Polymorphic compounds and their uses

Abstract

The present invention provides salt forms, as well as compositions and methods thereof, that are useful for treating a variety of conditions, such as cancer, by administering small molecule therapeutic agents that act as kinase inhibitors.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 356,755, filed June 29, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to indazole compounds useful in the treatment of cancer, pharmaceutical compositions comprising one or more such indazole compounds, and methods of using such indazole compounds in the treatment of cancer. [Background technology]

[0003] Kinase inhibitors are used to block the activity of kinases and thereby treat cancer (e.g., by inhibiting the mitotic process). These kinase inhibitors are often small molecules that target kinases to inhibit the development, growth, or spread of cancer.

[0004] However, while various inhibitors of kinases are known, there remains a need for selective inhibitors that can be used to treat diseases, such as hyperproliferative disorders, and that offer one or more advantages over current compounds. These advantages include improved activity and / or efficacy, beneficial kinase selectivity profiles tailored to the respective therapeutic needs, improved side effect profiles, such as fewer unwanted side effects, less intense side effects, or reduced (cyto)toxicity, improved targeting of mutant receptors in abnormal cells, improved physicochemical properties, such as solubility / stability in water, body fluids, and / or pharmaceutical formulations, improved pharmacokinetic properties, such as reduced dosages or simplified dosing regimens, and easier manufacture of drug substances, such as by shortening the synthetic route or facilitating purification.

[0005] Additional small molecule kinase compounds are needed. Summary of the Invention

[0006] The compounds of the present invention and compositions thereof have been found to be useful in treating, preventing, and / or reducing the risk of diseases, disorders, or conditions in kinase-mediated disorders. Such compounds are represented by the following chemical structure: Compound A [ka] A or a pharmaceutically acceptable salt thereof.

[0007] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful in treating a variety of kinase-mediated related diseases, disorders, or conditions, including those described herein. [Brief explanation of the drawings]

[0008] [Figure 1] 1 shows the XRPD pattern of Compound 1, Form I. [Figure 2] 1 shows the XRPD pattern of Compound 2, Form I. [Figure 3] 1 shows the DSC thermogram and TGA trace of Compound 2, Form I. [Figure 4] 1 shows the XRPD pattern of Compound 2, Form II. [Figure 5] 1 shows the XRPD pattern of Compound 2, Form III. [Figure 6] 1 shows the DSC thermogram and TGA trace of Compound 2, Form III. [Figure 7] 1 shows the XRPD pattern of Compound 2, Form IV. [Figure 8] 1 shows the XRPD pattern of Compound 2, Form V. [Figure 9] 1 shows the DSC thermogram and TGA trace of Compound 2, Form V. [Figure 10] 1 shows the XRPD pattern of Compound 2, Form VI. [Figure 11] 1 shows the XRPD pattern of Compound 2, Form VII. [Figure 12]1 shows the DSC thermogram and TGA trace of Compound 2, Form VII. [Figure 13] 1 shows the XRPD pattern of Compound 2, Form VIII. [Figure 14] 1 shows the XRPD pattern of Compound 2, Form IX. [Figure 15] 1 shows the XRPD pattern of Compound 2, Form X. [Figure 16] 1 shows the DSC thermogram and TGA trace of Compound 2, Form X. [Figure 17] 1 shows the XRPD pattern of Compound 2, Form XI. [Figure 18] 1 shows the DSC thermogram and TGA trace of Compound 2, Form XI. [Figure 19] 1 shows the XRPD pattern of Compound 2, Form XII. [Figure 20] 1 shows the DSC thermogram and TGA trace of Compound 2, Form XII. [Figure 21] 1 shows the XRPD pattern of Compound 2, Form XIII. [Figure 22] 1 shows the DSC thermogram and TGA trace of Compound 2, Form XIII. [Figure 23] 1 shows the XRPD pattern of Compound 3, Form I. [Figure 24] 1 shows the XRPD pattern of Compound 4, Form I. [Figure 25] 1 shows the XRPD pattern of Compound 5, Form I. [Figure 26] 1 shows the XRPD pattern of Compound 6, Form I. [Figure 27] 1 shows the XRPD pattern of Compound 7, Form I. [Figure 28] 1 shows the XRPD pattern of Compound 8, Form I. [Figure 29] 1 shows the XRPD pattern of Compound 10, Form I. [Figure 30] 1 shows the XRPD pattern of Compound 11, Form I. [Figure 31] 1 shows the XRPD pattern of Compound 12, Form I. [Figure 32] The XRPD pattern of compound 15 is shown. [Figure 33] 1 shows the DSC thermogram and TGA trace of compound 15. [Figure 34] The XRPD pattern of compound 16 is shown. [Figure 35] 1 shows the DSC thermogram and TGA trace of compound 16. [Figure 36] The XRPD pattern of compound 17 is shown. [Figure 37] 1 shows the DSC thermogram and TGA trace of compound 17. [Figure 38] The XRPD pattern of compound 18 is shown. [Figure 39] 1 shows the DSC thermogram and TGA trace of compound 18. [Figure 40] The XRPD pattern of compound 19 is shown. [Figure 41] 1 shows the DSC thermogram and TGA trace of compound 19. [Figure 42] The XRPD pattern of compound 20 is shown. [Figure 43] 1 shows the DSC thermogram and TGA trace of compound 20. [Figure 44] The XRPD pattern of compound 21 is shown. [Figure 45] 1 shows the DSC thermogram and TGA trace of compound 21. [Figure 46] The XRPD pattern of compound 22 is shown. [Figure 47] 1 shows the DSC thermogram and TGA trace of compound 22. [Figure 48] 1 shows the XRPD pattern of Compound 23, Form I. [Figure 49] 1 shows the DSC thermogram and TGA trace of Compound 23, Form I. [Figure 50] 1 shows the XRPD pattern of Compound 24, Form I. [Figure 51] 1 shows the DSC thermogram and TGA trace of Compound 24, Form I. [Figure 52] 1 shows the XRPD pattern of Compound 25, Form I. [Figure 53] 1 shows the DSC thermogram and TGA trace of Compound 25, Form I. [Figure 54] 1 shows the XRPD pattern of Compound 26, Form I. [Figure 55] 1 shows the DSC thermogram and TGA trace of Compound 26, Form I. [Figure 56] 1 shows the XRPD pattern of Compound 1, Form II. [Figure 57] 1 shows the DSC thermogram and TGA trace of Compound 1, Form II. [Figure 58] 1 shows the XRPD pattern of Compound 3, Form II. [Figure 59] 1 shows the DSC thermogram and TGA trace of Compound 3, Form II. [Figure 60] 1 shows the XRPD pattern of Compound 5, Form II. [Figure 61] 1 shows the DSC thermogram and TGA trace of Compound 5, Form II. [Figure 62] 1 shows the XRPD pattern of Compound 12, Form II. [Figure 63] 1 shows the DSC thermogram and TGA trace of Compound 12, Form II. DETAILED DESCRIPTION OF THE INVENTION

[0009] General Description of Certain Aspects of the Invention International Patent Application No. PCT / US2021 / 065679, filed December 30, 2021, which is incorporated herein by reference in its entirety, describes certain kinase inhibitors, including Compound A below. [ka] A

[0010] Compound A, 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole, is designated as Example 46 in International Patent Application No. PCT / US2021 / 065679.

[0011] The solid forms of Compound A described herein (e.g., as the free base or a salt thereof) exhibit improved properties, such as, for example, water solubility, improved stability, and ease of formulation. Accordingly, the present invention provides salt and free base forms of Compound A.

[0012] As used herein, the term "about" when referring to peaks from XRPD data means 2θ±0.2.

[0013] As used herein, the term "substantially similar" when referring to X-ray powder diffraction patterns in a figure refers to X-ray diffraction patterns that are sufficiently similar that one skilled in the art would understand that the figures represent the same form of the same compound.

[0014] As used herein, the HPLC method for determining organic impurities refers to an ultra-performance liquid chromatography (UPLC) method developed and validated to determine the content and impurities of the compounds described herein. Gradient UPLC analysis is performed using a Waters Cortex C18, 100 x 2.1 mm, 1.6 μm particle size (or equivalent) column, a mobile phase of 0.1% trifluoroacetic acid in water (A) and 0.1% trifluoroacetic acid in acetonitrile (B), and UV detection. Samples are reconstituted in methanol to a target compound concentration of 1.0 mg / mL.

[0015] Additionally, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen with deuterium or tritium, or the replacement of a carbon with 13 C or 14Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0016] Salt form of Compound A In some embodiments, the acid and Compound A are combined to form one of Compounds 1-12 and 23-26, as described below. It is believed that Compounds 1-12 and 23-26 can exist in various physical forms. For example, Compounds 1-12 and 23-26 can exist in solution, suspension, or solid form. In certain embodiments, Compounds 1-12 and 23-26 are in solid form. When Compounds 1-12 and 23-26 are in solid form, they can be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of Compounds 1-12 and 23-26 are described in more detail below.

[0017] Compound 1 (hydrochloride salt of Compound A) According to one embodiment, the present invention provides the hydrochloride salt of Compound A, designated Compound 1. [ka] 1

[0018] Those skilled in the art will understand that hydrochloric acid and Compound A ionically bond to form Compound 1. It is believed that Compound 1 can exist in various physical forms. For example, Compound 1 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 1 is in a solid form. When Compound 1 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0019] In some embodiments, the present invention provides Compound 1 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess hydrochloric acid, excess synthesis reagents, excess Compound A, residual solvent, or other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, the composition is at least about 95% by weight of Compound 1. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 1.

[0020] According to one embodiment, Compound 1 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, with percentages based on the total weight of the composition. According to another embodiment, Compound 1 contains less than or equal to about 3.0 HPLC area percent total organic impurities. The area percent of total organic impurities by HPLC can be assessed by one of ordinary skill in the art using conventional HPLC methods, for example, including a photodiode array detector. In certain embodiments, the HPLC area percent of total organic impurities is less than or equal to about 1.5 relative to the total area of the HPLC chromatogram. In other embodiments, Compound 1 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity relative to the total area of the HPLC chromatogram.

[0021] The structure shown for Compound 1 is also meant to include all tautomeric and isomeric forms of Compound 1.

[0022] It has been found that Compound 1 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0023] In certain embodiments, Compound 1 is a crystalline solid. In other embodiments, Compound 1 is a crystalline solid that is substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound does not contain significant amounts of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 1 is present.

[0024] It has been found that Compound 1 can exist in at least two polymorphic forms.

[0025] In some embodiments, the present invention provides a polymorphic form of Compound 1, referred to herein as Form I. In some embodiments, Form I of Compound 1 is substantially free of other polymorphic forms.

[0026] In certain embodiments, the present invention provides a polymorphic form of Compound 1, herein referred to as Form II. In some embodiments, Form II of Compound 1 is substantially free of other polymorphic forms.

[0027] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1.

[0028] Form I of Compound 1 In some embodiments, Form I of Compound 1 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] 1 In this and all subsequent tables, The position 2θ is within ±0.2.

[0029] In some embodiments, Compound 1 Form I is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 19.9, about 21.9, and about 25.7 degrees 2θ. In some embodiments, Compound 1 Form I is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 19.9, about 21.9, and about 25.7 degrees 2θ. In some embodiments, Compound 1 Form I is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 19.9, about 21.9, and about 25.7 degrees 2θ.

[0030] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0031] A method for preparing Form I of Compound 1 is described below.

[0032] Form II of Compound 1 In some embodiments, Form II of Compound 1 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 2 below. [Table 2-1] [Table 2-2]

[0033] In some embodiments, Form II of Compound 1 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 12.9, about 20.3, and about 22.2 degrees 2θ. In some embodiments, Form II of Compound 1 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 12.9, about 20.3, and about 22.2 degrees 2θ. In some embodiments, Form II of Compound 1 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 12.9, about 20.3, and about 22.2 degrees 2θ.

[0034] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0035] A method for preparing Form II of Compound 1 is described below.

[0036] In some embodiments, the present invention provides Compound 1, wherein the compound is crystalline.

[0037] In some embodiments, the present invention provides Compound 1, wherein said compound is a crystalline solid that is substantially free of amorphous Compound 1.

[0038] In some embodiments, the present invention provides Compound 1, wherein said compound is substantially free of impurities.

[0039] In some embodiments, the present invention provides a composition comprising Form I or Form II of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0040] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I or Form II of Compound 1, or a composition thereof, to the patient.

[0041] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient Form I or Form II of Compound 1, or a composition thereof, wherein Form I or Form II of Compound 1 is a crystalline form described herein. In some embodiments, the present invention provides a method of treating one or more of the diseases, disorders, or conditions described herein.

[0042] Compound 2 (besylate salt of Compound A) According to one embodiment, the present invention provides a besylate salt of Compound A, designated Compound 2. [ka] 2

[0043] Those skilled in the art will understand that benzenesulfonic acid and Compound A ionically bond to form Compound 2. It is believed that Compound 2 can exist in various physical forms. For example, Compound 2 can be in solution, suspension, or solid form. In certain embodiments, Compound 2 is in solid form. When Compound 2 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0044] In some embodiments, the present invention provides Compound 2 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvent, or other impurities that may result from the preparation and / or isolation of Compound 2. In certain embodiments, the composition is at least about 95% by weight of Compound 2. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 2.

[0045] According to one embodiment, Compound 2 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, Compound 2 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 2 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0046] The structure shown for Compound 2 is also meant to include all tautomeric and isomeric forms of Compound 2.

[0047] It has been found that Compound 2 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0048] In certain embodiments, Compound 2 is a crystalline solid. In other embodiments, Compound 2 is a crystalline solid that is substantially free of amorphous Compound 2. As used herein, the term "substantially free of amorphous Compound 2" means that the compound does not contain a significant amount of amorphous Compound 2. In certain embodiments, at least about 95% by weight of crystalline Compound 2 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 2 is present.

[0049] It has been found that compound 2 can exist in at least 13 polymorphic forms.

[0050] In some embodiments, the present invention provides a polymorphic form of Compound 2, referred to herein as Form I. In some embodiments, Form I of Compound 2 is substantially free of other polymorphic forms.

[0051] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein referred to as Form II. In some embodiments, Form II of Compound 2 is substantially free of other polymorphic forms.

[0052] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein referred to as Form III. In some embodiments, Form III of Compound 2 is substantially free of other polymorphic forms.

[0053] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein referred to as Form IV. In some embodiments, Form IV of Compound 2 is substantially free of other polymorphic forms.

[0054] In certain embodiments, the present invention provides a polymorphic form of Compound 2, referred to herein as Form V. In some embodiments, Form V of Compound 2 is substantially free of other polymorphic forms.

[0055] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein designated Form VI. In some embodiments, Form VI of Compound 2 is substantially free of other polymorphic forms.

[0056] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein designated Form VII. In some embodiments, Form VII of Compound 2 is substantially free of other polymorphic forms.

[0057] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein designated Form VIII. In some embodiments, Form VIII of Compound 2 is substantially free of other polymorphic forms.

[0058] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein designated Form IX. In some embodiments, Form IX of Compound 2 is substantially free of other polymorphic forms.

[0059] In certain embodiments, the present invention provides a polymorphic form of Compound 2, referred to herein as Form X. In some embodiments, Form X of Compound 2 is substantially free of other polymorphic forms.

[0060] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein designated Form XI. In some embodiments, Form XI of Compound 2 is substantially free of other polymorphic forms.

[0061] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein designated Form XII. In some embodiments, Form XII of Compound 2 is substantially free of other polymorphic forms.

[0062] In certain embodiments, the present invention provides a polymorphic form of Compound 2, herein designated Form XIII. In some embodiments, Form XIII of Compound 2 is substantially free of other polymorphic forms.

[0063] In some embodiments, Compound 2 is amorphous. In some embodiments, Compound 2 is amorphous and substantially free of crystalline Compound 2.

[0064] Form I of Compound 2 In some embodiments, Form I of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 3 below. [Table 3-1] [Table 3-2] [Table 3-3]

[0065] In some embodiments, Compound 2 Form I is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.3, about 20.0, and about 21.6 degrees 2θ. In some embodiments, Compound 2 Form I is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.3, about 20.0, and about 21.6 degrees 2θ. In some embodiments, Compound 2 Form I is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.3, about 20.0, and about 21.6 degrees 2θ.

[0066] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0067] A method for preparing Form I of Compound 2 is described below.

[0068] Form II of Compound 2 In some embodiments, Form II of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 4 below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0069] In some embodiments, Compound 2 Form II is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 5.9, about 19.9, and about 21.7 degrees 2θ. In some embodiments, Compound 2 Form II is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 5.9, about 19.9, and about 21.7 degrees 2θ. In some embodiments, Compound 2 Form II is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 5.9, about 19.9, and about 21.7 degrees 2θ.

[0070] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0071] A method for preparing Form II of Compound 2 is described below.

[0072] Form III of Compound 2 In some embodiments, Form III of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 5 below. [Table 5]

[0073] In some embodiments, Form III of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 6.8, about 18.9, and about 20.3 degrees 2θ. In some embodiments, Form III of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 6.8, about 18.9, and about 20.3 degrees 2θ. In some embodiments, Form III of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 6.8, about 18.9, and about 20.3 degrees 2θ.

[0074] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0075] A method for preparing Form III of Compound 2 is described below.

[0076] Form IV of Compound 2 In some embodiments, Form IV of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 6 below. [Table 6-1] [Table 6-2]

[0077] In some embodiments, Form IV of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 4.9, about 5.0, and about 25.0 degrees 2θ. In some embodiments, Form IV of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 4.9, about 5.0, and about 25.0 degrees 2θ. In some embodiments, Form IV of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 4.9, about 5.0, and about 25.0 degrees 2θ.

[0078] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0079] A method for preparing Form IV of Compound 2 is described below.

[0080] Form V of Compound 2 In some embodiments, Form V of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 7 below. [Table 7-1] [Table 7-2]

[0081] In some embodiments, Form V of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.0, about 20.7, and about 25.9 degrees 2θ. In some embodiments, Form V of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.0, about 20.7, and about 25.9 degrees 2θ. In some embodiments, Form V of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.0, about 20.7, and about 25.9 degrees 2θ.

[0082] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0083] A method for preparing Form V of Compound 2 is described below.

[0084] Form VI of Compound 2 In some embodiments, Form VI of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 8 below. [Table 8]

[0085] In some embodiments, Form VI of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 6.5, about 19.2, and about 20.2 degrees two-theta. In some embodiments, Form VI of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 6.5, about 19.2, and about 20.2 degrees two-theta. In some embodiments, Form VI of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 6.5, about 19.2, and about 20.2 degrees two-theta.

[0086] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0087] A method for preparing Form VI of Compound 2 is described below.

[0088] Form VII of Compound 2 In some embodiments, Form VII of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 9 below. [Table 9-1] [Table 9-2]

[0089] In some embodiments, Compound 2 Form VII is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 10.4, about 14.8, and about 24.9 degrees 2θ. In some embodiments, Compound 2 Form VII is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 10.4, about 14.8, and about 24.9 degrees 2θ. In some embodiments, Compound 2 Form VII is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 10.4, about 14.8, and about 24.9 degrees 2θ.

[0090] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0091] A method for preparing Form VII of Compound 2 is described below.

[0092] Form VIII of Compound 2 XRPD data indicated that Form VIII of Compound 2 is amorphous. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 13. Form VIII of Compound 2 was observed to convert to Form I of Compound 2 upon storage at room temperature for approximately one month.

[0093] Form IX of Compound 2 In some embodiments, Form IX of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 10 below. [Table 10]

[0094] In some embodiments, Form IX of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 6.3, about 6.7, and about 18.9 degrees 2θ. In some embodiments, Form IX of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 6.3, about 6.7, and about 18.9 degrees 2θ. In some embodiments, Form IX of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 6.3, about 6.7, and about 18.9 degrees 2θ.

[0095] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0096] A method for preparing Form IX of Compound 2 is described below.

[0097] Form X of Compound 2 In some embodiments, Form X of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 11 below. [Table 11]

[0098] In some embodiments, Form X of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 6.6, about 18.2, and about 19.8 degrees 2θ. In some embodiments, Form X of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 6.6, about 18.2, and about 19.8 degrees 2θ. In some embodiments, Form X of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 6.6, about 18.2, and about 19.8 degrees 2θ.

[0099] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0100] A method for preparing Form X of Compound 2 is described below.

[0101] Form XI of Compound 2 In some embodiments, Form XI of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 12 below. [Table 12]

[0102] In some embodiments, Compound 2 Form XI is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 7.0, about 20.0, and about 20.3 degrees 2θ. In some embodiments, Compound 2 Form XI is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 7.0, about 20.0, and about 20.3 degrees 2θ. In some embodiments, Compound 2 Form XI is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 7.0, about 20.0, and about 20.3 degrees 2θ.

[0103] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0104] A method for preparing Form XI of Compound 2 is described below.

[0105] Form XII of Compound 2 In some embodiments, Form XII of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 13 below. [Table 13-1] [Table 13-2] [Table 13-3]

[0106] In some embodiments, Form XII of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 5.8, about 5.9, and about 19.3 degrees 2θ. In some embodiments, Form XII of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 5.8, about 5.9, and about 19.3 degrees 2θ. In some embodiments, Form XII of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 5.8, about 5.9, and about 19.3 degrees 2θ.

[0107] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0108] A method for preparing Form XII of Compound 2 is described below.

[0109] Form XIII of Compound 2 In some embodiments, Form XIII of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 14 below. [Table 14]

[0110] In some embodiments, Form XIII of Compound 2 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 6.1, about 21.8, and about 22.8 degrees 2θ. In some embodiments, Form XIII of Compound 2 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 6.1, about 21.8, and about 22.8 degrees 2θ. In some embodiments, Form XIII of Compound 2 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 6.1, about 21.8, and about 22.8 degrees 2θ.

[0111] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0112] A method for preparing Form XIII of Compound 2 is described below.

[0113] In some embodiments, the present invention provides compound 2, wherein the compound is crystalline.

[0114] In some embodiments, the present invention provides Compound 2, wherein said compound is a crystalline solid substantially free of amorphous Compound 2.

[0115] In some embodiments, the present invention provides compound 2, wherein said compound is substantially free of impurities.

[0116] In some embodiments, the present invention provides a composition comprising Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII of Compound 2 and a pharmaceutically acceptable carrier or excipient.

[0117] In some embodiments, the present invention provides a method of treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering to said patient Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, or XIII of Compound 2 or a composition thereof.

[0118] In some embodiments, the invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to said patient Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII of Compound 2, wherein Form I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII or XIII of Compound 2 is a crystalline form described herein.

[0119] Compound 3 (maleate salt of Compound A) According to one embodiment, the present invention provides a maleate salt of Compound A, designated Compound 3. [ka] 3

[0120] [Those skilled in the art will understand that maleic acid and Compound A ionically bond to form Compound 3. It is believed that Compound 3 can exist in a variety of physical forms. For example, Compound 3 can be in solution, suspension, or solid form. In certain embodiments, Compound 3 is in solid form. When Compound 3 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0121] In some embodiments, the present invention provides Compound 3 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess maleic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 3. In certain embodiments, the composition is at least about 95% by weight of Compound 3. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 3.

[0122] According to one embodiment, compound 3 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 3 contains less than or equal to about 3.0 area percent total organic impurities by HPLC, and in certain embodiments, the area percent of total organic impurities by HPLC relative to the total area of the HPLC chromatogram is less than or equal to about 1.5. In other embodiments, compound 3 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity relative to the total area of the HPLC chromatogram.

[0123] The structure shown for compound 3 is also meant to include all tautomeric and isomeric forms of compound 3.

[0124] It has been found that Compound 3 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0125] It has been found that compound 3 can exist in at least two polymorphic forms.

[0126] In some embodiments, the present invention provides a polymorphic form of Compound 3, referred to herein as Form I. In some embodiments, Form I of Compound 3 is substantially free of other polymorphic forms.

[0127] In certain embodiments, the present invention provides a polymorphic form of Compound 3, herein referred to as Form II. In some embodiments, Form II of Compound 3 is substantially free of other polymorphic forms.

[0128] In certain embodiments, Compound 3 is a crystalline solid. In other embodiments, Compound 3 is a crystalline solid that is substantially free of amorphous Compound 3. As used herein, the term "substantially free of amorphous Compound 3" means that the compound does not contain a significant amount of amorphous Compound 3. In certain embodiments, at least about 95% by weight of crystalline Compound 3 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 3 is present.

[0129] In some embodiments, Compound 3 is amorphous. In some embodiments, Compound 3 is amorphous and substantially free of crystalline Compound 3.

[0130] Form I of Compound 3 In some embodiments, Form I of Compound 3 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 15 below. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4]

[0131] In some embodiments, Compound 3 Form I is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.8, about 25.5, and about 26.7 degrees 2θ. In some embodiments, Compound 3 Form I is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.8, about 25.5, and about 26.7 degrees 2θ. In some embodiments, Compound 3 Form I is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.8, about 25.5, and about 26.7 degrees 2θ.

[0132] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0133] A method for preparing Form I of Compound 3 is described below.

[0134] Form II of Compound 3 In some embodiments, Form II of Compound 3 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 16 below. [Table 16-1] [Table 16-2]

[0135] In some embodiments, Compound 3 Form II is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 15.2, about 18.6, and about 20.9 degrees 2θ. In some embodiments, Compound 3 Form II is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 15.2, about 18.6, and about 20.9 degrees 2θ. In some embodiments, Compound 3 Form II is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 15.2, about 18.6, and about 20.9 degrees 2θ.

[0136] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0137] A method for preparing Form II of Compound 3 is described below.

[0138] In some embodiments, the present invention provides compound 3, wherein the compound is crystalline.

[0139] In some embodiments, the present invention provides Compound 3, wherein said compound is a crystalline solid substantially free of amorphous Compound 3.

[0140] In some embodiments, the present invention provides compound 3, wherein said compound is substantially free of impurities.

[0141] In some embodiments, the present invention provides a composition comprising Form I or Form II of Compound 3 and a pharmaceutically acceptable carrier or excipient.

[0142] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I or Form II of Compound 3, or a composition thereof, to the patient.

[0143] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient Form I or Form II of Compound 3, or a composition thereof, wherein Form I or Form II of Compound 3 is a crystalline form described herein.

[0144] Compound 4 (tosylate salt of Compound A) According to one embodiment, the present invention provides a tosylate salt of Compound A, designated Compound 4. [ka] 4

[0145] "Tosylate" refers to p-toluenesulfonate, i.e., the ionic form of p-toluenesulfonic acid. Those skilled in the art will understand that p-toluenesulfonic acid and Compound A ionically bond to form Compound 4. It is believed that Compound 4 can exist in various physical forms. For example, Compound 4 can be in solution, suspension, or solid form. In certain embodiments, Compound 4 is in solid form. When Compound 4 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0146] In some embodiments, the present invention provides Compound 4 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess p-toluenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 4. In certain embodiments, the composition is at least about 95% by weight of Compound 4. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 4.

[0147] According to one embodiment, compound 4 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 4 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 4 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0148] The structure shown for compound 4 is also meant to include all tautomeric and isomeric forms of compound 4.

[0149] It has been found that compound 4 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0150] It has been found that Compound 4 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 4, referred to herein as Form I. In some embodiments, Form I of Compound 4 is substantially free of other polymorphic forms.

[0151] In certain embodiments, compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid that is substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound does not contain a significant amount of amorphous compound 4. In certain embodiments, at least about 95% by weight of crystalline compound 4 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 4 is present.

[0152] In some embodiments, Compound 4 is amorphous. In some embodiments, Compound 4 is amorphous and substantially free of crystalline Compound 4.

[0153] Form I of Compound 4 In some embodiments, Form I of Compound 1 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 17 below. [Table 17]

[0154] In some embodiments, Compound 4 Form I is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 17.8, about 19.5, and about 25.7 degrees 2θ. In some embodiments, Compound 4 Form I is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 17.8, about 19.5, and about 25.7 degrees 2θ. In some embodiments, Compound 4 Form I is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 17.8, about 19.5, and about 25.7 degrees 2θ.

[0155] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0156] A method for preparing Form I of Compound 4 is described below.

[0157] In some embodiments, the present invention provides compound 4, wherein the compound is crystalline.

[0158] In some embodiments, the present invention provides Compound 4, wherein said compound is a crystalline solid substantially free of amorphous Compound 4.

[0159] In some embodiments, the present invention provides compound 4, wherein the compound is substantially free of impurities.

[0160] In some embodiments, the present invention provides a composition comprising Form I of Compound 4 and a pharmaceutically acceptable carrier or excipient.

[0161] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 4, or a composition thereof, to the patient.

[0162] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient Form I of Compound 4, or a composition thereof, wherein Form I of Compound 4 is a crystalline form described herein.

[0163] Compound 5 (sulfate of Compound A) According to one embodiment, the present invention provides a sulfate salt of compound A, designated compound 5. [ka] 5

[0164] Those skilled in the art will understand that sulfuric acid and Compound A ionically bond to form Compound 5. It is believed that Compound 5 can exist in various physical forms. For example, Compound 5 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 5 is in a solid form. When Compound 5 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0165] In some embodiments, the present invention provides Compound 5 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess sulfuric acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 5. In certain embodiments, the composition is at least about 95% by weight of Compound 5. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 5.

[0166] According to one embodiment, compound 5 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 5 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 5 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0167] The structure shown for compound 5 is also meant to include all tautomeric and isomeric forms of compound 5.

[0168] It has been found that compound 5 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0169] It has been found that compound 5 can exist in at least two polymorphic forms.

[0170] In some embodiments, the present invention provides a polymorphic form of Compound 5, referred to herein as Form I. In some embodiments, Form I of Compound 5 is substantially free of other polymorphic forms.

[0171] In certain embodiments, the present invention provides a polymorphic form of Compound 5, herein referred to as Form II. In some embodiments, Form II of Compound 5 is substantially free of other polymorphic forms.

[0172] In certain embodiments, Compound 5 is a crystalline solid. In other embodiments, Compound 5 is a crystalline solid that is substantially free of amorphous Compound 5. As used herein, the term "substantially free of amorphous Compound 5" means that the compound does not contain a significant amount of amorphous Compound 5. In certain embodiments, at least about 95% by weight of crystalline Compound 5 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 5 is present.

[0173] In some embodiments, Compound 5 is amorphous. In some embodiments, Compound 5 is amorphous and substantially free of crystalline Compound 5.

[0174] Form I of Compound 5 In some embodiments, Form I of Compound 5 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 18 below. [Table 18-1] [Table 18-2] [Table 18-3]

[0175] In some embodiments, Compound 5 Form I is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 20.0, about 20.6, and about 24.5 degrees 2θ. In some embodiments, Compound 5 Form I is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 20.0, about 20.6, and about 24.5 degrees 2θ. In some embodiments, Compound 5 Form I is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 20.0, about 20.6, and about 24.5 degrees 2θ.

[0176] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0177] A method for preparing Form I of Compound 5 is described below.

[0178] Form II of Compound 5 In some embodiments, Form II of Compound 5 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 19 below. [Table 19-1] [Table 19-2]

[0179] In some embodiments, Compound 5 Form II is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 20.4, about 21.1, and about 26.2 degrees 2θ. In some embodiments, Compound 5 Form II is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 20.4, about 21.1, and about 26.2 degrees 2θ. In some embodiments, Compound 5 Form II is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 20.4, about 21.1, and about 26.2 degrees 2θ.

[0180] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0181] A method for preparing Form II of Compound 5 is described below.

[0182] In some embodiments, the present invention provides compound 5, wherein the compound is crystalline.

[0183] In some embodiments, the present invention provides Compound 5, wherein said compound is a crystalline solid substantially free of amorphous Compound 5.

[0184] In some embodiments, the present invention provides compound 5, wherein the compound is substantially free of impurities.

[0185] In some embodiments, the present invention provides a composition comprising Form I or Form II of Compound 5 and a pharmaceutically acceptable carrier or excipient.

[0186] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I or Form II of Compound 5, or a composition thereof, to the patient.

[0187] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient Form I or Form II of Compound 5, or a composition thereof, wherein Form I or Form II of Compound 5 is a crystalline form described herein.

[0188] Compound 6 (2-hydroxyethanesulfonic acid salt of Compound A) According to one embodiment, the present invention provides a 2-hydroxyethanesulfonic acid salt of compound A, represented by compound 6. [ka] 6

[0189] Those skilled in the art will understand that 2-hydroxyethanesulfonic acid and compound A ionically bond to form compound 6. It is believed that compound 6 can exist in various physical forms. For example, compound 6 can be in a solution, a suspension, or a solid form. In certain embodiments, compound 6 is in a solid form. When compound 6 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0190] In some embodiments, the present invention provides Compound 6 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess 2-hydroxyethanesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 6. In certain embodiments, the composition is at least about 95% by weight of Compound 6. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 6.

[0191] According to one embodiment, compound 6 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 6 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 6 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0192] The structure shown for compound 6 is also meant to include all tautomeric and isomeric forms of compound 6.

[0193] It has been found that compound 6 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0194] It has been found that Compound 6 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 6, referred to herein as Form I. In some embodiments, Form I of Compound 6 is substantially free of other polymorphic forms.

[0195] In certain embodiments, compound 6 is a crystalline solid. In other embodiments, compound 6 is a crystalline solid that is substantially free of amorphous compound 6. As used herein, the term "substantially free of amorphous compound 6" means that the compound does not contain a significant amount of amorphous compound 6. In certain embodiments, at least about 95% by weight of crystalline compound 6 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 6 is present.

[0196] In some embodiments, Compound 6 is amorphous. In some embodiments, Compound 6 is amorphous and substantially free of crystalline Compound 6.

[0197] Form I of Compound 6 In some embodiments, Form I of Compound 6 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 20 below. [Table 20-1] [Table 20-2]

[0198] In some embodiments, Form I of Compound 6 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 20.1, about 20.7, and about 25.6 degrees 2θ. In some embodiments, Form I of Compound 6 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 20.1, about 20.7, and about 25.6 degrees 2θ. In some embodiments, Form I of Compound 6 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 20.1, about 20.7, and about 25.6 degrees 2θ.

[0199] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0200] A method for preparing Form I of Compound 6 is described below.

[0201] In some embodiments, the present invention provides compound 6, wherein the compound is crystalline.

[0202] In some embodiments, the present invention provides Compound 6, wherein the compound is a crystalline solid that is substantially free of amorphous Compound 6.

[0203] In some embodiments, the present invention provides compound 6, wherein the compound is substantially free of impurities.

[0204] In some embodiments, the present invention provides a composition comprising Form I of Compound 6 and a pharmaceutically acceptable carrier or excipient.

[0205] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 6, or a composition thereof, to the patient.

[0206] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 6, or a composition thereof, to the patient, wherein Form I of Compound 6 is a crystalline form described herein.

[0207] Compound 7 (esylate salt of Compound A) According to one embodiment, the present invention provides an esylate salt of compound A, designated compound 7. [ka] 7

[0208] Those skilled in the art will understand that ethanesulfonic acid and Compound A ionically bond to form Compound 7. It is believed that Compound 7 can exist in a variety of physical forms. For example, Compound 7 can be in solution, suspension, or solid form. In certain embodiments, Compound 7 is in solid form. When Compound 7 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0209] In some embodiments, the present invention provides Compound 7 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess ethanesulfonic acid, excess synthesis reagents, excess Compound A, residual solvent, or other impurities that may result from the preparation and / or isolation of Compound 7. In certain embodiments, the composition is at least about 95% by weight of Compound 7. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 7.

[0210] According to one embodiment, compound 7 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 7 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 7 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0211] The structure shown for compound 7 is also meant to include all tautomeric and isomeric forms of compound 7.

[0212] It has been found that compound 7 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0213] It has been found that Compound 7 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 7, referred to herein as Form I. In some embodiments, Form I of Compound 7 is substantially free of other polymorphic forms.

[0214] In certain embodiments, compound 7 is a crystalline solid. In other embodiments, compound 7 is a crystalline solid that is substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound does not contain a significant amount of amorphous compound 7. In certain embodiments, at least about 95% by weight of crystalline compound 7 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 7 is present.

[0215] In some embodiments, compound 7 is amorphous. In some embodiments, compound 7 is amorphous and substantially free of crystalline compound 7.

[0216] Form I of Compound 7 In some embodiments, Form I of Compound 7 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 21 below. [Table 21-1] [Table 21-2]

[0217] In some embodiments, Form I of Compound 7 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.7, about 25.4, and about 26.4 degrees 2θ. In some embodiments, Form I of Compound 7 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.7, about 25.4, and about 26.4 degrees 2θ. In some embodiments, Form I of Compound 7 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.7, about 25.4, and about 26.4 degrees 2θ.

[0218] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0219] A method for preparing Form I of Compound 7 is described below.

[0220] In some embodiments, the present invention provides compound 7, wherein the compound is crystalline.

[0221] In some embodiments, the present invention provides Compound 7, wherein the compound is a crystalline solid that is substantially free of amorphous Compound 7.

[0222] In some embodiments, the present invention provides compound 7, wherein the compound is substantially free of impurities.

[0223] In some embodiments, the present invention provides a composition comprising Form I of Compound 7 and a pharmaceutically acceptable carrier or excipient.

[0224] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 7, or a composition thereof, to the patient.

[0225] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 7, or a composition thereof, to the patient, wherein Form I of Compound 7 is a crystalline form described herein.

[0226] Compound 8 (Mesylate of Compound A) According to one embodiment, the present invention provides a mesylate salt of compound A, designated compound 8. [ka] 8

[0227] Those skilled in the art will understand that methanesulfonic acid and compound A ionically bond to form compound 8. It is believed that compound 8 can exist in a variety of physical forms. For example, compound 8 can be in solution, suspension, or solid form. In certain embodiments, compound 8 is in solid form. When compound 8 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0228] In some embodiments, the present invention provides Compound 8 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess methanesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 8. In certain embodiments, the composition is at least about 95% by weight of Compound 8. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 8.

[0229] According to one embodiment, compound 8 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 8 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 8 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0230] The structure shown for compound 8 is also meant to include all tautomeric and isomeric forms of compound 8.

[0231] It has been found that compound 8 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0232] It has been found that Compound 8 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 8, referred to herein as Form I. In some embodiments, Form I of Compound 8 is substantially free of other polymorphic forms.

[0233] In certain embodiments, compound 8 is a crystalline solid. In other embodiments, compound 8 is a crystalline solid that is substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound does not contain a significant amount of amorphous compound 8. In certain embodiments, at least about 95% by weight of crystalline compound 8 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 8 is present.

[0234] In some embodiments, Compound 8 is amorphous. In some embodiments, Compound 8 is amorphous and substantially free of crystalline Compound 8.

[0235] Form I of Compound 8 In some embodiments, Form I of Compound 8 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 22 below. [Table 22]

[0236] In some embodiments, Form I of Compound 8 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 20.0, about 25.0, and about 25.6 degrees 2θ. In some embodiments, Form I of Compound 8 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 20.0, about 25.0, and about 25.6 degrees 2θ. In some embodiments, Form I of Compound 8 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 20.0, about 25.0, and about 25.6 degrees 2θ.

[0237] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0238] A method for preparing Form I of Compound 8 is described below.

[0239] In some embodiments, the present invention provides compound 8, wherein the compound is crystalline.

[0240] In some embodiments, the present invention provides Compound 8, wherein the compound is a crystalline solid that is substantially free of amorphous Compound 8.

[0241] In some embodiments, the present invention provides compound 8, wherein the compound is substantially free of impurities.

[0242] In some embodiments, the present invention provides a composition comprising Form I of Compound 8 and a pharmaceutically acceptable carrier or excipient.

[0243] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 8, or a composition thereof, to the patient.

[0244] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 8, or a composition thereof, to the patient, wherein Form I of Compound 8 is a crystalline form described herein.

[0245] Compound 9 (Dimesylate of Compound A) According to one embodiment, the present invention provides a dimesylate salt of compound A, designated compound 9. [ka] 9

[0246] Those skilled in the art will understand that methanesulfonic acid and Compound A ionically bond to form Compound 9. It is believed that Compound 9 can exist in various physical forms. For example, Compound 9 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 9 is in a solid form. When Compound 9 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0247] In some embodiments, the present invention provides Compound 9 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess methanesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 9. In certain embodiments, the composition is at least about 95% by weight of Compound 9. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 9.

[0248] According to one embodiment, compound 9 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 9 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 9 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0249] The structure shown for compound 9 is also meant to include all tautomeric and isomeric forms of compound 9.

[0250] It has been found that Compound 9 can exist in various solid forms. Exemplary such forms include the polymorphs described herein. In some embodiments, Compound 9 is substantially free of other polymorphic forms.

[0251] In certain embodiments, compound 9 is a crystalline solid. In other embodiments, compound 9 is a crystalline solid that is substantially free of amorphous compound 9. As used herein, the term "substantially free of amorphous compound 9" means that the compound does not contain a significant amount of amorphous compound 9. In certain embodiments, at least about 95% by weight of crystalline compound 9 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 9 is present.

[0252] In some embodiments, Compound 9 is amorphous. In some embodiments, Compound 9 is amorphous and substantially free of crystalline Compound 9.

[0253] A method for preparing Form I of Compound 9 is described below.

[0254] In some embodiments, the present invention provides compound 9, wherein the compound is crystalline.

[0255] In some embodiments, the present invention provides Compound 9, wherein the compound is a crystalline solid that is substantially free of amorphous Compound 9.

[0256] In some embodiments, the present invention provides compound 9, wherein the compound is substantially free of impurities.

[0257] In some embodiments, the present invention provides a composition comprising Form I of Compound 9 and a pharmaceutically acceptable carrier or excipient.

[0258] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 9, or a composition thereof, to the patient.

[0259] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 9 or a composition thereof to the patient, wherein Form I of Compound 9 is a crystalline form described herein.

[0260] Compound 10 (R-camsylate salt of Compound A) According to one embodiment, the present invention provides an R-camsylate salt of compound A, designated compound 10. [ka] 10

[0261] Those skilled in the art will understand that R-camphorsulfonic acid and compound A ionically bond to form compound 10. It is believed that compound 10 can exist in various physical forms. For example, compound 10 can be in a solution, a suspension, or a solid form. In certain embodiments, compound 10 is in a solid form. When compound 10 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0262] In some embodiments, the present invention provides compound 10 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess R-camphoric acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of compound 10. In certain embodiments, the composition is at least about 95% by weight of compound 10. In yet other embodiments of the present invention, the composition is at least about 99% by weight of compound 10.

[0263] According to one embodiment, compound 10 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 10 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 10 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0264] The structure shown for compound 10 is also meant to include all tautomeric and isomeric forms of compound 10.

[0265] It has been found that compound 10 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0266] It has been found that Compound 10 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 10, referred to herein as Form I. In some embodiments, Form I of Compound 10 is substantially free of other polymorphic forms.

[0267] In certain embodiments, Compound 10 is a crystalline solid. In other embodiments, Compound 10 is a crystalline solid that is substantially free of amorphous Compound 10. As used herein, the term "substantially free of amorphous Compound 10" means that the compound does not contain significant amounts of amorphous Compound 10. In certain embodiments, at least about 95% by weight of crystalline Compound 10 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 10 is present.

[0268] In some embodiments, compound 10 is amorphous. In some embodiments, compound 10 is amorphous and substantially free of crystalline compound 10.

[0269] Form I of Compound 10 In some embodiments, Form I of Compound 10 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 23 below. [Table 23-1] [Table 23-2]

[0270] In some embodiments, Form I of Compound 10 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 14.6, about 25.4, and about 26.5 degrees 2θ. In some embodiments, Form I of Compound 10 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 14.6, about 25.4, and about 26.5 degrees 2θ. In some embodiments, Form I of Compound 10 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 14.6, about 25.4, and about 26.5 degrees 2θ.

[0271] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0272] A method for preparing Form I of Compound 10 is described below.

[0273] In some embodiments, the present invention provides compound 10, wherein the compound is crystalline.

[0274] In some embodiments, the present invention provides Compound 10, wherein said compound is a crystalline solid substantially free of amorphous Compound 10.

[0275] In some embodiments, the present invention provides compound 10, wherein said compound is substantially free of impurities.

[0276] In some embodiments, the present invention provides a composition comprising Form I of Compound 10 and a pharmaceutically acceptable carrier or excipient.

[0277] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of compound 10, or a composition thereof, to the patient.

[0278] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 10, or a composition thereof, to the patient, wherein Form I of Compound 10 is a crystalline form described herein.

[0279] Compound 11 (S-camsylate salt of Compound A) According to one embodiment, the present invention provides an S-camsylate salt of compound A, designated compound 11. [ka] 11

[0280] Those skilled in the art will understand that S-camphorsulfonic acid and compound A ionically bond to form compound 11. It is believed that compound 11 can exist in various physical forms. For example, compound 11 can be in solution, suspension, or solid form. In certain embodiments, compound 11 is in solid form. When compound 11 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0281] In some embodiments, the present invention provides compound 11 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess S-camphoric acid, excess synthesis reagents, excess compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of compound 11. In certain embodiments, the composition is present in at least about 95% by weight of compound 11. In yet other embodiments of the present invention, the composition is present in at least about 99% by weight of compound 11.

[0282] According to one embodiment, compound 11 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 11 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 11 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0283] The structure shown for compound 11 is also meant to include all tautomeric and isomeric forms of compound 11.

[0284] It has been found that compound 11 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0285] It has been found that Compound 11 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 11, referred to herein as Form I. In some embodiments, Form I of Compound 11 is substantially free of other polymorphic forms.

[0286] In certain embodiments, compound 11 is a crystalline solid. In other embodiments, compound 11 is a crystalline solid that is substantially free of amorphous compound 11. As used herein, the term "substantially free of amorphous compound 11" means that the compound does not contain a significant amount of amorphous compound 11. In certain embodiments, at least about 95% by weight of crystalline compound 11 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 11 is present.

[0287] In some embodiments, compound 11 is amorphous. In some embodiments, compound 11 is amorphous and substantially free of crystalline compound 11.

[0288] Form I of Compound 11 In some embodiments, Form I of Compound 11 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 24 below. [Table 24]

[0289] In some embodiments, Form I of Compound 11 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 15.4, about 17.5, and about 26.0 degrees 2θ. In some embodiments, Form I of Compound 11 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 15.4, about 17.5, and about 26.0 degrees 2θ. In some embodiments, Form I of Compound 11 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 15.4, about 17.5, and about 26.0 degrees 2θ.

[0290] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0291] A method for preparing Form I of Compound 11 is described below.

[0292] In some embodiments, the present invention provides compound 11, wherein the compound is crystalline.

[0293] In some embodiments, the present invention provides Compound 11, wherein said compound is a crystalline solid substantially free of amorphous Compound 11.

[0294] In some embodiments, the present invention provides compound 11, wherein the compound is substantially free of impurities.

[0295] In some embodiments, the present invention provides a composition comprising Form I of Compound 11 and a pharmaceutically acceptable carrier or excipient.

[0296] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of compound 11, or a composition thereof, to the patient.

[0297] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 11, or a composition thereof, to the patient, wherein Form I of Compound 11 is a crystalline form described herein.

[0298] Compound 12 (hydrobromide salt of Compound A) According to one embodiment, the present invention provides the hydrobromide salt of compound A, designated compound 12. [ka] 12

[0299] Those skilled in the art will understand that S-camphorsulfonic acid and compound A ionically bond to form compound 12. It is believed that compound 12 can exist in various physical forms. For example, compound 12 can be in solution, suspension, or solid form. In certain embodiments, compound 12 is in solid form. When compound 12 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0300] In some embodiments, the present invention provides Compound 12 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess hydrobromic acid, excess synthesis reagents, excess Compound A, residual solvent, or other impurities that may result from the preparation and / or isolation of Compound 12. In certain embodiments, the composition is at least about 95% by weight of Compound 12. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 12.

[0301] According to one embodiment, compound 12 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 12 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 12 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0302] The structure shown for compound 12 is also meant to include all tautomeric and isomeric forms of compound 12.

[0303] It has been found that compound 12 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0304] It has been found that compound 12 can exist in at least two polymorphic forms.

[0305] In some embodiments, the present invention provides a polymorphic form of Compound 12, referred to herein as Form I. In some embodiments, Form I of Compound 12 is substantially free of other polymorphic forms.

[0306] In certain embodiments, the present invention provides a polymorphic form of Compound 12, herein referred to as Form II. In some embodiments, Form II of Compound 12 is substantially free of other polymorphic forms.

[0307] In certain embodiments, compound 12 is a crystalline solid. In other embodiments, compound 12 is a crystalline solid that is substantially free of amorphous compound 12. As used herein, the term "substantially free of amorphous compound 12" means that the compound does not contain a significant amount of amorphous compound 12. In certain embodiments, at least about 95% by weight of crystalline compound 12 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 12 is present.

[0308] In some embodiments, compound 12 is amorphous. In some embodiments, compound 12 is amorphous and substantially free of crystalline compound 12.

[0309] Form I of Compound 12 In some embodiments, Form I of Compound 12 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 25 below. [Table 25-1] [Table 25-2] [Table 25-3]

[0310] In some embodiments, Form I of Compound 12 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 16.6, about 19.4, and about 20.2 degrees 2θ. In some embodiments, Form I of Compound 12 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 16.6, about 19.4, and about 20.2 degrees 2θ. In some embodiments, Form I of Compound 12 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 16.6, about 19.4, and about 20.2 degrees 2θ.

[0311] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0312] A method for preparing Form I of Compound 12 is described below.

[0313] Form II of Compound 12 In some embodiments, Form II of Compound 12 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 26 below. [Table 26-1] [Table 26-2]

[0314] In some embodiments, Form II of Compound 12 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 16.9, about 19.6, and about 20.5 degrees 2θ. In some embodiments, Form II of Compound 12 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 16.9, about 19.6, and about 20.5 degrees 2θ. In some embodiments, Form II of Compound 12 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 16.9, about 19.6, and about 20.5 degrees 2θ.

[0315] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0316] A method for preparing Form II of Compound 12 is described below.

[0317] In some embodiments, the present invention provides compound 12, wherein the compound is crystalline.

[0318] In some embodiments, the present invention provides Compound 12, wherein said compound is a crystalline solid substantially free of amorphous Compound 12.

[0319] In some embodiments, the present invention provides compound 12, wherein said compound is substantially free of impurities.

[0320] In some embodiments, the present invention provides a composition comprising Form I or Form II of Compound 12 and a pharmaceutically acceptable carrier or excipient.

[0321] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I or Form II of Compound 12, or a composition thereof, to the patient.

[0322] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient Form I or Form II of Compound 12, or a composition thereof, wherein Form I or Form II of Compound 12 is a crystalline form described herein.

[0323] Compound 23 (phosphate salt of Compound A) According to one embodiment, the present invention provides a phosphate salt of Compound A, designated Compound 23. [ka] twenty three

[0324] Those skilled in the art will understand that phosphate and Compound A ionically bond to form Compound 23. It is believed that Compound 1 can exist in various physical forms. For example, Compound 23 can be in solution, suspension, or solid form. In certain embodiments, Compound 23 is in solid form. When Compound 23 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0325] In some embodiments, the present invention provides Compound 23 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess phosphoric acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 23. In certain embodiments, the composition is at least about 95% by weight of Compound 23. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 23.

[0326] According to one embodiment, compound 23 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, with percentages based on the total weight of the composition. According to another embodiment, compound 23 contains less than or equal to about 3.0 HPLC area percent of total organic impurities. The area percent of total organic impurities by HPLC can be assessed by one of ordinary skill in the art using conventional HPLC methods, for example, including a photodiode array detector. In certain embodiments, the HPLC area percent of total organic impurities is less than or equal to about 1.5, based on the total area of the HPLC chromatogram. In other embodiments, compound 23 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of the HPLC chromatogram.

[0327] The structure shown for compound 23 is also meant to include all tautomeric and isomeric forms of compound 23.

[0328] It has been found that compound 23 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0329] In certain embodiments, compound 23 is a crystalline solid. In other embodiments, compound 23 is a crystalline solid that is substantially free of amorphous compound 23. As used herein, the term "substantially free of amorphous compound 23" means that the compound does not contain significant amounts of amorphous compound 23. In certain embodiments, at least about 95% by weight of crystalline compound 23 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 23 is present.

[0330] It has been found that Compound 23 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 23, referred to herein as Form I. In some embodiments, Form I of Compound 23 is substantially free of other polymorphic forms.

[0331] In some embodiments, Compound 23 is amorphous. In some embodiments, Compound 23 is amorphous and substantially free of crystalline Compound 23.

[0332] Form I of Compound 23 In some embodiments, Form I of Compound 23 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 27 below. [Table 27-1] [Table 27-2]

[0333] In some embodiments, Form I of Compound 23 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 19.8, about 24.3, and about 25.4 degrees 2θ. In some embodiments, Form I of Compound 23 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 19.8, about 24.3, and about 25.4 degrees 2θ. In some embodiments, Form I of Compound 23 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 19.8, about 24.3, and about 25.4 degrees 2θ.

[0334] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0335] A method for preparing Form I of Compound 23 is described below.

[0336] In some embodiments, the present invention provides compound 23, wherein the compound is crystalline.

[0337] In some embodiments, the present invention provides Compound 23, wherein said compound is a crystalline solid substantially free of amorphous Compound 23.

[0338] In some embodiments, the present invention provides compound 23, wherein the compound is substantially free of impurities.

[0339] In some embodiments, the present invention provides a composition comprising Form I of Compound 23 and a pharmaceutically acceptable carrier or excipient.

[0340] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 23 or a composition thereof to the patient.

[0341] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 23, or a composition thereof, to the patient, wherein Form I of Compound 23 is a crystalline form described herein.

[0342] Compound 24 (Citrate of Compound A) According to one embodiment, the present invention provides the citrate salt of compound A, designated compound 24. [ka] twenty four

[0343] Those skilled in the art will understand that citric acid and Compound A ionically bond to form Compound 24. It is believed that Compound 1 can exist in various physical forms. For example, Compound 24 can be in solution, suspension, or solid form. In certain embodiments, Compound 24 is in solid form. When Compound 24 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0344] In some embodiments, the present invention provides Compound 24 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess citric acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 24. In certain embodiments, the composition is at least about 95% by weight of Compound 24. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 24.

[0345] According to one embodiment, compound 24 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, with percentages based on the total weight of the composition. According to another embodiment, compound 24 contains less than or equal to about 3.0 HPLC area percent of total organic impurities. The area percent of total organic impurities by HPLC can be assessed by one skilled in the art using conventional HPLC methods, for example, including a photodiode array detector. In certain embodiments, the HPLC area percent of total organic impurities is less than or equal to about 1.5, based on the total area of the HPLC chromatogram. In other embodiments, compound 24 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of the HPLC chromatogram.

[0346] The structure shown for compound 24 is also meant to include all tautomeric and isomeric forms of compound 24.

[0347] It has been found that compound 24 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0348] In certain embodiments, compound 24 is a crystalline solid. In other embodiments, compound 24 is a crystalline solid that is substantially free of amorphous compound 24. As used herein, the term "substantially free of amorphous compound 24" means that the compound does not contain a significant amount of amorphous compound 24. In certain embodiments, at least about 95% by weight of crystalline compound 24 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 24 is present.

[0349] It has been found that Compound 24 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 24, referred to herein as Form I. In some embodiments, Form I of Compound 24 is substantially free of other polymorphic forms.

[0350] In some embodiments, compound 24 is amorphous. In some embodiments, compound 24 is amorphous and substantially free of crystalline compound 24.

[0351] Form I of Compound 24 In some embodiments, Form I of compound 24 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 28 below. [Table 28-1] [Table 28-2] [Table 28-3]

[0352] In some embodiments, Form I of Compound 24 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 6.8, about 15.2, and about 19.8 degrees 2θ. In some embodiments, Form I of Compound 24 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 6.8, about 15.2, and about 19.8 degrees 2θ. In some embodiments, Form I of Compound 24 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 6.8, about 15.2, and about 19.8 degrees 2θ.

[0353] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0354] A method for preparing Form I of Compound 24 is described below.

[0355] In some embodiments, the present invention provides compound 24, wherein the compound is crystalline.

[0356] In some embodiments, the present invention provides compound 24, wherein said compound is a crystalline solid substantially free of amorphous compound 24.

[0357] In some embodiments, the present invention provides compound 24, wherein said compound is substantially free of impurities.

[0358] In some embodiments, the present invention provides a composition comprising Form I of compound 24 and a pharmaceutically acceptable carrier or excipient.

[0359] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 24 or a composition thereof to the patient.

[0360] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 24, or a composition thereof, to the patient, wherein Form I of Compound 24 is a crystalline form described herein.

[0361] Compound 25 (L-tartrate salt of Compound A) According to one embodiment, the present invention provides the L-tartrate salt of compound A, designated compound 25. [ka] twenty five

[0362] Those skilled in the art will understand that L-tartaric acid and Compound A ionically bond to form Compound 25. It is believed that Compound 1 can exist in various physical forms. For example, Compound 25 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 25 is in a solid form. When Compound 25 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0363] In some embodiments, the present invention provides Compound 25 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess L-tartaric acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 25. In certain embodiments, the composition is at least about 95% by weight of Compound 25. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 25.

[0364] According to one embodiment, compound 25 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, with percentages based on the total weight of the composition. According to another embodiment, compound 25 contains less than or equal to about 3.0 HPLC area percent of total organic impurities. The area percent of total organic impurities by HPLC can be assessed by one skilled in the art using conventional HPLC methods, for example, including a photodiode array detector. In certain embodiments, the HPLC area percent of total organic impurities is less than or equal to about 1.5, based on the total area of the HPLC chromatogram. In other embodiments, compound 25 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of the HPLC chromatogram.

[0365] The structure depicted for compound 25 is also meant to include all tautomeric and isomeric forms of compound 25. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C or 14 Compounds having the present structure except for the substitution at a C-rich carbon are within the scope of this invention.

[0366] It has been found that compound 25 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0367] In certain embodiments, compound 25 is a crystalline solid. In other embodiments, compound 25 is a crystalline solid that is substantially free of amorphous compound 25. As used herein, the term "substantially free of amorphous compound 25" means that the compound does not contain a significant amount of amorphous compound 25. In certain embodiments, at least about 95% by weight of crystalline compound 25 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 25 is present.

[0368] It has been found that Compound 25 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 25, referred to herein as Form I. In some embodiments, Form I of Compound 25 is substantially free of other polymorphic forms.

[0369] In some embodiments, Compound 25 is amorphous. In some embodiments, Compound 25 is amorphous and substantially free of crystalline Compound 25.

[0370] Form I of Compound 25 In some embodiments, Form I of Compound 25 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 29 below. [Table 29-1] [Table 29-2]

[0371] In some embodiments, Form I of Compound 25 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.9, about 24.0, and about 25.6 degrees 2θ. In some embodiments, Form I of Compound 25 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.9, about 24.0, and about 25.6 degrees 2θ. In some embodiments, Form I of Compound 25 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.9, about 24.0, and about 25.6 degrees 2θ.

[0372] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0373] A method for preparing Form I of Compound 25 is described below.

[0374] In some embodiments, the present invention provides compound 25, wherein the compound is crystalline.

[0375] In some embodiments, the present invention provides Compound 25, wherein said compound is a crystalline solid substantially free of amorphous Compound 25.

[0376] In some embodiments, the present invention provides compound 25, wherein said compound is substantially free of impurities.

[0377] In some embodiments, the present invention provides a composition comprising Form I of Compound 25 and a pharmaceutically acceptable carrier or excipient.

[0378] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 25 or a composition thereof to the patient.

[0379] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 25 or a composition thereof to the patient, wherein Form I of Compound 25 is a crystalline form described herein.

[0380] Compound 26 (Malonate of Compound A) According to one embodiment, the present invention provides a malonate salt of compound A, designated compound 26. [ka] 26

[0381] Those skilled in the art will understand that malonic acid and Compound A ionically bond to form Compound 26. It is believed that Compound 1 can exist in various physical forms. For example, Compound 26 can be in solution, suspension, or solid form. In certain embodiments, Compound 26 is in solid form. When Compound 26 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0382] In some embodiments, the present invention provides compound 26 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess malonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of compound 26. In certain embodiments, the composition is at least about 95% by weight of compound 26. In yet other embodiments of the present invention, the composition is at least about 99% by weight of compound 26.

[0383] According to one embodiment, compound 26 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, with percentages based on the total weight of the composition. According to another embodiment, compound 26 contains less than or equal to about 3.0 HPLC area percent of total organic impurities. The area percent of total organic impurities by HPLC can be assessed by one skilled in the art using conventional HPLC methods, for example, including a photodiode array detector. In certain embodiments, the HPLC area percent of total organic impurities is less than or equal to about 1.5, based on the total area of the HPLC chromatogram. In other embodiments, compound 26 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of the HPLC chromatogram.

[0384] The structure shown for compound 26 is also meant to include all tautomeric and isomeric forms of compound 26.

[0385] It has been found that compound 26 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0386] In certain embodiments, compound 26 is a crystalline solid. In other embodiments, compound 26 is a crystalline solid that is substantially free of amorphous compound 26. As used herein, the term "substantially free of amorphous compound 26" means that the compound does not contain a significant amount of amorphous compound 26. In certain embodiments, at least about 95% by weight of crystalline compound 26 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 26 is present.

[0387] It has been found that Compound 26 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 26, referred to herein as Form I. In some embodiments, Form I of Compound 26 is substantially free of other polymorphic forms.

[0388] In some embodiments, compound 26 is amorphous. In some embodiments, compound 25 is amorphous and substantially free of crystalline compound 26.

[0389] Form I of Compound 26 In some embodiments, Form I of compound 26 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 30 below. [Table 30-1] [Table 30-2]

[0390] In some embodiments, Form I of Compound 26 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 12.8, about 14.6, and about 19.1 degrees 2θ. In some embodiments, Form I of Compound 26 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 12.8, about 14.6, and about 19.1 degrees 2θ. In some embodiments, Form I of Compound 26 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 12.8, about 14.6, and about 19.1 degrees 2θ.

[0391] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0392] A method for preparing Form I of Compound 26 is described below.

[0393] In some embodiments, the present invention provides compound 26, wherein the compound is crystalline.

[0394] In some embodiments, the present invention provides compound 26, wherein said compound is a crystalline solid substantially free of amorphous compound 26.

[0395] In some embodiments, the present invention provides compound 26, wherein said compound is substantially free of impurities.

[0396] In some embodiments, the present invention provides a composition comprising Form I of Compound 26 and a pharmaceutically acceptable carrier or excipient.

[0397] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering Form I of Compound 26, or a composition thereof, to the patient.

[0398] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering Form I of Compound 26, or a composition thereof, to the patient, wherein Form I of Compound 26 is a crystalline form described herein.

[0399] Free base forms of compounds 13 and 14 It is believed that compounds 13 and 14 may exist in various physical forms. For example, compounds 13 and 14 may be in solution, suspension, or solid form. In certain embodiments, compounds 13 and 14 are in solid form. When compounds 13 and 14 are in solid form, the compounds may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms of compounds 13 and 14 are described in more detail below.

[0400] Compound 13(d6-Compound A) According to one embodiment, the present invention provides the free base form of deuterated Compound A, designated Compound 13. [ka] 13

[0401] It is believed that compound 13 can exist in various physical forms. For example, compound 13 can be in solution, suspension, or solid form. In certain embodiments, compound 13 is in solid form. When compound 13 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0402] In some embodiments, the present invention provides compound 13 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess synthesis reagents, excess Compound A, residual solvent, or other impurities that may result from the preparation and / or isolation of compound 13. In certain embodiments, the composition is at least about 95% by weight of compound 13. In yet other embodiments of the present invention, the composition is at least about 99% by weight of compound 13.

[0403] According to one embodiment, compound 13 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 13 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 13 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0404] The structure shown for compound 13 is also meant to include all tautomeric and isomeric forms of compound 13.

[0405] It has been found that compound 13 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0406] In certain embodiments, compound 13 is a crystalline solid. In other embodiments, compound 13 is a crystalline solid that is substantially free of amorphous compound 13. As used herein, the term "substantially free of amorphous compound 13" means that the compound does not contain a significant amount of amorphous compound 13. In certain embodiments, at least about 95% by weight of crystalline compound 13 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 13 is present.

[0407] It has been found that compound 13 can exist in at least one polymorphic form. In some embodiments, compound 13 is substantially free of other polymorphic forms.

[0408] In some embodiments, compound 13 is amorphous. In some embodiments, compound 13 is amorphous and substantially free of crystalline compound 13.

[0409] A method for preparing compound 13 is described below.

[0410] In some embodiments, the present invention provides compound 13, wherein the compound is crystalline.

[0411] In some embodiments, the present invention provides Compound 13, wherein said compound is a crystalline solid substantially free of amorphous Compound 13.

[0412] In some embodiments, the present invention provides compound 13, wherein the compound is substantially free of impurities.

[0413] In some embodiments, the present invention provides a composition comprising compound 13 and a pharmaceutically acceptable carrier or excipient.

[0414] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 13 or a composition thereof to the patient.

[0415] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 13 or a composition thereof, wherein compound 13 is in a crystalline form described herein.

[0416] Compound 14 (d3-Compound A) According to one embodiment, the present invention provides the free base form of deuterated Compound A, designated Compound 14. [ka] 14

[0417] It is believed that compound 14 can exist in various physical forms. For example, compound 14 can be in solution, suspension, or solid form. In certain embodiments, compound 14 is in solid form. When compound 14 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0418] In some embodiments, the present invention provides Compound 14 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess synthesis reagents, excess Compound A, residual solvent, or other impurities that may result from the preparation and / or isolation of Compound 14. In certain embodiments, the composition is at least about 95% by weight of Compound 14. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 14.

[0419] According to one embodiment, compound 14 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 14 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 14 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0420] The structure shown for compound 14 is also meant to include all tautomeric and isomeric forms of compound 14.

[0421] It has been found that compound 14 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0422] In certain embodiments, compound 14 is a crystalline solid. In other embodiments, compound 14 is a crystalline solid that is substantially free of amorphous compound 14. As used herein, the term "substantially free of amorphous compound 14" means that the compound does not contain a significant amount of amorphous compound 14. In certain embodiments, at least about 95% by weight of crystalline compound 14 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 14 is present.

[0423] It has been found that compound 14 can exist in at least one polymorphic form. In some embodiments, compound 14 is substantially free of other polymorphic forms.

[0424] In some embodiments, compound 14 is amorphous. In some embodiments, compound 14 is amorphous and substantially free of crystalline compound 14.

[0425] A method for preparing compound 14 is described below.

[0426] In some embodiments, the present invention provides compound 14, wherein the compound is crystalline.

[0427] In some embodiments, the present invention provides Compound 14, wherein said compound is a crystalline solid substantially free of amorphous Compound 14.

[0428] In some embodiments, the present invention provides compound 14, wherein the compound is substantially free of impurities.

[0429] In some embodiments, the present invention provides a composition comprising compound 14 and a pharmaceutically acceptable carrier or excipient.

[0430] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 14 or a composition thereof to the patient.

[0431] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 14 or a composition thereof, wherein compound 14 is in a crystalline form described herein.

[0432] The free base form of Compound A It is believed that compound A can exist in various physical forms.For example, compound A can be in solution, suspension or solid form.In certain embodiments, compound A is in solid form.When compound A is in solid form, the compound can be amorphous, crystalline or a mixture thereof.The exemplary solid form of compound A will be described in more detail below.

[0433] Compounds 15-22 (free base forms I, II, III, IV, V, VI, VII, and VIII of Compound A, respectively) It has been found that Compound A can exist in at least eight polymorphic forms.

[0434] In some embodiments, the present invention provides a polymorphic form of Compound 15, herein referred to as Compound A Form I. In some embodiments, Compound A Form I is substantially free of other polymorphic forms.

[0435] In certain embodiments, the present invention provides a polymorphic form of Compound 16, herein referred to as Form II of Compound A. In some embodiments, Form II of Compound A is substantially free of other polymorphic forms.

[0436] In certain embodiments, the present invention provides a polymorphic form of Compound 17, referred to herein as Form III of Compound A. In some embodiments, Form III of Compound A is substantially free of other polymorphic forms.

[0437] In certain embodiments, the present invention provides a polymorphic form of Compound 18, herein referred to as Form IV of Compound A. In some embodiments, Form IV of Compound A is substantially free of other polymorphic forms.

[0438] In certain embodiments, the present invention provides a polymorphic form of Compound 19, herein referred to as Form V of Compound A. In some embodiments, Form V of Compound A is substantially free of other polymorphic forms.

[0439] In certain embodiments, the present invention provides a polymorphic form of Compound 20, herein referred to as Form VI of Compound A. In some embodiments, Form VI of Compound A is substantially free of other polymorphic forms.

[0440] In certain embodiments, the present invention provides a polymorphic form of Compound 21, herein referred to as Form VII of Compound A. In some embodiments, Form VII of Compound A is substantially free of other polymorphic forms.

[0441] In certain embodiments, the present invention provides a polymorphic form of Compound 22, herein referred to as Form VIII of Compound A. In some embodiments, Form VIII of Compound A is substantially free of other polymorphic forms.

[0442] Compound 15 - Form I of Compound A According to one embodiment, the present invention provides the free base form I of Compound A, designated Compound 15.

[0443] In some embodiments, the present invention provides Compound 15 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 15. In certain embodiments, the composition is at least about 95% by weight of Compound 15. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 15.

[0444] According to one embodiment, compound 15 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 15 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 15 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0445] The structure shown for compound 15 is also meant to include all tautomeric and isomeric forms of compound 15.

[0446] It has been found that compound 15 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0447] In certain embodiments, Compound 15 is a crystalline solid. In other embodiments, Compound 15 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain significant amounts of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 15 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 15 is present.

[0448] In some embodiments, compound 15 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 31 below. [Table 31-1] [Table 31-2]

[0449] In some embodiments, compound 15 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 17.0, about 19.4, and about 20.9 degrees 2θ. In some embodiments, compound 15 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 17.0, about 19.4, and about 20.9 degrees 2θ. In some embodiments, compound 15 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 17.0, about 19.4, and about 20.9 degrees 2θ.

[0450] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0451] A method for preparing compound 15 is described below.

[0452] In some embodiments, the present invention provides compound 15, wherein the compound is crystalline.

[0453] In some embodiments, the present invention provides Compound 15, wherein said compound is a crystalline solid substantially free of amorphous Compound A.

[0454] In some embodiments, the present invention provides compound 15, wherein the compound is substantially free of impurities.

[0455] In some embodiments, the present invention provides a composition comprising compound 15 and a pharmaceutically acceptable carrier or excipient.

[0456] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 15 or a composition thereof to the patient.

[0457] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 15 or a composition thereof, wherein compound 15 is in a crystalline form described herein.

[0458] Compound 16 - Form II of Compound A According to one embodiment, the present invention provides the free base form II of Compound A, designated Compound 16.

[0459] In some embodiments, the present invention provides Compound 16 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 16. In certain embodiments, the composition is at least about 95% by weight of Compound 16. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 16.

[0460] According to one embodiment, compound 16 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 16 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 16 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0461] The structure shown for compound 16 is also meant to include all tautomeric and isomeric forms of compound 16.

[0462] It has been found that compound 16 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0463] In certain embodiments, Compound 16 is a crystalline solid. In other embodiments, Compound 16 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain significant amounts of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 16 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 16 is present.

[0464] In some embodiments, compound 16 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 32 below. [Table 32-1] [Table 32-2]

[0465] In some embodiments, compound 16 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 10.0, about 19.3, and about 22.2 degrees 2θ. In some embodiments, compound 16 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 10.0, about 19.3, and about 22.2 degrees 2θ. In some embodiments, compound 16 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 10.0, about 19.3, and about 22.2 degrees 2θ.

[0466] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0467] A method for preparing compound 16 is described below.

[0468] In some embodiments, the present invention provides compound 16, wherein the compound is crystalline.

[0469] In some embodiments, the present invention provides Compound 16, wherein said compound is a crystalline solid substantially free of amorphous Compound A.

[0470] In some embodiments, the present invention provides compound 16, wherein said compound is substantially free of impurities.

[0471] In some embodiments, the present invention provides a composition comprising compound 16 and a pharmaceutically acceptable carrier or excipient.

[0472] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 16 or a composition thereof to the patient.

[0473] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 16 or a composition thereof, wherein compound 16 is in a crystalline form described herein.

[0474] Compound 17 - Form III of Compound A According to one embodiment, the present invention provides the free base form III of Compound A, designated Compound 17.

[0475] In some embodiments, the present invention provides Compound 17 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 17. In certain embodiments, the composition is at least about 95% by weight of Compound 17. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 17.

[0476] According to one embodiment, compound 17 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 17 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 17 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0477] The structure shown for compound 17 is also meant to include all tautomeric and isomeric forms of compound 17.

[0478] It has been found that compound 17 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0479] In certain embodiments, Compound 17 is a crystalline solid. In other embodiments, Compound 17 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain significant amounts of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 17 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 17 is present.

[0480] In some embodiments, compound 17 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 33 below. [Table 33-1] [Table 33-2]

[0481] In some embodiments, compound 17 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.9, about 21.1, and about 22.5 degrees 2θ. In some embodiments, compound 17 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.9, about 21.1, and about 22.5 degrees 2θ. In some embodiments, compound 17 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.9, about 21.1, and about 22.5 degrees 2θ.

[0482] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0483] A method for preparing compound 17 is described below.

[0484] In some embodiments, the present invention provides compound 17, wherein the compound is crystalline.

[0485] In some embodiments, the present invention provides Compound 17, wherein the compound is a crystalline solid substantially free of amorphous Compound A.

[0486] In some embodiments, the present invention provides compound 17, wherein the compound is substantially free of impurities.

[0487] In some embodiments, the present invention provides a composition comprising compound 17 and a pharmaceutically acceptable carrier or excipient.

[0488] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 17 or a composition thereof to the patient.

[0489] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 17 or a composition thereof, wherein compound 17 is in a crystalline form described herein.

[0490] Compound 18 - Form IV of Compound A According to one embodiment, the present invention provides the free base form IV of Compound A, represented by Compound 18.

[0491] In some embodiments, the present invention provides Compound 18 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 18. In certain embodiments, the composition is at least about 95% by weight of Compound 18. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 18.

[0492] According to one embodiment, compound 18 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 18 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 18 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0493] The structure shown for compound 18 is also meant to include all tautomeric and isomeric forms of compound 18.

[0494] It has been found that compound 18 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0495] In certain embodiments, Compound 18 is a crystalline solid. In other embodiments, Compound 18 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain significant amounts of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 18 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 18 is present.

[0496] In some embodiments, compound 18 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 34 below. [Table 34-1] [Table 34-2] [Table 34-3]

[0497] In some embodiments, compound 18 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.7, about 20.2, and about 22.4 degrees 2θ. In some embodiments, compound 18 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.7, about 20.2, and about 22.4 degrees 2θ. In some embodiments, compound 18 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.7, about 20.2, and about 22.4 degrees 2θ.

[0498] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0499] A method for preparing compound 18 is described below.

[0500] In some embodiments, the present invention provides compound 18, wherein the compound is crystalline.

[0501] In some embodiments, the present invention provides Compound 18, wherein said compound is a crystalline solid substantially free of amorphous Compound A.

[0502] In some embodiments, the present invention provides compound 18, wherein said compound is substantially free of impurities.

[0503] In some embodiments, the present invention provides a composition comprising compound 18 and a pharmaceutically acceptable carrier or excipient.

[0504] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 18 or a composition thereof to the patient.

[0505] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 18 or a composition thereof, wherein compound 18 is in a crystalline form described herein.

[0506] Compound 19 - Form V of Compound A According to one embodiment, the present invention provides the free base form V of Compound A, designated Compound 19.

[0507] In some embodiments, the present invention provides Compound 19 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 19. In certain embodiments, the composition is at least about 95% by weight of Compound 19. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 19.

[0508] According to one embodiment, compound 19 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 19 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 19 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0509] The structure shown for compound 19 is also meant to include all tautomeric and isomeric forms of compound 19.

[0510] It has been found that compound 19 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0511] In certain embodiments, Compound 19 is a crystalline solid. In other embodiments, Compound 19 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain a significant amount of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 19 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 19 is present.

[0512] In some embodiments, compound 19 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 35 below. [Table 35-1] [Table 35-2]

[0513] In some embodiments, compound 19 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 16.2, about 17.8, and about 20.0 degrees 2θ. In some embodiments, compound 19 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 16.2, about 17.8, and about 20.0 degrees 2θ. In some embodiments, compound 19 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 16.2, about 17.8, and about 20.0 degrees 2θ.

[0514] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0515] A method for preparing compound 19 is described below.

[0516] In some embodiments, the present invention provides compound 19, wherein the compound is crystalline.

[0517] In some embodiments, the present invention provides Compound 19, wherein the compound is a crystalline solid substantially free of amorphous Compound A.

[0518] In some embodiments, the present invention provides compound 19, wherein the compound is substantially free of impurities.

[0519] In some embodiments, the present invention provides a composition comprising compound 19 and a pharmaceutically acceptable carrier or excipient.

[0520] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 19 or a composition thereof to the patient.

[0521] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 19 or a composition thereof, wherein compound 19 is in a crystalline form described herein.

[0522] Compound 20 - Form VI of Compound A According to one embodiment, the present invention provides the free base form VI of Compound A, represented by compound 20.

[0523] In some embodiments, the present invention provides Compound 20 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 20. In certain embodiments, the composition is at least about 95% by weight of Compound 20. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 20.

[0524] According to one embodiment, compound 20 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 20 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 20 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0525] The structure shown for compound 20 is also meant to include all tautomeric and isomeric forms of compound 20.

[0526] It has been found that compound 20 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0527] In certain embodiments, Compound 20 is a crystalline solid. In other embodiments, Compound 20 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain significant amounts of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 20 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 20 is present.

[0528] In some embodiments, compound 20 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 36 below. [Table 36-1] [Table 36-2]

[0529] In some embodiments, compound 20 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.2, about 18.7, and about 20.8 degrees 2θ. In some embodiments, compound 20 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.2, about 18.7, and about 20.8 degrees 2θ. In some embodiments, compound 20 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.2, about 18.7, and about 20.8 degrees 2θ.

[0530] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0531] A method for preparing compound 20 is described below.

[0532] In some embodiments, the present invention provides compound 20, wherein the compound is crystalline.

[0533] In some embodiments, the present invention provides Compound 20, wherein said compound is a crystalline solid substantially free of amorphous Compound A.

[0534] In some embodiments, the present invention provides compound 20, wherein said compound is substantially free of impurities.

[0535] In some embodiments, the present invention provides a composition comprising compound 20 and a pharmaceutically acceptable carrier or excipient.

[0536] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 20 or a composition thereof to the patient.

[0537] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 20 or a composition thereof, wherein compound 20 is in a crystalline form described herein.

[0538] Compound 21 - Form VII of Compound A According to one embodiment, the present invention provides the free base form VII of Compound A, represented by compound 21.

[0539] In some embodiments, the present invention provides Compound 21 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvents, or other impurities that may result from the preparation and / or isolation of Compound 21. In certain embodiments, the composition is at least about 95% by weight of Compound 21. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 21.

[0540] According to one embodiment, compound 21 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 21 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 21 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0541] The structure shown for compound 21 is also meant to include all tautomeric and isomeric forms of compound 21.

[0542] It has been found that compound 21 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0543] In certain embodiments, Compound 21 is a crystalline solid. In other embodiments, Compound 21 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain significant amounts of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 21 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 21 is present.

[0544] In some embodiments, compound 21 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 37 below. [Table 37-1] [Table 37-2]

[0545] In some embodiments, compound 21 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 14.4, about 18.0, and about 19.9 degrees 2θ. In some embodiments, compound 21 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 14.4, about 18.0, and about 19.9 degrees 2θ. In some embodiments, compound 21 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 14.4, about 18.0, and about 19.9 degrees 2θ.

[0546] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0547] A method for preparing compound 21 is described below.

[0548] In some embodiments, the present invention provides compound 21, wherein the compound is crystalline.

[0549] In some embodiments, the present invention provides Compound 21, wherein said compound is a crystalline solid substantially free of amorphous Compound A.

[0550] In some embodiments, the present invention provides compound 21, wherein said compound is substantially free of impurities.

[0551] In some embodiments, the present invention provides a composition comprising compound 21 and a pharmaceutically acceptable carrier or excipient.

[0552] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 21 or a composition thereof to the patient.

[0553] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 21 or a composition thereof, wherein compound 21 is in a crystalline form described herein.

[0554] Compound 22 - Form VIII of Compound A According to one embodiment, the present invention provides the free base form VIII of Compound A, represented by compound 22.

[0555] In some embodiments, the present invention provides Compound 22 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess benzenesulfonic acid, excess synthesis reagents, excess Compound A, residual solvent, or other impurities that may result from the preparation and / or isolation of Compound 22. In certain embodiments, the composition is at least about 95% by weight of Compound 22. In yet other embodiments of the present invention, the composition is at least about 99% by weight of Compound 22.

[0556] According to one embodiment, compound 22 is present in the composition in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent, percentages being based on the total weight of the composition. According to another embodiment, compound 22 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 22 contains less than or equal to about 1.0% HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, relative to the total area of the HPLC chromatogram.

[0557] The structure shown for compound 22 is also meant to include all tautomeric and isomeric forms of compound 22.

[0558] It has been found that compound 22 can exist in various solid forms. Exemplary such forms include the polymorphs described herein.

[0559] In certain embodiments, Compound 22 is a crystalline solid. In other embodiments, Compound 22 is a crystalline solid that is substantially free of amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain significant amounts of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound 22 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 22 is present.

[0560] In some embodiments, compound 22 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 38 below. [Table 38-1] [Table 38-2]

[0561] In some embodiments, compound 22 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from about 18.7, about 21.2, and about 23.0 degrees 2θ. In some embodiments, compound 22 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from about 18.7, about 21.2, and about 23.0 degrees 2θ. In some embodiments, compound 22 is characterized in an X-ray powder diffraction pattern having all three peaks selected from about 18.7, about 21.2, and about 23.0 degrees 2θ.

[0562] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0563] A method for preparing compound 22 is described below.

[0564] In some embodiments, the present invention provides compound 22, wherein the compound is crystalline.

[0565] In some embodiments, the present invention provides Compound 22, wherein said compound is a crystalline solid substantially free of amorphous Compound A.

[0566] In some embodiments, the present invention provides compound 22, wherein said compound is substantially free of impurities.

[0567] In some embodiments, the present invention provides a composition comprising compound 22 and a pharmaceutically acceptable carrier or excipient.

[0568] In some embodiments, the present invention provides a method for treating, preventing, and / or reducing the risk of a kinase-mediated disease, disorder, or condition in a patient, the method comprising administering compound 22 or a composition thereof to the patient.

[0569] In some embodiments, the present invention provides a method of treating cancer in a patient by inhibiting the activity of a kinase, the method comprising administering to the patient compound 22 or a composition thereof, wherein compound 22 is in a crystalline form described herein.

[0570] In some embodiments, the present invention provides Compound 1 (Form I), Compound 2 (Form I), Compound 2 (Form II), Compound 2 (Form III), Compound 2 (Form IV), Compound 2 (Form V), Compound 2 (Form VI), Compound 2 (Form VII), Compound 2 (Form VIII), Compound 2 (Form IX), Compound 2 (Form X), Compound 2 (Form XI), Compound 2 (Form XII), Compound 2 (Form XIII), Compound 3 (Form I), Compound 4 (Form I), Compound 5 (Form I), Compound 6 (Form I), Compound 7 (Form I), Compound 8 (Form I), Compound 9 (Form I), Compound 10 (Form I), Compound 11 (Form I), Compound 12 (Form I), Compound 13 (Form I), Compound 14 (Form I), Compound 15 (Form I), Compound 16 (Form I), Compound 17 (Form I), Compound 18 (Form I), Compound 19 ... Compound 5 (Form I), Compound 6 (Form I), Compound 7 (Form I), Compound 8 (Form I), Compound 9, Compound 10 (Form I), Compound 11 (Form I), Compound 12 (Form I), Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23 (Form I), Compound 24 (Form I), Compound 25 (Form I), and Compound 26 (Form I).

[0571] In some such embodiments, the invention provides compositions comprising one of the above compound forms and a pharmaceutically acceptable carrier or excipient. In some such embodiments, the invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0572] Embodiments of the present disclosure are directed to other salt forms of Compound A, including Compound A citrate, Compound A oxalate, Compound A malonate, Compound A succinate, Compound A fumarate, Compound A L(+)-tartrate, Compound A D(-)-tartrate, Compound A benzoate, Compound A ascorbate, Compound A phosphate, Compound A L-aspartate, Compound A ketoglutarate, Compound A gluconate, Compound A lactate, Compound A acetate, and Compound A pamoate.

[0573] General Methods for Providing Salt Compounds Compound A is prepared according to the methods detailed in the '500 publication, which is incorporated herein by reference in its entirety. Salt compounds of general formula X (which formula includes, among others, salt compounds 1-12 and 23-26, and / or specific forms thereof) are prepared from compound A according to the following general scheme: [ka]

[0574] For example, each of Compounds 1-12 and 23-26, and forms thereof, are prepared from Compound A by combining Compound A with an appropriate acid to form the acid salt. Accordingly, another aspect of the present invention provides methods for preparing Compounds 1-12 and 23-26, and forms thereof.

[0575] As generally described above, in some embodiments, the present invention provides a method for preparing a salt compound of general formula X: [ka] Salt Compound X This method is [ka] Compound A It involves combining compound A with a suitable acid and optionally a suitable solvent under conditions suitable to form a salt compound of general formula X.

[0576] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the present invention provides a method for preparing the hydrochloride salt of Compound A. In certain embodiments, the hydrochloride salt of Compound A is Compound 1. In certain embodiments, the hydrochloride salt of Compound A is Form I of Compound 1.

[0577] In some embodiments, the suitable acid is benzenesulfonic acid. In some embodiments, the present invention provides a method for preparing a besylate salt of Compound A. In certain embodiments, the besylate salt of Compound A is Compound 2. In certain embodiments, the besylate salt of Compound A is Form I of Compound 2. In certain embodiments, the besylate salt of Compound A is Form II of Compound 2. In certain embodiments, the besylate salt of Compound A is Form III of Compound 2. In certain embodiments, the besylate salt of Compound A is Form IV of Compound 2. In certain embodiments, the besylate salt of Compound A is Form V of Compound 2. In certain embodiments, the besylate salt of Compound A is Form VI of Compound 2. In certain embodiments, the besylate salt of Compound A is Form VII of Compound 2. In certain embodiments, the besylate salt of Compound A is Form VIII of Compound 2. In certain embodiments, the besylate salt of Compound A is Form IX of Compound 2. In certain embodiments, the besylate salt of Compound A is Form X of Compound 2. In certain embodiments, the besylate salt of Compound A is Form XI of Compound 2. In certain embodiments, the besylate salt of Compound A is Form XII of Compound 2. In certain embodiments, the besylate salt of Compound A is Form XIII of Compound 2.

[0578] In some embodiments, the suitable acid is maleic acid. In some embodiments, the present invention provides a method for preparing a maleate salt of Compound A. In certain embodiments, the maleate salt of Compound A is Compound 3. In certain embodiments, the maleate salt of Compound A is Form I of Compound 3.

[0579] In some embodiments, the suitable acid is p-toluenesulfonic acid. In some embodiments, the present invention provides a method for preparing a tosylate salt of Compound A. In certain embodiments, the tosylate salt of Compound A is Compound 4.

[0580] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the present invention provides a method for preparing a sulfate salt of Compound A. In certain embodiments, the sulfate salt of Compound A is Compound 5.

[0581] In some embodiments, the suitable acid is a sulfonic acid. In some embodiments, the present invention provides a method for preparing a sulfonate salt of Compound A. In one particular embodiment, the sulfonate salt of Compound A is Compound 6.

[0582] In some embodiments, the suitable acid is ethanesulfonic acid. In some embodiments, the present invention provides a method for preparing an esylate salt of Compound A. In certain embodiments, the esylate salt of Compound A is Compound 7.

[0583] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the present invention provides a method for preparing a mesylate salt of Compound A. In certain embodiments, the mesylate salt of Compound A is Compound 8.

[0584] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the present invention provides a method for preparing a dimesylate salt of Compound A. In certain embodiments, the dimesylate salt of Compound A is Compound 9.

[0585] In some embodiments, the suitable acid is R-camphorsulfonic acid. In some embodiments, the present invention provides a method for preparing the R-camsylate salt of Compound A. In certain embodiments, the R-camsylate salt of Compound A is Compound 10. In certain embodiments, the R-camsylate salt of Compound A is Form I of Compound 10.

[0586] In some embodiments, the suitable acid is S-camphorsulfonic acid. In some embodiments, the present invention provides a method for preparing the S-camsylate salt of Compound A. In one particular embodiment, the S-camsylate salt of Compound A is Compound 11.

[0587] In some embodiments, the suitable acid is hydrobromic acid. In some embodiments, the present invention provides a method for preparing a bromate salt of Compound A. In certain embodiments, the bromate salt of Compound A is Compound 12. In certain embodiments, the bromate salt of Compound A is Form I of Compound 12.

[0588] In some embodiments, the suitable acid is phosphoric acid. In some embodiments, the present invention provides a method for preparing a phosphate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound 23. In certain embodiments, the phosphate salt of Compound A is Form I of Compound 23.

[0589] In some embodiments, the suitable acid is citric acid. In some embodiments, the present invention provides a method for preparing a citrate salt of Compound A. In certain embodiments, the citrate salt of Compound A is Compound 24. In certain embodiments, the citrate salt of Compound A is Form I of Compound 24.

[0590] In some embodiments, the suitable acid is L-tartaric acid. In some embodiments, the present invention provides a method for preparing the L-tartrate salt of Compound A. In certain embodiments, the L-tartrate salt of Compound A is Compound 25. In certain embodiments, the L-tartrate salt of Compound A is Form I of Compound 25.

[0591] In some embodiments, the suitable acid is L-malonic acid. In some embodiments, the present invention provides a method for preparing a malonate salt of Compound A. In certain embodiments, the malonate salt of Compound A is Compound 26. In certain embodiments, the malonate salt of Compound A is Form I of Compound 26.

[0592] A suitable solvent can be any solvent system (eg, one solvent or mixture of solvents) in which Compound A and / or the acid are soluble or at least partially soluble.

[0593] Examples of suitable solvents useful in the present invention include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0594] In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, or acetone, where the solvent is anhydrous or combined with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, the suitable solvent is ethanol. In some embodiments, the suitable solvent is absolute ethanol. In some embodiments, the suitable solvent is MTBE.

[0595] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, the suitable solvent is a mixture of acetonitrile and water. In certain embodiments, the suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, the suitable solvent is diethyl ether. In certain embodiments, the suitable solvent is water. In certain embodiments, the suitable solvent is methyl ethyl ketone. In certain embodiments, the suitable solvent is toluene.

[0596] In some embodiments, the present invention provides a method for preparing a salt compound of general formula X, comprising one or more steps of removing a solvent and adding a solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. Means for solvent removal are known in the synthetic and chemical arts and include, but are not limited to, any of the means described herein and in the examples.

[0597] In some embodiments, the method for preparing the salt compound of general formula X includes one or more steps of heating or cooling the preparation.

[0598] In some embodiments, the method of preparing the salt compound of general formula X comprises one or more steps of stirring or agitating the preparation.

[0599] In some embodiments, the method for preparing a salt compound of general formula X comprises adding a suitable acid to a solution or slurry of compound A.

[0600] In some embodiments, the method for preparing the salt compound of general formula X includes a heating step.

[0601] In certain embodiments, the salt compound of formula X precipitates from the mixture. In other embodiments, the salt compound of formula X crystallizes from the mixture. In other embodiments, the salt compound of formula X crystallizes from the solution after seeding the solution (i.e., adding crystals of the salt compound of formula X to the solution).

[0602] The salt compound of formula X precipitates from the reaction mixture or is produced by removing some or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an anti-solvent such as heptane, by cooling, or by various combinations of these methods.

[0603] As generally described above, the salt compound of formula X is optionally isolated. It will be understood that the salt compound of formula X can be isolated by any suitable physical means known to those of skill in the art. In certain embodiments, the precipitated solid salt compound of formula X is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of formula X is separated from the supernatant by decanting the supernatant.

[0604] In certain embodiments, the salt compound of Formula X is separated from the supernatant by filtration.

[0605] In certain embodiments, the isolated salt compound of formula X is dried in air. In other embodiments, the isolated salt compound of formula X is dried under reduced pressure, optionally at elevated temperature.

[0606] Uses of the compounds and pharmaceutically acceptable compositions thereof FGFR receptors (FGFR1, FGFR2, FGFR3, and FGFR4) share several structural features, including three extracellular immunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain separated by a kinase insert domain, followed by a cytoplasmic C-terminal tail (Johnson et al., Adv. Cancer Res. 60:1-40, 1993; and Wilkie et al., Curr. Biol. 5:500-507, 1995). In FGFR1, the kinase insert domain spans positions 582-595 of the αA1 isoform of FGFR1. In FGFR2, the kinase insert domain spans positions 585-598 of the FGFR2 Ile isoform. In FGFR3, the kinase insert domain spans positions 576-589 of the FGFR3 Ile isoform. In FGFR4, the kinase insert domain spans positions 571-584 of FGFR4 isoform I. The c-terminal tail of the FGFR begins following the end of the tyrosine kinase domain and extends to the c-terminus of the protein. Several isoforms of each FGFR have been identified, which are the result of alternative splicing of the mRNA (Johnson et al., Mol. Cell. Biol. 11:4627-4634, 1995; and Chellaiah et al., J. Biol. Chem. 269:11620-11627, 1994).

[0607] Some of the receptor variants resulting from this alternative splicing have different ligand-binding specificities and affinities (Zimmer et al., J. Biol. Chem. 268:7899-7903, 1993; Cheon et al., Proc. Natl. Acad. Sci. USA 91:989-993, 1994; and Miki et al., Proc. Natl. Acad. Sci. USA 89:246-250, 1992). Protein sequences of FGFR proteins and nucleic acids encoding FGFR proteins are known in the art. Signal transduction by FGFRs controls major biological processes, including cell proliferation, survival, migration, and differentiation. Dysregulation of FGFR genes, FGFR proteins, or their expression, activity, or levels has been associated with many types of cancer. For example, dysregulation of FGFRs can occur through multiple mechanisms, including overexpression of FGFR genes, amplification of FGFR genes, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements leading to FGFR fusion proteins. Dysregulation of FGFR genes, FGFR proteins, or their expression or activity, or levels, can lead to (or partially cause) the development of various FGFR-associated cancers.

[0608] FGFR fusion proteins are known in the art. For example, Baroy et al.,PloS One;11(9):e0163859.doi:10.1371 / journal.pone.0163859,2016;Ren et al.,Int.J.Cancer,139(4):836-40,2016;Marchwicka et al.,Cell Biosci.,6:7.doi:10.1186 / s13578-016-0075-9,2016;PCT Patent Application Publication No.WO 2014 / 071419A2;USPatent Application Publication No.2015 / 0366866Al;PCT Patent Application Publication No.WO 2016 / 084883Al;PCT Patent Application Publication No.WO 2016 / 030509Al;PCT Patent Application Publication No.WO 2015 / 150900A2;PCT Patent Application Publication No.WO 2015 / 120094A2;Kasaian et al.,BMC Cancer.,15:984,2015;Vakil et al.,Neuro-Oncology,18:Supp.Supplement 3,pp.iii93.Abstract Number:LG-64,17 thInternational Symposium on Pediatric Neuro-Oncology,Liverpool,United Kingdom,2016;Astsaturov et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,Abstract Number:11504,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL;Heinrich et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,Abstract Number:11012,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL;Hall et al.,Molecular Cancer Therapeutics,Vol.14,No.12,Supp.2,Abstract Number:B151,AACR-NCI-EORTC International Conference:Molecular Targets and Cancer Therapeutics,2015;Reuther et al.,Journal of Molecular Diagnostics,Vol.17,No.6,pp.813,Abstract Number:ST02,2015 Annual Meeting of the Association for Molecular Pathology,Austin,TX;Moeini et al.,Clin.Cancer.Res.,22(2):291-300,2016;Schrock et al,J Thorac.Oneal.pii S1556-0864(18)30674-9,2018.doi:10.1016 / j.jtho.2018.05.027;Pekmezci et al,Acta Nurotapho / .Commun.6(1):47.doi:10.1186 / s40478-018-0551-z;Lowery et al.Clin Cancer Res.pii:clincanres.0078.2018.doi:10.1158 / 1078-0432.CCR-18-0078;Ryland et al.J Clin Patho / pii:jclinpath-2018-205195,2018.doi:10.1136 / jclinpath-2018-205195;Ferguson et al.J Neuropatho / Exp Neural 77(6):437-442,2018.doi:10.1093 / jnen / nly022;Wu et al,BMC Cancer 18(1):343,2018.doi:10.1186 / s12885-018-4236-6;Shibata et al,Cancer Sci 109(5):1282-1291,2018.doi:10.1111 / cas.13582;Papdopoulos et al,Br J Cancer,1117(11):1592-1599,2017.doi:10.1038 / bjc.2017.330;Hall et al,PLoS One,11(9):e1062594,2016.doi:0.1371 / journal.pone.0162594;Johnson et al,Oncologist,22(12):1478-1490,2017.doi:10.1634 / theoncologist.2017-0242;Yang et al,Am J Hum Genet,98(5):843-856,2016.doi:10.1016 / j.ajhg.2016.03.017;U.S.Patent Application Publication No.2013 / 009621;Babina and Turner,Nat Rev Cancer 17(5):318-332,2017.doi:10.1038 / nrc.2017.8;Ryland et al,J Clin Patho / .,2018 May 14.pii:jclinpath-2018-205195.doi:10.1136 / jclinpath-2018-205195;Kumar et al,Am J Clin Patho / .143(5):738-748,2015.doi:10.1309 / AJCPUD6W1JLQQMNA;Grand et al,Genes Chromosomes Cancer40(1):78-83,2004.doi:10.1002 / gcc.20023;Reeser,et al,J Mo / Diagn,19(5):682-696,2017.doi:10.1016 / j.jmoldx.2017.05.006;Basturk,et al,Mod Patho / ,30(12):1760-1772,2017.doi:10.1038 / modpathol.2017.60;Wang,et al,Cancer 123(20):3916-3924,2017.doi:10.1002 / cncr.30837;Kim,et al, Oncotarget, 8(9):15014-15022, 2017. doi:10.18632 / oncotarget.14788; Busse, et al, Genes Chromosomes Cancer, 56(10):730-749, 2017. doi:10.1002 / gcc.22477; Shi, et al, J Transl Med., 14(1):339, 2016. doi:10.1186 / s12967-016-1075-6, each of which is incorporated herein by reference.

[0609] UniParc entry UPI00000534B8;UniParc entry UPI000000lCOF;UniParc entry UPI000002A99A;UniParc entry UPI000012A72A;UniParc entry UPI000059D1C2;UniParc entry UPI000002A9AC;Uniparc entry UPI000012A72C;Uniparc entry UPI000012A72D; UPI000013EOB8;Uniparc entry UPI0001CE06A3;Gene bank entry BAD92868.l;Ang et al.,Diagn.Mo / .Patho / .Feb 24,2014;USPatent Application Publication No.2011 / 0008347;Gallo et al.,Cytokine Growth Factor Rev.26:425-449,2015;Davies et al.,J.Cancer Res.65:7591,2005;Kelleher et al.,Carcinogenesis 34:2198,2013;Cazier et al.,Nat.Commun.5:3756,2014;Liu et al al.,Genet.Mo / .Res.13:1109,2014;Trudel et al.,Blood 107:4039,2006;Gallo et al.,Cytokine Growth Factor Rev.26:425,2015;Liao et al.,Cancer Res.73:5195-5205,2013;Martincorena et al al.,Science 348:880(2015);USPatent Application Publication No.US2016 / 0235744Al;USPatent No.9254288B2;USPatent No.9267176B2;S2016 / 0215350Al;European Patent Application Publication No.EP3023101Al;PCT Patent Application Publication No.WO2016105503Al;Rivera et al.,Acta.Neuropatho / .,131(6):847-63,2016;Lo Iacono et al.,Oncotarget.,7(12):14394-404,2016;Deeken et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,pp.iii93.Abstract Number:el 7520,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL;Sullivan et al.,Journal of Clinical Oncology,34:Supp.Supplement 15,pp.iii93.Abstract Number:11596,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL;Nguyen et al.,Molecular Cancer Therapeutics,Vol.14,No.12,Supp.2,Abstract Number:C199,AACR-NCI-EORTC International Conference:Molecular Targets and Cancer Therapeutics,2015;Li et al.,Hum.Patho / .,55:143-50,2016;European Patent No.EP2203449B1;Yoza et al.,Genes Cells.,(10):1049-1058,2016;U.S.Patent No.9,254,288B2;European Patent Application Publication No.3023101Al;PCT Application Publication No.WO2015 / 099127Al;European Patent No.EP2203449Bl;Yoza et al.,Genes Cells.,(10):1049-1058,2016;Bunney et al.,EbioMedicine,2(3):194-204,2015;Byron et al. al.,Neop / asia,15(8):975-88,2013;European Patent Application Publication No.EP3023101Al;PCT Application Publication No.WO2015 / 099127Al;Thussbas et al.,J.Clin.Oneal.,24(23):375-88;Chell et al. al.,Oncogene,32(25):3059-70,2013;Tanizaki et al,Cancer Res.75(15):3149-3146 doi:10.1158 / 0008-5472.CAN-14-3771;Yang et al,EBioMedicine pii S2352-3964(18)30218-4.doi:10.1016 / j.ebiom.2018.06.011;Jakobsen,et al Oncotarget 9(40):26195-26208,2018.doi:10.18632 / oncotarget,Stone et al; 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[0610] The compounds of the present disclosure have been shown to inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4 and are therefore believed to be useful in treating diseases and disorders that can be treated with inhibitors of FGFR1, FGFR2, FGFR3, and / or FGFR4. For example, the compounds of the present disclosure may be useful in treating FGFR-related diseases and disorders, e.g., proliferative disorders such as cancer, including hematological cancers and solid tumors, and angiogenesis-related disorders. The compounds of the present disclosure may also be useful in treating disorders resulting from autosomal dominant mutations in FGFRs, e.g., FGFR3, including developmental disorders. Developmental disorders that can be treated with the compounds of the present disclosure include achondroplasia (Ach) and related chondrodysplastic syndromes, including hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and lethal skeletal dysplasia (TD).

[0611] Non-limiting examples of FGFR-related diseases and disorders include acanthosis nigricans, achondroplasia, Apert syndrome, Beare-Stevenson syndrome (BSS), camptodactyly, tall stature, and deafness syndrome (CATSHL), cleft lip and palate, congenital heart disease (e.g., with ambiguous genitalia), craniosynostosis, Crouzon syndrome, ectrodactyly, cerebrocranial dermatolipomatosis, Hartsfield syndrome, hypochondroplasia, hypogonadotropic hypogonadism (e.g., anosmia), and These conditions include hypogonadotropic hypogonadism with or without eczema, Kallmann syndrome, ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, microphthalmia, Muenke coronal synostosis, osteophytic dysplasia, Pfeiffer syndrome, seborrheic keratosis, syndactyly, lethal osteodysplasia (e.g., type I or type II), trigonocephaly (also known as metopic craniosynostosis), and tumor-induced osteomalacia.

[0612] Non-limiting examples of FGFR1-associated diseases and disorders include congenital heart disease (e.g., those with ambiguous genitalia), craniosynostosis, cerebrocranial dermatolipomatosis, Hartsfield's syndrome, hypogonadotropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without olfactory dysfunction, Kallmann syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, osteophytic dysplasia, Pfeiffer syndrome, trigonocephaly 1 (also known as metopic craniosynostosis), and tumor-induced osteomalacia.

[0613] Non-limiting examples of FGFR2-associated diseases and disorders include Apert syndrome, Beare-Stevenson syndrome (BSS), Crouzon syndrome, ectrodactyly, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, Pfeiffer syndrome, and syndactyly. Non-limiting examples of FGFR3-associated diseases and disorders include acanthosis nigricans, achondroplasia, camptodactyly, tall stature, and deafness syndrome (CATSHL), cleft lip and cleft palate, craniosynostosis, hypochondroplasia, microphthalmia, Muenke coronal synostosis, seborrheic keratosis, and lethal dysplasia (e.g., type I or type II). Also, UniParc entry UPI00000534B8;UniParc entry UPI000000lCOF;Uni Parc entry UPI000002A99A;UniParc entry UPI000012A72A;Yong-Xing et al.,Hum.Mol.Genet.9(13):2001-2008,2000;Eeva-Maria Laitinen et al.,PLoS One 7(6):e39450,2012;Hart et al.,Oncogene 19(29):3309-3320,2000;Shiang et al.,Cell 76:335-342,1994;Rosseau et al.,Nature 371:252-254,1994;Tavormina et al. al.,Nature Genet.9:321-328,1995;Bellus et al.,Nature Genet.10:357-359,1995;Muenke et al.,Nature Genet.8:269-274,1994;Rutland et al.,Nature Genet.9:173-176,1995;Reardon et al.,Nature Genet.8:98-103,1994;Wilkie et al.,Nature Genet.9:165-172,1995;Jabs et al.,Nature Genet.8:275-279,1994;Japanese Patent No.JP05868992B2;Ye et al. al.,Plast.Reconstr.Surg.,137(3):952-61,2016;USPatent No.9447098B2;Bellus et al.,Am.J.Med.Genet.85(1):53-65,1999;PCT Patent Application Publication No.WO2016139227Al;Australian Patent Application Publication No.AU2014362227Al;Chinese Patent No.CN102741256B;Ohishi et al.,Am.J.Med.Genet.A.,doi:10.1002 / ajmg.a.37992,2016;Nagahara et al.,Clin.Pediatr.Endocrinol.,25(3):103-106,2016;Hibberd et al.,Am.J.Med.Genet.A.,doi:10.1002 / ajmg.a.37862,2016;Dias et al.,Exp.Mol.Pathol.,101(1):116-23,2016;Lin et al.,Mol.Med.Rep.,14(3):1941-6,2016;Barnett et al.,Hum.Mutat.,37(9):955-63,2016;Krstevska-Konstantinova et al.,Med.Arch.,70(2):148-50,2016;Kuentz et al.,Br.J.Dermatol.,doi:10.1111 / bjd.14681,2016;Ron et al.,Am.J.Case Rep.,15;17:254-8,2016;Fernandes et al.,Am.J.Med.Genet.A.,170(6):1532-7,2016;Lindy et al.,Am.J.Med.Genet.A.,170(6):1573-9,2016;Bennett et al.,Am.J.Hum.Genet.,98(3):579-87,2016;lchiyama et al.,J.Eur.Acad.Dermatol.Venereal.,30(3):442-5,2016;Zhao et al.,Int.J.Clin.Exp.Med.,8(10):19241-9,2015;Hasegawa et al.,Am.J.Med.Genet.A.,170A(5):1370-2,2016;Legeai-Mallet,Endocr.Dev.,30:98-105,2016;Takagi,Am.J.Med.Genet.A.,167A(ll):2851-4,2015;Goncalves,Fertil.Steril.,104(5):1261-7.el,2015;Miller et al.,Journal of Clinical Oncology: Suppl. 15,pp.iii93.AbstractNumber:e22500,2016 Annual Meeting of the American Society of Clinical Oncology,Chicago,IL;Sarabipour et al.,J.Mol.Biol.,428(20):3903-3910,2016;Escobar et al. al.,Am.J.Med.Genet.A.,170(7):1908-11, 2016;Mazen et al.,Sex Dev.,10(1):16-22,2016;Taylan et al.,J Allergy Clin lmmunol,136(2):507-9,2015.doi:10.1016 / j.jaci.2015.02.010;Kant et al,EuroJourn Endocrinol,172(6):763-770,2015.doi:10.1530 / E-E-Gellez-Gellez-1945; et al,Am J med Genet A,176(1):161-166,2018.doi:10.1002 / ajmg.a.38526;Lei and Deng,Int J Biol Sci 13(9):1163:1171,2017.doi:10.7150 / ijbs.Eunie et al.,2972; Hum Genet,14(3):289-298,2006.doi:10.1038 / sj.ejhg.5201558;Karadimas et al,Prenat Diagn,26(3):258-261,2006.doi:10.1002 / pd.1392;Hum Momi et al. 13(19):2313-2324,2004.doi:10.1093 / hmg / ddh235; Trarbach et al, J Clin Endocrinol Metab., 91(10):4006-4012, 2006. doi:10.1210 / jc.2005-2793; Dode et al, Nat Genet, 33(4):463-465, 2003. doi:10.1038 / ng1122, each of which is incorporated herein by reference.

[0614] The term "angiogenesis-associated disorder" refers to a disease characterized by an increase in the number or size of blood vessels in the tissue of a subject or patient, in part, compared to the similar tissue of a subject not suffering from the disease. Non-limiting examples of angiogenesis-associated disorders include cancer (e.g., any of the exemplary cancers described herein, prostate cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, hepatocellular carcinoma, sarcoma, lymphoma, etc.), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, rubeosis iridis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

[0615] The compounds of the present disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the present disclosure inhibit mutated FGFR1, FGFR2, FGFR3, and / or FGFR4. In other embodiments, the compounds of the present disclosure inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4 containing an FGFR kinase inhibitor mutation.

[0616] In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is a blood cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is a solid tumor.

[0617] In some embodiments of any of the methods or uses described herein, the cancer (e.g., an FGFR-associated cancer) is lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine carcinoma, smoking-related lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial carcinoma, endometrial adenocarcinoma), breast cancer (e.g., hormone receptor-positive breast cancer, triple-negative breast cancer, breast neuroendocrine carcinoma), skin cancer (e.g., melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, large squamous cell carcinoma), gallbladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, mucinous type liposarcoma), pheochromocytoma, myoepithelial carcinoma, urothelial carcinoma, spermatocytic seminoma, gastric cancer, head and neck cancer (e.g., head and neck (squamous cell) carcinoma, head and neck adenoid cystadenocarcinoma), brain tumors (e.g., glioneuronal tumor, glioma, neuroblastoma, glioblastoma, pilocytic astrocytoma, rosette-forming glioneuronal tumor, dysplastic neuroepithelial tumor, anaplastic astrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma), malignant peripheral nerve sheath tumor, sarcoma (e.g., soft tissue sarcoma (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g., esophageal adenocarcinoma), lymphoma, bladder cancer (bladder urothelial carcinoma (e.g., transitional cell carcinoma)), cervical cancer ( For example, cervical squamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer (e.g., fallopian tube carcinoma), ovarian cancer (e.g., ovarian serous carcinoma, ovarian mucinous carcinoma), cholangiocarcinoma, adenoid cystic carcinoma, pancreatic cancer (e.g., pancreatic exocrine carcinoma, pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia), salivary gland cancer (e.g., pleomorphic salivary gland adenocarcinoma, salivary adenoid cystic carcinoma), oral cancer (e.g., oral squamous cell carcinoma), uterine cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor, myeloma (e.g., multiple myeloma), lymphoepithelioma, anal cancer (e.g., anal squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), renal cell carcinoma, thymic carcinoma, gastroesophageal junction adenocarcinoma, testicular cancer, striated muscle Sarcoma (e.g., alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma), papillary renal carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloproliferative disorders (also called myeloproliferative neoplasms (MPN), e.g., 8pll myeloproliferative syndrome (EMS, also called stem cell leukemia / lymphoma), acute myeloid leukemia (AML), chronic myeloid leukemia (CML)), lymphoma (e.g., T-cell lymphoma, T-lymphoblastic lymphoma, acute lymphoblastic leukemia (ALL), B-cell lymphoma), myeloid and lymphoid tumors, chronic neutrophilic leukemia, phosphaturic mesenchymal tumor, thyroid cancer (e.g.,anaplastic thyroid carcinoma) or bile duct carcinoma.

[0618] In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), young adult cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, cancer of unknown primary, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, site-specific tumor, tumor, Colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct carcinoma, eye cancer, fallopian tube cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic tumor, head and neck tumor, central nervous system tumor, primary central nervous system tumor, cardiac cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal carcinoma, intraocular melanoma , pancreatic islet cell tumors, pancreatic neuroendocrine tumors, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma, midline lining cell carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, tumors by site, tumors, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer Lung cancer, pulmonary tumors, lung cancer, lung tumors, respiratory tumors, bronchial cancer, bronchial tumors, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasms, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon tumors, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer,Selected from the group consisting of pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, carcinoma of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0619] In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is selected from the group consisting of leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), myeloma, e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and leukemias including leukemia, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), myelomas, e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and leukemias including leukemia, lymphomas (non-Hodgkin's lymphoma), leukemia, and leukemias including acute myelogenous leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and leukemias including acute myelogenous leukemia (ACML). Selected from the group consisting of chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM).

[0620] Other examples of hematological cancers include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocytopenia (ET), idiopathic primary myelofibrosis (IMF / IPF / PMF), etc. In some embodiments, the hematological cancer (e.g., a hematological cancer that is an FGFR-associated cancer) is AML or CMML.

[0621] In some embodiments, the cancer (e.g., an FGFR-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are FGFR-associated cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer), bladder cancer, colorectal cancer, brain cancer, testicular cancer, cholangiocarcinoma, cervical cancer, prostate cancer, and spermatocytic seminoma. See, e.g., Turner and Grose, Nat. Rev. Cancer, 10(2):116-129, 2010.

[0622] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0623] In some embodiments, the FGFR1-associated cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0624] In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer.

[0625] In some embodiments, the FGFR2-associated cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0626] In some embodiments, the FGFR3-associated cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0627] In some embodiments, the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0628] In some embodiments, the FGFR4-associated cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0629] In some embodiments, the compounds of the disclosure are useful in treating cancers associated with amplification or overexpression of FGFR1, such as breast cancer or carcinoma (e.g., hormone receptor positive breast cancer, ductal carcinoma (breast)), pancreatic ductal adenocarcinoma, pancreatic exocrine cancer, smoking-related lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, rhabdomyosarcoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), esophageal cancer, These compounds are useful in the treatment of cancers of the esophagus (e.g., esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma), hepatocellular carcinoma, renal cell carcinoma, colorectal cancer (e.g., colorectal adenocarcinoma), prostate cancer, salivary gland tumors, glioblastoma multiforme, bladder cancer, urothelial carcinoma, carcinoma of unknown primary site, non-pulmonary squamous cell carcinoma, gastric cancer, gastroesophageal junction cancer, adenoid cystic carcinoma, anal squamous cell carcinoma, oral squamous cell carcinoma, cholangiocarcinoma, hemangioendothelioma, leiomyosarcoma, melanoma, neuroendocrine carcinoma, squamous cell carcinoma, and uterine carcinosarcoma.

[0630] In some embodiments, the compounds of the present invention are useful for treating cancers associated with FGFR2 amplification, such as gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple-negative breast cancer), colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial carcinoma, bladder adenocarcinoma, carcinoma of unknown primary origin, cholangiocarcinoma, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder cancer, ovarian cancer, fallopian tube cancer, exocrine pancreatic carcinoma, sarcoma, and squamous cell carcinoma.

[0631] In some embodiments, the compounds of the present invention are useful in treating cancers associated with overexpression of FGFR2, such as mucinous lipoma, colon cancer, renal cell carcinoma, and breast cancer.

[0632] In some embodiments, the compounds of the present invention are useful for treating cancers associated with upregulated FGFR3 activity, such as colon cancer, hepatocellular carcinoma, and exocrine pancreatic cancer. In some embodiments, the compounds of the present invention are useful for treating cancers associated with overexpression of FGFR3 activity, such as multiple myeloma and thyroid cancer. In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with amplification of FGFR3 activity, such as bladder cancer and salivary adenoid cystic carcinoma, urothelial carcinoma, breast cancer, carcinoid, cancer of unknown primary origin, colon cancer (e.g., colon adenocarcinoma), gallbladder cancer, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, and exocrine pancreatic cancer.

[0633] In some embodiments, the compounds of the present disclosure are useful for treating cancers associated with FGFR4 amplification, such as rhabdomyosarcoma, prostate cancer or carcinoma, breast cancer, urothelial cancer, carcinoid, cancer of unknown primary origin, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, and renal cell carcinoma.

[0634] In some embodiments, the compounds of the present invention are useful in treating cancers associated with upregulated activity of FGFR4, such as colon cancer, hepatocellular carcinoma, adrenal cancer, and breast cancer.

[0635] In some embodiments, the compounds of the present invention are useful in treating cancers associated with overexpression of FGFR4 activity, such as pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.

[0636] In some aspects, the compounds of the present disclosure are more selective for one FGFR than another. As used herein, a compound being "selective" for a first target over a second target means that the compound exhibits more potent activity against the first target than the second target. The selectivity factor can be calculated by any method known in the art. For example, the selectivity factor can be calculated by dividing the IC50 value (or Kd value) of a compound for a second target (e.g., FGFR1) by the IC50 value of the same compound for a first target (e.g., FGFR2 or FGFR3). The IC50 value can be determined by any method known in the art. In some embodiments, the compound is first determined to have an activity of less than 500 nM against the first target. In some embodiments, the compound is first determined to have an activity of less than 500 nM against the second target.

[0637] For example, in some embodiments, the compounds of the present disclosure are more selective for FGFR3 over FGFR1. In some embodiments, the compounds are at least 3-fold selective for FGFR3 over FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000-fold selective for FGFR3 over FGFR1.

[0638] In some embodiments, the compounds of the present disclosure are more selective for FGFR2 over FGFR1. In some embodiments, the compounds are at least 3-fold selective for FGFR2 over FGFR1. In some embodiments, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000-fold selective for FGFR2 over FGFR1.

[0639] In some embodiments, the compounds of the present disclosure are more selective for a first FGFR family member (e.g., FGFR2 or FGFR3) over a second FGFR family member (e.g., FGFR1 or FGFR4). In some embodiments, the compounds of the present disclosure are at least 3-fold selective for a first FGFR family member over a second FGFR family member. In some embodiments, the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000-fold selective for a first FGFR family member over a second FGFR family member.

[0640] In some embodiments, the compounds of the present disclosure are more selective for FGFR kinase over other kinases other than FGFR kinase. In some embodiments, the compounds of the present disclosure are at least 3-fold selective for FGFR kinase over other kinases other than FGFR kinase. In some embodiments, the compounds of the present disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000-fold selective for FGFR kinase over other kinases other than FGFR kinase. Other kinases other than FGFR kinase include, for example, KDR kinase and Aurora B kinase.

[0641] In some embodiments, compounds of the present disclosure exhibit brain and / or central nervous system (CNS) penetrability. Such compounds can cross the blood-brain barrier and inhibit FGFR kinases in the brain and / or other CNS structures. In some embodiments, compounds provided herein can cross the blood-brain barrier in therapeutically effective amounts. For example, treating a subject with cancer (e.g., an FGFR-related cancer, such as an FGFR-related brain cancer or a central nervous system cancer) can include administering (e.g., orally administering) a compound to the subject. In such embodiments, compounds provided herein are useful for treating primary or metastatic brain tumors. For example, FGFR-related primary or metastatic brain tumors.

[0642] In some embodiments, compounds of the present disclosure exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

[0643] In some aspects, the compounds of the present disclosure can be used to treat a subject diagnosed with (or identified as having) an FGFR-related disease or disorder (e.g., an FGFR-related cancer), comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. Also provided herein are methods for treating a subject identified or diagnosed with an FGFR-related disease or disorder (e.g., an FGFR-related cancer), comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. In some embodiments, the subject has been identified or diagnosed with an FGFR-related disease or disorder (e.g., an FGFR-related cancer) through the use of a regulatory-approved, e.g., FDA-approved, test or assay to identify dysregulation of expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of them, in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the FGFR-related disease or disorder is an FGFR-related cancer. For example, an FGFR-associated cancer can be a cancer that contains one or more FGFR inhibitor-resistant mutations.

[0644] Also provided are methods for treating a disease or disorder in a subject in need thereof, the methods comprising: (a) detecting an FGFR-related disease or disorder in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering to the subject an additional therapy or treatment (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy). In some embodiments, the subject has previously been treated with the first FGFR inhibitor or has previously been treated with another therapy. In some embodiments, the subject is determined to have an FGFR-related disease or disorder through the use of a regulatory-approved, e.g., FDA-approved, test or assay to identify dysregulation of expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of them in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0645] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting an FGFR-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering to the subject an additional therapy or treatment (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or immunotherapy). In some embodiments, the subject has previously been treated with a first FGFR inhibitor or has previously been treated with another anti-cancer treatment (e.g., at least partial tumor resection or radiation therapy). In some embodiments, the subject is determined to have an FGFR-associated cancer through the use of a regulatory-approved, e.g., FDA-approved, test or assay to identify dysregulation of expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of them in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an FGFR-associated cancer. For example, FGFR-related cancer can be the cancer that contains one or more FGFR inhibitor-resistant mutations.In some embodiments, cancer is FGFR-related cancer.For example, FGFR-related cancer can be the cancer that contains one or more FGFR activating mutations.

[0646] Also provided are methods of treating a subject, comprising: performing an assay on a sample collected from the subject to determine whether the subject has dysregulated expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of them; and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, to the subject determined to have dysregulated expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of them. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the present disclosure, or an immunotherapy). In some embodiments of these methods, the subject has previously been treated with a first FGFR inhibitor or has previously been treated with another anti-cancer treatment (e.g., at least partial tumor resection or radiation therapy). In some embodiments, the subject is suspected of having an FGFR-related disease or disorder (e.g., an FGFR-related cancer), exhibits one or more symptoms of an FGFR-related disease or disorder (e.g., an FGFR-related cancer), or is at high risk for developing an FGFR-related disease or disorder (e.g., an FGFR-related cancer). In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, such as an FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Further, non-limiting assays that can be used in these methods are described herein. Additional assays are known in the art. In some embodiments, the dysregulation of expression, activity, or levels of an FGFR gene, an FGFR kinase, or any thereof, comprises one or more FGFR inhibitor-resistant mutations.

[0647] Also provided herein are methods for selecting a treatment for a subject, the methods comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of them (e.g., one or more FGFR inhibitor-resistant mutations); and identifying or diagnosing the subject determined to have dysregulated expression, activity, or levels of an FGFR gene, an FGFR kinase, or any of them as having an FGFR-associated cancer. Some embodiments further comprise administering the selected treatment to the subject identified or diagnosed with an FGFR-associated cancer. For example, in some embodiments, the selected treatment may comprise administering a therapeutically effective amount of a compound of the present disclosure to the subject identified or diagnosed with an FGFR-associated cancer. In some embodiments, the assay is an in vitro assay. For example, the assay utilizes next-generation sequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a kit approved by a regulatory agency, such as an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0648] Also provided herein are methods of treating an FGFR-associated cancer in a subject, the methods comprising: (a) administering a first FGFR kinase inhibitor one or more times (e.g., two or more, three or more, four or more, five or more, or ten or more times) to a subject (e.g., a subject identified or diagnosed as having an FGFR-associated cancer (e.g., any type of FGFR-associated cancer described herein) using any exemplary method described herein or known in the art; (b) determining the level of circulating tumor DNA in a biological sample (e.g., a biological sample comprising blood, serum, or plasma) obtained from the subject after step (a); and (c) administering a therapeutically effective amount of a second FGFR inhibitor or a compound of the present disclosure, as monotherapy or in combination with an additional therapy or therapeutic agent, to a subject identified as having approximately the same or elevated levels of circulating tumor DNA compared to a baseline level of circulating tumor DNA (e.g., any of the baseline levels of circulating tumor DNA described herein). In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from the subject before step (a). In some embodiments of these methods, the method further comprises determining the level of circulating tumor DNA in a biological sample obtained from the subject before step (a). In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of subjects with similar FGFR-associated cancers and similar stages of the FGFR-associated cancers but who have received ineffective treatments or placebos or have not yet received treatment, or the level of circulating tumor DNA in subjects with similar FGFR-associated cancers and similar stages of the FGFR-associated cancers but who have received ineffective treatments or placebos or have not yet received treatment).In some examples of these methods, the first FGFR inhibitor is ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Devio1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, surufatinib, TAS-120, or RLY-4008.

[0649] Combination therapy Depending upon the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may be administered.

[0650] The compounds of the present disclosure can also be administered with additional therapies or therapeutic agents. In some embodiments, the additional therapies or therapeutic agents include one or more of radiation therapy, chemotherapy (e.g., any of the exemplary chemotherapy agents described herein or known in the art), checkpoint inhibitors (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial resection of the tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).

[0651] The compounds of the present disclosure may also be useful as adjuvants in cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, e.g., chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, the compounds of the present disclosure may be used before the administration of the additional therapeutic agent or therapy. For example, a subject in need of treatment may receive one or more administrations of a compound of the present disclosure for a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more administrations of a compound of the present disclosure reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumors) that is refractory or intolerant to standard treatment (e.g., administration of a chemotherapeutic agent such as a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation therapy, or a platinum-based agent (e.g., cisplatin)). In some embodiments, the subject has cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to previous treatment (e.g., administration of a chemotherapeutic agent such as a first FGFR inhibitor or multikinase inhibitor, immunotherapy, radiation therapy, or a platinum-based agent (e.g., cisplatin)).

[0652] In some embodiments of any of the methods described herein, a compound of the present disclosure is administered in combination with at least one additional therapeutic agent (therapeutically effective amount) selected from one or more additional therapies or therapeutic agents (e.g., chemotherapeutic agents). Non-limiting examples of additional therapeutic agents include other FGFR-targeted therapeutic agents (i.e., first or second FGFR kinase inhibitors), other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways (e.g., obataclax), cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies, immune-targeted agents including immunotherapies, and radiation therapy.

[0653] Also provided herein are methods for treating a disease or disorder, the methods comprising administering to a subject in need of treatment a pharmaceutical composition for treating a disease or disorder comprising (a) a compound of the present disclosure, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for treating the disease or disorder, wherein the amounts of the disclosed compound and the additional therapeutic agent together are effective to treat the disease or disorder. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered sequentially in any order as separate dosages in jointly therapeutically effective amounts, e.g., daily or intermittent dosages. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the disease or disorder is an FGFR-related disease or disorder. In some embodiments, the subject has received one or more doses of a compound of the present disclosure prior to administration of the pharmaceutical composition.

[0654] In some embodiments, the treatment period is at least 7 days (e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).

[0655] In some embodiments, the treatment period is at least 21 days (e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).

[0656] Also provided herein are pharmaceutical compositions containing a compound of the present disclosure as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it is a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the compositions are formulated for oral administration. In some embodiments, the composition is formulated as a tablet or capsule.

[0657] Compositions containing the disclosed compounds may be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to a physically discrete unit for human and other subjects, each unit containing a predetermined amount of the active agent (i.e., a disclosed compound) to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient.

[0658] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of the active ingredient, i.e., a compound of the present disclosure. One of ordinary skill in the art will recognize that this embodies a compound or composition containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. One of ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of the active ingredient. One of ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

[0659] The active compounds are effective over a wide dosage range and are usually administered in a pharmaceutically effective amount, but it will be understood that the amount of compound actually administered will usually be determined by a physician depending on the relevant circumstances, such as the condition to be treated, the selected route of administration, the actual compound administered, the age, weight, response, and severity of the subject's symptoms, of the individual subject.

[0660] In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. It is, for example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, such administration can be once daily or twice daily (BID).

[0661] Pharmaceutically acceptable compositions The pharmaceutical compositions of the present invention are typically formulated to provide a therapeutically effective amount of a compound of the present invention as an active ingredient, or as a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In some embodiments, the pharmaceutical compositions contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.

[0662] The pharmaceutical composition of the present invention can be administered alone or in combination with one or more other drugs, which are typically administered in the form of a pharmaceutical composition. If necessary, one or more compounds of the present invention and the other drug(s) can be mixed in a preparation, or both components can be formulated into separate preparations and used separately or in combination at the same time.

[0663] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.10%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65 %, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or any number within a range defined by any two of the above numbers inclusive) w / w, w / v or v / v.

[0664] In some embodiments, the concentration of one or more compounds of the present invention is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50% ,14.25%14%,13.75%,13.50%,13.25%,13%,12.75%,12.50%,12.25%,12%,11.75%,11.50%,11.25%11%,10.75%,10.50%,10.25%10%,9.75%,9.50%,9.25%,9%,8.75%,8.50%,8.25%8%,7.75%,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75 %,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,1.25%,1%,0.9%,0.8%,0.7%,0.6%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%,0.06%,0.05%,0.04%,0.03%,0.02%,0. 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or any number within a range defined by any two of the above numbers inclusive) w / w, w / v or v / v.

[0665] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 10%, from about 0.09% to about 12%, from about 0.10% to about 13%, from about 0.11% to about 14%, from about 0.12% to about 15%, from about 0.13% to about 16%, from about 0.14% to about 17%, from about 0.15% to about 18%, from about 0.16% to about 19%, from about 0.17% to about 20%, from about 0.18% to about 22%, from about 0.19% to about 23%, from about 0.19% to about 24%, from about 0.19% to about 25%, from about 0.19% to about 26%, from about 0.19% to about 27%, from about 0.19% to about 28%, from about 0.19% to about 29%, from about 0.19% to about 25%, from about 0.19% to about 26 ...7%, from about 0.19% to about 28%, from about % to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v.

[0666] In some embodiments, the concentration of one or more compounds of the present invention ranges from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0667] In some embodiments, the amount of one or more compounds of the present invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g , 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or a range defined by any two of the above numbers inclusive).

[0668] In some embodiments, the amount of one or more compounds of the present invention is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004 ... g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0. 0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g , 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, , 0.15g, 0.2g, , 0.25g, 0.3g, , 0.35g, 0.4g, , 0.45g, 0.5g, 0.55g, 0.6g, , 0.65g, 0.7g, 0 More than 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or any number in a range defined by and including any two of the above numbers).

[0669] In some embodiments, the amount of one or more compounds of the present invention ranges from 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0670] In some embodiments, the compounds of the present invention are effective over a wide dosage range. For example, in the treatment of adults, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg / day, and 5 to 40 mg / day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg / day. The exact dosage will vary depending on the route of administration, the dosage form of the compound, the subject being treated, the subject's weight, and the preference and experience of the attending physician.

[0671] Unless otherwise specified, amounts of compounds described herein are provided on a free base basis, i.e., the amount refers to the amount of compound administered excluding, for example, solvent (such as a solvate) or counterion (such as a pharmaceutically acceptable salt).

[0672] Described below are non-limiting exemplary pharmaceutical compositions and methods for their preparation.

[0673] A pharmaceutical composition for oral administration. In some embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0674] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, which contains (i) an effective amount of a compound of the present invention, optionally (ii) an effective amount of a second pharmaceutical agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third pharmaceutical agent.

[0675] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions of the present invention suitable for oral administration may be present in discrete dosage forms such as capsules, cachets, tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms may be prepared by any method of pharmacy, but all methods include combining the active ingredient with a carrier, which constitutes one or more necessary ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired form. For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by mixing the active ingredient in a free-flowing form, such as a powder or granules, optionally with excipients such as binders, lubricants, inert diluents, and / or surfactants or dispersants, and compressing in a suitable machine. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0676] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can accelerate the degradation of some compounds. For example, in the pharmaceutical industry, water (e.g., 5%) may be added as a means of simulating long-term storage to determine properties such as shelf life and formulation stability over time. Anhydrous pharmaceutical compositions and dosage forms of the present invention may be prepared using anhydrous or low-moisture containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, such that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, unit-dose containers such as plastics, blister packs, and strip packs.

[0677] The active ingredient can be intimately mixed and combined with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the form of preparation desired for administration. When preparing compositions for oral administration, typical pharmaceutical vehicles can be used as carriers for oral liquid preparations (such as suspensions, solutions, elixirs, etc.) or aerosols, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., or for oral solid preparations, such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc., and in some embodiments, lactose is not used. For example, suitable carriers include powders, capsules, and tablets with solid oral preparations. If necessary, tablets can be coated by standard aqueous or nonaqueous techniques.

[0678] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0679] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0680] Disintegrants may be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. If too much disintegrant is used, the resulting tablets may disintegrate by bolting. If too little disintegrant is used, disintegration may be insufficient, thereby altering the release rate and amount of the active ingredient(s) from the dosage form. Therefore, dosage forms of the compounds disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much so as not to adversely affect the release of the active ingredient(s). The amount of disintegrant used will vary depending on the type of formulation and the method of administration, and is readily discernible to those skilled in the art. The pharmaceutical compositions may contain from about 0.5 to about 15 weight percent disintegrant, or from about 1 to about 5 weight percent disintegrant. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0681] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Optionally, a lubricant can be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0682] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein can be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweeteners or flavorings, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0683] Tablets may be uncoated or may be coated by conventional techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Oral administration formulations may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0684] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., mixtures of hydrophilic surfactants can be used, mixtures of lipophilic surfactants can be used, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0685] Suitable hydrophilic surfactants generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values are more lipophilic or hydrophobic and more soluble in oil, while surfactants with high HLB values are more hydrophilic and more soluble in aqueous solutions.

[0686] Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than about 10, and anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guide that is commonly used to enable the formulation of emulsions for industrial, pharmaceutical, and cosmetic applications.

[0687] The hydrophilic surfactant may be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides and polypeptides, glyceride derivatives of amino acids, oligopeptides and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, docusate sodium, acyl lactate salts, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0688] Ionic surfactants within the aforementioned group include, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfates, fatty acid salts, sodium docusate, acyl lactate salts, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0689] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate fatty acid esters, stearoyl-2-lactic acid, stearoyl milk The ionic forms of the fatty acids may be ionic, ionic, carboxylic acid, carboxylic acid monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholyl sarcosine, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, stearic acid, lauryl sulfate, teraceyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0690] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic transesterification products of at least one component of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols with a polyol, polyoxyethylene sterols, derivatives and analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils with a polyol. The polyol includes glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0691] Other hydrophilic nonionic surfactants include PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 diolate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 diolate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 pa Corn Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PE Examples of suitable sucrose monostearate include, but are not limited to, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0692] Suitable lipophilic surfactants include, for example, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, monoglycerides and diglycerides of lactic acid derivatives, glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, the hydrophobic transesterification product of at least one member of the group consisting of sterols and polyols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification product of at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides and polyols.

[0693] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as injectable compositions. Solubilizing agents may also be added to increase the solubility of other components, such as hydrophilic drugs and / or surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0694] Examples of suitable solubilizers include alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxybenzoates, ... Amides and other nitrogen-containing compounds such as dialkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone, etc., esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers, and other solubilizing agents known in the art, such as, but not limited to, dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0695] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0696] The content of solubilizer is not particularly limited. The amount of a particular solubilizer may be limited to a biotolerable amount, which can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize drug concentration, it may be advantageous to include a solubilizer in an amount significantly greater than the biotolerable amount, and the excess solubilizer is removed using conventional techniques such as distillation or evaporation before providing the composition to a subject. Thus, when present, the solubilizer may be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the total weight of the drug and other excipients. If necessary, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, may also be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0697] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavors, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0698] Additionally, acids or bases may be incorporated into the compositions to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation can be any convenient, pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0699] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0700] Pharmaceutical compositions for injection. In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the drugs in the composition are as described herein.

[0701] Forms into which the novel compositions of the present invention can be incorporated for injectable administration include aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0702] Aqueous solutions of physiological saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by using a coating such as lecithin to maintain the required particle size in the case of dispersions, and by using surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0703] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in a suitable solvent with various other ingredients as listed above, as needed, followed by filtration sterilization.Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary ingredients as listed above.In the case of sterile powders for preparing sterile injectable solutions, certain preferred preparation methods include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient and any additional ingredients from a previously sterile-filtered solution.

[0704] Pharmaceutical compositions for topical (eg, transdermal) delivery. In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0705] The composition of the present invention can be formulated into solid, semi-solid or liquid form preparations suitable for topical administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, the higher density carrier can make the active ingredient exposed to a specific area for a long time.In contrast, the solution formulation can make the active ingredient exposed to the selected area more quickly.

[0706] The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient, which is a compound that increases the penetration of or aids in the delivery of a therapeutic molecule through the stratum corneum permeability barrier of the skin. Many such penetration-enhancing molecules are known to those skilled in the art of topical formulations.

[0707] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0708] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without other agents.

[0709] The construction and use of transdermal patches for the delivery of pharmaceutical agents is known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0710] A pharmaceutical composition for inhalation. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or by attaching the nebulizing device to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from any means that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0711] Other pharmaceutical compositions. Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill,20037ybg;Goodman and Gilman,eds.,The Pharmacological Basis of Therapeutics,Tenth Edition,McGraw Hill,2001;Remingtons Pharmaceutical Sciences,20th Ed.,Lippincott Williams & Wilkins.,2000;Martindale,The Extra Pharmacopoeia,Thirty-Second Edition(The Pharmaceutical Press, London, 1999), all of which are incorporated herein by reference in their entireties.

[0712] The compounds or pharmaceutical compositions of the present invention can be administered by any method that can deliver the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (such as transdermal application), rectal administration, local delivery by catheter or stent, or administration by inhalation. The compounds can also be administered intraadiposely or intrathecally.

[0713] The amount of compound administered will vary depending on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. However, effective amounts range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this amounts to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned range may be more than sufficient, while in other cases, even larger dosages can be used without causing adverse side effects, for example, by dividing such a large dose into several smaller doses administered throughout the day.

[0714] In some embodiments, the compound of the invention is administered in a single dose.

[0715] Typically, such administration is by injection, e.g., intravenous injection, to rapidly introduce the drug. However, other routes may be used if desired. A single dose of the compound of the invention may also be used to treat acute conditions.

[0716] In some embodiments, the compound of the present invention is administered multiple times. The number of administrations may be about once, twice, three times, four times, five times, six times, or more than six times per day. The dosage may be about once a month, once every two weeks, once a week, or once a day. In another embodiment, the compound of the present invention and the other agent are administered together about once to about six times per day. In another embodiment, administration of the compound of the present invention and the agent continues for less than about seven days. In yet another embodiment, administration continues for about 6, 10, 14, 28 days, 2 months, 6 months, or a year or more. In some cases, continuous administration is achieved and maintained as long as necessary.

[0717] Administration of the compounds of the invention can be continued for as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered chronically on an ongoing basis, for example, to treat chronic effects.

[0718] An effective amount of the compounds of the present invention may be administered in single or multiple doses by any of the accepted modes of administration for drugs having similar uses, including rectal, buccal, intranasal and transdermal routes, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or by inhalant administration.

[0719] The compositions of the present invention can also be delivered via impregnated or coated devices, such as stents or cylindrical polymers inserted into an artery. Such administration can help prevent or ameliorate restenosis after procedures such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compounds of the present invention can be administered by local delivery, for example, from stent struts, stent grafts, grafts, or stent covers or sheaths. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix can be a polymer matrix that can serve to bind the compound to the stent. Suitable polymer matrices for such applications include, for example, polylactic acid, polycaprolactone glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, lactone-based polyesters or copolymers such as poly(ether ester) copolymers (e.g., PEO-PLLA), polydimethylsiloxane, poly(ethylene vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), and fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be non-degradable or may degrade over time to release the compound. The compounds of the present invention can be applied to the surface of a stent by various methods, including dip / spin coating, spray coating, dip coating, and / or brush coating. The compound can also be applied in a solvent, which is then evaporated to form a layer of compound on the stent. Alternatively, the compound can be disposed within the body of the stent or graft, e.g., within microchannels or micropores. Upon implantation, the compound diffuses from the stent body and contacts the arterial wall. Such stents can be prepared by immersing a stent fabricated to contain such micropores or microchannels in a solution of a compound of the invention dissolved in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent can be removed by additional brief solvent washing. In yet another embodiment, the compounds of the present invention can be covalently bonded to a stent or graft. A covalent linker can be used that decomposes in vivo, resulting in the release of the compounds of the present invention. Any biolabile bond can be used for this purpose, such as an ester bond, an amide bond, or a dehydration bond. The compounds of the present invention can also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compound via the pericardium or a prior application of the formulation of the present invention can also be performed to reduce restenosis.

[0720] Various stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: US Pat. No. 5,451,233; US Pat. No. 5,040,548; US Pat. No. 5,061,273; US Pat. No. 5,496,346; US Pat. No. 5,292,331; US Pat. No. 5,674,278; US Pat. No. 3,657,744; US Pat. No. 4,739,762; US Pat. No. 5,195,984; US Pat. No. 5,292,331; US Pat. No. 5,674,278; US Pat. No. 5,879,382; US Pat. No. 6,344,053.

[0721] The compound of the present invention can be administered according to dosage.It is known in the art that due to the subject-to-subject variation in the pharmacokinetics of compound, optimal treatment requires individualized administration schedule.The dosage of the compound of the present invention can be found by routine experiment in light of the present disclosure.

[0722] When a compound of the invention is administered in a composition containing one or more drugs, and the drug has a shorter half-life than the compound of the invention, the unit dosage forms of the drugs and the compound of the invention may be adjusted accordingly.

[0723] The pharmaceutical compositions of the present invention may be in the form of tablets, capsules, pills, powders, sustained-release formulations, solutions, or suspensions suitable for oral administration; sterile solutions, suspensions, or emulsions suitable for parenteral injection; ointments or creams suitable for topical administration; or suppositories suitable for rectal administration. The pharmaceutical compositions may be in unit dosage forms suitable for single administration of a precise dosage. The pharmaceutical composition comprises a conventional pharmaceutical carrier or excipient and the compound of the present invention as an active ingredient. In addition, it may contain other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0724] Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions, etc. Such dosage forms may be suitably buffered, if necessary.

[0725] All features of each aspect of the invention apply mutatis mutandis to all other aspects.

[0726] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

[0727] Case in point As illustrated in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While these general methods illustrate the synthesis of certain specific compounds of the invention, it will be understood that the following general methods, and others known to those of skill in the art, are applicable to all compounds, and subclasses and species of each of these compounds, as described herein.

[0728] General Procedure X-ray powder diffraction (XRPD) data collection strategy: XRPD patterns of samples were recorded at room temperature on an Aeris X-ray diffractometer (Almelo, The Netherlands) using Cu Kα radiation (λ = 1.54 Å) at 40 kV and 15 mA through a Ni monochromator. Data were collected in continuous scan mode over an angular range of 3° to 40° 2θ with a step size of 0.02° and a dwell time of 149 seconds. The sample was loaded into a zero-background holder and gently pressed with a clean glass slide to ensure coplanarity between the sample surface and the holder surface. The resulting diffractograms were analyzed and plotted using HighScore Plus software (v5.0, Almelo, The Netherlands).

[0729] Thermogravimetric analysis (TGA): TGA was performed using a Discovery TGA 5500 (TA® Instruments, New Castle, Delaware, USA) instrument equipped with TRIOS software (version 5.0). Samples were placed in aluminum containers. The sample cell was purged with dry nitrogen at a flow rate of 15 mL / min. A heating rate of 10 °C / min was used in all experiments, ranging from 25 to 350 °C.

[0730] Differential scanning calorimetry (DSC): Conventional DSC experiments were performed using a Q100 (TA® Instruments, New Castle, Delaware, USA) instrument equipped with a refrigerated cooling system (RCS90). The sample cell was purged with dry nitrogen at a flow rate of 50 mL / min. Accurately weighed samples (2–5 mg) placed in a TZero pan with a pinhole were scanned over the desired temperature range at a heating rate of 10 °C / min.

[0731] Dynamic Vapor Sorption (DVS): Moisture sorption / desorption data were collected on a DVS vapor sorption analyzer (Surface Measurement Systems NA, Allentown, PA, USA) and operated using the DVS control software (version 1.0.5.1). Samples were not dried prior to analysis. Adsorption and desorption data were collected under a nitrogen purge at a relative humidity (RH) range of 5% to 98% in 10% RH increments. The equilibration criteria used for analysis were a maximum equilibration time of 3 hours and a weight change of less than 0.005% over 10 minutes.

[0732] Example A. General Preparation of Compound A [ka] Compound A Compound A was prepared according to the procedures and intermediates described below (eg, Scheme 1). Scheme 1 [ka]

[0733] Step 1, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3-yl)-1H-indazole

[0734] A mixture of 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-indazole (25.0 g, 48.35 mmol, 1.0 equiv.), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxobromo)-2-oxo-2-methyl-2H-pyran-2-yl)-indazole in 1,4-dioxane (250 mL) and water (25 mL). A mixture of (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (12.94 g, 58.02 mmol, 1.2 equiv.), potassium carbonate (13.34 g, 96.70 mmol, 2.0 equiv.), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (3.56 g, 4.84 mmol, 0.1 equiv.) was sparged with nitrogen for 15 minutes and then heated at 100 °C for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a bed of Celite (250 g). The Celite bed was washed with ethyl acetate (100 mL), and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and purified on a silica plug (500 g), eluting with 20% ethyl acetate in heptane. The product-containing fractions were combined and concentrated to dryness under reduced pressure. The resulting light brown solid was triturated with acetonitrile (50 mL) at room temperature for 1 hour. The solid was vacuum filtered to give a white solid (16.77 g, 71% yield). Additional 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (25.0 g) was treated as above to give the compound as a white solid (16.25 g, 71% yield). The filtrates from both batches were combined and evaporated to dryness under reduced pressure. The resulting residue was purified on a Büchi automated chromatography system (Sorbtech 40 g silica gel column) eluting with a gradient of 0 to 30% ethyl acetate in heptane to give a white solid (10.2 g). The isolated white solids combined gave 43.2 g (90% yield). Analysis: LCMS: m / z = 487 (M+H).

[0735] Step 2, 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0736] A mixture of the compound (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoro-pyridin-3-yl)-1H-indazole (5 g, 10.28 mmol, 1.0 equivalent), 2-(methylsulfonyl)-2,6-diazaspiro[3.3]heptane dimesylate (4.55 g, 12.34 mmol, 1.2 equivalent), and potassium carbonate (4.25 g, 30.84 mmol, 3.0 equivalent) in 1-methyl-2-pyrrolidone (70 mL) was heated at 120 ° C. for 16 hours. The reaction mixture was cooled to room temperature, followed by the addition of water (150 mL). The resulting solid was collected and dried under vacuum at room temperature for 16 hours. The solid was further purified on a Büchi automated chromatography system (Sorbtech 80 g silica gel column) eluting with a gradient of 0 to 10% methanol in ethyl acetate to give a white solid (4.42 g, 67%). LCMS: m / z = 643.1 (M+H).

[0737] Step 3, (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole

[0738] A solution of 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.42 g, 6.88 mmol, 1.0 equiv) in dichloromethane (45 mL) was treated with trifluoroacetic acid (45 mL, 588.15 mmol, 85.0 equiv). After stirring at room temperature for 4 hours, the volatiles were removed under reduced pressure to give a brown oil. The residue was diluted with dichloromethane (100 mL) and poured onto crushed ice (35.0 g). The mixture was treated in portions with sodium bicarbonate (25.0 g) to adjust the pH to 8. The resulting suspension was filtered, and the filtrate was transferred to a separatory funnel. The mixture was washed with saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined organic layers were concentrated to dryness under reduced pressure. The resulting crude solid (5.0 g) was triturated with methanol (40 mL) at room temperature for 1 hour. The solid was filtered and dried under vacuum at room temperature for 16 hours to give an off-white solid (2.0 g, 55% yield).

[0739] LCMS: m / z = 559.1 (M+H); 1 H NMR (400 MHz,DMSO-d6) δ =12.99(s,1H),8.59(s,2H),8.52(d,J=1.7Hz,1H),7.87(dd,J=2.3,8.7Hz,1H),7.45(d,J=8.9Hz,1H),7.17(d,J=2.1Hz,1H),7.09 (dd,J=2.3,9.0Hz,1H),6.54(d,J=8.2Hz,1H),6.11(q,J=6.6Hz,1H),4.17(s,4H),4.12(s,4H),3.03(s,3H),1.76(d,J=6.6Hz,3H). Example 1, Forms I and II of Compound 1 [ka] compound 1

[0740] Form I of Compound 1 Form I of Compound 1 was prepared as follows: A suspension of Compound A (210 mg, 0.375 mmol) in ethanol (25 mL) was cooled in an ice bath, and a solution of 37% aqueous hydrochloric acid (1.1 equivalents) in ethanol (1 mL) was added. The mixture was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred overnight. The suspension was diluted with diethyl ether (10 mL), stirred for 15 minutes, and the solid was collected by filtration and washed with diethyl ether (40 mL). The solid was dried in a Büchner funnel for 10 minutes and then dried under vacuum at 40° C. for 5 hours to give a white solid (243 mg, 87% yield).

[0741] LCMS: m / z = 559.1 (M+H); 1 H NMR(400MHz,DMSO-d6) δ =13.32(brs,1H),8.59(s,2H),8.31(s,1H),8.26(brd,J=8.8Hz,1H),7.51(d,J=9.0Hz,1H),7.20(d,J=2.1Hz,1H),7.13(dd,J=2.3,9.0Hz, 1H),6.95(brd,J=8.6Hz,1H),6.14(q,J=6.6Hz,1H),4.45(s,4H),4.15(s,4H),3.04(s,3H),1.77(d,J=6.6Hz,3H);mp=181.4~215.7℃(decomposition).

[0742] Table 1 above is reproduced below and shows the X-ray diffraction peaks observed for Form I of Compound 1. [Table 39-1] [Table 39-2] [Table 39-3]

[0743] FIG. 1 shows the XRPD pattern of Form I of Compound 1.

[0744] Form II of Compound 1 The reaction of compound A (in THF) with HCl (in ethyl acetate) produced a crystalline material. TGA data showed a weight loss of approximately 3.58% from room temperature to 160 °C. DSC analysis showed an exothermic peak at 168.92 °C (peak temperature), followed by two endothermic events between 220 and 270 °C. Vapor sorption data (not shown) suggests a moderately hygroscopic material. XRPD data analysis (not shown) of the material collected from the DVS experiment suggests the material is stable.

[0745] Table 2 above is reproduced below and shows the X-ray diffraction peaks observed for Form II of Compound 1. [Table 40-1] [Table 40-2]

[0746] FIG. 56 shows the XRPD pattern of Form II of Compound 1.

[0747] FIG. 57 shows the DSC thermogram and TGA trace of Compound 2 Form II.

[0748] Example 2, Forms I-XIII of Compound 2 General synthesis of solid forms of compound 2 [ka] 2 Solid forms of Compound 2 were prepared according to either Method A or Method B described below.

[0749] Method A A suspension of compound A (5.0 g, 8.94 mmol, 1 equiv) in acetone (180 mL) was treated with a solution of benzenesulfonic acid (1.63 g, 10.32 mmol, 1.15 equiv) in acetone (17 mL) at room temperature. After 16 h, the precipitate was filtered, washed with a 1:1 mixture of acetone and ethyl ether (3 × 20 mL), and dried under vacuum at 50 °C for 5 h and at room temperature for 2.5 days to give an off-white solid (6.28 g, 98%). A second batch was repeated using compound A (4.05 g, 7.25 mmol, 1 equiv) in acetone (145 mL) and benzenesulfonic acid (1.32 g, 8.35 mmol, 1.15 equiv) in acetone (15 mL) at room temperature. After 16 h, the precipitate was filtered, washed with a 1:1 mixture of acetone and ethyl ether (2 × 12 mL), and dried to give an off-white solid (4.37 g, 84%). A suspension of the besylate salt (10.03 g, 13.98 mmol) in ethyl alcohol (1 L) was heated with stirring at 67 °C under a nitrogen atmosphere. After 16 h, the suspension was cooled to room temperature without stirring for 30 min, filtered, washed with cold ethyl alcohol (3 × 120 mL), and dried under vacuum at 50 °C for 5 h and at room temperature overnight to give a white solid (8.35 g, 83% yield, 99.5% purity).

[0750] LCMS: m / z = 559.1 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ =13.27(brs,1H),8.58(s,2H),8.36(d,J=1.7Hz,1H),8.24(brd,J=9.2Hz,1H),7. 65-7.56(m,2H),7.51(d,J=9.2Hz,1H),7.36-7.24(m,3H),7.21(d,J=2.2Hz,1H), 7.13(dd,J=2.3,9.0Hz,1H),6.94(brd,J=8.8Hz,1H),6.14(q,J=6.7Hz,1H),4.42 (s,4H),4.15(s,4H),3.04(s,3H),1.77(d,J=6.7Hz,3H);mp=186.6~191.4℃(decomposition).

[0751] Method B A suspension of compound A (0.200 g, 0.357 mmol) in acetonitrile (9 mL) was treated with benzenesulfonic acid (0.065 g, 0.441, 1.15 equiv.) at room temperature. After 3 h, diethyl ether (6 mL) was added and the mixture was stirred for 5 min. The resulting precipitate was filtered, washed with diethyl ether (2 × 3 mL), and dried under vacuum at room temperature to give a white solid (0.218 g, 85% yield).

[0752] LCMS: m / z = 559.1 (M+H); 1 H NMR (400 MHz, DMSO-d6) δ =13.33(brs,1H),8.58(s,2H),8.34(s,1H),8.31(brd,J=9.2Hz,1H),7.69-7 .56(m,2H),7.53(d,J=9.0Hz,1H),7.34-7.25(m,3H),7.23(d,J=2.0Hz,1H),7 .14(dd,J=2.2,9.0Hz,1H),7.01(d,J=9.3Hz,1H),6.14(q,J=6.6Hz,1H),4.4 7(s,4H),4.15(s,4H),3.04(s,3H),1.77(d,J=6.7Hz,3H);mp=194.3~201.3℃.

[0753] Synthesis of Forms I-XIII of Compound 2 Forms I-XIII of Compound 2 were prepared according to one of the crystallization methods described below, such as rapid crystallization, reaction crystallization, slurry crystallization, or antisolvent crystallization.

[0754] Rapid Crystallization Method: In a typical experiment, compound 2 (approximately 10 mg) was dissolved in a minimum amount of the specified solvent while heating to 80° C. The resulting solution was cooled to room temperature. Solutions that did not produce a precipitate were allowed to slowly evaporate at room temperature (RT). The results of the rapid crystallization studies are summarized below in Table 39. [Table 41] SE*: In the fast crystallization experiments, no solid was obtained and the resulting solution evaporated at room temperature.

[0755] Reaction Crystallization: A stock solution of benzenesulfonic acid (BSA) was prepared in THF and used for all reaction crystallization experiments. Compound A free base (approximately 30 mg) was dissolved in a minimum amount of the specified solvent while heating to 80°C. The resulting Compound A free base solution was cooled to room temperature and 1 equivalent of the BSA stock solution was added. Precipitation was observed in most reactions. Reactions that did not produce a precipitate were allowed to slowly evaporate at room temperature. The results of the reaction crystallization studies are summarized below in Table 40. [Table 42] SE*: In the fast crystallization experiments, no solid was obtained and the resulting solution evaporated at room temperature.

[0756] Slurry Crystallization at 40° C. Using Compound 2 Form I: In a typical experiment, Compound 2 (approximately 100 mg) was suspended in a minimum amount of the specified solvent while heating to 40° C. The resulting slurry was stirred at 40° C. for 3 days. The results of the slurry crystallization study are summarized below in Table 41. [Table 43]

[0757] Antisolvent crystallization: In a typical experiment, compound 2 (approximately 100 mg) was dissolved in a solubilizing solvent. 200 μL of antisolvent was slowly added to the solution. This was repeated until a precipitate was observed or a maximum solvent volume of approximately 15 mL was reached. The results of the antisolvent crystallization study are summarized in Table 42 below. [Table 44]

[0758] Form I of Compound 2 Table 3 above is reproduced below and shows the X-ray diffraction peaks observed for Form II of Compound 2. [Table 45-1] [Table 45-2] [Table 45-3]

[0759] FIG. 2 shows the XRPD pattern of Form I of Compound 2.

[0760] FIG. 3 shows the DSC thermogram and TGA trace of Form I of Compound 2.

[0761] Form II of Compound 2 Table 4 above is reproduced below and shows the X-ray diffraction peaks observed for Form II of Compound 2. [Table 46-1] [Table 46-2] [Table 46-3]

[0762] FIG. 4 shows the XRPD pattern of Form II of Compound 2.

[0763] Form III of Compound 2 Table 5 above is reproduced below and shows the X-ray diffraction peaks observed for Form III of Compound 2. [Table 47]

[0764] FIG. 5 shows the XRPD pattern of Form III of Compound 2.

[0765] FIG. 6 shows the DSC thermogram and TGA trace of Form III of Compound 2.

[0766] Form IV of Compound 2 Table 6 above is reproduced below and shows the X-ray diffraction peaks observed for Form IV of Compound 2. [Table 48-1] [Table 48-2]

[0767] FIG. 7 shows the XRPD pattern of Form IV of Compound 2.

[0768] Form V of Compound 2 Table 7 above is reproduced below and shows the X-ray diffraction peaks observed for Form V of Compound 2. [Table 49-1] [Table 49-2]

[0769] FIG. 8 shows the XRPD pattern of Form V of Compound 2.

[0770] FIG. 9 shows the DSC thermogram and TGA trace of Form V of Compound 2.

[0771] Form VI of Compound 2 Table 8 above is reproduced below and sho...

Claims

1. Compound 2. 【Chemistry 1】

2. The compound is crystalline. The compound is a crystalline solid that substantially does not contain amorphous compound 2, and / or The aforementioned compound is substantially free of impurities. The compound according to claim 1.

3. In XRPD, it has one or more peaks selected from approximately 18.3 degrees, approximately 20.0 degrees, and approximately 21.6 degrees 2θ, or In XRPD, it has at least two peaks selected from approximately 18.3 degrees, approximately 20.0 degrees, and approximately 21.6 degrees 2θ, or The compound is a compound of form I disclosed herein, or The XRPD is substantially the same as that shown in Figure 2. The compound according to claim 2.

4. In XRPD, there is one or more peaks selected from approximately 5.9 degrees, approximately 19.9 degrees, and approximately 21.7 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 5.9 degrees, approximately 19.9 degrees, and approximately 21.7 degrees 2θ, or The aforementioned compound is a compound of form II disclosed herein, or The XRPD is substantially the same as that shown in Figure 4. The compound according to claim 2.

5. In XRPD, it has one or more peaks selected from approximately 6.8 degrees, approximately 18.9 degrees, and approximately 20.3 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 6.8 degrees, approximately 18.9 degrees, and approximately 20.3 degrees 2θ, or The aforementioned compound is a compound of form III disclosed herein, or The XRPD is substantially the same as that shown in Figure 5. The compound according to claim 2.

6. In XRPD, there is one or more peaks selected from approximately 4.9 degrees, approximately 5.0 degrees, and approximately 25.0 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 4.9 degrees, approximately 5.0 degrees, and approximately 25.0 degrees 2θ, or The compound is a compound of form IV disclosed herein, or The XRPD is substantially the same as that shown in Figure 7. The compound according to claim 2.

7. In XRPD, it has one or more peaks selected from approximately 18.0 degrees, approximately 20.7 degrees, and approximately 25.9 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 18.0 degrees, approximately 20.7 degrees, and approximately 25.9 degrees 2θ, or The aforementioned compound is a compound of form V disclosed herein, or The XRPD is substantially the same as that shown in Figure 8. The compound according to claim 2.

8. In XRPD, it has one or more peaks selected from approximately 6.5 degrees, approximately 19.2 degrees, and approximately 20.2 degrees 2θ, or In XRPD, it has at least two peaks selected from approximately 6.5 degrees, approximately 19.2 degrees, and approximately 20.2 degrees 2θ, or The compound is a compound of form VI disclosed herein, or Having an XRPD substantially the same as that shown in Figure 10, The compound according to claim 2.

9. In XRPD, it has one or more peaks selected from approximately 10.4 degrees, approximately 14.8 degrees, and approximately 24.9 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 10.4 degrees, approximately 14.8 degrees, and approximately 24.9 degrees 2θ, or The aforementioned compound is a compound of form VII disclosed herein, or Having an XRPD substantially the same as that shown in Figure 11, The compound according to claim 2.

10. The aforementioned compound is a compound of form VIII, or The XRPD is substantially the same as that shown in Figure 13. The compound according to claim 1.

11. In XRPD, it has one or more peaks selected from approximately 6.3 degrees, approximately 6.7 degrees, and approximately 18.9 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 6.3 degrees, approximately 6.7 degrees, and approximately 18.9 degrees 2θ, or The aforementioned compound is a compound of form IX disclosed herein, or Having an XRPD substantially similar to that shown in Figure 14, or In XRPD, there is one or more peaks selected from approximately 6.6 degrees, approximately 18.2 degrees, and approximately 19.8 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 6.6 degrees, approximately 18.2 degrees, and approximately 19.8 degrees 2θ, or The aforementioned compound is a compound of form X disclosed herein, or Having an XRPD substantially similar to that shown in Figure 15, or In XRPD, it has one or more peaks selected from approximately 7.0 degrees, approximately 20.0 degrees, and approximately 20.3 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 7.0 degrees, approximately 20.0 degrees, and approximately 20.3 degrees 2θ, or The aforementioned compound is a compound of form XI disclosed herein, or Having an XRPD substantially similar to that shown in Figure 17, or In XRPD, there is one or more peaks selected from approximately 5.8 degrees, approximately 5.9 degrees, and approximately 19.3 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 5.8 degrees, approximately 5.9 degrees, and approximately 19.3 degrees 2θ, or The aforementioned compound is a compound of form XII, or Having an XRPD substantially similar to that shown in Figure 19, or In XRPD, there is one or more peaks selected from approximately 6.1 degrees, approximately 21.8 degrees, and approximately 22.8 degrees 2θ, or In XRPD, there are at least two peaks selected from approximately 6.1 degrees, approximately 21.8 degrees, and approximately 22.8 degrees 2θ, or The aforementioned compound is a compound of form XIII disclosed herein, or The XRPD is substantially the same as that shown in Figure 21. The compound according to claim 2.

12. Compound 1: 【Chemistry 2】 or its crystalline form, Compound 3: 【Transformation 3】 or its crystalline form, Compound 4: 【Chemistry 4】 or its crystalline form, Compound 5: 【Transformation 5】 or its crystalline form, Compound 6: 【Transformation 6】 or its crystalline form, Compound 7: 【Transformation 7】 or its crystalline form, Compound 8: 【Transformation 8】 or its crystalline form, Compound 9: 【Chemistry 9】 or its crystalline form, Compound 10: 【Chemistry 10】 or its crystalline form, Compound 11: 【Chemistry 11】 or its crystalline form, Compound 12: 【Chemistry 12】 or its crystalline form, Compound 13: 【Chemistry 13】 or its crystalline form, Compound 14: 【Chemistry 14】 or its crystalline form, Compound A of crystalline form I, II, III, IV, V, VI, VII, or VIII: 【Chemistry 15】 、 Compound 23: 【Chemistry 16】 or its crystalline form, Compound 24: 【Chemistry 17】 or its crystalline form, Compound 25: [Chemistry 18] or its crystalline form, Compound 26: 【Chemistry 19】 A compound selected from its crystalline form.

13. A pharmaceutically acceptable composition comprising a compound according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier, excipient, or vehicle.

14. A pharmaceutically acceptable composition according to claim 13 for use in a method of treating cancer in a patient, wherein the method comprises administering the pharmaceutically acceptable composition to the patient, and optionally further comprising administering an additional therapeutic agent to the patient.

15. A method for preparing a salt compound of formula X, 【Chemistry 20】 The step includes combining A with a suitable acid and optionally a solvent under conditions suitable for producing the compound of formula X, 【Chemistry 21】 Optional, (a) The appropriate acid is hydrochloric acid, the compound of formula X is the hydrochloride salt of compound A, and optionally the hydrochloride salt is crystallized into hydrochloride salt form I or form II as disclosed herein. (b) The appropriate acid is benzenesulfonic acid, the compound of formula X is a besilate of compound A, and optionally the besilate is crystallized to form a besilate of compound A form I, compound A form II, compound A form III, compound A form IV, compound A form V, compound A form VI, compound A form VII, compound A form IX, compound A form X, compound A form XI, compound A form XII, or compound A form XIII, respectively as described herein. (c) The appropriate acid is maleic acid, the compound of formula X is the maleate of compound A, and optionally the maleate is crystallized to form the maleate of compound A form I or form II as described herein. (d) The appropriate acid is p-toluenesulfonic acid, the compound of formula X is a tosylate of compound A, and optionally the tosylate is recrystallized to form the form I described herein. (e) The appropriate acid is sulfuric acid, the compound of formula X is the sulfate of compound A, and optionally the sulfate is recrystallized to form form I or form II as described herein. (f) The appropriate acid is a sulfonic acid, the compound of formula X is a sulfonate of compound A, and optionally the sulfonate is recrystallized to form form I described herein. (g) The appropriate acid is ethanesulfonic acid, the compound of formula X is the esylate of compound A, and optionally the esylate is recrystallized to form the form I described herein. (h) The appropriate acid is methanesulfonic acid, the compound of formula X is a mesylate of compound A, and optionally the mesylate is recrystallized to form form I described herein. (i) The appropriate acid is methanesulfonic acid, the compound of formula X is a dimethylate of compound A, and optionally the dimethylate is recrystallized to form the form I described herein. (j) The appropriate acid is R-camphor sulfonic acid, the compound of formula X is the R-cansylate of compound A, and optionally the R-cansylate is crystallized to form the form I described herein. (k) The appropriate acid is S-camphor sulfonic acid, the compound of formula X is the S-cansylate of compound A, and optionally the S-cansylate is crystallized to form the form I described herein. (l) The appropriate acid is hydrobromic acid, the compound of formula X is the bromate salt of compound A, and optionally the bromate salt is recrystallized to form form I or form II as described herein. (m) The appropriate acid is phosphoric acid, the compound of formula X is a phosphate of compound A, and optionally the phosphate is recrystallized to form the form I described herein. (n) The appropriate acid is citric acid, the compound of formula X is the citrate of compound A, and optionally the citrate is recrystallized to form the form I described herein. (o) The appropriate acid is L-tartaric acid, the compound of formula X is the L-tartrate of compound A, and optionally the L-tartrate is recrystallized to form the form I described herein, or (p) The appropriate acid is malonic acid, the compound of formula X is the malonate of compound A, and optionally the malonate is recrystallized to form the form I described herein. method.

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