Crystalline form of BET inhibitors

Abstract

Crystalline forms of bromodomain and extraterminal domain (BET) inhibitors, compositions thereof, methods for preparing them, and methods for using them are provided herein. In another embodiment, a method for treating a proliferative disorder, such as cancer, in an individual requiring treatment of the proliferative disorder is provided, comprising the step of administering to the individual a therapeutically effective dose of the crystalline form of the compound of formula (I) detailed herein. Also provided is a method for modulating BET in an individual, comprising the step of administering to the individual the crystalline form of the compound of formula (I) detailed herein. Crystalline forms of the compound of formula (I) detailed herein for use in therapeutics are also provided.

Description

Technical Field

[0001] Cross-reference to Related Applications This application claims the priority and benefit of U.S. Provisional Application No. 63 / 578,834, filed on August 25, 2023, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] Field Provided herein are crystalline forms of bromodomain and extra-terminal domain (BET) inhibitors, compositions thereof, methods of preparation thereof, and methods of use thereof.

Background Art

[0003] Background Epigenetic dysregulation plays an important role in generating aberrant gene expression that leads to various types of cancer. Many factors involved in epigenetic regulation have become promising targets for therapeutic intervention. Among them, proteins of the bromodomain and extra-terminal (BET) family have attracted significant attention in recent years. The BET family of proteins includes BRD2, BRD3, BRD4, and testis-specific BRDT. They bind via their bromodomain (BRD) to acetylated motifs, including acetylated histones in chromatin, with high affinity, thereby regulating gene transcription. Genes regulated by BET family proteins include many important oncogenes involved in cell survival and cell cycle progression.

[0004] BET proteins are novel targets in cancer, directly regulating oncogene expression in hematological and solid tumors. In addition to occupying gene promoters, BRD4 exhibits strong preference for enhancers and super-enhancers in key driver genes such as c-MYC (Loven et al, Cell 2013; 153(2):320-34). BET family proteins are also involved in mediating acute inflammatory responses via the standard NF-KB pathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)), and have been suggested to lead to the upregulation of genes involved in cytokine production (Nicodeme et al., Nature 468: 1119-1123, (2010)). Furthermore, bromodomain function is also involved in renal disease (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)). BRD2 function has also been associated with a predisposition to dyslipidemia or dysregulation of lipogenesis, an elevated inflammatory profile, and increased susceptibility to autoimmune diseases (Denis, Discovery Medicine 10: 489-499 (2010)). Human immunodeficiency virus utilizes BRD4 to initiate transcription of viral RNA from stably incorporated viral DNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain inhibitors have also been shown to reactivate HIV transcription in models of latent T cell infection and latent monocyte infection (Banerjee, et al., J. Leukocyte Biol. doi:10.1189 / jlb.0312165). BRDT plays a crucial role in spermatogenesis (Matzuk, et al., Cell 150: 673-684 (2012)). The development of therapies, including combination therapies, for the treatment of cancer using BET inhibitors is potentially desirable; the development of therapies for the treatment of chemotherapy-resistant cancer, or cancer that may become chemotherapy-resistant, is highly desirable. U.S. Patent Publication US2021 / 0002293 A1 or PCT Publication WO2021 / 003310 A1 (both incorporated herein by reference) has the following structure: [ka] We disclose N-ethyl-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide (hereinafter referred to as "compound of formula (I)"), which is a BD2-selective BET inhibitor that inhibits BRD4 (BRD4-BD1 IC2). 50 =2922nM;BRD4-BD2 IC 50 (=2nM). While not theoretically bound, BD1 inhibition may disrupt steady-state gene expression and cause toxicity. BD2 inhibition can prevent BET proteins from associating with histones and is effective in cancer disease models. BD2 selectivity can be tolerated by blocking the ability of cancer cells to induce resistance pathways and thus evading BD1 inhibition. Crystalline forms of the compound of formula (I) are disclosed herein. The crystalline forms disclosed herein may offer advantages in bioavailability and stability and may be suitable for use as active agents in pharmaceutical compositions. Changes in the crystalline structure of pharmaceutical raw materials may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.) and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.) of pharmaceutical formulations. Such changes may affect the methods of preparing or formulating pharmaceutical compositions in various dosage forms or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms such as amorphous or non-crystalline forms, crystalline forms can provide desired or preferred hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Therefore, the crystalline forms disclosed herein can offer advantages such as improving the manufacturing process of the active drug, improving the stability or storability of the formulation of the active drug, or having suitable bioavailability and / or stability as an active drug. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] U.S. Patent Application Publication No. 2021 / 0002293 [Patent Document 2] International Publication No. 2021 / 003310 [Non-patent literature]

[0006] [Non-Patent Document 1] Loven et al, Cell 2013; 153(2):320-34 [Non-Patent Document 2] Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009) [Non-Patent Document 3] Nicodeme et al., Nature 468: 1119-1123, (2010) [Non-Patent Document 4] Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012) [Non-Patent Document 5] Denis, Discovery Medicine 10: 489-499 (2010) [Non-Patent Document 6] Jang et al., Mol. Cell, 19: 523-534 (2005) [Non-Patent Document 7] Banerjee, et al., J. Leukocyte Biol. doi:10.1189 / jlb.0312165 [Non-Patent Document 8] Matzuk, et al., Cell 150: 673-684 (2012) [Overview of the project] [Means for solving the problem]

[0007] overview In one embodiment, a crystalline form of the compound of formula (I) disclosed herein is provided herein.

[0008] In another embodiment, a method for preparing the crystalline form of the compound of formula (I) disclosed herein is provided herein.

[0009] In another embodiment, compositions comprising a crystalline form of the compound of formula (I), such as pharmaceutical compositions comprising a crystalline form of the compound of formula (I) disclosed herein, are provided herein.

[0010] In another embodiment, a kit comprising a crystalline form of the compound of formula (I) disclosed herein is provided herein.

[0011] In another aspect, provided is a method of treating a proliferative disorder such as cancer in an individual in need of treatment of the proliferative disorder, comprising administering to the individual a therapeutically effective amount of a crystalline form of the compound of formula (I) as detailed herein. Also provided is a method of modulating BET in an individual, comprising administering to the individual a crystalline form of the compound of formula (I) as detailed herein. Also provided is a crystalline form of the compound of formula (I) as detailed herein for use in a method of treatment. Also provided is a crystalline form of the compound of formula (I) as detailed herein for use in a method of treating a proliferative disorder such as cancer. Also provided is the use of a crystalline form of the compound of formula (I) as detailed herein in the manufacture of a medicament for treating a proliferative disorder such as cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] [Figure 1A] Figure 1A shows an X-ray powder diffraction (XRPD) pattern of an anhydrous crystalline form (Form I) of the compound of formula (I).

[0013] [Figure 1B] Figure 1B shows graphs of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of Form I.

[0014] [Figure 1C] Figure 1C shows a dynamic vapor sorption (DVS) graph of Form I.

[0015] [Figure 1D] Figure 1D shows an XRPD overlay of a di-DCM solvate at 223K, the di-DCM solvate under ambient conditions, and a desolvated product of the di-DCM solvate.

[0016] [Figure 2A] Figure 2A shows an XRPD overlay of crystalline forms (in order from bottom to top: Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI).

[0017] [Figure 2B] Figure 2B shows graphs of DSC and TGA for morphology II.

[0018] [Figure 2C] Figure 2C shows the DVS graph for morphology II.

[0019] [Figure 3] Figure 3 shows the crystalline form of the XRPD overlay obtained by slurring the compound of formula (I) in MTBE, 2-MeTHF, and toluene.

[0020] [Figure 4] Figure 4 shows the simulated XRPD pattern of the monoacetone solvate.

[0021] [Figure 5] Figure 5 shows graphs of DSC and TGA for morphology X.

[0022] [Figure 6A] Figure 6A shows the XRPD pattern of the cumene solvate (form XI) of the compound of formula (I).

[0023] [Figure 6B] Figure 6B shows graphs of DSC and TGA for morphology XI.

[0024] [Figure 7A] Figure 7A shows the XRPD pattern of the heptane solvate (form XII) of the compound of formula (I).

[0025] [Figure 7B] Figure 7B shows graphs of DSC and TGA for morphology XII.

[0026] [Figure 8A] Figure 8A shows the XRPD pattern of the DMSO solvate (form XIII) of the compound of formula (I).

[0027] [Figure 8B] Figure 8B shows graphs of DSC and TGA for morphology XIII.

[0028] [Figure 9A] Figure 9A shows the XRPD pattern of the methyl ethyl ketone solvate (form XIV) of the compound of formula (I).

[0029] [Figure 9B] Figure 9B shows graphs of DSC and TGA for morphology XIV. [Modes for carrying out the invention]

[0030] Detailed explanation definition As used herein, unless otherwise clearly indicated, the use of terms such as “a,” “an,” etc., refers to one or more.

[0031] Where used herein, any reference to a value or parameter of “about” includes (and describes) embodiments relating to that value or parameter itself. For example, any description referring to “about X” includes any description of “X.” Where used herein, unless otherwise specified, the terms “about” and “approximately” mean, when used in relation to a dose, volume, or weight percentage of an ingredient in a composition or dosage form, a dose, volume, or weight percentage that is recognized by those skilled in the art as providing an equivalent pharmacological effect to that obtained from a specified dose, volume, or weight percentage. Specifically, where used in this context, the terms “about” and “approximately” refer to doses, volumes, or weight percentages within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a specified dose, volume, or weight percentage. Similarly, when the terms “about” and “approximately” are used in relation to a number or range of values, they indicate that the number or range of values ​​may vary within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified value or range.

[0032] As used herein, the term “crystalline form” refers to a crystalline solid form of a chemical compound (including, but not limited to, a single-component crystalline form or a multi-component crystalline form, e.g., a polymorph of a compound); or its solvates, hydrates, inclusion compounds, cocrystals, salts, or polymorphs. The terms “crystalline form” and related terms herein refer to various crystalline transformations of a given substance, including, but not limited to, polymorphs, solvates, hydrates, cocrystals, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and their polymorphs. Crystallized forms of a substance can be obtained by several methods known in the Art. Such methods include, but are not limited to, melt-recrystallization, melt-cooling, solvent-recrystallization, recrystallization in a confined space, e.g., in a nanopore or capillary; recrystallization on a surface or template, e.g., on a polymer; recrystallization in the presence of additives, e.g., cocrystal pair molecules; desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent-dropping grinding.

[0033] Unless otherwise explicitly indicated, “individual” as used herein refers to mammals, including but not limited to primates, humans, cattle, horses, cats, dogs, or rodents. In one variant, the individual is a human.

[0034] As used herein, “treatment” or “to treat” is an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms caused by the disease; reducing the severity of the disease; stabilizing the disease (e.g., preventing or delaying disease exacerbation); preventing or delaying the spread of the disease; delaying the onset or recurrence of the disease; delaying or slowing the progression of the disease; improving the disease state; achieving remission (partial or total) of the disease; reducing the dose of one or more other drug therapies required to treat the disease; enhancing the effect of another drug therapy; delaying disease progression; improving quality of life; and / or extending survival. The methods of the present invention envision any one or more of these aspects of treatment.

[0035] As used herein, the term “effective dose” means the amount of the compound or crystalline form of the present invention that should be effective in a given therapeutic configuration. As understood in the art, the effective dose may be a single dose or multiple doses; that is, a single dose or multiple doses may be required to achieve the desired treatment endpoint. The effective dose can be considered in a situation in which one or more therapeutic agents (e.g., compounds or crystalline forms) are administered, and a single agent may be considered to be given in an effective dose if, in combination with one or more other agents, a desirable or beneficial outcome can or does not occur. The preferred dose of any of the co-administered compounds or crystalline forms may be reduced as necessary due to the combined effects (e.g., additive or synergistic effects) of the compounds or crystalline forms.

[0036] As used herein, “therapeutic dose” refers to the amount of compound or crystalline form sufficient to produce the desired therapeutic outcome. It is understood that “therapeutic dose” and “effective dose” are interchangeable.

[0037] As used herein, “unit dosage form” refers to a physically distinct unit appropriate as a unit dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in conjunction with the required drug carrier. A unit dosage form may include monotherapy or combination therapy.

[0038] As used herein, the term “controlled-release” refers to a drug-containing formulation or fraction in which the release of the drug is not immediate; that is, in a “controlled-release” formulation, administration does not result in immediate release of the drug into the absorption pool. The term encompasses depot formulations designed to gradually release the drug compound or crystalline form over a long period of time. Controlled-release formulations generally include a wide variety of drug delivery systems, which involve mixing the drug compound or crystalline form with a carrier, polymer, or other compound having desired release properties (e.g., pH-dependent or pH-independent solubility, varying degrees of water solubility, etc.) and formulating the mixture according to a desired delivery route (e.g., injectable solutions containing coated capsules, embedded reservoirs, or biodegradable capsules, etc.).

[0039] As used herein, “pharmaceutically acceptable” or “pharmacologically acceptable” means a material that is not biologically or otherwise undesirable, for example, a material that can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable significant biological effect or interacting in an adverse manner with any of the other components of the composition in which it is contained. A pharmaceutically acceptable carrier or additive is preferably one that meets the standards required with respect to toxicological and manufacturing tests and / or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0040] As used herein, the term "additive" means an inactive or inert substance that can be used in the manufacture of a drug or pharmaceutical, such as a tablet, containing the compound of the present invention as an active ingredient. The term additive may encompass a wide range of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring agent, suspending / gelling agent, or wet granulator. Examples of binders include carbomer, povidone, and xanthan gum; examples of coatings include cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, and enteric coatings; examples of compression / encapsulation aids include calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; in combination with aspartame, cellulose, or microcrystalline cellulose as needed), starch dc, and sucrose; examples of disintegrants include croscarmellose sodium, gellan gum, and sodium starch glycolate; and examples of creams or lotions include Examples of lubricants include maltodextrin and carrageenan; examples of lubricants include magnesium stearate, stearic acid, and sodium stearyl fumarate; examples of chewable tablet materials include dextrose, fructose dc, and lactose (monohydrate, combined with aspartame or cellulose as needed); examples of suspending / gelling agents include carrageenan, sodium starch glycolate, and xanthan gum; examples of sweeteners include aspartame, dextrose, fructose dc, sorbitol, and sucrose dc; and examples of wet granulating agents include calcium carbonate, maltodextrin, and microcrystalline cellulose.

[0041] Unless otherwise specified, "substantially pure" refers to compositions containing approximately 10% or less impurities, for example, compositions containing less than approximately 9%, less than approximately 7%, less than approximately 5%, less than approximately 3%, less than approximately 1%, or less than approximately 0.5% impurities.

[0042] As used herein, the term “substantially represented,” for example, when referring to an XRPD pattern, DSC graph, TGA graph, or DVS graph, includes patterns or graphs that are not necessarily identical to those shown herein but which a person skilled in the art would consider to be within the limits of experimental error or deviation.

[0043] The embodiments and models described herein as "including" are understood to include embodiments that "consist of" and "essentially consist of". crystalline form

[0044] Crystalline forms of the compound of formula (I) are provided herein. In some embodiments, the crystalline form is the hydrate of the compound of formula (I). In some embodiments, the crystalline form is the solvate of the compound of formula (I). In some embodiments, the crystalline form of the compound of formula (I) is the anhydrous form. Also provided herein are crystalline forms of the compound of formula (I) prepared by processes detailed herein. Form I

[0045] In some embodiments, a crystalline form (Form I) of the compound of formula (I) is provided herein.

[0046] In some embodiments, Form I is substantially anhydrous (e.g., containing less than about 2 wt%, less than about 1 wt%, less than about 0.5 wt%, less than about 0.1 wt%, or less than about 0.01 wt% water). In some embodiments, Form I is anhydrous. In some embodiments, Form I is anhydrous but not a solvate. In some embodiments, Form I is prepared by desolvation of di-DCM solvate.

[0047] In some embodiments, morphology I has an XRPD pattern substantially as shown in Figure 1A when measured by Cu Kα radiation. The peak positions and relative peak intensities that may be observed for the crystalline morphology using XRPD are shown in Table 1. [Table 1-1] [Table 1-2]

[0048] In some embodiments, morphology I has an XRPD pattern containing the peaks presented in Table 1. In some embodiments, morphology I has an XRPD pattern containing one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks at 2-theta values ​​of the XRPD patterns substantially as shown in Figure 1A or presented in Table 1. It should be understood that relative intensity and peak assignment can vary depending on several factors, including the preparation, mounting, instruments and analytical procedures and settings used to obtain the spectrum, the effect of temperature on the unit cell, and the solvation of the sample, e.g., the degree of hydration. For example, the relative peak intensity and peak assignment disclosed herein for all crystalline morphologies (including morphologies I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, and XIV) can vary within the range of experimental error. In some embodiments, each peak assignment listed herein, including Form I, can independently vary by ±0.4 degrees, ±0.3 degrees, ±0.2 degrees, or ±0.1 degrees with respect to 2 theta. In some embodiments, each peak assignment listed herein can independently vary by ±0.4 degrees with respect to 2 theta. In some embodiments, each peak assignment listed herein can independently vary by ±0.3 degrees with respect to 2 theta. In some embodiments, each peak assignment listed herein can independently vary by ±0.2 degrees with respect to 2 theta. In some embodiments, each peak assignment listed herein can independently vary by ±0.1 degrees with respect to 2 theta. It is also understood that XRPD patterns, such as those substantially shown in any of the XRPD patterns disclosed herein, such as Figure 1A, can also include XRPD patterns in which the peak intensity of one or more peaks differs from the peak intensity of the corresponding peaks in the XRPD pattern.

[0049] In some embodiments, form I has an XRPD pattern including one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 1, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein when measured by Cu Kα rays. For example, morphology I may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, approximately 10.0 (e.g., 10.0 ± 0.2) degrees, approximately 11.6 (e.g., 11.6 ± 0.2) degrees, approximately 14.2 (e.g., 14.2 ± 0.2) degrees, approximately 17.0 (e.g., 17.0 ± 0.2) degrees, approximately 18.3 (e.g., 18.3 ± 0.2) degrees, approximately 23.4 (e.g., 23.4 ± 0.2) degrees, and / or approximately 24.9 (e.g., 24.9 ± 0.2) degrees, respectively. In some embodiments, Form I is approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, approximately 10.0 (e.g., 10.0 ± 0.2) degrees, approximately 11.6 (e.g., 11.6 ± 0.2) degrees, approximately 14.2 (e.g., 14.2 ± 0.2) degrees, approximately 17.0 (e.g., 17.0 ± 0.2) degrees, approximately 18.3 (e.g., 18.3 ± 0.2) degrees, approximately 18.5 (e.g., 18.5 ± 0.2) degrees, The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two-theta values ​​of approximately 23.4 (e.g., 23.4 ± 0.2) degrees and / or approximately 24.9 (e.g., 24.9 ± 0.2) degrees, respectively. In some embodiments, form I has an XRPD pattern having peaks attributed to two-theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, approximately 11.6 (e.g., 11.6 ± 0.2) degrees, approximately 17.0 (e.g., 17.0 ± 0.2) degrees and / or approximately 23.4 (e.g., 23.4 ± 0.2) degrees, respectively. In some embodiments, form I has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, and / or approximately 17.0 (e.g., 17.0 ± 0.2) degrees, respectively.In some embodiments, morphology I has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees and / or approximately 8.5 (e.g., 8.5 ± 0.2) degrees, respectively. In some embodiments, morphology I has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees. In some embodiments, morphology I has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, approximately 10.0 (e.g., 10.0 ± 0.2) degrees, approximately 11.6 (e.g., 11.6 ± 0.2) degrees, and / or approximately 14.2 (e.g., 14.2 ± 0.2) degrees, respectively.

[0050] In some embodiments, form I has a DSC graph substantially as shown in Figure 1B. In some embodiments, form I is characterized by having an endothermic onset at approximately 154.8°C (e.g., 154.8±10°C, 154.8±9°C, 154.8±8°C, 154.8±7°C, 154.8±6°C, 154.8±5°C, 154.8±4°C, 154.8±3°C, 154.8±2°C, 154.8±1°C, or 154.8±0.5°C). In some embodiments, morphology I is characterized by having an endothermic peak at approximately 163.1°C (e.g., 163.1±10°C, 163.1±9°C, 163.1±8°C, 163.1±7°C, 163.1±6°C, 163.1±5°C, 163.1±4°C, 163.1±3°C, 163.1±2°C, 163.1±1°C, or 163.1±0.5°C) when determined by DSC. In some embodiments, morphology I has a TGA graph substantially as shown in Figure 1B.

[0051] In some embodiments, form I has a DVS graph substantially as shown in Figure 1C. In some embodiments, form I is characterized by exhibiting a water absorption rate of approximately 2.7 wt% (e.g., 2.7 ± 0.2 wt%, 2.7 ± 0.1 wt%, 2.7 ± 0.09 wt%, 2.7 ± 0.08 wt%, 2.7 ± 0.07 wt%, 2.7 ± 0.06 wt%, 2.7 ± 0.05 wt%, 2.7 ± 0.04 wt%, 2.7 ± 0.03 wt%, 2.7 ± 0.02%, or 2.7 ± 0.01 wt%) at room temperature and relative humidity of approximately 80% when determined by DVS.

[0052] In some embodiments of Form I, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following (a) to (h) apply: (a) Morphology I, when measured by Cu Kα radiation, (i) Peaks that are attributed to a 2-theta value of approximately 6.1 (e.g., 6.1 ± 0.2), (ii) Peaks assigned to two theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees and / or approximately 8.5 (e.g., 8.5 ± 0.2) degrees, (iii) Peaks assigned to 2-theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, and / or approximately 17.0 (e.g., 17.0 ± 0.2) degrees, respectively. (iv) Peaks assigned to 2-theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, approximately 11.6 (e.g., 11.6 ± 0.2) degrees, approximately 17.0 (e.g., 17.0 ± 0.2) degrees, and / or approximately 23.4 (e.g., 23.4 ± 0.2) degrees, respectively. (v) Peaks attributed to 2-theta values ​​of approximately 6.1 (e.g., 6.1±0.2) degrees, approximately 8.5 (e.g., 8.5±0.2) degrees, approximately 10.0 (e.g., 10.0±0.2) degrees, approximately 11.6 (e.g., 11.6±0.2) degrees, approximately 14.2 (e.g., 14.2±0.2) degrees, approximately 17.0 (e.g., 17.0±0.2) degrees, approximately 18.3 (e.g., 18.3±0.2) degrees, approximately 23.4 (e.g., 23.4±0.2) degrees, and / or approximately 24.9 (e.g., 24.9±0.2) degrees, respectively, or (vi) Peaks assigned to 2-theta values ​​of approximately 6.1 (e.g., 6.1 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, approximately 10.0 (e.g., 10.0 ± 0.2) degrees, approximately 11.6 (e.g., 11.6 ± 0.2) degrees, and / or approximately 14.2 (e.g., 14.2 ± 0.2) degrees, respectively. It has an XRPD pattern that includes; (b) Morphology I has substantially the XRPD pattern shown in Figure 1A; (c) Morphology I is characterized by having an endothermic peak at approximately 163.1°C (e.g., 163.1±10°C, 163.1±9°C, 163.1±8°C, 163.1±7°C, 163.1±6°C, 163.1±5°C, 163.1±4°C, 163.1±3°C, 163.1±2°C, 163.1±1°C, or 163.1±0.5°C) as determined by DSC; (d) Form I has a DSC graph substantially as shown in Figure 1B; (e) Form I has a TGA graph substantially as shown in Figure 1B; (f) Morphology I is characterized by exhibiting a water absorption rate of approximately 2.7 wt% (e.g., 2.7 ± 0.2 wt%, 2.7 ± 0.1 wt%, 2.7 ± 0.09 wt%, 2.7 ± 0.08 wt%, 2.7 ± 0.07 wt%, 2.7 ± 0.06 wt%, 2.7 ± 0.05 wt%, 2.7 ± 0.04 wt%, 2.7 ± 0.03 wt%, 2.7 ± 0.02%, or 2.7 ± 0.01 wt%) at room temperature with a relative humidity of approximately 80%, as determined by DVS; and (g) Form I has a DVS graph substantially as shown in Figure 1C. Form II

[0053] In some embodiments, a crystalline form (form II) of the compound of formula (I) is provided herein.

[0054] In some embodiments, form II is a hydrate, or a solvate / hydrate of isopropyl alcohol and water. In some embodiments, form II is a hydrate. In some embodiments, form II is a solvate / hydrate of isopropyl alcohol and water. In some embodiments, form II exhibits the crystallographic parameters shown in Table 2A. In some embodiments, form II has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. The peak positions and relative peak intensities that may be observed for the crystalline morphology using XRPD are shown in Table 2B. [Table 2A] [Table 2B-1] [Table 2B-2] [Table 2B-3]

[0055] In some embodiments, form II has an XRPD pattern that, when measured by Cu Kα radiation, includes the peaks presented in Table 2B. In some embodiments, form II has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at 2-theta values ​​of the XRPD pattern substantially as shown in Figure 2A or provided in Table 2B.

[0056] In some embodiments, form II has an XRPD pattern that includes peaks assigned to 2-theta values ​​(degrees) listed in Table 2B, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology II may have an XRPD pattern that includes peaks attributed to 2-theta values ​​of 7.4 (e.g., 7.4±0.2) degrees, approximately 8.5 (e.g., 8.5±0.2) degrees, approximately 9.2 (e.g., 9.2±0.2) degrees, approximately 11.4 (e.g., 11.4±0.2) degrees, 10.2 (e.g., 10.2±0.2) degrees, approximately 18.1 (e.g., 18.1±0.2) degrees, approximately 18.5 (e.g., 18.5±0.2) degrees, approximately 19.8 (e.g., 19.8±0.2) degrees, approximately 24.7 (e.g., 24.7±0.2) degrees, and / or approximately 25.0 (e.g., 25.0±0.2) degrees, respectively. In some embodiments, form II is approximately 7.4 (e.g., 7.4 ± 0.2) degrees, approximately 8.5 (e.g., 8.5 ± 0.2) degrees, approximately 9.2 (e.g., 9.2 ± 0.2) degrees, approximately 11.4 (e.g., 11.4 ± 0.2) degrees, 10.2 (e.g., 10.2 ± 0.2) degrees, approximately 18.1 (e.g., 18.1 ± 0.2) degrees, approximately 18.5 (e.g., 18.5 ± 0.2) degrees, approximately 19.8 (e.g., 19.8 ± 0.2) degrees, approximately The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of 24.7 (e.g., 24.7 ± 0.2) degrees and / or about 25.0 (e.g., 25.0 ± 0.2) degrees, respectively. In some embodiments, form II has an XRPD pattern having peaks attributed to 2-theta values ​​of about 7.4 (e.g., 7.4 ± 0.2) degrees, about 9.2 (e.g., 9.2 ± 0.2) degrees, about 10.2 (e.g., 10.2 ± 0.2) degrees, about 18.1 (e.g., 18.1 ± 0.2) degrees and / or about 18.5 (e.g., 18.5 ± 0.2) degrees, respectively. In some embodiments, form II has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 7.4 (e.g., 7.4 ± 0.2) degrees and / or approximately 10.2 (e.g., 10.2 ± 0.2) degrees, respectively.In some embodiments, form II has an XRPD pattern that includes peaks attributed to 2-theta values ​​of approximately 7.4 (e.g., 7.4 ± 0.2) degrees, approximately 9.2 (e.g., 9.2 ± 0.2) degrees, and / or approximately 18.1 (e.g., 18.1 ± 0.2) degrees, respectively.

[0057] In some embodiments, form II (hydrate) has a DSC graph substantially as shown in Figure 2B. In some embodiments, form II is characterized by having an endothermic onset at approximately 87.4°C (e.g., 87.4±10°C, 87.4±9°C, 87.4±8°C, 87.4±7°C, 87.4±6°C, 87.4±5°C, 87.4±4°C, 87.4±3°C, 87.4±2°C, 87.4±1°C, or 87.4±0.5°C). In some embodiments, form II is characterized by having an endothermic peak at approximately 127.6°C (e.g., 127.6±10°C, 127.6±9°C, 127.6±8°C, 127.6±7°C, 127.6±6°C, 127.6±5°C, 127.6±4°C, 127.6±3°C, 127.6±2°C, 127.6±1°C, or 127.6±0.5°C) when determined by DSC.

[0058] In some embodiments, form II (hydrate) has a TGA graph substantially as shown in Figure 2B. In some embodiments, form II is characterized by exhibiting a weight loss of approximately 3.94% (e.g., 3.94±1%, 3.94±0.9%, 3.94±0.8%, 3.94±0.7%, 160.0±6%, 160.0±5%, 160.0±4%, 160.0±3%, 160.0±2%, 160.0±1%, or 160.0±0.5°C) after heating from room temperature to approximately 160.0°C as determined by TGA.

[0059] In some embodiments, form II has a DVS graph substantially as shown in Figure 2C after dehydration. In some embodiments, form II is characterized by exhibiting a water absorption rate of approximately 3 wt% (e.g., 3±0.30 wt%, 3±0.20 wt%, 3±0.10 wt%, 3±0.09 wt%, 3±0.08 wt%, 3±0.07 wt%, 3±0.06 wt%, 3±0.05 wt%, 3±0.04 wt%, 3±0.03 wt%, 3±0.02%, or 3±0.01 wt%) at room temperature and relative humidity of approximately 80%, as determined by DVS. Form III

[0060] In some embodiments, a crystalline form (Form III) of the compound of formula (I) is provided herein.

[0061] In some embodiments, form III is an isopropyl alcohol solvate. In some embodiments, form III is an unstable isopropyl alcohol solvate. In some embodiments, form III is an unstable isopropyl alcohol solvate that transforms into form VIII upon drying. In some embodiments, form III has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 3 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 3-1] [Table 3-2]

[0062] In some embodiments, form III has an XRPD pattern including the peaks presented in Table 3. In some embodiments, form III has an XRPD pattern including one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 2A or as presented in Table 3.

[0063] In some embodiments, Embodiment III has an XRPD pattern that includes peaks assigned to 2-theta values ​​(degrees) listed in Table 3, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology III may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 7.3 (e.g., 7.3±0.2) degrees, approximately 7.6 (e.g., 7.6±0.2) degrees, approximately 8.6 (e.g., 8.6±0.2) degrees, approximately 9.0 (e.g., 9.0±0.2) degrees, approximately 14.3 (e.g., 14.3±0.2) degrees, approximately 14.7 (e.g., 14.7±0.2) degrees, approximately 15.1 (e.g., 15.1±0.2) degrees, approximately 15.6 (e.g., 15.6±0.2) degrees, approximately 18.3 (e.g., 18.3±0.2) degrees, and / or approximately 23.8 (e.g., 23.8±0.2) degrees, respectively. In some embodiments, Form III is approximately 7.3 (e.g., 7.3 ± 0.2) degrees, approximately 7.6 (e.g., 7.6 ± 0.2) degrees, approximately 8.6 (e.g., 8.6 ± 0.2) degrees, approximately 9.0 (e.g., 9.0 ± 0.2) degrees, approximately 14.3 (e.g., 14.3 ± 0.2) degrees, approximately 14.7 (e.g., 14.7 ± 0.2) degrees, approximately 15.1 (e.g., 15.1 ± 0.2) degrees, approximately 15.6 (e.g., 15.6 ± 0.2) degrees, approximately The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of 18.3 (e.g., 18.3 ± 0.2) degrees and / or about 23.8 (e.g., 23.8 ± 0.2) degrees, respectively. In some embodiments, Form III has an XRPD pattern that has peaks attributed to 2-theta values ​​of about 7.3 (e.g., 7.3 ± 0.2) degrees and / or about 7.6 (e.g., 7.6 ± 0.2) degrees, respectively. In some embodiments, form III has an XRPD pattern that includes peaks attributed to 2-theta values ​​of approximately 7.3 (e.g., 7.3 ± 0.2) degrees, approximately 7.6 (e.g., 7.6 ± 0.2) degrees, approximately 8.6 (e.g., 8.6 ± 0.2) degrees, approximately 9.0 (e.g., 9.0 ± 0.2) degrees, and / or approximately 23.8 (e.g., 23.8 ± 0.2) degrees, respectively.In some embodiments, form III has an XRPD pattern that includes a peak attributed to a 2-theta value of approximately 7.6 (e.g., 7.6 ± 0.2). Form IV

[0064] In some embodiments, a crystalline form (form IV) of the compound of formula (I) is provided herein.

[0065] In some embodiments, form IV is ethyl acetate solvate or acetonitrile solvate. In some embodiments, form IV is ethyl acetate solvate. In some embodiments, form IV is acetonitrile solvate.

[0066] In some embodiments, morphology IV has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 4 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 4-1] [Table 4-2]

[0067] In some embodiments, form IV has an XRPD pattern including the peaks presented in Table 4. In some embodiments, form IV has an XRPD pattern including one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at 2-theta values ​​of the XRPD pattern substantially as shown in Figure 2A or as presented in Table 4.

[0068] In some embodiments, form IV has an XRPD pattern that includes peaks assigned to 2-theta values ​​(degrees) listed in Table 4, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology IV may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 6.0 (e.g., 6.0±0.2) degrees, approximately 6.9 (e.g., 6.9±0.2) degrees, approximately 11.7 (e.g., 11.7±0.2) degrees, approximately 13.5 (e.g., 13.5±0.2) degrees, approximately 15.0 (e.g., 15.0±0.2) degrees, approximately 16.4 (e.g., 16.4±0.2) degrees, approximately 16.1 (e.g., 16.1±0.2) degrees, approximately 18.0 (e.g., 18.0±0.2) degrees, approximately 19.3 (e.g., 19.3±0.2) degrees, and / or approximately 19.7 (e.g., 19.7±0.2) degrees, respectively. In some embodiments, form IV is approximately 6.0 (e.g., 6.0 ± 0.2) degrees, approximately 6.9 (e.g., 6.9 ± 0.2) degrees, approximately 11.7 (e.g., 11.7 ± 0.2) degrees, approximately 13.5 (e.g., 13.5 ± 0.2) degrees, approximately 15.0 (e.g., 15.0 ± 0.2) degrees, approximately 16.4 (e.g., 16.4 ± 0.2) degrees, approximately 16.1 (e.g., 16.1 ± 0.2) degrees, and approximately 18.0 (e.g., 18.0 ± 0.2) degrees. The XRPD pattern includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two theta values ​​of approximately 19.3 (e.g., 19.3 ± 0.2) degrees and / or approximately 19.7 (e.g., 19.7 ± 0.2) degrees, respectively. In some embodiments, form IV has an XRPD pattern including peaks attributed to two theta values ​​of approximately 6.0 (e.g., 6.0 ± 0.2) degrees and / or approximately 6.9 (e.g., 6.9 ± 0.2) degrees, respectively. In some embodiments, form IV has an XRPD pattern that includes peaks attributed to 2-theta values ​​of approximately 6.0 (e.g., 6.0 ± 0.2) degrees, approximately 6.9 (e.g., 6.9 ± 0.2) degrees, approximately 11.7 (e.g., 11.7 ± 0.2) degrees, approximately 15.0 (e.g., 15.0 ± 0.2) degrees, and / or approximately 16.4 (e.g., 16.4 ± 0.2) degrees, respectively.In some embodiments, form IV has an XRPD pattern that includes peaks attributed to two-theta values ​​of approximately 6.0 (e.g., 6.0 ± 0.2) degrees, approximately 6.9 (e.g., 6.9 ± 0.2) degrees, and / or approximately 15.0 (e.g., 15.0 ± 0.2) degrees, respectively. In some embodiments, form IV has an XRPD pattern that includes peaks at two-theta values ​​of approximately 6.0 (e.g., 6.0 ± 0.2) degrees and / or approximately 6.9 (e.g., 6.9 ± 0.2) degrees. In some embodiments, form IV has an XRPD pattern that includes a peak at two-theta value of approximately 6.9 (e.g., 6.9 ± 0.2) degrees.

[0069] In some embodiments, form IV is characterized by having an endothermic onset at approximately 139.2°C (e.g., 139.2±5°C, 139.2±4°C, 139.2±3°C, 139.2±2°C, 139.2±1°C, or 139.2±0.5°C) as determined by DSC. Form V

[0070] In some embodiments, a crystalline form (form V) of the compound of formula (I) is provided herein.

[0071] In some embodiments, morphology V is a THF solvate. In some embodiments, morphology V (THF solvate) has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 5A shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 5A-1] [Table 5A-2]

[0072] In some embodiments, the crystalline morphology obtained by slurring the compound of formula (I) in MTBE, 2-MeTHF, or toluene exhibits a morphology V-like XRPD pattern when measured by Cu Kα radiation, as shown in Figure 3. Table 5B shows representative peaks and relative peak intensities that may be observed for the crystalline morphology when measured by Cu Kα radiation. [Table 5B]

[0073] In some embodiments, form V (THF solvate) has an XRPD pattern including the peaks presented in Table 5A. In some embodiments, form V has an XRPD pattern including one or more peaks at 2-theta values ​​of the XRPD patterns substantially as shown in Figure 2A or presented in Table 5A (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten).

[0074] In some embodiments, form V has an XRPD pattern including one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 5, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology V may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 6.6 (e.g., 6.6±0.2) degrees, approximately 9.5 (e.g., 9.5±0.2) degrees, approximately 10.6 (e.g., 10.6±0.2) degrees, approximately 13.1 (e.g., 13.1±0.2) degrees, approximately 13.4 (e.g., 13.4±0.2) degrees, approximately 14.7 (e.g., 14.7±0.2) degrees, approximately 16.3 (e.g., 16.3±0.2) degrees, approximately 16.8 (e.g., 16.8±0.2) degrees, approximately 22.3 (e.g., 22.3±0.2) degrees, and / or approximately 23.1 (e.g., 23.1±0.2) degrees, respectively. In some embodiments, form V is approximately 6.6 (e.g., 6.6 ± 0.2) degrees, approximately 9.5 (e.g., 9.5 ± 0.2) degrees, approximately 10.6 (e.g., 10.6 ± 0.2) degrees, approximately 13.1 (e.g., 13.1 ± 0.2) degrees, approximately 13.4 (e.g., 13.4 ± 0.2) degrees, approximately 14.7 (e.g., 14.7 ± 0.2) degrees, approximately 16.3 (e.g., 16.3 ± 0.2) degrees, approximately 16.8 (e.g., 16.8 ± 0.2) degrees, The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of approximately 22.3 (e.g., 22.3 ± 0.2) degrees and / or approximately 23.1 (e.g., 23.1 ± 0.2) degrees, respectively. In some embodiments, form V has an XRPD pattern having peaks attributed to 2-theta values ​​of approximately 6.6 (e.g., 6.6 ± 0.2) degrees, approximately 9.5 (e.g., 9.5 ± 0.2) degrees, approximately 10.6 (e.g., 10.6 ± 0.2) degrees, approximately 14.7 (e.g., 14.7 ± 0.2) degrees and / or approximately 16.8 (e.g., 16.8 ± 0.2) degrees, respectively. In some embodiments, form V has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.6 (e.g., 6.6 ± 0.2) degrees, 9.5 (e.g., 9.5 ± 0.2) degrees, and / or approximately 10.6 (e.g., 10.6 ± 0.2) degrees, respectively.In some embodiments, morphology V has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.6 (e.g., 6.6 ± 0.2) degrees and / or 9.5 (e.g., 9.5 ± 0.2) degrees, respectively. Form VI

[0075] In some embodiments, a crystalline form (form VI) of the compound of formula (I) is provided herein.

[0076] In some embodiments, the crystalline form (monoacetone form) of the monoacetone solvate of the compound of formula (I) is provided herein. In some embodiments, the monoacetone form exhibits the crystallographic parameters shown in Table 6A. In some embodiments, the monoacetone form has a simulated XRPD pattern substantially as shown in Figure 4. The peak positions and relative peak intensities that may be observed for the crystalline form using the simulated XRPD are shown in Table 6B. [Table 6A-1] [Table 6A-2] [Table 6B-1] [Table 6B-2]

[0077] In some embodiments, the monoacetone form has an XRPD pattern containing the peaks shown in Table 6B. In some embodiments, the monoacetone form has an XRPD pattern containing one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks at 2-theta values ​​of the XRPD pattern substantially as shown in Figure 4 or as shown in Table 6B.

[0078] In some embodiments, the monoacetone form has an XRPD pattern comprising one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 6A, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, the monoacetone form may have an XRPD pattern containing peaks attributed to angle 2-theta at approximately 8.4° (e.g., 8.4±0.2)°, 9.0° (e.g., 9.0±0.2)°, 10.9° (e.g., 10.9±0.2)°, 14.4° (e.g., 14.4±0.2)°, 15.3° (e.g., 15.3±0.2)°, 16.4° (e.g., 16.4±0.2)°, 18.2° (e.g., 18.2±0.2)°, 19.0° (e.g., 19.0±0.2)°, 21.7° (e.g., 21.7±0.2)°, and / or approximately 24.5° (e.g., 24.5±0.2)°, respectively. In some embodiments, the monoacetone form is approximately 8.4°C (e.g., 8.4±0.2°C), approximately 9.0°C (e.g., 9.0±0.2°C), approximately 10.9°C (e.g., 10.9±0.2°C), approximately 14.4°C (e.g., 14.4±0.2°C), approximately 15.3°C (e.g., 15.3±0.2°C), approximately 16.4°C (e.g., 16.4±0.2°C), approximately 18.2°C (e.g., 18.2±0.2°C), and approximately 19.0°C (e.g., 19.0±0.2°C). The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two-theta values ​​of approximately 14.4 (e.g., 14.4 ± 0.2) degrees, approximately 16.4 (e.g., 16.4 ± 0.2) degrees, approximately 19.0 (e.g., 19.0 ± 0.2) degrees, approximately 21.7 (e.g., 21.7 ± 0.2) degrees, and / or 24.5 (e.g., 24.5 ± 0.2) degrees, respectively.In some embodiments, the monoacetone form has an XRPD pattern including peaks attributed to two theta values ​​of approximately 14.4°C (e.g., 14.4±0.2°C), approximately 16.4°C (e.g., 16.4±0.2°C), and / or approximately 24.5°C (e.g., 24.5±0.2°C), respectively. In some embodiments, the monoacetone form has an XRPD pattern including peaks attributed to two theta values ​​of approximately 14.4°C (e.g., 14.4±0.2°C), approximately 21.7°C (e.g., 21.7±0.2°C), and / or approximately 24.5°C (e.g., 24.5±0.2°C), respectively. In some embodiments, the monoacetone form has an XRPD pattern including peaks attributed to two theta values ​​of approximately 24.5°C (e.g., 24.5±0.2°C), respectively.

[0079] In some embodiments, form VI is a partially desolvated acetone solvate. In some embodiments, form VI has a stoichiometric ratio of 0.2:1 (acetone:API).

[0080] In some embodiments, morphology VI has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 6C shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 6C-1] [Table 6C-2]

[0081] In some embodiments, form VI has an XRPD pattern that includes the peaks presented in Table 6C. In some embodiments, form VI has an XRPD pattern that includes one or more of the peaks at 2-theta values ​​of the XRPD pattern substantially shown in Figure 2A or presented in Table 6C (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten).

[0082] In some embodiments, form VI has an XRPD pattern that includes one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 6, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology VI may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 8.4 degrees (e.g., 8.4 ± 0.2), approximately 11.0 degrees (e.g., 11.0 ± 0.2), approximately 14.6 degrees (e.g., 14.6 ± 0.2), approximately 15.4 degrees (e.g., 15.4 ± 0.2), approximately 16.4 degrees (e.g., 16.4 ± 0.2), approximately 16.7 degrees (e.g., 16.7 ± 0.2), approximately 17.1 degrees (e.g., 17.1 ± 0.2), approximately 18.4 degrees (e.g., 18.4 ± 0.2), approximately 19.2 degrees (e.g., 19.2 ± 0.2), and / or approximately 24.8 degrees (e.g., 24.8 ± 0.2). In some embodiments, form VI is approximately 8.4 (e.g., 8.4 ± 0.2) degrees, approximately 11.0 (e.g., 11.0 ± 0.2) degrees, approximately 14.6 (e.g., 14.6 ± 0.2) degrees, approximately 15.4 (e.g., 15.4 ± 0.2) degrees, approximately 16.4 (e.g., 16.4 ± 0.2) degrees, approximately 16.7 (e.g., 16.7 ± 0.2) degrees, approximately 17.1 (e.g., 17.1 ± 0.2) degrees, and approximately 18.4 (e.g., 18.4 ± 0.2) degrees. The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of approximately 14.6 (e.g., 14.6 ± 0.2) degrees, approximately 15.4 (e.g., 15.4 ± 0.2) degrees, approximately 16.4 (e.g., 16.4 ± 0.2) degrees, approximately 16.7 (e.g., 16.7 ± 0.2) degrees, and / or approximately 24.8 (e.g., 24.8 ± 0.2) degrees, respectively.In some embodiments, morphology VI has an XRPD pattern that includes peaks attributed to two-theta values ​​of approximately 14.6 degrees (e.g., 14.6 ± 0.2), approximately 16.4 degrees (e.g., 16.4 ± 0.2), and / or approximately 24.8 degrees (e.g., 24.8 ± 0.2). In some embodiments, morphology VI has an XRPD pattern that includes peaks attributed to two-theta values ​​of approximately 16.4 degrees (e.g., 16.4 ± 0.2), approximately 16.7 degrees (e.g., 16.7 ± 0.2), and / or approximately 24.8 degrees (e.g., 24.8 ± 0.2). In some embodiments, form VI has an XRPD pattern that includes peaks attributed to 2-theta values ​​of approximately 8.4 (e.g., 8.4 ± 0.2) degrees, approximately 16.4 (e.g., 16.4 ± 0.2) degrees, approximately 16.7 (e.g., 16.7 ± 0.2) degrees, and / or approximately 24.8 (e.g., 24.8 ± 0.2) degrees, respectively.

[0083] In some embodiments, form VI is characterized by having an endothermic peak at approximately 128.25°C (e.g., 128.25±10°C, 128.25±9°C, 128.25±8°C, 128.25±7°C, 128.25±6°C, 128.25±5°C, 128.25±4°C, 128.25±3°C, 128.25±2°C, 128.25±1°C, or 128.25±0.5°C) when determined by DSC. Form VII

[0084] In some embodiments, a crystalline form (form VII) of the compound of formula (I) is provided herein. In some embodiments, form VII is a solvate or hydrate with acetone and water.

[0085] In some embodiments, morphology VII has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 7 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 7-1] [Table 7-2]

[0086] In some embodiments, form VII has an XRPD pattern that includes the peaks presented in Table 7. In some embodiments, form VII has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 2A or as presented in Table 7.

[0087] In some embodiments, form VII has an XRPD pattern that includes one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 7, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology VII may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 7.6 (e.g., 7.6±0.2) degrees, approximately 8.7 (e.g., 8.7±0.2) degrees, approximately 10.5 (e.g., 10.5±0.2) degrees, approximately 13.2 (e.g., 13.2±0.2) degrees, approximately 15.3 (e.g., 15.3±0.2) degrees, approximately 16.5 (e.g., 16.5±0.2) degrees, approximately 16.7 (e.g., 16.7±0.2) degrees, approximately 18.8 (e.g., 18.8±0.2) degrees, approximately 21.7 (e.g., 21.7±0.2) degrees, and / or approximately 26.3 (e.g., 26.3±0.2) degrees, respectively. In some embodiments, form VII is approximately 7.6 (e.g., 7.6 ± 0.2) degrees, approximately 8.7 (e.g., 8.7 ± 0.2) degrees, approximately 10.5 (e.g., 10.5 ± 0.2) degrees, approximately 13.2 (e.g., 13.2 ± 0.2) degrees, approximately 15.3 (e.g., 15.3 ± 0.2) degrees, approximately 16.5 (e.g., 16.5 ± 0.2) degrees, approximately 16.7 (e.g., 16.7 ± 0.2) degrees, and approximately 18.8 (e.g., 18.8 ± 0.2) degrees. The XRPD pattern includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of approximately 21.7 (e.g., 21.7 ± 0.2) degrees and / or approximately 26.3 (e.g., 26.3 ± 0.2) degrees, respectively. In some embodiments, form VII has an XRPD pattern including peaks attributed to 2-theta values ​​of approximately 7.6 (e.g., 7.6 ± 0.2) degrees, approximately 8.7 (e.g., 8.7 ± 0.2) degrees, approximately 15.3 (e.g., 15.3 ± 0.2) degrees, approximately 16.5 (e.g., 16.5 ± 0.2) degrees and / or approximately 21.7 (e.g., 21.7 ± 0.2) degrees, respectively.In some embodiments, morphology VII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 7.6 (e.g., 7.6 ± 0.2) degrees, approximately 8.7 (e.g., 8.7 ± 0.2) degrees, and / or approximately 16.5 (e.g., 16.5 ± 0.2) degrees, respectively.

[0088] In some embodiments, form VII is characterized by having an onset of endothermic reaction at approximately 43.5°C (e.g., 43.5±5°C, 43.5±4°C, 43.5±3°C, 43.5±2°C, 43.5±1°C, or 43.5±0.5°C) and / or an onset of endothermic reaction at approximately 135.03°C (e.g., 135.03±5°C, 135.03±4°C, 135.03±3°C, 135.03±2°C, 135.03±1°C, or 135.03±0.5°C) as determined by DSC. Form VIII

[0089] In some embodiments, crystalline forms (form VIII) of the compound of formula (I) are provided herein.

[0090] In some embodiments, form VIII is an IPA solvate. In some embodiments, form VIII is isolated via form III, which transforms into form VIII upon drying.

[0091] In some embodiments, morphology VIII has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 8 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 8-1] [Table 8-2]

[0092] In some embodiments, form VIII has an XRPD pattern that includes the peaks presented in Table 8. In some embodiments, form VIII has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 2A or as presented in Table 8.

[0093] In some embodiments, form VIII has an XRPD pattern that includes one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 8, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology VIII may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 7.9 (e.g., 7.9±0.2) degrees, approximately 8.8 (e.g., 8.8±0.2) degrees, approximately 13.1 (e.g., 13.1±0.2) degrees, approximately 14.0 (e.g., 14.0±0.2) degrees, approximately 17.3 (e.g., 17.3±0.2) degrees, approximately 17.6 (e.g., 17.6±0.2) degrees, approximately 18.7 (e.g., 18.7±0.2) degrees, approximately 20.1 (e.g., 20.1±0.2) degrees, approximately 21.1 (e.g., 21.1±0.2) degrees, and / or approximately 23.2 (e.g., 23.2±0.2) degrees, respectively. In some embodiments, form VIII is approximately 7.9 (e.g., 7.9 ± 0.2) degrees, approximately 8.8 (e.g., 8.8 ± 0.2) degrees, approximately 13.1 (e.g., 13.1 ± 0.2) degrees, approximately 14.0 (e.g., 14.0 ± 0.2) degrees, approximately 17.3 (e.g., 17.3 ± 0.2) degrees, approximately 17.6 (e.g., 17.6 ± 0.2) degrees, approximately 18.7 (e.g., 18.7 ± 0.2) degrees, and approximately 20.1 (e.g., 20.1 ± 0.2) degrees. The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of approximately 7.9 (e.g., 7.9 ± 0.2) degrees, approximately 8.8 (e.g., 8.8 ± 0.2) degrees, approximately 14.0 (e.g., 14.0 ± 0.2) degrees, approximately 17.6 (e.g., 17.6 ± 0.2) degrees, and / or approximately 20.1 (e.g., 20.1 ± 0.2) degrees, respectively.In some embodiments, morphology VIII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 7.9 (e.g., 7.9 ± 0.2) degrees, approximately 8.8 (e.g., 8.8 ± 0.2) degrees, and / or approximately 14.0 (e.g., 14.0 ± 0.2) degrees, respectively. In some embodiments, morphology VIII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 7.9 (e.g., 7.9 ± 0.2) degrees and / or approximately 14.0 (e.g., 14.0 ± 0.2) degrees, respectively. In some embodiments, morphology VIII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 7.9 (e.g., 7.9 ± 0.2) degrees, respectively.

[0094] In some embodiments, form VIII is characterized by having an endothermic onset at approximately 108.4°C (e.g., 108.4±5°C, 108.4±4°C, 108.4±3°C, 108.4±2°C, 108.4±1°C, or 108.4±0.5°C) as determined by DSC. Form IX

[0095] In some embodiments, a crystalline form (form IX) of the compound of formula (I) is provided herein.

[0096] In some embodiments, morphology IX is an ethanol solvate. In some embodiments, morphology IX has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 9 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 9-1] [Table 9-2]

[0097] In some embodiments, morphology IX has an XRPD pattern that includes the peaks presented in Table 9. In some embodiments, morphology IX has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 2A or presented in Table 9.

[0098] In some embodiments, form IX has an XRPD pattern that includes one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 9, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology IX may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 7.8 (e.g., 7.8±0.2) degrees, approximately 8.2 (e.g., 8.2±0.2) degrees, approximately 8.9 (e.g., 8.9±0.2) degrees, approximately 13.4 (e.g., 13.4±0.2) degrees, approximately 15.7 (e.g., 15.7±0.2) degrees, approximately 16.8 (e.g., 16.8±0.2) degrees, approximately 17.9 (e.g., 17.9±0.2) degrees, approximately 18.5 (e.g., 18.5±0.2) degrees, approximately 20.4 (e.g., 20.4±0.2) degrees, and / or approximately 22.1 (e.g., 22.1±0.2) degrees, respectively. In some embodiments, form IX is approximately 7.8 (e.g., 7.8 ± 0.2) degrees, approximately 8.2 (e.g., 8.2 ± 0.2) degrees, approximately 8.9 (e.g., 8.9 ± 0.2) degrees, approximately 13.4 (e.g., 13.4 ± 0.2) degrees, approximately 15.7 (e.g., 15.7 ± 0.2) degrees, approximately 16.8 (e.g., 16.8 ± 0.2) degrees, approximately 17.9 (e.g., 17.9 ± 0.2) degrees, and approximately 18.5 (e.g., 18.5 ± 0.2) degrees. The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two-theta values ​​of approximately 20.4 (e.g., 20.4 ± 0.2) degrees and / or approximately 22.1 (e.g., 22.1 ± 0.2) degrees, respectively. In some embodiments, form IX has an XRPD pattern that has peaks attributed to two-theta values ​​of approximately 7.8 (e.g., 7.8 ± 0.2) degrees, approximately 8.2 (e.g., 8.2 ± 0.2) degrees, approximately 8.9 (e.g., 8.9 ± 0.2) degrees, approximately 13.4 (e.g., 13.4 ± 0.2) degrees and / or approximately 16.8 (e.g., 16.8 ± 0.2) degrees, respectively. In some embodiments, morphology IX has an XRPD pattern that includes peaks attributed to two-theta values ​​of approximately 7.8 (e.g., 7.8 ± 0.2) degrees, approximately 8.2 (e.g., 8.2 ± 0.2) degrees, and / or approximately 16.8 (e.g., 16.8 ± 0.2) degrees, respectively.In some embodiments, morphology IX has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 7.8 (e.g., 7.8 ± 0.2) degrees and / or approximately 8.2 (e.g., 8.2 ± 0.2) degrees, respectively.

[0099] In some embodiments, form IX has a DSC graph substantially as shown in Figure 9B. In some embodiments, form IX is characterized by having an endothermic peak at approximately 56.3°C (e.g., 56.3±5°C, 56.3±4°C, 56.3±3°C, 56.3±2°C, 56.3±1°C, or 56.3±0.5°C) and / or having an endothermic peak at approximately 101.3°C (e.g., 101.3±5°C, 101.3±4°C, 101.3±3°C, 101.3±2°C, 101.3±1°C, or 101.3±0.5°C). Form X

[0100] In some embodiments, a crystalline form (form X) of the compound of formula (I) is provided herein.

[0101] In some embodiments, form X is an acetone solvate. In some embodiments, form X remains unchanged after desolvation.

[0102] In some embodiments, morphology X has an XRPD pattern substantially as shown in Figure 2A when measured by Cu Kα radiation. Table 10 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 10-1] [Table 10-2]

[0103] In some embodiments, form X has an XRPD pattern that includes the peaks presented in Table 10. In some embodiments, form X has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 2A or as presented in Table 10.

[0104] In some embodiments, form X has an XRPD pattern including one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 10, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology X may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 16.7 degrees (e.g., 16.7±0.2), approximately 15.9 degrees (e.g., 15.9±0.2), approximately 19.5 degrees (e.g., 19.5±0.2), approximately 12.7 degrees (e.g., 12.7±0.2), approximately 16.9 degrees (e.g., 16.9±0.2), approximately 8.1 degrees (e.g., 8.1±0.2), approximately 11.6 degrees (e.g., 11.6±0.2), approximately 21.1 degrees (e.g., 21.1±0.2), approximately 19.3 degrees (e.g., 19.3±0.2), and / or approximately 9.4 degrees (e.g., 9.4±0.2). In some embodiments, form X is approximately 16.7 (e.g., 16.7 ± 0.2) degrees, approximately 15.9 (e.g., 15.9 ± 0.2) degrees, approximately 19.5 (e.g., 19.5 ± 0.2) degrees, approximately 12.7 (e.g., 12.7 ± 0.2) degrees, approximately 16.9 (e.g., 16.9 ± 0.2) degrees, approximately 8.1 (e.g., 8.1 ± 0.2) degrees, approximately 11.6 (e.g., 11.6 ± 0.2) degrees, and approximately 21.1 (e.g., 21.1 ± 0.2) degrees. The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of approximately 16.7 (e.g., 16.7 ± 0.2) degrees, approximately 15.9 (e.g., 15.9 ± 0.2) degrees, approximately 19.5 (e.g., 19.5 ± 0.2) degrees, approximately 12.7 (e.g., 12.7 ± 0.2) degrees, and / or approximately 16.9 (e.g., 16.9 ± 0.2) degrees, respectively.In some embodiments, morphology X has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 16.7 degrees (e.g., 16.7 ± 0.2), approximately 15.9 degrees (e.g., 15.9 ± 0.2), and / or approximately 19.5 degrees (e.g., 19.5 ± 0.2).

[0105] In some embodiments, form X has a DSC graph substantially as shown in Figure 5. In some embodiments, form X has an endothermic onset at approximately 27.2°C (e.g., 27.2±5°C, 27.2±4°C, 27.2±3°C, 27.2±2°C, 27.2±1°C, or 27.2±0.5°C) and / or has an endothermic onset at approximately 158.9°C (e.g., 158.9±5°C, 158.9±4°C, 158.9±3°C, 158.9±2°C, 158.9±1°C, or 158.9±0.5°C), It is characterized by having an endothermic peak at approximately 53.93°C (e.g., 53.93±5°C, 53.93±4°C, 53.93±3°C, 53.93±2°C, 53.93±1°C, or 53.93±0.5°C) and / or having an endothermic peak at approximately 170.48°C (e.g., 170.48±5°C, 170.48±4°C, 170.48±3°C, 170.48±2°C, 170.48±1°C, or 170.48±0.5°C).

[0106] In some embodiments, form X has a TGA graph substantially as shown in Figure 5. Form XI

[0107] In some embodiments, a crystalline form (form XI) of the compound of formula (I) is provided herein. In some embodiments, form XI is a cumene solvate.

[0108] In some embodiments, morphology XI has an XRPD pattern substantially as shown in Figure 6A when measured by Cu Kα radiation. Table 11 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 11-1] [Table 11-2]

[0109] In some embodiments, form XI has an XRPD pattern including the peaks presented in Table 11. In some embodiments, form XI has an XRPD pattern including one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at 2-theta values ​​of the XRPD patterns substantially as shown in Figure 6A or presented in Table 11.

[0110] In some embodiments, form XI has an XRPD pattern that includes one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 11, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology XI may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 6.7 (e.g., 6.7±0.2) degrees, approximately 9.3 (e.g., 9.3±0.2) degrees, approximately 10.5 (e.g., 10.5±0.2) degrees, approximately 13.2 (e.g., 13.2±0.2) degrees, approximately 14.6 (e.g., 14.6±0.2) degrees, approximately 16.4 (e.g., 16.4±0.2) degrees, approximately 18.6 (e.g., 18.6±0.2) degrees, approximately 20.9 (e.g., 20.9±0.2) degrees, approximately 22.1 (e.g., 22.1±0.2) degrees, and / or approximately 22.5 (e.g., 22.5±0.2) degrees, respectively. In some embodiments, form XI is approximately 6.7 (e.g., 6.7 ± 0.2) degrees, approximately 9.3 (e.g., 9.3 ± 0.2) degrees, approximately 10.5 (e.g., 10.5 ± 0.2) degrees, approximately 13.2 (e.g., 13.2 ± 0.2) degrees, approximately 14.6 (e.g., 14.6 ± 0.2) degrees, approximately 16.4 (e.g., 16.4 ± 0.2) degrees, approximately 18.6 (e.g., 18.6 ± 0.2) degrees, and approximately 20.9 (e.g., 20.9 ± 0.2) degrees. The XRPD pattern includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two-theta values ​​of approximately 22.1 (e.g., 22.1 ± 0.2) degrees and / or approximately 22.5 (e.g., 22.5 ± 0.2) degrees, respectively. In some embodiments, form XI has an XRPD pattern including peaks attributed to two-theta values ​​of approximately 9.3 (e.g., 9.3 ± 0.2) degrees, approximately 10.5 (e.g., 10.5 ± 0.2) degrees, approximately 14.6 (e.g., 14.6 ± 0.2) degrees, approximately 22.1 (e.g., 22.1 ± 0.2) degrees and / or approximately 22.5 (e.g., 22.5 ± 0.2) degrees, respectively.In some embodiments, morphology XI has an XRPD pattern including peaks attributed to two-theta values ​​of approximately 14.6 (e.g., 14.6 ± 0.2) degrees, approximately 22.1 (e.g., 22.1 ± 0.2) degrees, and / or approximately 22.5 (e.g., 22.5 ± 0.2) degrees, respectively. In some embodiments, morphology XI has an XRPD pattern including peaks attributed to two-theta values ​​of approximately 14.6 (e.g., 14.6 ± 0.2) degrees and / or approximately 20.9 (e.g., 20.9 ± 0.2) degrees, respectively. In some embodiments, morphology XI has an XRPD pattern including peaks attributed to two-theta values ​​of approximately 9.3 (e.g., 9.3 ± 0.2) degrees, approximately 14.6 (e.g., 14.6 ± 0.2) degrees, and / or approximately 20.9 (e.g., 20.9 ± 0.2) degrees, respectively. In some embodiments, form XI has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 14.6 (e.g., 14.6 ± 0.2) degrees, respectively.

[0111] In some embodiments, form XI has a DSC graph substantially as shown in Figure 6B. In some embodiments, form XI is characterized by having an endothermic onset at approximately 130.03°C (e.g., 130.03±5°C, 130.03±4°C, 130.03±3°C, 130.03±2°C, 130.03±1°C, or 130.03±0.5°C) and / or having an endothermic peak at approximately 130.19°C (e.g., 130.19±5°C, 130.19±4°C, 130.19±3°C, 130.19±2°C, 130.19±1°C, or 130.19±0.5°C).

[0112] In some embodiments, form XI has a TGA graph substantially as shown in Figure 6B. In some embodiments, form X1 is characterized by exhibiting a weight loss of about 17.3% (e.g., 17.3±0.10%, 17.3±0.09%, 17.3±0.08%, 17.3±0.07%, 17.3±0.06%, 17.3±0.05%, 17.3±0.04%, 17.3±0.03%, 17.3±0.02%, or 17.3±0.01%) after heating from room temperature to about 160.0°C (e.g., 160.0±5°C, 160.0±4°C, 160.0±4°C, 160.0±1°C, or 160.0±0.5°C) as determined by TGA. Form XII

[0113] In some embodiments, a crystalline form (form XII) of the compound of formula (I) is provided herein. In some embodiments, form XII is a heptane solvate.

[0114] In some embodiments, morphology XII has an XRPD pattern substantially as shown in Figure 7A when measured by Cu Kα radiation. Table 12 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 12]

[0115] In some embodiments, form XII has an XRPD pattern that includes the peaks presented in Table 12. In some embodiments, form XII has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 7A or presented in Table 12.

[0116] In some embodiments, form XII has an XRPD pattern comprising one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 12, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology XII may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 6.7 degrees (e.g., 6.7±0.2), 9.2 degrees (e.g., 9.2±0.2), 10.6 degrees (e.g., 10.6±0.2), 14.6 degrees (e.g., 14.6±0.2), 15.7 degrees (e.g., 15.7±0.2), 18.4 degrees (e.g., 18.4±0.2), 21.2 degrees (e.g., 21.2±0.2), 21.9 degrees (e.g., 21.9±0.2), 22.6 degrees (e.g., 22.6±0.2), and / or approximately 23.2 degrees (e.g., 23.2±0.2). In some embodiments, form XII is approximately 6.7 (e.g., 6.7 ± 0.2) degrees, approximately 9.2 (e.g., 9.2 ± 0.2) degrees, approximately 10.6 (e.g., 10.6 ± 0.2) degrees, approximately 14.6 (e.g., 14.6 ± 0.2) degrees, approximately 15.7 (e.g., 15.7 ± 0.2) degrees, approximately 18.4 (e.g., 18.4 ± 0.2) degrees, approximately 21.2 (e.g., 21.2 ± 0.2) degrees, and approximately 21.9 (e.g., 21.9 ± 0.2) degrees. The XRPD pattern includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two-theta values ​​of approximately 22.6 (e.g., 22.6 ± 0.2) degrees and / or approximately 23.2 (e.g., 23.2 ± 0.2) degrees, respectively. In some embodiments, form XII has an XRPD pattern including peaks attributed to two-theta values ​​of approximately 6.7 (e.g., 6.7 ± 0.2) degrees, approximately 9.2 (e.g., 9.2 ± 0.2) degrees, approximately 10.6 (e.g., 10.6 ± 0.2) degrees, approximately 14.6 (e.g., 14.6 ± 0.2) degrees and / or approximately 15.7 (e.g., 15.7 ± 0.2) degrees, respectively.In some embodiments, morphology XII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.7 (e.g., 6.7 ± 0.2) degrees, approximately 9.2 (e.g., 9.2 ± 0.2) degrees, and / or approximately 14.6 (e.g., 14.6 ± 0.2) degrees, respectively. In some embodiments, morphology XII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.7 (e.g., 6.7 ± 0.2) degrees and / or approximately 9.2 (e.g., 9.2 ± 0.2) degrees, respectively. In some embodiments, morphology XII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 9.2 (e.g., 9.2 ± 0.2) degrees, respectively.

[0117] In some embodiments, form XII has a DSC graph substantially as shown in Figure 7B. In some embodiments, form XII is characterized by having an endothermic onset at approximately 140.14°C (e.g., 140.14±5°C, 140.14±4°C, 140.14±3°C, 140.14±2°C, 140.14±1°C, or 140.14±0.5°C) and / or having an endothermic peak at approximately 149.69°C (e.g., 149.69±5°C, 149.69±4°C, 149.69±3°C, 149.69±2°C, 149.69±1°C, or 149.69±0.5°C).

[0118] In some embodiments, form XII has a TGA graph substantially as shown in Figure 7B. In some embodiments, form XII is characterized by exhibiting a weight loss of approximately 6.01% (e.g., 6.01±0.10%, 6.01±0.09%, 6.01±0.08%, 6.01±0.07%, 6.01±0.06%, 6.01±0.05%, 6.01±0.04%, 6.01±0.03%, 6.01±0.02%, or 6.01±0.01%) when determined by TGA after heating from room temperature to approximately 160°C (e.g., 160±5°C, 160±4°C, 160±3°C, 160±2°C, or 160±0.5°C). Form XIII

[0119] In some embodiments, a crystalline form (form XIII) of the compound of formula (I) is provided herein. In some embodiments, form XIII is a DMSO solvate.

[0120] In some embodiments, morphology XIII has an XRPD pattern substantially as shown in Figure 8A when measured by Cu Kα radiation. Table 13 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 13-1] [Table 13-2]

[0121] In some embodiments, form XIII has an XRPD pattern that includes the peaks presented in Table 13. In some embodiments, form XIII has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 8A or presented in Table 13.

[0122] In some embodiments, form XIII has an XRPD pattern comprising one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 13, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology XIII may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 6.5 degrees (e.g., 6.5±0.2), approximately 12.9 degrees (e.g., 12.9±0.2), approximately 16.3 degrees (e.g., 16.3±0.2), approximately 17.4 degrees (e.g., 17.4±0.2), approximately 19.3 degrees (e.g., 19.3±0.2), approximately 21.7 degrees (e.g., 21.7±0.2), approximately 23.0 degrees (e.g., 23.0±0.2), approximately 23.3 degrees (e.g., 23.3±0.2), approximately 23.6 degrees (e.g., 23.6±0.2), and / or approximately 24.6 degrees (e.g., 24.6±0.2). In some embodiments, form XIII is approximately 6.5 (e.g., 6.5 ± 0.2) degrees, approximately 12.9 (e.g., 12.9 ± 0.2) degrees, approximately 16.3 (e.g., 16.3 ± 0.2) degrees, approximately 17.4 (e.g., 17.4 ± 0.2) degrees, approximately 19.3 (e.g., 19.3 ± 0.2) degrees, approximately 21.7 (e.g., 21.7 ± 0.2) degrees, approximately 23.0 (e.g., 23.0 ± 0.2) degrees, and approximately 23.3 (e.g., 23.3 ± 0.2) degrees. The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to 2-theta values ​​of approximately 6.5 (e.g., 6.5 ± 0.2) degrees, approximately 12.9 (e.g., 12.9 ± 0.2) degrees, approximately 19.3 (e.g., 19.3 ± 0.2) degrees, approximately 21.7 (e.g., 21.7 ± 0.2) degrees, and / or approximately 23.3 (e.g., 23.3 ± 0.2) degrees, respectively.In some embodiments, morphology XIII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.5 (e.g., 6.5 ± 0.2) degrees, approximately 19.3 (e.g., 19.3 ± 0.2) degrees, and / or approximately 21.7 (e.g., 21.7 ± 0.2) degrees, respectively. In some embodiments, morphology XIII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.5 (e.g., 6.5 ± 0.2) degrees and / or approximately 21.7 (e.g., 21.7 ± 0.2) degrees, respectively. In some embodiments, morphology XIII has an XRPD pattern that includes peaks attributed to two theta values ​​of approximately 6.5 (e.g., 6.5 ± 0.2) degrees, respectively.

[0123] In some embodiments, form XIII has a DSC graph substantially as shown in Figure 8B. In some embodiments, form XIII is characterized by having an endothermic peak at approximately 50°C (e.g., 50±5°C, 50±4°C, 50±3°C, 50±2°C, 50±1°C, or 50±0.5°C) and / or having the onset of endothermic activity at approximately 84°C (e.g., 84±5°C, 84±4°C, 84±3°C, 84±2°C, 84±1°C, or 84±0.5°C) and / or having an endothermic peak at approximately 91°C (e.g., 91±5°C, 91±4°C, 91±3°C, 91±2°C, 91±1°C, or 91±0.5°C).

[0124] In some embodiments, form XIII has a TGA graph substantially as shown in Figure 8B. In some embodiments, form XIII, when determined by TGA, shows a weight loss of about 0.78% (e.g., 0.78±0.10%, 0.78±0.09%, 0.78±0.08%, 0.78±0.07%, 0.78±0.06%, 0.78±0.05%, 0.78±0.04%, 0.78±0.03%, 0.78±0.02%, or 0.78±0.01%) after heating from room temperature to about 65°C (e.g., 65±5°C, 65±0.5°C) and / or at about 65°C (e.g., 65±5°C, 65±0.5°C) It is characterized by exhibiting a weight loss of approximately 12.37% (for example, 12.37±0.10%, 12.37±0.09%, 12.37±0.08%, 12.37±0.07%, 12.37±0.06%, 12.37±0.05%, 12.37±0.04%, 12.37±0.03%, 12.37±0.02%, or 12.37±0.01%) after heating from ±4℃, 65±3℃, 65±2℃, 65±1℃, or 65±0.5℃ to approximately 175℃ (for example, 175±5℃, 175±4℃, 175±3℃, 175±2℃, 175±1℃, or 175±0.5℃). Form XIV

[0125] In some embodiments, a crystalline form (form XIV) of the compound of formula (I) is provided herein. In some embodiments, form XIV is a methyl ethyl ketone (MEK) solvate.

[0126] In some embodiments, morphology XIV has an XRPD pattern substantially as shown in Figure 9A when measured by Cu Kα radiation. Table 14 shows the possible peak positions and relative peak intensities that can be observed for the crystalline morphology using XRPD when measured by Cu Kα radiation. [Table 14]

[0127] In some embodiments, morphology XIV has an XRPD pattern that includes the peaks presented in Table 14. In some embodiments, morphology XIV has an XRPD pattern that includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) of the peaks at the 2-theta values ​​of the XRPD pattern substantially as shown in Figure 9A or presented in Table 14.

[0128] In some embodiments, form XIV has an XRPD pattern including one or more peaks assigned to 2-theta values ​​(degrees) listed in Table 14, each of which may be independently different in its assignment to the 2-theta angle (degrees) as described herein. For example, morphology XIV may have an XRPD pattern that includes peaks attributed to angle 2-theta at approximately 8.2 degrees (e.g., 8.2±0.2), 9.9 degrees (e.g., 9.9±0.2), 10.9 degrees (e.g., 10.9±0.2), 14.5 degrees (e.g., 14.5±0.2), 15.4 degrees (e.g., 15.4±0.2), 16.3 degrees (e.g., 16.3±0.2), 18.3 degrees (e.g., 18.3±0.2), 19.2 degrees (e.g., 19.2±0.2), 19.8 degrees (e.g., 19.8±0.2), and / or approximately 24.7 degrees (e.g., 24.7±0.2).

[0129] In some embodiments, form XIV is approximately 8.2 (e.g., 8.2 ± 0.2) degrees, approximately 9.9 (e.g., 9.9 ± 0.2) degrees, approximately 10.9 (e.g., 10.9 ± 0.2) degrees, approximately 14.5 (e.g., 14.5 ± 0.2) degrees, approximately 15.4 (e.g., 15.4 ± 0.2) degrees, approximately 16.3 (e.g., 16.3 ± 0.2) degrees, approximately 18.3 (e.g., 18.3 ± 0.2) degrees, and approximately 19.2 (e.g., 19.2 ± 0.2) degrees. The XRPD pattern includes one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two-theta values ​​of approximately 19.8 (e.g., 19.8 ± 0.2) degrees and / or approximately 24.7 (e.g., 24.7 ± 0.2) degrees, respectively. In some embodiments, form XIV has an XRPD pattern including peaks attributed to two-theta values ​​of approximately 8.2 (e.g., 8.2 ± 0.2) degrees, approximately 14.5 (e.g., 14.5 ± 0.2) degrees, approximately 15.4 (e.g., 15.4 ± 0.2) degrees, approximately 18.3 (e.g., 18.3 ± 0.2) degrees and / or approximately 19.2 (e.g., 19.2 ± 0.2) degrees, respectively. In some embodiments, morphology XIV has an XRPD pattern that includes peaks attributed to 2-theta values ​​of approximately 8.2 (e.g., 8.2 ± 0.2) degrees, approximately 9.9 (e.g., 9.9 ± 0.2) degrees, approximately 14.5 (e.g., 14.5 ± 0.2) degrees, and / or approximately 18.3 (e.g., 18.3 ± 0.2) degrees, respectively. In some embodiments, morphology XIV has an XRPD pattern that includes peaks attributed to 2-theta values ​​of approximately 8.2 (e.g., 8.2 ± 0.2) degrees, and / or approximately 9.9 (e.g., 9.9 ± 0.2) degrees, respectively. In some embodiments, morphology XIV has an XRPD pattern that includes peaks attributed to 2-theta values ​​of approximately 8.2 (e.g., 8.2 ± 0.2) degrees, respectively.

[0130] In some embodiments, form XIV has a DSC graph substantially as shown in Figure 14B. In some embodiments, form XIV is characterized by having an endothermic peak at approximately 115.9°C (e.g., 115.9±5°C, 115.9±4°C, 115.9±3°C, 115.9±2°C, 115.9±1°C, or 115.9±0.5°C) and / or having an endothermic peak at approximately 125.4°C (e.g., 125.4±5°C, 125.4±4°C, 125.4±3°C, 125.4±2°C, 125.4±1°C, or 125.4±0.5°C).

[0131] In some embodiments, form XIV has a TGA graph substantially as shown in Figure 14B. In some embodiments, form XIV is characterized by exhibiting a weight loss of approximately 8.74% (e.g., 8.74±0.10%, 8.74±0.09%, 8.74±0.08%, 8.74±0.07%, 8.74±0.06%, 8.74±0.05%, 8.74±0.04%, 8.74±0.03%, 8.74±0.02%, or 8.74±0.01%) after heating from room temperature to approximately 200°C (e.g., 200±5°C, 200±4°C, 200±3°C, 200±2°C, 200±1°C, or 200±0.5°C) as determined by TGA. In some embodiments, form XIV exhibits a weight loss of approximately 4.51% (e.g., 4.51±0.10%, 4.51±0.09%, 4.51±0.08%, 4.51±0.07%, 4.51±0.06%, 4.51±0.05%, 4.51±0.04%, 4.51±0.03%, 4.51±0.02%, or 4.51±0.01%) after heating from room temperature to approximately 105°C (e.g., 105±5°C, 105±4°C, 105±3°C, 105±2°C, 105±1°C, or 105±0.5°C) as determined by TGA, and / or after heating to approximately 105°C (e.g., 105 It is characterized by exhibiting a weight loss of approximately 4.24% (for example, 4.24±0.10%, 4.24±0.09%, 4.24±0.08%, 4.24±0.07%, 4.24±0.06%, 4.24±0.05%, 4.24±0.04%, 4.24±0.03%, 4.24±0.02%, or 4.24±0.01%) after heating from ±5℃, 105±4℃, 105±3℃, 105±2℃, 105±1℃, or 105±0.5℃) to approximately 200℃. Diacetone solvate

[0132] In some embodiments, the crystalline form (diacetone form) of the diacetone solvate of the compound of formula (I) is provided herein. In some embodiments, the diacetone form has the crystallographic parameters shown in Table 15A. [Table 15A] [Table 15B-1] [Table 15B-2]

[0133] In some embodiments, the monoacetone form has an XRPD pattern containing the peaks presented in Table 17B. In some embodiments, the monoacetone form has an XRPD pattern with one or more of the peaks (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) in an angle 2 theta of an XRPD pattern substantially like that shown in Figure 17A or presented in Table 17B.

[0134] In some embodiments, the monoacetone form has an XRPD pattern containing one or more peaks attributed to an angle of 2 theta (degrees) as listed in Table 17, each of which may be independently different in its assignment to an angle of 2 theta (degrees) as described herein. For example, the monoacetone form may have an XRPD pattern containing peaks attributed to angle 2-theta at approximately 6.7° (e.g., 6.7±0.2)°, 12.8° (e.g., 12.8±0.2)°, 13.7° (e.g., 13.7±0.2)°, 16.1° (e.g., 16.1±0.2)°, 19.5° (e.g., 19.5±0.2)°, 19.9° (e.g., 19.9±0.2)°, 21.1° (e.g., 21.1±0.2)°, 21.9° (e.g., 21.9±0.2)°, 23.8° (e.g., 23.8±0.2)°, and / or approximately 25.2° (e.g., 25.2±0.2)°, respectively. In some embodiments, the monoacetone form is approximately 6.7°C (e.g., 6.7±0.2°C), approximately 12.8°C (e.g., 12.8±0.2°C), approximately 13.7°C (e.g., 13.7±0.2°C), approximately 16.1°C (e.g., 16.1±0.2°C), approximately 19.5°C (e.g., 19.5±0.2°C), approximately 19.9°C (e.g., 19.9±0.2°C), approximately 21.1°C (e.g., 21.1±0.2°C), and approximately 21.9°C (e.g., 21.9±0.2°C). The XRPD pattern has one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks attributed to two theta angles of approximately 6.7 (e.g., 6.7 ± 0.2) degrees, approximately 16.1 (e.g., 16.1 ± 0.2) degrees, approximately 21.1 (e.g., 21.1 ± 0.2) degrees, approximately 21.9 (e.g., 21.9 ± 0.2) degrees, and / or approximately 23.8 (e.g., 23.8 ± 0.2) degrees, respectively.In some embodiments, the monoacetone form has an XRPD pattern including peaks attributed to two theta angles of approximately 6.7 degrees (e.g., 6.7 ± 0.2), approximately 16.1 degrees (e.g., 16.1 ± 0.2), and / or approximately 21.1 degrees (e.g., 21.1 ± 0.2).

[0135] In some embodiments, the crystalline form (di-DCM form) of the di-DCM solvate of the compound of formula (I) is provided herein. In some embodiments, the di-DCM form has substantially the XRPD pattern shown in Figure 1D. Preparation method Form I

[0136] Form I can be prepared according to the method disclosed in Example 2. For example, in some embodiments, a method for preparing Form I is provided, comprising the step of desolvating a di-DCM solvate of the compound of formula (I). In some embodiments, the di-DCM solvate is obtained by slurring the compound of formula (I) in DCM. In some embodiments, the di-DCM solvate is obtained by slurring the compound of formula (I) in DCM at room temperature. In some embodiments, the step of desolvating the di-DCM solvate comprises drying the di-DCM solvate. In some embodiments, the step of desolvating the di-DCM solvate comprises drying the di-DCM solvate at room temperature. In some embodiments, the step of desolvating the di-DCM solvate comprises drying the di-DCM solvate at a temperature between approximately 30°C and 40°C. In some embodiments, slurrying a compound of formula (I) in a solvent disclosed herein (e.g., DCM) includes (1) mixing the compound of formula (I) with the solvent to form a slurry, (2) stirring the slurry, and / or (3) isolating the solid (e.g., by vacuum filtration or centrifugal filtration). Form II

[0137] Form II can be prepared according to the method disclosed in Example 3. For example, in some embodiments, a method for preparing Form II is provided, comprising the step of slurring the compound of formula (I) in a mixture of IPA and water at room temperature. In some embodiments, a method for preparing Form II (hydrate) is provided, comprising the step of slurring Form X in water at 50°C. Form III

[0138] Form III can be prepared according to the method disclosed in Example 4. For example, in some embodiments, a method for preparing Form III is provided, comprising the step of slurring the compound of formula (I) in IPA at room temperature. Form IV

[0139] Form IV can be prepared according to the method disclosed in Example 5. For example, in some embodiments, a method for preparing Form IV is provided, comprising the step of slurring the compound of formula (I) in ¼ or ACN at room temperature. Form V

[0140] Form V can be prepared according to the method disclosed in Example 6. For example, in some embodiments, a method for preparing Form V is provided, which includes the step of slurring the compound of formula (I) in THF at room temperature. Form VI

[0141] Form VI can be prepared according to the method disclosed in Example 7. For example, in some embodiments, a method for preparing Form VI is provided, comprising the step of drying the product obtained by slurring the compound of formula (I) in acetone at room temperature. Form VII

[0142] Form VII can be prepared according to the method disclosed in Example 8. For example, in some embodiments, a method for preparing Form VII is provided, comprising the step of slurring the compound of formula (I) in a mixture of acetone and water at room temperature. Form VIII

[0143] Form VIII can be prepared according to the method disclosed in Example 9. For example, in some embodiments, a method for preparing Form VIII is provided, which includes the step of drying Form III. Form IX

[0144] Form IX can be prepared according to the method disclosed in Example 10. For example, in some embodiments, a method for preparing Form IX is provided, which includes the step of slurring the compound of formula (I) in EtOH at 5°C. Form X

[0145] Form X can be prepared according to the method disclosed in Example 11. For example, in some embodiments, a method for preparing Form X is provided, which includes the step of slurring the compound of formula (I) in acetone at 5°C. Form XI

[0146] Form XI can be prepared according to the method disclosed in Example 12. For example, in some embodiments, a method for preparing Form XI is provided, which includes the step of slurring the compound of formula (I) in cumene. Form XII

[0147] Form XII can be prepared according to the method disclosed in Example 13. For example, in some embodiments, a method for preparing Form XII is provided, which includes the step of slurring the compound of formula (I) in heptane. Form XIII

[0148] Form XIII can be prepared according to the method disclosed in Example 14. For example, in some embodiments, a method for preparing Form XIII is provided, comprising the step of slurring the compound of formula (I) in DMSO at room temperature. Form XIV

[0149] Form XIV can be prepared according to the method disclosed in Example 15. For example, in some embodiments, a method for preparing Form XIV is provided, which includes the step of slurring the compound of formula (I) in MEK at room temperature. Pharmaceutical compositions and formulations

[0150] Pharmaceutical compositions of any of the crystalline forms detailed herein are included in the scope of the present invention. Accordingly, the present invention includes pharmaceutical compositions comprising any one of the crystalline forms disclosed herein, for example, forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, and a pharmaceutically acceptable carrier or additive. In one embodiment, the pharmaceutical composition is a composition for controlled release of any of the crystalline forms detailed herein.

[0151] The crystalline forms or compositions disclosed herein can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical or transdermal delivery forms, or forms suitable for inhalation. The crystalline forms or compositions disclosed herein can be formulated with suitable carriers to provide delivery forms, including, but are not limited to, tablets, caplets, capsules (such as hard or soft gelatin capsules), cachets, lozenges, gums, dispersants, suppositories, ointments, poultices, pastes, powders, bandages, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0152] The crystalline forms disclosed herein can be used in the preparation of pharmaceutical formulations, such as drug formulations, by combining the crystalline form as an active ingredient with a pharmaceutically acceptable carrier, such as those described above. Depending on the therapeutic form of the system (e.g., transdermal patch or oral tablet), the carrier may be in various forms. In addition, the pharmaceutical formulation may also contain preservatives, solubilizers, stabilizers, re-wetting agents, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure. Formulations containing the compound may also contain other substances having beneficial therapeutic properties. The pharmaceutical formulation can be prepared by known pharmaceutical methods. A suitable formulation is, for example, Remington: The Science and Practice of Pharmacy, Academic Press, 23, which is incorporated herein by reference. rd This can be found in the ed. (2020).

[0153] The crystalline forms disclosed herein can be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions, such as tablets, coated tablets, and hard or soft-shelled gel capsules, emulsions, or suspensions. Examples of carriers that can be used in the preparation of such compositions include lactose, corn starch or its derivatives, talc, stearic acid or its salts. Acceptable carriers for gel capsules with soft shells include, for example, vegetable oils, waxes, fats, semi-solids, and liquid polyols. In addition, pharmaceutical formulations may also contain preservatives, solubilizers, stabilizers, re-wetters, emulsifiers, sweeteners, colorants, modifiers, and salts, buffers, coatings, or antioxidants for adjusting osmotic pressure. How to use

[0154] In some embodiments, methods for treating a disease in an individual are provided herein, comprising the step of administering to the individual an effective amount of any one of the crystalline forms disclosed herein, for example, forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV. Furthermore, methods for treating a proliferative disorder in an individual are provided herein, comprising the step of administering to the individual an effective amount of the crystalline form. Methods for treating cancer in an individual are also provided herein, comprising the step of administering to the individual an effective amount of the crystalline form. In some embodiments, the crystalline form is administered to the individual according to the dosage and / or method of administration described herein.

[0155] In some embodiments, the present invention provides a method for treating a disease mediated by proteins of the BET family in an individual, comprising the step of administering to the individual an effective amount of any one of the crystalline forms disclosed herein, for example, forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV. In one embodiment, the present invention provides a method for treating or preventing a disorder that is ameliorated by inhibition of BET.

[0156] In some embodiments, a method for treating cancer in an individual is provided, comprising the step of administering a therapeutically effective dose of any crystalline form disclosed herein to an individual in need of treatment for cancer. In some embodiments, the present invention relates to a method for treating cancer in an individual, comprising the step of administering a therapeutically effective dose of any one of the crystalline forms disclosed herein, for example, forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, to an individual in need of treatment for cancer.In certain embodiments, cancers include acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, and diffuse large B cell carcinoma. Follicular lymphoma, abnormal proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endometrial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-sensitive and non-sensitive prostate cancer, enzalutamide (XTANDI) and abiraterone-resistant prostate cancer before or after chemotherapy, leiomyosarcoma Leukemia, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell derived lymphoid malignancies, leukemia, lymphoma, bone marrow cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma The cancers are selected from the group consisting of (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal glandoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (carcinomas and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synoviomas, sweat gland carcinomas, thyroid cancer, Waldenström hypergammaglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. In some embodiments, the cancer in the individual has one or more mutations, amplifications, or overexpression of the gene encoding the BET protein. In some embodiments, the cancer in the individual has mutations, amplifications, or overexpression of BRD4.In some embodiments, cancer in an individual has a mutation, amplification, or overexpression of c-MYC. In some embodiments, cancer in an individual has a mutation, amplification, or overexpression of MYCN. In some embodiments, cancer in an individual is characterized by androgen receptor (AR) expression. In some embodiments, a method is provided for treating a disease in an individual, comprising the steps of (a) administering an effective amount of any one of the crystalline forms disclosed herein, e.g., forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, and (b) administering an effective amount of a DNA damage repair (DDR) pathway inhibitor. In some embodiments, any one of the crystalline forms disclosed herein, e.g., forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, is administered before or after the DDR pathway inhibitor, or co-administered concurrently. In some embodiments, one of the crystalline forms disclosed herein, for example, forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, is administered one hour or longer before or after the DDR pathway inhibitor (e.g., two hours or longer, four hours or longer, eight hours or longer, twelve hours or longer, 24 hours or longer, or 48 hours or longer). Examples of DDR pathway inhibitors include poly(ADP-ribose) polymerase (PARP) inhibitors (e.g., olaparib, rucaparib, niraparib, or talazoparib), ataxia telangiectasia mutation (ATM) protein inhibitors, ataxia telangiectasia and Rad3-related (ATR) protein inhibitors, checkpoint kinase 1 (Chk1) inhibitors, or combinations thereof. In some embodiments, the crystalline form is form I, form II, form III, form IV, form V, form VI, form VIII, form IX, form X, form XI, form XII, form XIII, form XIV, monoacetone solvate form, or diacetone solvate form.In some embodiments, the crystalline form is form I, form II, or form X. In any of the aforementioned embodiments, the crystalline form is form I. In any of the aforementioned embodiments, the crystalline form is form II. In any of the aforementioned embodiments, the crystalline form is form X. In some embodiments, a method is provided for treating a disease in an individual, comprising the steps of (a) administering an effective amount of any one of the crystalline forms disclosed herein, e.g., forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, and (b) administering an effective amount of an endocrine therapy agent. In some embodiments, the endocrine therapy is anti-estrogen therapy. In some embodiments, the endocrine therapy is a selective estrogen receptor degrader (SERD, e.g., fulvestrant). In some embodiments, the endocrine therapy is an aromatase inhibitor (e.g., letrozole). In some embodiments, the endocrine therapy is anti-androgen therapy (e.g., enzalutamide or apalutamide). In some embodiments, the endocrine therapy is a CYP17 inhibitor (such as abiraterone). In some embodiments, one of the crystalline forms disclosed herein, for example, forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, is administered before or after the endocrine therapy agent, or co-administered concurrently. In some embodiments, one of the crystalline forms disclosed herein, for example, forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, is administered one hour or longer before or after the endocrine therapy agent (for example, two hours or longer, four hours or longer, eight hours or longer, twelve hours or longer, twenty-four hours or longer, or forty-eight hours or longer). In some embodiments, the crystalline form is form I, form II, form III, form IV, form V, form VI, form VIII, form IX, form X, form XI, form XII, form XIII, form XIV, monoacetone solvate form, or diacetone solvate form.In some embodiments, the crystalline form is form I, form II, or form X. In any of the embodiments described above, the crystalline form is form I. In any of the embodiments described above, the crystalline form is form II. In any of the embodiments described above, the crystalline form is form X. kit

[0157] This disclosure further provides a kit for carrying out the method of the present invention, comprising one or more crystalline forms described herein or a composition comprising one or more crystalline forms described herein. The kit may use any of the crystalline forms disclosed herein. The kit may be used for one or more of the uses described herein and therefore may include instructions for the treatment of cancer.

[0158] The kit generally includes suitable packaging. The kit may include one or more containers containing any of the crystalline forms described herein. Each component (if there is more than one component) may be packaged in a separate container, or several components may be combined in a single container, if acceptable in terms of cross-reactivity and shelf life.

[0159] The kit may, if necessary, include a set of instructions, which are generally written instructions, regarding the use of the components of the method of the present invention, but an electronic storage medium (e.g., a magnetic diskette or optical disk) containing the instructions is also acceptable. The instructions included in the kit generally include information about the components and their administration to an individual.

[0160] The present invention can be further understood by referring to the following embodiments, which are provided as examples and are not intended to limit the invention. [Examples]

[0161] The following embodiments are provided to further aid in understanding the embodiments disclosed herein and presuppose an understanding of the prior art well known to those skilled in the art to which these embodiments belong. The specific materials and conditions described below are intended to illustrate specific aspects of the embodiments disclosed herein and should not be construed as limiting their reasonable scope.

[0162] The following abbreviations may be used in this specification. [Table 16]

[0163] The crystalline morphology was characterized using various analytical techniques, including XRPD, DSC, TGA, and DVS, following the procedures described below. XRPD

[0164] XRPD stands for Panalytical X' Pert 3 The X-ray Powder XRPD was used on a Si zero-background holder. The 2θ position was calibrated against a Panalytical Si standard disk. The XRPD parameters used are listed in the table below. [Table 17] TGA and DSC

[0165] TGA data were acquired using a TA Discovery 550 TGA from TA Instruments. DSC was performed using a TA Q2000 DSC from TA Instruments. The DSC was calibrated using indium standards, and the TGA was calibrated using nickel standards. The detailed parameters used are shown in the table below. [Table 18] DVS

[0166] DVS was measured via the SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters for the DVS test are listed in the table below. [Table 19] PLM

[0167] Polarized light microscope images were taken at room temperature using a Nikon DS-Fi2 upright microscope. single crystal

[0168] Single crystal indexing was performed via Bruker D8 Venture. (Example 1) Preparation of the compound of formula (I)

[0169] The compound of formula (I) was prepared as disclosed in U.S. Patent Publication No. US2021 / 0002293 A1, which is incorporated herein by reference in its entirety. (Example 2) Preparation of Morphology I

[0170] 25 mg of compound (I) was added to a vial, and DCM was added until a dilute slurry was obtained. The slurry was stirred at room temperature for 48 hours. The solid was filtered, dried, and analyzed. Form I was isolated via a di-DCM solvate prepared by slurring the compound (I) in DCM at room temperature, as described above. The di-DCM solvate was brittle and disintegrated under ambient conditions. Form I was obtained by desolvation of the di-DCM solvate. Figure 1D shows the XRPD overlay of the di-DCM solvate at 223 K, the di-DCM solvate under ambient conditions, and the desolvated di-DCM solvate. Despite the inclusion of additional solvent in the isolation process, this process consistently yielded the di-DCM solvate, which transformed into Form I upon drying. The product was analyzed by XRPD, DSC, TGA, and DVS. The XRPD pattern is shown in Figure 1A. The TGA and DSC graphs are shown in Figure 1B. The DVS graph is shown in Figure 1C. Furthermore, form I was also prepared by solvent-poor solvent experiment. A saturated solution of the compound of formula (I) was prepared in DCM, and heptane was added as a poor solvent until a precipitate was obtained. The solid was filtered, dried, and analyzed.

[0171] Form I was highly crystalline, with an endothermic onset temperature of 154.1°C and an enthalpy of approximately 46 J / g. Since this is a phase obtained by desolvation and not a true anhydrous phase melt, the onset of melting and enthalpy of melt may deviate somewhat from the above values. Form I was hygroscopic, exhibiting a water absorption rate of approximately 2.7 wt percent at RH 80%. Form I particles exhibited a plate-like morphology and withstood grinding without forming amorphous material. The free base of the compound of formula (I) was highly solvable, and no known directly isolateable anhydrous crystalline form was identified. (Example 3) Preparation of Morphology II

[0172] 25 mg of the compound of formula (I) was added to a vial, and a mixture of IPA and water (1:1) was added until a dilute slurry was obtained. The slurry was stirred at room temperature for 48 hours. The solid was filtered, dried, and analyzed. Form II (solvate with IPA and water, hydrate) was prepared by slurring the compound of formula (I) in a mixture of IPA and water at room temperature, as described above. Form II (pure hydrate) was prepared by slurring Form X in water at 50°C for 48 hours. The products were analyzed by XRPD, DSC, and TGA. The XRPD pattern is shown in Figure 2A. The graphs of TGA and DSC are shown in Figure 2B. The dehydrated hydrate product was analyzed by DVS. The graph of DVS is shown in Figure 2C.

[0173] Form II was obtained either as a cosolvate of water and an organic solvent, or as a pure hydrate. The unit cells were substantially identical between the two structures. The space groups were identical, and the difference in unit cell size was negligible, almost entirely attributable to the difference in collection temperature. The fractional coordinates in each solution were interchangeable, suggesting that the API molecules are likely isomorphic. No observable conformational differences were found between the two structures.

[0174] The DSC / TGA of Form II (pure hydrate) showed a weight loss of approximately 3.94%, with broad endothermic activity observed at a starting temperature of 87.4°C and an enthalpy of 114.3 J / g. The PLM of Form II (pure hydrate) exhibited an irregular morphology. When dehydrated Form II was subjected to DVS, a water absorption rate of approximately 3% was observed at RH 80% / room temperature. A broadening of the peak was observed after DVS, and the amount of adsorbed water was close to the stoichiometric water content of the monohydrate, which is 3.4%. (Example 4) Preparation of morphology III

[0175] 25 mg of compound (I) was added to a vial, and IPA was added until a dilute slurry was obtained. The slurry was stirred at room temperature for 48 hours. The solid was filtered, dried, and analyzed. Form III was prepared by slurring the compound (I) in IPA at room temperature, as described above. The product was analyzed by XRPD. The XRPD pattern is shown in Figure 2A. Form III was obtained as an unstable IPA solvate, which can be converted to Form VIII by oven drying. (Example 5) Preparation of Morphology IV

[0176] 25 mg of compound (I) was added to a vial, and siRNA or ACN was added until a dilute slurry was obtained. The slurry was stirred at room temperature for 48 hours. The solid was filtered, dried, and analyzed. Form IV was prepared as described above by slurring the compound (I) in siRNA or ACN at room temperature. The product was analyzed by XRPD, DSC, TGA, and DVS. The XRPD pattern is shown in Figure 2A. TGA / DSC of Form IV revealed a 2.7% weight loss and broad endothermic activity at a starting temperature of 139.2°C. DVS of Form IV showed a 4.4% weight change from RH 0% to 90%, indicating its hygroscopic nature. DVS experiments showed decreased crystallinity. (Example 6) Preparation of morphology V

[0177] 25 mg of compound (I) was added to a vial, and THF was added until a dilute slurry was obtained. The slurry was stirred at room temperature for 48 hours. The solid was filtered, dried, and analyzed. Morphology V was prepared by slurring compound (I) in THF at room temperature, as described above. Crystalline morphologies obtained by slurring compound (I) in MTBE, 2-MeTHF, or toluene at room temperature showed XRPD patterns similar to morphology V, as shown in Figure 3. The products were analyzed by XRPD, DSC, and TGA. The XRPD patterns are shown in Figure 2A. TGA / DSC showed an 8.4% weight loss and endothermic at 92.6°C (start). (Example 7) Preparation of Morphology VI

[0178] 25 mg of the compound of formula (I) was added to a vial, and acetone was added until a dilute slurry was obtained. The slurry was stirred at room temperature for 48 hours. The solid was filtered, dried, and analyzed. Form VI was prepared by drying the product obtained by slurring the compound of formula (I) in acetone at room temperature, as described above. The product was analyzed by XRPD, DSC, and TGA. The XRPD pattern is shown in Figure 2A.

[0179] Form VI was obtained as a partially desolvated acetone solvate, which was desolvated from monoacetone solvate and was stable at room temperature. TGA / DSC of Form VI showed a 2.3% weight loss corresponding to a stoichiometric ratio of 0.2:1 (acetone:API) and endothermic activity at 128.25°C (peak). Loss of crystallinity resulted from oven drying or removal of acetone under high humidity conditions. (Example 8) Preparation of morphology VII

[0180] 25 mg of the compound of formula (I) was added to a vial, and a mixture of acetone and water (1:1) was added until a dilute slurry was obtained. The slurry was stirred at room temperature for 48 hours. The solid was filtered, dried, and analyzed. Form VII was prepared as described above by slurring the compound of formula (I) in a mixture of acetone and water at room temperature. The product was analyzed by XRPD, DSC, and TGA. The XRPD pattern is shown in Figure 2A.

[0181] Form VII was obtained as a solvate and hydrate of acetone with water. XRPD of Form VII showed that it was crystalline. TGA / DSC revealed a 2.8% weight loss and endothermic reactions at two points: 43.5°C (start) and 135.03°C (start). (Example 9) Preparation of morphology VIII

[0182] Form VIII was prepared by drying Form III. The product was analyzed by XPRD, DSC and TGA. The XRPD pattern is shown in Figure 2A. TGA / DSC of the form showed a weight loss of 8.7% and a broad endotherm with an onset temperature of 108.4°C. (Example 10) Preparation of Form IX

[0183] 25 mg of the compound of formula (I) was added to a vial, and EtOH was added until a dilute slurry was obtained. The slurry was stirred at 5°C for 48 hours. The solid was filtered, dried and analyzed. Form IX was prepared by slurrying the compound of formula (I) in EtOH at 5°C as described above. The product was analyzed by XPRD, DSC and TGA. The XRPD pattern is shown in Figure 2A. Form IX was obtained as an EtOH solvate and was obtained at 5°C. XRPD of Form IX indicated that it is crystalline. TGA / DSC revealed a weight loss of 6% and two endotherms at 56.3°C (peak) and 101.3°C (peak), respectively. (Example 11) Preparation of Form X

[0184] 25 mg of the compound of formula (I) was added to a vial, and acetone was added until a dilute slurry was obtained. The slurry was stirred at 5°C for 48 hours. The solid was filtered, dried and analyzed. Form X was prepared by slurrying the compound of formula (I) in acetone at 5°C as described above. The product was analyzed by XPRD, DSC, and TGA. The XRPD pattern is shown in Figure 2A. No form change was observed in the XRPD overlay of the wet cake and the dry cake. TGA / DSC showed a weight loss of 4.1% and two endotherms: the endotherm at 27.2°C (onset) was attributed to solvent loss, and the endotherm at 158.9°C (onset) was attributed to melting of the desolvated phase. The heat of fusion of the melting endotherm was 34.8 J / g. No form change was observed after drying at ambient conditions and 40°C. Humidity testing showed that Form X is stable at 93% RH / room temperature. (Example 12) Preparation of Form XI

[0185] Form XI was prepared by slurrying the compound of formula (I) in cumene using temperature cycling. The product was analyzed by XPRD, DSC, and TGA. The XRPD pattern is shown in Figure 6A. The DSC and TGA graphs are shown in Figure 6B. The form was highly crystalline. Thermal data showed a weight loss of 17.3% in TGA and an endotherm at 130°C (onset) in DSC. Thermal analysis revealed that an amorphous form was obtained after heating the sample beyond the endotherm. (Example 13) Preparation of Form XII

[0186] Form XII was prepared by slurrying the compound of formula (I) in heptane using temperature cycling. The product was analyzed by XPRD, DSC and TGA. The XRPD pattern is shown in Figure 7A. The DSC and TGA graphs are shown in Figure 7B. XRPD showed that the form was crystalline. TGA and DSC of Form XII showed a 6% weight loss starting at about 50°C, and a broad endotherm with an onset temperature of 140°C. Heating Form XII to 160°C gave an amorphous phase. Based on the data, Form XII was determined to be a heptane solvate. (Example 14) Preparation of Form XIII

[0187] Form XIII was prepared by slurring the compound of formula (I) in DMSO at room temperature. The product was analyzed by XPRD, DSC, and TGA. The XRPD pattern is shown in Figure 8A. The DSC and TGA graphs are shown in Figure 8B. Form XIII was obtained as a stable DMSO solvate at room temperature. XRPD showed that Form XIII was crystalline. TGA / DSC of the form showed a 13.2% weight loss before decomposition and endothermic activity at two points; the smaller endothermic activity at 50°C (peak) corresponds to residual solvent loss, while the endothermic activity at 84°C (start) is due to simultaneous desolvation and melting. PLM revealed an irregular plate-like morphology. (Example 15) Preparation of morphology XIV

[0188] Morphology XIV was prepared by slurring the compound of formula (I) in MEK at room temperature. The product was analyzed by XPRD, DSC, and TGA. The XRPD pattern is shown in Figure 9A. The graphs of DSC and TGA are shown in Figure 9B. Morphology XIV was obtained as a MEK solvate stable at room temperature. The XPRD pattern of the morphology indicated low crystallinity. TGA showed a two-step weight loss, with a 4.5% loss in the first step followed by a 4.24% loss, and DSC showed endothermic activity at two points, 115.9°C and 125.4°C. PLM suggested an irregular morphology. (Example 16) Competitive Slurry

[0189] Since Form X remained unchanged after desolvation and storage under high humidity conditions, comparative stability tests were performed on desolvated Form X and Form I via competing slurries in DCM and at room temperature. Form I was obtained after 24 hours, indicating that Form I is the most stable phase in DCM.

[0190] All publications, including patents, patent applications, and scientific articles, referenced herein are incorporated herein by reference in whole for any purpose to the same extent as when individual publications, including patents, patent applications, or scientific articles, are specifically and individually indicated to be incorporated by reference.

Claims

1. Equation (I): 【Chemistry 2】 The crystalline form of the compound or its solvate or hydrate.

2. The crystalline form according to claim 1, which is an anhydrous crystalline form.

3. The crystalline form according to claim 2, characterized in that, when measured by Cu Kα radiation, it has an X-ray powder diffraction (XRPD) pattern that includes peaks at two theta values ​​of approximately 6.1 degrees and approximately 8.5 degrees.

4. The crystalline morphology according to claim 2 or 3, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.1 degrees, approximately 8.5 degrees, approximately 11.6 degrees, approximately 17.0 degrees, and approximately 23.4 degrees.

5. The crystalline form according to any one of claims 2 to 4, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.1 degrees, approximately 8.5 degrees, approximately 10.0 degrees, approximately 11.6 degrees, approximately 14.2 degrees, approximately 17.0 degrees, approximately 18.3 degrees, approximately 23.4 degrees, and approximately 24.9 degrees.

6. The crystalline form according to any one of claims 2 to 5, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern shown in Figure 1A.

7. The crystalline morphology according to any one of claims 2 to 6, characterized in that it has an endothermic peak at approximately 163.1°C when determined by DSC.

8. The crystalline form according to any one of claims 2 to 6, characterized by having a DSC graph substantially as shown in Figure 1B and / or a TGA graph substantially as shown in Figure 1B.

9. The crystalline form according to any one of claims 2 to 8, characterized in that, when determined by DVS, it has a water absorption rate of approximately 2.7 wt% at room temperature and relative humidity of approximately 80%.

10. The crystalline form according to any one of claims 2 to 9, characterized in that it substantially has a DVS graph as shown in Figure 1C.

11. The crystalline form according to claim 1, which is a hydrate, or a solvate or hydrate of isopropyl alcohol (IPA) and water.

12. The crystalline form according to claim 11, which is a solvate or hydrate of isopropyl alcohol and water.

13. The crystalline form according to claim 11, wherein the solvate is a hydrate.

14. The crystalline form according to any one of claims 11 to 13, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.4 degrees and approximately 10.2 degrees.

15. The crystalline morphology according to any one of claims 11 to 14, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.4, approximately 9.2, approximately 10.2, approximately 18.1, and approximately 18.

5.

16. The crystalline morphology according to any one of claims 11 to 15, characterized in that, when measured by Cu Kα radiation, it substantially has an XRPD pattern (morphology II) as shown in Figure 2A.

17. The crystalline morphology according to any one of claims 13 to 16, characterized in that it has an endothermic peak at approximately 127.6°C when determined by DSC.

18. The crystalline form according to any one of claims 13 to 17, characterized in that it has a DSC graph substantially as shown in Figure 2B.

19. The crystalline form according to any one of claims 13 to 18, characterized in that, when determined by TGA, it exhibits a weight loss of approximately 3.94% after heating from room temperature to approximately 160°C.

20. The crystalline form according to any one of claims 13 to 19, characterized in that it substantially has a TGA graph as shown in Figure 2B.

21. The crystalline form according to any one of claims 13 to 20, characterized in that, when determined by DVS, it exhibits a water absorption rate of approximately 3 wt% at room temperature and relative humidity of approximately 80% after dehydration.

22. The crystalline form according to any one of claims 13 to 21, characterized in that, after dehydration, it has a DVS graph substantially as shown in Figure 2C.

23. The crystalline form according to claim 1, which is an isopropyl alcohol solvate.

24. The crystalline morphology according to claim 23, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.3 degrees and approximately 7.6 degrees.

25. The crystalline morphology according to claim 23 or 24, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.3, approximately 7.6, approximately 8.6, approximately 9.0, and approximately 23.

8.

26. The crystalline morphology according to any one of claims 23 to 25, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern (morphology III) shown in Figure 2A.

27. The crystalline form according to claim 1, which is ethyl acetate solvate or acetonitrile solvate.

28. The crystalline form according to claim 27, which is an ethyl acetate solvate.

29. The crystalline form according to claim 27, which is an acetonitrile solvate.

30. The crystalline form according to any one of claims 27 to 29, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of 6.0 degrees and about 6.9 degrees.

31. The crystalline form according to any one of claims 27 to 30, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.0 degrees, approximately 6.9 degrees, approximately 11.7 degrees, approximately 15.0 degrees, and approximately 16.4 degrees.

32. The crystalline morphology according to any one of claims 27 to 31, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern (morphology IV) shown in Figure 2A.

33. The crystalline form according to claim 1, which is a tetrahydrofuran solvate.

34. The crystalline morphology according to claim 33, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.6 and 9.5 degrees.

35. The crystalline morphology according to claim 34, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.6 degrees, approximately 9.5 degrees, approximately 10.6 degrees, approximately 14.7 degrees, and approximately 16.8 degrees.

36. The crystalline morphology according to any one of claims 33 to 35, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern (morphology V) shown in Figure 2A.

37. The crystalline form according to claim 1, wherein the acetone solvate has a stoichiometric ratio of 0.2:1 (acetone: compound of formula (I)).

38. The crystalline morphology according to claim 37, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 16.4 degrees, approximately 16.7 degrees, and approximately 24.8 degrees.

39. The crystalline morphology according to claim 37 or 38, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of 14.6 degrees, about 15.4 degrees, about 16.4 degrees, about 16.7 degrees, and / or about 24.8 degrees.

40. The crystalline morphology according to any one of claims 37 to 39, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern (morphology VI) shown in Figure 2A.

41. The crystalline form according to claim 1, which is a solvate or hydrate of acetone and water.

42. The crystalline morphology according to claim 41, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.6 degrees, approximately 8.7 degrees, and approximately 16.5 degrees.

43. The crystalline morphology according to claim 41 or 42, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.6 degrees, approximately 8.7 degrees, approximately 15.3 degrees, approximately 16.5 degrees, and approximately 21.7 degrees.

44. The crystalline morphology according to any one of claims 41 to 43, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern (morphology VII) shown in Figure 2A.

45. The crystalline form according to any one of claims 1, which is an IPA solvate.

46. The crystalline morphology according to claim 45, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.9 degrees, approximately 8.8 degrees, and approximately 14.0 degrees.

47. The crystalline morphology according to claim 45 or 46, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.9 degrees, approximately 8.8 degrees, approximately 14.0 degrees, approximately 17.6 degrees, and 20.1 degrees.

48. The crystalline morphology according to any one of claims 43 to 45, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern (morphology VIII) shown in Figure 2A.

49. The crystalline form according to any one of claims 1, which is an ethanol solvate.

50. The crystalline morphology according to claim 49, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.8 degrees, approximately 8.2 degrees, and approximately 16.8 degrees.

51. The crystalline morphology according to claim 49 or 50, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 7.8 degrees, approximately 8.2 degrees, approximately 8.9 degrees, approximately 13.4 degrees, and approximately 16.8 degrees.

52. The crystalline morphology according to any one of claims 49 to 51, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern (morphology IX) shown in Figure 2A.

53. The crystalline form according to any one of claims 1, which is an acetone solvate.

54. The crystalline morphology according to claim 53, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 16.7 degrees, approximately 15.9 degrees, and approximately 19.5 degrees.

55. The crystalline morphology according to claim 53 or 54, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 16.7 degrees, approximately 15.9 degrees, approximately 19.5 degrees, approximately 12.7 degrees, and approximately 16.9 degrees.

56. The crystalline morphology according to any one of claims 53 to 55, characterized in that, when measured by Cu Kα radiation, it substantially has an XRPD pattern (morphology X) as shown in Figure 2A.

57. The crystalline form according to any one of claims 1, which is a cumene solvate.

58. The crystalline morphology according to claim 57, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 14.6 degrees, approximately 22.1 degrees, and approximately 22.5 degrees.

59. The crystalline morphology according to claim 57 or 58, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 9.3 degrees, approximately 10.5 degrees, approximately 14.6 degrees, approximately 22.1 degrees, and approximately 22.5 degrees.

60. The crystalline form according to any one of claims 57 to 59, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern shown in Figure 6A.

61. The crystalline form according to any one of claims 1, which is a heptane solvate.

62. The crystalline morphology according to claim 61, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.7 degrees, approximately 9.2 degrees, and approximately 14.6 degrees.

63. The crystalline morphology according to claim 61 or 62, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of 6.7 degrees, about 9.2 degrees, about 10.6 degrees, about 14.6 degrees, and about 15.7 degrees.

64. The crystalline form according to any one of claims 61 to 63, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern shown in Figure 7A.

65. The crystalline form according to any one of claims 1, which is a DMSO solvate.

66. The crystalline morphology according to claim 65, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.5 degrees, approximately 19.3 degrees, and approximately 21.7 degrees.

67. The crystalline morphology according to claim 65 or 66, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 6.5 degrees, approximately 12.9 degrees, approximately 19.3 degrees, approximately 21.7 degrees, and approximately 23.3 degrees.

68. The crystalline form according to any one of claims 65 to 67, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern shown in Figure 8A.

69. The crystalline form according to any one of claims 1, which is a methyl ethyl ketone (MEK) solvate.

70. The crystalline form according to claim 69, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 8.2 degrees and approximately 9.9 degrees.

71. The crystalline morphology according to claim 69 or 70, characterized in that, when measured by Cu Kα radiation, it has an XRPD pattern that includes peaks at two theta values ​​of approximately 8.2 degrees, approximately 9.9 degrees, approximately 14.5 degrees, and approximately 18.3 degrees.

72. The crystalline form according to any one of claims 69 to 71, characterized in that, when measured by Cu Kα radiation, it has substantially the XRPD pattern shown in Figure 9A.

73. A method for preparing the crystalline form according to any one of claims 2 to 10, comprising the step of desolvating the di-DCM solvate of the compound of formula (I).

74. The method according to claim 73, wherein the di-DCM solvate is obtained by slurring the compound of formula (I) in DCM.

75. The method according to claim 73 or 74, wherein the di-DCM solvate is obtained by slurring the compound of formula (I) in DCM at room temperature.

76. The method according to any one of claims 73 to 75, wherein the step of desolvating the di-DCM solvate includes drying the di-DCM solvate.

77. A method for preparing the crystalline form according to any one of claims 11 to 22, comprising the step of slurring the compound of formula (I) in a mixture of IPA and water at room temperature.

78. A method for preparing the crystalline form described in any one of claims 23 to 26, comprising the step of slurring the compound of formula (I) in IPA at room temperature.

79. A method for preparing the crystalline form according to any one of claims 27 to 32, comprising the step of slurring the compound of formula (I) in EtOAc or ACN at room temperature.

80. A method for preparing the crystalline form described in any one of claims 33 to 36, comprising the step of slurring the compound of formula (I) in THF at room temperature.

81. A method for preparing the crystalline form described in any one of claims 37 to 40, comprising the step of drying a product obtained by slurring a compound of formula (I) in acetone at room temperature.

82. A method for preparing the crystalline form according to any one of claims 41 to 44, comprising the step of slurring the compound of formula (I) in a mixture of acetone and water at room temperature.

83. A method for preparing the crystalline form described in any one of claims 45 to 48, comprising the step of drying the crystalline form described in any one of claims 23 to 26.

84. A method for preparing the crystalline form described in any one of claims 49 to 52, comprising the step of slurring the compound of formula (I) in EtOH at 5°C.

85. A method for preparing the crystalline form described in any one of claims 53 to 56, comprising the step of slurring the compound of formula (I) in acetone at 5°C.

86. A method for preparing the crystalline form described in any one of claims 57 to 60, comprising the step of slurring the compound of formula (I) in cumene.

87. A method for preparing the crystalline form described in any one of claims 61 to 64, comprising the step of slurring the compound of formula (I) in heptane.

88. A method for preparing the crystalline form described in any one of claims 65 to 68, comprising the step of slurring the compound of formula (I) in DMSO at room temperature.

89. A method for preparing the crystalline form described in any one of claims 69 to 72, comprising the step of slurring the compound of formula (I) in MEK at room temperature.

90. A composition comprising a crystalline form according to any one of claims 1 to 72 and a pharmaceutically acceptable additive.

91. A method for treating cancer in an individual requiring treatment, comprising the step of administering a therapeutically effective amount of a crystalline form according to any one of claims 1 to 72.

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