Crystalline forms of phosphoinositide 3 kinase (PI3K) inhibitor

Abstract

The present invention relates to salts and crystalline forms of 2-(3-(8-amino-6-(trifluoromethyl) imidazo [1, 2-a] pyrazin-3-yl)-4-methylphenyl)-3, 3, 3-trifluoro-2-hydroxypropanamide, 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1, 1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl) imidazo [1, 2-a] pyrazin-3-yl)-4-methylphenyl)-3, 3, 3-trifluoro-2-hydroxypropanamide, and a preparation method thereof. The present invention relates to crystalline forms of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d3)-5-(1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenyl) imidazo [1, 2-a] pyrazine-6-carboxamide, which are PI3K inhibitors useful in the treatment of cancer and other diseases, as well as crystalline forms of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d3)-5-(1, 1, 1-trifluoro-2-hydroxypropyl-2-yl) phenyl) imidazo [1, 2-a] pyrazine-6-carboxamide.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980071241.6 (filing date: September 4, 2019; invention title: Crystalline Forms of Phosphoinositide 3-Kinase (PI3K) Inhibitors). Technical Field

[0002] The present invention relates to salts and crystalline forms of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, and 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, which are PI3K inhibitors useful for treating cancer and other diseases. Background Art

[0003] The compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide of formula A, 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide of formula B, and 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide of formula C:

[0004]

[0005] are phosphoinositide 3-kinase (PI3K) inhibitors useful for treating various diseases including cancer. For drug development, it is generally desirable to use a drug form that has desirable properties in terms of its preparation, purification, reproducibility, stability, bioavailability, and other characteristics. Accordingly, the salts and crystalline forms of the compounds of formula A, formula B, and formula C provided herein address the continuing need to develop PI3K inhibitors for treating serious diseases. Summary of the Invention

[0007] The present invention provides salts and crystalline forms of the compound of formula A, crystalline forms of the compound of formula B, and crystalline forms of the compound of formula C:

[0008]

[0009] The present invention also provides a composition comprising a salt and a crystalline form of a compound of formula A provided herein and at least one pharmaceutically acceptable carrier. The present invention also provides a composition comprising a crystalline form of a compound of formula B and at least one pharmaceutically acceptable carrier. The present invention also provides a composition comprising a crystalline form of a compound of formula C and at least one pharmaceutically acceptable carrier.

[0010] The present invention also provides a method for preparing the salts and crystalline forms of the present invention.

[0011] The present invention also provides a method for treating a disease in a patient associated with an abnormal manifestation or activity of PI3K kinase, the method comprising administering to the patient a therapeutically effective amount of a salt or crystalline form of the present invention. Description of the Drawings

[0012] Figure 1 The XRPD pattern of crystalline form IA of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide is shown.

[0013] Figure 2 The DSC experimental results of crystalline form IA of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide are shown.

[0014] Figure 3 The TGA experimental results of crystalline form IA of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide are shown.

[0015] Figure 4 The XRPD pattern of crystalline form IIA of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide is shown.

[0016] Figure 5 The DSC experimental results of crystalline form IIA of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide are shown.

[0017] Figure 6Shows the TGA experimental results of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide crystalline form IIA.

[0018] Figure 7 Shows the XRPD pattern of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide crystalline form IIIA.

[0019] Figure 8 Shows the DSC experimental results of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide crystalline form IIIA.

[0020] Figure 9 Shows the TGA experimental results of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide crystalline form IIIA.

[0021] Figure 10 Shows the XRPD pattern of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide crystalline form IB.

[0022] Figure 11 Shows the DSC experimental results of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide crystalline form IB.

[0023] Figure 12 Shows the XRPD pattern of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide crystalline form IIB.

[0024] Figure 13 Shows the DSC experimental results of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide crystalline form IIB.

[0025] Figure 14Shows the XRPD pattern of crystalline form IC of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide.

[0026] Figure 15 Shows the DSC experimental results of crystalline form IC of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide.

[0027] Figure 16A Shows the asymmetric crystallization unit of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide methanol solvate form, where the thermal ellipsoids are drawn at the 30% probability level.

[0028] Figure 16B Shows the crystallization unit of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide, where the thermal ellipsoids are drawn at the 30% probability level. Detailed Description

[0029] The present invention particularly relates to salts and crystalline forms of the PI3K inhibitor 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide having formula A:

[0030]

[0031] They can be used, for example, to prepare solid dosage forms of the above compounds for use in the treatment of various diseases, including cancer.

[0032] The present invention also particularly relates to crystalline forms of the PI3K inhibitor 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide having formula B:

[0033]

[0034] The present invention also particularly relates to the PI3K inhibitor 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d3 )-5-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide crystalline forms:

[0035]

[0036] Generally, different crystalline forms of the same substance have different overall properties with respect to, for example, hygroscopicity, solubility, stability, etc. Forms with high melting points generally have good thermodynamic stability, which is beneficial for extending the shelf life of pharmaceutical formulations containing the solid form. Forms with lower melting points are generally less thermodynamically stable, but the advantage is that they have increased water solubility, which translates into increased drug bioavailability. Weakly hygroscopic forms are desirable due to their thermal and wet stability and resist degradation during long-term storage. Anhydrous forms are generally desirable because they can be consistently manufactured without concern for weight or composition changes due to solvent or water content variations. On the other hand, hydrated or solvated forms may be advantageous because they are less likely to be hygroscopic and may exhibit improved humidity stability under storage conditions.

[0037] As used herein, "crystalline form" is intended to refer to a particular lattice conformation of a crystalline substance. Different crystalline forms of the same substance generally have different lattices (e.g., unit cells), which is attributed to the different physical properties unique to each crystalline form. In some cases, different lattice conformations have different water or solvent contents. Different crystalline lattices can be identified by solid-state characterization methods, such as by X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid-state NMR, etc., also help to identify the crystalline form and to determine stability and solvent / water content.

[0038] The crystalline forms of a substance include solvated (e.g., hydrated) forms and non-solvated (e.g., anhydrous) forms. Hydrated forms are crystalline forms that include water in the crystal lattice. Hydrated forms can be stoichiometric hydrates, where water is present in the lattice in a certain water / molecule ratio, such as hemihydrate, monohydrate, dihydrate, etc. Hydrated forms can also be non-stoichiometric, where the water content is variable and depends on external conditions, such as humidity.

[0039] Crystalline forms are most commonly characterized by XRPD. The XRPD pattern of the reflections (peaks) is often regarded as a fingerprint of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely depending especially on the sample preparation technique, crystal size distribution, filter, sample mounting procedure, and the particular instrument employed. In some cases, new peaks may be observed or existing peaks may disappear, depending on the instrument type or settings (e.g., whether a Ni filter is used). As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. In addition, instrument variations and other factors can affect the 2θ values. Thus, peak assignments, such as those reported herein, may vary plus or minus about 0.2° (2θ), and the term "substantially" as used herein in the context of XRPD is intended to cover the variations mentioned above.

[0040] Similarly, temperature readings associated with DSC, TGA, or other thermal experiments can vary by about ±4 °C, depending on the instrument, particular settings, sample preparation, etc. For example, in the case of DSC, it is known that the observed temperature will depend on the rate of temperature change as well as the sample preparation technique and the particular instrument employed. Thus, as noted above, the values reported herein for DSC thermograms may vary by ±4 °C. Accordingly, crystalline forms having a DSC thermogram "substantially" as shown in any of the figures herein should be understood to include such variations.

[0041] Crystalline forms of the compound of formula A

[0042] The compound of formula A can be isolated in a variety of crystalline forms, including, for example, anhydrous and / or non-solvated or solvated crystalline forms. In some embodiments, the crystalline form of the compound of formula A is solvated. In some embodiments, the crystalline form of the compound of formula A is anhydrous. In some embodiments, the crystalline form of the compound of formula A is non-solvated. In some embodiments, the crystalline form of the compound of formula A is anhydrous and non-solvated. "Anhydrous" means that the crystalline form of the compound of formula A is substantially free of bound water in the crystal lattice structure, i.e., the compound does not form a crystalline hydrate.

[0043] In some embodiments, the present application provides a method for preparing a crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide. In some embodiments, the method comprises dissolving 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide in a solvent to form a mixture, and crystallizing the compound from the mixture.

[0044] In some embodiments, the solvent comprises isopropyl acetate. In some embodiments, the solvent further comprises heptane.

[0045] In some embodiments, the solvent comprises methanol.

[0046] In some embodiments, the method further comprises heating the mixture to a temperature of about 70 °C to about 90 °C.

[0047] In some embodiments, the method further comprises heating the mixture to a temperature of about 50 °C to about 70 °C.

[0048] In some embodiments, the method further comprises cooling the mixture to room temperature.

[0049] The present application also provides a crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, which is prepared according to the method provided herein. In some embodiments, the crystalline form is Form IA as described herein. In some embodiments, the crystalline form is Form IIA as described herein. In some embodiments, the crystalline form is Form IIIA as described herein.

[0050] In some embodiments, the present application provides a method for preparing the hydrobromide salt of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide. In some embodiments, the method comprises dissolving a compound of Formula A in a solvent to form a mixture, and adding hydrobromic acid to the mixture.

[0051] In some embodiments of the method for preparing the hydrobromide salt, the solvent comprises methanol.

[0052] In some embodiments of the method for preparing the hydrobromide salt, hydrobromic acid is added to the mixture as an aqueous solution of hydrobromic acid.

[0053] In some embodiments of the method for preparing the hydrobromide salt, an excess of hydrobromic acid is added to the mixture based on 1 equivalent of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide.

[0054] In some embodiments of the method for preparing the hydrobromide salt, about 1.1 to about 1.5 equivalents of hydrobromic acid are added to the mixture based on 1 equivalent of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide.

[0055] In some embodiments of the method for preparing the hydrobromide salt, the method further comprises substantially separating 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide.

[0056] In some embodiments of the method for preparing the hydrobromide salt, the 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide is separated as a crystalline form.

[0057] In some embodiments of the method for preparing the hydrobromide salt, the 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide is separated as a crystalline methanol solvate form.

[0058] In some embodiments, the present application also provides the hydrobromide salt of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, which is prepared according to the method provided herein. In some embodiments, the hydrobromide salt is crystalline. In some embodiments, the hydrobromide salt is in a solvated crystalline form. In some embodiments, the hydrobromide salt is in a crystalline methanol solvate form.

[0059] In some embodiments, the crystalline form of the present invention is substantially separated. "Substantially separated" means that the specific crystalline form of Compound A is at least partially separated from impurities. For example, in some embodiments, the crystalline form of the present invention contains less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1% or less than about 0.5% impurities. Impurities generally include any substances other than the substantially separated crystalline form, including, for example, other crystalline forms and other substances.

[0060] In some embodiments, the crystalline form of the compound of formula A is substantially free of other crystalline forms. The phrase "substantially free of other crystalline forms" means that the specific crystalline form of the compound of formula A comprises more than about 80%, more than about 90%, more than about 95%, more than about 98%, more than about 99%, or more than about 99.5% by weight of the specific crystalline form.

[0061] Crystalline Form IA of the compound of formula A

[0062] In some embodiments, the crystalline form of the compound of formula A is Form IA. In some embodiments, Crystalline Form IA of the compound of formula A is anhydrous and non-solvated. The preparation of Form IA of the compound of formula A is described in Example 1. Crystalline Form IA of the compound of formula A can generally be prepared as described in Example 2.

[0063] Crystalline Form IA of the compound of formula A can be identified by unique signatures associated with, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). In some embodiments, Crystalline Form IA of the compound of formula A is characterized by an XRPD pattern substantially as Figure 1 shown. The peaks of the XRPD pattern are listed in Table 1.

[0064] In some embodiments, Crystalline Form IA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 8.6° ± 0.2°. In some embodiments, Crystalline Form IA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 9.5° ± 0.2°. In some embodiments, Crystalline Form IA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 10.3° ± 0.2°. In some embodiments, Crystalline Form IA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 14.9° ± 0.2°.

[0065] In some embodiments, crystalline Form IA of the compound of Formula A has an XRPD pattern comprising the following peaks expressed as 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 13.0° ± 0.2°; 13.6° ± 0.2°; 14.2° ± 0.2°; and 14.9° ± 0.2°. In some embodiments, crystalline Form IA of the compound of Formula A has an XRPD pattern comprising the following peaks expressed as 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 14.9° ± 0.2°; 17.3° ± 0.2°; 17.8° ± 0.2°; 19.0° ± 0.2°; 19.2° ± 0.2°; 20.1° ± 0.2°; 20.6° ± 0.2°; 21.2° ± 0.2°; 22.2° ± 0.2°; 24.0° ± 0.2°; 26.8° ± 0.2°; and 28.7° ± 0.2°. In some embodiments, crystalline Form IA of the compound of Formula A has an XRPD pattern comprising the following peaks expressed as 2θ: 10.3° ± 0.2°; 14.9° ± 0.2°; 17.3° ± 0.2°; 19.2° ± 0.2°; and 24.0° ± 0.2°.

[0066] In some embodiments, crystalline Form IA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 13.0° ± 0.2°; 13.6° ± 0.2°; 14.2° ± 0.2°; 14.9° ± 0.2°; 17.3° ± 0.2°; 19.2° ± 0.2°; 20.6° ± 0.2°; 24.0° ± 0.2°; and 28.7° ± 0.2°. In some embodiments, crystalline Form IA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 14.9° ± 0.2°; 17.3° ± 0.2°; 17.8° ± 0.2°; 19.0° ± 0.2°; 19.2° ± 0.2°; 20.1° ± 0.2°; 20.6° ± 0.2°; 21.2° ± 0.2°; 22.2° ± 0.2°; 24.0° ± 0.2°; 26.8° ± 0.2°; and 28.7° ± 0.2°. In some embodiments, crystalline Form IA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 9.5° ± 0.2°; 10.3° ± 0.2°; 14.9° ± 0.2°; 17.3° ± 0.2°; 19.2° ± 0.2°; 20.6° ± 0.2°; 24.0° ± 0.2°; and 28.7° ± 0.2°.

[0067] In some embodiments, Form IA of the compound of Formula A is characterized by a DSC thermogram comprising an endothermic peak having a maximum at about 193°C. In some embodiments, crystalline Form IA of the compound of Formula A has substantially as Figure 2 shown in the DSC thermogram.

[0068] In some embodiments, crystalline Form IA of the compound of Formula A has substantially as Figure 3 shown in the TGA trace.

[0069] Crystalline Form IIA of the compound of Formula A

[0070] In some embodiments, the crystalline form of the compound of Formula A is Form IIA. In some embodiments, crystalline Form IIA of the compound of Formula A is anhydrous and non-solvated. This crystalline form can generally be prepared as described in Example 3.

[0071] The crystalline form IIA of the compound of formula A can be identified by unique signatures associated with, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern substantially as Figure 4 shown. The peaks of the XRPD pattern are listed in Table 2.

[0072] In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 9.1 ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 11.1° ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 21.9° ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 12.6° ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 13.6° ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 18.0° ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 19.0° ± 0.2°.

[0073] In some embodiments, the crystalline form IIA of the compound of formula A has an XRPD pattern comprising the following peaks at 2θ: 9.1° ± 0.2°; 11.1° ± 0.2°; 12.6° ± 0.2°; and 13.5° ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A has an XRPD pattern comprising the following peaks at 2θ: 9.1° ± 0.2°; 11.1° ± 0.2°; 12.6° ± 0.2°; 13.5° ± 0.2°; 16.1° ± 0.2°; 16.9° ± 0.2°; 18.0° ± 0.2°; 18.4° ± 0.2°; 19.0° ± 0.2°; 19.7° ± 0.2°; 20.1° ± 0.2°; 20.5° ± 0.2°; 21.9° ± 0.2°; 23.7° ± 0.2°; 23.8° ± 0.2°; 25.1° ± 0.2°; 25.3° ± 0.2°; 25.8° ± 0.2°; and 27.3° ± 0.2°. In some embodiments, the crystalline form IIA of the compound of formula A has an XRPD pattern comprising the following peaks at 2θ: 12.6° ± 0.2°; 18.0° ± 0.2°; 19.0° ± 0.2°; and 21.9° ± 0.2°.

[0074] In some embodiments, crystalline Form IIA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 9.1° ± 0.2°; 11.1° ± 0.2°; 12.6° ± 0.2°; 13.5° ± 0.2°; 18.0° ± 0.2°; 19.0° ± 0.2°; 20.5° ± 0.2°; and 21.9° ± 0.2°. In some embodiments, crystalline Form IIA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 9.1° ± 0.2°; 11.1° ± 0.2°; 12.6° ± 0.2°; 13.5° ± 0.2°; 16.1° ± 0.2°; 16.9° ± 0.2°; 18.0° ± 0.2°; 18.4° ± 0.2°; 19.0° ± 0.2°; 19.7° ± 0.2°; 20.1° ± 0.2°; 20.5° ± 0.2°; 21.9° ± 0.2°; 23.7° ± 0.2°; 23.8° ± 0.2°; 25.1° ± 0.2°; 25.3° ± 0.2°; 25.8° ± 0.2°; and 27.3° ± 0.2°. In some embodiments, crystalline Form IIA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 12.6° ± 0.2°; 18.0° ± 0.2°; 19.0° ± 0.2°; 20.5° ± 0.2°; and 21.9° ± 0.2°.

[0075] In some embodiments, Form IIA of the compound of Formula A is characterized by a DSC thermogram comprising an endothermic peak having a maximum at about 180°C. In some embodiments, crystalline Form IIA of the compound of Formula A has substantially as Figure 5 shown in the DSC thermogram.

[0076] In some embodiments, crystalline Form IIA of the compound of Formula A has substantially as Figure 6 shown in the TGA trace.

[0077] Crystalline Form IIIA of the compound of Formula A

[0078] In some embodiments, the crystalline form of the compound of Formula A is Form IIIA. In some embodiments, crystalline Form IIIA of the compound of Formula A is anhydrous and non-solvated. This crystalline form can generally be prepared as described in Example 4.

[0079] The crystalline form IIIA of the compound of formula A can be identified by unique signatures associated with, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). In some embodiments, the crystalline form IIIA of the compound of formula A is characterized by an XRPD pattern substantially as Figure 7 shown. Table 3 lists the peaks of the XRPD pattern.

[0080] In some embodiments, the crystalline form IIIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 8.1° ± 0.2°. In some embodiments, the crystalline form IIIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 10.6° ± 0.2°. In some embodiments, the crystalline form IIIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 13.5° ± 0.2°. In some embodiments, the crystalline form IIIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 14.2° ± 0.2°. In some embodiments, the crystalline form IIIA of the compound of formula A is characterized by an XRPD pattern comprising a peak at 2θ of 20.3° ± 0.2°.

[0081] In some embodiments, the crystalline form IIIA of the compound of formula A has an XRPD pattern comprising the following peaks at 2θ: 8.1° ± 0.2°; 10.6° ± 0.2°; 13.5° ± 0.2°; and 14.2° ± 0.2°. In some embodiments, the crystalline form IIIA of the compound of formula A has an XRPD pattern comprising the following peaks at 2θ: 10.6° ± 0.2°; 13.5° ± 0.2°; 14.2° ± 0.2°; 16.4° ± 0.2°; 17.1° ± 0.2°; 17.9° ± 0.2°; 20.3° ± 0.2°; 20.8° ± 0.2°; 24.1° ± 0.2°; 24.6° ± 0.2°; 24.8° ± 0.2°; and 27.5° ± 0.2°. In some embodiments, the crystalline form IIIA of the compound of formula A has an XRPD pattern comprising the following peaks at 2θ: 10.6° ± 0.2°; 13.5° ± 0.2°; 14.2° ± 0.2°; and 20.3° ± 0.2°.

[0082] In some embodiments, crystalline Form IIIA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 8.1° ± 0.2°; 10.6° ± 0.2°; 13.5° ± 0.2°; 14.2° ± 0.2°; 16.4° ± 0.2°; 17.1° ± 0.2°; 17.9° ± 0.2°; 20.3° ± 0.2°; and 24.1° ± 0.2°. In some embodiments, crystalline Form IIIA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 10.6° ± 0.2°; 13.5° ± 0.2°; 14.2° ± 0.2°; 16.4° ± 0.2°; 17.1° ± 0.2°; 17.9° ± 0.2°; 20.3° ± 0.2°; 20.8° ± 0.2°; 24.1° ± 0.2°; 24.6° ± 0.2°; 24.8° ± 0.2°; and 27.5° ± 0.2°. In some embodiments, crystalline Form IIIA of the compound of Formula A has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 10.6° ± 0.2°; 13.5° ± 0.2°; 14.2° ± 0.2°; 16.4° ± 0.2°; 17.1° ± 0.2°; 17.9° ± 0.2°; 20.3° ± 0.2°; and 24.1° ± 0.2°.

[0083] In some embodiments, Form IIIA of the compound of Formula A is characterized by a DSC thermogram comprising an endothermic peak having a maximum at about 143°C. In some embodiments, crystalline Form IIIA of the compound of Formula A has a DSC thermogram substantially as Figure 8 shown.

[0084] In some embodiments, crystalline Form IIIA of the compound of Formula A has a TGA trace substantially as Figure 9 shown.

[0085] The hydrobromide salt of Formula A

[0086] In some embodiments, the present application provides the hydrobromide salt of the compound of Formula A. In some embodiments, the hydrobromide salt of the compound of Formula A has a 1:1 stoichiometric ratio of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide to hydrobromic acid. The hydrobromide salt form can generally be prepared as described in Example 11.

[0087] In some embodiments, the hydrobromide salt of the compound of Formula A is crystalline. In some embodiments, the hydrobromide salt of the compound of Formula A is a solvated crystalline form. In some embodiments, the hydrobromide salt of the compound of Formula A is a methanol solvate crystalline form.

[0088] Crystalline forms of the compound of Formula B

[0089] The compound of Formula B can be isolated in multiple crystalline forms, including, for example, anhydrous and / or non-solvated crystalline forms. In some embodiments, the crystalline form of the compound of Formula B is anhydrous. In some embodiments, the crystalline form of the compound of Formula B is non-solvated. In some embodiments, the crystalline form of the compound of Formula B is anhydrous and non-solvated. "Anhydrous" means that the crystalline form of the compound of Formula B is substantially free of water of crystallization in the crystal lattice structure, i.e., the compound does not form a hydrate.

[0090] In some embodiments, the crystalline forms provided herein can be prepared, for example, by a method comprising dissolving 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide in a solvent to form a mixture and crystallizing the compound from the mixture.

[0091] In some embodiments, the method further comprises heating the mixture to a temperature of about 70 °C to about 90 °C. In some embodiments, the method further comprises cooling the mixture to room temperature.

[0092] In some embodiments, the solvent comprises isopropyl acetate. In some embodiments, the solvent further comprises heptane.

[0093] In some embodiments, the present application provides a crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, which is prepared according to the method provided herein. In some embodiments, the crystalline form is Form IB as described herein. In some embodiments, the crystalline form is Form IIB as described herein.

[0094] In some embodiments, the crystalline forms of the present invention are substantially separated. "Substantially separated" means that the specific crystalline form of Compound B is at least partially separated from impurities. For example, in some embodiments, the crystalline forms of the present invention contain less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% impurities. Impurities generally include any substances other than the substantially separated crystalline forms, including, for example, other crystalline forms and other substances.

[0095] In some embodiments, the crystalline form of Compound B is substantially free of other crystalline forms. The phrase "substantially free of other crystalline forms" means that the specific crystalline form of Compound B comprises more than about 80%, more than about 90%, more than about 95%, more than about 98%, more than about 99%, or more than about 99.5% by weight of the specific crystalline form.

[0096] Crystalline Form IB of Compound B

[0097] In some embodiments, the crystalline form of Compound B is Form IB. In some embodiments, Crystalline Form IB of Compound B is anhydrous and non-solvated. The preparation of Compound B is described in Examples 5 and 6. Crystalline Form IB can generally be prepared as described in Example 7.

[0098] Crystalline Form IB of Compound B can be identified by, for example, unique signatures associated with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). In some embodiments, Crystalline Form IB of Compound B is characterized by an XRPD pattern substantially as Figure 10 shown. Table 4 lists the peaks of the XRPD pattern.

[0099] In some embodiments, crystalline Form IB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 6.2° ± 0.2° in 2θ. In some embodiments, crystalline Form IB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 15.6° ± 0.2° in 2θ. In some embodiments, crystalline Form IB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 20.7° ± 0.2° in 2θ. In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising the following peaks in 2θ: 6.2° ± 0.2°; 15.6° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 23.2° ± 0.2°. In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising the following peaks in 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.4° ± 0.2°; 11.6° ± 0.2°; 12.0° ± 0.2°; 13.9° ± 0.2°; 14.4° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 23.2° ± 0.2°. In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising the following peaks in 2θ: 6.2° ± 0.2°; 12.0° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 19.3° ± 0.2°; 20.7° ± 0.2°; 23.2° ± 0.2°; and 27.1° ± 0.2°. In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising the following peaks in 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.4° ± 0.2°; 11.6° ± 0.2°; 12.0° ± 0.2°; 13.9° ± 0.2°; and 14.4° ± 0.2°.

[0100] In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.4° ± 0.2°; 11.6° ± 0.2°; 12.0° ± 0.2°; 13.9° ± 0.2°; 14.4° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 23.2° ± 0.2°. In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 6.2° ± 0.2°; 12.0° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 19.3° ± 0.2°; 20.7° ± 0.2°; 23.2° ± 0.2°; and 27.1° ± 0.2°. In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 6.2° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 23.2° ± 0.2°. In some embodiments, crystalline Form IB of the compound of formula B has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.4° ± 0.2°; 11.6° ± 0.2°; 12.0° ± 0.2°; 13.9° ± 0.2°; and 14.4° ± 0.2°.

[0101] In some embodiments, Form IB of the compound of formula B is characterized by a DSC thermogram comprising an endothermic peak having a maximum at about 174°C. In some embodiments, crystalline Form IB of the compound of formula B has a DSC thermogram substantially as Figure 11 shown.

[0102] Crystalline Form IIB of the compound of formula B

[0103] In some embodiments, the crystalline form of the compound of formula B is Form IIB. In some embodiments, crystalline Form IIB of the compound of formula B is anhydrous and non-solvated. This crystalline form can generally be prepared as described in Example 8.

[0104] The crystalline form IIB of the compound of formula B can be identified by unique signatures associated with, for example, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). In some embodiments, the crystalline form IIB of the compound of formula B is characterized by an XRPD pattern substantially as Figure 12 shown. Table 5 lists the peaks of the XRPD pattern.

[0105] In some embodiments, the crystalline form IIB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 4.2° ± 0.2° in 2θ. In some embodiments, the crystalline form IIB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 7.4° ± 0.2° in 2θ. In some embodiments, the crystalline form IIB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 13.3° ± 0.2° in 2θ. In some embodiments, the crystalline form IIB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 20.1° ± 0.2° in 2θ. In some embodiments, the crystalline form IIB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 17.0° ± 0.2° in 2θ. In some embodiments, the crystalline form IIB of the compound of formula B is characterized by an XRPD pattern comprising a peak at 18.8° ± 0.2° in 2θ.

[0106] In some embodiments, the crystalline form IIB of the compound of formula B has an XRPD pattern comprising the following peaks in 2θ: 4.3° ± 0.2°; 7.4° ± 0.2°; 13.3° ± 0.2°; and 15.3° ± 0.2°. In some embodiments, the crystalline form IIB of the compound of formula B has an XRPD pattern comprising the following peaks in 2θ: 4.3° ± 0.2°; 7.4° ± 0.2°; 15.3° ± 0.2°; 17.0° ± 0.2°; 18.8° ± 0.2°; and 20.1° ± 0.2°. In some embodiments, the crystalline form IIB of the compound of formula B has an XRPD pattern comprising the following peaks in 2θ: 4.3° ± 0.2°; 7.4° ± 0.2°; 13.3° ± 0.2°; 15.3° ± 0.2°; 15.5° ± 0.2°; 17.0° ± 0.2°; 17.2° ± 0.2°; 18.1° ± 0.2°; 18.8° ± 0.2°; 19.6° ± 0.2°; 20.1° ± 0.2°; 21.4° ± 0.2°; 23.5° ± 0.2°; 25.8° ± 0.2°; 26.2° ± 0.2°; and 27.3° ± 0.2°.

[0107] In some embodiments, crystalline Form IIB of the compound of formula B has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 4.3° ± 0.2°; 7.4° ± 0.2°; 13.3° ± 0.2°; 15.3° ± 0.2°; 15.5° ± 0.2°; 17.0° ± 0.2°; 17.2° ± 0.2°; 18.1° ± 0.2°; 18.8° ± 0.2°; 19.6° ± 0.2°; 20.1° ± 0.2°; 21.4° ± 0.2°; 23.5° ± 0.2°; 25.8° ± 0.2°; 26.2° ± 0.2°; and 27.3° ± 0.2°. In some embodiments, crystalline Form IIB of the compound of formula B has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 4.3° ± 0.2°; 7.4° ± 0.2°; 13.3° ± 0.2°; 15.3° ± 0.2°; 15.5° ± 0.2°; 17.0° ± 0.2°; 17.2° ± 0.2°; 18.8° ± 0.2°; and 20.1° ± 0.2°.

[0108] In some embodiments, Form IIB of the compound of formula B is characterized by a DSC thermogram comprising an endothermic peak having a maximum at about 165°C. In some embodiments, crystalline Form IIB of the compound of formula B has a DSC thermogram substantially as Figure 13 shown.

[0109] Crystalline forms of the compound of formula C

[0110] The compound of formula C can be isolated in a variety of crystalline forms, including, for example, anhydrous and / or non-solvated crystalline forms. In some embodiments, the crystalline form of the compound of formula C is anhydrous. In some embodiments, the crystalline form of the compound of formula C is non-solvated. In some embodiments, the crystalline form of the compound of formula C is anhydrous and non-solvated. "Anhydrous" means that the crystalline form of the compound of formula C is substantially free of water of hydration in the crystal lattice structure, i.e., the compound does not form a crystalline hydrate.

[0111] In some embodiments, the present application provides a method for preparing a crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide. In some embodiments, the method comprises combining 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3)-5-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide is dissolved in a solvent to form a mixture and the compound is crystallized from the mixture.

[0112] In some embodiments, the method further comprises heating the mixture to a temperature of about 70 °C to about 90 °C. In some embodiments, the method further comprises cooling the mixture to room temperature.

[0113] In some embodiments, the solvent comprises isopropyl acetate. In some embodiments, the solvent further comprises heptane.

[0114] This application also provides a crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, which is prepared according to the method provided herein. In some embodiments, the crystalline form is Form IC as described herein.

[0115] In some embodiments, the crystalline form of the compound of formula C is substantially isolated. "Substantially isolated" means that at least in part, a particular crystalline form of the compound of formula C is separated from impurities. For example, in some embodiments, the crystalline form of the present invention contains less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1% or less than about 0.5% impurities. Impurities generally include any substances other than the substantially isolated crystalline form, including, for example, other crystalline forms and other substances.

[0116] In some embodiments, the crystalline form of the compound of formula C is substantially free of other crystalline forms. The phrase "substantially free of other crystalline forms" means that a particular crystalline form of the compound of formula C accounts for more than about 80%, more than about 90%, more than about 95%, more than about 98%, more than about 99% or more than about 99.5% by weight of the particular crystalline form.

[0117] Crystalline Form IC of the compound of formula C

[0118] In some embodiments, the crystalline form of the compound of formula C is Crystalline Form IC. In some embodiments, Crystalline Form IC of the compound of formula C is anhydrous and non-solvated. Example 9 describes the preparation of the compound of formula C. Generally, Crystalline Form IC of the compound of formula C can be prepared as described in Example 10.

[0119] The crystalline form IC of the compound of formula C can be identified by unique signatures associated with, for example, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). In some embodiments, the crystalline form IC of the compound of formula C is characterized by an XRPD pattern substantially as Figure 14 shown. Table 6 lists the peaks of the XRPD pattern.

[0120] In some embodiments, the crystalline form IC of the compound of formula C is characterized by an XRPD pattern comprising a peak at 2θ of 6.2° ± 0.2°. In some embodiments, the crystalline form IC of the compound of formula C is characterized by an XRPD pattern comprising a peak at 2θ of 11.9° ± 0.2°. In some embodiments, the crystalline form IC of the compound of formula C is characterized by an XRPD pattern comprising a peak at 2θ of 16.7° ± 0.2°. In some embodiments, the crystalline form IC of the compound of formula C has an XRPD pattern comprising the following peaks at 2θ: 6.2° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 18.8° ± 0.2°; 19.9° ± 0.2°; 20.7° ± 0.2°; 21.2° ± 0.2°; 22.3° ± 0.2°; 23.2° ± 0.2°; and 27.0° ± 0.2°. In some embodiments, the crystalline form IC of the compound of formula C has an XRPD pattern comprising the following peaks at 2θ: 6.2° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; and 21.2° ± 0.2°. In some embodiments, the crystalline form IC of the compound of formula C has an XRPD pattern comprising the following peaks at 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.3° ± 0.2°; 11.9° ± 0.2°; and 12.5° ± 0.2°.

[0121] In some embodiments, the crystalline Form IC of the compound of Formula C has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 6.2° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 18.8° ± 0.2°; 19.9° ± 0.2°; 20.7° ± 0.2°; 21.2° ± 0.2°; 22.3° ± 0.2°; 23.2° ± 0.2°; and 27.0° ± 0.2°. In some embodiments, the crystalline Form IC of the compound of Formula C has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.3° ± 0.2°; 11.9° ± 0.2°; 12.5° ± 0.2°; 13.8° ± 0.2°; 14.4° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 21.2° ± 0.2°. In some embodiments, the crystalline Form IC of the compound of Formula C has an XRPD pattern comprising two or more, three or more, or four or more of the following peaks expressed as 2θ: 6.2° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 21.2° ± 0.2°.

[0122] In some embodiments, Form IC of the compound of Formula C is characterized by a DSC thermogram comprising an endothermic peak having a maximum at about 179°C. In some embodiments, the crystalline Form IC of the compound of Formula C has a DSC thermogram substantially as Figure 15 shown.

[0123] Method of Use

[0124] The compounds of the invention described herein (e.g., salts and crystalline forms) inhibit the activity of PI3Kγ kinase. Accordingly, the salts and crystalline forms of the invention described herein can be used in methods of inhibiting said kinase by contacting PI3Kγ kinase. In some embodiments, the salts and crystalline forms of the invention can be used in methods of inhibiting PI3Kγ activity in an individual / patient in need thereof by administering an effective amount of a salt or crystalline form described herein. In some embodiments, the modulation is inhibition. In some embodiments, the contacting occurs in vivo. In some embodiments, the contacting occurs ex vivo. Advantageously, the crystalline forms described herein have shown better efficacy as well as favorable safety and toxicity profiles in animal studies.

[0125] In some embodiments, PI3Kγ comprises a mutation. The mutation can be an amino acid substitution for another amino acid, or the deletion of one or more amino acids. In such embodiments, the mutation can be present in the kinase domain of PI3Kγ.

[0126] In some embodiments, the salt or crystalline form also inhibits PI3Kδ.

[0127] The salts and crystalline forms described herein can be selective. "Selective" means that the salt or crystalline form binds or inhibits PI3Kγ with a greater affinity or efficacy, respectively, compared to at least one other kinase. In some embodiments, the salts and crystalline forms of the invention are selective inhibitors that are more selective for PI3Kγ than for PI3Kδ, PI3Kα, and PI3Kβ. In some embodiments, the salts and crystalline forms of the invention are selective inhibitors that are more selective for PI3Kγ than for PI3Kα and PI3Kβ. In some embodiments, the selectivity can be at least about 2-fold, 3-fold, 5-fold, 10-fold, or 20-fold that of PI3Kδ, as measured by the assays described herein. In some embodiments, the selectivity of each enzyme can be tested at a 2 μM ATP concentration. In some embodiments, the selectivity of the salts and crystalline forms of the invention can be determined by a cellular assay related to the specific PI3K kinase activity.

[0128] Another aspect of the invention relates to a method of treating a kinase PI3Kγ-related disease or disorder in an individual (e.g., a patient) in need thereof by administering a therapeutically effective amount or dose of one or more salts or crystalline forms of the invention or a pharmaceutical composition thereof. PI3Kγ-related diseases or disorders can include any disease, disorder, or affliction directly or indirectly related to the manifestation or activity of PI3Kγ, including over-expression and / or abnormal activity levels.

[0129] In some embodiments, the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease.

[0130] In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is Askin's tumor, botryoid sarcoma, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangioendothelioma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

[0131] In some embodiments, the disease or disorder is mesothelioma or adenocarcinoma. In some embodiments, the disease or disorder is mesothelioma. In some embodiments, the disease or disorder is adenocarcinoma.

[0132] In some embodiments, the disease or disorder is acute myeloid leukemia (e.g., acute monocytic leukemia), small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, T cell acute lymphoblastic leukemia (T-ALL), cutaneous T cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) T cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma. In some embodiments, the mature (peripheral) T cell neoplasm (PTCL) is T cell prolymphocytic leukemia, T cell granular lymphocytic leukemia, aggressive NK cell leukemia, mycosis fungoides / Sezary syndrome, anaplastic large cell lymphoma (T cell type), enteropathy-type T cell lymphoma, adult T cell leukemia / lymphoma, or angioimmunoblastic T cell lymphoma. In some embodiments, anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.

[0133] In some embodiments, the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xeroderma pigmentosum, keratoacanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B-cell lymphoma.

[0134] MDSCs (myeloid-derived suppressor cells) are a heterogeneous population of immune cells that arise from the myeloid lineage (the family of cells derived from bone marrow stem cells). Due to alterations in hematopoiesis, MDSCs expand strongly in pathological situations such as chronic infections and cancer. MDSCs are distinguished from other myeloid cell types by their strong immunosuppressive activity rather than immunostimulatory properties. Similar to other myeloid cells, MDSCs interact with other immune cell types, including T cells, dendritic cells, macrophages, and natural killer cells, to regulate their functions. In some embodiments, compounds and the like described herein can be used in methods related to cancer tissues (e.g., tumors) with high MDSC infiltration, including solid tumors with high basal levels of macrophage and / or MDSC infiltration.

[0135] In some embodiments, the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B-cell lymphoma.

[0136] In some embodiments, the non-Hodgkin lymphoma (NHL) is relapsed NHL, refractory NHL, relapsed follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL).

[0137] In some embodiments, the diffuse large B-cell lymphoma is activated B-cell-like (ABC) diffuse large B-cell lymphoma or germinal center B-cell (GCB) diffuse large B-cell lymphoma.

[0138] In some embodiments, the Burkitt lymphoma is endemic Burkitt lymphoma, sporadic Burkitt lymphoma, or Burkitt-like lymphoma.

[0139] In some embodiments, the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, asthma, allergic reaction (such as allergic rhinitis), pancreatitis, psoriasis, allergy, glomerulonephritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hyperplasia, myasthenia gravis, Sjogren's syndrome, osteoarthritis, restenosis, or atherosclerosis.

[0140] In some embodiments, the disease or disorder is cardiac hypertrophy, cardiomyocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (such as hemolytic anemia, aplastic anemia, or pure red cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), idiopathic pulmonary fibrosis, autoimmune hemolytic anemia, vasculitis, lupus nephritis, pemphigus, or membranous nephropathy.

[0141] In some embodiments, the disease or disorder is cardiac hypertrophy, cardiomyocyte dysfunction, chronic obstructive pulmonary disease (COPD), elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (such as hemolytic anemia, aplastic anemia or pure red cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft rejection, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus or membranous nephropathy.

[0142] In some embodiments, the disease or disorder is Alzheimer's disease, central nervous system trauma or stroke.

[0143] In some embodiments, the idiopathic thrombocytopenic purpura (ITP) is recurrent ITP or refractory ITP.

[0144] In some embodiments, the vasculitis is Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemic vasculitis (primary or hepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP), allergic vasculitis, microscopic polyangiitis, Wegener's granulomatosis or antineutrophil cytoplasmic antibody-associated (ANCA) systemic vasculitis (AASV).

[0145] The present invention also provides the salts or crystalline forms described herein for use in any of the methods described herein.

[0146] The present invention also provides the use of the crystalline forms described herein or pharmaceutically acceptable salts thereof for the preparation of a medicament for use in any of the methods described herein.

[0147] As used herein, the term "contacting" means bringing the indicated moieties together in an in vitro system or in an in vivo system. By way of example, "contacting" PI3K with a salt or crystalline form of the present invention includes administering the crystalline form of the present invention to an individual or patient (such as a human) having PI3K, and also includes, for example, introducing a salt or crystalline form of the present invention into a sample containing PI3K-containing cells or a purified preparation.

[0148] It is believed that any of the salts and crystalline forms or embodiments thereof provided herein may have a satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolic and pharmacokinetic properties, solubility, and permeability. It should be understood that the determination of appropriate biopharmaceutical properties is within the knowledge of those skilled in the art, for example, determining cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity.

[0149] As used herein, the terms "individual" or "patient", which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0150] As used herein, the phrase "therapeutically effective amount" means an amount of an active salt, crystalline form, or agent that elicits the biological or medical response that a researcher, veterinarian, medical doctor, or other clinician is seeking in a tissue, system, animal, individual, or human.

[0151] As used herein, the term "treating" or "treatment" may refer to one or more of the following: (1) inhibiting a disease, e.g., inhibiting a disease, disorder, or condition in an individual who is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (i.e., arresting the further development of the pathology and / or symptomatology); and (2) ameliorating a disease, e.g., ameliorating a disease, disorder, or condition in an individual who is experiencing or displaying the pathology or symptomatology of the disease, disorder, or condition (i.e., reversing the pathology and / or symptomatology), such as reducing the severity of the disease.

[0152] In some embodiments, the salts and crystalline forms of the present invention can be used to prevent or reduce the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing the disease, disorder, or condition in an individual who may be predisposed to the disease, disorder, or condition but has not yet experienced or displayed the pathology or symptomatology of the disease.

[0153] Combination therapy

[0154] I. Immune Checkpoint Therapy

[0155] In some embodiments, the PI3Kγ inhibitors provided herein can be combined with one or more immune checkpoint inhibitors for treating cancers as described herein. In one embodiment, combination with one or more immune checkpoint inhibitors as described herein can be used for treating melanoma. The salts and crystalline forms of the present invention can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules against, such as, CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecules are stimulatory checkpoint molecules selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecules are inhibitory checkpoint molecules selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT and VISTA. In some embodiments, the salts and crystalline forms of the present invention provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRβ inhibitors.

[0156] In some embodiments, the PI3Kγ inhibitors provided herein can be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, OX40, GITR and CD137 (also known as 4-1BB).

[0157] In some embodiments, the immune checkpoint molecule inhibitor is an anti-PD1 antibody, an anti-PD-L1 antibody or an anti-CTLA-4 antibody.

[0158] In some embodiments, the immune checkpoint molecule inhibitor is a PD-1 inhibitor, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab Pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agents include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab).

[0159] In some embodiments, the immune checkpoint molecule inhibitor is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0160] In some embodiments, the immune checkpoint molecule inhibitor is an inhibitor of PD-1 and PD-L1, such as an anti-PD-1 / PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136.

[0161] In some embodiments, the inhibitor is MCLA-145.

[0162] In some embodiments, the immune checkpoint molecule inhibitor is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0163] In some embodiments, the immune checkpoint molecule inhibitor is a LAG3 inhibitor, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0164] In some embodiments, the immune checkpoint molecule inhibitor is a TIM3 inhibitor, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0165] In some embodiments, the immune checkpoint molecule inhibitor is a GITR inhibitor, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0166] In some embodiments, the immune checkpoint molecule inhibitor is an OX40 agonist, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0167] In some embodiments, the immune checkpoint molecule inhibitor is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0168] The salts and crystalline forms of the present invention can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or the TGFβ receptor.

[0169] In some embodiments, the PI3Kγ inhibitors provided herein can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0170] As provided throughout, other compounds, inhibitors, agents, etc. can be combined with the compounds of the present invention in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0171] II. Cancer Therapy

[0172] Cancer cell growth and survival can be affected through multiple signaling pathways. Accordingly, combinations of different enzyme / protein / receptor inhibitors that exhibit different preferences for the targets they regulate can be used to treat such disorders. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of developing drug resistance in a cell population and / or reduce the toxicity of the treatment.

[0173] The salts and crystalline forms of the invention can be used in combination with one or more other enzyme / protein / receptor inhibitors or one or more therapies for the treatment of numerous diseases such as cancer. Examples of diseases and indications treatable by combination therapy include those described herein. Examples of cancers include solid tumors and liquid tumors such as blood cancers.

[0174] One or more other agents such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressive agents, immuno-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, and FAK kinase inhibitors such as those described in WO 2006 / 056399. Other agents such as therapeutic antibodies can be used in combination with the salts and crystalline forms of the invention for the treatment of PI3K-related diseases, conditions, or disorders. The one or more other agents can be administered to a patient simultaneously or sequentially.

[0175] For example, the salts and crystalline forms disclosed herein can be combined with one or more inhibitors of the following kinases for the treatment of the cancers and other diseases or disorders described herein: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM kinase, phosphokinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Non-limiting examples of inhibitors that can be combined with the salts and crystalline forms of the present invention for the treatment of the cancers and other diseases and disorders described herein include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, such as INCB54828, INCB62079, and INCB63904), JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib, or INCB39110), IDO inhibitors (such as epacadostat, NLG919, or BMS-986205), LSD1 inhibitors (such as INCB59872 and INCB60003), TDO inhibitors, PI3Kδ inhibitors (such as INCB50797 and INCB50465), Pim inhibitors, CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), histone deacetylase inhibitors (HDAC) such as HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromodomain and extra-terminal family member inhibitors (such as bromodomain inhibitors or BET inhibitors, such as INCB54329 and INCB57643), and adenosine receptor antagonists or combinations thereof.

[0176] In some embodiments, the salts and crystalline forms described herein are administered in combination with a PI3Kδ inhibitor. In some embodiments, the salts and crystalline forms described herein are administered in combination with a JAK inhibitor. In some embodiments, the salts and crystalline forms described herein are administered in combination with a JAK1 or JAK2 inhibitor (such as baricitinib or ruxolitinib). In some embodiments, the salts and crystalline forms described herein are administered in combination with a JAK1 inhibitor. In some embodiments, the salts and crystalline forms described herein are administered in combination with a JAK1 inhibitor that is selective for JAK1 over JAK2.

[0177] Examples of antibodies for use in combination therapy include, but are not limited to, Trastuzumab (e.g., anti-HER2), Ranibizumab (e.g., anti-VEGF-A), Bevacizumab (trade name Avastin, e.g., anti-VEGF), Panitumumab (e.g., anti-EGFR), Cetuximab (e.g., anti-EGFR), Rituxan (anti-CD20), and antibodies against c-MET.

[0178] One or more of the following agents can be used in combination with the salts and crystalline forms of the present invention and are presented in the form of a non-limiting list: cell growth inhibitors, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS214662, IRESSA TM (gefitinib), TARCEVA TM(Erlotinib), antibodies against EGFR, introns, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, nitrogen mustard, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, thiotepa, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN TMOxaliplatin, pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinyl estradiol, diethylstilbestrol, testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, acrivastine, HERCEPTIN TM Trastuzumab, BEXXAR TM(tositumomab), VELCADE TM (bortezomib), ZEVALIN TM (ibritumomab tiuxetan), TRISENOX TM (arsenic trioxide), XELODA TM (capecitabine), vinorelbine, porfimer, ERBITUX TM (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, letrozole, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP and MDL-101,731.

[0179] The salts and crystalline forms of the present invention can also be used in combination with other methods for treating cancer, such as by chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, adoptive T cell transfer, Toll-like receptor agonists, STING agonists, oncolytic virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, etc. The salts and crystalline forms can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapeutic agents include any one of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, actinomycin, dalteparin sodium, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate (imatinibmesylate), interferon alpha-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprorelin acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, rucaparib, streptozocin, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib, talazoparib, and zoledronate.

[0180] Other examples of chemotherapeutic agents include proteasome inhibitors (e.g., bortezomib), thalidomide, Revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0181] Examples of steroids include corticosteroids such as dexamethasone or prednisone.

[0182] Examples of Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC TM) nilotinib, dasatinib, bosutinib, ponatinib, and pharmaceutically acceptable salts thereof. Other examples of suitable Bcr-Abl inhibitors include the compounds of the genera and species disclosed in U.S. Patent No. 5,521,184, WO 04 / 005281, and U.S. Serial No. 60 / 578,491 and their pharmaceutically acceptable salts.

[0183] Examples of suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib malate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397, and ASP2215 and their pharmaceutically acceptable salts. Other examples of suitable Flt-3 inhibitors include the compounds disclosed in WO 03 / 037347, WO 03 / 099771, and WO 04 / 046120 and their pharmaceutically acceptable salts.

[0184] Examples of suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib and their pharmaceutically acceptable salts. Other examples of suitable RAF inhibitors include the compounds disclosed in WO 00 / 09495 and WO 05 / 028444 and their pharmaceutically acceptable salts.

[0185] Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098 and their pharmaceutically acceptable salts. Other examples of suitable FAK inhibitors include the compounds disclosed in WO 04 / 080980, WO04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595, and WO 01 / 014402 and their pharmaceutically acceptable salts.

[0186] In some embodiments, the salts and crystalline forms of the invention can be used in combination with one or more other kinase inhibitors, including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.

[0187] In some embodiments, the salts and crystalline forms of the present invention can be combined with chemotherapeutic agents for treating cancer, and can improve the therapeutic response without exacerbating their toxic effects as compared to the response to the chemotherapeutic agent alone. In some embodiments, the salts and crystalline forms of the present invention can be used in combination with the chemotherapeutic agents provided herein. For example, other agents for treating multiple myeloma may include, but are not limited to, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Other additional agents for treating multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable outcomes of combining the PI3K inhibitors of the present invention with additional agents.

[0188] In some embodiments, the salts and crystalline forms of the present invention can be used in combination with JAK or PI3Kδ inhibitors.

[0189] The agent can be combined with the compounds of the present invention in a single or sequential dosage form, or the agent can be administered simultaneously or sequentially as separate dosage forms.

[0190] The salts and crystalline forms of the present invention can be combined with one or more other inhibitors or one or more therapies for treating infections. Examples of infections include viral infections, bacterial infections, fungal infections, or parasitic infections.

[0191] In some embodiments, a combination of a corticosteroid such as dexamethasone and a compound of the present invention is administered to a patient, wherein dexamethasone is administered intermittently as opposed to continuously.

[0192] The salts and crystalline forms of the present invention as described herein can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as gp100, MAGE antigens, Trp-2, MART1, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0193] The salts and crystalline forms of the invention described herein can be used in combination with vaccination regimens for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, the tumor vaccine comprises proteins from viruses associated with human cancers such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KHSV). In some embodiments, the salts and crystalline forms of the invention can be used in combination with tumor-specific antigens such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the salts and crystalline forms can be combined with dendritic cell immunization to activate an effective anti-tumor response.

[0194] The salts and crystalline forms of the invention can be used in combination with bispecific macrocyclic peptides that target effector cells expressing Feα or Feγ receptors to tumor cells. The salts and crystalline forms of the invention can also be combined with macrocyclic peptides that activate the host immunoreactivity.

[0195] In some other embodiments, the combination of the salts and crystalline forms of the invention with other therapeutic agents can be administered to a patient before, during, and / or after bone marrow transplantation or stem cell transplantation. The salts and crystalline forms of the invention can be used in combination with bone marrow transplantation for the treatment of various hematopoietic tumors.

[0196] The salts and crystalline forms can be used in combination with vaccines to stimulate an immune response against pathogens, toxins, and autoantigens. Examples of pathogens for which such a treatment method may be particularly applicable include pathogens for which there is currently no effective vaccine or for which traditional vaccines are not fully effective. These include, but are not limited to, HIV, hepatitis viruses (A, B, and C), influenza virus, herpes virus, flagellates, malaria, Leishmania, Staphylococcus aureus, and Pseudomonas aeruginosa.

[0197] Viruses that cause infections treatable by the methods of the present invention include, but are not limited to, human papillomavirus, influenza virus, hepatitis A, B, C or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes viruses (such as VZV, HSV-1, HAV-6, HSV-II and CMV, Epstein Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0198] Pathogenic bacteria that cause infections treatable by the methods of the present invention include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.

[0199] Pathogenic fungi that cause infections treatable by the methods of the present invention include, but are not limited to, Candida spp. (Candida albicans, Candida krusei, Candida glabrata, Candida tropicalis, etc.), Cryptococcus neoformans, Aspergillus spp. (Aspergillus fumigatus, Aspergillus niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum. Pathogenic parasites that cause infections treatable by the methods of the present invention include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0200] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those of skill in the art. Additionally, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference in its entirety as if set forth in full.

[0201] Pharmaceutical Compositions and Dosage Forms

[0202] When used as medicaments, the compounds of the present invention (e.g., salts and crystalline forms) can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be local (including percutaneous, epidermal, ophthalmic, and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial (e.g., intrathecal) or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous solutions, powders, or oily bases, thickening agents, and the like may be necessary or desirable.

[0203] The present invention also includes pharmaceutical compositions that contain a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for local administration. In the manufacture of the compositions of the present invention, the active ingredient is usually admixed with an excipient, diluted by the excipient, or enclosed within a carrier such as in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0204] When preparing the preparation, the active compound can be ground to provide an appropriate particle size and then combined with other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the preparation, for example, about 40 mesh.

[0205] The compounds of the present invention can be ground using known grinding procedures, such as wet grinding, to obtain a particle size suitable for tablet formation and for other types of preparations. Fine powder (nanoparticle) preparations of the compounds of the present invention can be prepared by methods known in the art, for example, see International Application No. WO 2002 / 000196.

[0206] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The preparations can additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents. The compositions of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0207] The compositions can be formulated in unit dosage form, each dosage containing from about 5 mg to about 1000 mg (1 g), more usually from about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect and associated with a suitable pharmaceutical excipient.

[0208] In some embodiments, the compositions of the present invention contain from about 5 mg to about 50 mg of the active ingredient. Those of ordinary skill in the art will appreciate that this includes compositions containing from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg of the active ingredient.

[0209] In some embodiments, the compositions of the present invention contain from about 50 to about 500 mg of the active ingredient. Those skilled in the art will appreciate that this includes compositions containing from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 350 mg to about 400 mg, or from about 450 mg to about 500 mg of the active ingredient.

[0210] In some embodiments, the compositions of the present invention contain from about 500 mg to about 1000 mg of the active ingredient. Those of ordinary skill in the art will appreciate that this includes compositions containing from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg of the active ingredient.

[0211] Similar doses can be used in the methods and uses of the compounds of the present invention described herein.

[0212] The active compounds can be effective over a wide dosage range and are generally administered in a therapeutically effective amount. However, it should be understood that the amount of the compound actually administered will generally be determined by the physician in accordance with the relevant circumstances, including the disorder to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.).

[0213] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition that contains a homogeneous mixture of the compounds of the present invention. When referring to these preformulation compositions as being homogeneous, the active ingredient is generally uniformly dispersed throughout the composition such that the composition can be readily redivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preparation is then redivided into the above-described type of unit dosage forms containing, for example, from about 0.1 mg to about 1000 mg of the active ingredient of the present invention.

[0214] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that affords the advantage of extended action. For example, the tablets or pills can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that is resistant to disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be released retarded. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0215] Liquid forms in which the compounds and compositions of the present invention may be incorporated for oral or parenteral administration include aqueous solutions, properly flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0216] Compositions for inhalation or insufflation include solutions and suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route to achieve local or systemic effects. The compositions may be nebulized using an inert gas. The nebulized solution may be breathed directly from the nebulizing device, or the nebulizing device may be connected to a face mask, tent, or intermittent positive pressure breathing machine. The solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0217] Topical formulations may contain one or more conventional carriers. In some embodiments, an ointment may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, and the like. The carrier composition of a cream may be based on a combination of water with glycerol and one or more other components such as glyceryl monostearate, PEG-glyceryl monostearate, and cetearyl alcohol. A gel may be formulated using a suitable combination of isopropyl alcohol and water with other components such as glycerol, hydroxyethyl cellulose, and the like. In some embodiments, the topical formulation contains at least about 0.1 wt%, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of the compound of the present invention. The topical formulation may be suitably packaged, for example, in a 100 g tube, which is optionally associated with instructions for treating the selected indication such as psoriasis or other skin disorders.

[0218] The amount of the compound or composition administered to a patient will vary depending on what is administered, the purpose of administration (e.g., prophylaxis or treatment), the patient's condition, the mode of administration, and the like. In therapeutic applications, the amount of the composition that may be administered to a patient who has a disease may be sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the disease disorder being treated and the judgment of the attending physician, who will take into account factors such as the severity of the disease, the patient's age, weight, and general condition, and the like.

[0219] The compositions administered to a patient can be in the form of the pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be packaged for use as such or can be lyophilized, and the lyophilized preparation can be combined with a sterile aqueous vehicle prior to administration. The pH of the compound preparation will generally be between 3 and 11, more preferably between 5 and 9 and most preferably between 7 and 8. It should be understood that using certain of the foregoing excipients, carriers or stabilizers will form pharmaceutical salts.

[0220] The therapeutic dose of the compounds of the invention can vary depending on, for example, the particular use for which the treatment is carried out, the mode of administration of the compound, the health condition and disorder of the patient and the judgment of the prescribing physician. The proportion or concentration of the compounds of the invention in the pharmaceutical composition can vary depending on many factors, including the dose, chemical characteristics (such as hydrophobicity) and route of administration. For example, the compounds of the invention can be provided in the form of an aqueous physiological buffer solution containing from about 0.1 w / v% to about 10 w / v% of the compound for parenteral administration. Some typical dose ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dose can be dependent on variables such as the type and severity of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients and its route of administration. The effective dose can be extrapolated from the dose-response curve obtained from in vitro or animal model test systems.

[0221] The compositions of the invention can also include one or more additional agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds or immunosuppressants, examples of which are listed herein.

[0222] Labeled compounds and assay methods

[0223] Another aspect of the invention relates to the compounds of the invention (such as salts and crystalline forms) labeled (radioactively labeled, fluorescently labeled, etc.), which can be used not only in imaging techniques but also in in vitro and in vivo assays for localizing and quantifying PI3K in tissue samples (including human) and for identifying PI3K ligands by inhibiting the binding of the labeled compound. Substituting one or more atoms of the compounds of the invention can also be used to generate differential ADME (absorption, distribution, metabolism and excretion). Accordingly, the invention includes PI3K assays containing such labeled or substituted compounds.

[0224] The present invention also includes isotopically labeled compounds of the present invention. An "isotopically labeled" or "radiolabeled" compound is a compound of the present invention in which one or more atoms have been replaced or substituted with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to 2 H (deuterium, also written as D), 3 H (tritium, also written as T), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I. By way of example, one or more hydrogen atoms in the compounds of the present invention may be replaced with deuterium atoms (e.g., one or more hydrogen atoms of the C 1-6 alkyl of formula (I) may optionally be replaced with deuterium atoms, such as -CD 3 substituting -CH 3 ). In some embodiments, the alkyl groups of the disclosed formulae and / or forms may be fully deuterated.

[0225] One or more of the constituent atoms of the compounds provided herein may be replaced or substituted with atomic isotopes present in natural or non-natural abundances. In some embodiments, the compound includes at least one deuterium atom. By way of example, one or more hydrogen atoms in the compounds provided herein may be replaced or substituted with deuterium (e.g., one or more hydrogen atoms of the C 1-6 alkyl may be replaced with deuterium atoms, such as -CD 3 substituting -CH 3 ). In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 1 - 2, 1 - 3, 1 - 4, 1 - 5, or 1 - 6 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compound may be replaced or substituted with deuterium atoms.

[0226] In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms of the carbon atom attached to any of the formula A substituents are each optionally replaced with deuterium atoms.

[0227] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey; and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolic experiments, and / or assays.

[0228] Replacement with a heavier isotope such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dose requirements, and may thus be preferred in some cases. (See, e.g., A. Kerekes et al., J. Med. Chem. 2011, 54, 201-210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308-312). Specifically, replacement at one or more metabolic sites can provide one or more therapeutic advantages.

[0229] The radionuclide incorporated into the radiolabeled compounds of the present invention will depend on the specific application of the radiolabeled compound. For example, for in vitro PI3K labeling and competitive assays, incorporation of 3 H, 14 C, 82 Br, 125 I, 131 I or 35 S compounds may be useful. For radioimaging applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br may be useful.

[0230] It should be understood that a "radioactive label" or "labeled compound" is a compound incorporating at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S, and 82 Br.

[0231] The present invention may also include synthetic methods for incorporating radioisotopes into the compounds of the present invention. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and those skilled in the art will readily identify methods suitable for the compounds of the present invention.

[0232] The labeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. For example, the ability of a compound (i.e., a test compound) to bind to PI3K can be evaluated by tracking the label to monitor changes in the concentration of the newly synthesized or identified labeled compound upon contact with PI3K. For example, the ability of a test compound (labeled) to reduce the binding of another compound (i.e., a standard compound) known to bind to PI3K can be evaluated. Thus, the ability of a test compound to compete with a standard compound for binding to PI3K is directly related to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is unlabeled. Thus, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, and thus to determine the relative binding affinity of the test compound.

[0233] Kit

[0234] The present invention also includes pharmaceutical kits that can be used, for example, to treat or prevent PI3K-related diseases or disorders (such as cancer), the kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a salt and a crystalline form of the present invention. As will be readily apparent to those skilled in the art, the kit may also include, if desired, one or more of a variety of conventional pharmaceutical kit components, for example, containers containing one or more pharmaceutically acceptable carriers, other containers, etc. The kit may also include instructions in the form of an insert or a label indicating the amount of the component to be administered, instructions regarding administration, and / or instructions regarding mixing the components.

[0235] The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily identify a number of non-critical parameters that can be varied or modified to produce substantially the same results. According to at least one of the assays described herein, the salts and crystalline forms of the examples have been found to be PI3Kγ inhibitors.

[0236] Example

[0237] Some of the prepared compounds were purified by preparative LC-MS on a Waters quality-directed fractionation system. The basic equipment settings, protocols, and control software for operating these systems have been described in detail in the literature (see, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004)). Analytical liquid chromatography-mass spectrometry (LCMS) of the separated compounds was typically performed under the following conditions for purity analysis: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire TM C 18 5 μm, 2.1 x 50 mm; Buffer: Mobile phase A: 0.025% aqueous TFA and Mobile phase B: acetonitrile; Gradient 2% to 80% B, 3 minutes, flow rate 2.0 mL / min.

[0238] Also as indicated in the examples, some of the prepared compounds were separated on a preparative scale by reverse-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) using an MS detector. Typical preparative reverse-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0239] pH = 2 purification: Waters Sunfire TM C 18 5 μm, 30 x 100 mm or Waters XBridge TM C 18A 5 μm, 30 x 100 mm column was eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) aqueous solution and mobile phase B: acetonitrile; the flow rate was 60 mL / min, and the separation gradient of each compound was optimized using the compound-specific method optimization protocol described in the literature (see, for example, "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

[0240] Purification at pH = 10: Waters XBridge TM C 18 A 5 μm, 30 x 100 mm column was eluted with mobile phase A: 0.1% NH 4 OH aqueous solution and mobile phase B: acetonitrile; the flow rate was 60 mL / min, and the separation gradient of each compound was optimized using the compound-specific method optimization protocol described in the literature (see, for example, "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)).

[0241] In the following examples, X-ray powder diffraction analysis was performed on a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument with the following parameters: the radiation source was Cu, and a LYNXEYE™ detector and X-ray power of 40 kV, 25 mA. The sample powder was dispersed on a zero-background sample holder. The general measurement conditions were: starting angle -3°; ending angle -30°; sampling -0.015°; and scan speed -2° / min.

[0242] Differential scanning calorimetry (DSC) was performed on a TA Instruments Discovery DSC2500 with an autosampler. The general experimental conditions were: 20 - 300 °C, 10 °C / min, nitrogen flow rate 50 mL / min, using aluminum sample pans.

[0243] Thermogravimetric analysis (TGA) was performed on a TA Instruments Thermogravimetric Analyzer TGA5500 equipped with an autosampler under the following conditions: heating from 25 °C to 600 °C at 10 °C / min; nitrogen purge flow rate of 25 mL / min for equilibration; and a platinum sample pan.

[0244] Example 1. 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide

[0245]

[0246] Step 1. 1-(3-Bromo-4-methylphenyl)-2,2,2-trifluoroethan-1-ol

[0247]

[0248] A solution of 3-bromo-4-methylbenzaldehyde (6.51 g, 32.7 mmol) [Aldrich, 565334] in tetrahydrofuran (65.4 mL) was cooled to 0 °C and treated with trimethyl(trifluoromethyl)silane (6.28 mL, 42.5 mmol). The yellow mixture was treated with 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (0.654 mL, 0.654 mmol) at 0 °C and stirred for several minutes at 0 °C. The ice bath was removed and the resulting reaction mixture was stirred for 1.5 h. The reaction mixture was cooled back to 0 °C and treated with water (6.48 mL, 360 mmol) and 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (6.54 mL, 6.54 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 30 min. The yellow reaction mixture was diluted with brine (150 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated ammonium chloride (100 mL), dried over sodium sulfate, filtered and concentrated to give a brown oil. Purification by flash column chromatography using methyl tert-butyl ether (MTBE) in hexanes (0% to 50%) gave the desired product as a yellow oil (8.42 g, 95.7%). LCMS C 9 H 7 BrF 3 (M-OH) + : m / z = 251.0, 253.0; found: 250.9, 252.8.

[0249] Step 2. 1-(3-Bromo-4-methylphenyl)-2,2,2-trifluoroethan-1-one

[0250]

[0251] The mixture of 1-(3-bromo-4-methylphenyl)-2,2,2-trifluoroethan-1-ol (8.41 g, 31.3 mmol) in dichloromethane (125 mL) was treated with Dess-Martin periodinane (19.9 g, 46.9 mmol) at 0 °C and stirred at room temperature for 2.5 h. The reaction mixture was concentrated (by rotary evaporation, with the water bath set at 30 °C) to an oily solid, diluted with diethyl ether (200 mL), which caused more solid to precipitate. The mixture was filtered and rinsed with additional diethyl ether (200 mL). The filtrate was washed with saturated sodium bicarbonate solution (3 x 200 mL) and brine, dried over sodium sulfate, filtered and concentrated to give an oily solid. The oily solid was partitioned between diethyl ether (150 mL) and water (100 mL). The organic layer was separated and washed with saturated sodium bicarbonate solution (2 x 75 mL) and brine, dried over sodium sulfate, filtered and concentrated to give the desired product as an oil (7.93 g, 95.0%), which was used without further purification. LCMS C H 9 H 7 BrF 3 O(M+H) + : m / z = 267.0, 269.0; found: 267.1, 268.9.

[0252] Step 3. 2-(3-bromo-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanenitrile

[0253]

[0254] A solution of 1-(3-bromo-4-methylphenyl)-2,2,2-trifluoroethan-1-one (7.92 g, 29.7 mmol) in dichloromethane (29.7 mL) was treated with trimethylsilyl cyanide (8.70 mL, 65.2 mmol), potassium cyanide (0.290 g, 4.45 mmol) and 18-crown-6 (0.290 g, 1.10 mmol) and stirred for 1 h. After the addition of 18-crown-6, the reaction mixture was cooled with an ice bath due to exotherm. The reaction mixture was concentrated (by rotary evaporation, with the water bath set at 28 °C) to give a rust-colored solid. The solid was dissolved in THF (29.6 mL), cooled to 0 °C, treated with 1.8 M HCl (10.9 mL, 19.6 mmol), and stirred at room temperature (rt) for 1.5 h. The reaction mixture was diluted with water (75 mL) and extracted with diethyl ether (3 x 75 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Further concentration from hexane gave the desired product as an orange solid (8.70 g, 99.8%), which was used without further purification. LCMS C9 H 7 BrF 3 O(M-CN) + : m / z = 267.0, 269.0; Experimental value: 266.9, 269.0.

[0255] Step 4. 2-(3-Bromo-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide (second eluted enantiomer)

[0256]

[0257] A solution of 2-(3-bromo-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanenitrile (8.70 g, 29.6 mmol) in 1,4-dioxane (59.2 mL) was treated with concentrated HCl (9.00 mL, 108 mmol) pre-cooled in an ice bath at 0 °C. While stirring at 0 °C, the reaction mixture was bubbled with HCl gas for 45 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 61 hours. The reaction mixture was bubbled with nitrogen for 10 minutes to remove some HCl, cooled to 0 °C, and diluted with brine (200 mL), water (50 mL), and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was diluted with water (100 mL) to dissolve the remaining solid. The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a brown oil. Purification by flash column chromatography using MTBE in hexane (0% to 60%) gave the racemic product as a yellow oily solid. The racemic mixture was separated by preparative chiral HPLC (Phenomenex Lux Amylose-1 [21.2 x 250 mm, 5 μm], eluting with 95% ethanol in hexane at a flow rate of 18 mL / min, loading approximately 100 mg in 2 mL of ethanol) to give the desired second eluted enantiomer as a viscous yellow oil (4.50 g, 48.8%). The retention time of the first eluted enantiomer was 4.0 minutes. The retention time of the second eluted enantiomer was 5.3 minutes.

[0258] Second Eluted Enantiomer : 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.85 (d, J = 1.9 Hz, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.63–7.53 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 2.35 (s, 3H). LCMSC 10 H 10 BrF 3 NO 2(M+H) + : m / z = 312.0, 314.0; Experimental value: 312.0, 314.0.

[0259] Step 5. 3,3,3-Trifluoro-2-hydroxy-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide

[0260]

[0261] Treat a solution of 2-(3-bromo-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide (3.57 g, 11.5 mmol) (Example 1, Step 4, second eluted enantiomer) in 1,4-dioxane (57.2 mL) with bis(pinacolato)diboron (3.49 g, 13.7 mmol) and potassium acetate (3.71 g, 37.8 mmol) and degas with nitrogen for 5 minutes. Treat the reaction mixture with bis(triphenylphosphine)palladium(II) chloride (0.482 g, 0.687 mmol), degas for 5 minutes, and stir at 100 °C for 2.5 hours. Dilute the reaction mixture with ethyl acetate (50 mL), filter, and wash with additional ethyl acetate (100 mL). Wash the filtrate with brine, dry over sodium sulfate, filter, and concentrate to a brown foam. Purify by flash column chromatography using MTBE in hexane (0% to 100%) to give the desired product as a thick yellow foam (3.35 g, 81.5%). Filter and wash with additional ethyl acetate (100 mL). Wash the filtrate with brine, dry over sodium sulfate, filter, and concentrate to a brown foam. Purify by flash column chromatography using MTBE in hexane (0% to 100%) to give the desired product as a thick yellow foam (3.35 g, 81.5%). 1 HNMR (400 MHz, DMSO-d 6 ) δ 7.96 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 7.9, 2.1 Hz, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 7.51–7.40 (m, 1H), 7.21 (d, J = 8.2 Hz, 1H), 2.46 (s, 3H), 1.30 (s, 12H). LCMSC 16 H 22 BF 3 NO 4 (M+H) + : m / z = 360.2; Experimental value: 360.1.

[0262] Step 6. 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide

[0263] The solution of 3-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-8-amine (7.50 g, 26.7 mmol) and 3,3,3-trifluoro-2-hydroxy-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (10.5 g, 29.4 mmol) (Example 1, Step 5) in 1,4-dioxane (133 mL) was treated with 1.0 M aqueous potassium carbonate solution (53.4 mL, 53.4 mmol), degassed with nitrogen for 5 minutes, treated with dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (3.27 g, 4.00 mmol), degassed with nitrogen for 5 minutes again, and stirred at 100 °C for 19 hours. The reaction mixture was treated with ethyl acetate (200 mL) and brine (50 mL), filtered through Celite and the Celite was rinsed with additional ethyl acetate. The aqueous layer was separated from the filtrate and extracted with ethyl acetate (200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to a brown foam. Purification by flash column chromatography using MeOH (0% to 10%) in dichloromethane gave the desired product as a red / brown foam, which was not completely pure. The material was further purified by flash column chromatography using MeOH (0% to 15%) in dichloromethane to give the desired product as an orange / brown foam, which was still not completely pure. The material was further purified by flash column chromatography using ethyl acetate (containing 5% MeOH) in hexane (0% to 100%) to give the desired product as a white foam, which still contained impurities. The material was further purified by flash column chromatography using acetonitrile (containing 5% MeOH) in dichloromethane (0% to 100%) to give the desired product as a white foam (4.67 g, 40.4%). 1 H NMR(600MHz,DMSO-d 6 )δ7.79(s,1H),7.76-7.71(m,2H),7.71-7.64(m,4H),7.61(d,J=3.5Hz,2H),7.51(d,J=8.2Hz,1H),2.23(s,3H).LCMSC 17 H 14 F 6 N 5 O 2 (M+H) + :m / z=434.1;Experimental value: 434.1.

[0264] Example 2: Preparation and Characterization of 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide Crystal Form IA (Free Base)

[0265] A vial was charged with 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide (0.050 g, 0.115 mmol) and stirred at 80 °C while a 1:2 premixed solution of isopropyl acetate (0.676 mL) / heptane (1.34 mL) was added dropwise. After adding 2 mL, the solid did not completely dissolve and some remained at the bottom of the vial. After almost all of the solid had dissolved, new solid formed on the vial walls. After stirring at 80 °C for 2 hours, more solid formed. After cooling to ambient temperature, the solid was filtered and washed with heptane. The solid was collected and dried under reduced pressure for 30 minutes to give 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide (Form IA) as a white solid (33.2 mg, 66.4%).

[0266] Form IA was confirmed to be a crystalline solid by XRPD analysis. Figure 1 The XRPD pattern of Form IA is shown in and the peak data are provided in Table 1 below.

[0267] Table 1. XRPD Peak Data for Form IA.

[0268]

[0269]

[0270] DSC analysis of Form IA showed an endothermic peak with an onset temperature of 191.9 °C and a maximum at 193.2 °C. Figure 2 The DSC thermogram is provided in.

[0271] TGA analysis of Form IA showed significant weight loss above 200 °C due to sample decomposition. Figure 3 The TGA thermogram is provided in.

[0272] Form IA was confirmed to be an anhydrous non-solvated crystalline form.

[0273] Example 3: Preparation and Characterization of 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide Crystal Form IIA (Free Base)

[0274] Dissolve approximately 100 mg of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide free base in 1 mL of isopropyl acetate in a 4 mL clear glass vial. Add 2 mL of heptane to the solution with stirring at ambient temperature. Heat the mixture with stirring at 80 °C for 2 hours. Cool the mixture to ambient temperature and stir for 1 hour. Collect the solid by filtration and air dry to obtain 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide (Form IIA).

[0275] Confirmation by XRPD analysis confirmed that Form IIA is a crystalline solid. Figure 4 The XRPD pattern of Form IIA is shown in and the peak data are provided in Table 2 below.

[0276] Table 2. XRPD peak data for Form IIA.

[0277]

[0278]

[0279] DSC analysis of Form IIA showed an endothermic peak with an onset temperature of 177.2 °C and a maximum at 179.7 °C. Figure 5 The DSC thermogram is provided in.

[0280] TGA analysis of Form IIA showed significant weight loss above 200 °C due to sample decomposition. Figure 6 The TGA thermogram is provided in.

[0281] It was confirmed that Form IIA is an anhydrous non-solvated crystalline form.

[0282] Example 4: Preparation and Characterization of Crystalline Form IIIA (Free Base) of 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide

[0283] Dissolve approximately 72 mg of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide free base in 1 mL of MeOH in a 4 mL clear glass vial. Evaporate the solution to dryness at ambient temperature. Dry the resulting solid (MeOH solvate) under vacuum at 60 °C overnight to obtain 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide (Form IIIA).

[0284] The confirmation of Form IIIA as a crystalline solid was based on XRPD analysis. Figure 7 The XRPD pattern of Form IIIA is shown in and the peak data are provided in Table 3 below.

[0285] Table 3. XRPD Peak Data for Form IIIA.

[0286]

[0287]

[0288] DSC analysis of Form IIIA showed an endothermic peak with an onset temperature of 134.3 °C and a maximum at 143.0 °C. Figure 8 The DSC thermogram is provided in.

[0289] TGA analysis of Form IIIA showed significant weight loss above 200 °C due to sample decomposition. Figure 9 The TGA thermogram is provided in.

[0290] It was confirmed that Form IIIA is an anhydrous non-solvated crystalline form.

[0291] Examples 5 to 6. 8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (Enantiomer 1 and Enantiomer 2)

[0292]

[0293] Step 1. 6,8-Dibromo-3-iodoimidazo[1,2-a]pyrazine

[0294]

[0295] To a solution of 6,8-dibromoimidazo[1,2-a]pyrazine (0.50 g, 1.8 mmol) [Combi-Blocks, OR-7964] in DMF (12 mL) was added N-iodosuccinimide (0.45 g, 2.0 mmol). The reaction mixture was then heated at 60 °C for 15.5 h. The reaction mixture was concentrated in vacuo. The resulting solid was dissolved in dichloromethane (DCM). The organic layer was washed successively with water and saturated Na 2 S 2 O 3 (aqueous solution). The organic layer was then dried over Na 2 SO 4 , filtered and concentrated to give the title compound as a pale yellow solid (0.64 g, 88%). LCMS C 6 H 3 Br 2 IN 3 (M+H) + : calcd m / z = 401.8, 403.8, 405.8; found 401.8, 403.7, 405.6.

[0296] Step 2. 6-Bromo-3-iodo-N-(4-methoxybenzyl)imidazo[1,2-a]pyrazin-8-amine

[0297]

[0298] A solution of 6,8-dibromo-3-iodoimidazo[1,2-a]pyrazine (1.67 g, 3.57 mmol), N,N-diisopropylethylamine (1.24 mL, 7.13 mmol) and (4-methoxyphenyl)methanamine (0.512 mL, 3.92 mmol) in iPrOH (11.9 mL) was heated in a microwave at 110 °C for 1 h. After cooling to room temperature, the solidified reaction mixture was diluted with isopropanol (75 mL) and water (19 mL) and stirred for 10 min. The solid was collected by filtration to give the desired product (1.41 g, 86.1%) which was used without further purification. LCMS C 14 H 13 BrIN 4 O(M+H) + : calcd m / z = 458.9, 460.9; found 459.0, 461.0.

[0299] Step 3. 6-Bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine trifluoroacetate

[0300]

[0301] A solution of 6-bromo-3-iodo-N-(4-methoxybenzyl)imidazo[1,2-a]pyrazin-8-amine (2.72 g, 5.92 mmol) in trifluoroacetic acid (TFA, 14.8 mL) was stirred at 55 °C for 5.5 h. The reaction mixture was concentrated and then concentrated again after dilution with acetonitrile (2x). The solid was diluted with ethyl acetate (12 mL) and stirred at room temperature for 1 h. The slurry was diluted dropwise with hexane (12 mL) and stirred at room temperature for 75 min. The solid was collected by filtration to give the desired product (2.03 g, 75.7%) which was used without further purification. LCMS C 6 H 5 BrIN 4 (M+H) + : calculated m / z = 338.9, 340.9; found 338.8, 340.8.

[0302] Step 4. 2-(3-Bromo-4-methylphenyl)-1,1,1-trifluoropropan-2-ol

[0303]

[0304] A solution of 1-(3-bromo-4-methylphenyl)ethan-1-one (1.20 g, 5.63 mmol) [Aldrich, 579734] in tetrahydrofuran (22.5 mL) was treated with trimethyl(trifluoromethyl)silane (1.00 mL, 6.76 mmol) [Aldrich, 488712] at 0 °C and stirred at 0 °C for 5 min. The reaction mixture was treated with 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (0.282 mL, 0.282 mmol) at 0 °C and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, treated with additional 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (6.76 mL, 6.76 mmol), and stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (2 x 75 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography using ethyl acetate in hexane (0%-30%) gave the desired product as a yellow oil (1.54 g, 96.7%). LCMS C 10 H 9 BrF 3 (M-OH) + : m / z = 265.0, 267.0; found: 264.9, 267.0.

[0305] Step 5. 1,1,1-Trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol

[0306]

[0307] A mixture of 2-(3-bromo-4-methylphenyl)-1,1,1-trifluoropropan-2-ol (0.252 g, 0.890 mmol), bis(pinacolato)diboron (0.294 g, 1.16 mmol), and potassium acetate (0.288 g, 2.94 mmol) in tetrahydrofuran (4.95 mL) was degassed with nitrogen for 5 minutes. The reaction mixture was treated with palladium(II) chloride triphenylphosphine complex (0.025 g, 0.036 mmol), degassed with nitrogen for an additional 5 minutes, and heated in a microwave at 135 °C for 20 minutes. The reaction mixture was diluted with ethyl acetate and filtered through a 0.5 μm syringe filter (rinsed with ethyl acetate). The filtrate was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography using ether in hexanes (0%-50%) afforded the desired product as a colorless oil (272 mg, 92.5%). LCMS C 16 H 23 BF 3 O 3 (M+H) + : m / z = 331.2; found: 331.2.

[0308] Step 6. 2-(3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol

[0309]

[0310] Treat 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine trifluoroacetate (Step 3, 0.855 g, 1.89 mmol), 1,1,1-trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (Step 5; 0.623 g, 1.89 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.131 g, 0.113 mmol) in ethanol (12.6 ml) with 2.0 M aqueous sodium carbonate solution (1.89 ml, 3.77 mmol), degas with nitrogen for 5 minutes, and heat in a microwave reactor at 130 °C for 2 hours. Partially concentrate the reaction mixture to remove ethanol and dilute with ethyl acetate and water. Remove the solid by filtration, separate the aqueous layer of the filtrate and extract with ethyl acetate (2x). Wash the combined organic layers with brine, dry over magnesium sulfate, filter, and concentrate to obtain a crude residue. Purify by flash column chromatography using methanol (0%-2%) in dichloromethane to give the desired product as a white foam (610 mg, 77.8%). LCMS C 16 H 15 BrF 3 N 4 O(M+H) + : m / z = 415.0, 417.0; found: 415.0, 417.0.

[0311] Step 7. Methyl 8-amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate

[0312]

[0313] Treat a solution of 2-(3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol (Step 6; 0.250 g, 0.602 mmol) in methanol (16.1 ml) with triethylamine (0.336 ml, 2.41 mmol) and degas with nitrogen for 5 minutes. With Pd(dppf) 2 CH 2 Cl 2(0.049 g, 0.060 mmol) was used to treat the reaction mixture, which was then degassed with nitrogen for 5 minutes. The gas was saturated by bubbling CO through the surface of the reactants for 3 minutes, and the mixture was heated overnight at 60 °C. The reaction mixture was concentrated and the resulting red oil was diluted with ethyl acetate, water, and saturated sodium bicarbonate. The aqueous layer was separated and re-extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a brown oil. Purification by flash column chromatography using methanol (0%-4%) in dichloromethane gave the desired product as an amber oily solid (158 mg, 66.5%). LCMS C 18 H 18 F 3 N 4 O 3 (M+H) + : m / z = 395.1; found: 395.1.

[0314] Step 8. 8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide

[0315] A solution of methyl 8-amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate (Step 7, 0.080 g, 0.203 mmol) in THF (3.38 mL) was treated with 1-amino-2-methylpropan-2-ol (0.181 g, 2.03 mmol), followed by trimethylaluminum (0.507 mL, 1.01 mmol) (2 M in toluene) and stirred overnight at 80 °C. The reaction mixture was treated with additional trimethylaluminum (0.70 ml, 1.40 mmol) (2 M in toluene) and stirred overnight at 80 °C. The reaction mixture was cooled to room temperature, diluted with methanol, and filtered through a pad. After rinsing with MeOH (2x), the filtrate was concentrated to an amber oil. Purification by silica gel chromatography (0-5% MeOH / DCM) gave the title compound as an oily solid (26 mg, 28%), which was a mixture of enantiomers. The racemic mixture was separated by preparative chiral HPLC (Phenomenex Lux Amylose-1 [21.2 x 250 mm, 5 μm], eluting with 12% ethanol in hexane at a flow rate of 18 mL / min, loading approximately 8 mg in 800 μL ethanol). The retention time of the first eluted peak was 11.9 minutes (Example 1; enantiomer 1). The retention time of the second eluted peak was 16.1 minutes (Example 2, enantiomer 2).

[0316] Example 5 (Enantiomer 1): 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (t, J = 6.1 Hz, 1H), 7.70 (d, J = 2.8 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.36 (s, 2H), 6.65 (s, 1H), 4.65 (s, 1H), 3.22 (d, J = 6.1 Hz, 2H), 2.15 (s, 3H), 1.70 (s, 3H), 1.09 (s, 6H). LCMS C 21 H 25 F 3 N 5 O 3 (M + H) + : m / z = 452.2; Experimental value: 452.1.

[0317] Example 6 (Enantiomer 2): 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.08 (t, J = 6.0 Hz, 1H), 7.70 (d, J = 3.0 Hz, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.36 (s, 2H), 6.65 (s, 1H), 4.65 (s, 1H), 3.22 (d, J = 6.1 Hz, 2H), 2.15 (s, 3H), 1.70 (s, 3H), 1.09 (s, 6H). LCMS C 21 H 25 F 3 N 5 O 3 (M + H) + : m / z = 452.2; Experimental value: 452.2.

[0318] Preparation and Characterization of Crystalline Form IB (Free Base) of 8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide

[0319] Charge a round-bottom flask with 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (enantiomer 2 from step 8 of Example 6; 184 g, 408 mmol) and isopropyl acetate (950 mL). Stir the mixture at 80 °C for 1 hour, cool to room temperature (RT), and stir overnight at room temperature. Collect the solid to afford 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (Form IB, 152 g, 82.8%).

[0320] The confirmation by XRPD analysis that Form IB is a crystalline solid. Figure 10 The XRPD pattern of Form IB is shown in and the peak data are provided in Table 4 below.

[0321] Table 4. XRPD peak data for Form IB.

[0322]

[0323]

[0324] DSC analysis of Form IB shows an endothermic peak with an onset temperature of 172.2 °C and a maximum at 174.2 °C. Figure 11 The DSC thermogram is provided in. It is confirmed that Form IB is an anhydrous non-solvated crystalline form.

[0325] Example 8: Preparation and Characterization of 8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide Crystalline Form IIB (Free Base)

[0326] A vial was charged with 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (enantiomer 2 from step 8 of Example 6; 252 mg, 0.559 mmol) and isopropyl acetate (1.25 mL) and the solid was slowly dissolved. The mixture was treated with heptane (0.35 mL) until the solid no longer changed. The mixture was heated at 80 °C for 30 minutes and stirred overnight at room temperature. The solid was collected to give 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (Form IIB, 116 mg, 46.0%).

[0327] The confirmation of Form IIB as a crystalline solid was based on XRPD analysis. Figure 12 The XRPD pattern of Form IIB is shown in and the peak data are provided in Table 5 below.

[0328] Table 5. XRPD peak data for Form IIB.

[0329]

[0330]

[0331] DSC analysis of Form IIB showed an endothermic peak with an onset temperature of 161.7 °C and a maximum at 165.4 °C. Figure 8 The DSC thermogram is provided in. It was confirmed that Form IIB is an anhydrous non-solvated crystalline form.

[0332] Example 9. 8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide

[0333]

[0334] Step 1. 1-(4-(methyl-d 3 )phenyl)ethan-1-one

[0335]

[0336] Degas a solution of (4-acetylphenyl)boronic acid (1.00 g, 6.10 mmol) [Aldrich, 470821], bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (0.108 g, 0.152 mmol), and cesium fluoride (3.24 g, 21.4 mmol) in DMF (10.2 mL) and water (2.03 mL) for 10 minutes, and treat with iodomethane-d 3 (1.44 mL, 23.2 mmol), and stir overnight at 45 °C. Cool the reaction mixture to room temperature and dilute with water and ethyl acetate. Separate the aqueous layer and extract with ethyl acetate (2x). Wash the combined organic extracts with water and brine, dry over magnesium sulfate, filter, and concentrate (60 - 70 Torr, 25 °C bath) to give the desired product as a yellow oil (546 mg, 65.3%) and use without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 2.58 (s, 3H). LCMS C 9 H 8 D 3 O (M + H) + : m / z = 138.1; found: 138.1.

[0337] Step 2. 1-(3-Bromo-4-(methyl-d 3 )phenyl)ethan-1-one

[0338]

[0339] Via syringe over 5 minutes, add 1-(4-(methyl-d 3) (Phenyl)ethan-1-one (6.35 g, 46.3 mmol) was treated dropwise with a suspension of aluminum chloride (13.6 g, 102 mmol) in dichloromethane (24 mL). The residue in the syringe was rinsed with dichloromethane (7.0 mL) and added dropwise to the reaction mixture. After an initial exotherm, the reaction mixture was allowed to cool to room temperature and held for 3 minutes, stirred at 35 °C for 5 minutes, and treated dropwise with bromine (2.38 mL, 46.3 mmol) over 5 minutes. The reaction mixture was stirred for 25 minutes and then slowly added to a mixture of dichloromethane (50 mL), 1 N HCl (100 mL), and ice. The residual reaction mixture was rinsed into the dichloromethane / HCl / ice mixture with additional dichloromethane. The mixture was warmed to room temperature (rt) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 75 mL). The combined organic layers were washed with saturated sodium bicarbonate and brine. The sodium bicarbonate and brine washes contained the product and these washes were combined, acidified with 1 M HCl, and extracted with dichloromethane (2 x 50 mL). All the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to give a yellow oil. Purification by flash column chromatography using ethyl acetate in hexanes (0%-15%) gave the desired product as a pale yellow solid (9.08 g, 90.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 7.9, 1.8 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 2.57 (s, 3H). LCMS C 9 H 7 D 3 BrO (M+H) + : m / z = 216.0, 218.0; found: 216.0, 218.0.

[0340] Step 3. 2-(3-Bromo-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol

[0341]

[0342] At 0 °C, 1-(3-Bromo-4-(methyl-d 3)A solution of phenyl)ethan-1-one (9.08 g, 42.0 mmol) in tetrahydrofuran (168 mL) was stirred for 5 minutes at 0 °C. The reaction mixture was treated with 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (2.10 mL, 2.10 mmol) at 0 °C and stirred for 1 hour at room temperature. The reaction mixture was treated with 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (12.6 mL, 12.6 mmol) and water (9.8 mL) and stirred for 30 minutes at room temperature. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a crude residue. Purification by flash column chromatography using ethyl acetate in hexane (0%-20%) gave the desired product as a yellow oil (13.3 g, 111%). 1 HNMR(400MHz,CDCl 3 )δ7.79–7.72(m,1H),7.48–7.35(m,1H),7.24(s,1H),2.41(br s,1H),1.76(s,3H).

[0343] Step 4. 1,1,1-Trifluoro-2-(4-(methyl-d 3 )-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol

[0344]

[0345] 2-(3-Bromo-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol (13.3 g, 41.8 mmol) was treated with bis(pinacolato)diboron (12.8 g, 50.2 mmol) and potassium acetate (8.63 ml, 138 mmol) in a suspension in dioxane (24 mL). The residual 2-(3-bromo-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol was rinsed with dioxane (106 mL) and added to the reaction mixture, and the mixture was degassed with nitrogen for 10 minutes. The reaction mixture was treated with bis(triphenylphosphine)palladium(II) dichloride (1.16 g, 1.67 mmol), degassed with nitrogen for another 10 minutes, and stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, degassed with nitrogen for 5 minutes, treated with additional bis(triphenylphosphine)palladium(II) dichloride (1.16 g, 1.67 mmol), degassed with nitrogen for 5 minutes, and stirred at 100 °C for 4 hours. The reaction mixture was passed through Filter and rinse with THF and ethyl acetate. Wash the filtrate with 1:1 water / brine (300 mL). Extract the aqueous layer with ethyl acetate again. Dry the combined organic layers over magnesium sulfate, filter, and concentrate to a brown oil. Purify by flash column chromatography using MTBE in hexanes (0%-20%) to give the desired product as a pale yellow oil (14.4 g, 84.7%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 2.3 Hz, 1H), 7.55–7.45 (m, 1H), 7.19 (d, J = 8.1 Hz, 1H), 2.43 (br s, 1H), 1.77 (s, 3H), 1.34 (s, 12H). LCMS C 16 H 20 D 3 BF 3 O 3 (M+H) + : m / z = 334.2; found: 334.3.

[0346] Step 5. 2-(3-(8-Amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol (racemic mixture)

[0347]

[0348] Treat a solution of 1,1,1-trifluoro-2-(4-(methyl-d 3 )-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (14.5 g, 35.6 mmol) in dioxane (178 mL) with 6-bromo-3-iodoimidazo[1,2-a]pyrazin-8-amine (12.1 g, 35.6 mmol), degas with nitrogen for 5 minutes, treat with dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.81 g, 7.11 mmol), and degas with nitrogen again for 5 minutes. Treat the reaction mixture with 1.0 M aqueous potassium carbonate (107 ml, 107 mmol), degas with nitrogen for 5 minutes, and stir at 80 °C overnight. Cool the reaction mixture to room temperature and filter. Rinse with ethyl acetate and water the filter cake. The filtrate was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to a dark oil. Purification was carried out by flash column chromatography using methanol in dichloromethane (0%-5%) and further purified by flash column chromatography using ethyl acetate in hexane (0%-100%) to give the desired product (13.8 g, 92.8%). LCMS C 16 H 12 D 3 BrF 3 N 4 O(M+H) + : m / z = 418.1, 420.1; found: 418.0, 420.0.

[0349] Step 6. Second eluting enantiomer of 2-(3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol

[0350]

[0351] The racemic mixture of 2-(3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol was separated by preparative chiral HPLC (Phenomenex Lux Amylose-1 [21.2 x 250 mm, 5 μm], eluting with 20% ethanol in hexane at a flow rate of 20 mL / min, loading approximately 200 mg in 4 mL ethanol). The retention time of the first eluting peak was 9.6 minutes. The retention time of the second eluting peak was 14.6 minutes.

[0352] Peak 2 : 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.66–7.59 (m, 2H), 7.59–7.53 (m, 3H), 7.46 (d, J = 8.1 Hz, 1H), 7.25 (s, 1H), 6.66 (s, 1H), 1.71 (s, 3H). LCMS C 16 H 12 D 3 BrF 3 N 4 O(M+H) + : m / z = 418.1, 420.1; found: 418.0, 420.0.

[0353] Step 7. Methyl 8-amino-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate (the single enantiomer prepared)

[0354]

[0355] Treat a solution of 2-(3-(8-amino-6-bromoimidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d3)phenyl)-1,1,1-trifluoropropan-2-ol (peak 2 from step 6, 4.95 g, 48.9 mmol) in methanol (163 mL) and DMF (40.7 mL) with triethylamine (6.81 mL, 48.9 mmol) and degas with nitrogen for 5 minutes. Treat the reaction mixture with Pd(dppf) 2 CH 2 Cl 2 (0.998 g, 1.22 mmol), degas with nitrogen for another 5 minutes, saturate the gas by bubbling CO through the surface of the reactants for 3 minutes, and heat overnight at 60 °C. Concentrate the reaction mixture and dilute the resulting oil with ethyl acetate and water. Separate the aqueous layer and extract again with ethyl acetate (3x). Wash the combined organic layers with water, saturated ammonium chloride solution and brine, dry over magnesium sulfate, filter and concentrate to a brown oil. Purify by flash column chromatography using methanol (0%-5%) in dichloromethane to give the desired product as an orange solid (4.49 g, 92.4%). LCMS C 18 H 15 D 3 F 3 N 4 O 3 (M+H) + : m / z = 398.1; found: 398.3

[0356] Step 8. 8-Amino-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylic acid (the single enantiomer prepared)

[0357]

[0358] Treat 8-amino-3-(2-(methyl-d 3)-Methyl (1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate (4.49 g, 11.3 mmol) (single enantiomer from Step 7) was dissolved in methanol (113 mL) and stirred at room temperature. The reaction mixture was concentrated to remove methanol, diluted with water (50 mL), and extracted with ethyl acetate (50 mL, then 20 mL). The combined ethyl acetate layers were extracted with additional 1.0 M sodium hydroxide (3 x 20 mL). The combined basic aqueous layers were adjusted to pH ~5 with citric acid (7.6 g). The aqueous layer was extracted with dichloromethane (2 x 150 mL). The aqueous layer was diluted with brine and extracted with ethyl acetate (150 mL). The combined organic layers were concentrated to give the desired product as a brown solid (4.06 g, 93.8%) and used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.76 (s, 1H), 7.71 (s, 1H), 7.65 (dd, J = 8.2, 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.30 (br s, 2H), 6.66 (s, 1H), 1.71 (s, 3H). LCMSC 17 H 13 D 3 F 3 N 4 O 3 (M+H) + : m / z = 384.1; found: 384.2.

[0359] Step 9. 8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide

[0360] 8-Amino-3-(2-(methyl-d 3)-5-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylic acid (4.06 g, 10.6 mmol) (single enantiomer from Step 8) in DMF (106 mL) was stirred for 15 minutes, treated with triethylamine (4.43 mL, 31.8 mmol) and stirred at room temperature for 3.5 hours. The reaction mixture was diluted with water (500 mL) and brine (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organics were washed with saturated ammonium chloride (150 mL), 11% sodium carbonate (150 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated to an amber oil. Purification by flash column chromatography using methanol in dichloromethane (0%-5%) gave the desired product as a foam (4.28 g, 89.0%). 1 HNMR(600MHz,DMSO-d 6 )δ8.14–8.05(m,1H),7.74–7.69(m,2H),7.66(d,J=7.9Hz,1H),7.62–7.54(m,1H),7.50(dd,J=8.2,2.0Hz,1H),7.38(s,2H),6.67(s,1H),4.67(s,1H),3.23(d,J=5.6Hz,2H),1.71(s,3H),1.10(s,6H). LCMS C 21 H 22 D 3 F 3 N 5 O 3 (M+H) + :m / z=455.2;Experimental value: 455.2.

[0361] Example 10: Preparation and Characterization of Crystalline Form IC (Free Base) of 8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d3)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide

[0362] A round bottom was charged with 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3)-5-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (4.60 g, 10.1 mmol) and isopropyl acetate (25.5 mL) were heated at 80 °C. The mixture was stirred at 80 °C and solids began to form within 5 minutes. The mixture was stirred at 80 °C for 1 hour. Heating was discontinued and the mixture was stirred for 1 hour while cooling to room temperature. The mixture was treated dropwise from an addition funnel with heptane (25.5 mL) over 35 minutes and stirred at room temperature for 40 minutes. The solid was collected, washed with 1:1 isopropyl acetate / heptane (10 mL) and dried under reduced pressure at 60 °C for 24 hours to give 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide (Form I) (4.16 g, 90.4%).

[0363] It was confirmed by XRPD analysis that Form IC is a crystalline solid. Figure 14 The XRPD pattern of Form IC is shown in Figure 14 and the peak data are provided in Table 6 below.

[0364] Table 6. XRPD peak data for Form IC.

[0365]

[0366]

[0367] DSC analysis of Form IC showed an endothermic peak with an onset temperature of 173.4 °C and a maximum at 179.0 °C. Figure 15 The DSC thermogram is provided in Figure 15 . It was confirmed that Form IC is an anhydrous non-solvated crystalline form.

[0368] Example 11. 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide (HBr) salt

[0369] The free base of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide (98.81 mg) was dissolved in 2.5 mL of methanol in a 4 mL clear glass vial. 42.4 μL of 6 M aqueous HBr solution (1.2 eq) was added to the solution and mixed well. The solution was evaporated at room temperature to obtain HBr salt crystals.

[0370] Example 12. Characterization of single crystal 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide (HBr) salt

[0371] Crystal Data : C35 H32 Br2 F12 N10 O5, from methanol, colorless, irregular flakes, approximately 0.450 x 0.210 x 0.060 mm, monoclinic, C2, β = 94.953(7), Z = 4, T = -40 °C, formula weight = 1060.52, density = 1.631 g / cm 3 , μ(Mo) = 1.98 mm -1 .

[0372] Data Collection : Data collection was carried out as follows: using a Bruker SMART APEX-II CCD system, MoKα radiation, standard focusing tube, anode power = 50 kV x 30 mA, crystal-to-plate distance = 5.0 cm, 512 x 512 pixels / frame, beam center = (259.19, 253.13), total number of frames = 2635, oscillation / frame = 0.50°, exposure / frame = 40.1 seconds / frame, SAINT integration, hkl min / max = (-26, 26, -12, 13, -27, 27), input shelx data = 38968, unique data = 9756, 2θ range = 4.51° to 55.43°, 2θ 55.43 completeness = 99.60%, R(int-xl) = 0.0672, SADABS correction applied.

[0373] Solution and Refinement : The crystal structure was solved using XS (Shelxtl) and refined using the shelxtl software package. The refinement was by full-matrix least squares on F 2 , scattering factors from Tables 4.2.6.8 and 6.1.1.4 of Int.Tab.Vol C, number of data = 9756, number of constraints = 1, number of parameters = 584, data / parameter ratio = 16.71, F2 goodness-of-fit = 1.14, R indices [I>4sigma(I)] R1 = 0.0648, wR2 = 0.1560, R indices (all data) R1 = 0.1004, wR2 = 0.1719, maximum difference peak and hole = 1.795 and refined flack parameter = 0.038(6). All hydrogen atoms were idealized using a riding model. Table 7 shows the atomic coordinates (x10 4 ) and equivalent isotropic displacement parameters U(eq) is defined as one-third of the trace of the orthogonalized Uij tensor. Table 8 shows the bond lengths and bond angles [°]. Table 9 shows the anisotropic displacement parameters

[0374] Results : This analysis confirmed the structure of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide. The asymmetric unit contains two 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide molecules, two bromines (to balance the charge), and one methanol solvent molecule, as Figures 16A to 16B shown. The enantiomeric configuration was assigned based on the Flack parameter refined to 0.038(6). This study determined the absolute configuration at the chiral centers C15 = S- and C35 = S-.

[0375] Table 7.

[0376]

[0377]

[0378] Table 8.

[0379]

[0380]

[0381]

[0382]

[0383] Table 9.

[0384]

[0385]

[0386] Example A. THP-1 RPS6 ELISA assay

[0387] To measure phosphorylated ribosomal protein S6 (RPS6) in cell lysates, THP-1 cells (human acute monocytic leukemia) were obtained from ATCC (Manassas, VA) and maintained in RPMI (Gibco / Life Technologies, Carlsbad, CA) containing 10% FBS. For the assay, THP-1 cells were serum-starved overnight in RPMI and then seeded at 2x10 5 cells / well (90 μL) in a 96-well flat-bottom tissue culture-treated plate (Corning, Corning, NY) in the presence or absence of a range of concentrations of the test compound in RPMI. The plates were incubated at 37 °C, 5% CO 2 for 2 hours, then treated for 15 minutes at 37 °C, 5% CO 2 in the presence or absence of 10 nM MCP-1 (MYBioSource, San Diego, CA). The plates were centrifuged at 1600 RPM and the supernatant removed. The cells were lysed in lysis buffer (Cell Signaling, Danvers, MA) containing protease inhibitors (Calbiochem / EMD, Germany), PMSF (Sigma, St Louis MO), HALTS (ThermoFisher, Rockford, IL) on wet ice for 30 minutes. The cell lysates were frozen at -80 °C prior to testing. The lysates were tested in a Human / Mouse / Rat Phospho-RPS6 ELISA (R&D Systems, Inc., Minn, MN). The plates were measured using a microplate reader (SpectraMax M5 – Molecular Devices, LLC Sunnyvale, CA) set to 450 nm with a wavelength correction of 540. IC 50 determination was performed by fitting a curve of percent inhibitor inhibition versus the logarithm of inhibitor concentration using GraphPad Prism 5.0 software.

[0388] Example B. PI3K-γ Scintillation Proximity Assay

[0389] Materials

[0390] [γ- was purchased from Perkin-Elmer (Waltham, MA). 33P]ATP (10 mCi / mL) and wheat germ agglutinin (WGA) YSi SPA scintillation beads. Lipid kinase substrate 4,5-bisphospho-D-myo-phosphatidylinositol (3-O-phosphate-linked PtdIns(4,5)P2) D(+)-sn-1,2-di-O-octanoyl glycerol (PIP2), CAS 204858-53-7) was purchased from Echelon Biosciences (Salt Lake City, UT). Recombinant human PI3Kγ (p110γ) protein was purchased from Life technology (Grand Island, NY). ATP, MgCl 2 , DTT, EDTA, MOPS and CHAPS were purchased from SigmaAldrich (St. Louis, MO).

[0391] Kinase reactions were carried out in a final volume of 25 μL in polystyrene 384-well Greiner Bio-one white plates from Thermo Fisher Scientific. First, the inhibitors were serially diluted in DMSO and added to the wells of the plate, and then the other reaction components were added. In the assay, the final concentration of DMSO was 2%. The PI3Kγ assay was carried out at room temperature in 20 mM MOPS pH 6.7, 10 mM MgCl 2 , 5 mM DTT and 0.03% CHAPS. The reaction was initiated by adding ATP, and the final reaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ- 33 P]ATP, 13 nM PI3Kγ. The reactants were incubated for 120 minutes and the reaction was terminated by adding 40 μL of SPA beads suspended in the following quenching buffer: 163 mM potassium phosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration of SPA beads was 1.0 mg / mL. After sealing the plate, the plate was shaken overnight at room temperature and centrifuged at 1500 rpm for 10 minutes, and the radioactivity of the product was measured by scintillation counting on a Topcount (Perkin-Elmer). The IC 50 was determined by fitting a curve of the percentage of solvent control activity versus the logarithm of the inhibitor concentration using GraphPad Prism 6.0 software.

[0392] Example C. PI3Kδ Scintillation Proximity Assay

[0393] Materials

[0394] [γ- 33P]ATP (10 mCi / mL) and wheat germ agglutinin (WGA) YSi SPA scintillation beads. Lipid kinase substrate 4,5-bisphospho-D-myo-phosphatidylinositol (3-O-phosphate-linked PtdIns(4,5)P2) D(+)-sn-1,2-di-O-octanoyl glycerol (PIP2), CAS 204858-53-7) was purchased from Echelon Biosciences (Salt Lake City, UT). Recombinant human protein of PI3Kδ (p110δ / p85α) was purchased from Eurofins (St Charles, MO). ATP, MgCl 2 , DTT, EDTA, MOPS and CHAPS were purchased from SigmaAldrich (St. Louis, MO).

[0395] Kinase reactions were carried out in a final volume of 25 μL in a polystyrene 384-well Greiner Bio-one white plate from Thermo Fisher Scientific. First, the inhibitors were serially diluted in DMSO and added to the wells of the plate, and then the other reaction components were added. In the assay, the final concentration of DMSO was 2%. The PI3Kδ assay was carried out at room temperature in 20 mM MOPS pH 6.7, 10 mM MgCl 2 , 5 mM DTT and 0.03% CHAPS. The reaction was initiated by adding ATP, and the final reaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ- 33 P]ATP, 3.4 nM PI3Kδ. The reactants were incubated for 120 minutes and the reaction was terminated by adding 40 μL of SPA beads suspended in the following quenching buffer: 163 mM potassium phosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration of SPA beads was 1.0 mg / mL. After sealing the plate, the plate was shaken overnight at room temperature and centrifuged at 1500 rpm for 10 minutes, and the radioactivity of the product was measured by scintillation counting on a Topcount (PerkinElmer). The IC 50 was determined by fitting a curve of the percentage of solvent control activity versus the logarithm of the inhibitor concentration using GraphPad Prism 6.0 software.

[0396] The compounds of Example 1, Example 5, Example 6 and Example 9 were tested in the assays described in Example A, Example B and Example C, and were found to have the IC 50 values shown in Table A below.

[0397] Table A. IC 50 values

[0398]

[0399] + refers to IC 50 ≤ 100 nM; ++ refers to IC 50 ≤ 500 nM; +++ refers to IC 50 < 2000 nM; ++++ refers to IC 50 ≥ 2000 nM.

[0400] # refers to IC 50 ≤ 100 nM; ## refers to IC 50 ≤ 500 nM; refers to IC 50 < 1000 nM; # refers to IC 50 ≥ 1000 nM.

[0401] In accordance with the foregoing description, various modifications to the present invention other than those described herein will also be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each of the various references cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

[0402] In summary, the present invention includes, but is not limited to, the following items:

[0403] 1. A crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide.

[0404] 2. The crystalline form according to item 1, wherein the crystalline form is anhydrous and non-solvated.

[0405] 3. The crystalline form according to item 1 or 2, wherein the crystalline form is Form IA.

[0406] 4. The crystalline form according to any one of items 1 to 3, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 8.6° ± 0.2°.

[0407] 5. The crystalline form according to any one of items 1 to 4, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 9.5° ± 0.2°.

[0408] 6. The crystalline form according to any one of items 1 to 5, wherein the crystalline form has an X-ray powder diffraction pattern comprising the following peaks expressed in 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 13.0° ± 0.2°; 13.6° ± 0.2°; 14.2° ± 0.2°; and 14.9° ± 0.2°.

[0409] 7. The crystalline form according to any one of items 1 to 6, wherein the crystalline form has an X-ray powder diffraction pattern comprising 4 or more of the following peaks expressed in 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 13.0° ± 0.2°; 13.6° ± 0.2°; 14.2° ± 0.2°; 14.9° ± 0.2°; 17.3° ± 0.2°; 19.2° ± 0.2°; 20.6° ± 0.2°; 24.0° ± 0.2°; and 28.7° ± 0.2°.

[0410] 8. The crystalline form according to any one of items 1 to 7, wherein the crystalline form has Figure 1 substantially the X-ray powder diffraction pattern as shown.

[0411] 9. The crystalline form according to any one of items 1 to 8, wherein the crystalline form has a DSC thermogram comprising an endothermic peak having a maximum at about 193°C.

[0412] 10. The crystalline form according to any one of items 1 to 9, wherein the crystalline form has Figure 2 substantially the differential scanning calorimetry thermogram (DSC) as shown.

[0413] 11. The crystalline form according to any one of items 1 to 10, wherein the crystalline form has Figure 3 substantially the thermogravimetric analysis (TGA) as shown.

[0414] 12. The crystalline form according to item 1 or 2, wherein the crystalline form is Form IIA.

[0415] 13. The crystalline form according to any one of items 1, 2, and 12, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak at 9.1° ± 0.2° expressed in 2θ.

[0416] 14. The crystalline form according to any one of items 1, 2, 12, and 13, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak at 11.1° ± 0.2° expressed in 2θ.

[0417] 15. The crystalline form according to any one of items 1, 2, and 12 to 14, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 12.6° ± 0.2°.

[0418] 16. The crystalline form according to any one of items 1, 2, and 12 to 15, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 13.5° ± 0.2°.

[0419] 17. The crystalline form according to any one of items 1, 2, and 12 to 16, wherein the crystalline form has an X-ray powder diffraction pattern comprising the following peaks represented by 2θ: 9.1° ± 0.2°; 11.1° ± 0.2°; 12.6° ± 0.2°; and 13.5° ± 0.2°.

[0420] 18. The crystalline form according to any one of items 1, 2, and 12 to 17, wherein the crystalline form has an X-ray powder diffraction pattern comprising 4 or more of the following peaks represented by 2θ: 9.1° ± 0.2°; 11.1° ± 0.2°; 12.6° ± 0.2°; 13.5° ± 0.2°; 18.0° ± 0.2°; 19.0° ± 0.2°; 20.5° ± 0.2°; and 21.9° ± 0.2°.

[0421] 19. The crystalline form according to any one of items 1, 2, and 12 to 18, wherein the crystalline form has substantially as Figure 4 shown in the X-ray powder diffraction pattern.

[0422] 20. The crystalline form according to any one of items 1, 2, and 12 to 19, wherein the crystalline form has a DSC thermogram comprising an endothermic peak having a maximum at about 180°C.

[0423] 21. The crystalline form according to any one of items 1, 2, and 12 to 20, wherein the crystalline form has substantially as Figure 5 shown in the differential scanning calorimetry thermogram (DSC).

[0424] 22. The crystalline form according to any one of items 1, 2, and 12 to 21, wherein the crystalline form has substantially as Figure 6 shown in the thermogravimetric analysis (TGA).

[0425] 23. The crystalline form according to item 1 or 2, wherein the crystalline form is Form IIIA.

[0426] 24. The crystalline form according to any one of items 1, 2, and 23, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 8.1° ± 0.2°.

[0427] 25. The crystalline form according to any one of items 1, 2, 23, and 24, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 10.6° ± 0.2°.

[0428] 26. The crystalline form according to any one of items 1, 2, and 23 to 25, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 13.5° ± 0.2°.

[0429] 27. The crystalline form according to any one of items 1, 2, and 23 to 26, wherein the crystalline form has an X-ray powder diffraction pattern comprising the following peaks represented by 2θ: 8.1° ± 0.2°; 10.6° ± 0.2°; 13.5° ± 0.2°; and 14.2° ± 0.2°.

[0430] 28. The crystalline form according to any one of items 1, 2, and 23 to 27, wherein the crystalline form has an X-ray powder diffraction pattern comprising 4 or more of the following peaks represented by 2θ: 8.1° ± 0.2°; 10.6° ± 0.2°; 13.5° ± 0.2°; 14.2° ± 0.2°; 16.4° ± 0.2°; 17.1° ± 0.2°; 17.9° ± 0.2°; 20.3° ± 0.2°; and 24.1° ± 0.2°.

[0431] 29. The crystalline form according to any one of items 1, 2, and 23 to 28, wherein the crystalline form has substantially the Figure 7 as shown X-ray powder diffraction pattern.

[0432] 30. The crystalline form according to any one of items 1, 2, and 23 to 29, wherein the crystalline form has a DSC thermogram comprising an endothermic peak having a maximum at about 143°C.

[0433] 31. The crystalline form according to any one of items 1, 2, and 23 to 30, wherein the crystalline form has substantially the Figure 8 as shown differential scanning calorimetry thermogram (DSC).

[0434] 32. The crystalline form according to any one of items 1, 2, and 23 to 31, wherein the crystalline form has substantially the Figure 9 as shown thermogravimetric analysis (TGA).

[0435] 33. A crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide.

[0436] 34. The crystalline form as described in item 33, wherein the crystalline form is anhydrous and non-solvated.

[0437] 35. The crystalline form as described in item 33 or 34, wherein the crystalline form is Form IB.

[0438] 36. The crystalline form as described in any one of items 33 to 35, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 6.2° ± 0.2°.

[0439] 37. The crystalline form as described in any one of items 33 to 36, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 15.6° ± 0.2°.

[0440] 38. The crystalline form as described in any one of items 33 to 37, wherein the crystalline form has an X-ray powder diffraction pattern comprising the following peaks represented by 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.4° ± 0.2°; 11.6° ± 0.2°; 12.0° ± 0.2°; 13.9° ± 0.2°; 14.4° ± 0.2°; 15.6° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 23.2° ± 0.2°.

[0441] 39. The crystalline form as described in any one of items 33 to 37, wherein the crystalline form has an X-ray powder diffraction pattern comprising 4 or more of the following peaks represented by 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.4° ± 0.2°; 11.6° ± 0.2°; 12.0° ± 0.2°; 13.9° ± 0.2°; 14.4° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 23.2° ± 0.2°.

[0442] 40. The crystalline form as described in any one of items 33 to 39, wherein the crystalline form has substantially as Figure 10 shown in the X-ray powder diffraction pattern.

[0443] 41. The crystalline form as described in any one of items 33 to 40, wherein the crystalline form has a DSC thermogram comprising an endothermic peak having a maximum at about 174°C.

[0444] 42. The crystalline form as described in any one of items 33 to 41, wherein the crystalline form has substantially as Figure 11 shown in the differential scanning calorimetry thermogram (DSC).

[0445] 43. The crystalline form as described in item 33 or 34, wherein the crystalline form is Form IIB.

[0446] 44. The crystalline form as described in any one of items 33, 34, and 43, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 4.2° ± 0.2°.

[0447] 45. The crystalline form as described in any one of items 33, 34, 43, and 44, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 13.3° ± 0.2°.

[0448] 46. The crystalline form as described in any one of items 33, 34, and 43 to 45, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 17.0° ± 0.2°.

[0449] 47. The crystalline form as described in any one of items 33, 34, and 43 to 46, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 18.8° ± 0.2°.

[0450] 48. The crystalline form as described in any one of items 33, 34, and 43 to 47, wherein the crystalline form has an X-ray powder diffraction pattern comprising the following peaks represented by 2θ: 4.3° ± 0.2°; 7.4° ± 0.2°; 13.3° ± 0.2°; and 15.3° ± 0.2°.

[0451] 49. The crystalline form as described in any one of items 33, 34, and 43 to 47, wherein the crystalline form has an X-ray powder diffraction pattern comprising 4 or more of the following peaks represented by 2θ: 4.3° ± 0.2°; 7.4° ± 0.2°; 13.3° ± 0.2°; 15.3° ± 0.2°; 15.5° ± 0.2°; 17.0° ± 0.2°; 17.2° ± 0.2°; 18.8° ± 0.2°; and 20.1° ± 0.2°.

[0452] 50. The crystalline form as described in any one of items 33, 34, and 43 to 49, wherein the crystalline form has substantially as Figure 12 shown in the X-ray powder diffraction pattern.

[0453] 51. The crystalline form as described in any one of items 33, 34, and 43 to 50, wherein the crystalline form has a DSC thermogram comprising an endothermic peak having a maximum at about 165°C.

[0454] 52. The crystalline form as described in any one of items 33, 34, and 43 to 50, wherein the crystalline form has substantially as Figure 13Differential scanning calorimetry thermogram (DSC) as shown.

[0455] 53. A crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide.

[0456] 54. The crystalline form according to item 53, which is anhydrous and non-solvated.

[0457] 55. The crystalline form according to item 53 or 54, which is Form IC.

[0458] 56. The crystalline form according to any one of items 53 to 55, which has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 6.2° ± 0.2°.

[0459] 57. The crystalline form according to any one of items 53 to 56, which has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 11.9° ± 0.2°.

[0460] 58. The crystalline form according to any one of items 53 to 57, which has an X-ray powder diffraction pattern comprising the following peaks represented by 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.3° ± 0.2°; 11.9° ± 0.2°; and 12.5° ± 0.2°.

[0461] 59. The crystalline form according to any one of items 53 to 58, which has an X-ray powder diffraction pattern comprising 4 or more of the following peaks represented by 2θ: 6.2° ± 0.2°; 10.4° ± 0.2°; 11.3° ± 0.2°; 11.9° ± 0.2°; 12.5° ± 0.2°; 13.8° ± 0.2°; 14.4° ± 0.2°; 15.6° ± 0.2°; 16.0° ± 0.2°; 16.7° ± 0.2°; 20.7° ± 0.2°; and 21.2° ± 0.2°.

[0462] 60. The crystalline form according to any one of items 53 to 59, which has an X-ray powder diffraction pattern substantially as Figure 14 shown.

[0463] 61. The crystalline form according to any one of items 53 to 60, which has a DSC thermogram comprising an endothermic peak having a maximum at about 179°C.

[0464] 62. The crystalline form according to any one of items 53 to 61, said crystalline form having substantially as Figure 15 shown in the differential scanning calorimetry thermogram (DSC).

[0465] 63. A salt, said salt being 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide.

[0466] 64. The salt according to item 63, said salt having a 1:1 stoichiometric ratio of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide to hydrobromic acid.

[0467] 65. The salt according to item 63 or 64, said salt being substantially isolated.

[0468] 66. The salt according to item 63 or 64, said salt being in crystalline form.

[0469] 67. The crystalline form according to item 66, said crystalline form being a solvated crystalline form.

[0470] 68. The crystalline form according to item 67, said crystalline form being a methanol solvate crystalline form.

[0471] 69. The crystalline form according to any one of items 1 to 62, 67 and 68, said crystalline form being substantially isolated.

[0472] 70. A composition, said composition comprising the crystalline form according to any one of items 1 to 62 and 67 to 69 or the salt according to any one of items 63 to 66.

[0473] 71. The composition according to item 70, wherein said composition further comprises at least one pharmaceutically acceptable carrier.

[0474] 72. A method for inhibiting the activity of PI3Kγ kinase, said method comprising contacting said kinase with the crystalline form according to any one of items 1 to 62 and 67 to 69 or the salt according to any one of items 63 to 66.

[0475] 73. The method according to item 72, wherein said crystalline form is an inhibitor that is selective for PI3Kγ over one or more of PI3Kα, PI3Kβ and PI3Kδ.

[0476] 74. A method of treating a disease or disorder in a patient, wherein the disease or disorder is associated with abnormal expression or activity of PI3Kγ kinase, the method comprising administering to the patient a therapeutically effective amount of a crystalline form as described in any one of items 1 to 62 and 67 to 69 or a salt as described in any one of items 63 to 66.

[0477] 75. The method according to item 74, wherein the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease or neurodegenerative disease.

[0478] 76. The method according to item 74, wherein the disease or disorder is lung cancer, melanoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, gastric cancer, seminoma, teratocarcinoma, astrocytoma, neuroblastoma, glioma or sarcoma.

[0479] 77. The method according to item 76, wherein the sarcoma is Askin's tumor, botryoid sarcoma, chondrosarcoma, Ewing's sarcoma, malignant angioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangioendothelioma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma or undifferentiated pleomorphic sarcoma.

[0480] 78. The method according to item 74, wherein the disease or disorder is acute myeloid leukemia, acute monocytic leukemia, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, T cell acute lymphoblastic leukemia (T-ALL), cutaneous T cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) T cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL) or lymphoblastic lymphoma.

[0481] 79. The method according to item 78, wherein the mature (peripheral) T cell neoplasm (PTCL) is T cell prolymphocytic leukemia, T cell granular lymphocytic leukemia, aggressive NK cell leukemia, mycosis fungoides / Sezary syndrome, anaplastic large cell lymphoma (T cell type), enteropathy-type T cell lymphoma, adult T cell leukemia / lymphoma or angioimmunoblastic T cell lymphoma.

[0482] 80. The method according to item 78, wherein the anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.

[0483] 81. The method according to item 74, wherein the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xeroderma pigmentosum, keratoacanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenström macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphoid tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, latent myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B-cell lymphoma.

[0484] 82. The method according to item 81, wherein the non-Hodgkin's lymphoma (NHL) is relapsed NHL, refractory NHL, relapsed follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL).

[0485] 83. The method according to item 81, wherein the diffuse large B-cell lymphoma is activated B-cell-like (ABC) diffuse large B-cell lymphoma or germinal center B-cell (GCB) diffuse large B-cell lymphoma.

[0486] 84. The method according to item 81, wherein the Burkitt's lymphoma is endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt-like lymphoma.

[0487] 85. The method according to item 84, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, asthma, allergic reaction, allergic rhinitis, pancreatitis, psoriasis, allergy, glomerulonephritis, inflammatory bowel disease, thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hyperplasia, myasthenia gravis, Sjögren's syndrome, osteoarthritis, restenosis, or atherosclerosis.

[0488] 86. The method according to item 84, wherein the disease or disorder is cardiac hypertrophy, cardiomyocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia, bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus or membranous nephropathy.

[0489] 87. The method according to item 86, wherein the idiopathic thrombocytopenic purpura (ITP) is recurrent ITP or refractory ITP.

[0490] 88. The method according to item 86, wherein the vasculitis is Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemic vasculitis (primary or hepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP), allergic vasculitis, microscopic polyangiitis, Wegener's granulomatosis or antineutrophil cytoplasmic antibody-associated (ANCA) systemic vasculitis (AASV).

[0491] 89. The method according to item 86, wherein the disease or disorder is Alzheimer's disease, central nervous system trauma or stroke.

[0492] 90. A method for preparing a crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, the method comprising dissolving the compound in a solvent to form a mixture, and crystallizing the compound from the mixture.

[0493] 91. The method according to item 90, wherein the solvent comprises isopropyl acetate.

[0494] 92. The method according to item 91, wherein the solvent further comprises heptane.

[0495] 93. The method according to any one of items 90 to 92, wherein the method further comprises heating the mixture to a temperature of about 70 °C to about 90 °C.

[0496] 94. The method according to item 93, wherein the method further comprises cooling the mixture to room temperature.

[0497] 95. The method according to item 90, wherein the solvent comprises methanol.

[0498] 96. The method according to item 90, wherein the method further comprises heating the mixture to a temperature of about 50 °C to about 70 °C.

[0499] 97. The method according to item 96, wherein the method further comprises cooling the mixture to room temperature.

[0500] 98. A crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, which crystalline form is prepared according to the method according to any one of items 90 to 97.

[0501] 99. The crystalline form according to item 98, which crystalline form is anhydrous and non-solvated.

[0502] 100. The crystalline form according to item 98 or 99, which crystalline form is Form IA.

[0503] 101. The crystalline form according to item 98 or 99, which crystalline form is Form IIA.

[0504] 102. The crystalline form according to item 98 or 99, which crystalline form is Form IIIA.

[0505] 103. A method for preparing a crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, the method comprising dissolving the compound in a solvent to form a mixture, and crystallizing the compound from the mixture.

[0506] 104. The method according to item 103, wherein the method further comprises heating the mixture to a temperature of about 70 °C to about 90 °C.

[0507] 105. The method according to item 103, wherein the method further comprises cooling the mixture to room temperature.

[0508] 106. The method according to any one of items 103 to 105, wherein the solvent comprises isopropyl acetate.

[0509] 107. The method according to item 106, wherein the solvent further comprises heptane.

[0510] 108. A crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, said crystalline form being prepared by the method according to any one of items 103 to 107.

[0511] 109. The crystalline form according to item 108, said crystalline form being anhydrous and non-solvated.

[0512] 110. The crystalline form according to item 108 or 109, said crystalline form being Form IB.

[0513] 111. The crystalline form according to item 108 or 109, said crystalline form being Form IIB.

[0514] 112. A method for preparing a crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, said method comprising dissolving the compound in a solvent to form a mixture, and crystallizing the compound from the mixture.

[0515] 113. The method according to item 112, wherein the method further comprises heating the mixture to a temperature of about 70 °C to about 90 °C.

[0516] 114. The method according to item 112, wherein the method further comprises cooling the mixture to room temperature.

[0517] 115. The method according to any one of items 112 to 114, wherein the solvent comprises isopropyl acetate.

[0518] 116. The method according to item 115, wherein the solvent further comprises heptane.

[0519] 117. A crystalline form of the compound 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, said crystalline form being prepared by the method according to any one of items 112 to 116.

[0520] 118. The crystalline form according to item 117, said crystalline form being anhydrous and non-solvated.

[0521] 119. The crystalline form as described in item 117 or 118, which is Form IC.

[0522] 120. A method for preparing the hydrobromide salt of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, the method comprising dissolving the compound in a solvent to form a mixture, and adding hydrobromic acid to the mixture.

[0523] 121. The method as described in item 120, wherein the solvent comprises methanol.

[0524] 122. The method as described in item 120 or 121, wherein the hydrobromic acid is added to the mixture in the form of an aqueous solution of hydrobromic acid.

[0525] 123. The method as described in any one of items 120 to 122, wherein an excess of hydrobromic acid is added to the mixture based on 1 equivalent of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide.

[0526] 124. The method as described in any one of items 120 to 123, wherein about 1.1 equivalents to about 1.5 equivalents of hydrobromic acid are added to the mixture based on 1 equivalent of the 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide.

[0527] 125. The method as described in any one of items 120 to 124, the method further comprising substantially separating the 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide.

[0528] 126. The method as described in item 125, wherein the 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide is separated as a crystalline form.

[0529] 127. The method as described in item 125 or 126, wherein the 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide hydrobromide is separated as a methanol solvate crystalline form.

[0530] 128. The hydrobromide of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, which is prepared according to the method described in any one of items 120 to 127.

[0531] 129. The hydrobromide according to item 128, wherein the hydrobromide is crystalline.

[0532] 130. The hydrobromide according to item 129, wherein the hydrobromide is in a solvated crystalline form.

[0533] 131. The hydrobromide according to item 129 or 130, wherein the hydrobromide is in a methanol solvate crystalline form.

Claims

1. A crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide.

2. The crystalline form according to claim 1, wherein the crystalline form is anhydrous and non-solvated.

3. The crystalline form according to claim 1 or 2, wherein the crystalline form is Form IA.

4. The crystalline form according to any one of claims 1 to 3, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 8.6° ± 0.2°.

5. The crystalline form according to any one of claims 1 to 4, wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak represented by 2θ at 9.5° ± 0.2°.

6. The crystalline form according to any one of claims 1 to 5, wherein the crystalline form has an X-ray powder diffraction pattern comprising the following peaks represented by 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 13.0° ± 0.2°; 13.6° ± 0.2°; 14.2° ± 0.2°; and 14.9° ± 0.2°.

7. The crystalline form according to any one of claims 1 to 6, wherein the crystalline form has an X-ray powder diffraction pattern comprising 4 or more of the following peaks represented by 2θ: 8.6° ± 0.2°; 9.5° ± 0.2°; 10.3° ± 0.2°; 13.0° ± 0.2°; 13.6° ± 0.2°; 14.2° ± 0.2°; 14.9° ± 0.2°; 17.3° ± 0.2°; 19.2° ± 0.2°; 20.6° ± 0.2°; 24.0° ± 0.2°; and 28.7° ± 0.2°.

8. The crystalline form according to any one of claims 1 to 7, wherein the crystalline form has an X-ray powder diffraction pattern substantially as shown in Figure 1.

9. The crystalline form according to any one of claims 1 to 8, wherein the crystalline form has a DSC thermogram comprising an endothermic peak having a maximum at about 193°C.

10. The crystalline form according to any one of claims 1 to 9, wherein the crystalline form has a differential scanning calorimetry thermogram (DSC) substantially as shown in Figure 2.

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