Salts of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-D]pyrimidine-7-carboxamide and their crystalline forms

Abstract

The present invention provides crystalline forms of salts of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide and pharmaceutical compositions containing same. [Solution] A compound in crystalline form selected from 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (compound of formula (I)) and its pharmaceutically acceptable salts, which is a methanesulfonate salt. TIFF2022191306000033.tif30154

Description

[Technical field]

[0001] The present invention relates to salts of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide, crystalline forms thereof and pharmaceutical compositions thereof. [Background technology]

[0002] The compound 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (herein referred to as formula (I)) is disclosed in PCT application WO 2013 / 100632. This compound is a pan-RAF inhibitor and has selective inhibitory activity against RAF, FMS, DDR1 and DDR2 kinases.

[0003] TIFF0007672372000001.tif30154

[0004] The compound of formula (I) prepared in the above cited references is an amorphous solid. Compared to crystalline forms, amorphous forms are generally less suitable for large-scale pharmaceutical production and are poorly soluble.

[0005] Different crystalline forms of a pharmaceutical agent may offer different and improved properties with respect to stability, solubility, dissolution rate, hardness, compressibility and melting point, among other physical and mechanical properties. DISCLOSURE OF THEINVENTION

[0006] [Technical issues] There is a need in the chemical and therapeutic drug arts for the identification of new salts and crystalline forms of formula (I) that have improved physiochemical properties, and methods for reproducibly making such salts and crystalline forms.

[0007] [Means to solve the problem] The present invention relates to salts and crystalline forms of a pan-RAF inhibitor of formula (I) having the systematic name 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide and may be represented by the following formula:

[0008] TIFF0007672372000002.tif30154

[0009] The compounds of formula (I) are described by their chemical structures and chemical names. In the event of a discrepancy between the chemical structures and the chemical names, the chemical structures shall prevail.

[0010] In some embodiments, there is provided a crystalline form of the compound of formula (I), 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0011] TIFF0007672372000003.tif30154

[0012] In some other embodiments, a salt of Formula (I) is provided, wherein the salt is selected from the group consisting of hydrochloride, hydrogen sulfate, p-toluenesulfonate, ethanesulfonate, and methanesulfonate.

[0013] In some such embodiments, the salt is selected from the group consisting of bishydrochloride, bishydrogensulfate, bisp-toluenesulfonate, bisethanesulfonate, and bismethanesulfonate.

[0014] In some other embodiments, polymorphic Form I of the crystalline bis-hydrochloride salt of formula (I) is provided as follows:

[0015] TIFF0007672372000004.tif37150

[0016] Polymorphic Form I of the bis-hydrochloride salt of formula (I): (a) is a trihydrate; and (b) is characterized by a powder X-ray diffraction pattern having three or more peaks selected from those having diffraction angles 2θ±0.2° values ​​of 5.89°, 7.77°, 8.31°, 11.80°, 16.68°, 23.22°, 23.69°, 26.89°, 27.51°, and 29.53°, when irradiated with a Cu-Kα source.

[0017] In some other embodiments, pharmaceutical compositions are provided that include any of the salts and crystalline forms of Formula (I) of the present invention and at least one pharma- ceutically acceptable excipient.

[0018] In some other embodiments, a method is provided for preventing or treating an abnormal cell proliferation disorder in a mammal, the abnormal cell proliferation disorder being caused by the abnormal activation of a protein kinase. The method comprises administering to the mammal a pharmaceutical composition comprising any of the salts and crystalline forms of Formula (I) of the present invention and at least one pharma- ceutically acceptable excipient. In some such embodiments, the mammal is a human.

[0019] In some other embodiments, a method for preparing a crystalline salt form of Formula (I) is provided. The method includes the steps of: (a) adding an organic solvent to the free base of the compound of Formula (I) to form a mixture; (b) adding 2-3 equivalents of an acid for each equivalent of the free base of Formula (I) in the mixture obtained in step (a) to form a slurry containing a solid crystalline salt of Formula (I); and (c) isolating the solid crystalline salt of Formula (I) from the slurry. The acid is selected from the group consisting of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, ethanesulfonic acid, methanesulfonic acid salts, and mixtures thereof.

[0020] In some other embodiments, a method for preparing the crystalline bis-hydrochloride polymorph Form I or Form V of Formula (I) is provided. The method includes the steps of: (a) mixing the free base of Formula (I) with a solvent; (b) adding about 2 to about 3 equivalents of hydrochloric acid per equivalent of Formula (I) to the mixture to form a slurry containing the solid crystalline bis-hydrochloride of Formula (I); (c) isolating the solid crystalline bis-hydrochloride of Formula (I) from the slurry; and (d) drying the crystalline bis-hydrochloride of Formula (I). When the solvent is ethanol, the dried crystalline bis-hydrochloride of Formula (I) is exposed to air containing water vapor, and the resulting polymorph is the Form I polymorph. When the solvent is dimethylformamide ("DMF"), the resulting polymorph is the Form V polymorph.

[0021] In some other embodiments, a method for preparing polymorphic Form I of the crystalline bis-hydrochloride salt of Formula (I) is provided. The method includes the steps of: (a) mixing the free base of Formula (I) with ethanol; (b) adding about 2 to about 3 equivalents of hydrochloric acid per equivalent of Formula (I) to the mixture to form a slurry containing the solid crystalline bis-hydrochloride salt of Formula (I); (c) isolating the solid crystalline bis-hydrochloride salt of Formula (I) from the slurry; and (d) drying the crystalline bis-hydrochloride salt of Formula (I). The dried crystalline bis-hydrochloride salt of Formula (I) is exposed to air containing water vapor, and the resulting polymorph is the Form I polymorph.

[0022] In some other embodiments, the free base, salts and crystalline forms of formula (I) include: polymorphic form I of crystalline bishydrochloride salt characterized by a powder X-ray diffraction ("PXRD") pattern according to Figure 35; polymorphic form II of crystalline bishydrochloride salt characterized by a PXRD pattern according to Figure 14; polymorphic form III of crystalline bishydrochloride salt characterized by a PXRD pattern according to Figure 17; polymorphic form IV of crystalline bishydrochloride salt characterized by a PXRD pattern according to Figure 20; polymorphic form V of crystalline bishydrochloride salt characterized by a PXRD pattern according to Figure 21; polymorphic form V of crystalline bishydrochloride salt characterized by a PXRD pattern according to Figure 22; crystalline bis(p-toluenesulfonate) polymorphic Form A characterized by a PXRD pattern according to Figure 26; crystalline bis(p-toluenesulfonate) polymorphic Form B characterized by a PXRD pattern according to Figure 27; crystalline bis(ethanesulfonate) polymorphic Form A characterized by a PXRD pattern according to Figure 28; crystalline bis(methanesulfonate) polymorphic Form B characterized by a PXRD pattern according to Figure 7; and crystalline free base characterized by a PXRD pattern according to Figure 29.

[0023] The present invention can provide new salts and crystalline forms of formula (I) that have improved physicochemical properties, and methods for reproducibly making such salts and crystalline forms. [Brief description of the drawings]

[0024] [Figure 1] 1 shows the powder X-ray diffraction ("PXRD") pattern of the crystalline bis-hydrochloride salt of formula (I).

[0025] [Diagram 2] 1 shows a differential scanning calorimetry ("DSC") diagram of the crystalline bis-hydrochloride salt of Formula (I).

[0026] [Diagram 3] FIG. 2 shows the dynamic vapor sorption ("DVS") diagram for the crystalline bis-hydrochloride salt of Formula (I).

[0027] [Figure 4] PXRD pattern of crystalline bishydrogen sulfate salt of formula (I).

[0028] [Diagram 5] 1 shows a DSC diagram of the crystalline bishydrogen sulfate salt of formula (I).

[0029] [Figure 6] 1 shows a DVS diagram of the crystalline bishydrogen sulfate salt of formula (I).

[0030] [Figure 7] 1 shows the PXRD pattern of the crystalline bismethanesulfonate salt of formula (I).

[0031] [Figure 8] 1 shows the PXRD pattern of the crystalline bisbenzenesulfonate salt of formula (I).

[0032] [Figure 9] PXRD pattern of the bishydrobromide salt of formula (I).

[0033] [Figure 10] FIG. 1 shows a DVS diagram of crystalline polymorphic Form I of the bis-hydrochloride salt of formula (I).

[0034] [Figure 11] FIG. 1 shows a DSC diagram of the crystalline polymorphic Form I of the bis-hydrochloride salt of formula (I).

[0035] [Figure 12] FIG. 1 shows a DSC diagram of the crystalline polymorphic Form I of the bis-hydrochloride salt of formula (I).

[0036] [Figure 13] FIG. 1 shows a DVS diagram of crystalline polymorphic Form I of the bis-hydrochloride salt of formula (I).

[0037] [Figure 14]FIG. 1 shows the PXRD pattern of crystalline polymorphic Form II of the bis-hydrochloride salt of formula (I).

[0038] [Figure 15] FIG. 2 shows a DSC diagram of crystalline polymorphic Form II of the bis-hydrochloride salt of formula (I).

[0039] [Figure 16] FIG. 2 shows the DVS diagram of crystalline polymorphic Form II of the bis-hydrochloride salt of formula (I).

[0040] [Figure 17] FIG. 1 shows the PXRD pattern of crystalline polymorphic Form III of the bis-hydrochloride salt of formula (I).

[0041] [Figure 18] FIG. 2 shows a DSC diagram of crystalline polymorphic Form III of the bis-hydrochloride salt of formula (I).

[0042] [Figure 19] FIG. 1 shows a DVS diagram of crystalline polymorphic Form III of the bis-hydrochloride salt of formula (I).

[0043] [Figure 20] FIG. 1 shows the PXRD pattern of crystalline polymorphic Form IV of the bis-hydrochloride salt of formula (I).

[0044] [Figure 21] FIG. 1 shows the PXRD pattern of crystalline polymorphic Form V of the bis-hydrochloride salt of formula (I).

[0045] [Figure 22] 1 shows the PXRD pattern of crystalline polymorphic Form VI of the bis-hydrochloride salt of formula (I).

[0046] [Diagram 23] FIG. 1 shows a DSC diagram of crystalline polymorphic Form VI of the bis-hydrochloride salt of formula (I).

[0047] [Figure 24]FIG. 1 shows the PXRD patterns of crystalline polymorphic forms I and VI of the bis-hydrochloride salt of formula (I).

[0048] [Diagram 25] As demonstrated in this example, the interconversion of polymorphic Form I of the bis-hydrochloride salt of formula (I) with Forms II-VI, as well as amorphous bis-hydrochloride salt of formula (I) is shown.

[0049] [Figure 26] FIG. 1 shows the PXRD pattern of the crystalline bis-p-toluenesulfonate Form A polymorph of formula (I).

[0050] [Figure 27] FIG. 1 shows the PXRD pattern of the Form B polymorph of the crystalline bis-p-toluenesulfonate salt of formula (I).

[0051] [Figure 28] 1 shows the PXRD pattern of the crystalline bis-ethanesulfonate salt of formula (I).

[0052] [Figure 29] 1 shows the PXRD pattern of crystalline free base of formula (I).

[0053] [Diagram 30] 1 shows the PXRD pattern of amorphous free base of formula (I).

[0054] [Diagram 31] 1 shows the PXRD pattern of the amorphous bis-hydrochloride salt of formula (I).

[0055] [Diagram 32] 1 shows the overlay of the PXRD patterns of crystalline polymorphic Forms I-VI of the bis-hydrochloride salt of formula (I) and amorphous bis-hydrochloride salt of formula (I).

[0056] [Diagram 33]PXRD patterns of crystalline bishydrochloride salt Form I of formula (I) after 6 months, 12 months, and 24 months of exposure to conditions of 20° C.-30° C. with protection from light and 60% relative humidity.

[0057] [Diagram 34] PXRD pattern of the crystalline bis-hydrochloride salt of formula (I).

[0058] [Diagram 35] FIG. 1 shows the PXRD pattern of crystalline polymorphic Form I of the bis-hydrochloride salt of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the invention. The invention is in no way limited to the methods and materials described. In the event that one or more of the cited literature, patents, and similar materials, including but not limited to defined terms, term usage, described procedures, etc., differs from or conflicts with this application, this application takes precedence. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0060] In accordance with the present invention, it has been discovered that the hydrochloride, sulfate, p-toluenesulfonate, ethanesulfonate and methanesulfonate salts of the compound of formula (I) and its crystalline forms have improved physicochemical properties compared to the amorphous and free base forms, including, for example, long-term stability without the need for specific storage conditions, and excellent water solubility.

[0061] The present invention provides crystalline forms of the compound of formula (I).The present invention still further provides various crystalline polymorphic forms of salts of the compound of formula (I).The present invention still further provides methods for preparing the various salts and crystalline polymorphic forms of the compound of formula (I).

[0062] Unless otherwise defined, all terms, including technical and scientific terms, used herein have the same meaning as commonly understood in context by one of ordinary skill in the art to which this invention belongs. However, unless otherwise noted, the terms set forth below have the meanings set forth below throughout the specification.

[0063] As used herein, the term "about" means within 5%, preferably within 1% to 2%, of a particular value or range. For example, "about 10%" means 9.5% to 10.5%, preferably 9.8% to 10.2%. In another example, "about 100°C" means 95°C to 105°C, preferably 98°C to 102°C.

[0064] As used herein, the term "free base" refers to the parent compound of formula (I) other than any salt thereof.

[0065] As used herein, the term "substantially pure" means at least 95% pure, preferably 99% pure, where 95% pure means that no more than 5% of any other form of the compound of formula (I) (e.g., other crystalline or amorphous forms) is present, and 99% pure means that no more than 1% is present. As used herein, the term "essentially" means at least 90%, at least 95%, at least 99%, at least 99.5% or at least 99.9% of the reference standard.

[0066] As used herein, "polymorph" or "polymorphism" refers to the ability of a substance to exist in more than one crystalline form, where different crystalline forms of a particular substance are called "polymorphs". In general, it is believed that polymorphism can be influenced by the ability of the molecules of a substance to change their conformation or form different inter- or intra-molecular interactions, particularly hydrogen bonds, reflected in different atomic arrangements in the crystal lattice of different polymorphs. Different polymorphs of a substance may possess different energies of the crystal lattice, so that in the solid state, they may exhibit different physical properties, such as, but not limited to, shape, density, melting point, color, stability, solubility, and dissolution rate, which in turn may affect properties such as, but not limited to, the stability, dissolution rate, and / or bioavailability of a given polymorph and its suitability for use as a medicament and in pharmaceutical compositions.

[0067] As used herein, with respect to salts of formula (I), the terms bis (e.g., bishydrochloride), 2- (e.g., 2HCl), and di- (e.g., dihydrochloride) are used interchangeably. For example, as used herein, bishydrochloride, bischloride, and dihydrochloride have the same meaning.

[0068] Crystalline forms may be characterized by the presence of observable peaks in the PXRD pattern measured for the crystalline form. The measured or calculated PXRD patterns for the salts and crystalline forms reported herein represent fingerprints that can be compared with other experimentally determined patterns to find a match. The identity of each crystalline form is established by the overlap or match of the experimentally determined PXRD pattern with the PXRD pattern of the crystalline forms reported herein. In various embodiments, the salts and crystalline forms are characterized by PXRD peaks. Thus, in various embodiments, the salts or crystalline forms are characterized by the match of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks; 2 or more peaks; 3 or more peaks; 4 or more peaks; 5 or more peaks, etc., from their respective PXRD patterns. In some embodiments, the salts or crystalline forms may be characterized by the match of peaks with a relative intensity (I / Io) of about 5% or more or about 10% or more, where I indicates the intensity of each peak and Io indicates the intensity of the highest peak.

[0069] It should be apparent to one of ordinary skill in the art that, unless otherwise noted, the peak values ​​from PXRD studies reported in this invention are relative to experimental error typically observable in the art. Specifically, unless otherwise noted, peaks are understood to be within ±0.5° of the values ​​reported herein, and more specifically, peaks are understood to be within ±0.2° of the values ​​reported herein.

[0070] In some embodiments, the percent crystallinity of any of the salts or crystalline forms of the compound of formula (I) described herein may vary with respect to the total amount of the compound of formula (I). In particular, certain embodiments provide a percent crystallinity of the salts or crystalline forms of the compound of formula (I) that is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, the percent crystallinity may be substantially 100%, where substantially 100% indicates that the entire amount of the compound of formula (I) appears to be crystalline, as best as possible, as determined using methods known in the art. Thus, pharmaceutical compositions and therapeutically effective amounts of the compound of formula (I) may include amounts that vary in crystallinity. These include cases where an amount of a compound of formula (I) in solid form is subsequently dissolved, partially dissolved, or suspended or dispersed in a liquid, including cases where the compound of formula (I) is used as an active pharmaceutical ingredient (API) in a variety of formulations and solid forms.

[0071] [Salt of the compound of formula (I)]

[0072] In some embodiments, the present invention provides a salt of a compound of Formula (I).

[0073] The free base of formula (I) is poorly soluble in water, with a solubility of less than 0.4 μg / mL.The salt form of the free base compound can provide improved water solubility.The salt form should also have the overall physicochemical properties required for pharmaceutical use, such as, but not limited to, reproducibility of the preparation of specific crystalline polymorphs, high degree of crystallinity, stability of crystalline form, chemical stability, and low hygroscopicity.

[0074] The free base compound of formula (I) can be prepared according to the procedures described in WO 2013 / 100632, which is incorporated herein by reference in its entirety.

[0075] In order to identify the appropriate salt type of the compound of formula (I), salts of the free base of the compound of formula (I) are prepared using various acids and solvents under various conditions and procedures, and the physicochemical properties of the salts thus obtained are evaluated. In some embodiments, the salts of formula (I) include hydrochloric acid salt (hydrochloride salt), sulfate salt (hydrogen sulfate salt), p-toluenesulfonic acid salt (p-toluenesulfonate salt), ethanesulfonic acid salt (ethanesulfonate salt) and methanesulfonic acid salt (methanesulfonate salt).

[0076] In some embodiments, the salt of Formula (I) is selected from the hydrochloride, hydrogen sulfate, p-toluenesulfonate, ethanesulfonate, and methanesulfonate salts.

[0077] In some embodiments, the salt of Formula (I) is selected from bishydrochloride, bishydrogensulfate, bisp-toluenesulfonate, bisethanesulfonate, and bismethanesulfonate.

[0078] In one embodiment, the salt of formula (I) is a bishydrochloride salt. In another embodiment, the salt of formula (I) is a bishydrogensulfate salt. In another embodiment, the salt of formula (I) is a bisp-toluenesulfonate salt. In another embodiment, the salt of formula (I) is a bisethanesulfonate salt. In another embodiment, the salt of formula (I) is a bismethanesulfonate salt.

[0079] In some embodiments, the salt of formula (I) is in amorphous form. In some embodiments, the salt of formula (I) is in crystalline form. In some embodiments, the salt of formula (I) is a mixture of amorphous and crystalline forms.

[0080] [Crystal forms of the compound of formula (I) and its salts]

[0081] In some embodiments, crystalline compounds of formula (I) and salts thereof are provided. Based on experiments to date, the crystalline forms of the salts of formula (I) provide improved physicochemical properties compared to the free base form and the amorphous form.

[0082] In some embodiments, the crystalline form of the compound of formula (I) is a free base. In some embodiments, the free base is characterized by a PXRD pattern according to Figure 29. In some such embodiments, the free base is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, or 7 peaks, 3 or more peaks, or 5 or more peaks selected from the peaks at diffraction angles 2θ±0.2° values ​​of 4.6°, 9.2°, 12.7°, 13.8°, 25.9°, 26.5°, and 27.0° when irradiated with a Cu-Kα light source. In some embodiments, the free base is characterized by a PXRD pattern having 1, 2, 3, 4, or 5 peaks, or 3 or more peaks selected from the peaks at diffraction angles 2θ±0.2° values ​​of 9.2°, 12.7°, 13.8°, 25.9°, and 27.0°.

[0083] In some other embodiments, the crystalline form of the compound of formula (I) is a salt. In some such embodiments, the salt is selected from hydrochloride, hydrogen sulfate, p-toluenesulfonate, ethanesulfonate, and methanesulfonate. In some such embodiments, the salt is selected from bishydrochloride, bishydrogen sulfate, bisp-toluenesulfonate, bisethanesulfonate, bismethanesulfonate, and bisbenzenesulfonate.

[0084] In one embodiment of the invention, various crystalline forms of the hydrochloride salt of the compound of formula (I) are provided.

[0085] In some embodiments, the salt of Formula (I) is polymorphic Form I of the bis-hydrochloride salt, characterized by a PXRD pattern according to Figure 35. In some such embodiments, polymorphic Form I of the bis-hydrochloride salt is characterized by a powder X-ray diffraction pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ values ​​of 5.89°, 7.77°, 8.31°, 11.80°, 16.68°, 23.22°, 23.69°, 26.89°, 27.51°, 28.29°, and 29.53° when illuminated with a Cu-Kα light source. In some such embodiments, polymorphic Form I of the bis hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ values ​​of 5.89°, 7.77°, 8.31°, 11.80°, 16.68°, 23.69°, 26.89°, and 27.51. In some embodiments, polymorphic Form I of the bis hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, or 5 peaks, or 3 or more peaks selected from peaks at diffraction angle 2θ values ​​of 5.89°, 7.77°, 8.31°, 16.68°, and 26.89° ±0.2°. In some embodiments, polymorphic Form I of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, or three peaks selected from those having diffraction angles 2θ±0.2° values ​​of 5.89°, 7.77°, and 8.31°. In some embodiments, polymorphic Form I of the bis hydrochloride salt is characterized by peaks having an I / Io ratio of 10% or greater at diffraction angles 2θ±0.2° values ​​of 5.89°, 7.77°, 8.31°, 11.80°, 16.68°, 23.22°, 23.69°, 26.89°, 27.51°, 28.29°, and 29.53°.

[0086] In some embodiments, polymorphic Form I of the crystalline bis-hydrochloride salt of Formula (I) is a trihydrate.

[0087] In some embodiments, the salt of Formula (I) is polymorphic Form II of the bis-hydrochloride salt, characterized by a PXRD pattern according to Figure 14. In some such embodiments, polymorphic Form II of the bis-hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8 or 9 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 6.19°, 6.55°, 7.00°, 9.01°, 9.85°, 11.64°, 12.86°, 14.05°, and 25.31°. In some embodiments, polymorphic Form II of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, three, four, or five peaks, or three or more peaks, selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.19°, 6.55°, 7.00°, 9.01°, and 12.86°. In some embodiments, polymorphic Form II of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, or three peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.19°, 6.55°, and 7.00°. In some embodiments, polymorphic Form II of the bishydrochloride salt is characterized by peaks having an I / Io ratio of 10% or greater at diffraction angle 2θ±0.2° values ​​of 6.19°, 6.55°, 7.00°, 9.01°, 9.85°, 11.64°, 12.86°, 14.05°, and 25.31°.

[0088] In some embodiments, the salt of Formula (I) is polymorphic Form III of the bis-hydrochloride salt, characterized by a PXRD pattern according to FIG. In some embodiments, polymorphic Form III of the bis-hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 6.01°, 9.00°, 11.47°, 12.05°, 14.48°, 16.33°, 16.83°, 18.13°, 19.01°, 19.26°, 22.63°, 23.10°, 24.51°±0.2°, 25.31°, 25.94°, 26.51°, 27.10°, 28.12°, 30.44°, and 31.25° when illuminated with a Cu-Kα light source. In some embodiments, polymorphic Form III of the bishydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 6.01°, 9.00°, 11.47°, 16.33°, 18.13°, 22.63°, 23.10°, 25.94°, 27.10°, and 30.44°. In some such embodiments, polymorphic Form III of the bis hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.01°, 9.00°, 11.47°, 14.48°, 16.33°, 18.13°, 22.63°, 23.10°, 27.10°, and 30.47°. In some embodiments, polymorphic Form III of the bis hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, or 5 peaks, or 3 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.01°, 9.00°, 11.47°, 16.33°, and 23.10°. In some embodiments, polymorphic Form III of the bishydrochloride salt is characterized by a PXRD pattern having one, two, or three peaks selected from those at diffraction angles 2θ±0.2° values ​​of 9.00°, 11.47°, and 6.33°.In some embodiments, polymorphic Form III of the bishydrochloride salt is characterized by peaks having an I / Io ratio of 10% or greater at diffraction angles 2θ±0.2° values ​​of 6.01°, 9.00°, 11.47°, 12.05°, 14.48°, 16.33°, 16.83°, 18.13°, 19.01°, 19.26°, 22.63°, 23.10°, 24.51°, 25.31°, 25.94°, 26.51°, 27.10°, 28.12°, 30.47°, and 31.25°.

[0089] In some embodiments, the salt of Formula (I) is polymorphic Form IV of the bis-hydrochloride salt, characterized by a PXRD pattern according to FIG. In some such embodiments, polymorphic Form IV of the bis-hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.56°, 6.64°, 7.15°, 9.07°, 11.22°, 11.76°, 12.12°, 13.30°, 14.28°, 15.57°, 17.26°, 18.25°, 22.26°, 22.95°, 23.69°, 24.77°, 25.06°, 25.88°, 28.20°, 29.92°, 31.33°, and 34.17° when illuminated with a Cu-Kα light source. In some such embodiments, polymorphic Form IV of the bis hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 6.64°, 7.15°, 9.07°, 11.22°, 11.76°, 13.30°, 22.95°, 23.69°, 24.77°, 25.06°, 28.20°, and 29.92°. In some such embodiments, polymorphic Form IV of the bis hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.64°, 7.15°, 9.07°, 11.22°, 11.76°, 13.30°, 22.95°, 23.69°, 24.77°, and 25.06°. In some embodiments, polymorphic Form IV of the bis hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, or 5 peaks, or 3 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.64°, 9.07°, 11.22°, 11.76°, and 13.30°. In some embodiments, polymorphic Form IV of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, or three peaks selected from those at diffraction angles 2θ±0.2° values ​​of 6.64°, 11.22°, and 11.76°.In some embodiments, polymorphic Form IV of the bis hydrochloride salt is characterized by peaks having an I / I ratio of 10% or greater at diffraction angle 2θ±0.2° values ​​of 5.56°, 6.64°, 7.15°, 9.07°, 11.22°, 11.76°, 12.12°, 13.30°, 14.28°, 15.57°, 17.26°, 18.2°, 22.3°, 22.9°, 23.7°, 24.8°, 25.1°, 25.9°, 28.2°, 29.9°, 31.3°, and 34.2° (2θ±0.2°).

[0090] In some embodiments, the salt of Formula (I) is polymorphic Form V of the bis-hydrochloride salt, characterized by a PXRD pattern according to FIG. In some such embodiments, polymorphic Form IV of the bis-hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.44°, 6.58°, 7.48°, 9.22°, 10.84°, 11.47°, 12.45°, 13.17°, 16.61°, 17.18°, 17.92°, 18.52°, 22.21°, 23.07°, 23.84°, 24.70°, 25.37°, 26.08°, 27.33°, 29.12°, 31.02°, 31.43°, 34.65°, and 37.46° when illuminated with a Cu-Kα light source. In some such embodiments, polymorphic Form V of the bishydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 6.58°, 7.48°, 9.22°, 10.84°, 11.47°, 13.17°, 16.61°, 17.18°, 18.52°, 22.21°, 23.07°, 23.84°, 24.70°, 25.37°, 26.08°, 27.33°, 29.12°. In some such embodiments, polymorphic Form V of the bishydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 6.58°, 7.48°, 9.22°, 10.84°, 11.47°, 13.17°, 17.18°, 18.52°, 23.07°, 23.84°, 24.70°, 25.37°, and 27.33°.In some such embodiments, polymorphic Form V of the bishydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 6.58°±0.2°, 7.48°±0.2°, 9.22°±0.2°, 10.84°±0.2°, 11.47°±0.2°, 13.17°±0.2°, 17.18°±0.2°, 23.07°±0.2°, 24.70°±0.2°, and 27.33°±0.2°. In some embodiments, polymorphic form V of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, three, four, or five peaks, or three or more peaks, selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.58°, 7.48°, 11.47°, 13.17°, and 23.07°. In some embodiments, polymorphic form V of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, or three peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 6.58°, 7.48°, and 11.47°. In some embodiments, polymorphic Form II of the bishydrochloride salt is characterized by peaks having an I / I ratio of 10% or greater at diffraction angle 2θ±0.2° values ​​of 5.44°, 6.58°, 7.48°, 9.22°, 10.84°, 11.47°, 12.45°, 13.17°, 16.61°, 17.18°, 17.92°, 18.52°, 22.21°, 23.07°, 23.84°, 24.70°, 25.37°, 26.08°, 27.33°, 29.12°, 31.02°, 31.43°, 34.65°, and 37.46°.

[0091] In some embodiments, the salt of Formula (I) is polymorphic Form VI of the bis-hydrochloride salt, characterized by a PXRD pattern according to Figure 22. In some such embodiments, polymorphic Form VI of the bis-hydrochloride salt is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.86°, 8.47°, 8.90°, 12.10°, 14.00°, 16.30°, 16.71°, and 23.49° when illuminated with a Cu-Kα light source. In some embodiments, the polymorphic form VI of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, three, four, or five peaks, or three or more peaks, selected from the peaks at diffraction angles 2θ±0.2° values ​​of 5.86°, 8.47°, 8.90°, 12.10°, and 23.49°. In some embodiments, the polymorphic form VI of the bis hydrochloride salt is characterized by a PXRD pattern having one, two, or three peaks selected from the peaks at diffraction angles 2θ±0.2° values ​​of 5.86°, 8.47°, and 8.90°. In some embodiments, the polymorphic form VI of the bis hydrochloride salt is characterized by peaks at diffraction angles 2θ±0.2° values ​​of 8.5° and 8.9° with an I / Io ratio of 10% or more.

[0092] In some embodiments, the salt of Formula (I) is a bishydrogen sulfate salt characterized by a PXRD pattern according to FIG. In some such embodiments, the bishydrogen sulfate salt of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.7°, 7.4°, 7.9°, 9.4°, 11.5°, 13.7°, 15.0°, 15.9°, 16.9°, 17.7°, 18.5°, 18.9°, 20.3°, 20.9°, 21.6°, 22.4°, 22.9°, 23.3°, 24.0°, 24.4°, 24.6°, 25.3°, 25.9°, 26.5°, 27.3°, 28.7°, and 33.7°. In some such embodiments, the bishydrogen sulfate salt of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.7°, 7.4°, 7.9°, 11.5°, 13.7°, 15.0°, 15.9°, 18.5°, 18.9°, 20.3°, 20.9°, 21.6°, 22.4°, 22.9°, 23.3°, 24.0°, 24.4°, 24.6°, 25.3°, 25.9°, 26.5°, and 27.3°. In some such embodiments, the bishydrogen sulfate salt of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 7.4°, 7.9°, 11.5°, 15.0°, 15.9°, 18.5°, 18.9°, 22.4°, 22.9°, 24.0°, 24.4°, 24.6°, 25.3°, and 25.9°. In some such embodiments, the bishydrogen sulfate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 7.4°, 7.9°, 15.0°, 15.9°, 18.5°, 22.4°, 24.0°, 24.4°, 25.3°, and 25.9°.In some such embodiments, the bishydrogen sulfate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, or 5 peaks, 3 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 7.9°, 15.0°, 15.9°, 18.5°, and 25.9°. In some embodiments, the bishydrogen sulfate salt is characterized by peaks having an I / I ratio of 10% or greater at diffraction angle 2θ±0.2° values ​​of 5.7°, 7.4°, 7.9°, 9.4°, 11.5°, 13.7°, 15.0°, 15.9°, 16.9°, 17.7°, 18.5°, 18.9°, 20.3°, 20.9°, 21.6°, 22.4°, 22.9°, 23.3°, 24.0°, 24.4°, 24.6°, 25.3°, 25.9°, 26.5°, 27.3°, 28.7°, and 33.7°.

[0093] In some embodiments, the salt of Formula (I) is a polymorph of bis-p-toluenesulfonate Form A, characterized by a PXRD pattern according to FIG. In some such embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 3.2°, 4.5°, 7.7°, 8.4°, 9.0°, 11.7°, 13.2°, 13.6°, 14.1°, 15.3°, 15.8°, 16.7°, 17.4°, 18.8°, 19.9°, 21.7°, 21.9°, 22.3°, 23.0°, 23.5°, 24.6°, 24.7°, 25.6°, 27.4°, and 29.0° when illuminated with a Cu-Kα light source. In some such embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 3.2°, 4.5°, 7.7°, 8.4°, 11.7°, 13.2°, 13.6°, 14.1°, 15.3°, 15.8°, 17.4°, 18.8°, 21.7°, 21.9°, 22.3°, 23.0°, 23.5°, 24.6°, 24.7°, 25.6°, 27.4°, and 29.0°. In some such embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 4.5°, 14.1°, 15.3°, 17.4°, 21.7°, 21.9°, 22.3°, 23.0°, 24.6°, 24.7°, 25.6°, and 27.4°.In some such embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 4.5°, 14.1°, 15.3°, 17.4°, 21.7°, 21.9°, 23.0°, 24.6°, 24.7°, and 25.6°. In some such embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 4.5°, 15.3°, 17.4°, 21.7°, 21.9°, 23.0°, 24.6°, and 24.7°. In some embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, or 5 peaks, or 3 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 4.5°, 15.3°, 17.4°, 21.7°, and 21.9°. In some embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by a PXRD pattern having one, two or three peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 4.5°, 15.3° and 21.7°. In some embodiments, the polymorph of bis-p-toluenesulfonate Form A of Formula (I) is characterized by peaks having an I / I ratio of 10% or greater at diffraction angle 2θ±0.2° values ​​of 3.2°, 4.5°, 7.7°, 8.4°, 9.0°, 11.7°, 13.2°, 13.6°, 14.1°, 15.3°, 15.8°, 16.7°, 17.4°, 18.8°, 19.9°, 21.7°, 21.9°, 22.3°, 23.0°, 23.5°, 24.6°, 24.7°, 25.6°, 27.4°, and 29.0°.

[0094] In some embodiments, the salt of Formula (I) is a bis-p-toluenesulfonate Form B polymorph characterized by a PXRD pattern according to Figure 27. In some such embodiments, the bis-p-toluenesulfonate Form B polymorph of Formula (I) has a PXRD pattern of 5.7°, 7.8°, 9.3°, 11.4°, 11.6°, 12.5°, 12.9°, 13.2°, 14.0°, 15.0°, 15.8°, 16.0°, 17.0°, 17.5°, 18.8°, 19.2°, 19.8°, 20.5°, 21.7°, 22.7°, 23.7°, 24.7°, 25.7°, 26.7°, 27.7°, 28.7°, 29.7°, 30.7°, 31.7°, 32.7°, 33.7°, 34.7°, 35.7°, 36.7°, 37.7°, 38.7°, 39.7°, 40.7°, 41.7°, 42.7°, 43.7°, 44.7°, 45.7°, 46.7°, 47.7°, 48.7°, 49.7°, 50.7°, 51.7°, 52.7°, 53.7°, 54.7°, 55.7°, 56.7°, 57.7°, 58.7°, 59.7°, 60.7°, 61.7°, 62.7°, 63.7°, 64.7°, 65.7°, The compound is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 0°, 21.4°, 21.9°, 22.4°, 22.8°, 23.4°, 24.2°, 24.9°, 26.2°, 27.2°, 28.1°, 29.1°, and 31.6°. In some such embodiments, the polymorph of bis p-toluenesulfonate Form B of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.7°, 7.8°, 11.4°, 11.6°, 12.9°, 13.2°, 14.0°, 15.0°, 15.8°, 16.0°, 17.0°, 17.5°, 18.8°, 19.2°, 19.8°, 20.5°, 21.4°, 21.9°, 22.4°, 22.8°, 23.4°, 24.9°, 26.2°, 27.2°, and 29.1°. In some such embodiments, the polymorph of bis-p-toluenesulfonate Form B of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.7°, 7.8°, 11.6°, 13.2°, 15.8°, 16.0°, 17.0°, 17.5°, 18.8°, 19.2°, 22.4°, 22.8°, 23.4°, 24.9°, and 26.2°.In some such embodiments, the polymorph of bis-p-toluenesulfonate Form B of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.7°, 11.6°, 13.2°, 15.8°, 17.0°, 18.8°, 19.2°, 22.4°, 23.4°, and 26.2°. In some such embodiments, the polymorph of bis-p-toluenesulfonate Form B of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, or 8 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 5.7°, 11.6°, 15.8°, 17.0°, 19.2°, 22.4°, 23.4°, and 26.2°. In some embodiments, the polymorph of bis-p-toluenesulfonate Form B of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5 peaks, or 3 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 5.7°, 11.6°, 15.8°, 17.0°, and 22.4°. In some embodiments, the polymorph of bis-p-toluenesulfonate Form B of Formula (I) is characterized by a PXRD pattern having one, two, or three peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.7°, 11.6°, and 22.4°. In some embodiments, the polymorph of bis-p-toluenesulfonate Form B of Formula (I) is characterized by peaks having an I / I ratio of 10% or greater at diffraction angle 2θ±0.2° values ​​of 5.7°, 7.8°, 9.3°, 11.4°, 11.6°, 12.5°, 12.9°, 13.2°, 14.0°, 15.0°, 15.8°, 16.0°, 17.0°, 17.5°, 18.8°, 19.2°, 19.8°, 20.5°, 21.0°, 21.4°, 21.9°, 22.4°, 22.8°, 23.4°, 24.2°, 24.9°, 26.2°, 27.2°, 28.1°, 29.1°, and 31.6°.

[0095] In some embodiments, the salt of Formula (I) is a bis-p-ethanesulfonate salt characterized by a PXRD pattern according to FIG. In some such embodiments, the bis-p-ethanesulfonate salt of Formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.7°, 6.8°, 7.4°, 11.5°, 14.8°, 15.2°, 17.6°, 18.4°, 20.2°, 20.5°, 22.1°, 22.3°, 23.2°, 23.6°, 23.8°, 25.2°, 25.6°, 25.8°, 26.4°, 27.5°, 28.1°, and 28.8°. In some such embodiments, the bis-p-ethanesulfonate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from the peaks at diffraction angles 2θ±0.2° values ​​of 6.8°, 7.4°, 14.8°, 15.2°, 18.4°, 20.5°, 22.3°, 25.2°, 25.6°, and 26.4°. In some such embodiments, the bis-p-ethanesulfonate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, or 5 peaks, or 3 or more peaks selected from the peaks at diffraction angles 2θ±0.2° values ​​of 6.8°, 7.4°, 14.8°, 15.2°, and 20.5°. In some such embodiments, the bis-p-ethanesulfonate salt of formula (I) is characterized by a PXRD pattern having one, two or three peaks selected from those having diffraction angles 2θ±0.2° values ​​of 6.8°, 7.4° and 14.8°. In some embodiments, the bis-p-ethanesulfonate salt of formula (I) is characterized by peaks having an I / Io ratio of 10% or more at diffraction angles 2θ±0.2° values ​​of 5.7°, 6.8°, 7.4°, 11.5°, 14.8°, 15.2°, 17.6°, 18.4°, 20.2°, 20.5°, 22.1°, 22.3°, 23.2°, 23.6°, 23.8°, 25.2°, 25.6°, 25.8°, 26.4°, 27.5°, 28.1° and 28.8°.

[0096] In some embodiments, the salt of formula (I) is a bis-p-methanesulfonate salt characterized by a PXRD pattern according to Figure 7. In some such embodiments, the bis-p-methanesulfonate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 5.6°, 7.1°, 7.6°, 11.4°, 15.1°, 15.4°, 16.6°, 18.2°, 20.4°, 21.5°, 22.3°, 22.7°, 23.1°, 24.4°, 24.9°, and 25.6°. In some such embodiments, the bis-p-methanesulfonate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angle 2θ±0.2° values ​​of 7.1°, 7.6°, 11.4°, 15.1°, 15.4°, 18.2°, 21.5°, 23.1°, 24.4°, 24.9°, and 25.6°. In some such embodiments, the bis-p-methanesulfonate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 7.1°, 7.6°, 15.1°, 15.4°, 18.2°, 21.5°, 23.1°, 24.4°, 24.9°, and 25.6°. In some such embodiments, the bis-p-methanesulfonate salt of formula (I) is characterized by a PXRD pattern having 1, 2, 3, 4, 5, or 6 peaks, 3 or more peaks, or 5 or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 7.1°, 7.6°, 15.4°, 18.2°, 21.5°, and 23.1°. In some such embodiments, the bis-p-methanesulfonate salt of formula (I) is characterized by a PXRD pattern having one, two, three, four, or five peaks, or three or more peaks selected from peaks at diffraction angles 2θ±0.2° values ​​of 7.1°, 7.6°, 15.4°, 18.2°, and 23.1°.In some such embodiments, the bis-p-methanesulfonate salt of formula (I) is characterized by a PXRD pattern having one, two, or three peaks selected from those having diffraction angles 2θ±0.2° values ​​of 7.1°, 7.6°, and 15.4°. In some embodiments, the bis-p-methanesulfonate salt of formula (I) is characterized by peaks having an I / Io ratio of 10% or greater at diffraction angles 2θ±0.2° values ​​of 5.6°, 7.1°, 7.6°, 11.4°, 15.1°, 15.4°, 16.6°, 18.2°, 20.4°, 21.5°, 22.3°, 22.7°, 23.1°, 24.4°, 24.9°, and 25.6°.

[0097] Preparation of crystalline forms of the compound of formula (I) and its salts

[0098] In some embodiments, the crystalline acid salt form of Formula (I) may be prepared by a process comprising the steps of: (a) combining an organic solvent with the free base of the compound of Formula (I) to form a mixture; (b) adding 2-3 equivalents of an acid per equivalent of Formula (I) to the mixture obtained in step (a) to form a slurry comprising a solid crystalline salt of Formula (I); and (c) isolating the crystalline salt of Formula (I) from the slurry. The salt may optionally be dried.

[0099] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, and mixtures thereof.

[0100] In some embodiments, the organic solvent is essentially anhydrous. Examples of organic solvents include, but are not limited to, methanol, ethanol, tetrahydrofuran ("THF"), isopropyl alcohol ("IPA"), DMF, acetone, ethyl acetate, acetonitrile ("ACN"), methyl ethyl ketone, and combinations thereof. In some embodiments, the solvent may further comprise water.

[0101] In some embodiments, the mixture of the solvent and Formula (I) is a solution. In some embodiments, the mixture of the solvent and Formula (I) is a suspension or slurry. In such embodiments, the minimum amount of solvent is that amount in which the free base of the compound of Formula (I) or a salt thereof is soluble at a suitable temperature (e.g., under reflux) or that the suspension can be stirred at a desired temperature. The maximum amount of solvent is not narrowly limited, but is the amount of solvent that results in a concentration of Formula (I) or a salt thereof suitable to produce a crystalline product of practical yield and acceptable purity.

[0102] The equivalent ratio of acid to the compound of formula (I) is about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9 or about 3.0, and ranges therebetween, for example, from about 2 to about 3, from about 2 to about 2.5, or from about 2.2 to about 2.3.

[0103] The crystalline form of the bis-hydrochloride salt of the compound of formula (I) can be prepared by a process comprising the steps of: mixing the free base of formula (I) with a solvent to form a mixture. The mixture can suitably be a slurry or a solution. In some embodiments, the mixture can be heated. In some embodiments, the mixture can be heated to reflux. About 2 to about 3 equivalents of hydrochloric acid per equivalent of formula (I) are added to the mixture to form a slurry comprising the solid crystalline bis-hydrochloride salt of formula (I). In some embodiments, the slurry can be cooled, for example, to less than about 25° C., to promote crystallization of the bis-hydrochloride salt of formula (I). The solid crystalline bis-hydrochloride salt of formula (I) can be isolated from the slurry by means known in the art, including, for example, filtration or centrifugation. The isolated crystalline bis-hydrochloride salt of formula (I) can be optionally washed to remove impurities. The crystals can then be dried by means known in the art, including, for example, vacuum oven drying or fluidized bed drying.

[0104] In some embodiments, the organic solvent is selected from methanol, ethanol, and mixtures thereof. In such embodiments, the dried crystalline bis-hydrochloride salt Form (I) of Formula (I) is hydrated by exposure to air containing water vapor. In some embodiments, the polymorphic Form I of the crystalline bis-hydrochloride salt of Formula (I) is a trihydrate.

[0105] In some particular embodiments, the free base of formula (I) can be optionally mixed with an alcohol solvent to form a solution followed by filtration. In some aspects, the solvent is ethanol or methanol, or is methanol. The concentration of the free base of formula (I) in the solution is suitably about 1 g / L to about 25 g / L, about 5 g / L to about 20 g / L, or about 10 g / L. The temperature is selected to provide a solution with a free base concentration of formula (I), for example, above 30°C, such as about 35°C to about 60°C or about 35°C to about 50°C. Activated carbon can be optionally added to the mixture with stirring. The mixture is then optionally filtered through a filter aid such as Celite® (diatomaceous earth). The filtrate can then be concentrated, for example by evaporation, to form a free base residue of formula (I). The residue is then suspended in ethanol. In some aspects, the ethanol is aqueous ethanol. In some embodiments, the aqueous alcohol is about 70% ethanol to about 90% ethanol, for example about 80% ethanol. The content of the free base of Formula (I) in the suspension is suitably about 10 g / L to about 150 g / L, about 25 g / L to about 75 g / L, or about 50 g / L. Hydrochloric acid is added to the suspension to form a mixture with an equivalent ratio of acid to free base of Formula (I), for example, about 2 to about 3, about 2 to about 2.5, or about 2.2 to about 2.3, as described elsewhere herein. The mixture is heated with stirring, for example at reflux, and held for a time sufficient to essentially complete the conversion of the free base of Formula (I) to the bis-hydrochloride salt of Formula (I). The mixture is then cooled, for example to less than about 35° C., and the bis-hydrochloride salt Form I of Formula (I) is isolated, for example by filtration. The bis-hydrochloride salt Form I of Formula (I) is dried under vacuum at a suitable temperature, such as about 40° C. to about 60° C. The dried solid may optionally be crushed or pulverized. The dried solid is then exposed to air containing water vapor to form the hydrated bis-hydrochloride crystalline polymorphic Form I of Formula (I). The humidified conditions are suitably about 30° C. to about 50° C. with exposure to air at about 50% RH to about 95% RH, about 60% RH to about 90% RH, or about 70% RH to about 80% RH.

[0106] In some embodiments, the organic solvent is DMF and the dried crystalline Formula (I) bis-hydrochloride salt is polymorphic Form V. In such embodiments, the free base of Formula (I) is combined with DMF to form a suspension having a content of Formula (I) of about 10 g / L to about 200 g / L, about 25 g / L to about 150 g / L, or about 50 g / L to about 75 g / L. The suspension is heated to form a solution. In some embodiments, the temperature is greater than 100° C., such as about 120° C., about 140° C., or at reflux. Hydrochloric acid is added to the solution in an equivalent ratio of acid to Formula (I) free base, as described elsewhere herein, to form a suspension comprising solid crystalline Formula (I) bis-hydrochloride Form V. In some embodiments, the solution is cooled to less than 100° C., such as about 80° C., prior to the addition of the acid. The suspension is then cooled and aged with stirring, for example at less than about 30° C. for at least 1 hour, and polymorphic Form V of the bis-hydrochloride salt of Formula (I) is isolated, for example by filtration. The bis-hydrochloride salt Form V of Formula (I) is dried under vacuum at a suitable temperature, such as from about 40° C. to about 60° C. The dried solid can optionally be crushed or pulverized.

[0107] Various crystalline forms of the bis-hydrochloride salt of formula (I) can be prepared from crystalline form I, including crystalline form II, crystalline form III, crystalline form IV, and crystalline form VI.

[0108] Figure 25 illustrates and summarizes the interpolymorphic interconversion between the polymorphs of the bishydrochloride salt of the compound of formula (I). Crystalline forms II, III, and IV as well as the amorphous form can be prepared by recrystallization of crystalline form I. Crystalline form V can be prepared from the free base of the compound of formula (I). Crystalline form VI can be converted to crystalline form I by moisture absorption (e.g., above 60% relative humidity). All other crystalline forms of formula (I) can be converted to crystalline form I under the same reflux conditions in about 80% ethanol.

[0109] In some embodiments, polymorphic Form II of the bis-hydrochloride salt of Formula (I) can be prepared from Form I. In some such embodiments, Form I of the bis-hydrochloride salt of Formula (I) is combined with methanol and THF, then heated, cooled and dried to produce Form II. The concentration of Form I in methanol / THF is suitably about 5 g / L to about 100 g / L, about 10 g / L to about 50 g / L, or about 10 g / L to about 30 g / L. The volume ratio of methanol to THF is suitably about 1.5:1 to about 0.25:1, about 1:1 to about 0.5:1, or about 0.75:1 to about 0.5:1. The temperature is suitably at least 60° C. or reflux. The mixture is then cooled and aged with stirring, for example below about 30° C., for at least 1 hour, and polymorphic Form II of the bis-hydrochloride salt of Formula (I) is isolated, for example by filtration. The Form II polymorph is dried under vacuum at a suitable temperature, such as, for example, about 40° C. to about 60° C. The dried solid may optionally be crushed or pulverized. The dried solid is then exposed to air containing water vapor to form hydrated Form II. Humidification conditions are suitably about 15° C. to about 50° C., or about 15° C. to about 35° C., and exposed to air at about 40% RH to about 90% RH, about 40% RH to about 80% RH, or about 50% RH to about 70% RH. Form I may be regenerated from Form II by heating in aqueous ethanol, isolation, drying, and humidification, as described elsewhere herein in connection with the preparation of Form I.

[0110] In some embodiments, polymorphic Form III of the bis-hydrochloride salt of Formula (I) can be prepared from Form I. In some such embodiments, Form I of the bis-hydrochloride salt of Formula (I) is combined with methanol and IPA, then heated, cooled and dried to produce Form II. The concentration of Form I in methanol / IPA is suitably about 5 g / L to about 100 g / L, about 10 g / L to about 50 g / L, or about 10 g / L to about 30 g / L. The volume ratio of methanol to IPA is suitably about 1.5:1 to about 0.25:1, about 1:1 to about 0.5:1, or about 0.75:1 to about 0.5:1. The temperature is suitably at least 60° C. or reflux. The mixture is then cooled and aged with stirring, for example below about 30° C., for at least 1 hour, and polymorphic Form III of the bis-hydrochloride salt of Formula (I) is isolated, for example by filtration. The Form III polymorph is dried under vacuum at a suitable temperature, such as, for example, about 40° C. to about 60° C. The dried solid may optionally be crushed or pulverized. The dried solid is then exposed to air containing water vapor to form hydrated Form III. Humidification conditions are suitably about 15° C. to about 50° C., or about 15° C. to about 35° C., and exposed to air at about 40% RH to about 90% RH, about 40% RH to about 80% RH, or about 50% RH to about 70% RH. Form I may be regenerated from Form III by heating in aqueous ethanol, isolation, drying, and humidification, as described elsewhere herein in connection with the preparation of Form I.

[0111] In some embodiments, polymorphic Form IV of the bis-hydrochloride salt of Formula (I) can be prepared from Form I. In some such embodiments, the bis-hydrochloride salt of Formula (I) in Form I is combined with DMF, followed by heating, cooling and drying to produce Form IV. The concentration of Form I in DMF is suitably from about 25 g / L to about 250 g / L, from about 50 g / L to about 150 g / L, or from about 75 g / L to about 125 g / L. A solution is suitably formed or refluxed at a temperature of at least 130° C. to form a solution. The mixture is then cooled and aged, for example, below about 30° C. for at least 1 hour with stirring. Seed crystals may optionally be added, such as during or after cooling. Polymorphic Form IV of the bis-hydrochloride salt of Formula (I) is isolated, for example, by filtration. The polymorphic Form IV is dried under vacuum at a suitable temperature, for example, from about 40° C. to about 60° C. The dried solid may optionally be crushed or pulverized. Form I can be regenerated from Form IV by heating in aqueous ethanol, isolating, drying, and wetting as described elsewhere herein in connection with the preparation of Form I.

[0112] In some embodiments, polymorphic Form VI of the bishydrochloride salt of Formula (I) can be prepared from Form I. In some such embodiments, Form I of the bishydrochloride salt of Formula (I) is dried under vacuum at a suitable temperature, such as about 40° C. to about 60° C. The dried solid can be optionally crushed or pulverized. In some embodiments, Form I can be regenerated from Form VI by water hydration at humidified conditions of about 15° C. to about 35° C. while exposed to air at about 40% RH to about 90% RH, about 40% RH to about 80% RH, or about 50% RH to about 70% RH. In some other embodiments, Form I can be regenerated from Form VI by water hydration at humidified conditions of about 15° C. to about 30° C. while exposed to air at about 10% RH to about 50% RH, or about 10% RH to about 30% RH for at least one day.

[0113] In some embodiments, the amorphous bis-hydrochloride salt of Formula (I) may be prepared in crystalline form (e.g., Form I). The bis-hydrochloride salt is combined with DMSO at a concentration of about 50 g / L to about 400 g / L, about 100 g / L to about 300 g / L, or about 150 g / L to about 250 g / L, followed by heating to at least 100° C., at least 110° C., or at least 120° C. with mixing to form a solution. The solution is cooled to below 35° C., followed by addition of an anti-solvent (e.g., acetone) to form a slurry of the amorphous bis-hydrochloride salt of Formula (I). The volume ratio of acetone to DMSO is suitably at least 0.5:1, at least 1:1, or at least 2:1. The amorphous bis-hydrochloride salt of Formula (I) is isolated, such as by filtration, and dried under vacuum at a suitable temperature, such as about 40° C. to about 60° C. The dried solids may optionally be crushed or ground.

[0114] In some embodiments, crystalline bishydrogen sulfate of Formula (I) can be prepared from the free base of Formula (I). In such embodiments, the free base of Formula (I) is combined with an alcohol solvent (e.g., methanol) to form a mixture at a suitable concentration of about 10 g / L to about 150 g / L, about 20 g / L to about 100 g / L, or about 25 g / L to about 75 g / L. In some embodiments, the methanol is aqueous methanol having a methanol content of about 70% to about 90%, such as about 80%. Sulfuric acid is added to the mixture to form a mixture with an equivalent ratio of acid to free base of Formula (I) as described elsewhere herein, for example, about 2 to about 3, about 2 to about 2.5, or about 2.2 to about 2.3. In some embodiments, the reaction can be carried out at ambient temperature. The mixture is stirred and held for a time sufficient to essentially complete the conversion of the free base of Formula (I) in suspension to the bishydrogen sulfate of Formula (I) in solid form. The bishydrogen sulfate salt of formula (I) is isolated, for example, by filtration and dried under vacuum at an appropriate temperature, for example, about 40° C. to about 60° C. The dried solid may be crushed or pulverized, if necessary.

[0115] In some embodiments, the crystalline bis-p-toluenesulfonate salt of Formula (I) Form A can be prepared from the free base of Formula (I). In such embodiments, the free base of Formula (I) is combined with acetone to form a mixture at an appropriate concentration of about 10 g / L to about 150 g / L, about 20 g / L to about 100 g / L, or about 25 g / L to about 75 g / L. p-Toluenesulfonic acid is added to the mixture to form a mixture at an equivalent ratio of acid to free base of Formula (I) as described elsewhere herein, for example, about 2 to about 3, about 2 to about 2.5, or about 2.2 to about 2.3. In some embodiments, the reaction can be carried out at ambient temperature. The mixture is stirred and held for a time sufficient to essentially complete the conversion of the free base of Formula (I) in suspension to the solid crystalline bis-p-toluenesulfonate salt of Formula (I) Form A, and the salt is isolated, such as by filtration, and dried under vacuum at an appropriate temperature, such as about 40° C. to about 60° C. The dried solids may optionally be crushed or ground.

[0116] In some embodiments, crystalline bis-p-toluenesulfonate salt of Formula (I) Form B may be prepared from the free base of Formula (I). In such embodiments, the free base of Formula (I) is combined with ACN to form a mixture at an appropriate concentration of about 10 g / L to about 150 g / L, about 20 g / L to about 100 g / L, or about 25 g / L to about 75 g / L. p-Toluenesulfonic acid is added to the mixture to form a mixture at an equivalent ratio of acid to free base of Formula (I) as described elsewhere herein, for example, about 2 to about 3, about 2 to about 2.5, or about 2.2 to about 2.3. In some embodiments, the reaction may be carried out at ambient temperature. The mixture is stirred and held for a time sufficient to essentially complete the conversion of the free base of Formula (I) in suspension to solid crystalline bis-p-toluenesulfonate salt of Formula (I) Form B, and the salt is isolated, such as by filtration, and dried under vacuum at an appropriate temperature, such as about 40° C. to about 60° C. The dried solids may optionally be crushed or ground.

[0117] In some embodiments, the crystalline bis-ethanesulfonate salt of Formula (I) can be prepared from the free base of Formula (I). In such embodiments, the free base of Formula (I) is combined with an alcohol solvent (e.g., ethanol) to form a mixture at an appropriate concentration of about 10 g / L to about 150 g / L, about 20 g / L to about 100 g / L, or about 25 g / L to about 75 g / L. Ethanesulfonic acid is added to the mixture to form a mixture with an equivalent ratio of acid to Formula (I) free base as described elsewhere herein, for example, about 2 to about 3, about 2 to about 2.5, or about 2.2 to about 2.3. In some embodiments, the reaction can be carried out at a temperature greater than about 70° C. or at reflux. The mixture is stirred and held at a temperature below about 35° C. for a time sufficient to essentially complete the conversion of the free base of Formula (I) in suspension to the solid crystalline ethanesulfonic acid salt of Formula (I), and the salt is isolated, such as by filtration, and dried under vacuum at a suitable temperature, such as from about 40° C. to about 60° C. The dried solid can optionally be crushed or pulverized.

[0118] In some embodiments, crystalline bismethanesulfonate salt of Formula (I) can be prepared from the free base of Formula (I). In such embodiments, the free base of Formula (I) is combined with an alcohol solvent (e.g., ethanol) to form a mixture at an appropriate concentration of about 10 g / L to about 150 g / L, about 20 g / L to about 100 g / L, or about 25 g / L to about 75 g / L. Methanesulfonic acid is added to the mixture to form a mixture at an equivalent ratio of acid to free base of Formula (I) as described elsewhere herein, e.g., about 2 to about 3, about 2 to about 2.5, or about 2.2 to about 2.3. In some embodiments, the reaction can be carried out at a temperature greater than about 70° C. or at reflux. The mixture is stirred and held at a temperature below about 35° C. for a time sufficient to essentially complete conversion of the free base of Formula (I) in suspension to the solid crystalline methanesulfonate salt of Formula (I), and the salt is isolated, such as by filtration, and dried under vacuum at a suitable temperature, such as from about 40° C. to about 60° C. The dried solid can optionally be crushed or pulverized.

[0119] [Medical Uses and Pharmaceutical Compositions]

[0120] As disclosed in WO 2013 / 100632, the compounds of formula (I) have been shown to be useful for the prevention or treatment of abnormal cell proliferation disorders caused by the abnormal activation of protein kinases.

[0121] In one embodiment, the present invention further provides a salt of a compound of formula (I), a crystalline form of a salt of a compound of formula (I), or a crystalline form of the free base of a compound of formula (I) as described herein, for use in the prevention or treatment of an abnormal cell proliferation disorder by inhibiting the activity of a protein kinase.

[0122] In a further embodiment, the present invention provides a method for preventing or treating an abnormal cell proliferation disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a salt of a compound of formula (I) or a crystalline form of a salt of a compound of formula (I) as described herein.

[0123] In further embodiments, the protein kinase is ALK, AMPK, Aurora A, Aurora B, Aurora C, Axl, Blk, Bmx, BTK, CaMK, CDK2 / cyclin E, CDK5 / p25, CHK1, CK2, A-Raf, B-Raf, C-Raf, DDR1, DDR2, DMPK, EGFR1, Her2, Her4, EphA1, EphB1, FAK, FGFR2, FGFR3, FGFR4, Flt-1, Flt-3, Flt-4, Fms (CSF-1), Fyn, GSK3 beta, H Selected from IPK1, IKK beta, IGFR-1R, IR, Itk, JAK2, JAK3, KDR, Kit, Lck, Lyn, MAPK1, MAPKAP-K2, MEK1, Met, MKK6, MLCK, NEK2, p70S6K, PAK2, PDGFR alpha, PDGFR beta, PDK1, Pim-1, PKA, PKB alpha, PKC alpha, Plk1, Ret, ROCK-I, Rsk1, SAPK2a, SGK, Src, Syk, Tie-2, Tec, Trk, and ZAP-70.

[0124] In a further embodiment, the abnormal cell proliferation disorder to be prevented or treated is selected from gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer, lymphoma, fibroadenoma, inflammation, diabetes, obesity, psoriasis, rheumatoid arthritis, hemangioma, acute and chronic kidney disease, coronary artery restenosis, autoimmune diseases, asthma, neurodegenerative diseases, acute infections, eye diseases caused by angiogenesis.

[0125] In this embodiment, the salt of the compound of formula (I) or the crystalline form of the salt of the compound of formula (I) may be used for the preparation of a pharmaceutical composition for preventing or treating abnormal cell proliferation disorders caused by abnormal activation of protein kinases. The pharmaceutical composition may be used for preventing or treating the same disorders as described above for the salt or the crystalline form of the salt.

[0126] Accordingly, the present invention provides a pharmaceutical composition comprising a salt of a compound of formula (I), preferably in crystalline form, or a crystalline form of the free base of the compound of formula (I), and at least one pharma- ceutically acceptable carrier or diluent, which may be used in the prophylaxis or treatment of abnormal cell proliferation disorders caused by the abnormal activation of protein kinases.

[0127] The dosage of the salt of the compound of formula (I), preferably in crystalline form, or a pharmaceutical composition containing it may vary depending on the subject being treated, the severity of the disease or the subject's health condition, the administration rate, and the physician's decision, but it may be conventionally administered to a human subject having a body weight of, for example, 70 kg, in an amount of 10 mg to 2000 mg, preferably 50 mg to 1000 mg, based on the compound of formula (I) as a free base, by oral or parenteral administration route, 1 to 4 times daily, or on / off schedule. In some cases, it may be more appropriate to administer lower doses than those mentioned above, higher doses than those mentioned above if they do not cause adverse side effects, and if a significantly larger dose is administered, administration may be carried out daily in several divided doses with smaller doses per administration.

[0128] The pharmaceutical compositions according to the present invention can be prepared in various formulations for oral administration or parenteral administration by conventional methods, for example, tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc.

[0129] The pharmaceutical compositions may contain any conventional non-toxic pharma- ceutically acceptable excipients, including carriers, diluents, adjuvants, and vehicles.

[0130] When the pharmaceutical composition of the present invention is prepared as a formulation for oral administration, the carrier used may include, but is not limited to, cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactant, suspending agent, emulsifier, diluent, and combinations thereof.In addition, when the pharmaceutical composition is prepared as a formulation for oral administration, the diluent used may include, but is not limited to, lactose, mannitol, sugar, microcrystalline cellulose, cellulose derivatives, corn starch, and combinations thereof.The formulation for oral administration may also include, but is not limited to, polymers (e.g., hydrophilic polymers such as polyvinylpyrrolidone), antioxidants, preservatives, wetting agents, lubricants, glidants, processing aids, granulating agents, dispersing agents, coloring agents, flavoring agents.

[0131] Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. The tablets can be optionally coated or scored. The tablets can be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used alone or with a wax, optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0132] When the pharmaceutical composition of the present invention is prepared as an injectable preparation, the carrier used includes, for example, but is not limited to, water, physiological saline, aqueous glucose solution, aqueous sugar solution, alcohol, glycol (e.g., polyethylene glycol 400), ether, oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifying agent, and combinations thereof.

[0133] When the binding target is in the brain, certain embodiments of the present invention provide a form of the compound of formula (I) that can cross the blood-brain barrier.Certain neurodegenerative diseases are associated with increased permeability of the blood-brain barrier, so that the compound of formula (I) can be easily introduced into the brain.When the blood-brain barrier remains intact, there are several approaches known in the art to transport molecules across it, including but not limited to physical methods, lipid-based methods, receptor- and channel-based methods.

[0134] Physical methods of transporting a compound of formula (I) across the blood-brain barrier include, but are not limited to, bypassing the blood-brain barrier entirely or creating an opening in the blood-brain barrier.

[0135] Bypass methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial injection / convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of a delivery device into the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers, Guildford).

[0136] Methods for creating openings in the barrier include, but are not limited to, ultrasound methods (see, e.g., U.S. Patent Application Publication No. 2002 / 0038086), osmotic methods (e.g., by administration of hyperosmolar mannitol (Neuwelt, EA, Implications of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, NY, 1989)), and permeabilization, for example, with bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0137] Lipid-based methods of transporting a compound of formula (I) across the blood-brain barrier include, but are not limited to, encapsulating a compound of formula (I) in a liposome coupled to an antibody binding fragment that binds to a receptor on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Application Publication No. 2002 / 0025313), and coating a compound of formula (I) with low density lipoprotein particles (see, e.g., U.S. Patent Application Publication No. 2004 / 0204354) or apolipoprotein E (see, e.g., U.S. Patent Application Publication No. 2004 / 0131692).

[0138] Receptor and channel-based methods of transporting the compounds of formula (I) across the blood-brain barrier include, but are not limited to, increasing the permeability of the blood-brain barrier using glucocorticoid blockers (see, e.g., U.S. Patent Application Publication Nos. 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533); activating potassium channels (see, e.g., U.S. Patent Application Publication No. 2005 / 0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Application Publication No. 2003 / 0073713), coating the compounds of formula (I) with transferrin to modulate the activity of one or more transferrin receptors (see, e.g., U.S. Patent Application Publication No. 2003 / 0129186), and cationizing antibodies (see, e.g., U.S. Patent Application Publication No. 5,004,697).

[0139] For intracerebral use, in certain embodiments, the pharmaceutical composition can be administered continuously by infusion into a fluid reservoir of the CNS, although bolus injections may be acceptable. The pharmaceutical composition can be administered into the ventricles or otherwise introduced into the CNS or spinal fluid. Administration can be performed by using a means of continuous administration, such as an indwelling catheter and pump, or can be administered by implantation, for example intracerebral implantation of a sustained release vehicle. More specifically, the pharmaceutical composition can be injected through a chronically implanted cannula or chronically infused with the aid of an osmotic minipump. Subcutaneous pumps are available that deliver proteins through small tubes into the ventricles. Highly sophisticated pumps can be refilled through the skin, and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems, including subcutaneous pump devices or continuous intraventricular infusion via fully implanted drug delivery systems, are those used to administer dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models of Parkinson's disease, as described in Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143, 1987.

[0140] The present invention will be described in more detail below with reference to examples. However, these examples are for illustrative purposes only, and the present invention is not intended to be limited by these examples.

[0141] [PXRD analysis apparatus and method]

[0142] PXRD analysis of the samples was performed using a D8 Advance (Bruker ASX, Germany) analyzer in the range of 3°2θ to 40°2θ. If the amount of a given sample was less than 100 mg, approximately 5 mg to 10 mg of the sample was gently pressed onto a glass slide mounted on a sample holder. If the amount of a given sample was greater than 100 mg, approximately 100 mg of the sample was gently pressed onto a plastic sample holder such that the sample surface was flat and just above the sample holder level.

[0143] Measurements were performed as follows: Anode material (Kα): CuKα (1.54056 Å). Scan range: 3°-40°. Generator settings: 100 mA, 40.0 kV. Scan speed: 1 sec / step. Diver slit: 0.3°. Anti-scatter slit: 0.3°. Temperature: 20°C. Step size: 0.02° 2θ. Rotation: used. Goniometer radius: 435 mm.

[0144] [Differential scanning calorimetry (DSC) analysis device and method]

[0145] Differential scanning calorimetry (DSC) analysis was carried out at 30 °C to 350 °C on a STA-1000 (Scinco, Korea). Samples in the amount of 5 mg to 10 mg were weighed and added to an aluminum DSC fan, and the fan was sealed in a non-hermetic manner with a perforated aluminum lid. The samples were then heated from 30 °C to 350 °C at a scan rate of 10 °C / min, and the generated heat flow reaction was monitored by DSC.

[0146] [Dynamic Vapor Sorption (DVS) Analysis Apparatus and Method]

[0147] Dynamic vapor sorption (DVS) analysis was carried out on a DVS Advantage (Surface Measurement Systems, UK) analyzer at 25 °C and relative humidity between 0% and 90%. A sample amount of 10 mg was placed in a wire mesh vapor sorption balance pan and then mounted on the DVS Advantage Dynamic Vapor Sorption Balance via the Surface Measurement System. The sample was subjected to a gradient profile of relative humidity from 0% to 90% in 10% increments, maintaining the sample at each step until a stable weight was achieved (99.5% step complete). Once the sorption cycle was completed, the sample was dried using the same process, while maintaining the relative humidity at 0%. The change in sample weight during the adsorption / desorption cycle (repeated three times) was recorded to measure the hygroscopicity of the sample. DVS isotherm diagrams are shown in Figures 1, 3, 6, 10, 13, 16 and 19. Here, Target PP (%) refers to relative humidity, "SORP" refers to adsorption and "DESORP" refers to desorption. EXAMPLES

[0148] [Preparation of crystalline forms of the salt of the compound of formula (I)]

[0149] Example 1: Salt Screening of Formula (I)

[0150] Various salt forms of formula (I) were prepared from the free base of formula (I) and characterized by water solubility, PXRD, DSC, DVS and hygroscopicity.

[0151] Example 1A: Evaluation of the pKa value of the bis-hydrochloride salt of formula (I)

[0152] The bishydrochloride salt of formula (I) was prepared as described below. The pKa values ​​were measured by the GLpKa method and determined to be 3.86 (pKa1), 4.73 (pKa2), and 10.30 (pKa3). Based on these pKa values, formula (I) is considered to be a weakly basic compound.

[0153] Example 1B: Preparation and Evaluation of Acid Salts of Formula (I)

[0154] For each salt of Example 1B, a mixture of 40 mL (20 v / w) of an appropriate solvent and 2 g of the free base of formula (I) was stirred at room temperature. The indicated acid (2.2 equivalents) was added to the mixture and salt formation was monitored by visual inspection. The resulting solid bis-acid salt was stirred at room temperature for 24 hours, then filtered and washed with an appropriate solvent.

[0155] The bis hydrochloride salt of formula (I) was prepared and characterized by PXRD, DSC and DVS.

[0156] The PXRD results for the bis-hydrochloride salt are shown in Figure 34 and Table 1, the DSC results are shown in Figure 2, and the DVS results are shown in Figure 3. In Table 1, the diffraction angles are reported in 2θ degrees, the d values ​​are reported in Angstroms, and the intensities are reported in counts / second.

[0157] Table 1

[0158] TIFF0007672372000005.tif72162

[0159] 2θ: diffraction angle; d: distance between crystal planes; I / I0 (%): relative intensity (I indicates the intensity of each peak; I0 indicates the intensity of the highest peak)

[0160] The hygroscopicity of the bis-hydrochloride salt of formula (I) was measured at 25° C. and 75% RH and the water content was determined to increase from 6.2% to 11.7%.

[0161] The bishydrogen sulfate salt of formula (I) was prepared and characterized by PXRD, DSC and DVS.

[0162] The PXRD results of the bishydrogen sulfate are shown in FIG. 4 and Table 2, the DSC results are shown in FIG. 5, and the DVS results are shown in FIG.

[0163] Table 2

[0164] TIFF0007672372000006.tif71165

[0165] The hygroscopicity of the bishydrogen sulfate of formula (I) was measured at 25° C. and 75% RH and the water content was determined to increase from 2.6% to 17.1%.

[0166] The bismethanesulfonate salt of formula (I) was prepared and characterized by PXRD, DSC and DVS.

[0167] The PXRD results of the bismethanesulfonate salt are shown in FIG.

[0168] Table 3

[0169] TIFF0007672372000007.tif37164

[0170] The bisbenzenesulfonate salt of formula (I) was prepared and characterized by PXRD, DSC and DVS.

[0171] The PXRD results for the bisbenzenesulfonate salt are shown in Figure 8. The characteristic peaks at 2θ±0.2 degrees are shown at 7.17 and 7.58.

[0172] The bis hydrobromide salt of formula (I) was prepared and characterized by PXRD, DSC and DVS.

[0173] The PXRD results for the bis hydrobromide salt are shown in Figure 9, which indicates that the salt is amorphous.

[0174] The water content, water solubility (mg / mL), appearance, salt yield (%) and PXRD results of each salt of Example 1B are summarized in Table 4. In the table, "MsOH" refers to methanesulfonic acid; "BsOH" refers to benzenesulfonic acid; "OW" refers to off-white; "W" refers to white; "Cryst" refers to crystalline; "Amorph" refers to amorphous. Solubility was measured by HPLC according to the general chapters of KP, USP and EP. In summary, the salts were generally poorly soluble in water, very poorly soluble in buffers with pH 1.6, and poorly soluble in buffers with pH greater than 3.

[0175] Table 4

[0176] TIFF0007672372000008.tif48140

[0177] Example 2: Physicochemical properties of polymorphic form I of the crystalline bis-hydrochloride salt of formula (I)

[0178] Polymorphic Form I of the bis-hydrochloride salt of formula (I) was prepared by the method of Example 3.

[0179] The physicochemical properties of Form I of the bis-hydrochloride salt of formula (I) were determined including appearance, hygroscopicity, pH of aqueous solutions, melting point / thermal analysis, dissociation constant, partition coefficient and morphology (i.e., crystalline or amorphous).

[0180] The appearance was evaluated according to the test detailed in the Korean Pharmacopoeia, 10th edition. The appearance was determined to be a light brown or off-white powder.

[0181] The solubility was measured by HPLC according to the general chapters of KP, USP and EP. The bis-hydrochloride salt of formula (I) was very poorly soluble in buffers of pH 1.2 and pH 2.0, and practically insoluble in buffers above pH 3.0 and in water. The bis-hydrochloride salt of formula (I) was freely soluble in dimethylsulfoxide ("DMSO"), sparingly soluble in methanol, very poorly soluble in ethanol, and practically insoluble in dichloromethane, ACN, ethyl acetate, n-hexane, and ethyl ether. The solubility results were the same between the HPLC test and the observation test. The solubility results from the HPLC test and the observation test are shown in Table 5.

[0182] Table 5

[0183] TIFF0007672372000009.tif153149

[0184] Hygroscopicity was measured by DVS and the DVS curve of the bis-hydrochloride salt of formula (I) was recorded on a DVS Advantage I analyzer (SMS, UK). The DVS was operated at 25° C. from 0% RH to 90% RH over three cycles to measure the surface adsorption effect of water. Figure 10 shows the water sorption behavior of the bis-hydrochloride salt form I of formula (I).

[0185] The DVS results show the change in water content (%) due to water absorption and desorption from 0% RH to 90% RH. Water absorption occurred rapidly (about 9.4% from 0% RH to 20% RH), and then the water absorption rate increased to 14.1% from 20% RH to 90% RH. Water desorption occurred slowly from 90% RH to 10% RH to about 5.2%, and then water desorption rapidly decreased to about 8.9% from 10% RH to about 0% RH. The water content results were reproducible during the absorption-desorption process. It was confirmed that the water absorption was about 14.1% from 0% RH to 90% RH. The DVS chart of the bishydrochloride salt of formula (I) is shown in Figure 10.

[0186] The pH of the aqueous solutions was measured by preparing 0.01%, 0.1%, and 1% aqueous solutions of the bishydrochloride salt of formula (I) and then shaking the solutions at room temperature for 30 minutes before filtering. The pH of the filtered aqueous solutions was measured with a S2K713 pocket pH meter (ISFETCOM, Japan) according to the method of the Korean Pharmacopoeia.

[0187] The pH of an aqueous solution of the bis-hydrochloride salt of formula (I) (concentration=1%) was about 1.8 at room temperature. The pH decreased with concentration. The pH of a 0.1 mg / mL (0.01%) solution was 3.9; the pH of a 1 mg / mL (0.1%) solution was 2.6; and the pH of a 10 mg / mL (1%) solution was 1.8.

[0188] Melting point and thermal analysis were measured by DSC, and the DSC thermogram of the bis-hydrochloride salt of formula (I) was recorded on a STA S-1000DSC (Scinco, Korea) operated at a rate of 10°C / min. The DSC curves were obtained from 30°C to 350°C in a standard aluminum cup.

[0189] The results of the DSC thermogram show that the melting point (decomposition point) of the bis-hydrochloride salt of formula (I) is between 197 °C and 225 °C. A weight loss and broad endothermic peak caused by volatile substances was observed between 40 °C and 150 °C, and another endothermic peak caused by melting and decomposition was observed between 197 °C (onset) and 225 °C (maximum). The bis-hydrochloride salt of formula (I) decomposed between 230 °C and 233 °C by visual observation. The DSC plot is shown in Figure 11.

[0190] Polymorphic Form I of the crystalline bis-hydrochloride salt of formula (I) is believed to be a trihydrate. As shown in FIG. 11, in the TGA / DSC test, a weight loss of about 10% was observed between 40° C. and 150° C., which is due to water loss. The initial amount of water was confirmed by Karl Fischer titration. The amount of water lost in the TGA / DSC test is generally believed to correspond to the theoretical amount of water in the trihydrate of 8.92%. This conclusion was reached even though the water content in the production batches of the bis-hydrochloride salt of formula (I) was higher than the theoretical value (8.92%) (e.g., about 9 to 13% water). Without being bound to any particular theory, it is believed that the water content above about 8.92% results from excess water that is likely derived from the humidification process used to obtain the trihydrate. One example of such a process is as follows: (i) filtering the bis-hydrochloride salt of formula (I) (as the trihydrate) precipitated in the final crystallization step; (ii) drying the filtered wet cake to remove residual organic solvent at elevated temperature (which is believed to remove some of the water corresponding to the trihydrate); and (iii) restoring to the trihydrate by a humidification step. It is believed that the polymorphic form I of the bis-hydrochloride salt in the production batch remains as the trihydrate, despite the water content being greater than about 8.92%.

[0191] As shown in Figure 10, the DVS analysis indicates that the water content of polymorphic Form I of the bis-hydrochloride trihydrate of formula (I) changed from about 9% to about 14% at 20% to 90% relative humidity, and from about 14% to about 9% at 90% to 20% relative humidity. Without being bound to any particular theory, it is believed that the water content above about 8.92% (up to about 5% excess water for a total water content of about 14%) resulted from adsorption of water to the trihydrate and not from the formation of the tetrahydrate by crystallization (the tetrahydrate can have a theoretical water content of about 11.6%). This is because the PXRD spectrum of the trihydrate sample did not change with up to about 5% additional water content.

[0192] The dissociation pKa was measured with a T3 (Sirius Analytical Instrument Ltd., UK). Approximately 1 mg of the bishydrochloride salt of formula (I) was transferred to a GLpKa beaker and dissolved in 43% to 53% MDM solution (ISA water / MeOH / ACN / p-dioxane = 40 / 20 / 20 / 20, Sirius), adjusted to pH 1.8 with 0.5 N HCl, and titrated to pH 12.2 with 0.5 N KOH. The pKa in aqueous solution was calculated by extrapolation.

[0193] The dissociation constants (pKa) of the bis-hydrochloride salt of formula (I) were determined to be 3.86 (pKa1), 4.73 (pKa2), and 10.30 (pKa3) in aqueous solution. The dissociation constant data is shown in Table 6.

[0194] Table 6

[0195] TIFF0007672372000010.tif25166

[0196] The partition coefficient LogP was measured on a T3 (Sirius Analytical Instrument Ltd., UK). Approximately 1 mg of the bishydrochloride salt of formula (I) was added to a 15 mL GLpKa beaker, dissolved in octanol / 150 mM KCl, adjusted to pH 1.8 with 0.5 N HCl and titrated to pH 12.2 with 0.5 N KOH. The partition coefficient in the octanol-water system was determined by correcting the difference between the titration curve and the blank titration curve by inserting the value of the previously measured dissociation constant.

[0197] The partition coefficient (LogD) of the bis-hydrochloride salt of formula (I) was determined to be 5.24 at pH 7.4, and the partition ratio of the bis-hydrochloride salt of formula (I) in octanol versus aqueous phase was determined to be about 200,000 to 1. The bis-hydrochloride salt of formula (I) exists in a neutral state at pH 11 or higher, with a LogP of 4.33, and the partition ratio of the bis-hydrochloride salt of formula (I) in octanol versus aqueous phase is about 200,000 to 1. The partition coefficient results of the bis-hydrochloride salt of formula (I) are shown in Table 7.

[0198] Table 7:

[0199] TIFF0007672372000011.tif78149

[0200] The solid form (crystalline or amorphous) was determined by PXRD recorded on a D8 ADVANCE manufactured by BRUKER AXS, Germany, operating at 25° C., 40.0 KV and 100 mA using CuKα (1.54056 Å) radiation and spin.

[0201] The bishydrochloride salt of formula (I) has a crystalline form, as shown in Figure 1. The peak data of the diffraction pattern is shown in Table 8.

[0202] Table 8

[0203] TIFF0007672372000012.tif40149

[0204] Example 3: Preparation of the crystalline form of the dihydrochloride salt of the compound of formula (I) (Form I)

[0205] The crude dihydrochloride salt of compound of formula (I) (98.3% purity) was prepared from the free base of formula (I) prepared according to the method disclosed in WO 2013 / 100632, incorporated herein by reference, or an analogous method thereto, incorporated herein by reference. 200 g of compound of formula (I) and 10 L of methanol were placed in a 20 L reactor, followed by activated carbon (20 g). The reaction mixture was heated to 40-45° C. and then stirred for 2 hours. The reaction mixture was cooled to about 30° C., filtered through a pad of celite and washed with 1 L of methanol. The filtrate was concentrated in vacuo. The residue was suspended in 4.0 L of 80% aqueous ethanol, and then concentrated HCl solution was added. The mixture was stirred at reflux for 2 hours and then cooled to 30° C. to form a precipitate. The precipitate was filtered for 4 hours and then washed with 2.0 L of ethanol. The filtered solid was dried in a vacuum oven at 50° C. for 24 hours. The dried solid was ground and stored overnight in a humidity chamber (40° C., 75% RH). Yield: 198 g (99.0%); Moisture: 12%; HCl content by ion chromatography IC: 13.0% (theoretical 13.0% for 2HCl).

[0206] [Characteristics Analysis]

[0207] The results of the PXRD analysis of the crystalline form prepared in Example 3 are shown in FIG. 35, the DSC results in FIG. 12, and the DVS results in FIG.

[0208] Form I was characterized by a melting point with an onset temperature (DSC) of about 221° C. (FIG. 12).

[0209] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 9. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 5.89°, 7.77°, 8.31°, 11.80°, 16.68°, 23.22°, 23.69°, 26.89°, 27.51°, 28.29°, and 29.53° (2θ±0.2°).

[0210] Table 9

[0211] TIFF0007672372000013.tif131165

[0212] Example 4: Preparation of a crystalline form of the dihydrochloride salt of the compound of formula (I) (Form II)

[0213] 25 g of the crystalline form of the dihydrochloride salt of compound of formula (I) (Form I) prepared in Example 3 was placed in a reactor, followed by the addition of 500 mL of methanol and 750 mL of THF. The resulting suspension was heated at reflux for 18 hours. The reaction mixture was cooled to 20-25°C. The resulting precipitate was filtered and then washed with 125 mL of THF. The filtered solid was dried in a vacuum oven at 50°C for 21 hours. The resulting solid was crushed and stored in a humidity chamber (25°C, 60% RH) for 21 hours. Yield: 17.8 g (71.0%); Moisture: 13.9%; HCl content by IC: 13.2% (theoretical 13.0% for 2HCl).

[0214] [Characteristics Analysis]

[0215] The results of the PXRD analysis of the crystalline form prepared in Example 4 are shown in FIG. 14, the DSC results in FIG. 15, and the DVS results in FIG.

[0216] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 10. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 6.19°, 6.55°, 7.00°, 9.01°, 9.85°, 11.64°, 12.86°, 14.05°, and 25.31° (2θ±0.2°).

[0217] Form II was characterized by a melting point with an onset temperature (DSC) of about 213° C. (FIG. 15).

[0218] Table 10

[0219] TIFF0007672372000014.tif54163

[0220] Example 5: Preparation of a crystalline form of the dihydrochloride salt of the compound of formula (I) (Form III)

[0221] 25 g of the crystalline form of the dihydrochloride salt of compound of formula (I) (Form I) prepared in Example 3 was placed in a reactor, followed by the addition of 500 mL of methanol and 750 mL of IPA. The resulting suspension was heated at reflux for 18 hours. The reaction mixture was cooled to 20-25°C. The resulting precipitate was filtered and then washed with 125 mL of IPA. The filtered solid was dried in a vacuum oven at 50°C for 21 hours. The resulting solid was crushed and stored in a humidity chamber (25°C, 60% RH) for 21 hours. Yield: 18.4 g (74.0%); Moisture: 0.4%; ID: and HCl content was 13.2% (theoretical value as 2HCl 13.0%); Residual solvent: 2% methanol.

[0222] [Characteristics Analysis]

[0223] The results of the PXRD analysis of the crystalline form prepared in Example 5 are shown in FIG. 17, the DSC results in FIG. 18, and the DVS results in FIG.

[0224] Form II was characterized by a melting point with an onset temperature (DSC) of about 254° C. (FIG. 18).

[0225] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 11. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 6.01°, 9.00°, 11.47°, 12.05°, 14.48°, 16.33°, 16.83°, 18.13°, 19.01°, 19.26°, 22.63°, 23.10°, 24.51°, 25.31°, 25.94°, 26.51°, 27.10°, 28.12°, 30.47°, and 31.25° (2θ±0.2°).

[0226] Table 11

[0227] TIFF0007672372000015.tif156162

[0228] Example 6: Preparation of a crystalline form of the dihydrochloride salt of the compound of formula (I) (Form IV)

[0229] 5 g of the crystalline form of the dihydrochloride salt of compound of formula (I) (Form I) prepared in Example 3 was placed in a reactor, followed by the addition of 50 mL of DMF. The mixture was heated at reflux for 1 hour. The reaction mixture was cooled to 20-25° C. Seeding compound was added at 20-25° C. The resulting solid was stirred at 20-25° C. for 24 hours, filtered, and then washed with 50 mL of n-heptane. The filtered solid was dried in a vacuum oven at 50° C. for 21 hours. Yield: 0.72 g (14.4%); residual solvent: 2.1% DMF.

[0230] [Characteristics Analysis]

[0231] The results of the PXRD analysis of the crystalline form prepared in Example 6 are shown in FIG.

[0232] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 12. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 5.56°, 6.64°, 7.15°, 9.07°, 11.22°, 11.76°, 12.12°, 13.30°, 14.28°, 15.57°, 17.26°, 18.2°, 22.3°, 22.9°, 23.7°, 24.8°, 25.1°, 25.9°, 28.2°, 29.9°, 31.3°, and 34.2° (2θ±0.2°).

[0233] Table 12

[0234] TIFF0007672372000016.tif83163

[0235] Example 7: Preparation of a crystalline form of the dihydrochloride salt of the compound of formula (I) (Form V)

[0236] 20 g of the free base of the compound of formula (I) (99.7% purity, <0.1% HO) was placed in a reactor, followed by the addition of 300 mL of DMF. The mixture was heated to 140°C. The reaction mixture was cooled to 80°C, followed by the addition of 8 mL of concentrated HCl. The resulting solid was stirred at 20-25°C for 2.5 hours, filtered, and then washed with 50 mL of n-heptane. The filtered solid was dried in a vacuum oven at 50°C for 21 hours. Yield: 26 g (110%); residual solvent: 12.4% DMF.

[0237] [Characteristics Analysis]

[0238] The results of the PXRD analysis of the crystalline form prepared in Example 7 are shown in FIG.

[0239] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 13. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 5.44°, 6.58°, 7.48°, 9.22°, 10.84°, 11.47°, 12.45°, 13.17°, 16.61°, 17.18°, 17.92°, 18.52°, 22.21°, 23.07°, 23.84°, 24.70°, 25.37°, 26.08°, 27.33°, 29.12°, 31.02°, 31.43°, 34.65°, and 37.46° (2θ±0.2°).

[0240] Table 13

[0241] TIFF0007672372000017.tif94163

[0242] Example 8: Preparation of a crystalline form of the dihydrochloride salt of the compound of formula (I) (Form VI)

[0243] 20 g of the crystalline form of the dihydrochloride salt of compound of formula (I) (Form I) prepared in Example 1 was dried in a vacuum oven at 50° C. for 24 hours. Yield: 17.4 g (87.0%); Moisture: 0.7%.

[0244] [Characteristics Analysis]

[0245] The results of the PXRD analysis of the crystalline form prepared in Example 8 are shown in FIG. 22, and the DSC results are shown in FIG.

[0246] Form VI was characterized by a melting point with an onset temperature (DSC) of about 220° C. (FIG. 23).

[0247] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are shown below in Table 14. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 8.5° and 8.9° (2θ±0.2°).

[0248] Table 14

[0249] TIFF0007672372000018.tif46161

[0250] Example 9: Preparation of polymorphic Form I of the bis-hydrochloride salt of formula (I) from Form VI

[0251] Crystalline Form VI was converted to Form I in two ways. In the first method, Form VI was exposed to 60% relative humidity at 25° C. In the second method, Form VI was exposed to 20% relative humidity at 21° C. The PXRD results for the conversion of Form VI to Form I are shown in FIG. 24. Depicted are (i) Form I; (ii) Form VI prepared by drying Form I in a vacuum oven at 50° C. for 24 hours; (iii) Form VI exposed to 21° C. and 20% RH for 3 hours resulting in a moisture content of 8.0%; (iv) Form VI exposed to 21° C. and 20% RH for 6 hours resulting in a moisture content of 10.4%; (v) Form V exposed to 21° C. and 20% RH for 5 days resulting in a moisture content of 10.1%; and (vi) Form VI exposed to 25° C. and 60% RH resulting in a moisture content of 11.3%.

[0252] Example 10: Summary of Interconversion of the Bis-hydrochloride Polymorphs of Formula (I)

[0253] FIG. 25 summarizes the interconversion of polymorphic Form I of the bis-hydrochloride salt of Formula (I) with Forms II-VI, as well as to amorphous bis-hydrochloride salt of Formula (I), described in this Example.

[0254] Example 11: Preparation of the crystalline form of the disulfate salt of the compound of formula (I)

[0255] 500 mg of the free base of the compound of formula (I) was placed in a reactor, followed by the addition of 10 mL of 80% methanol (MeOH). To the suspension mixture was added sulfuric acid (2.2 equivalents). The resulting solid was stirred at 20-25°C for 12 hours. The resulting solid was filtered, followed by washing with 10 mL of 80% MeOH. The filtered solid was dried in a vacuum oven at 50°C for 18 hours. 648 mg of the title compound was obtained (yield: 92%).

[0256] [Characteristics Analysis]

[0257] The results of the PXRD analysis of the crystalline form prepared in Example 11 are shown in FIG.

[0258] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 15. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 5.7°, 7.4°, 7.9°, 9.4°, 11.5°, 13.7°, 15.0°, 15.9°, 16.9°, 17.7°, 18.5°, 18.9°, 20.3°, 20.9°, 21.6°, 22.4°, 22.9°, 23.3°, 24.0°, 24.4°, 24.6°, 25.3°, 25.9°, 26.5°, 27.3°, 28.7°, and 33.7° (2θ±0.2°).

[0259] Table 15

[0260] TIFF0007672372000019.tif138156

[0261] Example 12: Preparation of the crystalline form (Form A) of the di(p-toluenesulfonate) salt of the compound of formula (I) Step 1: Preparation of the amorphous form of the di(p-toluenesulfonate) salt of the compound of formula (I)

[0262] 0.5 g of the free base of the compound of formula (I) was placed in a reactor, followed by the addition of 10 mL of acetone (AC). To the suspension mixture was added p-toluenesulfonic acid monohydrate (2.2 eq.). The resulting solid was stirred at 20-25°C for 24 hours, then filtered, and washed with 2.5 mL of AC. The filtered solid was dried in an oven at 50°C for 18 hours. Yield: 0.3 g (35%).

[0263] Step 2: Preparation of the crystalline form (Form A) of the di(p-toluenesulfonate) salt of the compound of formula 2

[0264] 15 g of the amorphous form of compound of formula (I) was placed in a reactor, then 300 mL of ethyl acetate (EA) was added. The suspension mixture was stirred at reflux for 24 hours, filtered, then washed with 75 mL of EA. The filtered solid was dried in a vacuum oven at 50° C. for 18 hours. Yield: 11 g (73%)

[0265] [Characteristics Analysis]

[0266] The results of the PXRD analysis of the crystalline form prepared in Example 12 are shown in FIG.

[0267] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 16. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 3.2°, 4.5°, 7.7°, 8.4°, 9.0°, 11.7°, 13.2°, 13.6°, 14.1°, 15.3°, 15.8°, 16.7°, 17.4°, 18.8°, 19.9°, 21.7°, 21.9°, 22.3°, 23.0°, 23.5°, 24.6°, 24.7°, 25.6°, 27.4°, and 29.0° (2θ±0.2°).

[0268] Table 16

[0269] TIFF0007672372000020.tif121152

[0270] Example 13: Preparation of the crystalline form (Form B) of the di(p-toluenesulfonate) salt of compound of formula (I) 3 g of the free base of the compound of formula (I) was placed in a reactor, followed by the addition of 50 mL of ACN. To the suspension mixture was added p-toluenesulfonic acid monohydrate (2.2 eq.) in ACN (10 mL). The resulting solid was stirred at 20-25° C. for 24 hours, filtered, and then washed with 50 mL of ACN. The filtered solid was dried in an oven at 50° C. for 18 hours. Yield: 4.92 g (95%).

[0271] [Characteristics Analysis]

[0272] The results of the PXRD analysis of the crystalline form prepared in Example 13 are shown in FIG.

[0273] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 17. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 5.7°, 7.8°, 9.3°, 11.4°, 11.6°, 12.5°, 12.9°, 13.2°, 14.0°, 15.0°, 15.8°, 16.0°, 17.0°, 17.5°, 18.8°, 19.2°, 19.8°, 20.5°, 21.0°, 21.4°, 21.9°, 22.4°, 22.8°, 23.4°, 24.2°, 24.9°, 26.2°, 27.2°, 28.1°, 29.1°, and 31.6° (2θ±0.2°).

[0274] Table 17

[0275] TIFF0007672372000021.tif163156

[0276] Example 14: Preparation of the crystalline form of the diethanesulfonic acid salt of the compound of formula (I) Step 1: Preparation of the crude diethanesulfonic acid salt of compound of formula (I)

[0277] 10 g of the free base of the compound of formula (I) was placed in a reactor, followed by the addition of 200 mL of ethanol (EtOH). To the suspension mixture was added ethanesulfonic acid (2.2 eq.). The resulting solid was stirred at reflux for 12 hours and then at 20-25°C for 2 hours. The resulting solid was filtered and then washed with 50 mL of EtOH. The filtered solid was dried in an oven at 50°C for 18 hours. Yield: 12 g (80%).

[0278] Step 2: Preparation of the crystalline form of the diethanesulfonate salt of the compound of formula (I)

[0279] 12 g of the crude diethanesulfonate salt of compound of formula (I) was placed in a reactor, followed by 240 mL of EtOH. The resulting solid was stirred at reflux for 12 hours, then at 20-25° C. for 2 hours. The resulting solid was filtered, then washed with 60 mL of EtOH. The filtered solid was dried in an oven at 50° C. for 18 hours. Yield: 11 g (92%).

[0280] [Characteristics Analysis]

[0281] The results of the PXRD analysis of the crystalline form prepared in Example 14 are shown in FIG.

[0282] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 18. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 5.7°, 6.8°, 7.4°, 11.5°, 14.8°, 15.2°, 17.6°, 18.4°, 20.2°, 20.5°, 22.1°, 22.3°, 23.2°, 23.6°, 23.8°, 25.2°, 25.6°, 25.8°, 26.4°, 27.5°, 28.1° and 28.8° (2θ±0.2°).

[0283] Table 18

[0284] TIFF0007672372000022.tif240170

[0285] Example 15: Preparation of a crystalline form of the dimethanesulfonate salt of the compound of formula (I) Step 1: Preparation of the crude dimethanesulfonate salt of compound of formula (I)

[0286] 3 g of the free base of the compound of formula (I) was placed in a reactor, followed by the addition of 60 mL of EtOH. To the suspension mixture was added methanesulfonic acid (2.2 eq.). The resulting solid was stirred at reflux for 18 h and then at 20-25° C. for 2 h. The resulting solid was filtered and then washed with 15 mL of EtOH. The filtered solid was dried in an oven at 80° C. for 18 h. Yield: 4.25 g (101%).

[0287] Step 2: Preparation of the Crystalline Form of the Dimethanesulfonate Salt of the Compound of Formula (I)

[0288] 3.6 g of the crude dimethanesulfonate salt of compound of formula (I) was placed in a reactor, followed by the addition of 72 mL of EtOH. To the suspension mixture was added methanesulfonic acid (2.0 equiv.). The resulting solid was stirred at reflux for 18 h and then at 20-25° C. for 2 h. The resulting solid was filtered and then washed with 18 mL of EtOH. The filtered solid was dried in an oven at 80° C. for 18 h. Yield: 3.68 g (102%).

[0289] [Characteristics Analysis]

[0290] The results of the PXRD analysis of the crystalline form prepared in Example 15 are shown in FIG.

[0291] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are given below in Table 19. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 5.6°, 7.1°, 7.6°, 11.4°, 15.1°, 15.4°, 16.6°, 18.2°, 20.4°, 21.5°, 22.3°, 22.7°, 23.1°, 24.4°, 24.9°, and 25.6° (2θ±0.2°).

[0292] Table 19

[0293] TIFF0007672372000023.tif222154

[0294] Example 16: Preparation of a crystalline form of the free base of the compound of formula (I) 200.0 g of the crystalline form of the dihydrochloride salt (2HCl) of the compound of formula (I) was placed in a 10 L reactor, followed by the addition of 1.0 L of DMSO and 4.0 L of MeOH. The resulting suspension was heated to 55-60° C. and stirred with a mechanical stirrer to dissolve the compound of formula (I). 347 mL of DIPEA was added to the reaction mixture over 2 hours while maintaining the reactor temperature at 55-60° C. and stirring at 200 rpm. The resulting mixture was heated and stirred for 36 hours while maintaining the reactor temperature at 55-60° C. and stirring weakly at 50-60 rpm to form a precipitate. The reaction mixture was cooled to 20-25° C. and then stirred for 6 hours. The formed precipitate was filtered and then washed with 10.0 L of MeOH. The filtered solid was dried in a vacuum oven at 40° C. for 48 hours. Yield: 146g (94.6%).

[0295] [Characteristics Analysis]

[0296] The results of the PXRD analysis of the crystalline form prepared in Example 16 are shown in FIG.

[0297] The peaks having a relative intensity (I / Io) of 3% or greater in the PXRD spectrum of the above crystalline forms are shown below in Table 20. For peaks having an I / Io ratio of 10% or greater, the diffraction angles were 9.2°, 12.7°, 13.8°, and 26.5° (2θ±0.2°).

[0298] Table 20

[0299] TIFF0007672372000024.tif88164

[0300] Comparative Example 1: Preparation of an amorphous form of the free base compound of formula (I)

[0301] The amorphous form of the compound of formula (I) was prepared according to the methods disclosed in WO 2013 / 100632, which is incorporated herein by reference.

[0302] [Characteristics Analysis]

[0303] The results of the PXRD analysis of the amorphous form prepared in Comparative Example 1 are shown in FIG.

[0304] The amorphous form did not show any particular diffraction pattern in the PXRD spectrum.

[0305] Comparative Example 2: Preparation of an amorphous form of the bis-hydrochloride salt of the compound of formula (I)

[0306] 5 g of the bishydrochloride salt of formula (I) (100.2% assay, 12.0% HO) was placed in a reactor, followed by the addition of 25 mL of DMSO. The suspension mixture was heated to 130°C for 1.5 hours to form a yellow clear solution. The reaction mixture was cooled to 20-25°C. 50 mL of acetone was added dropwise at 20-25°C for 15 minutes to form a slurry, the resulting solid was stirred at 20-25°C for 18 hours, then the slurry was filtered and washed with 50 mL of acetone. The filtered solid was dried in a vacuum oven at 50°C for 24 hours. Yield: 4.26 g (85%), moisture: 5.5%, residual solvent: 12% DMSO.

[0307] FIG. 31 shows a PXRD pattern characterized by the absence of sharp peaks, indicating an amorphous form of the bis-hydrochloride salt of formula (I).

[0308] FIG. 32 shows the overlay of the PXRD patterns of crystalline forms I-VI of the bis-hydrochloride salt of formula (I) and amorphous bis-hydrochloride salt of formula (I).

[0309] Test example 1: Stress stability test

[0310] To compare the physicochemical stability between the crystalline forms prepared in Example 3 (crystalline bis-hydrochloride Form I of Formula (I)) and 16 (crystalline free base of Formula (I)) and the amorphous form prepared in Comparative Example 1, stress stability studies were performed by storing the samples at 60° C. for various periods up to 4 weeks. The results are summarized in Table 21 below.

[0311] Table 21

[0312] TIFF0007672372000025.tif46157

[0313] As shown in Table 21 above, the crystalline form of the free base and the crystalline form of the dihydrochloride salt (Form I) exhibited significantly greater stability than the amorphous form, which showed no change in purity after 7 days. Thus, it can be seen that the crystalline form of the present invention exhibits greater physicochemical stability than the amorphous form.

[0314] The stability of the crystalline bis-hydrochloride salt Form I of formula (I) was evaluated at 3, 6, 9, 12, 18 and 24 months under conditions of 20°C-30°C and protection from light at 60% relative humidity. Stability criteria included the following criteria: At each interval from 3 to 24 months, the crystalline bis-hydrochloride salt Form I of formula (I) appeared as a light brown to off-white powder. Characterization was performed by IR, PXRD, and HPLC methods as described elsewhere herein, with results reported as pass / fail. Purity was determined by HPLC using known impurities at relative retention times ("RRT") of 1.1, 1.7, and 2.1. The results are shown in Table 22. In the table, "Init" refers to initial, "Iden" refers to identification, "Imp" refers to impurities, "AUI" refers to any unspecified impurity, "TUI" refers to total unspecified impurities, "TI" refers to total impurities, and "ND" refers to not detected. The PXRD results for initial, 6 month, 12 month and 24 month are shown in FIG.

[0315] Table 22

[0316] TIFF0007672372000026.tif108169

Claims

1. A crystalline form of the compound of formula (I): A compound selected from the pharma- ceutically acceptable salts of A compound which is a bismethanesulfonate salt and is characterized by a powder X-ray diffraction pattern having four or more peaks selected from peaks at diffraction angle 2θ values ​​of 7.1°±0.2°, 7.6°±0.2°, 15.1°±0.2°, 15.4°±0.2°, 18.2°±0.2°, 21.5°±0.2°, 23.1°±0.2°, 24.4°±0.2°, 24.9°±0.2°, and 25.6°±0.2° when irradiated with a Cu-Kα light source.

2. 2. The compound according to claim 1, wherein the bismethanesulfonate salt is characterized by a powder X-ray diffraction pattern having three or more peaks selected from peaks having diffraction angle 2θ values ​​of 7.1°±0.2°, 7.6°±0.2°, 15.4°±0.2°, 18.2°±0.2°, and 23.1°±0.2° when irradiated with a Cu-Kα light source.

3. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2 and at least one pharma- ceutically acceptable excipient.

4. 4. The pharmaceutical composition according to claim 3 for treating an abnormal cell proliferation disorder in a mammal, wherein the abnormal cell proliferation disorder is caused by the abnormal activation of a protein kinase.

Images