg / ml) at 90 ° C for three days to obtain Form Ib. Alternatively, form Ib was obtained by crystallization from ethanol: water at 65 ° C. Form Ib was confirmed by X-ray diffraction (purity by HPLC> 99%). Example 8 Polymorph Form Ha Form II of Example 2 was suspended in water (approximately 20-40 mg / ml) at room temperature for 7 days to obtain the Ha form. The Ha form was confirmed by X-ray diffraction (HPLC purity). > 99%). Example 9 Polymorph Form IIb Form II of Example 2 was suspended in water (approximately 20-40 mg / ml) at 90 ° C for three days and then at room temperature for 17 days to obtain the form llb. Form llb was confirmed by X-ray diffraction. Example 10 Polymorph Form Illa Form III of Example 3 was placed at 93% relative humidity at room temperature for ten days or suspended in water (approximately 20-40 mg / ml) at room temperature for seven days to obtain the Illa form. The Illa form was confirmed by X-ray diffraction. Example 11 Polymorph Form III The form Illa of Example 10 was dried at 50 ° C under vacuum to obtain the form IIIb. Form lllb was confirmed by X-ray diffraction. Example 12 Polymorph Form IVa Form IV of Example 4 was suspended in water (approximately 20-40 mg / mL) at room temperature for seven days to obtain Form IVa. The IVa form was confirmed by X-ray diffraction and DSC. Example 13 Polymorph Form Va Form V of Example 5 was suspended in water (approximately 20-40 mg / ml) at room temperature for seven days to obtain the Va form. The Va form was confirmed by X-ray diffraction. Example 14 Polymorph Form VI Form Ib of Example 7 was heated at 140 ° C for 10 minutes to obtain Form VI. Form VI was confirmed by X-ray diffraction. Example 15 Amorphous form The amorphous form was prepared by dropwise dilution in water (ratio about 1:10) of the compound of formula I in polyethylene glycol 400 solution, or was prepared by rotary evaporation of the compound of formula I in methanol or THF solution, or was prepared by lyophilization of the compound of formula I in solution of t-butanol. Example 16 Polymorph Form Ibm-2 Form Ib of Example 7 was heated at 50 ° C under vacuum to obtain the Ibm-2 form, which was confirmed by X-ray diffraction which was a mixture of the polymorph form Ib and the form polymorph VI. Example 17 Use of polymorph Ib in a hyaluronate suspension formulation Sodium hyaluronate (1% w / w) is dissolved in isotonic sodium phosphate buffer solution at pH 7.4 containing 0.85% sodium chloride. sodium, 0.022% sodium dibasic phosphate, 0.004% sodium monobasic phosphate, and 97.15% water to form a viscous solution. The solution is then sterilized by filtration. Form Ib of Example 7 (0.1-1.0% w / w) reduced to powder and sterilized is then added to form a homogeneous suspension by gentle mixing in turbine. Example 18 Use of polymorph Ib in a suspension formulation of CMC Sodium carboxymethylcellulose (CMC) (0), 5% w / w) in water and then sterilized by filtration. An appropriate amount of Form Ib of Example 7 (0.1-1.0% w / w) is then added to form a homogeneous suspension by vortexing and sonicating up to 10 minutes. Many modifications and other embodiments of the invention will come to the mind of one skilled in the art to which this invention is relevant having the benefit of the teachings presented in the preceding description. Therefore, it will be understood that the invention is not limited to the specific embodiments described and that the modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are used in this document, they are used only in a generic and descriptive sense and not for purposes of limitation.

Claims (15)

1. A crystalline form of the. { 2-fluoro-5- [3 - ((E) -2-pyridin-2-yl-vinyl) -1H-indazol-6-ylamino] -phenyl} 2,5-dimethyl-2H-pyrazole-3-carboxylic acid amide, or a pharmaceutically acceptable salt thereof.

2. The crystalline form of claim 1, wherein the crystalline form is a substantially pure polymorph of any of the forms I, II, III, IV, V, la, Ib, Ha, llb, Illa, IIIb, IVa, Va, or VI.

3. The crystalline form of claim 1, wherein the crystalline form is a substantially pure polymorph of the Ib form.

4. The crystalline form of claim 3, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2T) of 10.2 and 13.8.

5. The crystalline form of claim 3, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2T) of 10.2, 13.8, 20.1, and 26, 2.

6. The crystalline form of claim 3, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2T) essentially equal to those shown in Figure 7A.

7. The crystalline form of claim 3, wherein the crystalline form is characterized by a Raman spectrum essentially the same as that shown in Figure 7C.

8. An amorphous form of the. { 2-fluoro-5- [3 - ((E) -2-pyridin-2-yl-viny] -1H-indazol-6-ylamino] -phenyl} 2,5-dimethyl-2H-pyrazole-3-carboxylic acid amide, or a pharmaceutically acceptable salt thereof.

9. A solid form of the. { 2-fluoro-5- [3 - ((E) -2-pyridin-2-yl-vinyl) -1H-indazol-6-ylamino] -phenyl} 2,5-dimethyl-2H-pyrazole-3-carboxylic acid amide, in which the solid form is a mixture comprising at least two of the following solid forms: polymorphic forms I, II, III, IV, V, , Ib, Ha, llb, Illa, lllb, IVa, Va, VI, and an amorphous form.

10. The crystalline form of claim 1, wherein the crystalline form is a substantially pure polymorph of the Ibm-2 form.

11. A pharmaceutical composition comprising any of the crystalline or solid forms of claims 2-10.

12. A method for treating a mammalian condition mediated by protein kinase activity, comprising administering to a mammal in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 11.

13. A method according to claim 12, wherein the mammalian affection is associated with tumor growth, cell proliferation, or angiogenesis.

14. A method for modulating the activity of a protein kinase receptor, comprising contacting the kinase receptor with an effective amount of a crystalline or solid form according to claims 2-10.

15. The method according to claim 14, wherein the protein kinase receptor is a VEGF receptor.