Crystalline forms and salts of PI3K inhibitors and methods of making and using same

Abstract

Provided herein are salt and crystalline forms of Compound I, as well as salts, solvates, and salt solvates thereof. Also provided herein are pharmaceutical compositions comprising the crystalline forms, as well as therapeutic uses of the crystalline forms and compositions thereof. [Formula 1] TIFF2025509950000066.tif54165

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to patent application number PCT / CN2022 / 082752, filed March 24, 2022, the contents of which are hereby incorporated by reference in their entirety for all purposes. [Background technology]

[0002] Phosphatidylinositol 3-kinases (PI3Ks) comprise a family of lipid kinases that catalyze the transfer of phosphate to the 3-position of the inositol ring of phosphatidylinositol and its derivatives to produce phosphoinositol-3-phosphate (PI(3)P), phosphoinositol-3,4-bisphosphate (PI(3,4)P), and phosphoinositol-3,4-bisphosphate (PI(3,4)P). 2 ) and phosphoinositol-3,4,5-triphosphate (PI(3,4,5)P 3), which in turn act as second messengers in signal transduction cascades by docking pleckstrin homology, FYVE, Phox, and other phospholipid-binding domain-containing proteins into various signaling complexes, often at the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 17:615 (2001)). PI3Ks have been classified into three classes based on their structural properties and substrate specificity: Class IA, Class IV ... PI3K is a heterodimer composed of a p110 catalytic subunit and a p85 regulatory subunit. In mammals, there are three genes, PIK3CA, PIK3CB, and PIK3CD, which encode the p110 catalytic isoforms (p110α, p110β, and p110δ, respectively). There are also three genes, PIK3R1, PIK3R2, and PIK3R3, which encode the p85α (and its splice variants p55α and p50α), p85β, and p55γ regulatory subunits, respectively, collectively referred to as p85. The modular domain of the p85 / 55 / 50 subunit contains a Src homology (SH2) domain that binds to phosphotyrosine residues in specific sequence contexts of activated receptors and cytoplasmic tyrosine kinases, resulting in the activation and localization of class 1A PI3Ks. Class IB PI3K is a heterodimer composed of the catalytic subunit p110γ and the regulatory subunit p101. p110γ is expressed primarily in leukocytes and can be directly activated by GPCRs. Class II PI3K is a monomer with only a single catalytic subunit. Class III PI3K is composed of a single catalytic subunit, Vps34 (homolog of yeast vacuolar protein sorting defective 34).The phospholipid products of class I PI3Ks link upstream receptors to downstream cellular activities including proliferation, survival, chemotaxis, cell trafficking, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 64:281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)). There is interest and an ongoing need to bind and regulate PI3K for the treatment of various diseases. Summary of the Invention

[0003] The present disclosure relates to a crystalline form of a phosphoinositide 3-kinase (PI3K) inhibitor, Compound I, or a pharma- ceutically acceptable salt, solvate, or salt solvate thereof.

[0004] [ka]

[0005] In embodiments, crystalline forms of Compound I are provided herein.

[0006] In embodiments, the crystalline form of Compound I is anhydrous or non-solvated.

[0007] In embodiments, provided herein is a crystalline form of a pharmaceutical salt of Compound I, or a pharma- ceutically acceptable salt solvate thereof.

[0008] In embodiments, crystalline forms of pharmaceutical salts of Compound I are provided herein.

[0009] In embodiments, crystalline forms of solvates of Compound I are provided herein.

[0010] In embodiments, provided herein are compositions comprising a crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof.

[0011] In embodiments, the present disclosure also relates to a method of treating various diseases or conditions with compound I, including diseases or conditions in which irreversible inhibition of PI3K, such as PIK3α, provides therapeutic benefit to a subject having the disease or condition.In embodiments, the present disclosure provides a method of treating cancer in a subject in need of such treatment.The method includes administering an effective amount of compound I, or a crystalline form of its pharmaceutically acceptable salt, solvate, or salt solvate, or a pharmaceutical composition comprising compound I, or a pharmaceutically acceptable salt, solvate, or salt solvate.

[0012] In an embodiment, the present disclosure provides a method of inhibiting phosphoinositide 3 kinase (PI3K) to a subject in need thereof. The method comprises administering an effective amount of a crystalline form of compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, or a pharmaceutical composition comprising compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof. In an embodiment, the present invention is a means for inhibiting phosphoinositide 3 kinase (PI3K). In another embodiment, the present invention may be a salt means for inhibiting PI3K. In another embodiment, the present invention may be a crystalline means for inhibiting PI3K. In another embodiment, the present invention may be an amorphous means for inhibiting PI3K. In certain embodiments, the crystalline form may include Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, and / or Form H6.

[0013] In one embodiment, the present invention is a pharmaceutical composition comprising a means or means for inhibiting phosphoinositide 3 kinase (PI3K) and a pharma- ceutically acceptable carrier. In certain embodiments, the means may be in the form of a salt. In another embodiment, the composition may be in the form in which the means is in a crystalline form. In certain embodiments, the crystalline form may include Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, and / or Form H6. [Brief description of the drawings]

[0014] [Figure 1A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A of Compound I. [Figure 1B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form A of Compound I. [Figure 1C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline Form A of Compound I. [Figure 1D] 1 shows a dynamic vapor sorption (DVS) isotherm plot of crystalline Form A of Compound I. [Figure 2A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A* of Compound I phosphate. [Figure 2B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A* of Compound I phosphate. [Figure 2C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline form A* of Compound I phosphate. [Figure 2D] 1 shows a dynamic vapor sorption (DVS) isotherm plot of crystalline form A* of Compound I phosphate. [Figure 3A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A** of compound I benzenesulfonate salt. [Figure 3B]1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A** of Compound I benzenesulfonate salt. [Figure 3C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline form A** of Compound I benzenesulfonate salt. [Figure 3D] 1 shows a dynamic vapor sorption (DVS) isotherm plot for crystalline form A** of Compound I benzenesulfonate salt. [Figure 4A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form B* of Compound I maleate salt. [Figure 4B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form B* of Compound I maleate salt. [Figure 4C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline form B* of Compound I maleate salt. [Figure 4D] 1 shows a dynamic vapor sorption (DVS) isotherm plot of crystalline form B* of Compound I maleate salt. [Figure 5A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-1 of Compound I hydrochloride. [Figure 5B] 1 shows a differential scanning calorimetry (DSC) thermogram of Form A-1 of Compound I hydrochloride. [Figure 6A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form B-1 of Compound I hydrochloride. [Figure 6B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form B-1 of Compound I hydrochloride. [Figure 7A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-2 of Compound I sulfate. [Figure 7B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-2 of Compound I sulfate salt. [Figure 8A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form B-2 of Compound I sulfate. [Figure 8B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form B-2 of Compound I sulfate salt. [Figure 9A]1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-3 of Compound I mesylate. [Figure 9B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-3 of Compound I mesylate. [Figure 10A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form B-3 of Compound I mesylate. [Figure 10B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form B-3 of Compound I mesylate. [Figure 11A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form C-3 of Compound I mesylate. [Figure 11B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form C-3 of Compound I mesylate. [Figure 12A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-4 of Compound I tosylate salt. [Figure 12B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-4 of Compound I tosylate salt. [Figure 13A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-5 of Compound I fumarate salt. [Figure 13B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-5 of Compound I fumarate salt. [Figure 14A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-6 of Compound I maleate salt. [Figure 14B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-6 of Compound I maleate salt. [Figure 15A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-7 of Compound I L-tartrate salt. [Figure 15B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-7 of Compound I L-tartrate salt. [Figure 16A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form B-7 of Compound I L-tartrate salt. [Figure 16B]1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form B-7 of Compound I L-tartrate salt. [Figure 17A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-8 of Compound I citrate salt. [Figure 17B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-8 of Compound I citrate salt. [Figure 18A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form B-8 of Compound I citrate salt. [Figure 18B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form B-8 of Compound I citrate salt. [Figure 19A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form A-9 of Compound I succinate salt. [Figure 19B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form A-9 of Compound I succinate salt. [Figure 20] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form B of Compound I phosphate. [Figure 21A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form C of Compound I phosphate. [Figure 21B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form C of Compound I phosphate. [Figure 21C] 1 shows a thermogravimetric analysis (TGA) thermogram of Compound I phosphate crystalline form C. [Figure 22A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form J of Compound I phosphate. [Figure 22B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form J of Compound I phosphate. [Figure 22C] 1 shows a thermogravimetric analysis (TGA) thermogram of Compound I phosphate crystalline form J. [Figure 23A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form K of Compound I phosphate. [Figure 23B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form K of Compound I phosphate. [Figure 23C] 1 shows a thermogravimetric analysis (TGA) thermogram of Compound I phosphate crystalline form K. [Figure 24] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form H2 of Compound I phosphate. [Figure 25A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form E of Compound I phosphate. [Figure 25B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form E of Compound I phosphate. [Figure 25C] 1 shows a thermogravimetric analysis (TGA) thermogram of Compound I phosphate crystalline form E. [Figure 26A] 1 shows an X-ray powder diffraction (XRPD) spectrum of crystalline form F of Compound I phosphate. [Figure 26B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form F of Compound I phosphate. [Figure 26C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline form F of Compound I phosphate. [Figure 27A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form G of Compound I phosphate. [Figure 27B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form G of Compound I phosphate. [Figure 27C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline form G of Compound I phosphate. [Figure 28A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline Form I of Compound I phosphate. [Figure 28B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline Form I of Compound I phosphate. [Figure 28C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline Form I of Compound I phosphate. [Figure 29A] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form H1 of Compound I phosphate. [Figure 29B] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline form H1 of Compound I phosphate. [Figure 29C] 1 shows a thermogravimetric analysis (TGA) thermogram of crystalline form H1 of Compound I phosphate. [Diagram 30] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form H3 of Compound I phosphate. [Diagram 31] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form H4 of Compound I phosphate. [Diagram 32] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form H5 of Compound I phosphate. [Diagram 33] 1 shows the X-ray powder diffraction (XRPD) spectrum of crystalline form H6 of Compound I phosphate.

[0015] definition For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0016] Throughout this specification, the terms "about" and / or "approximately" may be used in conjunction with numerical values ​​and / or ranges. The term "about" is understood to mean a value close to the stated value. Additionally, the phrases "less than about [value]" or "greater than about [value]" should be understood in light of the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably.

[0017] Throughout this specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges include all subranges within that range. Thus, a range of "50 to 80" includes all possible ranges within that range (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Furthermore, all values ​​within a given range may be endpoints of the ranges encompassed within that range (e.g., a range of 50 to 80 includes ranges having endpoints such as 55 to 80, 50 to 75, etc.).

[0018] The term "a" or "an" refers to one or more of the entity. For example, "PI3-kinase (PI3K) modulator" refers to one or more PI3-kinase (PI3K) modulators, or at least one PI3-kinase (PI3K) modulator. In an embodiment, the PI3-kinase (PI3K) modulator is a PI3K alpha modulator. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein. In addition, reference to an "inhibitor" by the indefinite article "a" or "an" does not exclude the possibility that there is more than one inhibitor, unless the context clearly requires that there is one and only one of the inhibitors.

[0019] As used herein, the verb "comprise" and variations thereof as used in the description and claims are used in their open-ended sense, meaning that the items that follow the word are included, but not the exclusion of items not specifically mentioned. The disclosure may suitably "comprise", "consist of", or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0020] Moreover, it should be noted that the claims may be drafted to exclude any element, and thus, this statement is intended to serve as a predicate for the use of exclusive terminology such as "solely," "only," or "negative" limitations in connection with the recitation of claim elements.

[0021] Pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compound with an appropriate inorganic or organic acid by any of several known methods.

[0022] As used herein, "solvate" refers to a complex formed by solvation (a combination of a solvent molecule and a molecule or ion of an active agent of the present invention) or an aggregate consisting of a solute ion or molecule (active agent of the present invention) and one or more solvent molecules. In an embodiment, the solvate is a hydrate. Examples of hydrates include, but are not limited to, channel hydrates, hemihydrates, monohydrates, dihydrates, trihydrates, hexahydrates, sesquihydrates, and the like. Those skilled in the art should understand that the pharma- ceutically acceptable salts of the compounds of the present invention may also exist in solvate form (solvate salts). Solvates are usually formed by hydration, which is either part of the preparation of the compounds of the present invention or due to the natural absorption of water by the anhydrous compounds of the present invention. Solvates, including hydrates, may be composed of stoichiometric ratios, e.g., 2, 3, 4 salt molecules per solvate or per hydrate molecule. Another possibility is, for example, that two salt molecules are stoichiometrically associated with 3, 5, 7 solvent or hydrate molecules. Solvents used for crystallization may be embedded in the crystal lattice, examples being alcohols (especially methanol and ethanol), aldehydes, ketones (especially acetone), esters (e.g. ethyl acetate). Pharmaceutically acceptable solvents are preferred.

[0023] The term "treating" refers to one or more of alleviating, ameliorating, delaying, reducing, ameliorating, or managing at least one symptom of a condition in a subject. The term "treating" can also refer to one or more of preventing, delaying the onset (i.e., the period before clinical signs of a pathology), or reducing the risk of development or worsening of a condition.

[0024] "An effective amount" means the amount of a formulation according to the invention that, when administered to a patient for treating a state, disorder or condition, is sufficient to effect such treatment. An "effective amount" will vary depending on the active ingredient, the state, disorder or condition being treated and its severity, as well as the age, weight, health and responsiveness of the mammal being treated.

[0025] The term "therapeutically effective" as applied to a dose or amount refers to that amount of a compound or pharmaceutical formulation sufficient to result in a desired clinical benefit following administration to a patient in need thereof.

[0026] As used herein, a "subject" may be a human, a non-human primate, a mammal, a rat, a mouse, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, etc. In embodiments, the subject is a human. In embodiments, the subject may be suspected of having cancer or may be at risk of having cancer.

[0027] "Mammal" includes humans and both domesticated animals, such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals, such as wild animals.

[0028] All weight percentages referred to herein (ie, "weight %" and "wt %" and "w / w") are quoted relative to the total weight of the pharmaceutical composition, unless otherwise indicated.

[0029] As used herein, "substantially" or "substantially" refers to the complete or nearly complete extent or degree of an action, feature, characteristic, state, structure, item, or result. For example, in the case of an object that is "substantially" sealed, it means that the object is completely sealed or nearly completely sealed. The exact degree of acceptable deviation from absolute perfection may depend on the particular situation in some cases. Generally speaking, however, the closeness of completion is such that the overall result is the same as if absolute and total perfection had been obtained. The use of "substantially" applies equally when used in a negative sense to refer to the complete or nearly complete lack of an action, feature, characteristic, state, structure, item, or result. For example, a composition that is "substantially free" of other active agents is either completely devoid of the other active agent, or nearly completely devoid of the other active agent to such an extent that the effect is the same as if the other active agent were completely absent. In other words, a composition that is "substantially free" of a component or element or another active agent may still contain such an item, so long as there is no measurable effect of that item.

[0030] Polymorphism can be characterized as the ability of a compound to crystallize into different crystalline formations while maintaining the same chemical formula. A crystalline polymorph of a given drug substance is chemically identical to any other crystalline polymorph of that drug substance in that they contain the same atoms bonded to each other in the same manner, but the crystalline forms differ, which may affect one or more physical properties, examples of which include stability, solubility, melting point, bulk density, flow properties, bioavailability, etc.

[0031] The following description contains information that may be useful in understanding the present invention. No admission is made that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Throughout this disclosure, various patents, patent applications, and publications are referenced. The disclosures of these patents, patent applications, and publications in their entireties are incorporated by reference into this disclosure for all purposes in order to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, the present disclosure will control.

[0033] Compound I and Salts and Solid Forms Compound I is methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate having the following structure: Compound I is disclosed in WO2021 / 055747, which is hereby incorporated by reference in its entirety. In an embodiment, compound I is a phosphoinositide 3-kinase (PI3K) inhibitor. In an embodiment, compound I is an irreversible inhibitor of PI3K. In an embodiment, compound I is an irreversible inhibitor of PI3Kα. In an embodiment, compound I can form a covalent bond with an amino acid of PI3K, e.g., PI3Kα. In an embodiment, compound I can form a covalent bond with a cysteine ​​in PI3K, e.g., PI3Kα (e.g., via a Michael reaction).

[0034] [ka]

[0035] In embodiments, the disclosure relates to a salt or solvate of Compound I. In embodiments, the disclosure relates to a crystalline form of Compound I or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a solvate of a salt thereof.

[0036] In one embodiment, the disclosure relates to an anhydrous or non-solvated crystalline form of compound I or a pharma- ceutically acceptable salt thereof. In one embodiment, the disclosure relates to an anhydrous or non-solvated crystalline form of compound I (but not a salt). In one embodiment, the disclosure relates to a crystalline form of compound I (but not a salt). In one embodiment, the disclosure relates to a solvated crystalline form of compound I or a pharma- ceutically acceptable salt thereof. In one embodiment, the disclosure relates to a hydrated crystalline form of compound I or a pharma- ceutical acceptable salt thereof. In one embodiment, the disclosure relates to a hydrated crystalline form of compound I (but not a salt). In one embodiment, the disclosure relates to a hydrated crystalline form of a pharma- ceutical acceptable salt of compound I. In one embodiment, the disclosure relates to a solvated crystalline form of compound I (but not a salt). In one embodiment, the disclosure relates to a solvated crystalline form of a pharma- ceutical acceptable salt of compound I. In an embodiment, the pharma- ceutical acceptable salt of compound I is a pharma- ceutical acceptable acid. In an embodiment, the pharma- ceutical acceptable salt is obtained by reacting compound I with an acid. In embodiments, the acid is selected from the group consisting of phosphoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, L-tartaric acid, citric acid, and succinic acid. In embodiments, the acid is phosphoric acid. In embodiments, the acid is hydrochloric acid. In embodiments, the acid is sulfuric acid. In embodiments, the acid is methanesulfonic acid. In embodiments, the acid is benzenesulfonic acid. In embodiments, the acid is p-toluenesulfonic acid. In embodiments, the acid is fumaric acid. In embodiments, the acid is maleic acid. In embodiments, the acid is tartaric acid. In embodiments, the acid is L-tartaric acid. In embodiments, the acid is citric acid. In embodiments, the acid is succinic acid. In embodiments, the solvate of Compound I is a pharma- ceutically acceptable acid. In embodiments, the solvated crystalline form of Compound I, or a solvated crystalline form of a pharma- ceutically acceptable salt of Compound I, is a solvate selected from the group consisting of water, acetone, benzyl alcohol, DMF, DMSO, THF, TFE, or a combination thereof.

[0037] In embodiments, the disclosure provides a compound of formula (IA):

[0038] [ka] wherein X is a pharma- ceutically acceptable acid; a is about 0.5 to about 2.

[0039] In embodiments, the disclosure provides a compound of formula (IB):

[0040] [ka] During the ceremony, Y is a solvent; X is a pharma- ceutically acceptable acid; a is an integer from about 0.5 to about 2, and b is an integer of about 0.5 to about 5.

[0041] In embodiments, the disclosure provides a compound of formula (IC):

[0042] [ka] where Y is a solvent; b is about 0.5 to about 5.

[0043] In an embodiment of the compound of formula (IA) or formula (IB), a is from about 1 to about 2.

[0044] In an embodiment of the compound of Formula (IA) or Formula (IB), a is about 0.5. In an embodiment, a is about 1. In an embodiment, a is about 1.5. In an embodiment, a is about 2.

[0045] In an embodiment of a compound of formula (IA) or formula (IB), X is phosphoric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, L-tartaric acid, citric acid, or succinic acid. In an embodiment, X is phosphoric acid. In an embodiment, X is hydrochloric acid. In an embodiment, X is sulfuric acid. In an embodiment, X is methanesulfonic acid. In an embodiment, X is benzenesulfonic acid. In an embodiment, X is p-toluenesulfonic acid. In an embodiment, X is fumaric acid. In an embodiment, X is maleic acid. In an embodiment, X is L-tartaric acid. In an embodiment, X is citric acid. In an embodiment, X is succinic acid.

[0046] In an embodiment of the compound of formula (IB) or formula (IC), the solvent is water, acetone, benzyl alcohol, DMF, DMSO, THF, TFE, or a combination thereof. In an embodiment of the compound of formula (IB) or formula (IC), the solvent is water. In an embodiment of the compound of formula (IB) or formula (IC), the solvent is acetone. In an embodiment of the compound of formula (IB) or formula (IC), the solvent is benzyl alcohol. In an embodiment of the compound of formula (IB) or formula (IC), the solvent is DMF. In an embodiment of the compound of formula (IB) or formula (IC), the solvent is DMSO. In an embodiment of the compound of formula (IB) or formula (IC), the solvent is THF. In an embodiment of the compound of formula (IB) or formula (IC), the solvent is TFE.

[0047] In embodiments of the compound of Formula (IB) or Formula (IC), b is about 0.5 to about 5. In embodiments, b is about 1.5 to about 2. In embodiments, b is about 5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, or about 4.5.

[0048] In one embodiment, the crystalline form is characterized by the interlattice plane intervals determined by X-ray powder diffraction (XRPD) patterns. The spectrum of the XRPD is usually represented as a plot of the intensity of the peaks versus the position of the peaks, i.e., the diffraction angle 2θ (2 theta), in degrees. The intensity is often indicated in parentheses with the following abbreviations: very strong=vst, strong=st, medium=m, weak=w, and very weak=vw. The characteristic peaks of a given XRPD can be selected according to the peak positions and their relative intensities to conveniently distinguish this crystalline structure from other crystalline structures. The intensity of the peaks as a percentage relative to the most intense peak can be expressed as I / Io.

[0049] Those skilled in the art recognize that measurements of XRPD peak positions and / or intensities for a given crystalline form of the same compound will vary within an error range. The value of the angle 2θ will provide an appropriate error range. Typically, the error range is expressed as "±". For example, a 2θ degree of about "17.48±0.2" indicates a 2θ range of about 17.46 to 17.50 degrees. Depending on the sample preparation technique, the calibration technique applied to the instrument, human operational variability, etc., those skilled in the art recognize that an appropriate error range for XRPD can be about ±0.7, ±0.6, ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, ±0.05, or less.

[0050] Additional details of the methods and equipment used for the XRPD analysis are provided in the Examples section.

[0051] In one embodiment, the crystalline form is characterized by differential scanning calorimetry (DSC). A DSC thermogram is typically represented by a plot of heat flow normalized in units of watts / gram ("W / g") versus the measured sample temperature (in degrees Celsius). DSC thermograms are typically evaluated for extrapolated onset and end temperatures (starting temperatures), peak temperatures, and heat of fusion. The peak characteristic values ​​of the DSC thermogram are often used as characteristic peaks to distinguish this crystalline structure from others.

[0052] Those skilled in the art recognize that measurements of DSC thermograms for a given crystalline form of the same compound will vary within an error range. The value of a single peak characteristic value expressed in degrees Celsius provides an appropriate error range. Typically, the error range is expressed as "±".

[0053] For example, a single peak characteristic value of about "17.48±0.2" indicates a range of about 17.46 to 17.50. Depending on the sample preparation technique, the calibration technique applied to the instrument, human operational variability, etc., one skilled in the art will recognize that a suitable error range for the single peak characteristic value may be ±2.5, ±2.0, ±1.5, ±1.0, ±0.5, or less.

[0054] Additional details of the methods and equipment used for DSC thermogram analysis are provided in the Examples section.

[0055] In one embodiment, the crystalline form is characterized by dynamic vapor sorption (DVS). A DVS profile is typically represented as a plot of the relative humidity (RH) of a sample versus the percent change in mass. The DVS profile provides information about the hygroscopicity of the crystalline form at various RH conditions.

[0056] Additional details of the method and apparatus used for DVS are provided in the "Examples" section.

[0057] In embodiments, the crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is at least about 99.9%, at least about 99.8%, at least about 99.7%, at least about 99.6%, at least about 99.5%, at least about 99%, at least about 98%, at least about 97%, at least about 96%, at least about 95%, at least about 94%, at least about 93%, at least about 92%, at least about 91%, at least about 90%, at least about 85%, at least about 80%, at least about 97%, at least about 98%, at least about 9 ... The polymorphic purity may be at least about 75%, at least about 70%, at least about 65%, at least about 60%, at least about 55%, or at least about 50% of a single crystalline form (e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, or Form H6). Polymorphic purity may be determined using methods known to those of skill in the art, including, for example, X-ray powder crystallography.

[0058] In embodiments, a crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein, e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form D, Form E, Form F, Form I ... Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, or Form H6) has a purity of about 99.9% or more, about 99.8% or more, about 99.7% or more, about 99.6% or more, about 99.5% or more, about 99% or more, about 98% or more, about 97% or more, about 96% or more, about 95% or more, about 94% or more, about 93% or more, about 92% or more, about 91% or more, about 90% or more, about 85% or more, or about 80% or more. In embodiments, the crystalline form has a purity in the range of about 80% to about 99%. In embodiments, the crystalline form has a purity in the range of about 80% to about 99.5%. In embodiments, the crystalline form has a purity in the range of about 80% to about 99.9%. In embodiments, the crystalline form has a purity ranging from about 80% to about 100%. In embodiments, the purity is determined by HPLC.

[0059] In embodiments, a crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (as disclosed herein, e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5 or Form H6) is greater than or equal to about 99.9% pure by weight, greater than or equal to about 99.8% pure by weight, greater than or equal to about 99.7% pure by weight, greater than or equal to about 99.6% pure by weight, greater than or equal to about 99.5% pure by weight, greater than or equal to about 99% pure by weight, greater than or equal to about 98% pure by weight, greater than or equal to about 97% pure by weight, greater than or equal to about 96% pure by weight, greater than or equal to about 95% pure by weight, greater than or equal to about 94% pure by weight, greater than or equal to about 93% pure by weight, greater than or equal to about 92% pure by weight, greater than or equal to about 91% pure by weight, greater than or equal to about 90% pure by weight, greater than or equal to about 85% pure by weight, or greater than or equal to about 80% pure by weight. In embodiments, the crystalline form has a purity ranging from about 80% purity to about 99% purity by weight of a single crystalline form (e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, or Form H6 as disclosed herein). In embodiments, the purity is determined by HPLC.

[0060] In embodiments, the crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, is at least about 95% pure by weight and contains no more than about 5% impurities by weight. In some embodiments, the crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, is about 95.0% to 100% pure by weight and contains 0% to about 5% impurities by weight of the crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, solvate thereof, or salt solvate thereof. In some embodiments, the crystalline form of Compound I, or a pharma- ceutical acceptable salt thereof, solvate thereof, or salt solvate thereof, is about 98% to 100% pure by weight and contains 0% to about 2% impurities by weight of the crystalline form of Compound I, or a pharma- ceutical acceptable salt thereof, solvate thereof, or salt solvate thereof. In some embodiments, the crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, is about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, and contains about 2%, about 1.5%, about 1%, about 0.5%, or 0% impurities by weight of the crystalline form of Compound I, or a pharma-ceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, respectively. In some embodiments, the crystalline form of Compound I, or a pharma-ceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, is about 99.5%, about 99.9%, or about 99.95% pure by weight, and contains about 0.5%, about 0.1%, or about 0.05% impurities by weight of the crystalline form of Compound I, or a pharma-ceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, respectively.

[0061] In some embodiments, purity or impurity is determined by high performance liquid chromatography (HPLC).

[0062] Compound I Form A In embodiments, the present disclosure relates to a crystalline form of Compound I, namely Form A.

[0063] In embodiments, the present disclosure relates to Form A, a crystalline form of Compound I that is anhydrous or non-solvated.

[0064] In an embodiment, the crystalline form A of compound I or a composition thereof comprises a mixture of one or more forms of polymorphs of compound I. In an embodiment, the crystalline form of compound I comprises a substantially pure form of one polymorphic type. In an embodiment, the crystalline form of compound I may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form A of compound I. In another embodiment, the crystalline form of compound I may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form A of compound I. In some embodiments, the crystalline form of Compound I may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of Form A of Compound I.

[0065] In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern including peaks at about 9.11, 22.21, and 24.99 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern including peaks at about 9.11, 16.93, 18.70, 22.21, and 24.99 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern comprising peaks at about 9.11, 16.93, 18.70, 20.54, 20.78, 22.21, and 24.99 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern further comprising at least two peaks selected from about 4.47, 12.45, 14.51, 22.70, and 26.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern further comprising at least three peaks selected from about 4.47, 12.45, 14.51, 22.70 and 26.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern further comprising at least four peaks selected from about 4.47, 12.45, 14.51, 22.70 and 26.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern further comprising peaks at about 4.47, 12.45, 14.51, 22.70, and 26.54 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern including peaks at about 9.11, 14.51, 16.93, 18.70, 20.54, 20.78, 22.21, 22.70, 24.99 and 26.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0066] In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern comprising peaks at about 9.11±0.2, 22.21±0.2, and 24.99±0.2 degrees two-theta.

[0067] In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern comprising peaks at about 9.11±0.2, 16.93±0.2, 18.70±0.2, 22.21±0.2, and 24.99±0.2 degrees two-theta.

[0068] In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern comprising peaks at about 9.11±0.2, 16.93±0.2, 18.70±0.2, 20.54±0.2, 20.78±0.2, 22.21±0.2, and 24.99±0.2 degrees two-theta.

[0069] In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern further comprising at least two peaks selected from about 4.47±0.2, 12.45±0.2, 14.51±0.2, 22.70±0.2, and 26.54±0.2 degrees two-theta.

[0070] In embodiments, crystalline Form A of Compound I exhibits an XRPD pattern comprising peaks at about 9.11±0.2, 14.51±0.2, 16.93±0.2, 18.70±0.2, 20.54±0.2, 20.78±0.2, 22.21±0.2, 22.70±0.2, 24.99±0.2 and 26.54±0.2 degrees two-theta.

[0071] In some embodiments, the crystalline form of Compound I exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 1.

[0072] In one embodiment, crystalline Form A of Compound I exhibits an XRPD comprising the peaks shown in Table 1 below.

[0073] In embodiments, Compound I crystalline Form A exhibits an XRPD pattern substantially similar to FIG. 1A.

[0074] [Table 1]

[0075] In an embodiment, crystalline form A of compound I exhibits a DSC thermogram with an endothermic peak at about 199° C. (onset) with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A of compound I exhibits a DSC thermogram with an endothermic peak at about 202° C. (peak) with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A of compound I exhibits a DSC thermogram with an endothermic peak at 11.8° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0076] In one embodiment, Compound I crystalline Form A exhibits a DSC thermogram substantially similar to FIG. 1B.

[0077] In embodiments, Compound I crystalline Form A exhibits a TGA thermogram substantially similar to Figure 1C. In embodiments, Compound I crystalline Form A exhibits a weight percent loss of about 0.6% between about 25°C and about 160°C by thermogravimetric analysis (TGA).

[0078] Compound I Phosphate Formation A* In one embodiment, the disclosure relates to Compound I phosphate or a solvate thereof. In an embodiment, the disclosure relates to a crystalline form of Compound I phosphate, namely Form A*.

[0079] In embodiments, the present disclosure relates to Form A*, a crystalline form of Compound I phosphate, which is a hydrate.

[0080] In embodiments, the crystalline form of compound I phosphate is a hydrate, and the ratio of compound I phosphate molecules to water molecules in the crystalline form is about 5:1, about 4:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4 or about 1:5.

[0081] In embodiments, the crystalline form of the phosphate salt of Compound I is a channel hydrate.

[0082] In an embodiment, the crystalline form of compound I phosphate comprises a mixture of one or more polymorphic forms of compound I phosphate. In an embodiment, the crystalline form of compound I phosphate comprises a substantially pure form of one polymorphic type. In an embodiment, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form A* of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form A* of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form A* of compound I phosphate.

[0083] In embodiments, crystalline form A* of compound I phosphate exhibits an XRPD pattern including peaks at about 5.33, 15.97, and 22.97 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A* of compound I phosphate exhibits an XRPD pattern including peaks at about 5.33, 10.63, 15.97, 20.95, and 22.97 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A* of compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.33, 10.63, 15.97, 20.26, 20.95, 22.71, and 22.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A* of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 7.24, 14.94, 18.64, 18.99, and 21.34 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A* of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 7.24, 14.94, 18.64, 18.99, and 21.34 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A* of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 7.24, 14.94, 18.64, 18.99, and 21.34 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A* of Compound I phosphate exhibits an XRPD pattern further comprising peaks at about 7.24, 14.94, 18.64, 18.99, and 21.34 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A* of Compound I phosphate exhibits an XRPD pattern including peaks at about 5.33, 7.24, 10.63, 14.94, 15.97, 18.64, 20.26, 20.95, 22.71 and 22.97 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0084] In embodiments, crystalline Form A* of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 5.33±0.2, 15.97±0.2, and 22.97±0.2 degrees two-theta.

[0085] In embodiments, crystalline Form A* of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 5.33±0.2, 10.63±0.2, 15.97±0.2, 20.95±0.2, and 22.97±0.2 degrees two-theta.

[0086] In embodiments, crystalline Form A* of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 5.33±0.2, 10.63±0.2, 15.97±0.2, 20.26±0.2, 20.95±0.2, 22.71±0.2, and 22.97±0.2 degrees two-theta.

[0087] In embodiments, crystalline Form A* of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least two peaks selected from about 7.24±0.2, 14.94±0.2, 18.64±0.2, 18.99±0.2, and 21.34±0.2 degrees two-theta.

[0088] In embodiments, crystalline Form A* of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 5.33±0.2, 7.23±0.2, 10.63±0.2, 14.94±0.2, 15.97±0.2, 18.64±0.2, 20.26±0.2, 20.95±0.2, 22.71±0.2, and 22.97±0.2 degrees two-theta.

[0089] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 2.

[0090] In one embodiment, crystalline form A* of Compound I phosphate exhibits an XRPD comprising the peaks shown in Table 2 below.

[0091] In embodiments, crystalline Form A* of Compound I phosphate exhibits an XRPD pattern substantially similar to FIG. 2A.

[0092] [Table 2]

[0093] In an embodiment, crystalline form A* of compound I phosphate exhibits a DSC thermogram with an endothermic peak at about 8.5° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A* of compound I phosphate exhibits a DSC thermogram with an endothermic peak at about 8.5° C., which is likely due to dehydration. In an embodiment, crystalline form A* of compound I phosphate exhibits a DSC thermogram with an endothermic peak with an onset at about 189° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A* of compound I phosphate exhibits a DSC thermogram with an endothermic peak with an onset at about 189° C., which is likely due to decomposition. In embodiments, crystalline form A* of Compound I phosphate exhibits a DSC thermogram comprising an endothermic peak at about 199° C. (peak) with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0094] In some embodiments, crystalline Form A* of Compound I phosphate exhibits a DSC thermogram substantially similar to FIG. 2B.

[0095] In some embodiments, crystalline Form A* of Compound I phosphate exhibits a TGA thermogram substantially similar to Figure 2C. In embodiments, crystalline Form A* of Compound I phosphate exhibits a weight percent loss of about 3.75% between about 34°C and about 170°C by thermogravimetric analysis (TGA).

[0096] Compound I benzenesulfonate salt form A**

[0097] In one embodiment, the present disclosure relates to a benzenesulfonate salt or a solvate thereof of Compound I. In an embodiment, the present disclosure relates to a crystalline form of Compound I benzenesulfonate salt, namely Form A**.

[0098] In embodiments, the present disclosure relates to Form A**, a crystalline form of Compound I benzenesulfonate salt, that is anhydrous.

[0099] In an embodiment, the crystal of compound I benzenesulfonate comprises a mixture of one or more polymorphic forms of compound I benzenesulfonate. In an embodiment, the crystalline form of compound I benzenesulfonate comprises a substantially pure form of one polymorphic type. In an embodiment, the crystalline form of compound I benzenesulfonate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form A** of compound I benzenesulfonate. In another embodiment, the crystalline form of compound I benzenesulfonate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form A** of compound I benzenesulfonate. In some embodiments, the crystalline form of compound I benzenesulfonate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of Form A** of compound I benzenesulfonate.

[0100] In embodiments, crystalline Form A** of Compound I benzenesulfonate exhibits an XRPD pattern including peaks at about 7.36, 18.92, and 19.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A** of Compound I benzenesulfonate exhibits an XRPD pattern including peaks at about 7.36, 14.71, 18.52, 18.92, and 19.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A** of Compound I benzenesulfonate exhibits an XRPD pattern including peaks at about 7.36, 10.08, 14.71, 18.52, 18.92, 19.54, and 21.31 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form A** of Compound I benzenesulfonate exhibits an XRPD pattern further including at least two peaks selected from about 15.50±0.2, 18.23±0.2, 22.72±0.2, 23.22±0.2, and 24.63±0.2 degrees two-theta. In an embodiment, crystalline Form A** of Compound I benzenesulfonate exhibits an XRPD pattern further comprising at least three peaks selected from about 15.50±0.2, 18.23±0.2, 22.72±0.2, 23.22±0.2, and 24.63±0.2 degrees two-theta. In an embodiment, crystalline Form A** of Compound I benzenesulfonate exhibits an XRPD pattern further comprising at least four peaks selected from about 15.50±0.2, 18.23±0.2, 22.72±0.2, 23.22±0.2, and 24.63±0.2 degrees two-theta. In embodiments, crystalline Form A** of Compound I benzenesulfonate salt exhibits an XRPD pattern further comprising peaks at about 15.50±0.2, 18.23±0.2, 22.72±0.2, 23.22±0.2, and 24.63±0.2 degrees two-theta.In embodiments, crystalline Form A** of Compound I benzenesulfonate salt exhibits an XRPD pattern including peaks at about 7.36, 10.08, 14.71, 18.52, 18.92, 19.54, 21.31, 23.22, and 24.63 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0101] In embodiments, crystalline Form A** of Compound I benzenesulfonate salt exhibits an XRPD pattern comprising peaks at about 7.36±0.2, 18.92±0.2, and 19.54±0.2 degrees two-theta.

[0102] In embodiments, crystalline Form A** of Compound I benzenesulfonate salt exhibits an XRPD pattern comprising peaks at about 7.36±0.2, 14.71±0.2, 18.52±0.2, 18.92±0.2, and 19.54±0.2 degrees two-theta.

[0103] In embodiments, crystalline Form A** of Compound I benzenesulfonate salt exhibits an XRPD pattern comprising peaks at about 7.36±0.2, 10.08±0.2, 14.71±0.2, 18.52±0.2, 18.92±0.2, 19.54±0.2, and 21.31±0.2 degrees two-theta.

[0104] In embodiments, crystalline Form A** of Compound I benzenesulfonate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 15.50±0.2, 18.23±0.2, 22.72±0.2, 23.22±0.2, and 24.63±0.2 degrees two-theta.

[0105] In embodiments, crystalline Form A** of Compound I benzenesulfonate salt exhibits an XRPD pattern including peaks at about 7.36±0.2, 10.08±0.2, 14.71±0.2, 18.52±0.2, 18.92±0.2, 19.54±0.2, 21.31±0.2, 23.22, and 24.63 degrees two-theta.

[0106] In some embodiments, the crystalline form of Compound I benzenesulfonate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 3.

[0107] In an embodiment, crystalline form A** of compound I benzenesulfonate salt exhibits an XRPD comprising the peaks shown in Table 3 below.

[0108] In embodiments, crystalline form A** of compound I benzenesulfonate salt exhibits an XRPD pattern substantially similar to FIG. 3A.

[0109] [Table 3]

[0110] In embodiments, crystalline form A** of compound I benzenesulfonate salt exhibits a DSC thermogram showing decomposition at about 250° C. (upon dissolution) with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0111] In embodiments, crystalline Form A** of Compound I benzenesulfonate exhibits a TGA thermogram substantially similar to Figure 3 C. In embodiments, crystalline Form A** of Compound I benzenesulfonate exhibits a weight percent loss of about 1.1% between about 34°C and about 190°C by thermogravimetric analysis (TGA).

[0112] Compound I Maleate In one embodiment, the present disclosure relates to compound I maleate or a solvate thereof.In an embodiment, the crystalline form of compound I maleate comprises a mixture of one or more polymorphic forms of compound I maleate.In an embodiment, the crystalline form of compound I maleate comprises a substantially pure form of one polymorphic type.

[0113] Compound I Maleate Form B* In embodiments, the present disclosure relates to a crystalline form of Compound I maleate, namely Form B*.

[0114] In embodiments, the present disclosure relates to Form B*, a crystalline form of Compound I maleate, which is a hydrate.

[0115] In one embodiment, the crystalline form of compound I maleate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form B* of compound I maleate. In another embodiment, the crystalline form of compound I maleate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form B* of compound I maleate. In some embodiments, the crystalline form of compound I maleate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form B* of compound I maleate.

[0116] In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern including peaks at about 4.78, 7.07, and 19.83 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern including peaks at about 4.78, 7.07, 12.27, 19.83, and 20.84 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0117] In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern comprising peaks at about 4.78, 7.07, 12.27, 19.83, 20.84, 20.98, and 24.35 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 18.25, 18.45, 22.88, 23.82, and 23.84 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 18.25, 18.45, 22.88, 23.82 and 23.84 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 18.25, 18.45, 22.88, 23.82 and 23.84 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern further comprising peaks at about 18.25, 18.45, 22.88, 23.82, and 23.84 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B* of compound I maleate salt exhibits an XRPD pattern further comprising peaks at about 4.78, 7.07, 12.27, 18.25, 19.83, 20.84, 20.98, 22.88, and 24.35 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0118] In an embodiment, crystalline form B* of Compound I maleate exhibits an XRPD pattern including peaks.

[0119] In an embodiment, crystalline form B* of Compound I maleate salt exhibits an XRPD pattern comprising peaks at about 4.78±0.2, 7.07±0.2, and 19.83±0.2 degrees two-theta.

[0120] In an embodiment, crystalline form B* of Compound I maleate salt exhibits an XRPD pattern comprising peaks at about 4.78±0.2, 7.07±0.2, 12.27±0.2, 19.83±0.2, and 20.84±0.2 degrees two-theta.

[0121] In an embodiment, crystalline form B* of Compound I maleate salt exhibits an XRPD pattern comprising peaks at about 4.78±0.2, 7.07±0.2, 12.27±0.2, 19.83±0.2, 20.84±0.2, 20.98±0.2 and 24.35±0.2 degrees two-theta.

[0122] In an embodiment, crystalline form B* of Compound I maleate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 18.25±0.2, 18.45±0.2, 22.88±0.2, 23.82±0.2, and 23.84±0.2 degrees two-theta.

[0123] In an embodiment, crystalline form B* of Compound I maleate salt exhibits an XRPD pattern comprising peaks at about 4.78±0.2, 7.07±0.2, 12.27±0.2, 18.25±0.2, 19.83±0.2, 20.84±0.2, 20.98±0.2, 22.88±0.2 and 24.35±0.2 degrees two-theta.

[0124] In some embodiments, the crystalline form of Compound I maleate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 4.

[0125] In an embodiment, crystalline form B* of compound I maleate salt exhibits an XRPD pattern comprising the peaks shown in Table 4 below.

[0126] In an embodiment, crystalline form B* of Compound I maleate salt exhibits an XRPD pattern substantially similar to FIG. 4A.

[0127] [Table 4]

[0128] In an embodiment, crystalline form B* of compound I maleate exhibits a DSC thermogram with an endothermic peak at about 10° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form B* of compound I maleate exhibits a DSC thermogram with an endothermic peak at about 10° C., which is likely due to dehydration. In an embodiment, crystalline form B* of compound I maleate exhibits a DSC thermogram with an endothermic peak with an onset at about 166° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form B* of compound I maleate exhibits a DSC thermogram with an endothermic peak with an onset at about 166° C., which is likely due to decomposition. In embodiments, crystalline form B* of compound I maleate salt exhibits a DSC thermogram comprising an endothermic peak at about 185° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0129] In some embodiments, crystalline form B* of compound I maleate salt exhibits a DSC thermogram substantially similar to FIG. 4B.

[0130] In some embodiments, crystalline form B* of compound I maleate exhibits a TGA thermogram substantially similar to Figure 4C. In embodiments, crystalline form B* of compound I maleate exhibits a weight percent loss of about 1.8% between about 34°C and about 130°C by thermogravimetric analysis (TGA).

[0131] Compound I Maleate Form A-6

[0132] In embodiments, the present disclosure relates to a crystalline form of Compound I maleate, namely Form A-6.

[0133] In one embodiment, the crystalline form of compound I maleate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form A-6 of compound I maleate. In another embodiment, the crystalline form of compound I maleate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form A-6 of compound I maleate. In some embodiments, the crystalline form of compound I maleate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form A-6 of compound I maleate.

[0134] In embodiments, crystalline form A-6 of compound I maleate exhibits an XRPD pattern including peaks at about 3.99, 23.84, and 25.40 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-6 of compound I maleate exhibits an XRPD pattern including peaks at about 3.99, 23.70, 23.74, 23.84, and 25.40 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 11.84, 17.48, 18.85, 19.59, 19.97, 22.75, 24.86, and 25.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 11.84, 17.48, 18.85, 19.59, 19.97, 22.75, 24.86, and 25.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 11.84, 17.48, 18.85, 19.59, 19.97, 22.75, 24.86, and 25.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern further comprising at least five peaks selected from about 11.84, 17.48, 18.85, 19.59, 19.97, 22.75, 24.86, and 25.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 11.84, 17.48, 18.85, 19.59, 19.97, 22.75, 24.86, and 25.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 11.84, 17.48, 18.85, 19.59, 19.97, 22.75, 24.86, and 25.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern further comprising peaks at about 11.84, 17.48, 18.85, 19.59, 19.97, 22.75, 24.86, and 25.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0135] In an embodiment, crystalline form A-6 of Compound I maleate salt exhibits an XRPD pattern comprising peaks at about 3.99±0.2, 23.84±0.2, and 25.40±0.2 degrees two-theta.

[0136] In an embodiment, crystalline form A-6 of Compound I maleate salt exhibits an XRPD pattern comprising peaks at about 3.99±0.2, 23.70±0.2, 23.74±0.2, 23.84±0.2, and 25.40±0.2 degrees two-theta.

[0137] In an embodiment, crystalline form A-6 of compound I maleate salt exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least two peaks selected from about 11.84±0.2, 17.48±0.2, 18.85±0.2, 19.59±0.2, 19.97±0.2, 22.75±0.2, 24.86±0.2, and 25.97±0.2 degrees two-theta.

[0138] In some embodiments, the crystalline form of Compound I maleate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 14.

[0139] In an embodiment, crystalline form A-6 of compound I maleate salt exhibits an XRPD pattern comprising the peaks shown in Table 14 below.

[0140] In an embodiment, crystalline form A-6 of Compound I maleate salt exhibits an XRPD pattern substantially similar to FIG. 14A.

[0141] [Table 5]

[0142] In an embodiment, crystalline form A-6 of compound I maleate exhibits a DSC thermogram with an endothermic peak at about 40° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A-6 of compound I maleate exhibits a DSC thermogram with an endothermic peak with an onset at about 171° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A-6 of compound I maleate exhibits a DSC thermogram with an endothermic peak at about 179° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0143] In some embodiments, crystalline form A-6 of compound I maleate salt exhibits a DSC thermogram substantially similar to FIG. 14B.

[0144] Compound I Hydrochloride In one embodiment, the present disclosure relates to compound I hydrochloride or a solvate thereof. In an embodiment, the crystalline form of compound I hydrochloride comprises a mixture of one or more polymorphic forms of compound I hydrochloride. In an embodiment, the crystalline form of compound I hydrochloride comprises a substantially pure form of one polymorphic type.

[0145] Compound I Hydrochloride Form A-1 In embodiments, the present disclosure relates to a crystalline form of Compound I hydrochloride, namely Form A-1.

[0146] In one embodiment, the crystalline form of compound I hydrochloride may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form A-1 of compound I hydrochloride. In another embodiment, the crystalline form of compound I hydrochloride may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form A-1 of compound I hydrochloride. In some embodiments, the crystalline form of compound I hydrochloride may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form A-1 of compound I hydrochloride.

[0147] In embodiments, crystalline form A-1 of compound I hydrochloride salt exhibits an XRPD pattern including peaks at about 4.83, 7.14, and 9.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-1 of compound I hydrochloride salt exhibits an XRPD pattern including peaks at about 4.83, 5.38, 7.14, 9.20, and 22.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least two peaks selected from about 15.03±0.2, 20.32±0.2, 21.12±0.2, 22.45±0.2, 23.57±0.2, 24.66±0.2, and 27.45±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least three peaks selected from about 15.03±0.2, 20.32±0.2, 21.12±0.2, 22.45±0.2, 23.57±0.2, 24.66±0.2, and 27.45±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least four peaks selected from about 15.03±0.2, 20.32±0.2, 21.12±0.2, 22.45±0.2, 23.57±0.2, 24.66±0.2, and 27.45±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least five peaks selected from about 15.03±0.2, 20.32±0.2, 21.12±0.2, 22.45±0.2, 23.57±0.2, 24.66±0.2, and 27.45±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least six peaks selected from about 15.03±0.2, 20.32±0.2, 21.12±0.2, 22.45±0.2, 23.57±0.2, 24.66±0.2, and 27.45±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising peaks at about 15.03±0.2, 20.32±0.2, 21.12±0.2, 22.45±0.2, 23.57±0.2, 24.66±0.2, and 27.45±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0148] In an embodiment, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern comprising peaks at about 4.83±0.2, 7.14±0.2, and 9.20±0.2 degrees two-theta.

[0149] In an embodiment, crystalline Form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern comprising peaks at about 4.83±0.2, 5.38±0.2, 7.14±0.2, 9.20±0.2, and 22.78±0.2 degrees two-theta.

[0150] In an embodiment, crystalline Form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least two peaks selected from about 15.03±0.2, 20.32±0.2, 21.12±0.2, 22.45±0.2, 23.57±0.2, 24.66±0.2 and 27.45±0.2 degrees two-theta.

[0151] In some embodiments, a crystalline form of Compound I hydrochloride salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 5.

[0152] In an embodiment, crystalline form A-1 of Compound I hydrochloride salt exhibits an XRPD pattern comprising the peaks shown in Table 5 below.

[0153] In an embodiment, crystalline form A-1 of the hydrochloride salt of Compound I exhibits an XRPD pattern substantially similar to FIG. 5A.

[0154] [Table 6]

[0155] In an embodiment, crystalline form A-1 of compound I hydrochloride exhibits a DSC thermogram including an endothermic peak at about 4.2° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A-1 of compound I hydrochloride exhibits a DSC thermogram including an endothermic peak with an onset at about 171° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A-1 of compound I hydrochloride exhibits a DSC thermogram including an endothermic peak at about 182° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0156] In some embodiments, crystalline form A-1 of compound I hydrochloride salt exhibits a DSC thermogram substantially similar to Figure 5B.

[0157] Compound I Hydrochloride Form B-1 In embodiments, the present disclosure relates to a crystalline form of Compound I hydrochloride, namely Form B-1.

[0158] In one embodiment, the crystalline form of compound I hydrochloride may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form B-1 of compound I hydrochloride. In another embodiment, the crystalline form of compound I hydrochloride may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form B-1 of compound I hydrochloride. In some embodiments, the crystalline form of compound I hydrochloride may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form B-1 of compound I hydrochloride.

[0159] In embodiments, crystalline form B-1 of compound I hydrochloride salt exhibits an XRPD pattern including peaks at about 7.40, 23.26, and 24.21 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-1 of compound I hydrochloride salt exhibits an XRPD pattern including peaks at about 4.48, 7.40, 7.79, 23.26, and 24.21 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-1 of compound I hydrochloride salt exhibits an XRPD pattern further comprising at least two peaks selected from about 9.73, 10.12, 12.93, 13.96, 16.08, 18.93, 20.79 and 22.33 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least three peaks selected from about 9.73, 10.12, 12.93, 13.96, 16.08, 18.93, 20.79 and 22.33 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least four peaks selected from about 9.73, 10.12, 12.93, 13.96, 16.08, 18.93, 20.79 and 22.33 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least five peaks selected from about 9.73, 10.12, 12.93, 13.96, 16.08, 18.93, 20.79, and 22.33 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least six peaks selected from about 9.73, 10.12, 12.93, 13.96, 16.08, 18.93, 20.79 and 22.33 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 9.73, 10.12, 12.93, 13.96, 16.08, 18.93, 20.79 and 22.33 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-1 of compound I hydrochloride salt exhibits an XRPD pattern further comprising peaks selected from about 9.73, 10.12, 12.93, 13.96, 16.08, 18.93, 20.79 and 22.33 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0160] In an embodiment, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern comprising peaks at about 7.40±0.2, 23.26±0.2, and 24.21±0.2 degrees two-theta.

[0161] In an embodiment, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern comprising peaks at about 4.48±0.2, 7.40±0.2, 7.79±0.2, 23.26±0.2, and 24.21±0.2 degrees two-theta.

[0162] In an embodiment, crystalline Form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern further comprising at least two peaks selected from about 9.73±0.2, 10.12±0.2, 12.93±0.2, 13.96±0.2, 16.08±0.2, 18.93±0.2, 20.79±0.2 and 22.33±0.2 degrees two-theta.

[0163] In some embodiments, a crystalline form of Compound I hydrochloride salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 6.

[0164] In an embodiment, crystalline form B-1 of Compound I hydrochloride salt exhibits an XRPD pattern comprising the peaks shown in Table 6 below.

[0165] In embodiments, crystalline Form B-1 of Compound I hydrochloride salt has an XRPD pattern substantially similar to FIG. 6A.

[0166] [Table 7]

[0167] In embodiments, crystalline form B-1 of compound I hydrochloride exhibits a DSC thermogram with an endothermic peak at about 73° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-1 of compound I hydrochloride exhibits a DSC thermogram with an endothermic peak having an onset at about 170° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-1 of compound I hydrochloride exhibits a DSC thermogram with an endothermic peak at about 163° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-1 of compound I hydrochloride exhibits a DSC thermogram including an endothermic peak with an onset at about 182° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-1 of compound I hydrochloride exhibits a DSC thermogram including an endothermic peak at about 192° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0168] In some embodiments, crystalline form B-1 of compound I hydrochloride salt exhibits a DSC thermogram substantially similar to Figure 6B.

[0169] Compound I Sulfate In one embodiment, the present disclosure relates to compound I sulfate or a solvate thereof. In an embodiment, the crystalline form of compound I sulfate comprises a mixture of one or more polymorphic forms of compound I sulfate. In an embodiment, the crystalline form of compound I sulfate comprises a substantially pure form of one polymorphic type.

[0170] Compound I sulfate form A-2 In embodiments, the present disclosure relates to a crystalline form of Compound I sulfate, namely Form A-2.

[0171] In embodiments, the crystalline form of compound I sulfate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form A-2 of compound I sulfate. In another embodiment, the crystalline form of compound I sulfate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form A-2 of compound I sulfate. In some embodiments, the crystalline form of compound I sulfate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form A-2 of compound I sulfate.

[0172] In embodiments, crystalline form A-2 of compound I sulfate salt exhibits an XRPD pattern including peaks at about 6.95, 9.52, and 9.82 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-2 of compound I sulfate salt exhibits an XRPD pattern including peaks at about 6.95, 9.52, 9.82, 12.92, and 19.46 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-2 of compound I sulfate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 13.77±0.2, 15.30±0.2, and 25.63±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-2 of compound I sulfate salt exhibits an XRPD pattern further comprising three peaks selected from about 13.77±0.2, 15.30±0.2, and 25.63±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0173] In embodiments, crystalline form A-2 of Compound I sulfate salt exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.95±0.2, 9.52±0.2, and 9.82±0.2 degrees two-theta.

[0174] In embodiments, crystalline form A-2 of Compound I sulfate salt exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 6.95±0.2, 9.52±0.2, 9.82±0.2, 12.92±0.2, and 19.46±0.2 degrees two-theta.

[0175] In embodiments, crystalline form A-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 13.77±0.2, 15.30±0.2, and 25.63±0.2 degrees two-theta.

[0176] In some embodiments, the crystalline form of Compound I sulfate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks at ±0.2 degrees 2-theta in Table 7.

[0177] In an embodiment, crystalline form A-2 of Compound I sulfate salt exhibits an XRPD pattern comprising the peaks shown in Table 7 below.

[0178] In embodiments, crystalline form A-2 of Compound I sulfate salt exhibits an XRPD pattern substantially similar to FIG. 7A.

[0179] [Table 8]

[0180] In embodiments, crystalline form A-2 of compound I sulfate exhibits a DSC thermogram including an endothermic peak at about 54° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-2 of compound I sulfate exhibits a DSC thermogram including an endothermic peak with an onset at about 163° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-2 of compound I sulfate exhibits a DSC thermogram including an endothermic peak at about 173° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0181] In some embodiments, crystalline form A-2 of Compound I sulfate exhibits a DSC thermogram substantially similar to Figure 7B.

[0182] Compound I sulfate form B-2 In embodiments, the present disclosure relates to a crystalline form of Compound I sulfate, namely, Form B-2.

[0183] In embodiments, the crystalline form of compound I sulfate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form B-2 of compound I sulfate. In another embodiment, the crystalline form of compound I sulfate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form B-2 of compound I sulfate. In some embodiments, the crystalline form of compound I sulfate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form B-2 of compound I sulfate.

[0184] In embodiments, crystalline form B-2 of Compound I sulfate exhibits an XRPD pattern including peaks at about 17.85, 20.29, and 24.63 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-2 of Compound I sulfate exhibits an XRPD pattern including peaks at about 17.85, 20.29, 23.26, 24.63, and 24.74 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 8.96, 12.77, 15.31, 16.68, 19.14, 20.95, 20.96, and 27.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 8.96, 12.77, 15.31, 16.68, 19.14, 20.95, 20.96, and 27.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 8.96, 12.77, 15.31, 16.68, 19.14, 20.95, 20.96, and 27.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least five peaks selected from about 8.96, 12.77, 15.31, 16.68, 19.14, 20.95, 20.96, and 27.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 8.96, 12.77, 15.31, 16.68, 19.14, 20.95, 20.96, and 27.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 8.96, 12.77, 15.31, 16.68, 19.14, 20.95, 20.96, and 27.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising peaks at about 8.96, 12.77, 15.31, 16.68, 19.14, 20.95, 20.96, and 27.78 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0185] In an embodiment, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern comprising peaks at about 17.85±0.2, 20.29±0.2, and 24.63±0.2 degrees two-theta.

[0186] In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern comprising peaks at about 17.85±0.2, 20.29±0.2, 23.26±0.2, 24.63±0.2, and 24.74±0.2 degrees two-theta.

[0187] In embodiments, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 8.96±0.2, 12.77±0.2, 15.31±0.2, 16.68±0.2, 19.14±0.2, 20.95±0.2, 20.96±0.2, and 27.78±0.2 degrees two-theta.

[0188] In some embodiments, the crystalline form of Compound I sulfate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks at ±0.2 degrees 2-theta in Table 8.

[0189] In an embodiment, crystalline form B-2 of Compound I sulfate salt exhibits an XRPD pattern comprising the peaks shown in Table 8 below.

[0190] In an embodiment, crystalline form B-2 of Compound I sulfate salt has an XRPD pattern substantially similar to FIG. 8A.

[0191] [Table 9]

[0192] In embodiments, crystalline form B-2 of compound I sulfate exhibits a DSC thermogram with an endothermic peak at about 46° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-2 of compound I sulfate exhibits a DSC thermogram with an endothermic peak having an onset at about 185° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-2 of compound I sulfate exhibits a DSC thermogram with an endothermic peak at about 192° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0193] In some embodiments, crystalline form B-2 of Compound I sulfate exhibits a DSC thermogram substantially similar to Figure 8B.

[0194] Compound I Mesylate In one embodiment, the present disclosure relates to compound I mesylate or a solvate thereof. In an embodiment, the crystalline form of compound I mesylate comprises a mixture of one or more polymorphic forms of compound I mesylate. In an embodiment, the crystalline form of compound I mesylate comprises a substantially pure form of one polymorphic type.

[0195] Compound I Mesylate Form A-3 In embodiments, the present disclosure relates to a crystalline form of Compound I mesylate, namely Form A-3.

[0196] In embodiments, the crystalline form of compound I mesylate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form A-3 of compound I mesylate. In another embodiment, the crystalline form of compound I mesylate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form A-3 of compound I mesylate. In some embodiments, the crystalline form of compound I mesylate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form A-3 of compound I mesylate.

[0197] In embodiments, crystalline form A-3 of compound I mesylate exhibits an XRPD pattern including peaks at about 10.23, 14.18, and 18.56 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-3 of compound I mesylate exhibits an XRPD pattern including peaks at about 5.41, 7.09, 10.23, 14.18, and 18.56 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least two peaks at about 3.55, 10.78, 12.45, 18.76, 19.82, 21.89, 22.32, and 23.24 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least three peaks at about 3.55, 10.78, 12.45, 18.76, 19.82, 21.89, 22.32, and 23.24 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least four peaks at about 3.55, 10.78, 12.45, 18.76, 19.82, 21.89, 22.32, and 23.24 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least five peaks at about 3.55, 10.78, 12.45, 18.76, 19.82, 21.89, 22.32, and 23.24 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least six peaks at about 3.55, 10.78, 12.45, 18.76, 19.82, 21.89, 22.32, and 23.24 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least seven peaks at about 3.55, 10.78, 12.45, 18.76, 19.82, 21.89, 22.32, and 23.24 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-3 of compound I mesylate salt exhibits an XRPD pattern further comprising peaks at about 3.55, 10.78, 12.45, 18.76, 19.82, 21.89, 22.32, and 23.24 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0198] In an embodiment, crystalline form A-3 of Compound I mesylate salt exhibits an XRPD pattern comprising peaks at about 10.23±0.2, 14.18±0.2, and 18.56±0.2 degrees two-theta.

[0199] In an embodiment, crystalline form A-3 of Compound I mesylate salt exhibits an XRPD pattern comprising peaks at about 5.41±0.2, 7.09±0.2, 10.23±0.2, 14.18±0.2, and 18.56±0.2 degrees two-theta.

[0200] In an embodiment, crystalline form A-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 3.55±0.2, 10.78±0.2, 12.45±0.2, 18.76±0.2, 19.82±0.2, 21.89±0.2, 22.32±0.2, and 23.24±0.2 degrees two-theta.

[0201] In some embodiments, the crystalline form of Compound I mesylate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 9.

[0202] In an embodiment, crystalline form A-3 of Compound I mesylate salt exhibits an XRPD pattern comprising the peaks shown in Table 9 below.

[0203] In embodiments, crystalline form A-3 of Compound I mesylate salt exhibits an XRPD pattern substantially similar to Figure 9A.

[0204] [Table 10]

[0205] In embodiments, crystalline form A-3 of compound I mesylate exhibits a DSC thermogram with an endothermic peak at about 89° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-3 of compound I mesylate exhibits a DSC thermogram with an endothermic peak with an onset at about 146° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-3 of compound I mesylate exhibits a DSC thermogram with an endothermic peak at about 162° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0206] In some embodiments, crystalline form A-3 of compound I mesylate salt exhibits a DSC thermogram substantially similar to Figure 9B.

[0207] Compound I Mesylate Form B-3 In embodiments, the present disclosure relates to a crystalline form of Compound I mesylate, namely Form B-3.

[0208] In embodiments, the crystalline form of compound I mesylate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form B-3 of compound I mesylate. In another embodiment, the crystalline form of compound I mesylate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form B-3 of compound I mesylate. In some embodiments, the crystalline form of compound I mesylate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form B-3 of compound I mesylate.

[0209] In embodiments, crystalline form B-3 of compound I mesylate exhibits an XRPD pattern including peaks at about 4.80, 7.20, and 19.93 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-3 of compound I mesylate exhibits an XRPD pattern including peaks at about 4.80, 7.20, 18.28, 19.93, and 21.17 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 12.43, 14.77, 16.08, 18.56, 22.77, 23.04, 23.86, and 24.43 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 12.43, 14.77, 16.08, 18.56, 22.77, 23.04, 23.86, and 24.43 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 12.43, 14.77, 16.08, 18.56, 22.77, 23.04, 23.86, and 24.43 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least five peaks selected from about 12.43, 14.77, 16.08, 18.56, 22.77, 23.04, 23.86, and 24.43 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 12.43, 14.77, 16.08, 18.56, 22.77, 23.04, 23.86, and 24.43 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 12.43, 14.77, 16.08, 18.56, 22.77, 23.04, 23.86, and 24.43 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising peaks at about 12.43, 14.77, 16.08, 18.56, 22.77, 23.04, 23.86, and 24.43 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0210] In an embodiment, crystalline form B-3 of Compound I mesylate salt exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.80±0.2, 7.20±0.2, and 19.93±0.2 degrees two-theta.

[0211] In an embodiment, crystalline form B-3 of Compound I mesylate salt exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at about 4.80±0.2, 7.20±0.2, 18.28±0.2, 19.93±0.2, and 21.17±0.2 degrees two-theta.

[0212] In an embodiment, crystalline form B-3 of Compound I mesylate salt exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least two peaks selected from about 12.43±0.2, 14.77±0.2, 16.08±0.2, 18.56±0.2, 22.77±0.2, 23.04±0.2, 23.86±0.2, and 24.43±0.2 degrees two-theta.

[0213] In some embodiments, the crystalline form of Compound I mesylate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 10.

[0214] In an embodiment, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern comprising the peaks in Table 10 below.

[0215] In an embodiment, crystalline form B-3 of Compound I mesylate salt exhibits an XRPD pattern substantially similar to FIG. 10A.

[0216] [Table 11]

[0217] In embodiments, crystalline form B-3 of compound I mesylate exhibits a DSC thermogram with an endothermic peak at about 42° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-3 of compound I mesylate exhibits a DSC thermogram with an endothermic peak having an onset at about 164° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form B-3 of compound I mesylate exhibits a DSC thermogram with an endothermic peak at about 175° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0218] In some embodiments, crystalline form B-3 of Compound I mesylate exhibits a DSC thermogram substantially similar to Figure 10B.

[0219] Compound I mesylate form C-3 In embodiments, the present disclosure relates to a crystalline form of Compound I mesylate, namely, Form C-3.

[0220] In embodiments, the crystalline form of compound I mesylate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form C-3 of compound I mesylate. In another embodiment, the crystalline form of compound I mesylate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form C-3 of compound I mesylate. In some embodiments, the crystalline form of compound I mesylate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form C-3 of compound I mesylate.

[0221] In embodiments, crystalline form C-3 of compound I mesylate exhibits an XRPD pattern including peaks at about 7.09, 16.73, and 22.68 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form C-3 of compound I mesylate exhibits an XRPD pattern including peaks at about 6.89, 7.09, 16.73, 22.34, and 22.68 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form C-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 9.24, 16.02, 16.73, 19.86, 21.29, 21.81, 23.93, 24.54, and 27.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form C-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 9.24, 16.02, 16.73, 19.86, 21.29, 21.81, 23.93, 24.54, and 27.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form C-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 9.24, 16.02, 16.73, 19.86, 21.29, 21.81, 23.93, 24.54, and 27.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form C-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least five peaks selected from about 9.24, 16.02, 16.73, 19.86, 21.29, 21.81, 23.93, 24.54, and 27.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form C-3 of compound I mesylate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 9.24, 16.02, 16.73, 19.86, 21.29, 21.81, 23.93, 24.54, and 27.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form C-3 of Compound I mesylate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 9.24, 16.02, 16.73, 19.86, 21.29, 21.81, 23.93, 24.54, and 27.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form C-3 of compound I mesylate salt exhibits an XRPD pattern further comprising peaks at about 9.24, 16.02, 16.73, 19.86, 21.29, 21.81, 23.93, 24.54, and 27.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0222] In an embodiment, crystalline form C-3 of Compound I mesylate salt exhibits an XRPD pattern comprising peaks at about 7.09±0.2, 16.73±0.2, and 22.68±0.2 degrees two-theta.

[0223] In an embodiment, crystalline form C-3 of Compound I mesylate salt exhibits an XRPD pattern comprising peaks at about 6.89±0.2, 7.09±0.2, 16.73±0.2, 22.34±0.2, and 22.68±0.2 degrees two-theta.

[0224] In an embodiment, crystalline form C-3 of Compound I mesylate salt exhibits an XRPD pattern comprising peaks at about 9.24±0.2, 16.02±0.2, 16.73±0.2, 19.86±0.2, 21.29±0.2, 21.81±0.2, 23.93±0.2, 24.54±0.2, and 27.40±0.2 degrees two-theta.

[0225] In some embodiments, the crystalline form of Compound I mesylate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 11.

[0226] In an embodiment, crystalline form C-3 of Compound I mesylate salt exhibits an XRPD pattern comprising the peaks in Table 11 below.

[0227] In an embodiment, crystalline form C-3 of Compound I mesylate salt exhibits an XRPD pattern substantially similar to FIG. 11A.

[0228] [Table 12]

[0229] In embodiments, crystalline form C-3 of compound I mesylate exhibits a DSC thermogram including an endothermic peak at about 42° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form C-3 of compound I mesylate exhibits a DSC thermogram including an endothermic peak at about 220° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0230] In some embodiments, crystalline form C-3 of compound I mesylate salt exhibits a DSC thermogram substantially similar to FIG. 11B.

[0231] Compound I Tosylate In one embodiment, the present disclosure relates to compound I tosylate or a solvate thereof. In an embodiment, the crystalline form of compound I tosylate comprises a mixture of one or more polymorphic forms of compound I tosylate. In an embodiment, the crystalline form of compound I tosylate comprises a substantially pure form of one polymorphic type.

[0232] Compound I Tosylate Form A-4

[0233] In embodiments, the present disclosure relates to a crystalline form of Compound I tosylate salt, namely Form A-4.

[0234] In embodiments, the crystalline form of compound I tosylate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form A-4 of compound I tosylate. In another embodiment, the crystalline form of compound I tosylate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form A-4 of compound I tosylate. In some embodiments, the crystalline form of compound I tosylate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form A-4 of compound I tosylate.

[0235] In embodiments, crystalline form A-4 of compound I tosylate salt exhibits an XRPD pattern including peaks at about 7.46, 9.99, and 19.09 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-4 of compound I tosylate salt exhibits an XRPD pattern including peaks at about 7.46, 9.99, 14.89, 19.09, and 22.39 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 10.61, 15.36, 17.64, 18.27, 19.65, 19.97, 23.10, and 25.30 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 10.61, 15.36, 17.64, 18.27, 19.65, 19.97, 23.10, and 25.30 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 10.61, 15.36, 17.64, 18.27, 19.65, 19.97, 23.10, and 25.30 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising at least five peaks selected from about 10.61, 15.36, 17.64, 18.27, 19.65, 19.97, 23.10, and 25.30 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 10.61, 15.36, 17.64, 18.27, 19.65, 19.97, 23.10, and 25.30 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 10.61, 15.36, 17.64, 18.27, 19.65, 19.97, 23.10, and 25.30 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising peaks at about 10.61, 15.36, 17.64, 18.27, 19.65, 19.97, 23.10, and 25.30 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0236] In an embodiment, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern comprising peaks at about 7.46±0.2, 9.99±0.2, and 19.09±0.2 degrees two-theta.

[0237] In an embodiment, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern comprising peaks at about 7.46±0.2, 9.99±0.2, 14.89±0.2, 19.09±0.2, and 22.39±0.2 degrees two-theta.

[0238] In an embodiment, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 10.61±0.2, 15.36±0.2, 17.64±0.2, 18.27±0.2, 19.65±0.2, 19.97±0.2, 23.10±0.2 and 25.30±0.2 degrees two-theta.

[0239] In some embodiments, the crystalline form of Compound I tosylate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 12.

[0240] In an embodiment, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern comprising the peaks in Table 12.

[0241] In embodiments, crystalline form A-4 of Compound I tosylate salt exhibits an XRPD pattern substantially similar to FIG. 12A.

[0242] [Table 13]

[0243] In some embodiments, crystalline form A-4 of compound I tosylate salt exhibits a DSC thermogram substantially similar to Figure 12B.

[0244] Compound I Fumarate In one embodiment, the present disclosure relates to compound I fumarate or a solvate thereof.In an embodiment, the crystalline form of compound I fumarate comprises a mixture of one or more polymorphic forms of compound I fumarate.In an embodiment, the crystalline form of compound I fumarate comprises a substantially pure form of one polymorphic type.

[0245] Compound I Fumarate Salt Form A-5 In embodiments, the present disclosure relates to a crystalline form of Compound I fumarate salt, namely Form A-5.

[0246] In embodiments, the crystalline form of compound I fumarate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form A-5 of compound I fumarate. In another embodiment, the crystalline form of compound I fumarate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form A-5 of compound I fumarate. In some embodiments, the crystalline form of compound I fumarate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form A-5 of compound I fumarate.

[0247] In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern including peaks at about 18.12, 23.11, and 23.59 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern including peaks at about 5.31, 18.12, 19.79, 23.11, and 23.59 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 8.50, 9.42, 13.23, 19.12, 21.16, 25.17, 25.68, and 28.82 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 8.50, 9.42, 13.23, 19.12, 21.16, 25.17, 25.68, and 28.82 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 8.50, 9.42, 13.23, 19.12, 21.16, 25.17, 25.68, and 28.82 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern further including at least two 5's selected from about 8.50, 9.42, 13.23, 19.12, 21.16, 25.17, 25.68, and 28.82 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 8.50, 9.42, 13.23, 19.12, 21.16, 25.17, 25.68, and 28.82 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 8.50, 9.42, 13.23, 19.12, 21.16, 25.17, 25.68, and 28.82 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-5 of compound I fumarate salt exhibits an XRPD pattern with additional peaks at about 8.50, 9.42, 13.23, 19.12, 21.16, 25.17, 25.68, and 28.82 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0248] In an embodiment, crystalline form A-5 of Compound I fumarate salt exhibits an XRPD pattern comprising peaks at about 18.12±0.2, 23.11±0.2, and 23.59±0.2 degrees two-theta.

[0249] In an embodiment, crystalline form A-5 of Compound I fumarate salt exhibits an XRPD pattern comprising peaks at about 5.31±0.2, 18.12±0.2, 19.79±0.2, 23.11±0.2, and 23.59±0.2 degrees two-theta.

[0250] In an embodiment, crystalline form A-5 of Compound I fumarate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 8.50±0.2, 9.42±0.2, 13.23±0.2, 19.12±0.2, 21.16±0.2, 25.17±0.2, 25.68±0.2, and 28.82±0.2 degrees two-theta.

[0251] In some embodiments, the crystalline form of Compound I fumarate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 13.

[0252] In an embodiment, crystalline form A-5 of Compound I fumarate salt exhibits an XRPD pattern comprising the peaks shown in Table 13 below.

[0253] In embodiments, crystalline form A-5 of Compound I fumarate salt exhibits an XRPD pattern substantially similar to FIG. 13A.

[0254] [Table 14]

[0255] In an embodiment, crystalline form A-5 of compound I fumarate exhibits a DSC thermogram with an endothermic peak at about 52° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A-5 of compound I fumarate exhibits a DSC thermogram with an endothermic peak with an onset at about 179° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In an embodiment, crystalline form A-5 of compound I fumarate exhibits a DSC thermogram with an endothermic peak at about 184° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0256] In some embodiments, crystalline form A-5 of compound I fumarate salt exhibits a DSC thermogram substantially similar to Figure 13B.

[0257] Compound I L-tartrate In one embodiment, the present disclosure relates to compound I L-tartrate or a solvate thereof.In an embodiment, the crystalline form of compound I L-tartrate comprises a mixture of one or more polymorphic forms of compound I L-tartrate.In an embodiment, the crystalline form of compound I L-tartrate comprises a substantially pure form of one polymorphic type.

[0258] Compound I L-tartrate salt form A-7 In embodiments, the present disclosure relates to a crystalline form of Compound I L-tartrate salt, namely Form A-7.

[0259] In embodiments, the crystalline form of Compound I L-tartrate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Form A-7 of Compound I L-tartrate. In another embodiment, the crystalline form of Compound I L-tartrate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Form A-7 of Compound I L-tartrate. In some embodiments, the crystalline form of compound I L-tartrate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form A-7 of compound I L-tartrate.

[0260] In embodiments, crystalline form A-7 of compound I L-tartrate salt exhibits an XRPD pattern including peaks at about 5.61, 6.93, and 19.66 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-7 of compound I L-tartrate salt exhibits an XRPD pattern including peaks at about 5.61, 6.93, 17.51, 19.66, and 21.75 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0261] In an embodiment, crystalline form A-7 of Compound I L-tartrate salt exhibits an XRPD pattern comprising peaks at about 5.61±0.2, 6.93±0.2, and 19.66±0.2 degrees two-theta.

[0262] In an embodiment, crystalline form A-7 of Compound I L-tartrate salt exhibits an XRPD pattern comprising peaks at about 5.61±0.2, 6.93±0.2, 17.51±0.2, 19.66±0.2, and 21.75±0.2 degrees two-theta.

[0263] In some embodiments, a crystalline form of Compound I L-tartrate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 15.

[0264] In an embodiment, crystalline form A-7 of Compound I L-tartrate salt exhibits an XRPD pattern comprising the peaks shown in Table 15 below.

[0265] In embodiments, crystalline form A-7 of Compound I L-tartrate salt exhibits an XRPD pattern substantially similar to Figure 15A.

[0266] [Table 15]

[0267] In embodiments, crystalline form A-7 of compound I L-tartrate salt exhibits a DSC thermogram with an endothermic peak at about 52° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-7 of compound I L-tartrate salt exhibits a DSC thermogram with an endothermic peak with an onset at about 139° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-7 of compound I L-tartrate salt exhibits a DSC thermogram with an endothermic peak at about 147° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-7 of compound I L-tartrate salt exhibits a DSC thermogram including an endothermic peak with an onset at about 164° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-7 of compound I L-tartrate salt exhibits a DSC thermogram including an endothermic peak at about 186° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0268] In some embodiments, crystalline form A-1 of compound I hydrochloride salt exhibits a DSC thermogram substantially similar to Figure 15B.

[0269] Compound I L-tartrate salt form B-7 In embodiments, the present disclosure relates to a crystalline form of Compound I L-tartrate salt, namely, Form B-7.

[0270] In embodiments, the crystalline form of Compound I L-tartrate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Form B-7 of Compound I L-tartrate. In another embodiment, the crystalline form of Compound I L-tartrate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Form B-7 of Compound I L-tartrate. In some embodiments, the crystalline form of compound I L-tartrate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form B-7 of compound I L-tartrate.

[0271] In embodiments, crystalline form B-7 of Compound I L-tartrate salt exhibits an XRPD pattern including a peak at about 5.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0272] In embodiments, crystalline form B-7 of Compound I L-tartrate salt exhibits an XRPD pattern including a peak at about 5.36±0.2 degrees 2-theta.

[0273] In some embodiments, a crystalline form of Compound I L-tartrate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 16.

[0274] In an embodiment, crystalline form B-7 of Compound I L-tartrate salt exhibits an XRPD pattern comprising the peaks shown in Table 16 below.

[0275] In embodiments, crystalline form B-7 of Compound I L-tartrate salt exhibits an XRPD pattern substantially similar to FIG. 16A.

[0276] [Table 16]

[0277] In some embodiments, crystalline form B-7 of compound I L-tartrate salt exhibits a DSC thermogram substantially similar to Figure 16B.

[0278] Compound I Citrate In one embodiment, the present disclosure relates to compound I citrate or a solvate thereof.In an embodiment, the crystalline form of compound I citrate comprises a mixture of one or more polymorphic forms of compound I citrate.In an embodiment, the crystalline form of compound I citrate comprises a substantially pure form of one polymorphic type.

[0279] Compound I Citrate Form A-8 In embodiments, the present disclosure relates to a crystalline form of Compound I citrate salt, namely Form A-8.

[0280] In embodiments, the crystalline form of compound I citrate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form A-8 of compound I citrate. In another embodiment, the crystalline form of compound I citrate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form A-8 of compound I citrate. In some embodiments, the crystalline form of compound I citrate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form A-8 of compound I citrate.

[0281] In embodiments, crystalline form A-8 of compound I citrate salt exhibits an XRPD pattern including peaks at about 4.56, 9.15, and 12.05 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-8 of compound I citrate salt exhibits an XRPD pattern including peaks at about 4.56, 9.15, 12.05, 17.43, and 18.63 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least five peaks selected from about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising peaks at about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0282] In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern comprising peaks at about 4.56±0.2, 9.15±0.2, and 12.05±0.2 degrees two-theta.

[0283] In an embodiment, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern comprising peaks at about 4.56±0.2, 9.15±0.2, 12.05±0.2, 17.43±0.2, and 18.63±0.2 degrees two-theta.

[0284] In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 7.94±0.2, 15.77±0.2, 18.27±0.2, 19.10±0.2, 20.23±0.2, 20.88±0.2, 22.31±0.2, and 24.02±0.2 degrees two-theta.

[0285] In some embodiments, the crystalline form of Compound I citrate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 17.

[0286] In an embodiment, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern comprising the peaks shown in Table 17 below.

[0287] In embodiments, crystalline form A-8 of Compound I citrate salt exhibits an XRPD pattern substantially similar to FIG. 17A.

[0288] [Table 17]

[0289] In an embodiment, crystalline form A-8 of Compound I citrate salt exhibits a.

[0290] In embodiments, crystalline form A-8 of compound I citrate salt exhibits a DSC thermogram including an endothermic peak at about 60° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form A-8 of compound I citrate salt exhibits a DSC thermogram including an endothermic peak at about 156° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0291] In some embodiments, crystalline form A-8 of Compound I citrate salt exhibits a DSC thermogram substantially similar to Figure 17B.

[0292] Compound I Citrate Form B-8 In embodiments, the present disclosure relates to a crystalline form of Compound I citrate salt, namely Form B-8.

[0293] In embodiments, the crystalline form of compound I citrate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form B-8 of compound I citrate. In another embodiment, the crystalline form of compound I citrate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form B-8 of compound I citrate. In some embodiments, the crystalline form of compound I citrate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form B-8 of compound I citrate.

[0294] In embodiments, crystalline form B-8 of compound I citrate salt exhibits an XRPD pattern including peaks at about 5.36, 6.85, and 20.59 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-8 of compound I citrate salt exhibits an XRPD pattern including peaks at about 5.36, 6.85, 17.81, 20.59, and 22.81 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-8 of compound I citrate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 16.08, 21.20, 25.81, and 27.02 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-8 of compound I citrate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 16.08, 21.20, 25.81, and 27.02 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B-8 of Compound I citrate salt exhibits an XRPD pattern further comprising peaks at about 16.08, 21.20, 25.81, and 27.02 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0295] In an embodiment, crystalline form B-8 of Compound I citrate salt exhibits an XRPD pattern comprising peaks at about 5.36±0.2, 6.85±0.2, and 20.59±0.2 degrees two-theta.

[0296] In an embodiment, crystalline form B-8 of Compound I citrate salt exhibits an XRPD pattern comprising peaks at about 5.36±0.2, 6.85±0.2, 17.81±0.2, 20.59±0.2, and 22.81±0.2 degrees two-theta.

[0297] In an embodiment, crystalline form B-8 of Compound I citrate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 16.08±0.2, 21.20±0.2, 25.81±0.2, and 27.02±0.2 degrees two-theta.

[0298] In some embodiments, the crystalline form of Compound I citrate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 18.

[0299] In an embodiment, crystalline form B-8 of Compound I citrate salt exhibits an XRPD pattern comprising the peaks shown in Table 18 below.

[0300] In embodiments, crystalline form B-8 of Compound I citrate salt exhibits an XRPD pattern substantially similar to FIG. 18A.

[0301] [Table 18]

[0302] In some embodiments, crystalline form B-8 of Compound I citrate salt exhibits a DSC thermogram substantially similar to Figure 18B.

[0303] Compound I succinate form A-9 In one embodiment, the present disclosure relates to Compound I succinate or a solvate thereof. In an embodiment, the present disclosure relates to a crystalline form of Compound I succinate, namely Form A-9.

[0304] In embodiments, the crystalline form of compound I succinate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form A-9 of compound I succinate. In another embodiment, the crystalline form of compound I succinate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form A-9 of compound I succinate. In some embodiments, the crystalline form of compound I succinate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form A-9 of compound I succinate.

[0305] In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern including peaks at about 8.73, 20.05, and 26.15 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern including peaks at about 4.08, 8.16, 8.73, 20.05, and 26.15 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 6.76, 8.96, 12.30, 19.63, 21.10, 22.76, 25.88, and 31.55 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising at least three peaks selected from about 6.76, 8.96, 12.30, 19.63, 21.10, 22.76, 25.88, and 31.55 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising at least four peaks selected from about 6.76, 8.96, 12.30, 19.63, 21.10, 22.76, 25.88, and 31.55 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising at least five peaks selected from about 6.76, 8.96, 12.30, 19.63, 21.10, 22.76, 25.88, and 31.55 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising at least six peaks selected from about 6.76, 8.96, 12.30, 19.63, 21.10, 22.76, 25.88, and 31.55 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising at least seven peaks selected from about 6.76, 8.96, 12.30, 19.63, 21.10, 22.76, 25.88, and 31.55 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising peaks at about 6.76, 8.96, 12.30, 19.63, 21.10, 22.76, 25.88, and 31.55 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0306] In an embodiment, crystalline form A-9 of Compound I succinate salt exhibits an XRPD pattern comprising peaks at about 8.73±0.2, 20.05±0.2, and 26.15±0.2 degrees two-theta.

[0307] In an embodiment, crystalline form A-9 of Compound I succinate salt exhibits an XRPD pattern comprising peaks at about 4.08±0.2, 8.16±0.2, 8.73±0.2, 20.05±0.2, and 26.15±0.2 degrees two-theta.

[0308] In an embodiment, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern further comprising at least two peaks selected from about 6.76±0.2, 8.96±0.2, 12.30±0.2, 19.63±0.2, 21.10±0.2, 22.76±0.2, 25.88±0.2, and 31.55±0.2 degrees two-theta.

[0309] In some embodiments, the crystalline form of Compound I succinate salt exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 19.

[0310] In an embodiment, crystalline form A-9 of compound I succinate salt exhibits an XRPD pattern comprising the peaks shown in Table 19 below.

[0311] In embodiments, crystalline form A-9 of Compound I succinate salt exhibits an XRPD pattern substantially similar to FIG. 19A.

[0312] [Table 19]

[0313] In embodiments, crystalline form A-9 of Compound I succinate salt exhibits a DSC thermogram substantially similar to FIG. 19B.

[0314] Compound I Phosphate Form B In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form B.

[0315] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form B of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form B of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form B of compound I phosphate.

[0316] In embodiments, crystalline form B of compound I phosphate exhibits an XRPD pattern including peaks at about 5.73, 17.02, and 23.23 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form B of compound I phosphate exhibits an XRPD pattern including peaks at about 5.73, 11.37, 17.02, 22.70, and 23.23 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In an embodiment, crystalline form B of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 6.85, 7.39, 10.90, 14.65, 16.13, 19.77, 19.99 and 20.40 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In an embodiment, crystalline form B of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 6.85, 7.39, 10.90, 14.65, 16.13, 19.77, 19.99 and 20.40 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In embodiments, crystalline Form B of Compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 6.85, 7.39, 10.90, 14.65, 16.13, 19.77, 19.99, and 20.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form B of Compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 6.85, 7.39, 10.90, 14.65, 16.13, 19.77, 19.99, and 20.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In an embodiment, crystalline form B of compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 6.85, 7.39, 10.90, 14.65, 16.13, 19.77, 19.99 and 20.40 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In an embodiment, crystalline form B of compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 6.85, 7.39, 10.90, 14.65, 16.13, 19.77, 19.99 and 20.40 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In embodiments, crystalline Form B of Compound I phosphate exhibits an XRPD pattern further comprising peaks at about 6.85, 7.39, 10.90, 14.65, 16.13, 19.77, 19.99, and 20.40 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0317] In an embodiment, crystalline Form B of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.73±0.2, 17.02±0.2, and 23.23±0.2 degrees two-theta.

[0318] In an embodiment, crystalline Form B of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.73±0.2, 11.37±0.2, 17.02±0.2, 22.70±0.2, and 23.23±0.2 degrees two-theta.

[0319] In embodiments, crystalline Form B of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 6.85±0.2, 7.39±0.2, 10.90±0.2, 14.65±0.2, 16.13±0.2, 19.77±0.2, 19.99±0.2 and 20.40±0.2 degrees two-theta.

[0320] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta of Table 20.

[0321] In an embodiment, crystalline Form B of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 20 below.

[0322] In an embodiment, crystalline Form B of Compound I phosphate exhibits an XRPD pattern substantially similar to FIG.

[0323] [Table 20]

[0324] Compound I Phosphate Form C In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form C.

[0325] In embodiments, the present disclosure relates to Form C, a crystalline form of Compound I phosphate, which is a hydrate.

[0326] In embodiments, the crystalline form of compound I phosphate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of compound I phosphate form C. In another embodiment, the crystalline form of compound I phosphate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of compound I phosphate form C. In some embodiments, the crystalline form of compound I phosphate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of compound I phosphate form C.

[0327] In embodiments, crystalline Form C of Compound I phosphate exhibits an XRPD pattern including peaks at about 7.66, 17.15, and 22.09 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form C of Compound I phosphate exhibits an XRPD pattern including peaks at about 5.22, 7.66, 17.15, 22.09, and 24.96 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least two peaks selected from about 10.55, 11.06, 16.81, 17.60, 19.32, 20.88, 21.39, and 26.46 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least three peaks selected from about 10.55, 11.06, 16.81, 17.60, 19.32, 20.88, 21.39, and 26.46 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least four peaks selected from about 10.55, 11.06, 16.81, 17.60, 19.32, 20.88, 21.39, and 26.46 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least five peaks selected from about 10.55, 11.06, 16.81, 17.60, 19.32, 20.88, 21.39, and 26.46 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least six peaks selected from about 10.55, 11.06, 16.81, 17.60, 19.32, 20.88, 21.39, and 26.46 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least seven peaks selected from about 10.55, 11.06, 16.81, 17.60, 19.32, 20.88, 21.39, and 26.46 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising peaks at about 10.55, 11.06, 16.81, 17.60, 19.32, 20.88, 21.39, and 26.46 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0328] In an embodiment, crystalline Form C of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 7.66±0.2, 17.15±0.2, and 22.09±0.2 degrees two-theta.

[0329] In an embodiment, crystalline Form C of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.22±0.2, 7.66±0.2, 17.15±0.2, 22.09±0.2, and 24.96±0.2 degrees two-theta.

[0330] In embodiments, crystalline Form C of Compound I phosphate exhibits an X-ray powder diffraction (XRPD) pattern further comprising at least two peaks selected from about 10.55±0.2, 11.06±0.2, 16.81±0.2, 17.60±0.2, 19.32±0.2, 20.88±0.2, 21.39±0.2, and 26.46±0.2 degrees two-theta.

[0331] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 21.

[0332] In an embodiment, crystalline Form C of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 21 below.

[0333] In embodiments, crystalline Form C of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 21A.

[0334] [Table 21]

[0335] In embodiments, crystalline form C of compound I phosphate exhibits a DSC thermogram including an endothermic peak at about 6° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form C of compound I phosphate exhibits a DSC thermogram including an endothermic peak with an onset at about 161° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form C of compound I phosphate exhibits a DSC thermogram including an endothermic peak at about 171° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0336] In some embodiments, crystalline Form C of Compound I phosphate exhibits a DSC thermogram substantially similar to Figure 21B.

[0337] In embodiments, crystalline Form C of Compound I phosphate exhibits a TGA thermogram substantially similar to Figure 21 C. In embodiments, crystalline Form C of Compound I phosphate exhibits a weight percent loss of about 5% between about 32°C and about 130°C by thermogravimetric analysis (TGA).

[0338] Compound I Phosphate Form J In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form J.

[0339] In embodiments, the present disclosure relates to Form J, a crystalline form of Compound I phosphate, which is a hydrate.

[0340] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form J of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form J of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form J of compound I phosphate.

[0341] In embodiments, crystalline form J of compound I phosphate exhibits an XRPD pattern including peaks at about 4.97, 8.09, and 23.89 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form J of compound I phosphate exhibits an XRPD pattern including peaks at about 4.97, 8.09, 17.46, 23.89, and 30.74 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0342] In an embodiment, crystalline Form J of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 4.97±0.2, 8.09±0.2, and 23.89±0.2 degrees two-theta.

[0343] In an embodiment, crystalline Form J of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 4.97±0.2, 8.09±0.2, 17.46±0.2, 23.89±0.2, and 30.74±0.2 degrees two-theta.

[0344] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 22.

[0345] In an embodiment, crystalline Form J of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 22 below.

[0346] In embodiments, crystalline Form J of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 22A.

[0347] [Table 22]

[0348] In embodiments, crystalline form J of compound I phosphate exhibits a DSC thermogram including an endothermic peak at about 60.5° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form J of compound I phosphate exhibits a DSC thermogram including an endothermic peak at about 157.7° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form J of compound I phosphate exhibits a DSC thermogram including an endothermic peak having an onset at about 193° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form J of compound I phosphate exhibits a DSC thermogram comprising an endothermic peak at about 194° C. with an error margin of error of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0349] In some embodiments, crystalline form J of compound I phosphate exhibits a DSC thermogram substantially similar to FIG. 22B.

[0350] In embodiments, crystalline Form J of Compound I phosphate exhibits a TGA thermogram substantially similar to Figure 22C. In embodiments, crystalline Form J of Compound I phosphate exhibits a weight percent loss of about 7.1% between about 32°C and about 160°C by thermogravimetric analysis (TGA).

[0351] Compound I phosphate form K In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form K.

[0352] In embodiments, the present disclosure relates to Form K, a crystalline form of Compound I phosphate, which is a hydrate.

[0353] In embodiments, the crystalline form of compound I phosphate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form K of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form K of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form K of compound I phosphate.

[0354] In embodiments, crystalline form K of compound I phosphate exhibits an XRPD pattern including peaks at about 4.59, 13.75, and 21.37 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form K of compound I phosphate exhibits an XRPD pattern including peaks at about 4.59, 8.53, 13.75, 21.37, and 23.02 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form K of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 6.58±0.2, 10.08±0.2, 11.08±0.2, 24.21±0.2, and 31.80±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form K of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 6.58±0.2, 10.08±0.2, 11.08±0.2, 24.21±0.2, and 31.80±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form K of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 6.58±0.2, 10.08±0.2, 11.08±0.2, 24.21±0.2, and 31.80±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form K of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 6.58±0.2, 10.08±0.2, 11.08±0.2, 24.21±0.2, and 31.80±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0355] In an embodiment, crystalline form K of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 4.59±0.2, 13.75±0.2, and 21.37±0.2 degrees two-theta.

[0356] In an embodiment, crystalline form K of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 4.59±0.2, 8.53±0.2, 13.75±0.2, 21.37±0.2, and 23.02±0.2 degrees two-theta.

[0357] In an embodiment, crystalline form K of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 6.58±0.2, 10.08±0.2, 11.08±0.2, 24.21±0.2, and 31.80±0.2 degrees two-theta.

[0358] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 23.

[0359] In an embodiment, crystalline form K of compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 23 below.

[0360] In embodiments, crystalline form K of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 23A.

[0361] [Table 23]

[0362] In embodiments, crystalline form K of compound I phosphate exhibits a DSC thermogram including an endothermic peak at about 61.3° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form K of compound I phosphate exhibits a DSC thermogram including an endothermic peak with an onset at about 152.6° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0363] In some embodiments, crystalline form K of compound I phosphate exhibits a DSC thermogram substantially similar to Figure 23B.

[0364] In embodiments, crystalline form K of compound I phosphate exhibits a TGA thermogram substantially similar to Figure 23 C. In embodiments, crystalline form K of compound I phosphate exhibits a weight percent loss of about 5.8% between about 32°C and about 120°C by thermogravimetric analysis (TGA).

[0365] Compound I phosphate form H2 In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form H2.

[0366] In embodiments, the present disclosure relates to Form H2, a crystalline form of Compound I phosphate, which is a hydrate.

[0367] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form H2 of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form H2 of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form H2 of compound I phosphate.

[0368] In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern including peaks at about 10.66, 21.99, and 22.38 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern including peaks at about 10.66, 18.78, 21.99, 22.38, and 23.56 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 8.49, 11.51, 13.62, 14.02, 15.37, 21.35, 23.20, and 24.13 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 8.49, 11.51, 13.62, 14.02, 15.37, 21.35, 23.20, and 24.13 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 8.49, 11.51, 13.62, 14.02, 15.37, 21.35, 23.20, and 24.13 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 8.49, 11.51, 13.62, 14.02, 15.37, 21.35, 23.20, and 24.13 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 8.49, 11.51, 13.62, 14.02, 15.37, 21.35, 23.20, and 24.13 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 8.49, 11.51, 13.62, 14.02, 15.37, 21.35, 23.20, and 24.13 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H2 of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 8.49, 11.51, 13.62, 14.02, 15.37, 21.35, 23.20, and 24.13 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0369] In an embodiment, crystalline form H2 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 10.66±0.2, 21.99±0.2, and 22.38±0.2 degrees two-theta.

[0370] In an embodiment, crystalline form H2 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 10.66±0.2, 18.78±0.2, 21.99±0.2, 22.38±0.2, and 23.56±0.2 degrees two-theta.

[0371] In an embodiment, crystalline form H2 of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 8.49±0.2, 11.51±0.2, 13.62±0.2, 14.02±0.2, 15.37±0.2, 21.35±0.2, 23.20±0.2, and 24.13±0.2 degrees two-theta.

[0372] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 24.

[0373] In an embodiment, crystalline form H2 of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 24 below.

[0374] In an embodiment, crystalline form H2 of Compound I phosphate exhibits an XRPD pattern substantially similar to FIG.

[0375] [Table 24]

[0376] Compound I Phosphate Form E In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form E.

[0377] In an embodiment of the disclosure, crystalline form E of compound I phosphate is a solvate.

[0378] In an embodiment of the disclosure, crystalline form E of compound I phosphate is a DMSO solvate.

[0379] In embodiments, the crystalline form of compound I phosphate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form E of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form E of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form E of compound I phosphate.

[0380] In embodiments, crystalline form E of compound I phosphate exhibits an XRPD pattern including peaks at about 20.42, 20.94, and 21.65 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form E of compound I phosphate exhibits an XRPD pattern including peaks at about 7.21, 10.18, 20.42, 20.94, and 21.65 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form E of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 5.30, 14.41, 15.95, 19.76, 24.22, 25.28, 27.56, and 28.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form E of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 5.30, 14.41, 15.95, 19.76, 24.22, 25.28, 27.56, and 28.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form E of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 5.30, 14.41, 15.95, 19.76, 24.22, 25.28, 27.56, and 28.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form E of compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 5.30, 14.41, 15.95, 19.76, 24.22, 25.28, 27.56, and 28.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form E of compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 5.30, 14.41, 15.95, 19.76, 24.22, 25.28, 27.56, and 28.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In an embodiment, crystalline form E of compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 5.30, 14.41, 15.95, 19.76, 24.22, 25.28, 27.56 and 28.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less. In an embodiment, crystalline form E of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 5.30, 14.41, 15.95, 19.76, 24.22, 25.28, 27.56 and 28.97 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05 or less.

[0381] In an embodiment, crystalline Form E of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 20.42±0.2, 20.94±0.2, and 21.65±0.2 degrees two-theta.

[0382] In an embodiment, crystalline Form E of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 7.21±0.2, 10.18±0.2, 20.42±0.2, 20.94±0.2, and 21.65±0.2 degrees two-theta.

[0383] In an embodiment, crystalline Form E of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 5.30±0.2, 14.41±0.2, 15.95±0.2, 19.76±0.2, 24.22±0.2, 25.28±0.2, 27.56±0.2, and 28.97±0.2 degrees two-theta.

[0384] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 25.

[0385] In an embodiment, crystalline form E of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 25 below.

[0386] In embodiments, crystalline Form E of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 25A.

[0387] [Table 25]

[0388] In embodiments, crystalline form E of compound I phosphate exhibits a DSC thermogram with an endothermic peak at about 95.2° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form E of compound I phosphate exhibits a DSC thermogram with an endothermic peak at about 128.6° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form E of compound I phosphate exhibits a DSC thermogram with an endothermic peak having an onset at about 168° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0389] In some embodiments, crystalline form E of compound I phosphate exhibits a DSC thermogram substantially similar to Figure 25B.

[0390] In embodiments, crystalline Form E of Compound I phosphate exhibits a TGA thermogram substantially similar to Figure 25C. In embodiments, crystalline Form E of Compound I phosphate exhibits a weight percent loss of about 0.9% between about 34°C and about 190°C by thermogravimetric analysis (TGA).

[0391] Compound I Phosphate Form F In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form F.

[0392] In an embodiment of the disclosure, crystalline form F of compound I phosphate is a solvate.

[0393] In an embodiment of the disclosure, crystalline form F of compound I phosphate is a DMSO solvate.

[0394] In embodiments, the crystalline form of compound I phosphate may comprise greater than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form F of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form F of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form F of compound I phosphate.

[0395] In embodiments, crystalline form F of compound I phosphate exhibits an XRPD pattern including peaks at about 11.11, 20.77, and 21.32 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form F of compound I phosphate exhibits an XRPD pattern including peaks at about 10.10, 11.11, 20.77, 21.32, and 24.20 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form F of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 15.84, 16.81, 20.19, 22.57, 22.71, 23.15, 25.23, and 25.60 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form F of Compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 15.84, 16.81, 20.19, 22.57, 22.71, 23.15, 25.23, and 25.60 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form F of Compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 15.84, 16.81, 20.19, 22.57, 22.71, 23.15, 25.23, and 25.60 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form F of compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 15.84, 16.81, 20.19, 22.57, 22.71, 23.15, 25.23, and 25.60 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline Form F of Compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 15.84, 16.81, 20.19, 22.57, 22.71, 23.15, 25.23, and 25.60 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form F of Compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 15.84, 16.81, 20.19, 22.57, 22.71, 23.15, 25.23, and 25.60 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form F of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 15.84, 16.81, 20.19, 22.57, 22.71, 23.15, 25.23, and 25.60 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0396] In an embodiment, crystalline Form F of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 11.11±0.2, 20.77±0.2, and 21.32±0.2 degrees two-theta.

[0397] In an embodiment, crystalline Form F of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 10.10±0.2, 11.11±0.2, 20.77±0.2, 21.32±0.2, and 24.20±0.2 degrees two-theta.

[0398] In an embodiment, crystalline Form F of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 15.84±0.2, 16.81±0.2, 20.19±0.2, 22.57±0.2, 22.71±0.2, 23.15±0.2, 25.23±0.2, and 25.60±0.2 degrees two-theta.

[0399] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 26.

[0400] In an embodiment, crystalline Form F of Compound I phosphate exhibits an XRPD pattern comprising the peaks set forth in Table 26 below.

[0401] In embodiments, crystalline Form F of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 26A.

[0402] [Table 26]

[0403] In embodiments, crystalline form F of compound I phosphate exhibits a DSC thermogram comprising an endothermic peak at about 43° C. and / or an endothermic peak at about 142° C. and / or an endothermic peak at about 161° C. and / or an endothermic peak at about 192.5° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form F of compound I phosphate exhibits a DSC thermogram comprising an endothermic peak having an onset at about 172.5° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0404] In some embodiments, crystalline form F of compound I phosphate exhibits a DSC thermogram substantially similar to Figure 26B.

[0405] In embodiments, crystalline form F of compound I phosphate exhibits a TGA thermogram substantially similar to Figure 26C. In embodiments, crystalline form F of compound I phosphate exhibits a weight percent loss of about 3.2% by thermogravimetric analysis (TGA) between about 32°C and about 70°C. In embodiments, crystalline form F of compound I phosphate exhibits a weight percent loss of about 3.8% by thermogravimetric analysis (TGA) between about 69°C and about 140°C. In embodiments, crystalline form F of compound I phosphate exhibits a weight percent loss of about 14.2% by thermogravimetric analysis (TGA) between about 140°C and about 240°C.

[0406] Compound I Phosphate Form G In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form G.

[0407] In an embodiment of the disclosure, crystalline form G of compound I phosphate is a solvate.

[0408] In an embodiment of the disclosure, crystalline form G of compound I phosphate is a DMSO water solvate.

[0409] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of form G of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of form G of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of form G of compound I phosphate.

[0410] In embodiments, crystalline form G of compound I phosphate exhibits an XRPD pattern including peaks at about 5.28, 15.77, and 18.95 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form G of compound I phosphate exhibits an XRPD pattern including peaks at about 5.28, 15.77, 18.39, 18.95, and 21.00 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form G of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 10.54, 14.81, 15.03, 20.27, 21.79, 22.76, 23.06, and 25.10 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form G of Compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 10.54, 14.81, 15.03, 20.27, 21.79, 22.76, 23.06, and 25.10 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form G of Compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 10.54, 14.81, 15.03, 20.27, 21.79, 22.76, 23.06, and 25.10 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form G of Compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 10.54, 14.81, 15.03, 20.27, 21.79, 22.76, 23.06, and 25.10 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline Form G of Compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 10.54, 14.81, 15.03, 20.27, 21.79, 22.76, 23.06, and 25.10 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form G of Compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 10.54, 14.81, 15.03, 20.27, 21.79, 22.76, 23.06, and 25.10 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form G of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 10.54, 14.81, 15.03, 20.27, 21.79, 22.76, 23.06, and 25.10 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0411] In an embodiment, crystalline Form G of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.28±0.2, 15.77±0.2, and 18.95±0.2 degrees two-theta.

[0412] In embodiments, the crystalline form G of Compound I phosphate is about 5.28±0.2, 15.77±0.2, 18.39±0.2

[0413] , 18.95±0.2 and 21.00±0.2 degrees 2-theta.

[0414] In an embodiment, crystalline Form G of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 10.54±0.2, 14.81±0.2, 15.03±0.2, 20.27±0.2, 21.79±0.2, 22.76±0.2, 23.06±0.2, and 25.10±0.2 degrees two-theta.

[0415] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 27.

[0416] In an embodiment, crystalline form G of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 27 below.

[0417] In embodiments, crystalline Form G of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 27A.

[0418] [Table 27]

[0419] In embodiments, crystalline form G of compound I phosphate exhibits a DSC thermogram comprising an endothermic peak at about 46° C. and / or an endothermic peak at about 142° C. and / or an endothermic peak at about 194° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form G of compound I phosphate exhibits a DSC thermogram comprising an endothermic peak having an onset at about 176° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0420] In some embodiments, crystalline form G of compound I phosphate exhibits a DSC thermogram substantially similar to Figure 27B.

[0421] In embodiments, crystalline Form G of Compound I phosphate exhibits a TGA thermogram substantially similar to Figure 27C. In embodiments, crystalline Form G of Compound I phosphate exhibits a weight percent loss of about 4.8% by thermogravimetric analysis (TGA) between about 32°C and about 100°C. In embodiments, crystalline Form G of Compound I phosphate exhibits a weight percent loss of about 13.2% by thermogravimetric analysis (TGA) between about 100°C and about 250°C.

[0422] Compound I Phosphate Form I In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form I.

[0423] In an embodiment of the present disclosure, crystalline Form I of Compound I phosphate is a solvate.

[0424] In an embodiment of the disclosure, crystalline Form I of Compound I phosphate is a 2,2,2-trifluoroethanol (TFE) solvate.

[0425] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, or about 99.0% of Form I of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Form I of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Form I of compound I phosphate.

[0426] In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern including peaks at about 8.56, 9.63, and 20.48 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern including peaks at about 8.56, 9.63, 17.91, 20.48, and 23.87 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 14.85, 19.61, 21.10, 21.60, 22.68, 23.31, 26.98, and 29.87 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 14.85, 19.61, 21.10, 21.60, 22.68, 23.31, 26.98, and 29.87 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 14.85, 19.61, 21.10, 21.60, 22.68, 23.31, 26.98, and 29.87 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 14.85, 19.61, 21.10, 21.60, 22.68, 23.31, 26.98, and 29.87 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 14.85, 19.61, 21.10, 21.60, 22.68, 23.31, 26.98, and 29.87 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 14.85, 19.61, 21.10, 21.60, 22.68, 23.31, 26.98, and 29.87 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising peaks at about 14.85, 19.61, 21.10, 21.60, 22.68, 23.31, 26.98, and 29.87 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0427] In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 8.56±0.2, 9.63±0.2, and 20.48±0.2 degrees two-theta.

[0428] In an embodiment, crystalline Form I of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 8.56±0.2, 9.63±0.2, 17.91±0.2, 20.48±0.2, and 23.87±0.2 degrees two-theta.

[0429] In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 14.85±0.2, 19.61±0.2, 21.10±0.2, 21.60±0.2, 22.68±0.2, 23.31±0.2, 26.98±0.2, and 29.87±0.2 degrees two-theta.

[0430] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 28.

[0431] In an embodiment, crystalline Form I of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 28 below.

[0432] In embodiments, crystalline Form I of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 28A.

[0433] [Table 28]

[0434] In embodiments, crystalline Form I of Compound I phosphate exhibits a DSC thermogram that includes a broad desolvation peak from about 126.2° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits a DSC thermogram that includes an endothermic peak with an onset at about 171° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline Form I of Compound I phosphate exhibits a DSC thermogram that includes an endothermic peak at about 185.6° C., with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0435] In some embodiments, crystalline Form I of Compound I phosphate exhibits a DSC thermogram substantially similar to Figure 28B.

[0436] In embodiments, crystalline Form I of Compound I phosphate exhibits a TGA thermogram substantially similar to Figure 28C. In embodiments, crystalline Form I of Compound I phosphate exhibits a weight percent loss of about 20% between about 33°C and about 230°C by thermogravimetric analysis (TGA).

[0437] Compound I phosphate form H1 In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form H1.

[0438] In an embodiment of the disclosure, crystalline form H1 of Compound I phosphate is a solvate.

[0439] In an embodiment of the disclosure, crystalline form H1 of compound I phosphate is a dimethylformamide (DMF)-water heterosolvate.

[0440] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form H1 of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form H1 of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form H1 of compound I phosphate.

[0441] In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern including peaks at about 5.37, 10.69, and 22.05 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern including peaks at about 5.37, 8.53, 10.69, 18.86, and 22.05 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 3.74, 15.39, 17.99, 18.80, 21.46, 22.29, 23.47, and 23.61 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 3.74, 15.39, 17.99, 18.80, 21.46, 22.29, 23.47, and 23.61 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 3.74, 15.39, 17.99, 18.80, 21.46, 22.29, 23.47, and 23.61 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 3.74, 15.39, 17.99, 18.80, 21.46, 22.29, 23.47, and 23.61 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 3.74, 15.39, 17.99, 18.80, 21.46, 22.29, 23.47, and 23.61 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 3.74, 15.39, 17.99, 18.80, 21.46, 22.29, 23.47, and 23.61 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 3.74, 15.39, 17.99, 18.80, 21.46, 22.29, 23.47, and 23.61 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0442] In an embodiment, crystalline form H1 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.37±0.2, 10.69±0.2, and 22.05±0.2 degrees two-theta.

[0443] In an embodiment, crystalline form H1 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.37±0.2, 8.53±0.2, 10.69±0.2, 18.86±0.2, and 22.05±0.2 degrees two-theta.

[0444] In an embodiment, crystalline form H1 of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 3.74±0.2, 15.39±0.2, 17.99±0.2, 18.80±0.2, 21.46±0.2, 22.29±0.2, 23.47±0.2, and 23.61±0.2 degrees two-theta.

[0445] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 29.

[0446] In an embodiment, crystalline form H1 of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 29 below.

[0447] In embodiments, crystalline form H1 of Compound I phosphate exhibits an XRPD pattern substantially similar to Figure 29A.

[0448] [Table 29]

[0449] In embodiments, crystalline form H1 of compound I phosphate exhibits a DSC thermogram with an endothermic peak at about 48° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits a DSC thermogram with an endothermic peak at about 110° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form H1 of compound I phosphate exhibits a DSC thermogram with an endothermic peak having an onset at about 160° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less. In embodiments, crystalline form H1 of Compound I phosphate exhibits a DSC thermogram comprising an endothermic peak at about 190.9° C. with an error range of about ±2.5, about ±2.0, about ±1.5, about ±1.0, about ±0.5, or less.

[0450] In some embodiments, crystalline form H1 of compound I phosphate exhibits a DSC thermogram substantially similar to Figure 29B.

[0451] In embodiments, crystalline form H1 of Compound I phosphate exhibits a TGA thermogram substantially similar to Figure 29C. In embodiments, crystalline form H1 of Compound I phosphate exhibits a weight percent loss of about 4.6% between about 33°C and about 150°C by thermogravimetric analysis (TGA).

[0452] Compound I phosphate form H3 In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form H3.

[0453] In an embodiment of the disclosure, crystalline form H3 of Compound I phosphate is a solvate.

[0454] In an embodiment of the disclosure, crystalline form H3 of Compound I phosphate is an acetone solvate.

[0455] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form H3 of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form H3 of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form H3 of compound I phosphate.

[0456] In embodiments, crystalline form H3 of compound I phosphate exhibits an XRPD pattern including peaks at about 10.67, 18.77, and 22.04 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H3 of compound I phosphate exhibits an XRPD pattern including peaks at about 10.67, 17.95, 18.77, 22.04, and 23.64 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising at least two peaks selected from about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising at least three peaks selected from about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising at least four peaks selected from about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising at least five peaks selected from about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta, with an error margin of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising at least six peaks selected from about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising at least seven peaks selected from about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising peaks at about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0457] In an embodiment, crystalline form H3 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 10.67±0.2, 18.77±0.2, and 22.04±0.2 degrees two-theta.

[0458] In an embodiment, crystalline form H3 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 10.67±0.2, 17.95±0.2, 18.77±0.2, 22.04±0.2, and 23.64±0.2 degrees two-theta.

[0459] In an embodiment, crystalline form H3 of Compound I phosphate exhibits an XRPD further comprising at least two peaks selected from about 5.35±0.2, 7.46±0.2, 8.50±0.2, 11.51±0.2, 13.63±0.2, 15.36±0.2, 21.35±0.2, and 25.55±0.2 degrees two-theta.

[0460] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta of Table 30.

[0461] In an embodiment, crystalline form H3 of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 30 below.

[0462] In an embodiment, crystalline form H3 of Compound I phosphate exhibits an XRPD pattern substantially similar to FIG.

[0463] [Table 30]

[0464] Compound I phosphate form H4 In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form H4.

[0465] In an embodiment of the disclosure, crystalline form H4 of Compound I phosphate is a solvate.

[0466] In an embodiment of the disclosure, crystalline form H4 of Compound I phosphate is a THF solvate.

[0467] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form H4 of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form H4 of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form H4 of compound I phosphate.

[0468] In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern including peaks at about 5.32, 22.00, and 22.34 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern including peaks at about 5.32, 10.63, 18.74, 22.00, and 22.34 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 7.41, 8.47, 11.48, 11.75, 13.62, 14.01, 17.90, 23.05, and 23.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 7.41, 8.47, 11.48, 11.75, 13.62, 14.01, 17.90, 23.05, and 23.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 7.41, 8.47, 11.48, 11.75, 13.62, 14.01, 17.90, 23.05, and 23.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 7.41, 8.47, 11.48, 11.75, 13.62, 14.01, 17.90, 23.05, and 23.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 7.41, 8.47, 11.48, 11.75, 13.62, 14.01, 17.90, 23.05, and 23.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 7.41, 8.47, 11.48, 11.75, 13.62, 14.01, 17.90, 23.05, and 23.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 7.41, 8.47, 11.48, 11.75, 13.62, 14.01, 17.90, 23.05, and 23.54 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0469] In an embodiment, crystalline form H4 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.32±0.2, 22.00±0.2, and 22.34±0.2 degrees two-theta.

[0470] In an embodiment, crystalline form H4 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.32±0.2, 10.63±0.2, 18.74±0.2, 22.00±0.2, and 22.34±0.2 degrees two-theta.

[0471] In embodiments, crystalline form H4 of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 7.41±0.2, 8.47±0.2, 11.48±0.2, 11.75±0.2, 13.62±0.2, 14.01±0.2, 17.90±0.2, 23.05±0.2, and 23.54±0.2 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0472] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 31.

[0473] In an embodiment, crystalline form H4 of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 31 below.

[0474] In an embodiment, crystalline form H4 of Compound I phosphate exhibits an XRPD pattern substantially similar to FIG.

[0475] [Table 31]

[0476] Compound I phosphate form H5 In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form H5.

[0477] In an embodiment of the disclosure, crystalline form H5 of Compound I phosphate is a solvate.

[0478] In an embodiment of the disclosure, crystalline form H5 of Compound I phosphate is a DMSO solvate.

[0479] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form H5 of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form H5 of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form H5 of compound I phosphate.

[0480] In embodiments, crystalline form H5 of compound I phosphate exhibits an XRPD pattern including peaks at about 15.55, 18.84, and 21.66 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H5 of compound I phosphate exhibits an XRPD pattern including peaks at about 5.33, 15.55, 18.84, 21.30, and 21.66 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H5 of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 7.54, 10.63, 11.32, 13.54, 17.98, 20.90, 22.52, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In an embodiment, crystalline form H5 of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 7.54, 10.63, 11.32, 13.54, 17.98, 20.90, 22.52, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H5 of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 7.54, 10.63, 11.32, 13.54, 17.98, 20.90, 22.52, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In an embodiment, crystalline form H5 of compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 7.54, 10.63, 11.32, 13.54, 17.98, 20.90, 22.52, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form H5 of compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 7.54, 10.63, 11.32, 13.54, 17.98, 20.90, 22.52, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In an embodiment, crystalline form H5 of compound I phosphate exhibits an XRPD pattern further comprising at least seven peaks selected from about 7.54, 10.63, 11.32, 13.54, 17.98, 20.90, 22.52, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H5 of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 7.54, 10.63, 11.32, 13.54, 17.98, 20.90, 22.52, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0481] In an embodiment, crystalline form H5 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 15.55±0.2, 18.84±0.2, and 21.66±0.2 degrees two-theta.

[0482] In an embodiment, crystalline form H5 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.33±0.2, 15.55±0.2, 18.84±0.2, 21.30±0.2, and 21.66±0.2 degrees two-theta.

[0483] In an embodiment, crystalline form H5 of Compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 7.54±0.2, 10.63±0.2, 11.32±0.2, 13.54±0.2, 17.98±0.2, 20.90±0.2, 22.52±0.2 and 23.36±0.2 degrees two-theta.

[0484] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 32.

[0485] In an embodiment, crystalline form H5 of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 32 below.

[0486] In an embodiment, crystalline form H5 of Compound I phosphate exhibits an XRPD pattern substantially similar to FIG.

[0487] [Table 32]

[0488] Compound I phosphate form H6 In embodiments, the present disclosure relates to a crystalline form of Compound I phosphate, namely Form H6.

[0489] In an embodiment of the disclosure, crystalline form H6 of Compound I phosphate is a solvate.

[0490] In an embodiment of the disclosure, crystalline form H6 of Compound I phosphate is a benzyl alcohol solvate.

[0491] In embodiments, the crystalline form of compound I phosphate may comprise more than about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of form H6 of compound I phosphate. In another embodiment, the crystalline form of compound I phosphate may comprise more than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of form H6 of compound I phosphate. In some embodiments, the crystalline form of compound I phosphate may comprise more than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of form H6 of compound I phosphate.

[0492] In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern including peaks at about 5.27, 21.64, and 22.35 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern including peaks at about 5.27, 18.67, 21.64, 21.99, and 22.35 degrees 2-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern further comprising at least two peaks selected from about 8.38, 10.55, 11.47, 11.71, 13.44, 13.96, 15.45, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern further comprising at least three peaks selected from about 8.38, 10.55, 11.47, 11.71, 13.44, 13.96, 15.45, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern further comprising at least four peaks selected from about 8.38, 10.55, 11.47, 11.71, 13.44, 13.96, 15.45, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern further comprising at least five peaks selected from about 8.38, 10.55, 11.47, 11.71, 13.44, 13.96, 15.45, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern further comprising at least six peaks selected from about 8.38, 10.55, 11.47, 11.71, 13.44, 13.96, 15.45, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less. In embodiments, crystalline form H6 of compound I phosphate exhibits an XRPD pattern further comprising peaks at about 8.38, 10.55, 11.47, 11.71, 13.44, 13.96, 15.45, and 23.36 degrees two-theta, with an error range of about ±0.5, about ±0.4, about ±0.3, about ±0.2, about ±0.1, about ±0.05, or less.

[0493] In an embodiment, crystalline form H6 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.27±0.2, 21.64±0.2, and 22.35±0.2 degrees two-theta.

[0494] In an embodiment, crystalline form H6 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 8.38±0.2, 10.55±0.2, 11.47±0.2, 11.71±0.2, 13.44±0.2, 13.96±0.2, 15.45±0.2, and 23.36±0.2 degrees two-theta.

[0495] In an embodiment, crystalline form H6 of Compound I phosphate exhibits an XRPD pattern comprising peaks at about 5.27±0.2, 18.67±0.2, 21.64±0.2, 21.99±0.2, and 22.35±0.2 degrees two-theta.

[0496] In an embodiment, crystalline form H6 of Compound I phosphate exhibits an XRPD pattern comprising at least two peaks selected from about 8.38±0.2, 10.55±0.2, 11.47±0.2, 11.71±0.2, 13.44±0.2, 13.96±0.2, 15.45±0.2 and 23.36±0.2 degrees two-theta.

[0497] In some embodiments, the crystalline form of Compound I phosphate exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks or 10 peaks at ±0.2 degrees 2-theta in Table 33.

[0498] In an embodiment, crystalline form H6 of Compound I phosphate exhibits an XRPD pattern comprising the peaks shown in Table 33 below.

[0499] In an embodiment, crystalline form H6 of Compound I phosphate exhibits an XRPD pattern substantially similar to FIG.

[0500] [Table 33]

[0501] The crystalline forms of Compound I phosphate are summarized in Table 34 below.

[0502] [Table 34]

[0503] Pharmaceutical Compositions and Formulations In an embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, as an active ingredient, in combination with a pharma- ceutically acceptable excipient or carrier, as disclosed herein.In an embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, examples of which include Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, or Form H6. In embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form A* of Compound I and a pharma- ceutically acceptable excipient or carrier. Excipients are added to formulations for a variety of purposes.

[0504] In one embodiment of the present disclosure, the pharmaceutical composition comprises Compound I or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof as a mixture of various forms.

[0505] In embodiments, the pharmaceutical composition comprises a crystalline form of Compound I or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C-10, Form C-11, Form C-12, Form C-13, Form C-14, Form C-15, Form C-16, Form C-17, Form C-18, Form C-19, Form C-20, Form C-21, Form C-22, Form C-23, Form C-24, Form C-25, Form C-26, Form C-27, Form C-28, Form C-29, Form C-30, Form C-31, Form C-32, Form C-33, Form C-34, Form C-35, Form C-36, Form C-37, Form C-38, Form C-39, Form C-40, Form C-41, Form C-42, Form C-43, Form C-44, Form C-45, Form C-46, Form C-47, Form C-48, Form C-49, Form C-49, Form C-50, Form C-51, Form C-52, Form C-53, Form C-54, Form C-55, Form C-56, Form C-57, Form C-58, Form C-59, Form C-60, Form C-61, Form C-62, Form C-63, Form C-64, Form C-65, Form C-66, Form C-67, Form C-68, Form C-69, Form C-70 Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5 or Form H6) in about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1% or about 99.0% of the total amount of Compound I or a pharma- ceutically acceptable salt thereof, solvate thereof, or a salt solvate thereof. In embodiments, the pharmaceutical composition comprises a crystalline form of Compound I or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-7, Form A-6, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, or Form H6) in about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% of the total amount of Compound I or a pharma-ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof.In embodiments, the pharmaceutical composition comprises a crystalline form of Compound I or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B-10, Form B-11, Form B-12, Form B-13, Form B-14, Form B-15, Form B-16, Form B-17, Form B-18, Form B-19, Form B-20, Form B-21, Form B-22, Form B-23, Form B-24, Form B-25, Form B-26, Form B-27, Form B-28, Form B-29, Form B-30, Form B-31, Form B-32, Form B-33, Form B-34, Form B-35, Form B-36, Form B-37, Form B-38, Form B-39, Form B-40, Form B-41, Form B-42, Form B-43, Form B-44, Form B-45, Form B-46, Form B-47, Form B-48, Form B-49, Form B-50, Form B-51, Form B-52, Form B-53, Form B-54, Form B-55, Form B-56, Form B-57, Form B-58, Form B-59, Form B-60, Form B-61, Form B-62, Form B-63, Form B-64, Form B-65, Form B-66, Form B-67, Form B-68, Form B-69, Form B-70, Form B-71, Form B Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5 or Form H6) in about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25% or 20% of the total amount of Compound I or a pharma- ceutically acceptable salt thereof, solvate thereof, or solvate of a salt thereof. In one embodiment, the pharmaceutical composition comprises a crystalline form of Compound I or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, Form H6, Form H7, Form H8, Form H9, Form H10, Form H11, Form H12, Form H13, Form H14, Form H15, Form H16, Form H17, Form H18, Form H19, Form H20, Form H21, Form H22, Form H23, Form H24, Form H25, Form H26, Form H27, Form H28, Form H29, Form H30, Form H31, Form H32, Form H33, Form H34, Form H35, Form H36, Form H37, Form H38, Form H39, Form H40, Form H41, Form H42, Form H43, Form H44, Form H45, Form H46, Form H47, Form H48, Form H49, Form H50, Form H51, Form H52, Form H53, Form H54, Form H55, Form H56, Form H57, Form H58, Form H59, Form H60, Form H61, Form H62, Form H63, Form H64, Form H65, Form H66, Form H67, Form H68, Form H69, Form H70, Form H71, Form H7 4, Form H5 or Form H6) at about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 18% or 20% of the total amount of Compound I or a pharma- ceutically acceptable salt, solvate thereof, or a salt solvate thereof.

[0506] In an embodiment, compound I can be present in the pharmaceutical composition as a pharmaceutically acceptable salt. In an embodiment, compound I can be present in the pharmaceutical composition as a pharmaceutical solvate. In an embodiment, compound I can be present in the pharmaceutical composition as a pharmaceutical salt solvate. In an embodiment, compound I can be present in the pharmaceutical composition as a crystalline form of anhydrous free base of compound I. In an embodiment, compound I can be present in the pharmaceutical composition as a crystalline form of anhydrous pharmaceutically acceptable salt.

[0507] In embodiments, the pharmaceutical compositions described herein further comprise one or more additional therapeutically active agents, hi embodiments, the one or more additional therapeutically active agents are selected from therapeutic agents useful in the treatment of cancer, neurodegenerative diseases, autoimmune disorders, and aging.

[0508] In a further embodiment of the present disclosure, there is provided a pharmaceutical composition comprising one or more solid forms of Compound I or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., a crystalline form such as Form A, Form A*, Form A**, Form B*, Form A-1, Form B-1, Form A-2, Form B-2, Form A-3, Form B-3, Form C-3, Form A-4, Form A-5, Form A-6, Form A-7, Form B-7, Form A-8, Form B-8, Form A-9, Form B, Form C, Form J, Form K, Form H2, Form E, Form F, Form G, Form I, Form H1, Form H3, Form H4, Form H5, or Form H6), and a pharma- ceutically acceptable excipient or adjuvant. Pharmaceutically acceptable excipients and adjuvants are added to compositions or formulations for various purposes. In another embodiment, the pharmaceutical composition comprising one or more solid forms of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, further comprises a pharma- ceutically acceptable carrier. In one embodiment, the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable excipient, binder, and / or diluent. In one embodiment, suitable pharma- ceutically acceptable excipients include, but are not limited to, water, salt solution, alcohol, polyethylene glycol, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0509] In certain embodiments, the pharmaceutical composition of the present disclosure may further comprise other auxiliary components conventionally found in pharmaceutical compositions at their established technical level of use. Thus, for example, the pharmaceutical composition may comprise additional compatible pharmacoactive substances, such as, for example, antipruritic agents, astringents, local anesthetics, or anti-inflammatory agents, or may comprise additional substances, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickeners, and stabilizers, that are useful in physically formulating various dosage forms of the composition of the present invention. However, when added, such substances should not unduly interfere with the biological activity of the components of the composition of the present invention. The formulation may be sterilized and, if desired, mixed with auxiliary substances, examples of which include lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, flavorings, and / or aromatic substances that do not adversely interact with the oligonucleotide(s) of the formulation.

[0510] For the purpose of this disclosure, the solid form of Compound I of the present disclosure can be formulated for administration by various means, including oral, parenteral, inhalation spray, topical, or rectal administration in a formulation containing pharmaceutically acceptable carriers, adjuvants, and vehicles.As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, and intraarterial injections by various injection techniques.As used herein, intraarterial and intravenous injections include administration by catheter.

[0511] The solid form of compound I disclosed herein can be formulated according to routine procedures adapted to the desired route of administration. Thus, the solid form of compound I disclosed herein can take the form of a suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending agents, stabilizing agents and / or dispersing agents. The solid form of compound I disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the solid form of compound I can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle (an example of which is sterilized pyrogen-free water) before use. Suitable formulations for each of these administration methods can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0512] In certain embodiments, pharmaceutical compositions of the present disclosure are prepared using known techniques including, but not limited to, mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping or tabletting processes.

[0513] In an embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (IA), (IB), (IC), or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, as disclosed herein, in combination with a pharma- ceutically acceptable carrier. In one embodiment, suitable pharma- ceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are known to those skilled in the art and include, but are not limited to, about 0.01 to about 0.1 M, preferably 0.05 M, phosphate buffer or 0.8% saline. Such pharma- ceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

[0514] Aqueous carriers suitable for use in this application include, but are not limited to, water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets, and the like.

[0515] Liquid carriers suitable for use in this application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and pressurized compounds. The active ingredient can be dissolved or suspended in a pharma- ceutically acceptable liquid carrier, such as water, an organic solvent, a mixture of both, or a pharma- ceutically acceptable oil or lipid. The liquid carrier may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, coloring agents, viscosity regulators, stabilizers, or osmotic pressure regulators.

[0516] Liquid carriers suitable for use in this application include, but are not limited to, water (partially containing the above-mentioned additives, e.g., cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, carriers can also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful for parenteral administration in sterile liquid form, including solid forms of Compound I. Liquid carriers for pressurized compounds disclosed herein can be halogenated hydrocarbons or other pharma- ceutically acceptable propellants.

[0517] Suitable solid carriers for use in this application include, but are not limited to, inert materials such as lactose, starch, glucose, methylcellulose, magnesium stearate, calcium hydrogen phosphate, mannitol, etc. The solid carrier may further comprise one or more substances that act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, flow agents, compression aids, binders, or tablet disintegrants, and may also be encapsulating materials. In powders, the carrier may be a finely divided solid, which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted into the desired shape and size. Powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes, and ion exchange resins. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, which is optionally mixed with binders (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surfactants or dispersants, in a suitable machine. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets can be optionally coated or marked, and can be formulated to provide slow or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose in different proportions to obtain the desired release profile. The tablets can optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

[0518] Parenteral carriers suitable for use in this application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as antimicrobials, antioxidants, chelating agents, and inert gases and the like.

[0519] Carriers suitable for use in this application may be mixed with disintegrants, diluents, granulating agents, lubricants, binders, etc., as necessary, using conventional techniques known in the art. The carriers may also be sterilized using methods that do not deleteriously react with the compounds, as is known in the art.

[0520] Diluents may be added to the formulations of the present invention. Diluents may increase the bulk of solid pharmaceutical compositions and / or combinations, making pharmaceutical dosage forms containing the compositions and / or combinations easier for patients and caregivers to handle. Diluents for solid compositions and / or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0521] Further embodiments relate to pharmaceutical formulations selected from the group consisting of solids, powders, liquids and gels. In certain embodiments, the pharmaceutical compositions of the present invention are solids (e.g., powders, tablets, capsules, granules, and / or aggregates). In some such embodiments, the solid pharmaceutical compositions include one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrants.

[0522] Solid pharmaceutical compositions that are compressed into dosage forms such as tablets may contain excipients whose function includes helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions and / or pharmaceutical combinations include gum arabic, alginic acid, carbomers (e.g., Carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, tragacanth gum, hydrogenated vegetable oils, hydroxyethylcellulose, hydroxypropylcellulose (e.g., KLUCEL), hydroxypropylmethylcellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.

[0523] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by adding a disintegrant to the composition and / or combination, which includes alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.

[0524] Glidants may be added to improve the flowability of non-compacted solid compositions and / or combinations to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0525] When a powder composition is compressed to produce a dosage form such as a tablet, the composition is subjected to pressure from a punch and a die. Some excipients and active ingredients tend to adhere to the surfaces of the punch and die, which can cause the product to have holes and other surface irregularities. A lubricant can be added to the composition and / or combination to reduce adhesion and facilitate the release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0526] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common pharmaceutical flavoring agents and flavor enhancers that may be included in the compositions and / or combinations of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0527] Solid and liquid compositions may also be colored using any pharma- ceutically acceptable colorant to improve their appearance and / or to facilitate patient identification of the product and unit dosage levels.

[0528] In certain embodiments, the pharmaceutical compositions of the present invention are liquids (e.g., suspensions, elixirs and / or solutions). In some such embodiments, liquid pharmaceutical compositions are prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents.

[0529] Liquid pharmaceutical compositions can be prepared using one or more solid forms of Compound I, or a pharma- ceutically acceptable salt, solvate thereof, or salt solvate thereof, and any other solid excipient in which the ingredient is dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0530] For example, formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols, e.g., polyethylene glycol, vegetable oils, hydrogenated naphthalenes, and the like. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients for controlling the release of active compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration may contain, as excipients, e.g., lactose, or may be aqueous solutions, e.g., polyoxyethylene-9-auryl ether, glycocholate, and deoxycholate, or oily solutions for administration in the form of nasal drops, or gels to be applied intranasally. Formulations for parenteral administration may also contain glycocholate for buccal administration, methoxysalicylic acid for rectal administration, or citric acid for vaginal administration.

[0531] Liquid pharmaceutical compositions may contain emulsifying agents to disperse active ingredients or other excipients that are not soluble in the liquid carrier uniformly throughout the composition and / or combination. Emulsifying agents that may be useful in the liquid compositions and / or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methylcellulose, carbomer, cetostearyl alcohol and cetyl alcohol.

[0532] Liquid pharmaceutical compositions may also contain viscosity enhancing agents to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract, such agents include acacia, alginic acid, bentonite, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, tragacanth and xanthan gum.

[0533] Sweetening agents, such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar, may be added to improve taste.

[0534] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.

[0535] The liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. The selection of excipients and the amounts to be used can be readily determined by the formulation scientist based on experience in the art and consideration of standard procedures and references.

[0536] In one embodiment, the pharmaceutical composition is prepared for administration by injection (e.g., intravenously, subcutaneously, intramuscularly, etc.). In some such embodiments, the pharmaceutical composition includes a carrier and is formulated in an aqueous solution, such as water or a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer, etc. In certain embodiments, other ingredients (e.g., ingredients that aid in solubility or act as preservatives) are included. In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents, etc. Certain pharmaceutical compositions for injection are provided in unit dosage form, for example, in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions, or emulsions in oily or aqueous vehicles and may include formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. Particular solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents which increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.

[0537] Sterile injectable preparations may also be prepared as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as a solution in 1,3-butanediol, or as lyophilized powders. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, may similarly be used in the preparation of injectable drugs. Formulations for intravenous administration may include a solution in a sterile, isotonic aqueous buffer. If necessary, the formulation may also include a solubilizing agent and a local anesthetic to ease pain at the site of injection. Generally, the ingredients are supplied either separately or mixed together in a unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a sealed container, such as an ampoule or sachet indicating the quantity of active agent. If the solid form of Compound I is to be administered by infusion, the formulation can be dispensed with an infusion bottle containing sterile pharmaceutical grade water, saline, or dextrose / water. If the solid form of Compound I is to be administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0538] Suitable formulations further include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes which render the formulation isotonic with the body fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0539] In certain embodiments, the pharmaceutical composition of the present invention is formulated as depot preparation.Some of such depot preparations generally have a longer effect than non-depot preparations.In certain embodiments, such preparations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection.In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (e.g., emulsion in acceptable oil) or ion exchange resin, or as poorly soluble derivatives, for example, as poorly soluble salts.

[0540] In certain embodiments, the pharmaceutical composition of the present invention comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for the preparation of certain pharmaceutical compositions, including pharmaceutical compositions that comprise hydrophobic compounds. In certain embodiments, certain organic solvents, such as dimethylsulfoxide, are used.

[0541] In certain embodiments, the pharmaceutical composition of the present invention includes a co-solvent system. Some of such co-solvent systems include, for example, benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of 3 w / v% benzyl alcohol, 8 w / v% of the non-polar surfactant polysorbate 80, and 65 w / v% polyethylene glycol 300 in absolute ethanol. The proportions of such co-solvent systems can be varied significantly without significantly changing their solubility and toxicity properties. Furthermore, the identity of the co-solvent components can be varied, for example, other surfactants can be used in place of polysorbate 80, the fraction size of polyethylene glycol can be changed, other biocompatible polymers can replace polyethylene glycol, e.g., polyvinylpyrrolidone, and other sugars or polysaccharides can replace dextrose.

[0542] In certain embodiments, the pharmaceutical composition of the present invention comprises a sustained release system. A non-limiting example of such a sustained release system is a semipermeable matrix of solid hydrophobic polymers. In certain embodiments, sustained release systems may release drug over a period of hours, days, weeks, or months, depending on their chemical nature.

[0543] Suitable pharmaceutical compositions of the present disclosure can be determined according to any clinically accepted route of administration of the composition to a subject. The manner in which the composition is administered depends in part on the cause and / or location. Those skilled in the art will recognize the advantages of a particular route of administration. The method includes administering an effective amount (e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, the symptoms of the pathology (e.g., oncology and neurological disorders) to be treated) of one or more solid forms of a therapeutically active agent or compound I (or a composition comprising a therapeutic agent or compound I) to achieve a desired biological response. In various embodiments, the route of administration is systemic, for example, orally or by injection. The therapeutic agent or compound I, or a pharma- ceutically acceptable salt or derivative thereof, is administered orally, intranasally, transdermally, intrapulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneously, intramuscularly, intravenously, intrarectally, intrapleurally, intrathecally, intraportally, and parenterally. Alternatively or additionally, the route of administration is local, for example, locally intratumoral and peritumoral. In some embodiments, a solid form of Compound I is administered orally.

[0544] In certain embodiments, the pharmaceutical composition of the present disclosure is prepared for oral administration. In some such embodiments, the pharmaceutical composition is formulated by combining one or more agents with a pharma- ceutically acceptable carrier. Some such carriers allow the pharmaceutical composition to be formulated as a tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. for oral ingestion by a subject. Suitable excipients include, but are not limited to, bulking agents such as sugars, including lactose, sucrose, mannitol, or sorbitol, and cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). In certain embodiments, such mixtures are optionally milled and auxiliary agents are optionally added. In certain embodiments, the pharmaceutical composition is formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents are added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0545] In certain embodiments, the dragee core is coated. In certain such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings.

[0546] In certain embodiments, the pharmaceutical composition for oral administration is a push-fit capsule made of gelatin. Some of such push-fit capsules contain one or more of the agents of the present invention mixed with one or more fillers, such as lactose, binders, such as starch, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In certain embodiments, the pharmaceutical composition for oral administration is a sealed soft capsule made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more of the agents of the present invention are dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added.

[0547] In certain embodiments, pharmaceutical compositions are prepared for buccal administration. Some such pharmaceutical compositions are tablets or lozenges formulated in a conventional manner.

[0548] In certain embodiments, pharmaceutical compositions are prepared for transmucosal administration. In some of these embodiments, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0549] In certain embodiments, pharmaceutical compositions are prepared for administration by inhalation. Some of such pharmaceutical compositions for inhalation are prepared in the form of aerosol spray in pressurized packs or nebulizers. Some of such pharmaceutical compositions contain a propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using pressurized aerosol, the dosage unit can be determined by a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in inhalers or inhalers may be formulated. Some of such formulations include a powder mix of the agent of the present invention and a suitable powder base, such as lactose or starch.

[0550] In other embodiments, the solid form of Compound I of the present disclosure is administered by the intravenous route. In further embodiments, parenteral administration may be provided in a bolus or by infusion.

[0551] In certain embodiments, the pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema. Some such pharmaceutical compositions include known ingredients such as cocoa butter and / or other glycerides.

[0552] In certain embodiments, pharmaceutical compositions are prepared for topical administration.Some of such pharmaceutical compositions include a mild moisturizing base such as ointment or cream.Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum and volatile silicone, and lanolin and water-in-oil emulsion.Exemplary suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment.

[0553] In certain embodiments, a therapeutically effective amount is sufficient to prevent, alleviate, or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art.

[0554] In certain embodiments, one or more solid forms of Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, are formulated as a prodrug. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to a form that is more biologically, pharma- ceutical or therapeutically active.

[0555] The concentration of the disclosed solid form of Compound I in the pharma- ceutically acceptable mixture varies depending on several factors, including the dose of the solid form of Compound I administered, the pharmacokinetic properties of the solid form(s) employed, and the route of administration. The agent may be administered in a single dose or multiple doses. The dosing regimen utilizing the solid form of Compound I of the present invention is selected depending on various factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition to be treated, the route of administration, and the particular solid form or salt thereof employed. Daily or more frequent treatment may be performed depending on several factors, including the overall health of the patient, the formulation of the form(s) selected, and the route of administration.

[0556] Compound I, or a pharma- ceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, or a solid form of a pharmaceutical composition of the disclosure may be prepared and / or administered in single or multiple unit dosage forms.

[0557] Therapeutic Use The crystal forms and pharmaceutical compositions of the present disclosure are used in a number of ways. For example, in some embodiments, the crystal forms and pharmaceutical compositions are useful in methods for modulating phosphoinositide 3 kinase (PI3K). In embodiments, the modulation of phosphoinositide 3 kinase (PI3K) activity is performed in mammalian cells. In embodiments, the modulation of phosphoinositide 3 kinase (PI3K) can be performed in a subject in need thereof (e.g., a mammalian subject) for the treatment of a condition or disease described herein, including those conditions or disease states in which irreversible inhibition of PI3K provides therapeutic benefit to a subject having the disease or condition.

[0558] In one embodiment, the modulation of PI3K is binding to PI3K. In another embodiment, the modulation of PI3K is inhibiting PI3K, which includes irreversibly inhibiting the activity of PI3K. In an embodiment, the inhibition of PI3K is inhibiting PI3Kα, which includes irreversibly inhibiting the activity of PI3Kα, for example, by forming a covalent bond with the cysteine ​​residue on PI3Kα.

[0559] In an embodiment, the modulation of phosphoinositide 3 kinase (PI3K) activity is for the treatment of a disease or condition in which irreversible inhibition of PI3K provides a therapeutic benefit to a subject having the disease or condition. In an embodiment, the modulation of phosphoinositide 3 kinase (PI3K) activity is for the treatment of at least one indication selected from the group consisting of cancer, neurodegenerative disease, autoimmune disease, and aging. In an embodiment, the modulation of phosphoinositide 3 kinase (PI3K) activity is for the treatment of at least one indication selected from the group consisting of ampullary cancer, anal cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, blood cancer, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, kidney cancer, salivary gland cancer, skin cancer, vaginal cancer, and urothelial cancer. In embodiments, modulation of phosphoinositide 3-kinase (PI3K) activity is for the treatment of cancers associated with mutations in the PIK3CA gene.

[0560] In embodiments of the present disclosure, methods of treating cancer, a neurodegenerative disease, an autoimmune disease, or aging are provided.

[0561] In an embodiment of the present disclosure, a method for treating a pathology associated with cell proliferation in a patient in need of treatment is provided.In one embodiment, the present disclosure provides a method for treating cancer or tumor (e.g., solid tumor).In an embodiment, the present disclosure provides a method for treating cancer associated with mutation of PIK3CA gene.In another embodiment, the present disclosure provides a method for treating ampullary cancer, anal cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, blood cancer, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, kidney cancer, salivary gland cancer, skin cancer, vaginal cancer or urothelial cancer.

[0562] In an embodiment of the present disclosure, a method of reducing, inhibiting or improving cell proliferation in a patient in need thereof is provided. In an embodiment, the reduction, inhibition or improvement in the method disclosed herein is performed in vivo. In another embodiment, the reduction, inhibition or improvement is performed in vitro. In an embodiment, the cell in the method disclosed herein is a cancer cell. In an embodiment, the cancer cell is a prostate cancer cell.

[0563] In an embodiment, the cell proliferation-related condition or disease is cancer. In an embodiment, the cancer has a mutation in the PIK3CA gene. In an embodiment of the method disclosed herein, the cancer is selected from the group consisting of ampullary cancer, anal cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, blood cancer, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, kidney cancer, salivary gland cancer, skin cancer, vaginal cancer and urothelial cancer.

[0564] In an embodiment of the present disclosure, a method for reducing or preventing tumor growth is provided, comprising contacting a tumor cell with a compound or pharmaceutical composition as disclosed herein. In one embodiment, reducing or preventing tumor growth comprises a reduction in tumor volume. In one embodiment, reducing or preventing tumor growth comprises complete removal of the tumor. In one embodiment, reducing or preventing tumor growth comprises stopping or halting an existing tumor from growing. In one embodiment, reducing or preventing tumor growth comprises a slowing down of the rate of tumor growth. EXAMPLES

[0565] The present disclosure will now be generally described, but will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention.

[0566] The following examples are intended as illustrative and efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be considered within the knowledge of one of ordinary skill in the art. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar or TCI, and used without further purification unless otherwise indicated.

[0567] [Table 35-1]

[0568] [Table 35-2]

[0569] [Table 35-3]

[0570] [Table 35-4]

[0571] Example 1: Synthesis and characterization of a crystalline form of methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Compound I Form A)

[0572] [ka]

[0573] Synthesis of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1).

[0574] [ka]

[0575] Diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate. A 20 L reaction vessel was charged with diethyl 1H-pyrrole-2,4-dicarboxylate (1002 g, 1 eq, 4.507 mol) and NMP (7.8 L). Potassium tert-butoxide (557.3 g, 1.1 eq, 4.967 mol) was then added, the mixture turned pink and the temperature reached 37° C. The mixture was stirred until all the potassium tert-butoxide was dissolved and cooled to 21° C. Then O-(4-nitrobenzoyl)hydroxylamine (839.6 g, 1.02 eq, 4.610 mol) was added in portions (exothermic, reaching 36° C.). The reaction mixture turned into a deep purple suspension. The reaction mixture was stirred at 45° C. overnight (T slowly decreases and the mixture turns orange). A sample was taken after 18 hours and diluted with ACN / water for HPLC analysis. A solution of sodium dithionite (478.6 g, 0.6 equiv, 2.749 mol) in water (2.5 L) was then added slowly while keeping the temperature below 30°. The reaction mixture was transferred to a 50 L separatory funnel. Toluene (15 L) and water (5 L) were added and the phases were separated. The aqueous phase was extracted with toluene (3x1 L). The combined organic phase was washed with water (5x1 L), saturated sodium bicarbonate (5x1 L) and brine (1 L), dried over sodium sulfate, filtered and concentrated to give diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate (1077 g, 3.90 mol, 86%) as an orange oil (QNMR purity 81%) that solidified on standing. 1 H NMR (299MHz, DMSO-d6) δ 7.52(d, J=2.1Hz, 1H), 7.03(d, J=2.1Hz, 1H), 6.51(d, J=1.8Hz, 2H), 4.34-4.06(m, 4H), 1.38-1.14(m, 6H). LCMS(ESI): Observed value 227.0 [M+H] + (Calculated value 227.1 [M+H] + ).

[0576] Lithium 1-amino-4-(ethoxycarbonyl)-1H-pyrrole-2-carboxylate. A 10 L reaction vessel was charged with diethyl 1-amino-1H-pyrrole-2,4-dicarboxylate (1077 g, 1 eq, 3.90 mol), ethanol (3.8 L), and water (1.9 L). Lithium hydroxide monohydrate (163.9 g, 56 wt%, 0.99 eq, 3.831 mol) was added and the mixture was stirred at 60° C. The conversion was monitored by LCMS analysis. After 6 h the reaction was stopped and cooled to room temperature. The mixture was diluted with 2 L toluene and the layers were separated. The aqueous phase was washed with toluene (3×750 ml) and concentrated on a rotary evaporator at 60° C. The resulting solid was suspended in TBME (2 L), filtered, and washed with TBME (1 L). Lithium 1-amino-4-(ethoxycarbonyl)-1H-pyrrole-2-carboxylate (853.1 g, 3.50 mol, 90%) was obtained as a pale yellow solid (QNMR purity 83%). 1 H NMR (400MHz, DMSO-D6) δ 7.37(s, 2H), 7.09(d, J=2.2Hz, 1H), 6.63(d, J=2.2Hz, 1H), 4.12(q, J=7.1Hz, 2H), 1.22(t, J=7.1Hz, 3H). LCMS(ESI): Observed value 199.0 [M-Li+2H] + (Calculated value 199.1 [M-Li+2H] + ).

[0577] Ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1). To a suspension of lithium 1-amino-4-(ethoxycarbonyl)-1H-pyrrole-2-carboxylate (835.8 g, 1 equiv, 3.399 mmol) in a mixture of DMF (3.4 L) / MeTHF (8.5 mL) was added ammonium carbonate (2939 g, 9.00 equiv, 30.59 mol), followed by HOBt (1041 g, 2.0 equiv, 6.797 mol), EDCI HCl (1303 g, 2.0 equiv, 6.797 mol) and DIPEA (2.96 L, 5 equiv, 16.99 mol). The addition of the reagents causes an endothermic reaction. The flask was stirred at room temperature (suspension) for 3 days. The change was monitored by LCMS analysis. The solid was filtered, washed with MeTHF (2 L) and the filtrate was concentrated at 60° C. The crude material (2 kg) was redissolved in MeTHF (10 L) and washed with saturated sodium bicarbonate solution (2×2 L). Three phases were formed. The upper phase (product fraction) was separated, dried over sodium sulfate, filtered and concentrated to dryness. The resulting crude material (908 g) was recrystallized from EtOH (1.8 L). The solid was filtered, washed with EtOH (200 mL) and dried to give the first crop of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (67 g) as a white solid. The mother liquor was concentrated (794 g) and purified by column chromatography (silica 2 kg, gradient: DCM to 5% MeOH). The purified material (505 g) was recrystallized from EtOH (750 mL) and washed with EtOH (100 mL) to give a second crop of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (68 g). The concentrated mother liquor (435 g) was purified once more by column chromatography (6 kg silica, gradient: DCM to 5% MeOH). An additional crop of 61 g of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate was obtained by recrystallization of the product fraction. All crops were combined to give ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1) (195.7 g, 992.4 mmol, 29%) as a white solid. 1H NMR(299MHz, DMSO-d6) δ 7.96(s, 1H), 7.36(d, J=2.0Hz, 1H), 7.31(s, 1H), 7.13(d, J=2.1Hz, 1H), 6.86(d, J=1.8Hz, 2H), 4.18(q, J=7.1Hz, 2H), 1.25(t, J=7.1Hz, 3H). LCMS(ESI): Observed value 198.0 [M+H] + (Calculated value 198.1 [M+H] + ).

[0578] Synthesis of 6-amino-4-(trifluoromethyl)nicotinaldehyde

[0579] [ka]

[0580] 6-Amino-4-(trifluoromethyl)nicotinaldehyde (2). A 5 L three-neck flask equipped with a thermometer and under nitrogen was charged with 5-bromo-4-(trifluoromethyl)-2-pyridylamine (200.0 g, 1 equiv, 829.8 mmol) and dry THF (2000 mL). The solution was cooled to -70°C. A 2.5 M solution of n-butyllithium in hexanes (995.8 mL, 3.00 equiv, 2.49 mol) was added dropwise over 90 min, keeping the temperature below -60°C. The mixture was stirred at -70°C for 15 min. DMF (160.6 mL, 2.50 equiv, 2.074 mol) was then added dropwise over 45 min, keeping the temperature below -60°C. The mixture was stirred at -70°C for 30 min. The mixture was warmed to -40°C and carefully quenched with water (74.8mL, 5eq, 4.149mol). The resulting solution was allowed to warm to room temperature and stirred overnight. The mixture was further diluted with water / ethyl acetate (1L / 1L) and transferred to a separatory funnel. The organic layer was washed with water (5x300mL). The combined aqueous phase was extracted with ethyl acetate (3x300mL). The combined organic phase was washed with brine (300mL), dried over sodium sulfate, filtered and concentrated until a small amount of solvent remained and a solid formed. The mixture was cooled to room temperature and diluted with heptane (300mL). The mixture was filtered and the solid was washed with heptane and dried to give 6-amino-4-(trifluoromethyl)nicotinaldehyde (2) (51.5g, 271mmol, 33%) as an orange solid. 1 H NMR (299MHz, DMSO-d6) δ 9.80(q, J=1.7Hz, 1H), 8.63(d, J=2.1Hz, 1H), 7.73(s, 2H), 6.84(d, J=2.0Hz, 1H). LCMS(ESI): Observed value 191.0 [M+H] + (Calculated value 191.0 [M+H] + ).

[0581] Step 1: Synthesis of ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (3).

[0582] [ka]

[0583] A 3 L three-neck flask was fitted with a condenser, temperature probe and mechanical stirrer and charged with a solution of ethyl 1-amino-5-carbamoyl-1H-pyrrole-3-carboxylate (1) (195.7 g, 1.00 equiv., 962.7 mmol) and 6-amino-4-(trifluoromethyl)nicotinaldehyde (2) (192.7 g, 1.00 equiv., 962.7 mmol) in DMSO (1.9 L). Cupric chloride dihydrate (213.4 g, 1.30 equiv., 633.4 mmol) was then added and the mixture was stirred at 100° C. for 18 h. The mixture was cooled to room temperature and poured into ice water (10 L) causing precipitation of the product. The suspension was stirred for 30 min and then filtered (Buchner filter). The light brown filter cake was washed with water (3×1 L) and TBME (3×1 L). The solid was stripped with toluene (3×1 L) on a rotary evaporator to remove residual water, affording ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (3) (340.6 g, 760.0 mmol, 79%) as a solid. 1 H NMR(299MHz, DMSO-d6) δ 12.20(s, 1H), 8.08(d, J=1.8Hz, 1H), 7.23(d, J=1.8Hz, 1H), 7.05(s, 1H), 6.87(s, 1H), 4.26(q, J=6.9Hz, 2H), 1.29(t, J=7.1, 3H). LCMS(ESI): Observed value 368.0 [M+H] + (Calculated value 368.1 [M+H] + );366.0 [MH] - (Calculated value 366.1 [MH] - ).

[0584] Step 2: Synthesis of ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4).

[0585] [ka]

[0586] Ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (3) (335.6 g, 1 eq, 749.2 mmol), DMF (2.5 L) and morpholine (400 mL, 6.2 eq, 2.580 mol) were charged to a 5 L three-neck flask equipped with a thermometer under nitrogen. PyBOP (606.9 g, 1.55 eq, 1.166 mol) was then added in portions while keeping the temperature around 15° C. (exothermic). The mixture was stirred at room temperature for 48 hours. The reaction mixture was transferred to a 20 L vessel and water (12.5 L) was added slowly. The suspension was filtered through a Büchner filter and washed with water (3×5 L) and TBME (2×5 L). The remaining clayey material was redissolved in ethyl acetate at reflux. The hot suspension was filtered through a glass filter with Celite to remove copper and the filtrate was concentrated. The remaining solid was suspended in ethyl acetate (1 L) at 60 °C. The suspension was centrifuged at 3000 rpm. The resulting solution was decanted and concentrated. The residue was treated with warm ethyl acetate three more times. All organic phases were concentrated and the resulting solid was filtered, washed with TBME and dried under vacuum at 60 °C. The solid was stripped with toluene (2 × 1 L) to give ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4) (206.5 g, 473.2 mmol, 63%) as a pale yellow solid with a QNMR purity of 91%. 1 H NMR (300MHz, cdc 3) δ 8.56(s, 1H), 8.09(d, J=1.6Hz, 1H), 7.19(d, J=1.6Hz, 1H), 6.81(s, 1H), 4.88(s, 2H), 4.37(q, J=7.1Hz, 2H), 4.08(t, J=4.8Hz, 4H), 3.84(t, J=4.8Hz, 4H), 1.39(t, J=7.1Hz, 3H). LCMS(ESI): Observed value 437.2 [M+H] + (Calculated value 437.2 [M+H] + ).

[0587] Step 3: Synthesis of tert-butyl 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperazine-1-carboxylate (5)

[0588] [ka]

[0589] Ethyl 2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (4) (206.5 g, 91 wt%, 1 eq, 473.2 mmol) and THF (2 L) were charged to a 3 L three-neck flask under nitrogen. tert-Butyl piperazine-1-carboxylate (440.7 g, 5.0 eq, 2.366 mol) and TBD (65.87 g, 1.0 eq, 473.2 mmol) were then added and the solution was stirred at 65° C. for 2 days. The conversion was monitored by LCMS and proton NMR analysis. The reaction mixture was concentrated at 50° C. to remove most of the THF. The material was dissolved in ethyl acetate (1 L) and washed with 1 M potassium bisulfate solution (2 x 500 mL), water (3 x 500 ml, diluted with brine to improve separation), and brine (250 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated at 50 °C (foamy brown oil). The brown foam was stripped with toluene (1.5 L) to remove traces of ethyl acetate to give tert-butyl 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperazine-1-carboxylate (5) (382.0 g, 464 mmol, 98%) as a brown foam with QNMR purity of 70%. 1 H NMR (300MHz, cdc 3 ) δ 8.52(s, 1H), 7.77(d, J=1.6Hz, 1H), 6.98(d, J=1.7Hz, 1H), 6.80(s, 1H), 4.06(t, J=4.9Hz, 4H), 3.82(t, J=4.9Hz, 4H), 3.77-3.66(m, overlaps with THF signal but subtracts separate THF signal to give 4H), 3.48(t, J=5.0Hz, 4H), 1.47(m, 27H). LCMS(ESI): Observed 577.2 [M+H] + (Calculated value 577.3 [M+H] + ).

[0590] Step 4: tert-Butyl 4-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (6).

[0591] [ka]

[0592] A 5 L three-neck flask was charged with tert-butyl 4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)piperazine-1-carboxylate (5) (271.0 g, 1 equiv., 470.0 mmol) and dry THF (2 L) under nitrogen. The resulting solution was cooled to 0° C. and a solution of TMS-Cl (107.0 nmol, 1.80 equiv., 846.0 mmol) in dry THF (100 mL) was added (the mixture forms a brown suspension). The mixture was further cooled to −20° C. and 2.4 M LiAlH in THF was added. 4 (294.0 mL, 1.50 equiv, 705.0 mmol) was added over 80 min. The reaction mixture was stirred at -20 °C for 60 min. A 2 M solution of Rochelle's salt (1 L) was added slowly (very exothermic at first, gas evolution occurred) between -20 °C and -10 °C (the mixture became very thick and a solid formed after 100 ml addition). The solid slowly dissolved at -8 °C and became easy to stir again. The mixture was allowed to warm to room temperature overnight. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (6 kg silica, eluent: DCM / 3.5 M NH 3 in MeOH) to give tert-butyl 4-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (6) (172.2 g, 306.1 mmol, 65%) as an off-white fluffy solid.1 H NMR (299MHz, cdc 3 ) δ 8.53(s, 1H), 7.58(d, J=1.5Hz, 1H), 6.80(s, 1H), 6.67(d, J=1.6Hz, 1H), 4.82(s, 2H), 4.14-3.95(m, 4H), 3.82(t, J=4.8Hz, 4H), 3.58(s, 2H), 3.44(t, J=5.3Hz, 4H), 2.43(t, J=5.1Hz, 4H), 1.45(d, J=1.4Hz, 9H). LCMS(ESI): Observed value 563.3 [M+H] + (Calculated value 563.3 [M+H] + );561.2 [MH] - (Calculated value 561.3 [MH] - ).

[0593] Step 5: tert-Butyl 4-((2-(6-((methoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (7).

[0594] [ka]

[0595] A 3 L three-neck flask was charged with tert-butyl 4-((2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (6) (172.2 g, 1 equiv, 306.1 mmol), DCM (1.4 L) and pyridine (74 mL, 3.0 equiv, 918.2 mmol) and the solution was cooled to 0° C. To the reaction mixture was added methyl carbonochloridate (26.1 mL, 1.10 equiv, 336.7 mmol) over 30 min. The mixture was allowed to slowly warm to room temperature and stirred overnight. HPLC analysis showed approximately 90% conversion. Additional methyl carbonochloridate (2.4 mL, 0.10 equiv., 30.6 mmol) was added dropwise over 5 min and the mixture was stirred at room temperature. After 4 h, HPLC analysis indicated complete conversion was achieved. The reaction mixture was poured into cold water (500 ml) and transferred to a separatory funnel. The organic layer was collected, washed with water (3×500 ml) and brine, dried over sodium sulfate, filtered, and concentrated. The residue was stripped with toluene to give tert-butyl 4-((2-(6-((methoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (7) (174.1 g, 280.5 mmol, 92% yield) as a solid. 1 H NMR (299MHz, cdc 3 ) δ 8.87(s, 1H), 8.74(s, 1H), 8.43(s, 1H), 7.59(d, J=1.5Hz, 1H), 6.69(d, J=1.6Hz, 1H), 4.05(t, J=4.8Hz, 4H), 3.84(d, J=7.1Hz, 7H), 3.59(s, 2H), 3.45(t, J=5.1Hz, 4H), 2.44(t, J=4.9Hz, 4H), 1.45(s, 9H). LCMS(ESI): Observed value 621.3 [M+H] + (Calculated value 621.8 [M+H] + );619.2 [MH] - (Calculated value 619.3 [MH] - ).

[0596] Step 6: Methyl (5-(4-morpholino-6-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate hydrochloride (8).

[0597] [ka]

[0598] A flask under nitrogen was charged with tert-butyl 4-((2-(6-((methoxycarbonyl)amino)-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-6-yl)methyl)piperazine-1-carboxylate (7) (172.1 g, 1 equiv, 277.3 mmol) and CPME (1.0 L) (white suspension) and the mixture was cooled to 6° C. A solution of HCl in CPME (1.5 L, 3.0 molar, 16.2 equiv, 4.50 mol) was added over 30 min (only a slight exotherm) and the mixture was stirred at room temperature overnight (a yellow precipitate formed immediately). HPLC analysis showed complete conversion. The mixture was filtered and the solid was washed with 250 ml CPME and 500 ml TBME. The solid was transferred to a flask, but since it was very sticky (likely hygroscopic), MeOH was used to transfer the solid. The mixture was concentrated on a rotary evaporator and the solid was dried to give 198 g of crude product. The material was stripped with toluene (2×1 L) and then recrystallized. The crude material (191 g) was recrystallized from MeOH (300 mL). The solid was collected by filtration, washed with cold MeOH (50 mL), and dried to give methyl (5-(4-morpholino-6-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate dihydrochloride (8) (88.8 g, 150 mmol, 54% yield) as a solid. 1H NMR(400MHz, DMSO-D6) δ 12.13(s, 1H), 10.92(s, 1H), 9.59(s, 2H), 8.73(s, 1H), 8.31(s, 1H), 8.07(s, 1H), 7.38(s, 1H), 4.41(s, 2H), 4.02(t, J=4.9Hz, 4H), 3.80-3.69(m, 8H), 3.69-3.33(m, 13H), 3.16(s, 3H). LCMS(ESI): Observed value 521.2 [M+H] + (Calculated value 521.2 [M+H] + ).

[0599] Step 7: Methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (compound 1).

[0600] [ka] Acryloylglycine. A 2 L RBF was charged with glycine (200 g, 1.0 equiv, 2.66 mol), deionized water (88 mL), and sodium hydroxide (710 mL, 30 wt%, 2.0 equiv, 5.32 mol). The mixture was cooled to -5°C, and then acryloyl chloride (225 mL, 96 wt%, 1.0 equiv, 2.66 mol) was added while maintaining the temperature around 0°C. The mixture was stirred at 0°C for 1 h. After 1 h, the mixture was acidified with HCl (310 mL, 12 molar, 1.4 equiv, 3.72 mol) to pH 2. The mixture was saturated with sodium sulfate (±100 g) and diluted with warm MeTHF (300 mL). The phases were separated and the aqueous phase was extracted with MeTHF (3 x 250 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, and concentrated. A solvent exchange to ethyl acetate (an additional 500 mL) was performed in a volume of approximately 500 mL. After removing 500 mL of ethyl acetate, the solvent switch was repeated two more times. The resulting slurry was stirred at room temperature for 1 h, after which the solid was collected, rinsed with ethyl acetate (2×60 mL), dried under vacuum, and further dried on a rotary evaporator to give acryloylglycine (76.00 g, 588.6 mmol, 22% yield) as a white solid. 1 H NMR(299MHz, DMSO-d6) δ 12.58(s, 1H), 8.42(t, J=6.0Hz, 1H), 6.30(ddd, J=17.1, 10.1, 0.8Hz, 1H), 6.10(ddd, J=17.2, 2.3, 0.8Hz, 1H), 5.62(ddd, J=10.1, 2.3, 0.8Hz, 1H), 3.84(ddd, J=6.0, 0.8Hz, 2H). LCMS(ESI): Observed value 130.1 [M+H] + (Calculated value 130.1 [M+H] + ).

[0601] To a suspension of methyl (5-(4-morpholino-6-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate dihydrochloride (8) (73.2 g, 1 equiv., 123 mmol) in THF (750 mL) was added DIPEA (100 mL, 4.7 equiv., 416 mmol), the mixture slowly went into solution and then became cloudy again. Acryloylglycine (23.9 g, 1.5 equiv., 185 mmol) was added, followed by HATU (93.8 g, 2 equiv., 247 mmol), and the mixture (yellow) was stirred at room temperature. After 20 min, the mixture became a black suspension. After 1 h, the reaction was complete and was diluted with 600 mL of ethyl acetate and quenched with 600 mL of saturated sodium bicarbonate solution. The organic phase was separated and washed with saturated sodium bicarbonate solution (600 mL) and brine (2×400 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give 147.2 g of crude material as a red sticky oil. The crude material was dissolved in NMP (600 mL) at room temperature and water (1.5 L) was added dropwise. The mixture was stirred at room temperature for 1 h and then filtered. The residue was washed thoroughly with water and TBME to remove most of the NMP. The resulting solid was dissolved in DMSO (470 mL) and precipitated by adding water (900 mL). Once again the residue was washed thoroughly with water and TBME to remove most of the NMP and DMSO. After drying the material overnight in a circulating oven at 40° C., methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (compound I) (57.7 g, 91.4 mmol, 74% yield) was obtained as a solid. 1H NMR(400MHz, DMSO-D6) δ 10.89(s, 1H), 8.72(s, 1H), 8.30(s, 1H), 8.20(t, J=5.5Hz, 1H), 7.75(d, J=1.5Hz, 1H), 6.97(d, J=1.6Hz, 1H), 6.37(dd, J=17.1, 10.2Hz, 1H), 6.09(dd, J=17.1, 2.2Hz, 1H), 5.59(dd, J=10.2, 2.2Hz, 1H), 4.02(d, J=5.5Hz, 2H), 3.98(t, J=4.9Hz, 4H), 3.74(d, J=4.4Hz, 7H), 3.57(s, 2H), 3.52-3.37(m, 4H), 2.39(dt, J=17.8, 4.9Hz, 4H). LCMS(ESI): Observed value 632.4 [M+H] + (Calculated value 632.3 [M+H] + );630.2 [MH] - (Calculated value 630.2 [MH] - ).

[0602] Compound I Free Base Form A

[0603] The chemical purity by HPLC was 97.1% [area %].

[0604] X-ray powder diffraction (XRPD) analysis was performed on the solid crystals of crystalline form A of compound I. The XRPD is shown in Figure 1A. The characteristic peaks include one or more of the peaks shown in Table 1. Form A was successfully determined in this study, and the results show that it is anhydrous.

[0605] DSC and TGA thermograms were also obtained for Form A of Compound I, as shown in Figures 1B and 1C, respectively. The DSC showed a small endothermic peak at about 12 °C, which is due to the evaporation of free water and a T of 199.2 °C. onset It decomposes upon melting. TGA shows a weight loss of about 0.6% at about 160°C. 1 H-NMR shows no detectable residual solvent.

[0606] DVS (Dynamic Vapor Sorption) analysis at 25 °C was performed on compound I form A, as shown in Figure 1D. Compound I form A is slightly hygroscopic, picking up approximately 1.4% water at 40%-95% RH. After DVS testing, the obtained sample was still free base pattern A.

[0607] Example 2: Preparation and characterization of salt polymorphs of Compound I The experiment was carried out as follows.

[0608] Condition A: Approximately 30 mg of the free base form A of compound I and 1 equivalent of acid were added to DCM in a 2 mL glass vial. The resulting mixture was stirred at 25° C. for at least 72 hours.

[0609] Conditions B / C: Approximately 30 mg of the free base form A of compound I and 1 equivalent of acid were added to MeOH or acetone in a 2 mL glass vial. The resulting mixture was stirred at 50° C. for 2 hours and then at 25° C. for at least 72 hours.

[0610] The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. After drying under vacuum at 50° C. for 2 hours, the solid was analyzed by XRPD. See, e.g., Figures 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17, 18A, and 19A.

[0611] The results are summarized in Table A below.

[0612] [Table 36-1]

[0613] [Table 36-2]

[0614] Example 3: Preparation and characterization of a crystalline form of methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate phosphate (Compound I phosphate Form A*).

[0615] 3-1: Crystallization from MeOH / water system

[0616] Crystalline Form A* of Compound I phosphate was prepared using the following procedure.

[0617] 500 mg of compound I free base form A was weighed into a 20 mL glass vial. 6 mL of MeOH and 40 μL of water were added to the vial under stirring at 50° C. Then, about 1.05 equivalents of phosphoric acid was added to the resulting suspension. Then, about 2 mg of compound I phosphate form A* seeds were added to the suspension. The suspension was stirred at 50° C. for about 2 hours, then cooled to 25° C., and continued to stir at 25° C. for about 5 days. Then, 500 mg of compound I free base form A was weighed into a 20 mL glass vial and added to the above suspension, and another 4 mL of MeOH and 40 μL of water were added to the vial. The resulting suspension was stirred at 50° C., about 1.05 equivalents of phosphoric acid was added to the suspension, and the resulting suspension was stirred at 50° C. for about 2 hours, then cooled to 25° C., and continued to stir at 25° C. for about 1 day. The solid was collected by suction filtration and then dried under vacuum at 50° C. for about 2 hours to give 1.1 g of crystalline Form A* of Compound I phosphate in 95% yield, with a chemical purity of 97.4% [area %] by HPLC.

[0618] X-ray powder diffraction (XRPD) analysis was performed on the solid crystals of crystalline form A* of compound I phosphate. The XRPD is shown in Figure 2A. The characteristic peaks include one or more of the peaks shown in Table 2. Form A was successfully determined in this study, and the results show that it is a hydrate. Karl Fischer (KF) shows that crystalline form A* of compound I phosphate contains about 4.5% water by weight, which is equivalent to 1.9 water molecules.

[0619] DSC and TGA thermograms were also obtained for Form A* of Compound I phosphate, as shown in Figures 2B and 2C, respectively. The DSC showed a dehydration peak at about 9°C and a T of 188.7°C. onset It decomposes upon melting. TGA shows a weight loss of about 3.7% at about 170°C. Ion chromatography (IC) shows the free base:PO 4 3- This indicates that the ratio is 1:1.1. 1 H-NMR shows no detectable residual solvent.

[0620] As shown in FIG. 2D, DVS (Dynamic Vapor Sorption) analysis was performed on Compound I phosphate Form A* at 25° C. Compound I phosphate Form A* is slightly hygroscopic below 90% RH. As a result, it becomes hygroscopic and shows 3.3% water uptake from 40% RH to 95% RH. Compound I phosphate Form A* dehydrates below 30% RH and changes to a hydrate form above 30% RH. After the DVS test, the obtained sample was still Compound I phosphate Form A*.

[0621] Variable humidity XRPD (VH-XRPD) experiment.

[0622] Approximately 10 mg of Compound I phosphate Form A* was used as starting material. XRPD analysis was performed at each specific relative humidity at 25° C. Steps: 40% RH (initial)-60% RH (4 hrs)-80% RH (4 hrs)-40% RH (4 hrs)-20% RH (4 hrs)-0% RH (4 hrs)-40% RH (4 hrs).

[0623] [Table 37]

[0624] Variable humidity XRPD experiments and DVS isotherms showed that when the relative humidity was below 20% RH, Compound I phosphate Form A* dehydrated and gradually changed to Compound I phosphate anhydrous crystalline Form B. Compound I phosphate anhydrous Form B reverted to Compound I phosphate hydrate Form A* above 20% RH.

[0625] [Table 38]

[0626] Humidification and drying treatment

[0627] To avoid morphological changes during drying, the following humidification drying process was developed.

[0628] Test 1: The wet sample was humid-dried for 43 hours at 25 °C and 30-40% relative humidity (RH), revealing less than 0.01% EtOH, approximately 6.0% KF, and the crystal form was Form A* of Compound I phosphate.

[0629] Test 2: The wet sample was humid-dried at 30°C and 60-70% RH for 43 hours, revealing less than 0.01% EtOH, approximately 6.3% KF, and the crystal form was Form A* of Compound I phosphate.

[0630] Test 3: The wet sample was humid-dried at 35°C and 30-40% relative humidity (RH) for 67 hours, revealing less than 0.01% EtOH, approximately 5.7% KF, and the crystalline form was Form A* of Compound I phosphate.

[0631] Test 4: The wet sample was humid-dried at 35°C and 60-70% relative humidity (RH) for 67 hours, revealing less than 0.01% EtOH, approximately 6.1% KF, and the crystalline form was Form A* of Compound I phosphate.

[0632] Example 4: Preparation and characterization of a crystalline form of methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate benzenesulfonate (Compound I benzenesulfonate Form A**).

[0633] Crystalline Form A** of Compound I benzenesulfonate salt was prepared using the following procedure.

[0634] 500 mg of compound I free base form A was weighed into a 20 mL glass vial. 2.5 mL of MeOH was added to the vial and the resulting suspension was stirred at 50° C. Then, about 1.05 equivalents of benzenesulfonic acid was dissolved in 1 mL of MeOH and added to the suspension. Then, about 2 mg of compound I benzenesulfonate seed crystal form A** was added to the above suspension. The resulting suspension was stirred at 50° C. for about 2 hours, then cooled to 25° C., and continued to stir at 25° C. for about 5 days. 500 mg of compound I free base form A was weighed into a 20 mL glass vial and added to the above suspension. Another 4.5 mL of MeOH was added to the vial and the suspension was stirred at 50° C. Then, about 1.05 equivalents of benzenesulfonic acid was dissolved in 1 mL of MeOH and then this clear solution was added to the suspension. The resulting suspension was stirred at 50° C. for about 2 hours, then cooled to 25° C. and continued to stir at 25° C. for about 1 day. The solids were collected by suction filtration and then dried under vacuum at 50° C. for about 2 hours to give 1.14 g of crystalline form A** of compound I benzenesulfonate in 91% yield. Chemical purity by HPLC was 97.3% [area %].

[0635] X-ray powder diffraction (XRPD) analysis was performed on the solid crystals of crystalline form A** of compound I benzenesulfonate. The XRPD is shown in Figure 3A. Characteristic peaks include one or more of the peaks shown in Table 3. Form A was successfully determined in this study, and the results show that it is anhydrous.

[0636] DSC and TGA thermograms were also obtained for Form A** of Compound I benzenesulfonate salt, as shown in Figures 3B and 3C, respectively. DSC shows that it decomposed upon melting (around 250°C). TGA shows a weight loss of about 1.1% at about 190°C. 1 H-NMR shows a 1:1 ratio of free base to benzenesulfonic acid. 1 H-NMR shows no detectable residual solvent.

[0637] DVS (Dynamic Vapor Sorption) analysis was performed on Form A** of Compound I Benzene Sulfonate at 25 °C, as shown in Figure 3D. Form A** of Compound I Benzene Sulfonate is slightly hygroscopic, picking up approximately 1.4% water at 40%-95% RH. After the DVS test, the obtained sample was still Form A** of Compound I Benzene Sulfonate.

[0638] Example 5: Preparation and characterization of a crystalline form of methyl (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate maleate (Compound I maleate Form B*).

[0639] Crystalline Form B* of Compound I maleate salt was prepared using the following procedure.

[0640] 1.0 g of the free base form A of compound I was weighed into a 20 mL glass vial, 11 mL of MeOH and 40 μL of water were added to the vial, and the resulting suspension was stirred at 50° C. Maleic acid (1.05 equivalents) was added to the suspension, followed by about 2 mg of seeds of crystalline form B* of compound I maleate. The resulting suspension was stirred at 50° C. for about 2 hours, then cooled to 25° C., and continued to stir at 25° C. for about 2 days. The solid was collected by suction filtration and then dried under vacuum at 50° C. for about 2 hours to give 1.1 g of crystalline form B* of compound I maleate in 92% yield. Chemical purity by HPLC was 97.9% [area %].

[0641] X-ray powder diffraction (XRPD) analysis was performed on the solid crystals of crystalline form B* of compound I maleate. The XRPD is shown in Figure 4A. The characteristic peaks include one or more of the peaks shown in Table 4. In this study, the form B* of compound I maleate was successfully determined, and the results show that it is a hydrate. KF shows that it contains about 3.2% water by weight, which is equivalent to 1.4 water molecules.

[0642] DSC and TGA thermograms were also obtained for Form B* of Compound I maleate, as shown in Figures 4B and 4C. The DSC showed a dehydration peak at approximately 10°C and a T of 166.2°C. onset It decomposes upon melting. TGA shows a weight loss of about 1.8% at about 130°C. 1 H-NMR shows a 1:1.1 ratio of free base:maleic acid. 1 H-NMR also shows no detectable residual solvent.

[0643] As shown in Figure 4D, DVS (dynamic vapor sorption) analysis at 25 °C was performed on form B* of compound I maleate. Form B* of compound I maleate exhibits nearly monotonic moisture sor...

Claims

1. Crystal morphology of compound I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, its solvate, or its salt solvate.

2. The crystalline form according to claim 1, wherein compound I is anhydrous or non-solvated.

3. a) X-ray powder diffraction (XRPD) pattern including peaks at two thetas of approximately 9.11±0.2, 22.21±0.2, and 24.99±0.2 degrees; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 9.11±0.2, 16.93±0.2, 18.70±0.2, 22.21±0.2 and 24.99±0.2 degrees in the 2-theta; or c) The crystalline form according to claim 1, which exhibits an X-ray powder diffraction (XRPD) pattern with peaks at approximately 9.11±0.2, 16.93±0.2, 18.70±0.2, 20.54±0.2, 20.78±0.2, 22.21±0.2 and 24.99±0.2 degrees in a two-theta plane.

4. The crystalline morphology according to claim 3, wherein the XRPD pattern further includes at least two peaks selected from two thetas of approximately 4.47±0.2, 12.45±0.2, 14.51±0.2, 22.70±0.2, and 26.54±0.2 degrees.

5. a) showing an XRPD pattern including the peaks in Table 1; and / or b) Exhibiting an XRPD pattern substantially similar to that of Figure 1A; and / or c) A differential scanning calorimetry (DSC) thermogram showing an endothermic peak beginning at approximately 199°C; and / or d) The crystalline form according to claim 1, which exhibits a weight percentage loss of about 0.6% between about 25°C and about 160°C as determined by thermogravimetric analysis (TGA).

6. The crystalline form according to claim 1, which is a crystalline form of the phosphate of compound I or its solvate.

7. The crystalline form according to claim 6, wherein the crystalline form is a hydrate.

8. a) X-ray powder diffraction (XRPD) pattern including peaks at two thetas of approximately 5.33±0.2, 15.97±0.2, and 22.97±0.2 degrees; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.33±0.2, 10.63±0.2, 15.97±0.2, 20.95±0.2 and 22.97±0.2 degrees in the 2-theta; or c) The crystalline form according to claim 6, which exhibits an X-ray powder diffraction (XRPD) pattern including peaks at approximately 5.33±0.2, 10.63±0.2, 15.97±0.2, 20.26±0.2, 20.95±0.2, 22.71±0.2 and 22.97±0.2 degrees in a two-theta region.

9. The crystalline morphology according to claim 8, wherein the XRPD pattern further includes at least two peaks selected from two thetas of approximately 7.24±0.2, 14.94±0.2, 18.64±0.2, 18.99±0.2, and 21.34±0.2 degrees.

10. a) showing an XRPD pattern including the peaks in Table 2; and / or b) Exhibiting an XRPD pattern substantially similar to that of Figure 2A; and / or c) A differential scanning calorimetry (DSC) thermogram showing an endothermic peak at approximately 8.5°C; and / or d) A differential scanning calorimetry (DSC) thermogram showing an endothermic peak beginning at approximately 189°C; and / or e) The crystalline form according to claim 6, which exhibits a weight percent loss of approximately 3.75% between approximately 34°C and approximately 170°C, as determined by thermogravimetric analysis (TGA).

11. The crystalline form of the benzenesulfonate salt of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 7.36±0.2, 18.92±0.2, and 19.54±0.2 degrees in the two theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 7.36±0.2, 14.71±0.2, 18.52±0.2, 18.92±0.2 and 19.54±0.2 degrees in a two-theta; or c) The crystal morphology according to claim 1, which exhibits an X-ray powder diffraction (XRPD) pattern including peaks at approximately 7.36±0.2, 10.08±0.2, 14.71±0.2, 18.52±0.2, 18.92±0.2, 19.54±0.2 and 21.31±0.2 degrees in a two-theta region.

12. The crystalline form of the maleate of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.78±0.2, 7.07±0.2, and 19.83±0.2 degrees in the 2-theta region; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.78±0.2, 7.07±0.2, 12.27±0.2, 19.83±0.2 and 20.84±0.2 degrees in a two-theta; or c) The crystal morphology according to claim 1, which exhibits an X-ray powder diffraction (XRPD) pattern including peaks at approximately 4.78±0.2, 7.07±0.2, 12.27±0.2, 19.83±0.2, 20.84±0.2, 20.98±0.2 and 24.35±0.2 degrees in a two-theta plane.

13. The crystalline form of the hydrochloride salt of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.83±0.2, 7.14±0.2, and 9.20±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.83±0.2, 5.38±0.2, 7.14±0.2, 9.20±0.2 and 22.78±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 7.40±0.2, 23.26±0.2, and 24.21±0.2 degrees in theta; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.48±0.2, 7.40±0.2, 7.79±0.2, 23.26±0.2, and 24.21±0.2 degrees in the 2-theta; e) XRPD pattern including the peaks in Table 5; or f) The crystal morphology according to claim 1, which shows an XRPD pattern including the peaks in Table 6.

14. The crystalline form of the sulfate of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 6.95±0.2, 9.52±0.2, and 9.82±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 6.95±0.2, 9.52±0.2, 9.82±0.2, 12.92±0.2, and 19.46±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 17.85±0.2, 20.29±0.2, and 24.63±0.2 degrees in the 2-theta region; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 17.85±0.2, 20.29±0.2, 23.26±0.2, 24.63±0.2 and 24.74±0.2 degrees in the 2-theta; e) XRPD pattern including the peaks in Table 7; or f) The crystal morphology according to claim 1, which shows an XRPD pattern including the peaks in Table 8.

15. The crystalline form of the mesylate salt or solvate of compound I, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 10.23±0.2, 14.18±0.2, and 18.56±0.2 degrees in two theta positions; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.41±0.2, 7.09±0.2, 10.23±0.2, 14.18±0.2 and 18.56±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern further including at least two peaks selected from 2-theta at approximately 3.55±0.2, 10.78±0.2, 12.45±0.2, 18.76±0.2, 19.82±0.2, 21.89±0.2, 22.32±0.2 and 23.24±0.2 degrees; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.80±0.2, 7.20±0.2, and 19.93±0.2 degrees in the 2-theta; e) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.80±0.2, 7.20±0.2, 18.28±0.2, 19.93±0.2 and 21.17±0.2 degrees in the 2-theta; f) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 7.09±0.2, 16.73±0.2, and 22.68±0.2 degrees in the 2-theta region; g) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 6.89±0.2, 7.09±0.2, 16.73±0.2, 22.34±0.2, and 22.68±0.2 degrees in the 2-theta; h) XRPD pattern including the peaks in Table 9; i) XRPD pattern including the peaks in Table 10; or j) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 11.

16. The crystalline form of the tosylate of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 7.46±0.2, 9.99±0.2, and 19.09±0.2 degrees in the 2-theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 7.46±0.2, 9.99±0.2, 14.89±0.2, 19.09±0.2 and 22.39±0.2 degrees in the 2-theta; or c) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 12.

17. The crystalline form of the fumarate of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 18.12±0.2, 23.11±0.2, and 23.59±0.2 degrees in the two theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.31±0.2, 18.12±0.2, 19.79±0.2, 23.11±0.2 and 23.59±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 3.99±0.2, 23.84±0.2, and 25.40±0.2 degrees in theta; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 3.99±0.2, 23.70±0.2, 23.74±0.2, 23.84±0.2 and 25.40±0.2 degrees in theta; or e) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 13.

18. The crystalline form of the L-tartrate salt of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.61±0.2, 6.93±0.2, and 19.66±0.2 degrees in the 2-theta region; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.61±0.2, 6.93±0.2, 17.51±0.2, 19.66±0.2 and 21.75±0.2 degrees in the 2-theta; or c) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 15.

19. The crystalline form of the citrate of compound I or its solvate, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.56±0.2, 9.15±0.2, and 12.05±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.56±0.2, 9.15±0.2, 12.05±0.2, 17.43±0.2 and 18.63±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.36±0.2, 6.85±0.2, and 20.59±0.2 degrees in the 2-theta region; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.36±0.2, 6.85±0.2, 17.81±0.2, 20.59±0.2, and 22.81±0.2 degrees in the 2-theta; e) XRPD pattern including the peaks in Table 17; or f) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 18.

20. The succinate of compound I or its solvate is in a crystalline form, a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 8.73±0.2, 20.05±0.2, and 26.15±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.08±0.2, 8.16±0.2, 8.73±0.2, 20.05±0.2, and 26.15±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.73±0.2, 17.02±0.2, and 23.23±0.2 degrees in theta; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.73±0.2, 11.37±0.2, 17.02±0.2, 22.70±0.2, and 23.23±0.2 degrees in the 2-theta; e) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 7.66±0.2, 17.15±0.2, and 22.09±0.2 degrees in theta; f) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.22±0.2, 7.66±0.2, 17.15±0.2, 22.09±0.2, and 24.96±0.2 degrees in the 2-theta; g) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.97±0.2, 8.09±0.2, and 23.89±0.2 degrees in the 2-theta; h) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.97±0.2, 8.09±0.2, 17.46±0.2, 23.89±0.2 and 30.74±0.2 degrees in the 2-theta; i) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.59±0.2, 13.75±0.2, and 21.37±0.2 degrees in theta; j) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 4.59±0.2, 8.53±0.2, 13.75±0.2, 21.37±0.2, and 23.02±0.2 degrees in the 2-theta; k) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 10.66±0.2, 21.99±0.2, and 22.38±0.2 degrees in the 2-theta region; l) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 10.66±0.2, 18.78±0.2, 21.99±0.2, 22.38±0.2 and 23.56±0.2 degrees in the 2-theta; m) XRPD pattern including the peaks in Table 19; n) XRPD pattern including the peaks in Table 20; o) XRPD pattern including the peaks in Table 21; p) XRPD pattern including the peaks in Table 22; q) XRPD pattern including the peaks in Table 23; or r) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 24.

21. The aforementioned crystalline form is dimethyl sulfoxide (DMSO) solvate. a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 20.42±0.2, 20.94±0.2, and 21.65±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) patterns containing peaks at approximately 7.21±0.2, 10.18±0.2, 20.42±0.2, 20.94±0.2, and 21.65±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 11.11±0.2, 20.77±0.2, and 21.32±0.2 degrees in the two thetas; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 10.10±0.2, 11.11±0.2, 20.77±0.2, 21.32±0.2 and 24.20±0.2 degrees in the 2-theta; e) XRPD pattern including the peaks in Table 25; or f) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 26.

22. The aforementioned crystalline form is dimethyl sulfoxide (DMSO)-aqueous solvate. a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.28±0.2, 15.77±0.2, and 18.95±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.28±0.2, 15.77±0.2, 18.39±0.2, 18.95±0.2 and 21.00±0.2 degrees in theta; or c) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 27.

23. The aforementioned crystalline form is 2,2,2-trifluoroethanol (TFE) solvate. a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 8.56±0.2, 9.63±0.2, and 20.48±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 8.56±0.2, 9.63±0.2, 17.91±0.2, 20.48±0.2 and 23.87±0.2 degrees in the 2-theta; or c) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 28.

24. The aforementioned crystalline form is a dimethylformamide (DMF)-water heterosolvate. a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.37±0.2, 10.69±0.2, and 22.05±0.2 degrees in the 2-theta region; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.37±0.2, 8.53±0.2, 10.69±0.2, 18.86±0.2 and 22.05±0.2 degrees in the 2-theta; or c) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 29.

25. The aforementioned crystalline form is acetone solvate. a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 10.67±0.2, 18.77±0.2, and 22.04±0.2 degrees in the 2-theta region; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 10.67±0.2, 17.95±0.2, 18.77±0.2, 22.04±0.2 and 23.64±0.2 degrees in the 2-theta; or c) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 30.

26. The aforementioned crystalline form is tetrahydrofuran (THF) solvate. a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.32±0.2, 22.00±0.2, and 22.34±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.32±0.2, 10.63±0.2, 18.74±0.2, 22.00±0.2, and 22.34±0.2 degrees in the 2-theta; c) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 15.55±0.2, 18.84±0.2, and 21.66±0.2 degrees in the 2-theta region; d) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.33±0.2, 15.55±0.2, 18.84±0.2, 21.30±0.2, and 21.66±0.2 degrees in the 2-theta; e) XRPD pattern including the peaks in Table 31; or f) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 32.

27. The aforementioned crystalline form is a benzyl alcohol solvate. a) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.27±0.2, 21.64±0.2, and 22.35±0.2 degrees in theta; b) X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.27±0.2, 18.67±0.2, 21.64±0.2, 21.99±0.2 and 22.35±0.2 degrees in the 2-theta; or c) The crystal morphology according to claim 1, showing an XRPD pattern including the peaks in Table 33.

28. A composition comprising a crystalline form according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

29. The composition according to claim 28 for the treatment of cancer.

30. The composition according to claim 29, wherein the cancer has a mutation in the PIK3CA gene.

31. The composition according to claim 29, wherein the cancers are papillary cancer, anal cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, hematological cancer, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, kidney cancer, salivary gland cancer, skin cancer, vaginal cancer, and urothelial cancer.

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