Solid forms and methods of use

Abstract

The present disclosure provides, in part, crystalline forms of a compound of formula (I). Also provided are pharmaceutical compositions comprising the crystalline forms of a compound of formula (I), and methods of treating various conditions, diseases, and conditions using the crystalline forms and pharmaceutical compositions of a compound of formula (I). # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 388,342, filed on July 12, 2022, the contents of which are hereby incorporated by reference in their entirety. Background Art

[0003] Cbl-b is an E3 ubiquitin-protein ligase that acts as a negative regulator of T cell activation. Modulation of Cbl-b has been shown to be a therapeutic target for a variety of diseases and conditions. There remains an unmet need to develop solid forms (e.g., crystalline forms) of compounds that inhibit Cbl-b that are suitable for administration to patients with a disorder, disease, or condition such as cancer. Summary of the invention

[0004] In one aspect, provided herein are crystalline forms (e.g., anhydrous crystalline forms, crystalline solvates, and crystalline salts) of compounds of Formula (I):

[0005]

[0006] In various embodiments, the crystalline form of the compound of formula (I):

[0007]

[0008] wherein the crystalline form is characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of 6.0°±0.2°, 8.6°±0.2°, 14.3°±0.2°, and 16.3°±0.2° 2θ.

[0009] In various embodiments, the crystalline solvate of the compound of formula (I):

[0010]

[0011] In various embodiments, the crystalline acetone solvate of the compound of formula (I):

[0012]

[0013] In various embodiments, the crystalline p-dioxane solvate of the compound of formula (I):

[0014]

[0015] In various embodiments, the crystalline tetrahydrofuran solvate of the compound of formula (I):

[0016]

[0017] In various embodiments, the crystalline citrate salt of the compound of formula (I):

[0018]

[0019] In another aspect, provided herein is a pharmaceutical composition comprising a crystalline form of a compound of Formula (I) described herein and a pharmaceutically acceptable excipient.

[0020] On the other hand, provided herein are crystalline forms (e.g., anhydrous crystalline forms, crystalline solvates, and crystalline salts) and pharmaceutical compositions of compounds of formula (I), which can be used to treat various disorders, diseases, and conditions described herein in subjects in need thereof. In certain embodiments, the disorder, disease, or condition is associated with cell proliferation. In certain embodiments, the disorder, disease, or condition associated with cell proliferation is hyperplasia or cancer. In certain embodiments, the cancer is a blood cancer (e.g., lymphoma, leukemia, and myeloma). In certain embodiments, the cancer is a non-hematological cancer (e.g., cancer or sarcoma). In certain embodiments, administration of a crystalline form or pharmaceutical composition of a compound of formula (I) described herein causes the subject to exhibit one or more of the following: increased T cell activation, increased T cell proliferation, reduced T cell exhaustion, reduced T cell anergy, and reduced T cell tolerance. In certain embodiments, increased T cell activation includes increased cytokine production. In certain embodiments, administration of a crystalline form or pharmaceutical composition of a compound of formula (I) described herein causes the subject to exhibit increased NK cell activation. In certain embodiments, increased NK cell activation includes increased cytokine production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is an exemplary X-ray powder diffraction (XRPD) pattern of an anhydrous crystalline form of the compound of Formula (I), as further described in Example 2.

[0022] Figure 2 is an atomic displacement ellipsoid diagram of an anhydrous crystalline form of the compound of formula (I), as further described in Example 2.

[0023] Figure 3 is an exemplary proton NMR ( 1 H NMR) spectrum, as further described in Example 2.

[0024] Figure 4 Shown are exemplary differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) thermograms of an anhydrous crystalline form of the compound of Formula (I), as further described in Example 2.

[0025] Figure 5 is an exemplary water adsorption isotherm for an anhydrous crystalline form of the compound of Formula (I), as further described in Example 2.

[0026] Figure 6 is an exemplary XRPD pattern of the crystalline acetone solvate of the compound of Formula (I), as further described in Example 3.

[0027] Figure 7 is an exemplary XRPD analysis of the crystalline acetone solvate of the compound of Formula (I), as further described in Example 3.

[0028] Figure 8 is an exemplary crystalline acetone solvate of a compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectroscopy, as further described in Example 3.

[0029] Fig. 9 Exemplary DSC and TGA thermograms of a crystalline acetone solvate of the compound of formula (I) are shown, as further described in Example 3.

[0030] Fig.10 is an exemplary XRPD pattern of the crystalline p-dioxane solvate of the compound of Formula (I), as further described in Example 4.

[0031] Fig.11 is an exemplary XRPD indexing analysis of the crystals of the compound of Formula (I) versus dioxane solvate, as further described in Example 4.

[0032] Fig.12 is an exemplary embodiment of a crystalline dioxane solvate of a compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectroscopy, as further described in Example 4.

[0033] Fig.13 Exemplary DSC and TGA thermograms of the crystalline p-dioxane solvate of the compound of Formula (I) are shown, as further described in Example 4.

[0034] Fig.14 is an exemplary XRPD pattern of a crystalline tetrahydrofuran (THF) solvate of a compound of Formula (I), as further described in Example 5.

[0035] Fig.15 is an exemplary XRPD analysis of a crystalline THF solvate of the compound of Formula (I), as further described in Example 5.

[0036] Fig.16 is an exemplary crystalline THF solvate of a compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectroscopy, as further described in Example 5.

[0037] Fig.17 Exemplary DSC and TGA thermograms of a crystalline THF solvate of the compound of Formula (I) are shown, as further described in Example 5.

[0038] Fig.18 is an exemplary XRPD pattern of an acetone solvated crystalline citrate salt of the compound of Formula (I), as further described in Example 6.

[0039] Fig.19 is an exemplary XRPD analysis of the acetone solvated crystalline citrate salt of the compound of Formula (I), as further described in Example 6.

[0040] Fig. 20 is an exemplary crystalline citrate salt of an acetone solvated compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectroscopy, as further described in Example 6.

[0041] Fig.21 Exemplary DSC and TGA thermograms of the acetone solvated crystalline citrate salt of the compound of Formula (I) are shown, as further described in Example 6.

[0042] Fig. 22 is an exemplary XRPD pattern of the acetonitrile-solvated crystalline citrate salt of the compound of Formula (I), as further described in Example 7.

[0043] Fig.23 is an exemplary XRPD analysis of the acetonitrile-solvated crystalline citrate salt of the compound of Formula (I), as further described in Example 7.

[0044] Fig.24 is an exemplary XRPD pattern of an anhydrous crystalline citrate salt of the compound of Formula (I), as further described in Example 8.

[0045] Fig.25 is an exemplary XRPD analysis of the anhydrous crystalline citrate salt of the compound of Formula (I), as further described in Example 8.

[0046] Fig.26 is an exemplary anhydrous crystalline citrate salt of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1H NMR spectroscopy, as further described in Example 8.

[0047] Fig. 27 is an exemplary TGA thermogram of the anhydrous crystalline citrate salt of the compound of Formula (I), as further described in Example 8.

[0048] Fig.28 is an exemplary DSC thermogram of the anhydrous crystalline citrate salt of the compound of Formula (I), as further described in Example 8.

[0049] Fig.29 is an exemplary water adsorption isotherm for the anhydrous crystalline citrate salt of the compound of Formula (I), as further described in Example 8.

[0050] Fig.30 is an overlay of (i) the XRPD pattern of the anhydrous crystalline form of the compound of formula (I) calculated from single crystal X-ray diffraction data (top graph); and (ii) the XRPD pattern of the anhydrous crystalline form of the compound of formula (I) obtained experimentally (bottom graph), as further described in Example 2.

[0051] Fig.31 is an overlay of (i) an XRPD pattern of an anhydrous crystalline form of a compound of Formula (I) before analysis by dynamic vapor adsorption (top graph); and (ii) an XRPD pattern of an amorphous form of a compound of Formula (I) after analysis of the amorphous crystalline form by dynamic vapor adsorption (bottom graph), as further described in Example 8. DETAILED DESCRIPTION

[0052] As generally described herein, the present disclosure provides crystalline forms (e.g., anhydrous crystalline forms, crystalline solvates, and crystalline salts) of compounds of Formula (I), pharmaceutical compositions containing the same, and methods of using the crystalline forms and pharmaceutical compositions to treat medical conditions, diseases, and disorders (e.g., conditions associated with cell proliferation (e.g., hyperplasia or cancer)) in subjects in need thereof.

[0053] definition

[0054] To facilitate understanding of the present invention, a number of terms and phrases are defined below.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. Chemical structures and formulae shown herein are constructed according to standard rules of chemical valence known in the chemical art.

[0056] Throughout the specification, when compositions and kits are described as having, including, or comprising specific components, or when processes and methods are described as having, including, or comprising specific steps, it is contemplated that, in addition, the compositions and kits of the invention consist essentially of or consist of the recited components, and the processes and methods according to the invention consist essentially of or consist of the recited processing steps.

[0057] In the application, when it is said that an element or component is included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from two or more of the recited elements or components.

[0058] In addition, it should be understood that the elements and / or features of the compositions or methods described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention (whether it is clear or implicit herein). For example, unless otherwise explained according to the context, when referring to a specific compound, the compound can be used in various embodiments of the compositions of the present invention and / or the methods of the present invention. In other words, in the present application, embodiments have been described and depicted in a manner that can clearly and concisely write and draw applications, but it is intended and will be understood that embodiments can be combined or separated differently without departing from the present teachings and inventions. For example, it should be understood that all features described and depicted herein are applicable to all aspects of the present invention described and depicted herein.

[0059] The articles "an" and "an" are used in this disclosure to refer to one or more than one (e.g., at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element. For example, "an analogue" means one analogue or more than one analogue.

[0060] The term "and / or" used in this disclosure means "and" or "or" unless otherwise stated.

[0061] It should be understood that, unless otherwise explained in the context and usage, the expression "at least one" includes individually expressing each of the objects listed thereafter and various combinations of two or more of the objects listed. Unless otherwise explained in the context, the expression "and / or" related to three or more objects listed should be understood to have the same meaning.

[0062] Unless otherwise clearly stated or understood from the context, use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing" (including grammatical equivalents thereof) should generally be understood to be open-ended and non-limiting, e.g., not excluding other elements or steps not listed.

[0063] When the term "about" is used before a quantitative value, unless otherwise expressly specified, the present invention also includes the specific quantitative value itself. Unless otherwise indicated or inferred from the context, as used herein, the term "about" refers to ±10%, ±5%, ±3%, ±2% or ±1% variation relative to the nominal value.

[0064] Due to experimental variability well known to those of ordinary skill in the art, each differential scanning calorimetry (DSC) endotherm or exotherm value is usually preceded by the term "about", or by an appropriate range defining the experimental variability. Unless otherwise stated, for the purpose of the data reported herein, the value is ±10°C. Unless otherwise stated, the DSC endotherms / exotherms cited herein are usually reported with this variability of ±10°C, and unless the context dictates otherwise, the DSC endotherms / exotherms cited herein are intended to be reported with variability, whenever disclosed herein, whether or not the word "about" is present.

[0065] When molecular weights (eg, of a polymer) are provided rather than absolute values, the molecular weight is understood to be an average molecular weight unless the context indicates or explains otherwise.

[0066] It should be understood that the order of steps or the order in which certain operations are performed is not important as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0067] In various places of this specification, variables or parameters are disclosed in groups or ranges. This description is clearly intended to include each and every individual subcombination of such group members and range members. For example, integers within the range of 0 to 40 are particularly intended to disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 and 40, and integers within the range of 1 to 20 are particularly intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20.

[0068] The use of any and all examples or exemplary language (e.g., "such as" or "including") herein is intended only to better illustrate the invention and will not impose limitations on the scope of the invention unless otherwise required. Language in this specification should not be construed as indicating any non-required element as essential to the practice of the invention.

[0069] As used herein, "pharmaceutically acceptable" and "pharmacologically acceptable" refer to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce side effects, allergies or other adverse reactions when administered to animals or humans, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by the FDA Office of Biologics Standards.

[0070] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, coatings, isotonic agents, absorption delaying agents, etc. that are compatible with drug administration. Pharmaceutically acceptable carriers may include phosphate buffered saline, water, emulsions (e.g., such as oil / water emulsions or water / oil emulsions) and various types of wetting agents. The composition may also contain stabilizers and preservatives.

[0071] As used herein, "pharmaceutically acceptable salts" refer to salts of any acidic or basic groups that may be present in the compounds of the present disclosure (e.g., compounds of formula (I)), which are compatible with drug administration. As known to those skilled in the art, "salts" of compounds of the present disclosure may be derived from inorganic or organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluceptate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0072] As used herein, "subjects" contemplated for administration include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., youth, middle-aged or elderly)) and / or non-human animals, such as mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0073] As used herein, and unless otherwise indicated, the terms "treat," "treating," and treatment encompass actions that occur while a subject is suffering from a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition, or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also encompass actions that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0074] As used herein, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses both therapeutic and prophylactic amounts.

[0075] As used herein, and unless otherwise indicated, a "therapeutically effective amount" of a compound (e.g., a compound of the invention) is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound (e.g., a compound of the invention) means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" may encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0076] Unless otherwise indicated or explained in the context, as used herein, "disease", "disorder", "illness" or "illness" can be used interchangeably to refer to the state of being or health of a patient or subject that can be treated with the compounds, pharmaceutical compositions or methods provided herein. In some embodiments, the compounds and methods described herein include reducing or eliminating one or more symptoms of a disease, disorder or illness, for example, by administering a compound of formula (I) or a stereoisomer and / or a pharmaceutically acceptable salt thereof.

[0077] As used herein, "administering" means oral administration to a subject, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or implantation of a sustained-release device, for example, a small osmotic pump. Administered by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other delivery methods include, but are not limited to, the use of liposome formulations, intravenous infusions, transdermal patches, etc. "Co-administering" means administering the composition described herein before, after or simultaneously with one or more other therapies (e.g., anticancer agents, chemotherapeutic agents or for the treatment of neurodegenerative diseases). The compounds of the present invention may be administered to a patient alone or may be administered to a patient together. Co-administration is intended to include administering the compound alone or in combination (more than one compound) simultaneously or sequentially. Thus, the formulations may also be combined with other active substances, if desired (eg, to reduce metabolic degradation).

[0078] For clarity, various aspects of the present disclosure are described herein in the form of titles and / or sections; however, it should be understood that all aspects, embodiments or features of the present disclosure described in a particular section are not limited to that particular section, but are applicable to any aspect, embodiment or feature of the present disclosure.

[0079] Solid form

[0080] The compound of formula (I), also known as 2-(3-((R)-cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)imidazo[1,5-a]pyridin-3(2H)-one, is a Cbl-b inhibitor.

[0081]

[0082] In one aspect, provided herein is a solid form of a compound of Formula (I).

[0083] In various embodiments, the solid form of the compound of formula (I) is a crystalline form. In certain embodiments, the compound of formula (I) exists in a crystalline form in the form of its free base. In certain embodiments, the compound of formula (I) exists in a crystalline form as a pharmaceutically acceptable salt (e.g., citrate). In certain embodiments, the crystalline form is a solvated crystalline form. In certain embodiments, the crystalline form is a non-solvated crystalline form.

[0084] 1. Crystalline form of the free base of the compound of formula (I)

[0085] In various embodiments, provided herein is a crystalline form of the free base of a compound of formula (I). In certain embodiments, the crystalline form of the free base of a compound of formula (I) is an anhydrous crystalline form. In various embodiments, the crystalline form of the free base of a compound of formula (I) is a solvated crystalline form. In certain embodiments, the crystalline form of the free base of a compound of formula (I) is a solvated crystalline form.

[0086] (i) Anhydrous crystalline form

[0087] In various embodiments, provided herein is a crystalline form of a compound of formula (I):

[0088]

[0089] wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from the group consisting of 6.0°±0.2°, 8.6°±0.2°, 14.3°±0.2°, and 16.3°±0.2° 2θ.

[0090] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising the following peaks: 6.0°±0.2°, 8.6°±0.2°, 14.3°±0.2°, and 16.3°±0.2° 2θ.

[0091] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 15.6°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 19.9°±0.2°, 20.4°±0.2°, and 21.5°±0.2° 2θ.

[0092] In certain embodiments, the XRPD pattern further comprises the following peaks: 15.6°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 19.9°±0.2°, 20.4°±0.2°, and 21.5°±0.2° 2θ.

[0093] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising one or more peaks selected from 6.0°±0.2°, 8.6°±0.2°, 14.3°±0.2°, 15.6°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 19.9°±0.2°, 20.4°±0.2°, and 21.5°±0.2° 2θ.

[0094] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising the following peaks: 6.0°±0.2°, 8.6°±0.2°, 14.3°±0.2°, 15.6°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 19.9°±0.2°, 20.4°±0.2°, and 21.5°±0.2° 2θ.

[0095] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of 7.1°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 22.0°±0.2°, 22.3°±0.2°, 22.7°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 25.3°±0.2°, 26.7°±0.2°, 27.8°±0.2°, 28.9°±0.2°, 29.1°±0.2°, 30. 2θ: 2°, 23.2°±0.2°, 24.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 26.1°±0.2°, 26.4°±0.2°, 27.1°±0.2°, 27.5°±0.2°, 28.1°±0.2°, 28.5°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.8°±0.2°, and 30.5°±0.2° 2θ.

[0096] In certain embodiments, the XRPD pattern further comprises the following peaks: 7.1°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 22.0°±0.2°, 22.3°±0.2°, 22.7°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 25.3°±0.2°, 26.4°±0.2°, 27. 2θ: 3.2°±0.2°, 24.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 26.1°±0.2°, 26.4°±0.2°, 27.1°±0.2°, 27.5°±0.2°, 28.1°±0.2°, 28.5°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.8°±0.2°, and 30.5°±0.2° 2θ.

[0097] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 6.0°±0.2°, 7.1°±0.2°, 8.6°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.6°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 2θ is 20.4° ± 0.2°, 21.5° ± 0.2°, 22.0° ± 0.2°, 22.3° ± 0.2°, 22.7° ± 0.2°, 23.0° ± 0.2°, 23.2° ± 0.2°, 24.4° ± 0.2°, 24.8° ± 0.2°, 25.2° ± 0.2°, 25.6° ± 0.2°, 26.1° ± 0.2°, 26.4° ± 0.2°, 27.1° ± 0.2°, 27.5° ± 0.2°, 28.1° ± 0.2°, 28.5° ± 0.2°, 28.7° ± 0.2°, 29.3° ± 0.2°, 29.8° ± 0.2°, and 30.5° ± 0.2° 2θ.

[0098] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising the following peaks: 6.0°±0.2°, 7.1°±0.2°, 8.6°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.6°±0.2°, 16.3°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 21.1°±0.2°, 22.3°±0.2°, 23.4°±0.2°, 24.6°±0.2°, 25.8°±0.2°, 26.9°±0.2°, 27. 2θ is 21.5°±0.2°, 22.0°±0.2°, 22.3°±0.2°, 22.7°±0.2°, 23.0°±0.2°, 23.2°±0.2°, 24.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 26.1°±0.2°, 26.4°±0.2°, 27.1°±0.2°, 27.5°±0.2°, 28.1°±0.2°, 28.5°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.8°±0.2°, and 30.5°±0.2° 2θ.

[0099] In certain embodiments, the crystalline form is characterized by Figure 1 Essentially the same XRPD pattern is shown.

[0100] In certain embodiments, the crystalline form exists in the orthorhombic system and has a space group of P212121. In certain embodiments, the crystalline form is characterized by the crystallographic unit cell parameters as shown in Table 1.

[0101] Table 1 - Unit cell parameters of anhydrous crystalline form

[0102]

[0103] In certain embodiments, the crystalline form dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is characterized by a proton NMR ( 1 H NMR) spectrum: 8.327, 7.744, 7.741, 7.738, 7.701, 7.699, 7.697, 7.696, 7.687, 7.686, 7.684, 7.682, 7.646, 7.452, 7.439, 7.426, 7.305, 7.199, 7.186, 7.003, 6.539, 6.395, 6.367, 6.354, 6.328, 5.769, 4.571, 4.561, 4.552, 4.500, 4.270, 4.252, 3.430, 3.327, 3.245, 3.227, 3.216, 3.211, 3.198, 2.765, 2.740, 2.725, 2.511, 2.508, 2.505, 2.502, 2.499, 2.081, 2.075, 2.068, 2.063, 1.906, 1.889, 1 .872, 1.850, 1.847, 1.837, 1.834, 1.829, 1.823, 1.813, 1.804, 1.800, 1.794, 1.788, 1.786, 1.780, 1.774, 1.769, 1.757, 1.752, 1.732, 1.718, 1.714, 1.700, 1.686, 1.673, 1.669, 1.654, 1.637, 1. .633, 1.612, 1.600, 1.583, 1.579, 1.560, 1.554, 1.549, 1.543, 1.484, 1.478, 1.472, 1.463, 1.458, 1.452, 1.443, 1.437, 1.432, 1.417, 1.410, 1.231, 1.144, 0.882, 0.875, 0.860, 0.829 and 0.819 ppm.

[0104] In certain embodiments, the crystalline form dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is characterized by Figure 3 Basically the same as shown in 1 H NMR spectrum.

[0105] The crystalline form of the compound of Formula (I) can also be characterized using thermal analysis techniques such as differential scanning calorimetry (DSC). Thus, in certain embodiments, the crystalline form is characterized by an endotherm with a peak onset of about 165°C to about 180°C as determined by DSC. In certain embodiments, the crystalline form is characterized by an endotherm with a peak onset of about 170°C to about 180°C as determined by DSC. In certain embodiments, the crystalline form is characterized by an endotherm with a peak onset of about 175°C as determined by DSC. In certain embodiments, the crystalline form is characterized by a melting point onset of about 165°C to about 180°C as determined by DSC. In certain embodiments, the crystalline form is characterized by a melting point onset of about 170°C to about 180°C as determined by DSC. In certain embodiments, the crystalline form has a melting point onset of about 175°C as determined by DSC. In certain embodiments, the crystalline form has a melting point onset of about 175°C as determined by DSC. Figure 4 Essentially the same DSC thermograms are shown.

[0106] The crystalline form may also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline form exhibits a mass loss of about 0.1% to about 1.6% by weight when heated to about 230°C as determined by thermogravimetric analysis (TGA). In certain embodiments, the crystalline form exhibits a mass loss of less than or equal to about 1.6% by weight when heated to about 230°C as determined by TGA analysis. In certain embodiments, the crystalline form has a mass loss of about 1.6% by weight when heated to about 230°C. Figure 4 Essentially the same TGA thermogram is shown.

[0107] The crystalline form may also be characterized according to its water absorption properties. Thus, in certain embodiments, the crystalline form exhibits a mass gain of less than or equal to about 0.4% by weight at 95% relative humidity and a temperature of 25°C as determined by dynamic vapor sorption (DVS). In certain embodiments, the crystalline form has a relative humidity of about 0.1% or less when measured at 25°C. Figure 5 Essentially the same water absorption isotherm is shown in .

[0108] In certain embodiments, the crystalline form is an anhydrous crystalline form.

[0109] (ii) Crystalline acetone solvate

[0110] In various embodiments, provided herein is a crystalline acetone solvate of a compound of formula (I):

[0111]

[0112] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 6.4°±0.2°, 16.2°±0.2°, 17.2°±0.2°, and 22.0°±0.2° 2θ.

[0113] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising the following peaks: 6.4°±0.2°, 16.2°±0.2°, 17.2°±0.2°, and 22.0°±0.2° 2θ.

[0114] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 12.0°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 21.8°±0.2°, and 22.6°±0.2° 2θ.

[0115] In certain embodiments, the XRPD pattern further comprises the following peaks: 12.0°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 21.8°±0.2°, and 22.6°±0.2° 2θ.

[0116] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising one or more peaks selected from 6.4°±0.2°, 12.0°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.0°±0.2°, and 22.6°±0.2° 2θ.

[0117] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising the following peaks: 6.4°±0.2°, 12.0°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.2°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.0°±0.2°, and 22.6°±0.2° 2θ.

[0118] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of 7.8°±0.2°, 9.8°±0.2°, 10.4°±0.2°, 12.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.5°±0.2°, 21.2°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 24.8°±0.2°, 25.1°±0.2°, 26.8°±0.2°, 27.8°±0.2°, 28.6°±0.2°, 29.8°±0.2°, 30.8°±0.2°, 31.3°±0.2°, 32.4°±0.2°, 33.5°±0.2°, 34.6°±0.2°, 35.7°±0.2°, 36.8°±0.2°, 37. .2°, 24.0°±0.2°, 24.3°±0.2°, 24.9°±0.2°, 25.0°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 26.1°±0.2°, 26.3°±0.2°, 27.0°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.7°±0.2°, 30.1°±0.2°, 30.6°±0.2°, and 31.1°±0.2° 2θ.

[0119] In certain embodiments, the XRPD pattern further comprises the following peaks: 7.8°±0.2°, 9.8°±0.2°, 10.4°±0.2°, 12.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.5°±0.2°, 21.2°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 2θ: 24.0°±0.2°, 24.3°±0.2°, 24.9°±0.2°, 25.0°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 26.1°±0.2°, 26.3°±0.2°, 27.0°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.7°±0.2°, 30.1°±0.2°, 30.6°±0.2° and 31.1°±0.2° 2θ.

[0120] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 6.4°±0.2°, 7.8°±0.2°, 9.8°±0.2°, 10.4°±0.2°, 12.0°±0.2°, 12.8°±0.2°, 14.1°±0.2°, 14.3°±0.2°, 15.1°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 17.8°±0.2°, 18.4°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 20.5°±0.2°, 21.2°±0.2°, °, 21.8°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 24.3°±0.2°, 24.9°±0.2°, 25.0°±0.2°, 25.4°±0.2°, 25.8° ±0.2°, 26.1°±0.2°, 26.3°±0.2°, 27.0°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.7°±0.2°, 30.1°±0.2°, 30.6°±0.2°, and 31.1°±0.2° 2θ.

[0121] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising the following peaks: 6.4°±0.2°, 7.8°±0.2°, 9.8°±0.2°, 10.4°±0.2°, 12.0°±0.2°, 12.8°±0.2°, 14.1°±0.2°, 14.3°±0.2°, 15.1°±0.2°, 15.7°±0.2°, 16.2°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 17.8°±0.2°, 18.4°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.2°±0.2°, 20.5°±0.2°, 21.2°±0.2°, 21.6°±0.2°, 22. .8°±0.2°, 22.0°±0.2°, 22.6°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 23.6°±0.2°, 24.0°±0.2°, 24.3°±0.2°, 24.9°±0.2°, 25.0°±0.2°, 25.4°±0.2°, 25.8°±0.2° .2°, 26.1°±0.2°, 26.3°±0.2°, 27.0°±0.2°, 27.7°±0.2°, 28.3°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.7°±0.2°, 30.1°±0.2°, 30.6°±0.2°, and 31.1°±0.2° 2θ.

[0122] In certain embodiments, the crystalline acetone solvate is characterized by Figure 6 Essentially the same XRPD pattern is shown.

[0123] In certain embodiments, the crystalline acetone solvate exists in the orthorhombic system and has a space group of P212121. In certain embodiments, the crystalline acetone solvate is characterized by the crystallographic unit cell parameters as shown in Table 2.

[0124] Table 2 - Unit cell parameters of crystalline acetone solvates

[0125]

[0126] In certain embodiments, a crystalline acetone solvate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is characterized by having one, two, three, four, five or more of the following peaks: 1H NMR spectrum: 8.323, 7.740, 7.737, 7.734, 7.696, 7.694, 7.693, 7.684, 7.683, 7.681, 7.679, 7.643, 7.451, 7.438, 7.424, 7.303, 7.197, 7.184, 7.002, 4.547, 4.267, 4.249, 3.542, 3.426, 3.400, 3.378, 3 .349, 3.320, 3.307, 3.296, 3.265, 3.242, 3.224, 3.213, 3.208, 3.195, 3.181, 3.129, 2.763, 2.738, 2.723, 2.617, 2.614, 2.611, 2.523, 2.520, 2.508, 2.505, 2.502, 2.499, 2.496, 2.481, 2.389, 2. 386, 2.109, 2.096, 2.087, 2.081, 2.073, 2.066, 2.060, 1.979, 1.904, 1.888, 1.869, 1.849, 1.846, 1.836, 1.827, 1.822, 1.812, 1.803, 1.799, 1.793, 1.788, 1.785, 1.779, 1.773, 1.767, 1.756, 1. 750, 1.730, 1.715, 1.711, 1.698, 1.684, 1.656, 1.638, 1.612, 1.596, 1.580, 1.560, 1.554, 1.478, 1.471, 1.458, 1.452, 1.443, 1.437, 1.432, 1.416, 1.141, 0.883, 0.876, 0.861, 0.830 and 0.820 ppm.

[0127] In certain embodiments, the crystalline acetone solvate is characterized by Figure 8 Shown is essentially the same 1 HNMR spectrum.

[0128] The crystalline acetone solvate of the compound of formula (I) can also be characterized using thermal analysis techniques such as DSC. Thus, in certain embodiments, the crystalline acetone solvate is characterized by one or more endotherms having a peak maximum selected from about 100°C, about 107°C, and about 173°C as determined by DSC. In certain embodiments, the crystalline acetone solvate is characterized by an endotherm having a peak onset of about 90°C as determined by DSC. In certain embodiments, the crystalline acetone solvate has a peak maximum of about 100°C, about 107°C, and about 173°C. Fig. 9 Essentially the same DSC thermograms are shown.

[0129] The crystalline acetone solvate may also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline acetone solvate exhibits a mass loss of less than or equal to about 5.3% by weight when heated to about 121° C. as determined by TGA. In certain embodiments, the crystalline acetone solvate has a mass gain / mass loss as determined by TGA as described above. Fig. 9 Essentially the same TGA thermogram is shown.

[0130] In certain embodiments, the crystalline acetone solvate is a monoacetone solvate.

[0131] (iii) Crystalline p-dioxane solvate

[0132] In various embodiments, provided herein is a crystalline p-dioxane solvate of a compound of Formula (I):

[0133]

[0134] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 6.3°±0.2°, 16.0°±0.2°, 17.0°±0.2°, and 21.8°±0.2° 2θ.

[0135] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern comprising the following peaks: 6.3°±0.2°, 16.0°±0.2°, 17.0°±0.2°, and 21.8°±0.2° 2θ.

[0136] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 11.8°±0.2°, 14.2°±0.2°, 17.5°±0.2°, 20.0°±0.2°, and 21.6°±0.2° 2θ.

[0137] In certain embodiments, the XRPD pattern further comprises the following peaks: 11.8°±0.2°, 14.2°±0.2°, 17.5°±0.2°, 20.0°±0.2°, and 21.6°±0.2° 2θ.

[0138] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern comprising one or more peaks selected from 6.3°±0.2°, 11.8°±0.2°, 14.2°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.5°±0.2°, 20.0°±0.2°, 21.6°±0.2°, and 21.8°±0.2° 2θ.

[0139] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern comprising the following peaks: 6.3°±0.2°, 11.8°±0.2°, 14.2°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.5°±0.2°, 20.0°±0.2°, 21.6°±0.2°, and 21.8°±0.2° 2θ.

[0140] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of 5.2°±0.2°, 7.7°±0.2°, 10.3°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 15.4°±0.2°, 15.5°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.4°±0.2°, 20.2°±0.2°, 21.4°±0.2°, 23.2°±0.2°, 24.8°±0.2°, 25.9°±0.2°, 26.1°±0.2°, 27.8°±0.2°, 28.8°±0.2°, 29.9°±0.2°, 30. 2θ: 2°, 21.0°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.0°±0.2°, 24.7°±0.2°, 25.2°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, 28.0°±0.2°, 28.3°±0.2°, and 28.9°±0.2° 2θ.

[0141] In certain embodiments, the XRPD pattern further comprises the following peaks: 5.2°±0.2°, 7.7°±0.2°, 10.3°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 15.4°±0.2°, 15.5°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.4°±0.2°, 20.2°±0.2°, 21.2°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.9°±0.2°, 26.1°±0.2°, 27. 2θ: 1.0°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.0°±0.2°, 24.7°±0.2°, 25.2°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, 28.0°±0.2°, 28.3°±0.2° and 28.9°±0.2° 2θ.

[0142] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.2°±0.2°, 6.3°±0.2°, 7.7°±0.2°, 10.3°±0.2°, 11.8°±0.2°, 12.6°±0.2°, 14.2°±0.2°, 14.9°±0.2°, 15.4°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19. .2°, 19.4°±0.2°, 20.0°±0.2°, 20.2°±0.2°, 21.0°±0.2°, 21.6°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.0°±0.2°, 24.7°±0.2°, 25.2°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, 28.0°±0.2°, 28.3°±0.2°, and 28.9°±0.2° 2θ.

[0143] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern comprising the following peaks: 5.2°±0.2°, 6.3°±0.2°, 7.7°±0.2°, 10.3°±0.2°, 11.8°±0.2°, 12.6°±0.2°, 14.2°±0.2°, 14.9°±0.2°, 15.4°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.0°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.2°±0.2°, 19.3°±0.2°, 19.4°±0.2°, 19.6°±0.2°, 19.8°±0.2°, 20. 2θ: 19.4°±0.2°, 20.0°±0.2°, 20.2°±0.2°, 21.0°±0.2°, 21.6°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.0°±0.2°, 24.7°±0.2°, 25.2°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, 28.0°±0.2°, 28.3°±0.2° and 28.9°±0.2° 2θ.

[0144] In certain embodiments, the crystalline p-dioxane solvate is characterized by being Fig.10 Essentially the same XRPD pattern is shown.

[0145] In certain embodiments, the crystalline p-dioxane solvate exists in the orthorhombic system and has a space group of P212121. In certain embodiments, the crystalline p-dioxane is characterized by the crystallographic unit cell parameters as shown in Table 3.

[0146] Table 3 - Unit cell parameters of crystalline p-dioxane solvate

[0147]

[0148] In certain embodiments, a crystalline p-dioxane solvate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is characterized by having one, two, three, four, five or more of the following peaks: 1H NMR spectrum: 10.800, 10.202, 10.076, 9.754, 8.989, 8.796, 8.714, 8.622, 8.586, 8.547, 8.496, 8.395, 8.360, 8.325, 8.316, 8.303, 8.288, 8.260, 8.199, 8. 147, 8.061, 8.042, 7.871, 7.819, 7.799, 7.773, 7.741, 7.738, 7.735, 7.716, 7.699, 7.697, 7.695, 7.694, 7.685, 7.684, 7.682, 7.680, 7.647, 7.611, 7.584, 7.571, 7.557, 7.541, 7.477, 7.464, 7.451, 7.438, 7.425, 7.369, 7.329, 7.304, 7.271, 7.258, 7.245, 7.234, 7.226, 7.198, 7.185, 7.176, 7.14 1, 7.135, 7.116, 7.063, 7.050, 7.004, 6.974, 6.961, 6.911, 6.899, 6.863, 6.835, 6.822, 6.789, 6.541, 6.528, 6.508, 6.497, 4.268, 4.250, 4.134, 4.1 24, 4.116, 4.106, 3.694, 3.688, 3.686, 3.682, 3.678, 3.673, 3.652, 3.648, 3.632, 3.604, 3.593, 3.569, 3.554, 3.543, 3.511, 3.455, 3.451, 3.447, 3 .445, 3.440, 3.427, 3.401, 3.379, 3.371, 3.360, 3.350, 3.321, 3.308, 3.297, 3.247, 3.226, 3.214, 3.209, 3.196, 3.182, 3.136, 2.743, 2.728, 2.618 , 2.615, 2.612, 2.524, 2.521, 2.509, 2.506, 2.503, 2.500, 2.497, 2.390, 2.387, 2.384, 2.079, 2.074, 2.066, 2.061, 1.891, 1.874, 1.850, 1.846, 1.8 36, 1.828, 1.822, 1.812, 1.803, 1.799, 1.793, 1.788, 1.785, 1.779, 1.773, 1.768, 1.756, 1.751, 1.730, 1.716, 1.712, 1.698, 1.684, 1.668, 1.656, 1.638, 1.634, 1.603, 1.598, 1.586, 1.581, 1.486, 1.480, 1.474, 1.460, 1.454, 1.445, 1.439, 1.425, 1.418, 1.412, 1.244, 1.233, 0.884, 0.878, 0.858, 0.846, 0.831, 0.820 and 0.791 ppm.

[0149] In certain embodiments, the crystalline p-dioxane solvate is characterized by being Fig.12 Shown is essentially the same 1 H NMR spectrum.

[0150] The crystalline p-dioxane solvate of the compound of Formula (I) may also be characterized using thermal analysis techniques such as DSC. Thus, in certain embodiments, the crystalline p-dioxane solvate is characterized by an endotherm with a peak maximum at about 106° C. as determined by DSC. In certain embodiments, the crystalline p-dioxane solvate is characterized by an endotherm with a peak onset at about 94° C. as determined by DSC. In certain embodiments, the crystalline p-dioxane solvate has a thermal conductivity similar to that of the compound of Formula (I). Fig.13 Essentially the same DSC thermograms are shown.

[0151] The crystalline p-dioxane solvate may also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline p-dioxane solvate exhibits a mass loss of less than or equal to about 3.9% by weight when heated to about 119° C. as determined by TGA. In certain embodiments, the crystalline p-dioxane solvate has a mass gain / mass loss as determined by TGA as described above. Fig.13 Essentially the same TGA thermogram is shown.

[0152] In certain embodiments, the crystalline p-dioxane solvate is a mono-p-dioxane solvate.

[0153] (iv) Crystalline Tetrahydrofuran (THF) Solvate

[0154] In various embodiments, provided herein is a crystalline THF solvate of a compound of formula (I):

[0155]

[0156] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 6.3°±0.2°, 16.1°±0.2°, 17.3°±0.2°, and 22.9°±0.2° 2θ.

[0157] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising the following peaks: 6.3°±0.2°, 16.1°±0.2°, 17.3°±0.2°, and 22.9°±0.2° 2θ.

[0158] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of: 17.1°±0.2°, 17.9°±0.2°, and 22.4°±0.2° 2θ.

[0159] In certain embodiments, the XRPD pattern further comprises the following peaks: 17.1°±0.2°, 17.9°±0.2°, and 22.4°±0.2° 2θ.

[0160] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 6.3°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.3°±0.2°, 17.9°±0.2°, 22.4°±0.2°, and 22.9°±0.2° 2θ.

[0161] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising the following peaks: 6.3°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.3°±0.2°, 17.9°±0.2°, 22.4°±0.2°, and 22.9°±0.2° 2θ.

[0162] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of 7.7°±0.2°, 11.4°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 12.5°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 20.1°±0.2°, 21.2°±0.2°, 23.4°±0.2°, 24.8°±0.2°, 25.6°±0.2°, 26.7°±0.2°, 27.9°±0.2°, 28. 2θ: 1.0°±0.2°, 21.7°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 24.6°±0.2°, 25.3°±0.2°, 25.9°±0.2°, 27.1°±0.2°, 27.3°±0.2°, 28.4°±0.2°, 28.9°±0.2°, 29.5°±0.2°, 30.0°±0.2° and 30.8°±0.2° 2θ.

[0163] In certain embodiments, the XRPD pattern further comprises the following peaks: 7.7°±0.2°, 11.4°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 12.5°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 22.1°±0.2°, 23.1°±0.2°, 24.2°±0.2°, 25.3°±0.2°, 26.4°±0.2°, 27.8°±0.2°, 28. 0.2°, 21.7°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 24.6°±0.2°, 25.3°±0.2°, 25.9°±0.2°, 27.1°±0.2°, 27.3°±0.2°, 28.4°±0.2°, 28.9°±0.2°, 29.5°±0.2°, 30.0°±0.2°, and 30.8°±0.2° 2θ.

[0164] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 6.3°±0.2°, 7.7°±0.2°, 11.4°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 12.5°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.3°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19. .8°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 22.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 24.6°±0.2°, 25.3°±0.2°, 25.9°±0.2°, 27.1°±0.2°, 27.3°±0.2°, 28.4°±0.2°, 28.9°±0.2°, 29.5°±0.2°, 30.0°±0.2° and 30.8°±0.2° 2θ.

[0165] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising the following peaks: 6.3°±0.2°, 7.7°±0.2°, 11.4°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 12.5°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 17.1°±0.2°, 17.3°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 19.9°±0.2°, 20.1°±0.2°, 21.1°±0.2°, 22. 2θ: 0.2°, 20.1°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 21.9°±0.2°, 22.4°±0.2°, 22.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 24.6°±0.2°, 25.3°±0.2°, 25.9°±0.2°, 27.1°±0.2°, 27.3°±0.2°, 28.4°±0.2°, 28.9°±0.2°, 29.5°±0.2°, 30.0°±0.2°, and 30.8°±0.2° 2θ.

[0166] In certain embodiments, the crystalline THF solvate is characterized by Fig.14 Essentially the same XRPD pattern is shown.

[0167] In certain embodiments, the crystalline THF solvate exists in the orthorhombic system and has a space group of P212121. In certain embodiments, the crystalline THF solvate is characterized by the crystallographic unit cell parameters as shown in Table 4.

[0168] Table 4 - Unit cell parameters of crystalline THF solvates

[0169]

[0170] In certain embodiments, a crystalline THF solvate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is characterized by having one, two, three, four, five or more of the following peaks: 1H NMR spectrum: 10.797, 10.076, 8.712, 8.568, 8.322, 8.314, 8.301, 8.285, 7.738, 7.735, 7.732, 7.696, 7.695, 7.693, 7.691, 7.683, 7.682, 7.679, 7.678, 7.644, 7.451, 7.438, 7.425, 7.304, 7.197, 7.184, 7.004, 4.266, 4.249, 4.123, 4.105, 3.719, 3.692, .674, 3.633, 3.628, 3.622, 3.618, 3.615, 3.612, 3.611, 3.608, 3.605, 3.601, 3.597, 3.594, 3.592, 3.590, 3.588, 3.585, 3.580, 3.574, 3.570, 3.551, 3.541, 3.477, 3.426, 3.399, 3.377, 3.369, 3.358, 3.348, 3.317, 3.293, 3.243, 3.223, 3.212, 3.20 7, 3.194, 3.180, 3.134, 2.741, 2.616, 2.613, 2.610, 2.607, 2.538, 2.522, 2.519, 2.516, 2.507, 2.504, 2.501, 2.498, 2.495, 2.388, 2.385, 2.382, 2.108, 2.096, 2.090, 2.084, 2.078, 2.072, 2.065, 1.888, 1.870, 1.845, 1.836, 1.827, 1.821, 1.808, ppm.

[0171] In certain embodiments, the crystalline THF solvate is characterized by Fig.16 Shown is essentially the same 1 HNMR spectrum.

[0172] The crystalline THF solvate of the compound of formula (I) can also be characterized using thermal analysis techniques such as DSC. Thus, in certain embodiments, the crystalline THF solvate is characterized by an endotherm with a peak maximum at about 97°C as determined by DSC. In certain embodiments, the crystalline THF solvate is characterized by an endotherm with a peak onset of about 85°C as determined by DSC. In certain embodiments, the crystalline THF solvate has a thermal conductivity similar to that of the compound of formula (I). Fig.17 Essentially the same DSC thermograms are shown.

[0173] The crystalline THF solvate may also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline THF solvate exhibits a mass loss of less than or equal to about 4.5% by weight when heated to about 112° C. as determined by TGA. In certain embodiments, the crystalline THF solvate has a mass gain / mass loss as determined by TGA as described above. Fig.17 Essentially the same TGA thermogram is shown.

[0174] In certain embodiments, the crystalline THF solvate is a mono-THF solvate.

[0175] 2. Crystalline citrate form

[0176] In one aspect, provided herein is a citrate salt of a compound of formula (I):

[0177]

[0178] In certain embodiments, the crystalline citrate is anhydrous crystalline citrate. In certain embodiments, the crystalline citrate is a solvated crystalline citrate (e.g., acetone solvate, acetonitrile solvate). In certain embodiments, the crystalline citrate described herein is a monocitrate.

[0179] (i) Acetone-solvated crystalline citrate

[0180] In certain embodiments, the crystalline citrate salt is an acetone-solvated crystalline citrate salt.

[0181] In certain embodiments, the acetone-solvated crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.0±0.2°, 6.6±0.2°, 17.6±0.2°, and 18.2±0.2° 2θ.

[0182] In certain embodiments, the acetone solvated crystalline citrate salt is characterized by an XRPD pattern comprising the following peaks: 5.0±0.2°, 6.6±0.2°, 17.6±0.2°, and 18.2±0.2° 2θ.

[0183] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 15.0±0.2°, 15.3±0.2°, 16.9±0.2°, 19.7±0.2°, 20.1±0.2°, 22.6±0.2°, 22.8±0.2°, and 24.8±0.2° 2θ.

[0184] In certain embodiments, the XRPD pattern further comprises the following peaks: 15.0±0.2°, 15.3±0.2°, 16.9±0.2°, 19.7±0.2°, 20.1±0.2°, 22.6±0.2°, 22.8±0.2°, and 24.8±0.2° 2θ.

[0185] In certain embodiments, the acetone solvated crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from 5.0±0.2°, 6.6±0.2°, 15.0±0.2°, 15.3±0.2°, 16.9±0.2°, 17.6±0.2°, 18.2±0.2°, 19.7±0.2°, 20.1±0.2°, 22.6±0.2°, 22.8±0.2°, and 24.8±0.2° 2θ.

[0186] In certain embodiments, the acetone solvated crystalline citrate salt is characterized by an XRPD pattern comprising peaks at 5.0±0.2°, 6.6±0.2°, 15.0±0.2°, 15.3±0.2°, 16.9±0.2°, 17.6±0.2°, 18.2±0.2°, 19.7±0.2°, 20.1±0.2°, 22.6±0.2°, 22.8±0.2°, and 24.8±0.2° 2θ.

[0187] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of: 8.6 ± 0.2°, 10.0 ± 0.2°, 11.0 ± 0.2°, 11.5 ± 0.2°, 13.2 ± 0.2°, 13.3 ± 0.2°, 14.6 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 16.5 ± 0.2°, 21.0 ± 0.2°, 2 1.5 ± 0.2°, 21.8 ± 0.2°, 23.2 ± 0.2°, 23.4 ± 0.2°, 23.9 ± 0.2°, 24.6 ± 0.2°, 25.2 ± 0.2°, 26.0 ± 0.2°, 26.6 ± 0.2°, 27.3 ± 0.2°, 28.9 ± 0.2°, 29.5 ± 0.2°, 29.8 ± 0.2°, and 30.4 ± 0.2° 2θ.

[0188] In certain embodiments, the XRPD pattern further comprises the following peaks: 8.6 ± 0.2°, 10.0 ± 0.2°, 11.0 ± 0.2°, 11.5 ± 0.2°, 13.2 ± 0.2°, 13.3 ± 0.2°, 14.6 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 16.5 ± 0.2°, 21.0 ± 0.2°, 21.5 ± 0.2°, 21.8±0.2°, 23.2±0.2°, 23.4±0.2°, 23.9±0.2°, 24.6±0.2°, 25.2±0.2°, 26.0±0.2°, 26.6±0.2°, 27.3±0.2°, 28.9±0.2°, 29.5±0.2°, 29.8±0.2°, and 30.4±0.2° 2θ.

[0189] In certain embodiments, the acetone solvated crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.0±0.2°, 6.6±0.2°, 8.6±0.2°, 10.0±0.2°, 11.0±0.2°, 11.5±0.2°, 13.2±0.2°, 13.3±0.2°, 14.6±0.2°, 15.0±0.2°, 15.3±0.2°, 15.9±0.2°, 16.3±0.2°, 16.5±0.2°, 16.9±0.2°, 17.6±0.2°, 18.2 0.2°, 26.0±0.2°, 26.6±0.2°, 27.3±0.2°, 28.9±0.2°, 29.5±0.2°, 29.8±0.2°, and 30.4±0.2° 2θ.

[0190] In certain embodiments, the acetone solvated crystalline citrate salt is characterized by an XRPD pattern comprising the following peaks: 5.0±0.2°, 6.6±0.2°, 8.6±0.2°, 10.0±0.2°, 11.0±0.2°, 11.5±0.2°, 13.2±0.2°, 13.3±0.2°, 14.6±0.2°, 15.0±0.2°, 15.3±0.2°, 15.9±0.2°, 16.3±0.2°, 16.5±0.2°, 16.9±0.2°, 17.6±0.2°, 18.2±0.2°, 19. 0.2°, 26.0±0.2°, 26.6±0.2°, 27.3±0.2°, 28.9±0.2°, 29.5±0.2°, 29.8±0.2°, and 30.4±0.2° 2θ.

[0191] In certain embodiments, the acetone-solvated crystalline citrate salt is characterized by being Fig.18 Essentially the same XRPD pattern is shown.

[0192] In certain embodiments, the acetone solvated crystalline citrate salt exists in the orthorhombic system and has a space group of P212121. In certain embodiments, the acetone solvated crystalline citrate salt is characterized by the crystallographic unit cell parameters as shown in Table 5.

[0193] Table 5 - Unit cell parameters of crystalline citrate salts solvated with acetone

[0194]

[0195] In certain embodiments, the crystalline citrate salt solvated by acetone in dimethyl sulfoxide-d6 containing trimethylsilane is characterized by having one, two, three, four, five or more of the following peaks: 1H NMR spectrum: 11.318, 10.869, 10.666, 10.081, 9.432, 8.823, 8.499, 8.327, 8.316, 8.303, 8.288, 8.231, 8.150, 8.136, 8.089, 7.822, 7.723, 7.720, 7.717, 7.696, 7.694, 7.692, 7.691, 7.68 2, 7.681, 7.679, 7.677, 7.475, 7.462, 7.448, 7.435, 7.346, 7.314, 7.301, 7.288, 7.223, 7.210, 7.082, 7.028, 7.015, 6.559, 6.147, 4.273, 4.256, 3.634, 3.429, 3.401, 3.324, 3.225, 3.213, 3.208, 2.679, 2.654, 2.593, 2.568, 2.509, 2.506, 2.503, 2.500, 2.497, 2.086, 2.081, 2.072, 2.065, 2.059, 2.005, 1.846, 1.837, 1.829, 1.823, 1.814, 1.811, 1.804, 1.801, 1 .797, 1.790, 1.786, 1.780, 1.775, 1.768, 1.756, 1.751, 1.732, 1.713, 1.710, 1.699, 1.686, 1.554, 1.533, 1.235, 0.960, 0.942, 0.922, 0.868, 0.858, 0.837, 0.826, 0.762, and 0.752 ppm.

[0196] In certain embodiments, the acetone-solvated crystalline citrate salt is characterized by being Fig. 20 Shown is essentially the same 1 H NMR spectra.

[0197] The acetone solvated crystalline citrate salt of the compound of formula (I) can also be characterized using thermal analysis techniques such as DSC. Thus, in certain embodiments, the acetone solvated crystalline citrate salt is characterized by an endotherm with a peak maximum at about 117°C as determined by DSC. In certain embodiments, the acetone solvated crystalline citrate salt is characterized by an endotherm with a peak onset of about 110°C as determined by DSC. In certain embodiments, the acetone solvated crystalline citrate salt has a thermal conductivity similar to that of the compound of formula (I). Fig.21 Essentially the same DSC thermograms are shown.

[0198] The acetone-solvated crystalline citrate salt may also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the acetone-solvated crystalline citrate salt exhibits a mass loss of less than or equal to about 7% by weight when heated to about 131° C. as determined by TGA. In certain embodiments, the acetone-solvated crystalline citrate salt has a mass loss of less than or equal to about 7% by weight as determined by TGA. Fig.21 Essentially the same TGA thermogram is shown.

[0199] In certain embodiments, the acetone-solvated crystalline citrate salt comprises 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, or 2 moles of acetone per mole of the compound of Formula (I).

[0200] (ii) Acetonitrile-solvated crystalline citrate

[0201] In certain embodiments, the crystalline citrate salt is an acetonitrile-solvated crystalline citrate salt.

[0202] In certain embodiments, the acetonitrile-solvated crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.1 ± 0.2°, 6.9 ± 0.2°, 17.8 ± 0.2°, and 18.7 ± 0.2° 2θ.

[0203] In certain embodiments, the acetonitrile-solvated crystalline citrate salt is characterized by an XRPD pattern comprising the following peaks: 5.1 ± 0.2°, 6.9 ± 0.2°, 17.8 ± 0.2°, and 18.7 ± 0.2° 2θ.

[0204] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of 17.2±0.2°, 22.3±0.2°, 23.3±0.2°, and 23.6±0.2° 2θ.

[0205] In certain embodiments, the XRPD pattern further comprises the following peaks: 17.2±0.2°, 22.3±0.2°, 23.3±0.2°, and 23.6±0.2° 2θ.

[0206] In certain embodiments, the acetonitrile-solvated crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from 5.1±0.2°, 6.9±0.2°, 17.2±0.2°, 17.8±0.2°, 18.7±0.2°, 22.3±0.2°, 23.3±0.2°, and 23.6±0.2° 2θ.

[0207] In certain embodiments, the acetonitrile-solvated crystalline citrate salt is characterized by an XRPD pattern comprising peaks at 5.1±0.2°, 6.9±0.2°, 17.2±0.2°, 17.8±0.2°, 18.7±0.2°, 22.3±0.2°, 23.3±0.2°, and 23.6±0.2° 2θ.

[0208] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from the group consisting of 5.4±0.2°, 8.6±0.2°, 9.2±0.2°, 10.1±0.2°, 10.8±0.2°, 11.7±0.2°, 13.2±0.2°, 13.9±0.2°, 14.0±0.2°, 14.8±0.2°, 15.2±0.2°, 15.4±0.2°, 16.1±0.2°, 16.9±0.2°, 17.4±0.2°, 18.0±0.2°, 19.1±0.2°, 19.5±0.2°, 19.6±0.2°, 19.8±0.2°, 19.9±0.2°, 19.1±0.2°, 19.9±0.2°, 19.1±0.2°, 19.8±0.2°, 19.9±0.2°, 19.1±0.2°, 19.9±0.2°, 19. .7±0.2°, 19.9±0.2°, 20.2±0.2°, 20.4±0.2°, 20.9±0.2°, 21.1±0.2°, 21.8±0.2°, 21.9±0.2°, 22.6±0.2°, 22.8±0.2°, 23.8±0. 2°, 24.1±0.2°, 24.4±0.2°, 25.2±0.2°, 25.5±0.2°, 26.0±0.2°, 26.5±0.2°, 26.7±0.2°, 27.4±0.2°, 27.9±0.2°, 28.4±0.2°2θ.

[0209] In certain embodiments, the XRPD pattern further comprises the following peaks: 5.4±0.2°, 8.6±0.2°, 9.2±0.2°, 10.1±0.2°, 10.8±0.2°, 11.7±0.2°, 13.2±0.2°, 13.9±0.2°, 14.0±0.2°, 14.8±0.2°, 15.2±0.2°, 15.4±0.2°, 16.1±0.2°, 16.9±0.2°, 17.4±0.2°, 18.0±0.2°, 19.1±0.2°, 19.5±0.2°, 19.7±0.2°, 19.8±0.2°, 19.9±0.2°, 11.1±0.2°, 11.3±0.2°, 11.4±0.2°, 11.6±0.2°, 11.8±0.2°, 11.9±0.2°, 12. .2°, 19.9±0.2°, 20.2±0.2°, 20.4±0.2°, 20.9±0.2°, 21.1±0.2°, 21.8±0.2°, 21.9±0.2°, 22.6±0.2°, 22.8±0.2°, 23.8±0.2° , 24.1±0.2°, 24.4±0.2°, 25.2±0.2°, 25.5±0.2°, 26.0±0.2°, 26.5±0.2°, 26.7±0.2°, 27.4±0.2°, 27.9±0.2°, 28.4±0.2°2θ.

[0210] In certain embodiments, the acetonitrile-solvated crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.1±0.2°, 5.4±0.2°, 6.9±0.2°, 8.6±0.2°, 9.2±0.2°, 10.1±0.2°, 10.8±0.2°, 11.7±0.2°, 13.2±0.2°, 13.9±0.2°, 14.0±0.2°, 14.8±0.2°, 15.2±0.2°, 15.4±0.2°, 16.1±0.2°, 16.9±0.2°, 17.2±0.2°, 17.4±0.2°, 17.8±0.2°, 18.0±0.2°, 18.7±0.2°, 19.1±0.2°, 19. 0.2°, 19.5±0.2°, 19.7±0.2°, 19.9±0.2°, 20.2±0.2°, 20.4±0.2°, 20.9±0.2°, 21.1±0.2°, 21.8±0.2°, 21.9±0.2°, 22.3±0.2°, 22.6±0.2°, 22.8±0.2°, 23. 3±0.2°, 23.6±0.2°, 23.8±0.2°, 24.1±0.2°, 24.4±0.2°, 25.2±0.2°, 25.5±0. 2°, 26.0±0.2°, 26.5±0.2°, 26.7±0.2°, 27.4±0.2°, 27.9±0.2°, 28.4±0.2°2θ.

[0211] In certain embodiments, the acetonitrile-solvated crystalline citrate salt is characterized by an XRPD pattern comprising the following peaks: 5.1±0.2°, 5.4±0.2°, 6.9±0.2°, 8.6±0.2°, 9.2±0.2°, 10.1±0.2°, 10.8±0.2°, 11.7±0.2°, 13.2±0.2°, 13.9±0.2°, 14.0±0.2°, 14.8±0.2°, 15.2±0.2°, 15.4±0.2°, 16.1±0.2°, 16.9±0.2°, 17.2±0.2°, 17.4±0.2°, 17.8±0.2°, 18.0±0.2°, 18.7±0.2°, 19.1±0.2° , 19.5±0.2°, 19.7±0.2°, 19.9±0.2°, 20.2±0.2°, 20.4±0.2°, 20.9±0.2°, 21.1±0.2°, 21.8±0.2°, 21.9±0.2°, 22.3±0.2°, 22.6±0.2°, 22.8±0.2°, 23.3± 0.2°, 23.6±0.2°, 23.8±0.2°, 24.1±0.2°, 24.4±0.2°, 25.2±0.2°, 25.5±0.2 °, 26.0±0.2°, 26.5±0.2°, 26.7±0.2°, 27.4±0.2°, 27.9±0.2°, 28.4±0.2°2θ.

[0212] In certain embodiments, the crystalline citrate salt solvated with acetonitrile is characterized by Fig. 22 Essentially the same XRPD pattern is shown.

[0213] In certain embodiments, the acetonitrile-solvated crystalline citrate salt exists in the orthorhombic system and has a space group of P212121. In certain embodiments, the acetonitrile-solvated crystalline citrate salt is characterized by the crystallographic unit cell parameters as shown in Table 6.

[0214] Table 6 - Unit cell parameters of crystalline citrate salts solvated with acetonitrile

[0215]

[0216] In certain embodiments, the acetonitrile-solvated crystalline citrate salt comprises 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, or 2 moles of acetonitrile per mole of the compound of Formula (I).

[0217] (iii) Anhydrous crystalline citrate

[0218] In certain embodiments, the crystalline citrate salt is an anhydrous crystalline citrate salt.

[0219] In certain embodiments, the crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from 5.3±0.2°, 6.4±0.2°, 17.6±0.2°, and 23.0±0.2° 2θ.

[0220] In certain embodiments, the crystalline citrate salt is characterized by an XRPD pattern comprising the following peaks: 5.3±0.2°, 6.4±0.2°, 17.6±0.2°, and 23.0±0.2° 2θ.

[0221] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 8.5±0.2°, 10.6±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 18.2±0.2°, 21.4±0.2°, and 22.4±0.2° 2θ.

[0222] In certain embodiments, the XRPD pattern further comprises the following peaks: 8.5±0.2°, 10.6±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 18.2±0.2°, 21.4±0.2°, and 22.4±0.2° 2θ.

[0223] In certain embodiments, the crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from 5.3±0.2°, 6.4±0.2°, 8.5±0.2°, 10.6±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 17.6±0.2°, 18.2±0.2°, 21.4±0.2°, 22.4±0.2°, and 23.0±0.2° 2θ.

[0224] In certain embodiments, the crystalline citrate salt is characterized by an XRPD pattern comprising peaks at 5.3±0.2°, 6.4±0.2°, 8.5±0.2°, 10.6±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 17.6±0.2°, 18.2±0.2°, 21.4±0.2°, 22.4±0.2°, and 23.0±0.2° 2θ.

[0225] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 7.6±0.2°, 9.1±0.2°, 12.8±0.2°, 14.4±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 19.0±0.2°, 19.3±0.2°, 19.5±0.2°, 20.1±0.2°, 20.9±0.2°, 24.3±0.2°, 25.7±0.2°, 25.8±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.0±0.2° 2θ.

[0226] In certain embodiments, the XRPD pattern further comprises the following peaks: 7.6±0.2°, 9.1±0.2°, 12.8±0.2°, 14.4±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 19.0±0.2°, 19.3±0.2°, 19.5±0.2°, 20.1±0.2°, 20.9±0.2°, 24.3±0.2°, 25.7±0.2°, 25.8±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.0±0.2° 2θ.

[0227] In certain embodiments, the crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.3±0.2°, 6.4±0.2°, 7.6±0.2°, 8.5±0.2°, 9.1±0.2°, 10.6±0.2°, 12.8±0.2°, 14.4±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 16.7±0.2°, 17.0±0.2°, 17. 3±0.2°, 17.6±0.2°, 18.2±0.2°, 19.0±0.2°, 19.3±0.2°, 19.5±0.2°, 20.1±0.2°, 20.9±0.2°, 21.4±0.2°, 22.4±0.2°, 23.0±0.2°, 24.3±0.2°, 25.7±0.2°, 25.8±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.0±0.2° 2θ.

[0228] In certain embodiments, the crystalline citrate salt is characterized by an XRPD pattern comprising the following peaks: 5.3±0.2°, 6.4±0.2°, 7.6±0.2°, 8.5±0.2°, 9.1±0.2°, 10.6±0.2°, 12.8±0.2°, 14.4±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 16.7±0.2°, 17.0±0.2°, 17.3±0.2°. 0.2°, 17.6±0.2°, 18.2±0.2°, 19.0±0.2°, 19.3±0.2°, 19.5±0.2°, 20.1±0.2°, 20.9±0.2°, 21.4±0.2°, 22.4±0.2°, 23.0±0.2°, 24.3±0.2°, 25.7±0.2°, 25.8±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.0±0.2° 2θ.

[0229] In certain embodiments, the crystalline citrate salt is characterized by Fig.24 Essentially the same XRPD pattern is shown.

[0230] In certain embodiments, the crystalline citrate salt exists in the orthorhombic system and has a space group of P212121. In certain embodiments, the crystalline citrate salt is characterized by the crystallographic unit cell parameters as shown in Table 7.

[0231] Table 7 - Unit cell parameters of anhydrous crystalline citrate

[0232]

[0233] In certain embodiments, crystalline citrate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is characterized by having one, two, three, four, five or more of the following peaks: 1H NMR spectrum: 11.967, 8.325, 7.820, 7.718, 7.715, 7.694, 7.693, 7.691, 7.689, 7.681, 7.679, 7.677, 7.676, 7.461, 7.448, 7.434, 7.345, 7.222, 7.209, 7.082, 4.272, 4. 254, 3.630, 3.543, 3.428, 3.399, 3.348, 3.317, 3.294, 3.249, 3.237, 3.224, 3.211, 3.194, 3.180, 3.016, 2.683, 2.658, 2.616, 2.613, 2.610, 2.596, 2.570, 2.53 7, 2.522, 2.519, 2.516, 2.507, 2.504, 2.501, 2.498, 2.495, 2.388, 2.385, 2.382, 2.274, 2.107, 2.094, 2.089, 2.083, 2.077, 2.071, 2.064, 2.010, 1.837, 1.828, 1.822, 1.814, 1.810, 1.803, 1.795, 1.789, 1.785, 1.780, 1.775, 1.767, 1.756, 1.750, 1.731, 1.712, 1.698, 1.685, 1.549, 1.235, 0.960, 0.943, 0.868 and 0.858 ppm.

[0234] In certain embodiments, the crystalline citrate salt is characterized by Fig.26 Shown is essentially the same 1 H NMR spectrum.

[0235] The crystalline citrate salt of the compound of formula (I) can also be characterized using thermal analysis techniques such as DSC. Thus, in certain embodiments, the crystalline citrate salt is characterized by an endothermic peak maximum at about 131°C as determined by DSC. In certain embodiments, the crystalline citrate salt is characterized by a melting point onset of about 131°C as determined by DSC. In certain embodiments, the crystalline citrate salt has a similar Fig.28 Essentially the same DSC thermograms are shown.

[0236] The crystalline citrate salt may also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline citrate salt exhibits a mass loss of less than or equal to about 0.1% by weight when heated to about 138° C. as determined by TGA. In certain embodiments, the crystalline citrate salt has a mass loss as measured by TGA of less than or equal to about 0.1% by weight. Fig. 27 Essentially the same TGA thermogram is shown.

[0237] The crystalline citrate salt may also be characterized according to its water absorption properties. Thus, in certain embodiments, at a relative humidity of 74% and a temperature of 25°C, the crystalline citrate salt exhibits a mass increase of less than or equal to about 1.2% by weight as determined by DVS. In certain embodiments, at a relative humidity of 96% and a temperature of 25°C, the crystalline citrate salt exhibits a mass increase of less than or equal to about 15.8% by weight as determined by DVS. In certain embodiments, the crystalline citrate salt has a relative humidity of less than or equal to about 1.2% by weight as determined by DVS at a relative humidity of 74% and a temperature of 25°C. Fig.29 Essentially the same water absorption isotherm is shown in .

[0238] Pharmaceutical compositions and routes of administration

[0239] The crystalline form of the compound of formula (I) disclosed herein is usually applied in the form of a pharmaceutical composition. In one aspect, a pharmaceutical composition is provided herein, which contains a crystalline form of a compound of formula (I) as described herein and one or more pharmaceutically acceptable excipients and / or carriers (including but not limited to inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. The pharmaceutical composition described herein can be applied alone or in combination with other therapeutic agents. Such pharmaceutical compositions are prepared in a manner well known in the pharmaceutical field (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (GS Banker and CT Rhodes ed.)).

[0240] The pharmaceutical compositions described herein can be administered in single or multiple doses by any accepted mode of administration of agents having similar utility, such as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via an impregnated or coated device (e.g., such as a stent) or an arterial inserted cylindrical polymer.

[0241] A mode of administration is parenteral administration, particularly by injection. The form for injection administration that can be incorporated into the pharmaceutical composition of the present disclosure includes aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions and similar pharmaceutical vehicles. Aqueous solutions in saline are also commonly used for injection, but are less preferred in the context of the present disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils can also be used. Suitable fluidity can be, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersant and by using a surfactant to maintain. Preventing the action of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal (thimerosal) etc.).

[0242] Sterile injection solutions are prepared in the following manner: the desired amount of the crystalline form of the compound according to formula (I) of the present disclosure is optionally incorporated into a suitable solvent together with the various other ingredients listed above, and then, for example, sterilized by filtration. Typically, dispersions are prepared by incorporating a variety of sterilized active ingredients into a sterile vehicle containing an alkaline dispersion medium and the required other ingredients from those ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying techniques and freeze drying techniques, which produce a powder of active ingredients plus any additional required ingredients from its previous sterile filtered solution.

[0243] Oral administration is another route of administration of the crystalline form of the compound of formula (I) according to the present disclosure. Administration can be carried out via capsules or enteric coated tablets, etc. In the preparation of pharmaceutical compositions comprising the crystalline form of the compound of formula (I) described herein, the active ingredient (e.g., the crystalline form of the compound of formula (I)) is usually diluted with an excipient and / or encapsulated in a carrier that can be in the form of a capsule, a sachet, paper or other container. When an excipient is used as a diluent, it can be in the form of a solid, semisolid or liquid material (as described above), thereby acting as a vehicle, carrier or medium for the active ingredient. Therefore, the pharmaceutical composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions and sterile packaged powders.

[0244] Examples of some suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally contain: lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0245] The pharmaceutical composition of the present disclosure can be formulated to provide a rapid, continuous or delayed release of active ingredients (e.g., compounds of formula (I)) after being administered to a patient by a procedure known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents No. 3,845,770, No. 4,326,525, No. 4,902,514 and No. 5,616,345. Another formulation used in the method of the present disclosure adopts a transdermal delivery device ("patch"). This transdermal patch can be used to provide a continuous or discontinuous infusion of a controlled amount of a compound of formula (I). The construction and use of transdermal patches for delivering medicaments are well known in the art. See, for example, U.S. Patents No. 5,023,252, No. 4,992,445 and No. 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0246] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined amount of active material associated with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule), the active material being calculated to produce the desired therapeutic effect. The compound (e.g., a compound of formula (I)) is usually administered in a pharmaceutically effective amount. However, it should be understood that the amount of the compound actually administered is usually determined by the physician according to relevant circumstances, including the disease being treated, the selected route of administration, the compound actually administered and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0247] To prepare solid compositions such as tablets, the main active ingredient (e.g., a crystalline form of a compound of Formula (I) described herein) is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. When referring to these preformulation mixtures as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0248] Tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form with an advantage of prolonged action, or to protect it from the influence of gastric acid conditions. For example, tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being the coating form of the former. These two components can be separated by an enteric layer, which is used to resist disintegration in the stomach, and allows the inner component to enter the duodenum intact or delay release. Various materials can be used for such enteric layers or coatings, and such materials include a mixture of multiple polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0249] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. The composition in a preferably pharmaceutically acceptable solvent may be atomized by the use of an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be connected to a mask tent or an intermittent positive pressure breathing machine. The solution, suspension or powder composition may be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0250] In some embodiments, a pharmaceutical composition comprises a disclosed crystalline form of a compound of Formula (I) and a pharmaceutically acceptable carrier.

[0251] Treatment

[0252] In various embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, the method comprising the step of administering to the subject a crystalline form of a compound of formula (I) according to the present disclosure.

[0253] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, the method comprising the step of administering to the subject an effective amount of a crystalline form of a compound of formula (I) according to the present disclosure.

[0254] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, the method comprising the step of administering to the subject an effective amount of an anhydrous crystalline form of a compound of formula (I) as described herein.

[0255] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, comprising the step of administering to the subject an effective amount of a crystalline acetone solvate of a compound of formula (I) as described herein.

[0256] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, comprising the step of administering to the subject an effective amount of a crystalline p-dioxane solvate of a compound of Formula (I) described herein.

[0257] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, comprising the step of administering to the subject an effective amount of a crystalline tetrahydrofuran solvate of a compound of Formula (I) as described herein.

[0258] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, comprising the step of administering to the subject an effective amount of an acetone-solvated crystalline citrate salt of a compound of Formula (I) as described herein.

[0259] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, comprising the step of administering to the subject an effective amount of an acetonitrile-solvated crystalline citrate salt of a compound of Formula (I) as described herein.

[0260] In various embodiments, provided herein is a method for treating or lessening the severity of a disease or disorder associated with cell proliferation (e.g., cancer) in a patient, the method comprising the step of administering to the subject an effective amount of an anhydrous crystalline citrate salt of a compound of formula (I) as described herein.

[0261] As used herein, the term "disease or condition associated with cell proliferation" means any disease or other deleterious condition in which cell proliferation is known to play a role. Therefore, certain embodiments of the present disclosure are directed to treating or lessening the severity of one or more diseases in which cell proliferation is known to play a role. In certain embodiments, the disease or condition associated with cell proliferation is hyperplasia or cancer. In certain embodiments, the disease or condition associated with cell proliferation is cancer.

[0262] In certain embodiments, administration of a crystalline form of the present disclosure (e.g., a crystalline form of a compound of Formula (I) as described herein) results in mitotic arrest. In certain embodiments, mitotic arrest is defined as a 10%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 20%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 30%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 40%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 50%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 60%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 70%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 80%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 90%-100% reduction in mitosis. In certain embodiments, mitotic arrest is defined as a 100% reduction in mitosis.

[0263] In certain embodiments, the crystalline forms and pharmaceutical compositions according to the methods of the present disclosure can be administered using any amount and any route of administration that is effective to treat cancer or reduce its severity. The exact amount required will vary with the subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, etc. For ease of administration and uniformity of dosage, the crystalline forms of the present disclosure are preferably formulated in dosage unit form.

[0264] In certain embodiments, the cancer is a blood cancer. In certain embodiments, the blood cancer is selected from the group consisting of lymphoma, leukemia, and myeloma. In certain embodiments, the blood cancer is a lymphoma. In certain embodiments, the blood cancer is a leukemia. In certain embodiments, the blood cancer is a myeloma.

[0265] In certain embodiments, the cancer is a non-hematological cancer. In certain embodiments, the non-hematological cancer is a sarcoma or a carcinoma. In certain embodiments, the non-hematological cancer is a sarcoma. In certain embodiments, the non-hematological cancer is a carcinoma.

[0266] In certain embodiments, after administration of the crystalline form of the present disclosure, the subject has one or more of the following: increased T cell activation, increased T cell proliferation, reduced T cell exhaustion, reduced T cell anergy, and reduced T cell tolerance. In some embodiments, administration of the crystalline form of the present disclosure to a subject in need thereof results in one or more of the following: increased T cell activation, increased T cell proliferation, reduced T cell exhaustion, reduced T cell anergy, and reduced T cell tolerance.

[0267] In certain embodiments, the subject has increased NK cell activation.In certain embodiments, increased NK cell activation comprises increased cytokine production.

[0268] In certain embodiments, the pharmaceutically acceptable compositions of the present disclosure may be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the crystalline forms of the present disclosure may be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, once or more per day to obtain the desired therapeutic effect.

[0269] In certain embodiments, one or more additional therapeutic agents may also be administered in combination with the crystalline form of the compound of formula (I) disclosed herein. In certain embodiments, the crystalline form of the compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered as part of a multiple dose regimen. In certain embodiments, the crystalline form of the compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered simultaneously, sequentially or over a period of time. In certain embodiments, the crystalline form of the compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered within five hours of each other. In certain embodiments, the crystalline form of the compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered within 24 hours of each other. In certain embodiments, the crystalline form of the compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered within one week of each other.

[0270] In certain embodiments, a crystalline form of a compound of Formula (I) disclosed herein and one or more additional therapeutic agents may be formulated in a single dosage form (eg, a fixed dose combination).

[0271] Example

[0272] The following representative examples are intended to help illustrate the present disclosure and are not intended, nor should they be construed, to limit the scope of the present disclosure.

[0273] abbreviation

[0274] ACN Acetonitrile

[0275] DCM Dichloromethane

[0276] DIPE Diisopropyl ether

[0277] DSC Differential Scanning Calorimetry

[0278] DVS Dynamic Vapor Sorption

[0279] EtOAc Ethyl acetate

[0280] EtOH

[0281] IPA Isopropyl Alcohol

[0282] IPOAc Isopropyl propionate

[0283] MeOH Methanol

[0284] MBTE Methyl tert-butyl ether

[0285] 1 H NMR Proton nuclear magnetic resonance

[0286] TGA Thermogravimetric Analysis

[0287] THF Tetrahydrofuran

[0288] XRD X-ray diffraction

[0289] XRPD X-ray powder diffraction

[0290] wt. weight

[0291] Example 1 - Analytical Methods

[0292] (i) XRPD

[0293] The XRPD data presented herein were collected using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced by an Optix long fine focus source. Cu Kα X-rays were focused through the sample and onto the detector using an elliptical gradient multilayer mirror. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify the Si 111 peak position. Samples of the sample were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam blocker and a short anti-scatter extension were used to minimize the background generated by air. For both the incident and diffracted beams, a Soller slit was used to minimize the broadening caused by axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) at a distance of 240 mm from the sample and Data Collector software v.5.5.

[0294] (ii) XRPD Peak Identification

[0295] In most cases, peaks were selected that were within a maximum of approximately 30° 2θ. A rounding algorithm was used to round each peak to the nearest 0.1° 2θ. The positions of the peaks on the x-axis (° 2θ) in the figures and tables were determined using proprietary software and rounded to one significant decimal place. The peak position variability is given as ±0.2° 2θ based on the recommendations given in the USP discussion of variability in X-ray powder diffraction. For the interplanar spacing tabulations, the wavelength used to calculate the interplanar spacing is Cu-K α1 Wavelength. The variability associated with the interplanar spacing estimates was calculated at each interplanar spacing according to USP recommendations and is provided in the corresponding data tables.

[0296] (iii) Indexed XRPD data

[0297] XRPD patterns of the crystalline forms described in Examples 3-8 were indexed using X'Pert High-Score Plus 2.2a (2.2.1). Unless otherwise stated, successful indexing of the pattern indicates that the sample consists primarily or entirely of a single crystalline phase. Space groups consistent with the assigned extinction sign, unit cell parameters, and derived quantities were tabulated.

[0298] (iv) Single crystal X-ray diffraction

[0299] Standard uncertainties are expressed in crystallographic bracket notation, for example 0.123(4) is equivalent to 0.123±0.004.

[0300] (a) Data collection

[0301] The size is about 0.27×0.04×0.03mm 3 Light orange needles of the anhydrous form of the compound of formula (I) (described in Example 2) were mounted on the polymer ring in a random orientation. Preliminary examination and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube. and Dectris Pilatus3 R 200K hybrid pixel array detector.

[0302] The unit cell constants and orientation matrix for data collection were obtained by least squares refinement using 7350 reflections in the range of 4.3060° <θ < 75.1220°. The space group was determined to be P212121 (International Table No. 19) by the program CRYSALISPRO (CrysAlisPro1.171.41.93a (Rigaku Oxford Diff raction, 2020)).

[0303] Data were collected at room temperature to a maximum diffraction angle (2θ) of 151.71°.

[0304] (b) Data Simplification

[0305] The frames were integrated with CRYSALISPRO. A total of 13966 reflections were collected, of which 5799 were unique. Lorentz correction and polarization correction were applied to the data. For Cu Kα radiation, the linear absorption coefficient was 0.762 mm -1 An empirical absorption correction using CRYSALISPRO was applied. The transmission coefficient ranged from 0.951 to 1.000. The intensities of the equivalent reflections were averaged. The average consistency factor based on intensity was 2.11%.

[0306] (c) Structural analysis and refinement

[0307] The structure was solved by direct methods using SHELXT (Sheldrick, GM Acta Cryst. 2015, A71, 3-8). The remaining atoms were located in subsequent differential Fourier synthesis. The structure was refined using SHELXL-2014 (Sheldrick, GM Acta Cryst., 2008, A64, 112–122.). Hydrogen atoms were included in the refinement but were restricted to atoms bonded to them. The structure was refined in the full matrix least squares method by minimizing the following function:

[0308] ∑w|(F o | 2 -|F c | 2 ) 2

[0309] The weight w is defined as 1 / [σ 2 (F o 2 )+(0.0834P) 2 +(0.2745P)], where P = (F o 2 +2F c 2 ) / 3.

[0310] The scattering factors are taken from the International Tables for Crystallo graphy, Volume C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.1.4. Of the 5799 reflections used in the refinement, only reflections (5239) with intensities greater than twice their uncertainty [I>2σ(I)] were used to calculate the fitting residual R. The final refinement cycle included 354 variable parameters, 0 restrictions, and converged under the corresponding unweighted and weighted consistency factors:

[0311] R=∑|F o -F c | / ∑F o =0.0456

[0312]

[0313] The standard deviation of the observations with unit weight (goodness of fit) is 1.05. The electron density of the highest peak in the final difference Fourier transform is The value of the smallest negative peak is

[0314] (d) Calculation of XRPD pattern

[0315] The calculated XRPD pattern for Cu radiation was generated using MERCURY (Macrae, CF Edgington, PR McCabe, P. Pidcock, E. Shields, GP Taylor, R. Towler M. and van de Streek, J J Appl. Cryst., 2006, 39, 453-457.) and atomic coordinates, space group and unit cell parameters obtained from the single crystal structure.

[0316] (e) Atomic displacement ellipsoid and stacking diagram

[0317] Atomic displacement ellipsoids were prepared using mercury. Atoms are represented by anisotropic thermal ellipsoids with a probability of 50%.

[0318] (v) 1 H NMR

[0319] Solution NMR spectra were acquired using an Avance 600 MHz NMR spectrometer.Samples of the crystalline form described herein were prepared by dissolving approximately 4-7 mg of sample in dimethyl sulfoxide-d6 containing trimethylsilane.

[0320] (vi) DSC / TGA

[0321] DSC / TGA analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using calcium oxalate, indium, tin, and zinc. The sample was placed in an aluminum pan. The sample was sealed, the lid was pierced, and then inserted into the TG furnace. The furnace was heated under a nitrogen flow rate of 50 mg / mL. The typical method involved heating from ambient temperature to 350°C at a heating rate of 10°C / min.

[0322] (vii) DVS

[0323] Vapor sorption data were collected on a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Adsorption and desorption data were collected over a RH range of 5% to 95% in 10% RH increments under a nitrogen purge. The equilibrium criterion for analysis was a weight change of less than 0.0100% in 5 minutes, with a maximum equilibrium time of 3 hours.

[0324] Table 8 - Hygroscopicity classification (Ph.Eur.10.0)

[0325] Classification Weight increase at 80%RH(25℃) Non-hygroscopic <0.2％ Slightly hygroscopic ≥0.2% and <2% Moisture absorption ≥ 2% and < 15% Very hygroscopic ≥15％ Deliquescent Absorbs enough water to form a liquid

[0326] Example 2 - Anhydrous crystalline form of the compound of formula (I)

[0327] (i) Preparation of anhydrous crystalline form

[0328] The anhydrous crystalline form of the compound of formula (I) was prepared as follows: 55 mg of the compound of formula (I) was dissolved in ethyl acetate (0.3 ml) at 60° C. The solution was filtered through a 0.2 μm nylon filter into a preheated (60° C.) vial. The vial was capped and the sample was placed in a refrigerator at -15° C. to -25° C. A solid precipitated from the solution and was isolated by syringe filtration.

[0329] Single crystals of anhydrous crystalline form of the compound of formula (I) for single crystal XRD analysis were prepared as follows: 104 mg of the compound of formula (I) was dissolved in acetonitrile (1 ml) at about 60° C. The solution was then allowed to cool at ambient temperature. Appropriate single crystals were then harvested for analysis.

[0330] (ii) Characterization of anhydrous crystalline form

[0331] The XRPD pattern of the anhydrous crystalline form of the compound of formula (I) is provided at Figure 1 middle. Figure 1 The tabulated characteristics of the XRPD pattern are provided in Table 9, which lists the diffraction angle 2θ, the interplanar spacing and relative intensity (expressed as a percentage of the most intense peak).

[0332] Anhydrous crystalline form of a compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 HNMR spectra provided by Figure 3 middle. 1 The H NMR spectrum was consistent with the structure of the compound of formula (I).

[0333] The DSC thermogram of the anhydrous crystalline form of the compound of formula (I) is provided at Figure 4 The DSC thermogram exhibits an endothermic event with an onset of about 175.5 °C and a peak maximum at about 178.2 °C.

[0334] The TGA thermogram of the anhydrous crystalline form of the compound of formula (I) is provided at Figure 4 Negligible weight loss (<0.1 wt %) was observed, indicating that the crystalline form was anhydrous.

[0335] The water adsorption isotherm of the anhydrous crystalline form of the compound of formula (I) is provided in Figure 5 The data indicate that the anhydrous crystalline form is slightly hygroscopic. During the adsorption step, the material exhibited a weight gain of 0.4% from 5% to 95% relative humidity (RH) or 0.1 mol of water per mol of API. The weight gain was lost upon desorption with very slight hysteresis.

[0336] Table 9 - XRPD pattern data of anhydrous crystalline form of compound of formula (I)

[0337]

[0338]

[0339]

[0340] Select a suitable single crystal of the anhydrous crystalline form of the compound of formula (I) and analyze it by single crystal X-ray diffraction measurement. 3 The light orange needles of 200 μm are mounted on the polymer rings in random orientations. The unit cell parameters of the anhydrous crystalline form and the data collection and structure refinement methods are shown in Table 10.

[0341] The quality of the obtained structure is high, as shown by the fit residual R of 0.0456 (4.56%). R factors in the range of 2%-6% are considered to be the most reliably determined structures (Glusker, Jenny Pickworth; Trueblood, Kenneth N. Crystal Structure Analysis: A Primer, 3rd edition; Oxford University press: New York, 2010; p. 97). The atomic displacement ellipsoids of the anhydrous crystalline form are shown in Figure 2 The asymmetric unit contains one molecule of the compound of formula (I), and the chiral centers are S (C2 near the piperidine ring) and R (C22 near the cyclobutane ring). The XRPD pattern of the anhydrous crystalline form calculated based on the single crystal XRD data and the superposition of the experimental XRPD pattern are located at Fig.30 The experimental and calculated XRPD patterns match well.

[0342] Table 10 - Crystal data and data collection parameters for anhydrous crystalline form

[0343]

[0344]

[0345] (iii) Solubility determination

[0346] Aliquots of various solvents are added to a measured amount of anhydrous crystalline form of the compound of formula (I) at different temperatures under ultrasound or stirring. The solubility is calculated based on the total solvent used to form the solution; the actual solubility may be greater due to the volume or slow dissolution rate of the solvent portion used. If no dissolution occurs as determined by visual assessment, the value is reported as "<". If dissolution occurs in the first aliquot, the value is reported as ">".

[0347] The solubility of the anhydrous crystalline form in various solvents is provided in Table 11.

[0348] Table 11 - Solubility of anhydrous crystalline forms of the compound of formula (I) in different solvent systems

[0349]

[0350]

[0351] Example 3 - Crystalline Acetone Solvate of the Compound of Formula (I)

[0352] (i) Preparation of crystalline acetone solvate

[0353] The crystalline acetone solvate of the compound of formula (I) was prepared as follows: 161 mg of the anhydrous crystalline form of the compound of formula (I) (see Example 2) was stirred in acetone (0.7 ml) at 55° C. The resulting suspension was then stirred at ambient temperature. After 6 days, the solid was isolated by syringe filtration.

[0354] (ii) Characterization of crystalline acetone solvates

[0355] The XRPD pattern of the crystalline acetone solvate of the compound of formula (I) is provided at Figure 6 middle. Figure 6 The tabulated characteristics of the XRPD pattern are provided in Table 12, which lists the diffraction angle 2θ, the interplanar spacing and relative intensity (expressed as a percentage of the most intense peak).

[0356] Crystalline acetone solvate of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectra provided by Figure 8 middle. 1 The H NMR spectrum was consistent with the structure of the compound of formula (I) and contained approximately 1 mole of acetone.

[0357] The DSC thermogram of the crystalline acetone solvate of the compound of formula (I) is provided at Fig. 9 The DSC thermogram shows two endothermic events: (1) an onset of about 89.9 °C and a peak maximum at about 100.1 °C and (2) a peak maximum at about 173.1 °C.

[0358] The TGA thermogram of the crystalline acetone solvate of the compound of formula (I) is provided at Fig. 9 The data show that the weight loss from 61°C to 121°C is 5.3%, corresponding to about 0.5 mole of acetone.

[0359] Table 12 - XRPD pattern data of the crystalline acetone solvate of the compound of formula (I)

[0360]

[0361]

[0362]

[0363] The XRPD pattern of the crystalline acetone solvate of the compound of formula (I) was successfully indexed ( Figure 7 The volume of the unit cell indicated that it was large enough to contain 1 mol of acetone per molecule of the compound of formula (I) (Table 13).

[0364] Table 13 - Unit cell parameters of the crystalline acetone solvate of the compound of formula (I)

[0365]

[0366]

[0367] Example 4 - Crystalline p-dioxane solvate of the compound of formula (I)

[0368] (i) Preparation of crystalline p-dioxane solvate

[0369] The crystalline p-dioxane solvate of the compound of formula (I) was prepared as follows: 160 mg of the anhydrous crystalline form of the compound of formula (I) (see Example 2) was stirred in a mixture of heptane (0.5 ml) and p-dioxane (0.5 ml) at 55° C. The resulting suspension was then stirred at ambient temperature for 6 days. The solid was isolated by syringe filtration.

[0370] Alternative method: 74 mg of the compound of formula (I) was dissolved in heptane (0.5 ml) and p-dioxane (0.5 ml) at 60°C. The solution was filtered through a 0.2 μm nylon filter into a preheated (60°C) vial. The vial was capped and the sample was cooled to ambient temperature at 6°C / h. The solid was isolated by syringe filtration.

[0371] (ii) Characterization of crystalline p-dioxane solvates

[0372] The XRPD pattern of the crystalline p-dioxane solvate of the compound of formula (I) is provided at Fig.10 middle. Fig.10 The tabulated characteristics of the XRPD pattern are provided in Table 14, which lists the diffraction angle 2θ, the interplanar spacing and relative intensity (expressed as a percentage of the most intense peak).

[0373] Crystalline solution of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectra provided by Fig.12 middle. 1 The H NMR spectrum was consistent with the structure of the compound of formula (I) and contained approximately 0.9 moles of p-dioxane.

[0374] The DSC thermogram of the crystalline dioxane solvate of the compound of formula (I) is provided at Fig.13 The DSC thermogram exhibits a single endothermic event with an onset of about 94.2 °C and a peak maximum at about 106.3 °C.

[0375] The TGA thermogram of the crystalline dioxane solvate of the compound of formula (I) is provided at Fig.13The data show a weight loss of 3.9% from 51°C to 120°C, or a loss of 0.2 moles of p-dioxane.

[0376] Table 14 - XRPD pattern data of crystalline p-dioxane solvate of compound of formula (I)

[0377]

[0378]

[0379]

[0380] The XRPD pattern of the crystalline p-dioxane solvate of the compound of formula (I) was successfully indexed ( Fig.11 The volume of the unit cell indicates that each mole of the compound of formula (I) may contain 1 mole of p-dioxane (Table 15).

[0381] Table 15 - Unit cell parameters of the crystallization of the compound of formula (I) p-dioxane solvate

[0382]

[0383] Example 5 - Crystalline THF Solvate of Compound of Formula (I)

[0384] (i) Preparation of crystalline THF solvate

[0385] The crystalline THF solvate of the compound of formula (I) was prepared as follows: 144 mg of the anhydrous crystalline form of the compound of formula (I) (see Example 2) was stirred in heptane (0.5 ml) and tetrahydrofuran (0.5 ml) at 55° C. The resulting suspension was stirred at ambient temperature. After 6 days, the solid was isolated by syringe filtration.

[0386] Alternative method: 51 mg of the compound of formula (I) was dissolved in a mixture of cyclohexane (0.5 ml) and tetrahydrofuran (0.4 ml) at 60°C. The solution was filtered through a 0.2 μm nylon filter into a preheated (60°C) vial. The sample was then cooled to ambient temperature at 6°C / h. The solid was isolated by syringe filtration.

[0387] (ii) Characterization of crystalline THF solvate

[0388] The XRPD pattern of the crystalline THF solvate of the compound of formula (I) is provided at Fig.14 middle. Fig.14 The tabulated characteristics of the XRPD pattern are provided in Table 16, which lists the diffraction angle 2θ, the interplanar spacing and relative intensity (expressed as a percentage of the most intense peak).

[0389] Crystalline THF solvate of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectra provided by Fig.16 middle. 1 The H NMR spectrum was consistent with the structure of the compound of formula (I) and contained approximately 0.7 moles of THF and 0.1 moles of cyclohexane.

[0390] The DSC thermogram of the crystalline THF solvate of the compound of formula (I) is provided at Fig.17 The DSC thermogram exhibits a single endothermic event with an onset of about 84.8 °C and a peak maximum at about 97.5 °C.

[0391] The TGA thermogram of the crystalline THF solvate of the compound of formula (I) is provided at Fig.17 The data show that there is a 4.5% weight loss from 56°C to 112°C, or a loss of 0.4 moles of THF.

[0392] Table 16 - XRPD pattern data of the crystalline THF solvate of the compound of formula (I)

[0393]

[0394]

[0395]

[0396] The XRPD pattern of the crystalline THF solvate of the compound of formula (I) was successfully indexed ( Fig.15 The volume of the unit cell indicates that each mole of the compound of formula (I) may contain 1 mole of THF (Table 17).

[0397] Table 17 - Unit cell parameters of the crystalline THF solvate of the compound of formula (I)

[0398]

[0399] Example 6 - Acetone-solvated crystalline citrate salt of the compound of formula (I)

[0400] (i) Preparation of crystalline citrate salt by acetone solvation.

[0401] The acetone solvated crystalline citrate of the compound of formula (I) is prepared as follows: via column chromatography of the compound of formula (I), then evaporation, the amorphous form of the compound of formula (I) is prepared. 71 mg of the amorphous solid of the compound of formula (I) and 1 molar equivalent of citric acid (25 mg) are stirred at ambient temperature for 1 day in acetone (0.5 ml). Thick slurries are obtained and additional acetone (0.5 ml) is added. The mixture is stirred for another 3 days at ambient temperature. The solid is obtained by syringe filtration separation using a Swinnex filter assembly.

[0402] (ii) Characterization of crystalline citrate salt solvated with acetone

[0403] The XRPD pattern of the acetone solvated crystalline citrate salt of the compound of formula (I) is provided at Fig.18 middle. Fig.18 The tabulated characteristics of the XRPD pattern are provided in Table 18, which lists the diffraction angle 2θ, the interplanar spacing and relative intensity (expressed as a percentage of the most intense peak).

[0404] Acetone solvated crystalline citrate salt of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 H NMR spectra provided by Fig. 20 middle. 1 The H NMR spectrum is consistent with the structure of the compound of formula (I) and contains about 1 mole of citric acid. About 2 moles of acetone are also observed in the spectrum, however, it is worth noting that the peaks of acetone and the compound of formula (I) are observed to overlap, and the actual amount of acetone may be less than 2 moles.

[0405] The DSC thermogram of the acetone solvated crystalline citrate salt of the compound of formula (I) is provided at Fig.21 The DSC thermogram exhibits a single endothermic event with an onset at about 109.8 °C and a peak maximum at about 117.4 °C.

[0406] The TGA thermogram of the acetone solvated crystalline citrate salt of the compound of formula (I) is provided at Fig.21 The data show that there is a 7.0% weight loss from 46°C to 131°C and is most likely due to acetone (0.9 moles).

[0407] Table 18 - XRPD pattern data of the acetone-solvated crystalline citrate salt of the compound of formula (I)

[0408]

[0409]

[0410] The XRPD pattern of the acetone solvated crystalline citrate salt of the compound of formula (I) was successfully indexed ( Fig.19 The volume of the unit cell indicates the presence of solvated monocitrate. (Table 19).

[0411] Table 19 - Unit cell parameters of the crystalline citrate salt of the acetone solvated compound of formula (I)

[0412]

[0413] Example 7 - ACN-solvated crystalline citrate salt of the compound of formula (I)

[0414] (i) Preparation of ACN-solvated crystalline citrate

[0415] The ACN solvated crystalline citrate salt of the compound of formula (I) was prepared as follows: 42 mg of the anhydrous crystalline form of the compound of formula (I) (see Example 2) and 0.75 molar equivalents of citric acid (20 mg) were stirred in acetonitrile (2.5 ml) at ambient temperature for about 2 weeks. The solid was isolated by syringe filtration using a Swinnex filter assembly.

[0416] (ii) Characterization of ACN-solvated crystalline citrate

[0417] The XRPD pattern of the ACN solvated crystalline citrate salt of the compound of formula (I) is provided at Fig. 22 middle. Fig. 22 The tabulated characteristics of the XRPD pattern are provided in Table 20, which lists the diffraction angle 2θ, the interplanar spacing and relative intensity (expressed as a percentage of the most intense peak).

[0418] Table 20 - XRPD pattern data of the ACN solvated crystalline citrate salt of the compound of formula (I)

[0419]

[0420]

[0421]

[0422]

[0423] The XRPD pattern of the ACN solvated crystalline citrate salt of the compound of formula (I) was successfully indexed ( Fig.23 The volume of the unit cell indicates the presence of solvated monocitrate. (Table 21).

[0424] Table 21 - Unit cell parameters of the ACN solvated crystalline citrate salt of the compound of formula (I)

[0425]

[0426] Example 8 - Anhydrous crystalline citrate salt of the compound of formula (I)

[0427] (i) Preparation of Anhydrous Crystalline Citrate

[0428] The anhydrous crystalline citrate salt of the compound of formula (I) was prepared as follows: The ACN-solvated crystalline citrate salt of the compound of formula (I) (see Example 7) was placed in a vial and covered with perforated aluminum foil. The sample was then placed in a vacuum oven at room temperature for 1 day.

[0429] Alternative method: The ACN solvated crystalline citrate salt of the compound of formula (I) (see Example 7) was placed in a vial and covered with perforated aluminum foil. The sample was then placed in a vacuum oven at 44°C for 1 day.

[0430] (ii) Characterization of Anhydrous Crystalline Citrate

[0431] The XRPD pattern of the anhydrous crystalline citrate salt of the compound of formula (I) is provided at Fig.24 middle. Fig.24 The tabulated characteristics of the XRPD pattern are provided in Table 22, which lists the diffraction angle 2θ, the interplanar spacing and relative intensity (expressed as a percentage of the most intense peak).

[0432] Anhydrous crystalline form of a compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 HNMR spectra provided by Fig.26 middle. 1 The H NMR spectrum was consistent with the structure of the compound of formula (I) and contained approximately 1 mole of citric acid.

[0433] The DSC thermogram of the anhydrous crystalline form of the compound of formula (I) is provided at Fig.28 The DSC thermogram exhibits an endothermic event with a peak maximum at about 131.5° C. A second endotherm was observed immediately after this event, which may be due to decomposition.

[0434] The TGA thermogram of the anhydrous crystalline form of the compound of formula (I) is provided at Fig. 27 Negligible weight loss (<0.1 wt %) was observed, indicating that the crystalline form was anhydrous.

[0435] The water adsorption isotherm of the anhydrous crystalline form of the compound of formula (I) is provided in Fig.29The isotherms showed a weight gain of 1.2% wt. from 5% to 74% RH and a weight gain of 14.6% wt. from 75% to 96% RH. The total weight gain was 15.8% or 7.6 moles of water. Significant hysteresis was observed upon desorption and the sample showed signs of partial deliquescence. XRPD analysis of the post-DVS sample indicated that the material was amorphous ( Fig.31 ).

[0436] Table 22 - XRPD pattern data of anhydrous crystalline citrate salt of compound of formula (I)

[0437]

[0438]

[0439]

[0440] The XRPD pattern of the anhydrous crystalline citrate salt of the compound of formula (I) was successfully indexed ( Fig.25 The volume of the unit cell is consistent with that of the anhydrous monocitrate salt (Table 23).

[0441] Table 23 - Unit cell parameters of anhydrous crystalline citrate salt of compound of formula (I)

[0442]

[0443] (iii) Water solubility of anhydrous crystalline citrate

[0444] The water solubility of the anhydrous crystalline citrate salt of the compound of formula (I) at 25°C was determined by solvent addition to be >111 mg / ml (same solubility determination method as described in Example 2).

[0445] Incorporated by Reference

[0446] The entire disclosure of each patent document and scientific article cited herein is incorporated by reference for all purposes.

[0447] Equivalent

[0448] Without departing from the spirit or essential features of the present disclosure, the present disclosure may be implemented in other specific forms. Therefore, the foregoing embodiments should be considered in all respects as illustrative rather than limiting the present disclosure described herein. Therefore, the scope of the present disclosure is indicated by the appended claims rather than by the above description, and all changes within the meaning and scope of the equivalence of the claims are intended to be included herein.

Claims

1. A crystalline form of a compound of formula (I):

2. The crystalline form of claim 1, wherein the crystalline form is a crystalline salt.

3. The crystalline form of claim 1 or 2, wherein the crystalline form is a non-solvated crystalline form.

4. The crystalline form of claim 1 or 2, wherein the crystalline form is a crystalline solvate.

5. A crystalline form of a compound of formula (I): wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from the group consisting of 6.0°±0.2°, 8.6°±0.2°, 14.3°±0.2°, and 16.3°±0.2° 2θ.

6. The crystalline form of claim 5, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 15.6°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 19.9°±0.2°, 20.4°±0.2°, and 21.5°±0.2° 2θ.

7. The crystalline form of claim 5 or 6, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 7.1°±0.2°, 11.7°±0.2°, 12.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.6°±0.2°, 20.9°±0.2°, 22.0°±0.2°, 22.3°±0.2°, 22.7°±0.2°, 23. 2θ: 3.0°±0.2°, 23.2°±0.2°, 24.4°±0.2°, 24.8°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 26.1°±0.2°, 26.4°±0.2°, 27.1°±0.2°, 27.5°±0.2°, 28.1°±0.2°, 28.5°±0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.8°±0.2°, and 30.5°±0.2° 2θ.

8. The crystalline form of any one of claims 5-7, wherein the crystalline form is characterized by an XRPD pattern substantially the same as that shown in Figure 1.

9. The crystalline form of any one of claims 5-8, wherein the crystalline form exists in the orthorhombic system and has a P212121 space group.

10. The crystalline form of claim 9, wherein the crystalline form is characterized by the following crystallographic unit cell parameters:

11. The crystalline form of any one of claims 5-10, characterized by an endotherm with a peak onset of about 165°C to about 180°C as determined by differential scanning calorimetry.

12. The crystalline form of any one of claims 5-11, wherein the crystalline form is an anhydrous crystalline form.

13. A crystalline solvate of a compound of formula (I):

14. The crystalline solvate of claim 13, wherein the crystalline solvate is an acetone solvate, a p-dioxane solvate or a tetrahydrofuran solvate.

15. A crystalline acetone solvate of a compound of formula (I):

16. The crystalline acetone solvate of claim 15, wherein the acetone solvate is a monoacetone solvate.

17. The crystalline acetone solvate of claim 15 or 16, wherein the crystalline acetone solvate is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from the group consisting of 6.4°±0.2°, 16.2°±0.2°, 17.2°±0.2°, and 22.0°±0.2° 2θ.

18. The crystalline acetone solvate of claim 17, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 12.0°±0.2°, 14.3°±0.2°, 15.7°±0.2°, 17.8°±0.2°, 20.2°±0.2°, 21.8°±0.2°, and 22.6°±0.2° 2θ.

19. The crystalline acetone solvate of claim 17 or 18, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 7.8°±0.2°, 9.8°±0.2°, 10.4°±0.2°, 12.8°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 17.6°±0.2°, 18.4°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 20.5°±0.2°, 21.2°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 2θ is 2.1° ± 0.2°, 2.8° ± 0.2°, 2.1° ± 0.2°, 2.2° ± 0.2°, 2.3° ± 0.2°, 2.4° ± 0.2°, 2.5° ± 0.2°, 2.6° ± 0.2°, and 31.1° ± 0.2° 2θ.

20. The crystalline acetone solvate of any one of claims 17-19, wherein the crystalline acetone solvate is characterized by an XRPD pattern substantially the same as that shown in Figure 6.

21. The crystalline acetone solvate of any one of claims 15 to 20, wherein the crystalline acetone solvate exists in an orthorhombic crystal system and has a space group of P212121.

22. The crystalline acetone solvate of claim 21, wherein the crystalline acetone solvate is characterized by the following crystallographic unit cell parameters:

23. The crystalline acetone solvate of any one of claims 15-22, wherein the crystalline acetone solvate is characterized by one or more endotherms having peak maxima selected from about 100°C, about 107°C, and about 173°C as determined by differential scanning calorimetry.

24. A crystalline p-dioxane solvate of a compound of formula (I):

25. The crystalline p-dioxane solvate of claim 24, wherein the p-dioxane solvate is a mono-p-dioxane solvate.

26. The crystalline p-dioxane solvate of claim 24 or 25, wherein the crystalline p-dioxane solvate is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from the group consisting of 6.3°±0.2°, 16.0°±0.2°, 17.0°±0.2°, and 21.8°±0.2° 2θ.

27. The crystalline p-dioxane solvate of claim 26, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 11.8°±0.2°, 14.2°±0.2°, 17.5°±0.2°, 20.0°±0.2°, and 21.6°±0.2° 2θ.

28. The crystalline p-dioxane solvate of claim 26 or 27, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 5.2°±0.2°, 7.7°±0.2°, 10.3°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 15.4°±0.2°, 15.5°±0.2°, 18.1°±0.2°, 18.4°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.4°±0.2°. 2θ: 2°, 20.2°±0.2°, 21.0°±0.2°, 22.4°±0.2°, 23.0°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.0°±0.2°, 24.7°±0.2°, 25.2°±0.2°, 25.4°±0.2°, 25.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, 28.0°±0.2°, 28.3°±0.2°, and 28.9°±0.2° 2θ.

29. The crystalline p-dioxane solvate of any one of claims 26-28, wherein the crystalline p-dioxane solvate is characterized by an XRPD pattern substantially the same as shown in Figure 10.

30. The crystalline p-dioxane solvate of any one of claims 24-29, wherein the crystalline p-dioxane solvate exists in an orthorhombic crystal system and has a P212121 space group.

31. The crystalline p-dioxane solvate of claim 30, wherein the crystalline p-dioxane solvate is characterized by the following crystallographic unit cell parameters:

32. The crystalline p-dioxane solvate of any one of claims 24-31, wherein the crystalline p-dioxane solvate is characterized by an endotherm with a peak onset of about 94°C as determined by differential scanning calorimetry.

33. A crystalline tetrahydrofuran solvate of a compound of formula (I):

34. The crystalline tetrahydrofuran solvate of claim 33, wherein the tetrahydrofuran solvate is a monotetrahydrofuran solvate.

35. The crystalline tetrahydrofuran solvate of claim 33 or 34, wherein the crystalline tetrahydrofuran solvate is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from the group consisting of 6.3°±0.2°, 16.1°±0.2°, 17.3°±0.2°, and 22.9°±0.2° 2θ.

36. The crystalline tetrahydrofuran solvate of claim 35, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 17.1°±0.2°, 17.9°±0.2°, and 22.4°±0.2° 2θ.

37. The crystalline tetrahydrofuran solvate of claim 35 or 36, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 7.7°±0.2°, 11.4°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 12.5°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 15.5°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 20. .1°±0.2°, 21.0°±0.2°, 21.7°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, 24.6°±0.2°, 25.3°±0.2°, 25.9°±0.2°, 27.1°±0.2°, 27.3°±0.2°, 28.4°±0.2°, 28.9°±0.2°, 29.5°±0.2°, 30.0°±0.2° and 30.8°±0.2° 2θ.

38. The crystalline tetrahydrofuran solvate of any one of claims 35-37, wherein the crystalline tetrahydrofuran solvate is characterized by an XRPD pattern substantially the same as shown in Figure 14.

39. The crystalline tetrahydrofuran solvate of any one of claims 33-38, wherein the crystalline tetrahydrofuran solvate exists in an orthorhombic crystal system and has a P212121 space group.

40. The crystalline tetrahydrofuran solvate of claim 39, wherein the crystalline tetrahydrofuran solvate is characterized by the following crystallographic unit cell parameters:

41. The crystalline tetrahydrofuran solvate of any one of claims 33-40, wherein the crystalline tetrahydrofuran solvate is characterized by an endotherm with a peak onset of about 85°C as determined by differential scanning calorimetry.

42. A crystalline citrate salt of a compound of formula (I):

43. The crystalline citrate salt of claim 42, wherein the crystalline citrate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from the group consisting of 5.0±0.2°, 6.6±0.2°, 17.6±0.2°, and 18.2±0.2° 2θ.

44. The crystalline citrate salt of claim 43, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 15.0 ± 0.2°, 15.3 ± 0.2°, 16.9 ± 0.2°, 19.7 ± 0.2°, 20.1 ± 0.2°, 22.6 ± 0.2°, 22.8 ± 0.2°, and 24.8 ± 0.2° 2θ.

45. The crystalline citrate salt of claim 43 or 44, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 8.6 ± 0.2°, 10.0 ± 0.2°, 11.0 ± 0.2°, 11.5 ± 0.2°, 13.2 ± 0.2°, 13.3 ± 0.2°, 14.6 ± 0.2°, 15.9 ± 0.2°, 16.3 ± 0.2°, 16.5 ± 0.2°, 21. .0±0.2°, 21.5±0.2°, 21.8±0.2°, 23.2±0.2°, 23.4±0.2°, 23.9±0.2°, 24.6±0.2°, 25.2±0.2°, 26.0±0.2°, 26.6±0.2°, 27.3±0.2°, 28.9±0.2°, 29.5±0.2°, 29.8±0.2°, and 30.4±0.2° 2θ.

46. ​​The crystalline citrate salt of any one of claims 43-45, wherein the crystalline citrate salt is characterized by an XRPD pattern substantially the same as shown in Figure 18.

47. The crystalline citrate salt of any one of claims 42-46, wherein the crystalline citrate salt exists in an orthorhombic system and has a P212121 space group.

48. The crystalline citrate salt of claim 47, wherein the crystalline citrate salt is characterized by the following crystallographic unit cell parameters:

49. The crystalline citrate salt of any one of claims 42-48, wherein the crystalline citrate salt is characterized by an endotherm with a peak onset of about 110°C as determined by differential scanning calorimetry.

50. The crystalline citrate salt of any one of claims 42-49, wherein the crystalline citrate salt is an acetone solvated crystalline citrate salt.

51. The crystalline citrate salt of claim 42, wherein the crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.1 ± 0.2°, 6.9 ± 0.2°, 17.8 ± 0.2°, and 18.7 ± 0.2° 2θ.

52. The crystalline citrate salt of claim 51, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 17.2±0.2°, 22.3±0.2°, 23.3±0.2°, and 23.6±0.2° 2θ.

53. The crystalline citrate salt of claim 51 or 52, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 5.4±0.2°, 8.6±0.2°, 9.2±0.2°, 10.1±0.2°, 10.8±0.2°, 11.7±0.2°, 13.2±0.2°, 13.9±0.2°, 14.0±0.2°, 14.8±0.2°, 15.2±0.2°, 15.4±0.2°, 16.1±0.2°, 16.9±0.2°, 17.4±0.2°, 18.0±0.2°, 19.1±0.2°, 19. 5±0.2°, 19.7±0.2°, 19.9±0.2°, 20.2±0.2°, 20.4±0.2°, 20.9±0.2°, 21.1±0.2°, 21.8±0.2°, 21.9±0.2°, 22.6±0.2°, 22.8±0.2°, 23 .8±0.2°, 24.1±0.2°, 24.4±0.2°, 25.2±0.2°, 25.5±0.2°, 26.0±0.2°, 26.5±0.2°, 26.7±0.2°, 27.4±0.2°, 27.9±0.2°, 28.4±0.2°2θ.

54. The crystalline citrate salt of any one of claims 51-53, wherein the crystalline citrate salt is characterized by an XRPD pattern substantially the same as shown in Figure 22.

55. The crystalline citrate salt of any one of claims 42 and 51-54, wherein the crystalline citrate salt exists in an orthorhombic system and has a P212121 space group.

56. The crystalline citrate salt of claim 55, wherein the crystalline citrate salt is characterized by the following crystallographic unit cell parameters:

57. The crystalline citrate salt of any one of claims 42 and 51-56, wherein the crystalline citrate salt is an acetonitrile-solvated crystalline citrate salt.

58. The crystalline citrate salt of claim 42, wherein the crystalline citrate salt is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of 5.3 ± 0.2°, 6.4 ± 0.2°, 17.6 ± 0.2°, and 23.0 ± 0.2° 2θ.

59. The crystalline citrate salt of claim 58, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 8.5 ± 0.2°, 10.6 ± 0.2°, 16.0 ± 0.2°, 17.0 ± 0.2°, 17.3 ± 0.2°, 18.2 ± 0.2°, 21.4 ± 0.2°, and 22.4 ± 0.2° 2θ.

60. The crystalline citrate salt of claim 58 or 59, wherein the XRPD pattern further comprises one or more peaks selected from the group consisting of 7.6±0.2°, 9.1±0.2°, 12.8±0.2°, 14.4±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 19.0±0.2°, 19.3±0.2°, 19.5±0.2°, 20.1±0.2°, 20.9±0.2°, 24.3±0.2°, 25.7±0.2°, 25.8±0.2°, 26.4±0.2°, 27.4±0.2°, and 28.0±0.2° 2θ.

61. The crystalline citrate salt of any one of claims 58-60, wherein the crystalline citrate salt is characterized by an XRPD pattern substantially the same as shown in Figure 24.

62. The crystalline citrate salt of any one of claims 42 and 58-61, wherein the crystalline citrate salt exists in an orthorhombic system and has a P212121 space group.

63. The crystalline citrate salt of claim 62, wherein the crystalline citrate salt is characterized by the following crystallographic unit cell parameters:

64. The crystalline citrate salt of any one of claims 42 and 58-63, wherein the crystalline citrate salt is characterized by an endotherm with a peak maximum at about 131 °C as determined by differential scanning calorimetry.

65. The crystalline citrate salt of any one of claims 42 and 58-64, wherein the crystalline citrate salt is an anhydrous citrate salt.

66. The crystalline citrate salt of any one of claims 42-65, wherein the citrate salt is a monocitrate salt.

67. A pharmaceutical composition comprising: The crystalline form of any one of claims 1-12, the crystalline solvate of any one of claims 13-41, or the crystalline citrate of any one of claims 42-66; and Pharmaceutically acceptable excipients.

68. A method of treating a disease or disorder associated with cell proliferation, the method comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form of any one of claims 1-12, the crystalline solvate of any one of claims 13-41, the crystalline citrate of any one of claims 42-66, or the pharmaceutical composition of claim 67.

69. The method of claim 68, wherein the disease or disorder associated with cell proliferation is hyperplasia or cancer.

70. The method of claim 69, wherein the cancer is a hematological cancer.

71. The method of claim 70, wherein the blood cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

72. The method of claim 69, wherein the cancer is a non-hematological cancer.

73. The method of claim 72, wherein the non-hematological cancer is a sarcoma or a carcinoma.

74. The method of any one of claims 68-73, wherein following administration of the crystalline form of any one of claims 1-12, the crystalline solvate of any one of claims 13-41, the crystalline citrate salt of any one of claims 42-66, or the pharmaceutical composition of claim 67, the subject has one or more of: increased T cell activation, increased T cell proliferation, reduced T cell exhaustion, reduced T cell anergy, and reduced T cell tolerance.

75. The method of claim 74, wherein increased T cell activation comprises increased cytokine production.

76. The method of any one of claims 68-73, wherein the subject has increased NK cell activation.

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