Solid Forms of Triazine Derivatives as CBL-B Modulators

Abstract

The present disclosure provides, in part, crystalline forms of a compound of formula (I). Also provided are pharmaceutical compositions comprising a crystalline form of a compound of formula (I), and the use of the crystalline form of the compound of formula (I) and the pharmaceutical composition in methods for treating various conditions, diseases, and disorders. TIFF2025522079000067.tif54128

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Patent Application No. 63 / 388,342, filed on July 12, 2022, the content of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background Cbl - b is an E3 ubiquitin - protein ligase that functions as a negative regulator of T - cell activation. The modulation of Cbl - b has been shown to be a therapeutic target for various diseases and disorders. There remains an unmet need to develop solid forms (e.g., crystalline forms) of compounds that inhibit CBL - b suitable for administration to patients having a condition, disease, or disorder such as cancer.

Summary of the Invention

[0003] Summary In one aspect, provided herein are crystalline forms (e.g., anhydrous crystalline forms, crystalline solvates, and crystalline salts) of a compound of formula (I): TIFF2025522079000002.tif54128.

[0004] In various embodiments, a crystalline form of a compound of formula (I): TIFF2025522079000003.tif54128, characterized by an X - ray powder diffraction pattern comprising one or more peaks selected from 6.0° ± 0.2°, 8.6° ± 0.2°, 14.3° ± 0.2°, and 16.3° ± 0.2° 2θ.

[0005] In various embodiments, a crystalline solvate of a compound of formula (I): TIFF2025522079000004.tif54128.

[0006] In various embodiments, a compound of formula (I): TIFF2025522079000005.tif The crystalline acetone solvate of 54128.

[0007] In various embodiments, the compound of formula (I): TIFF2025522079000006.tif The crystalline p-dioxane solvate of 54128.

[0008] In various embodiments, the compound of formula (I): TIFF2025522079000007.tif The crystalline tetrahydrofuran solvate of 54128.

[0009] In various embodiments, the compound of formula (I): TIFF2025522079000008.tif The crystalline citrate salt of 54128.

[0010] In another aspect, provided herein is a pharmaceutical composition comprising a crystalline form of the compound of formula (I) described herein and a pharmaceutically acceptable excipient.

[0011] In another aspect, provided herein are crystalline forms (e.g., anhydrous crystalline forms, crystalline solvates, and crystalline salts) of the compounds of formula (I) and pharmaceutical compositions useful for the treatment of the various conditions, diseases, or disorders described herein in a subject in need thereof. In some embodiments, the condition, disease, or disorder is related to cell proliferation. In some embodiments, the condition, disease, or disorder related to cell proliferation is hyperplasia or cancer. In certain embodiments, the cancer is a hematological cancer (e.g., lymphoma, leukemia, and myeloma). In some embodiments, the cancer is a non-hematological cancer (e.g., carcinoma or sarcoma). In certain embodiments, administration of a crystalline form of a compound of formula (I) or a pharmaceutical composition described herein results in a subject demonstrating one or more of the following: increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, decreased T cell anergy, and decreased T cell tolerance. In certain embodiments, the increased T cell activation includes increased cytokine production. In certain embodiments, administration of a crystalline form of a compound of formula (I) or a pharmaceutical composition described herein results in a subject demonstrating increased NK cell activation. In certain embodiments, the increased NK cell activation includes increased cytokine production. BRIEF DESCRIPTION OF THE DRAWINGS

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Mode for Carrying Out the Invention

[0043] Detailed Description As generally described herein, the present disclosure provides crystalline forms of the compound of formula (I) (e.g., anhydrous crystalline forms, crystalline solvates, and crystalline salts), pharmaceutical compositions containing the same, and methods of using the crystalline forms and pharmaceutical compositions to effect treatment of medical conditions, diseases, and disorders (e.g., conditions associated with cell proliferation (e.g., hyperplasia or cancer)) in a subject in need thereof.

[0044] Definitions To facilitate understanding of the present invention, several terms and phrases are defined below.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Abbreviations used herein have their ordinary meaning within the scope of chemical and biological arts. Chemical structures and formulas described herein are constructed according to standard rules of chemical valence known in the chemical art.

[0046] Throughout this description, when a composition and kit are described as having, including, or comprising certain components, or when a process and method are described as having, including, or comprising certain steps, it is contemplated that, in addition, there exist compositions and kits of the invention consisting essentially of, or consisting of, the recited components, and processes and methods according to the invention consisting essentially of, or consisting of, the recited process steps.

[0047] In this application, when an element or component is said to be 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 a group comprising two or more of the recited elements or components.

[0048] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether explicit or implicit herein, can be combined in various ways without departing from the spirit and scope of the invention. For example, when referring to a particular compound, that compound can be used in various embodiments of the compositions of the invention and / or in the methods of the invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables clear and concise application writing, but it is intended and understood that the embodiments can be variously combined or separated without departing from the present teachings and invention(s). For example, it will be understood that all features described and depicted herein are applicable to all aspects of the invention described and depicted herein.

[0049] The articles "a" and "an" are used in this disclosure to refer to one or more (i.e., at least one) of the grammatical objects of the article, unless the context is inappropriate. By way of example, "an element" means one element or more than one element. As a further example, "an analogue" means one analogue or more than one analogue.

[0050] The term "and / or" is used in this disclosure to mean either "and" or "or", unless otherwise indicated.

[0051] The expression "at least one of" should be understood to individually include each of the objects listed before that expression, and various combinations of two or more of the listed objects, unless otherwise understood from the context and usage. Also, the expression "and / or" relating to three or more of the listed objects should be understood to have the same meaning, unless otherwise understood from the context.

[0052] The use of the terms "include", "includes", "including", "have", "has", "having", "contain", "contains", or "containing", including their grammatical equivalents, is generally open-ended and non-limiting, unless specifically stated otherwise or understood from the context, and is not intended to exclude additional unrecited elements or steps, for example.

[0053] When the term "about" is used before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically described otherwise. As used herein, the term "about" refers to a variation of ±10%, ±5%, ±3%, ±2%, or ±1% from the nominal value, unless otherwise indicated or inferred from the context.

[0054] Due to the causes of experimental variability well known to those skilled in the art, each differential scanning calorimetry (DSC) endothermic or exothermic value is usually given the term "about" or is carried out within an appropriate range defining the experimental variability. For the purposes of the data reported herein, unless otherwise stated, the value is ±10 °C. The DSC endotherms / exotherms listed herein are generally reported with this variability of ±10 °C, unless otherwise stated, and are intended to be reported with such variability, whether or not the word "about" is present, whenever disclosed herein and unless otherwise indicated by the context.

[0055] For example, when the molecular weight is provided rather than the absolute value of the polymer, the molecular weight should be understood to be the average molecular weight, unless otherwise stated or understood from the context.

[0056] It should be understood that the order of steps or the order in which particular acts are performed is not important, as long as the present invention is practicable. Furthermore, two or more steps or acts may be performed simultaneously.

[0057] Throughout various places in this specification, variables or parameters are disclosed in groups or ranges. It is specifically intended that the description include each and every individual partial combination of the members of such groups and ranges. By way of example, integers within the range of 0 to 40 are specifically intended to individually 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 specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0058] All examples, or exemplary expressions, such as "such as" or "including" used in this specification are merely intended to better explain the present invention and do not limit the scope of the present invention unless otherwise claimed. No language in this specification should be construed as indicating that any unclaimed element is essential for the practice of the invention.

[0059] As used herein, "pharmaceutically acceptable" and "pharmacologically acceptable" refer, as appropriate, to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce adverse reactions, allergic reactions, or other unwanted reactions when administered to animals or humans. In the case of administration to humans, the preparation should meet the sterility, pyrogenicity, general safety and purity standards required by the FDA Office of Biologics standards.

[0060] As used herein, "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" include any solvent, dispersion medium, coating, isotonic agent, absorption delaying agent, and the like that are compatible with pharmaceutical administration. Pharmaceutically acceptable carriers can include phosphate buffered saline, water, emulsions (e.g., oil-in-water or water-in-oil emulsions), and various types of wetting agents. The compositions may also include stabilizers and preservatives.

[0061] As used herein, "pharmaceutically acceptable salts" refers to any salts of acidic or basic groups that may be present in the compounds of the present disclosure (e.g., compounds of formula (I)) and are compatible with pharmaceutical administration. As is known to those skilled in the art, the "salts" of the compounds of the present disclosure can 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 of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, 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. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4(Alkyl)4 salts are mentioned. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, 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, etc.

[0062] As used herein, the "subject" for which administration is contemplated includes humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals including primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs, etc., but is not limited thereto. 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.

[0063] As used herein and unless otherwise specified, the terms "treat", "treating", and "treatment" contemplate an action (a "therapeutic treatment") that occurs while a subject is suffering from a designated disease, disorder, or condition and reduces the severity of the disease, disorder, or condition, or delays or mitigates the progression of the disease, disorder, or condition, and also contemplate an action (a "preventive treatment") that occurs before a subject begins to suffer from a designated disease, disorder, or condition.

[0064] As used herein, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and the age, health, and condition of the subject. Effective amounts include therapeutic and preventive treatments.

[0065] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound (e.g., a compound of the present 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 present invention) means the amount of the therapeutic agent alone or in combination with other therapies that provide a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall therapy, alleviates or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0066] As used herein, "disease", "disorder", "condition", or "ailment" are used interchangeably unless otherwise corresponded or understood from the context, and refer to the existing state or health condition 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 condition, or ailment, for example, through administration of a compound of formula (I), or a stereoisomer and / or pharmaceutically acceptable salt thereof.

[0067] 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 such as a small osmotic pump, for example. Administration may be 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, intracardiac, and intracranial. Other delivery forms include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Co-administering" means that the compositions described herein are administered simultaneously with, immediately prior to, or immediately following the administration of one or more additional therapies (e.g., an anti-cancer agent, a chemotherapeutic agent, or a therapeutic agent for a neurodegenerative disease). The compounds of the invention can be administered to a patient alone or co-administered. Co-administering means including the simultaneous or sequential administration of the compounds, individually or in combination (plural compounds or agents). Thus, the preparations can also, if desired, be combined with other active substances (e.g., to reduce metabolic degradation).

[0068] Various aspects of the present disclosure are described herein in headings and / or sections for clarity. However, it is understood that all aspects, embodiments, or features of the present disclosure described in one particular section are not limited to that particular section, but can be applied to any aspect, embodiment, or feature of the present disclosure.

[0069] Solid form 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. TIFF2025522079000009.tif54128

[0070] In one aspect, provided herein is a solid form of a compound of formula (I).

[0071] 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 of its free base form. 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.

[0072] 1. Crystalline form of the free base of the compound of formula (I) 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 the compound of formula (I) is an anhydrous crystalline form. In certain embodiments, the crystalline form of the free base of the compound of formula (I) is a solvated crystalline form. In certain embodiments, the crystalline form of the free base of the compound of formula (I) is a non-solvated crystalline form.

[0073] (i) Anhydrous crystalline form In various embodiments, provided herein is a compound of formula (I): A crystalline form of TIFF2025522079000010.tif54128, characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from 6.0° ± 0.2°, 8.6° ± 0.2°, 14.3° ± 0.2°, and 16.3° ± 0.2° 2θ, is provided.

[0074] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising peaks at 6.0° ± 0.2°, 8.6° ± 0.2°, 14.3° ± 0.2°, and 16.3° ± 0.2° 2θ.

[0075] 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.

[0076] In certain embodiments, the XRPD pattern further comprises peaks at 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.

[0077] 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.

[0078] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising peaks at 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.

[0079] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 2θ 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°, 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°.

[0080] In certain embodiments, the XRPD pattern further comprises peaks at 2θ 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°, 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°.

[0081] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising one or more peaks selected from 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°, 21.5°±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.

[0082] In certain embodiments, the crystalline form is characterized by an XRPD pattern having peaks at 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°, 21.5°±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.

[0083] In certain embodiments, the crystalline form is characterized by an XRPD pattern that is substantially the same as that shown in FIG. 1.

[0084] In certain embodiments, the crystalline form exists in the orthorhombic system and has the P212121 space group. In certain embodiments, the crystalline form is characterized by the crystallographic unit cell parameters shown in Table 1. TIFF2025522079000011.tif57165

[0085] In certain embodiments, the crystalline form dissolved in dimethyl sulfoxide-d6 containing trimethylsilane has one, two, three, four, five, or more peaks at 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 and is characterized by a proton nuclear magnetic resonance ( 1 1H NMR) spectrum.

[0086] In certain embodiments, the crystalline form dissolved in dimethyl sulfoxide-d6 containing trimethylsilane has a 1H NMR spectrum that is substantially the same as that shown in Figure 3 1 and is characterized thereby.

[0087] The crystalline forms of the compounds 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 when 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 when determined by DSC. In certain embodiments, the crystalline form is characterized by an endotherm with a peak onset of about 165°C to about 180°C when determined by DSC. In certain embodiments, the crystalline form is characterized by a melting point onset of about 165°C to about 180°C when determined by DSC. In certain embodiments, the crystalline form is characterized by a melting point onset of about 170°C to about 180°C when determined by DSC. In certain embodiments, the crystalline form is characterized by a melting point onset of about 175°C when determined by DSC. In certain embodiments, the crystalline form has a DSC thermogram substantially the same as that shown in Figure 4.

[0088] The crystalline form can also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline form shows a mass loss of about 0.1 wt% to about 1.6 wt% when heated to about 230°C when determined by thermogravimetric analysis (TGA). In certain embodiments, the crystalline form shows a mass loss of about 1.6 wt% or less when heated to about 230°C when determined by TGA analysis. In certain embodiments, the crystalline form has a TGA thermogram substantially the same as that shown in Figure 4.

[0089] The crystalline form can also be characterized according to its water adsorption properties. Thus, in certain embodiments, the crystalline form shows a mass gain of about 0.4 wt% or less at 95% relative humidity and a temperature of 25°C when determined by dynamic vapor sorption (DVS). In certain embodiments, the crystalline form has a water adsorption isotherm substantially the same as that shown in Figure 5 when measured at 25°C.

[0090] In certain embodiments, the crystalline form is an anhydrous crystalline form.

[0091] (ii) Crystalline acetone solvate In various embodiments, as used herein, a compound of formula (I): The crystalline acetone solvate of TIFF2025522079000012.tif54128 is provided.

[0092] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising one or more peaks selected from 6.4° ± 0.2°, 16.2° ± 0.2°, 17.2° ± 0.2°, and 22.0° ± 0.2° 2θ.

[0093] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising peaks at 6.4° ± 0.2°, 16.2° ± 0.2°, 17.2° ± 0.2°, and 22.0° ± 0.2° 2θ.

[0094] 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.

[0095] In certain embodiments, the XRPD pattern further comprises peaks at 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.

[0096] 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.

[0097] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern comprising peaks at 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.

[0098] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 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°, 24.0° ± 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.

[0099] In certain embodiments, the XRPD pattern further comprises peaks at 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°, 24.0° ± 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.

[0100] In certain embodiments, the crystalline form is characterized by an XRPD pattern comprising one or more peaks selected from 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.

[0101] In certain embodiments, the crystalline form is characterized by an XRPD pattern having peaks at 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.

[0102] In certain embodiments, the crystalline acetone solvate is characterized by an XRPD pattern that is substantially the same as that shown in FIG. 6.

[0103] In certain embodiments, the crystalline acetone solvate exists in the orthorhombic system and has the P212121 space group. In certain embodiments, the crystalline acetone solvate is characterized by the crystallographic unit cell parameters shown in Table 2. TIFF2025522079000013.tif44165

[0104] In certain embodiments, the crystalline acetone solvate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane has one, two, three, four, five, or more peaks at 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. 1 Characterized by an 1 H NMR spectrum.

[0105] In certain embodiments, the crystalline acetone solvate is substantially the same as that shown in FIG. 8 1 Characterized by an 1 H NMR spectrum.

[0106] 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 peak maxima 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 DSC thermogram substantially the same as that shown in FIG. 9.

[0107] The crystalline acetone solvate can also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline acetone solvate shows a mass loss of about 5.3 wt% or less when heated to about 121 °C as determined by TGA. In certain embodiments, the crystalline acetone solvate has a TGA thermogram substantially the same as that shown in FIG. 9.

[0108] In certain embodiments, the crystalline acetone solvate is a monoacetone solvate.

[0109] (iii) Crystalline p-dioxane solvate In various embodiments, herein provided is a crystalline p-dioxane solvate of a compound of formula (I): TIFF2025522079000014.tif54128

[0110] 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°, 16.0° ± 0.2°, 17.0° ± 0.2°, and 21.8° ± 0.2° 2θ.

[0111] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern that includes peaks at 6.3° ± 0.2°, 16.0° ± 0.2°, 17.0° ± 0.2°, and 21.8° ± 0.2° 2θ.

[0112] In certain embodiments, the XRPD pattern further includes 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.

[0113] In certain embodiments, the XRPD pattern further includes peaks at 11.8° ± 0.2°, 14.2° ± 0.2°, 17.5° ± 0.2°, 20.0° ± 0.2°, and 21.6° ± 0.2° 2θ.

[0114] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern that includes 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.

[0115] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern that includes peaks at 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.

[0116] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 2θ 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°, 21.0° ± 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°.

[0117] In certain embodiments, the XRPD pattern further comprises peaks at 2θ 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°, 21.0° ± 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°.

[0118] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern comprising one or more peaks selected from 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°, 19.4° ± 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.

[0119] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern having peaks at 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°, 19.4° ± 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.

[0120] In certain embodiments, the crystalline p-dioxane solvate is characterized by an XRPD pattern that is substantially the same as that shown in Figure 10.

[0121] In certain embodiments, the crystalline p-dioxane solvate is present in the orthorhombic system and has the P212121 space group. In certain embodiments, the crystalline p-dioxane is characterized by the crystallographic unit cell parameters shown in Table 3. TIFF2025522079000015.tif44165

[0122] In certain embodiments, the crystalline p-dioxane solvate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane has the following chemical shifts: 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, 7.141, 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, 4.124, 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, 1.836, 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.Having one, two, three, four, five, or more peaks at 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. 1 Characterized by an 1H NMR spectrum.

[0123] In certain embodiments, the crystalline p-dioxane solvate is substantially the same as that shown in Figure 12 1 Characterized by an 1H NMR spectrum.

[0124] The crystalline p-dioxane solvate of the compound of formula (I) can 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 of about 106 °C as determined by DSC. Thus, in certain embodiments, the crystalline p-dioxane solvate is characterized by an endotherm with a peak onset of about 94 °C as determined by DSC. In certain embodiments, the crystalline p-dioxane solvate has a DSC thermogram substantially the same as that shown in Figure 13.

[0125] The crystalline p-dioxane solvate can also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline p-dioxane solvate shows a mass loss of about 3.9 wt% or less when heated to about 119 °C as determined by TGA. In certain embodiments, the crystalline p-dioxane solvate has a TGA thermogram substantially the same as that shown in Figure 13.

[0126] In certain embodiments, the crystalline p-dioxane solvate is a mono p-dioxane solvate.

[0127] (iv) Crystalline tetrahydrofuran (THF) solvate In various embodiments, as used herein, a compound of formula (I): The crystalline THF solvate of TIFF2025522079000016.tif54128 is provided.

[0128] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising one or more peaks selected from 6.3° ± 0.2°, 16.1° ± 0.2°, 17.3° ± 0.2°, and 22.9° ± 0.2° 2θ.

[0129] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising peaks at 6.3° ± 0.2°, 16.1° ± 0.2°, 17.3° ± 0.2°, and 22.9° ± 0.2° 2θ.

[0130] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 17.1° ± 0.2°, 17.9° ± 0.2°, and 22.4° ± 0.2° 2θ.

[0131] In certain embodiments, the XRPD pattern further comprises peaks at 17.1° ± 0.2°, 17.9° ± 0.2°, and 22.4° ± 0.2° 2θ.

[0132] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising one or more peaks selected from 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.

[0133] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising peaks at 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.

[0134] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 2θ 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°.

[0135] In certain embodiments, the XRPD pattern further comprises peaks at 2θ 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°.

[0136] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern comprising one or more peaks selected from 2θ 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°.

[0137] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern having peaks at 2θ 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°.

[0138] In certain embodiments, the crystalline THF solvate is characterized by an XRPD pattern that is substantially the same as that shown in Figure 14.

[0139] In certain embodiments, the crystalline THF solvate is present in the orthorhombic system and has the P212121 space group. In certain embodiments, the crystalline THF solvate is characterized by the crystallographic unit cell parameters shown in Table 4. TIFF2025522079000017.tif44165

[0140] In certain embodiments, the crystalline THF solvate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane has one, two, three, four, five, or more peaks at 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, 3.674, 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, 3.207, 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, 1.803, 1.799, 1.795, 1.793, 1.788, 1.783, 1.779, 1.771, 1.766, 1.760, 1.757, 1.754, 1.749, 1.737, 1.729, 1.714, 1.710, 1.697, 1.683, 1.660, 1.639, 1.582, 1.521, 1.480, 1.460, 1.441, 1.398, 1.355, 1.235, 0.862, 0.833, 0.822, 0.792, and 0.781 ppm. 1 Characterized by an 1H NMR spectrum.

[0141] In certain embodiments, the crystalline THF solvate is substantially the same as that shown in Figure 16 1 and is characterized by its 1H NMR spectrum.

[0142] 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 of about 97 °C as determined by DSC. Thus, 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 DSC thermogram that is substantially the same as that shown in Figure 17.

[0143] The crystalline THF solvate can also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the crystalline THF solvate shows a mass loss of about 4.5 wt% or less when heated to about 112 °C as determined by TGA. In certain embodiments, the crystalline THF solvate has a TGA thermogram that is substantially the same as that shown in Figure 17.

[0144] In certain embodiments, the crystalline THF solvate is a mono-THF solvate.

[0145] 2. Crystalline citrate forms In one aspect, provided herein is a crystalline citrate of a compound of formula (I): TIFF2025522079000018.tif54128.

[0146] In certain embodiments, the crystalline citrate is an anhydrous crystalline citrate. In certain embodiments, the crystalline citrate is a solvated crystalline citrate (e.g., an acetone solvate, an acetonitrile solvate). In certain embodiments, the crystalline citrate described herein is a monocitrate.

[0147] (i)Acetone solvated crystalline citrate In certain embodiments, the crystalline citrate is an acetone solvate crystalline citrate.

[0148] In certain embodiments, the acetone solvate crystalline citrate is characterized by an XRPD pattern comprising one or more peaks selected from 5.0±0.2°, 6.6±0.2°, 17.6±0.2°, and 18.2±0.2° 2θ.

[0149] In certain embodiments, the acetone solvate crystalline citrate is characterized by an XRPD pattern comprising peaks at 5.0±0.2°, 6.6±0.2°, 17.6±0.2°, and 18.2±0.2° 2θ.

[0150] 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.

[0151] In certain embodiments, the XRPD pattern further comprises peaks at 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.

[0152] In certain embodiments, the acetone solvate crystalline citrate 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.

[0153] In certain embodiments, the acetone solvated crystalline citrate is characterized by an XRPD pattern that includes 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.

[0154] In certain embodiments, the XRPD pattern further includes one or more peaks selected from 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.

[0155] In certain embodiments, the XRPD pattern further includes peaks at 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.

[0156] In certain embodiments, the acetone solvate crystalline citrate is characterized by an XRPD pattern comprising one or more peaks selected from 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°, 19.7±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, 21.8±0.2°, 22.6±0.2°, 22.8±0.2°, 23.2±0.2°, 23.4±0.2°, 23.9±0.2°, 24.6±0.2°, 24.8±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.

[0157] In certain embodiments, the acetone solvate crystalline citrate is characterized by an XRPD pattern having peaks at 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°, 19.7±0.2°, 20.1±0.2°, 21.0±0.2°, 21.5±0.2°, 21.8±0.2°, 22.6±0.2°, 22.8±0.2°, 23.2±0.2°, 23.4±0.2°, 23.9±0.2°, 24.6±0.2°, 24.8±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.

[0158] In certain embodiments, the acetone solvate citrate is characterized by an XRPD pattern that is substantially the same as that shown in Figure 18.

[0159] In certain embodiments, the acetone solvate citrate is present in the orthorhombic system and has the P212121 space group. In certain embodiments, the acetone solvate citrate is characterized by the crystallographic unit cell parameters shown in Table 5. TIFF2025522079000019.tif44165

[0160] In certain embodiments, the acetone solvate citrate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane has one, two, three, four, five, or more peaks at 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, 7.682, 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. 1Characterized by its 1H NMR spectrum.

[0161] In certain embodiments, the acetone solvate crystalline citrate is substantially the same as that shown in Figure 20 1 Characterized by its 1H NMR spectrum.

[0162] The acetone solvate crystalline citrate of the compound of formula (I) can also be characterized using thermal analysis techniques such as DSC. Thus, in certain embodiments, the acetone solvate crystalline citrate is characterized by an endotherm with a peak maximum of about 117 °C when determined by DSC. In certain embodiments, the acetone solvate crystalline citrate is characterized by an endotherm with a peak onset of about 110 °C when determined by DSC. In certain embodiments, the acetone solvate crystalline citrate has a DSC thermogram substantially the same as that shown in Figure 21.

[0163] The acetone solvate crystalline citrate can also be characterized according to its mass gain / mass loss as a function of temperature. Thus, in certain embodiments, the acetone solvate crystalline citrate shows a mass loss of about 7 wt% or less when heated to about 131 °C when determined by TGA. In certain embodiments, the acetone solvate crystalline citrate has a TGA thermogram substantially the same as that shown in Figure 21.

[0164] In certain embodiments, the acetone solvate crystalline citrate contains 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).

[0165] (ii) Acetonitrile solvated crystalline citrate In certain embodiments, the crystalline citrate is an acetonitrile solvate crystalline citrate.

[0166] In certain embodiments, the acetonitrile solvate citrate is characterized by an XRPD pattern comprising one or more peaks selected from 5.1 ± 0.2°, 6.9 ± 0.2°, 17.8 ± 0.2°, and 18.7 ± 0.2° 2θ.

[0167] In certain embodiments, the acetonitrile solvate citrate is characterized by an XRPD pattern comprising peaks at 5.1 ± 0.2°, 6.9 ± 0.2°, 17.8 ± 0.2°, and 18.7 ± 0.2° 2θ.

[0168] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 17.2 ± 0.2°, 22.3 ± 0.2°, 23.3 ± 0.2°, and 23.6 ± 0.2° 2θ.

[0169] In certain embodiments, the XRPD pattern further comprises peaks at 17.2 ± 0.2°, 22.3 ± 0.2°, 23.3 ± 0.2°, and 23.6 ± 0.2° 2θ.

[0170] In certain embodiments, the acetonitrile solvate citrate 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.

[0171] In certain embodiments, the acetonitrile solvate citrate 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.

[0172] In certain embodiments, the XRPD pattern further comprises one or more peaks selected from 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.

[0173] In certain embodiments, the XRPD pattern further comprises peaks at 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.

[0174] In certain embodiments, the acetonitrile solvated crystalline citrate is characterized by an XRPD pattern comprising one or more peaks selected from 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.

[0175] In certain embodiments, the acetonitrile solvate citrate is characterized by an XRPD pattern that includes peaks at 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.

[0176] In certain embodiments, the acetonitrile solvate citrate is characterized by an XRPD pattern that is substantially the same as that shown in Figure 22.

[0177] In certain embodiments, the acetonitrile solvate citrate exists in the orthorhombic system and has the P212121 space group. In certain embodiments, the acetonitrile solvate citrate is characterized by the crystallographic unit cell parameters shown in Table 6. TIFF2025522079000020.tif44165

[0178] In certain embodiments, the acetonitrile solvate citrate includes 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).

[0179] (iii) Anhydrous crystalline citrate In certain embodiments, the crystalline citrate is the anhydrous crystalline citrate.

[0180] In certain embodiments, the crystalline citrate 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.

[0181] In certain embodiments, the crystalline citrate is characterized by an XRPD pattern comprising peaks at 5.3±0.2°, 6.4±0.2°, 17.6±0.2°, and 23.0±0.2° 2θ.

[0182] 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.

[0183] In certain embodiments, the XRPD pattern further comprises peaks at 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.

[0184] In certain embodiments, the crystalline citrate 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.

[0185] In certain embodiments, the crystalline citrate is characterized by an XRPD pattern that includes 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.

[0186] In certain embodiments, the XRPD pattern further includes 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.

[0187] In certain embodiments, the XRPD pattern further includes peaks at 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.

[0188] In certain embodiments, the crystalline citrate is characterized by an XRPD pattern comprising one or more peaks selected from 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.

[0189] In certain embodiments, the crystalline citrate is characterized by an XRPD pattern having peaks at 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.

[0190] In certain embodiments, the crystalline citrate is characterized by an XRPD pattern that is substantially the same as that shown in Figure 24.

[0191] In certain embodiments, the crystalline citrate is present in the orthorhombic system and has the P212121 space group. In certain embodiments, the crystalline citrate is characterized by the crystallographic unit cell parameters shown in Table 7. TIFF2025522079000021.tif44165

[0192] In certain embodiments, crystalline citrate dissolved in dimethyl sulfoxide-d6 containing trimethylsilane has one, two, three, four, five, or more peaks at 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, 2.537, 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. 1 Characterized by 1H NMR spectrum.

[0193] In certain embodiments, the crystalline citrate is substantially the same as that shown in Figure 26 1 Characterized by 1H NMR spectrum.

[0194] 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 endotherm with a peak maximum of 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 DSC thermogram substantially the same as that shown in Figure 28.

[0195] The crystalline citrate salt can also be characterized according to its mass gain / loss as a function of temperature. Thus, in certain embodiments, the crystalline citrate salt shows a mass loss of about 0.1 wt% or less when heated to about 138 °C as determined by TGA. In certain embodiments, the crystalline citrate salt has a TGA thermogram substantially the same as that shown in Figure 27.

[0196] The crystalline citrate salt can also be characterized according to its water adsorption properties. Thus, in certain embodiments, the crystalline citrate salt shows a mass gain of about 1.2 wt% or less at a relative humidity of 74% and a temperature of 25 °C as determined by DVS. In certain embodiments, the crystalline citrate salt shows a mass gain of about 15.8 wt% or less at a relative humidity of 96% and a temperature of 25 °C as determined by DVS. In certain embodiments, the crystalline citrate salt has a water adsorption isotherm substantially the same as that shown in Figure 29 when measured at 25 °C.

[0197] Pharmaceutical Compositions and Routes of Administration The crystalline forms of the compounds of formula (I) disclosed herein are typically administered in the form of pharmaceutical compositions. In one aspect, provided herein are pharmaceutical compositions containing a crystalline form of a compound of formula (I) 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, solubilizing agents, and adjuvants. The pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such pharmaceutical compositions are prepared in manners well known in the pharmaceutical art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)).

[0198] The pharmaceutical compositions described herein can be administered, for example, by rectal, buccal, intranasal, and subcutaneous routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent or an arterial insertion cylindrical polymer, by any of the acceptable modes of administration of agents having similar utility described in those patents and patent applications incorporated herein by reference, in either single or multiple doses.

[0199] One mechanism for administration is parenteral, particularly by injection. Forms in which the pharmaceutical compositions of the present disclosure can be incorporated for administration by infusion include aqueous or oily suspensions, or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in physiological saline can also be used conventionally for injection, but are less preferred in the context of the present disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0200] Sterile injectable solutions can be prepared by incorporating the crystalline form of the compound of formula (I) according to the present disclosure in a suitable solvent having the various other ingredients mentioned above, and then, if necessary, filtering sterilizing, for example. Generally, dispersions are prepared by incorporating the various sterilized active ingredients in a sterile vehicle containing a basic dispersion medium and the other ingredients required from those mentioned above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is by vacuum drying and lyophilization techniques which yield a powder of the active ingredient plus any additional desired ingredients from its previously sterile filtered solution.

[0201] Oral administration is another route of administration of the crystalline forms of the compounds of formula (I) according to the present disclosure. The administration can be via capsules or enteric-coated tablets, etc. When preparing a pharmaceutical composition containing 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 by an excipient and / or encapsulated in such a carrier which can be in the form of capsules, sachets, paper, or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material (such as those above) acting as a vehicle, carrier, or medium for the active ingredient. Thus, 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), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0202] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation can additionally contain lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propyl hydroxybenzoates, sweetening agents, and flavoring agents.

[0203] The pharmaceutical compositions of the present disclosure can be formulated to provide rapid, sustained, or delayed release of the active ingredient (compound of formula (I)) after administration to a patient by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems, including polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Pat. Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present disclosure employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compound of formula (I) in a controlled amount. The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of the drug.

[0204] The composition is preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampule). Compounds such as the compound of formula (I) are generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of the compound administered will usually be determined by a physician in view of relevant circumstances including the condition being treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0205] For example, to prepare a solid composition such as a tablet, the main active ingredient (e.g., a crystalline form of the compound of formula (I) described herein) is mixed with a pharmaceutical excipient to form a solid preliminary formulation composition containing a homogeneous mixture of the compounds of the present disclosure. When referring to these preliminary formulation compositions being homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0206] The tablets or pills of the present disclosure can provide a dosage form that provides the advantage of long-term action or can be formulated by coating or other means to protect from the acidic state of the stomach. For example, a tablet or pill can include an inner administration component and an outer administration component, the latter being in the form of a coating that covers the former. The two components can be separated by an enteric layer that is resistant to disintegration in the stomach and serves to allow the inner component to enter the duodenum intact or be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, such materials including many polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0207] Compositions for inhalation or insufflation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. Liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by the oral or nasal respiratory route for local or systemic effects. Preferably, the composition in a pharmaceutically acceptable solvent can be nebulized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0208] In some embodiments, the pharmaceutical composition comprises a crystalline form of the compound of formula (I) and a pharmaceutically acceptable carrier.

[0209] Treatment method In various embodiments, the present disclosure provides a method for treating or reducing the severity of a disease or condition associated with cell proliferation in a patient (e.g., cancer), the method comprising administering to the subject a crystalline form of a compound of formula (I) according to the present disclosure.

[0210] In various embodiments, provided herein is a method for treating or reducing the severity of a disease or condition associated with cell proliferation in a patient (e.g., cancer), the method comprising administering to the subject an effective amount of a crystalline form of a compound of formula (I) according to the present disclosure.

[0211] In various embodiments, provided herein is a method for treating or reducing the severity of a disease or condition associated with cell proliferation in a patient (e.g., cancer), the method comprising administering to the subject an effective amount of an anhydrous crystalline form of a compound of formula (I) described herein.

[0212] In various embodiments, provided herein is a method for treating or reducing the severity of a disease or condition associated with cell proliferation in a patient (e.g., cancer), the method comprising administering to the subject an effective amount of a crystalline acetone solvate of a compound of formula (I) described herein.

[0213] In various embodiments, provided herein is a method for treating or reducing the severity of a disease or condition associated with cell proliferation in a patient (e.g., cancer), the method comprising administering to the subject an effective amount of a crystalline p-dioxane solvate of a compound of formula (I) described herein.

[0214] In various embodiments, provided herein is a method of treating or reducing the severity of a disease or condition associated with cell proliferation (e.g., cancer) in a patient, the method comprising administering to the subject an effective amount of a crystalline tetrahydrofuran solvate of a compound of formula (I) described herein.

[0215] In various embodiments, provided herein is a method of treating or reducing the severity of a disease or condition associated with cell proliferation (e.g., cancer) in a patient, the method comprising administering to the subject an effective amount of an acetone solvate crystal citrate of a compound of formula (I) described herein.

[0216] In various embodiments, provided herein is a method of treating or reducing the severity of a disease or condition associated with cell proliferation (e.g., cancer) in a patient, the method comprising administering to the subject an effective amount of an acetonitrile solvate crystal citrate of a compound of formula (I) described herein.

[0217] In various embodiments, provided herein is a method of treating or reducing the severity of a disease or condition associated with cell proliferation (e.g., cancer) in a patient, the method comprising administering to the subject an effective amount of an anhydrous crystal citrate of a compound of formula (I) described herein.

[0218] As used herein, the term "disease or condition associated with cell proliferation" means any disease or other adverse condition known to involve cell proliferation. Thus, certain embodiments of the present disclosure relate to treating or reducing the severity of one or more diseases known to involve cell proliferation. 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.

[0219] In certain embodiments, administration of the crystalline forms of the present disclosure (e.g., crystalline forms of the compounds of formula (I) described herein) arrests mitosis. In some embodiments, mitotic arrest is defined as a 10 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 20 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 30 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 40 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 50 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 60 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 70 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as an 80 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 90 - 100% decrease in mitosis. In some embodiments, mitotic arrest is defined as a 100% decrease in mitosis.

[0220] In certain embodiments, the crystalline forms and compositions described herein by the methods of the present disclosure can be administered using any amount and any route of administration effective to treat cancer or reduce its severity. The exact amount required varies for each subject depending on the subject's species, age, and general condition, the severity of the infection, the particular agent, its mechanism of administration, and the like. The crystalline forms of the present disclosure are preferably formulated in unit dosage forms for ease of administration and uniformity of dosage.

[0221] 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 lymphoma. In certain embodiments, the blood cancer is leukemia. In certain embodiments, the blood cancer is myeloma.

[0222] In certain embodiments, the cancer is a non-blood cancer. In certain embodiments, the non-blood cancer is a sarcoma or carcinoma. In certain embodiments, the non-blood cancer is a sarcoma. In certain embodiments, the non-blood cancer is a carcinoma.

[0223] In certain embodiments, the subject experiences an increase in T cell activation, an increase in T cell proliferation, a decrease in T cell exhaustion, a decrease in T cell anergy, and a decrease in T cell tolerance, one or more of which occur after administration of the crystalline form of the present disclosure. In some embodiments, administering the crystalline form of the present disclosure to a patient in need thereof results in an increase in T cell activation, an increase in T cell proliferation, a decrease in T cell exhaustion, a decrease in T cell anergy, and a decrease in T cell tolerance, one or more of which occur.

[0224] In certain embodiments, the subject has increased NK cell activation. In certain embodiments, the increase in NK cell activation includes an increase in cytokine production.

[0225] In certain embodiments, the pharmaceutically acceptable compositions of the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), buccally, by oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the crystalline form of the present disclosure can be administered orally or parenterally one or more times a day at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, based on the subject's body weight, to obtain the desired therapeutic effect.

[0226] In certain embodiments, one or more additional therapeutic agents may also be administered in combination with a crystalline form of a compound of formula (I) disclosed herein. In certain embodiments, the crystalline form of a 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 a compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered simultaneously, sequentially, or within a defined period of time. In certain embodiments, the crystalline form of a compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered within 5 hours of each other. In certain embodiments, the crystalline form of a 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 a compound of formula (I) disclosed herein and one or more additional therapeutic agents may be administered within 1 week of each other.

[0227] In certain embodiments, the crystalline form of a compound of formula (I) disclosed herein and one or more additional therapeutic agents may be formulated into a single dosage form (e.g., a fixed-dose combination).

Examples

[0228] The representative examples that follow are intended to be useful in illustrating the present disclosure and are not intended to limit, nor should they be construed as limiting, the scope of the present disclosure. Abbreviations ACN Acetonitrile DCM Dichloromethane DIPE Diisopropyl ether DSC Differential scanning calorimetry DVS Dynamic vapor sorption EtOAc Ethyl acetate EtOH Ethanol IPA Isopropanol IPOAc Isopropyl acetate MeOH Methanol MBTE Methyl t-butyl ether 11H NMR Proton Nuclear Magnetic Resonance TGA Thermogravimetric Analysis THF Tetrahydrofuran XRD X-ray Diffraction XRPD X-ray Powder Diffraction wt. Weight

[0229] Example 1 - Analysis Method (i) XRPD The XRPD data provided herein was collected on a PANalytical X’Pert PRO MPD diffractometer using an incident beam of Cu radiation generated by an Optix long fine focus source. An elliptically graded multilayer mirror was used to focus the Cu Kα X-rays onto the detector through the specimen. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the position of the Si 111 peak. The specimen of the sample was sandwiched between 3-μm thick films and analyzed in transmission geometry. A beam stop and short anti-scatter extensions were used to minimize the background generated by air. Soller slits were used on both the incident and diffracted beams to minimize the spread from axial divergence. A scanning position-sensitive detector (X’Celerator) located 240 mm from the specimen, and Data Collector software v.5.5 were used to collect the diffraction pattern.

[0230] (ii) Identification of XRPD peaks In most situations, peaks within a range of up to approximately 30° 2θ were selected. A rounding algorithm was used to round each peak to the nearest 0.1° 2θ. The position (° 2θ) of the peaks along the x-axis in both the figures and tables was determined using proprietary software and rounded to one decimal place. The variation in peak positions was given within ±0.2° 2θ based on the recommendations outlined in the USP regarding the variation in X-ray powder diffraction. For the d-spacing list, the wavelength used to calculate the d-spacing was 1.5405929 Å, Cu-K α1 wavelength. The variability associated with the estimated d-spacing values was calculated from the USP recommendations for each d-spacing and provided in each data table.

[0231] (iii) Indexing of XRPD data The XRPD patterns of the crystalline forms described in Examples 3 to 8 were indexed using X’Pert High-Score Plus 2.2a (2.2.1). When the indexing of the pattern was successful, unless otherwise stated, it indicated that the sample was mainly composed of a single crystal phase or was composed of only a single crystal phase. The assigned extinction symbols, unit cell parameters, and space groups consistent with the derived quantities were tabulated.

[0232] (iv) Single crystal X-ray diffraction The standard uncertainty was described in the crystallographic bracket notation. For example, 0.123(4) corresponds to 0.123 ± 0.004.

[0233] (a) Data collection Approximately 0.27 × 0.04 × 0.03 mm 3 The pale orange needles of the anhydrous form of the compound of formula (I) (described in Example 2) were randomly oriented and attached to a polymer loop. Preliminary tests and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (Cu K = 1.54184 Å) and a Dectris Piratus3 R 200K hybrid pixel array detector.

[0234] The cell constants and orientation matrices for data collection were obtained from least-squares refinement using the setting angles of 7350 reflections in the range of 4.3060° < θ < 75.1220°. The space group was determined to be P212121 (International Table Number 19) by the program CrysAlisPro (CrysAlisPro 1.171.41.93a (Rigaku Oxford Diffraction, 2020)).

[0235] Data were collected at room temperature up to a maximum diffraction angle (2θ) of 151.71°.

[0236] (b) Data reduction The frame was integrated with CrysAlisPro. A total of 13966 reflections were collected, of which 5799 were unique. Lorentz and polarization corrections were applied to the data. The linear absorption coefficient is 0.762 mm for Cu Kα radiation. -1 Experimental absorption corrections using CrysAlisPro were applied. The transmission factors ranged from 0.951 to 1.000. The intensities of equivalent reflections were averaged. The agreement factor for the averaging was 2.11% based on intensity.

[0237] (c) Structure analysis and refinement The structure was solved by the direct method using Shelxt (Sheldrick, G. M. Acta Cryst. 2015, A71, 3 - 8). The remaining atoms were located by subsequent difference Fourier syntheses. The structure was refined using Shelxl - 2014 (Sheldrick, G. M. Acta Cryst., 2008, A64, 112 - 122). Hydrogen atoms were included in the refinement but were restrained to ride on their parent atoms. The structure was refined by full - matrix least - squares minimization of the function: TIFF2025522079000022.tif8128 with the weight w defined as 1 / [σ 2 (F o 2 )+(0.0834P) 2 +(0.2745P)] where P=(F o 2 +2F c 2 ) / 3).

[0238] The scattering factors were obtained from "International Tables for Crystallography" (International Tables for Crystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.1.4.). Of the 5799 reflections used for refinement, only 5239 reflections with intensities [I>2(I)] greater than twice the uncertainty were used for the calculation of the fit residual R. The final cycle of refinement included 354 variable parameters, 0 restraints, and the following unweighted and weighted agreement factors respectively: Converged to TIFF2025522079000023.tif18128.

[0239] The standard deviation of the observations per unit weight (goodness of fit) was 1.05. The highest peak in the final difference Fourier was 0.315 e / Å 3 in electron density. The minimum negative peak had a value of -0.255 e / Å 3 .

[0240] (d) Calculated XRPD pattern Using Mercury (Macrae, C.F., Edgington, P.R., McCabe, P.P., Pidcock, E., Shields, G.P., Taylor, R., Towler, M. and van de Streek, J., J. Appl. Cryst., 2006, 39, 453 - 457.), the calculated XRPD pattern was generated for Cu radiation, as well as the atomic coordinates, space group, and unit cell parameters from the single crystal structure.

[0241] (e) Atomic displacement ellipsoids and packing diagrams The atomic displacement ellipsoid diagrams were created using Mercury. The atoms are represented by anisotropic thermal ellipsoids at a probability of 50%.

[0242] (v) 1 H NMR The nuclear magnetic resonance spectrum of the solution was obtained using an Avance 600 MHz NMR spectrometer. Samples of the crystalline forms described herein were prepared by dissolving approximately 4 - 7 mg of the sample in dimethyl sulfoxide - d6 containing trimethylsilane.

[0243] (vi) DSC / TGA 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 nitrogen at a flow rate of 50 mg / mL. The normal procedure includes heating from ambient temperature to 350 °C at a heating rate of 10 °C / min.

[0244] (vii) DVS Water vapor adsorption data was collected using a Surface Measurement System DVS Intrinsic device. The samples were not dried before analysis. Adsorption and desorption data were collected under nitrogen purge in 10% RH increments over the range of 5% - 95% RH. The equilibrium criterion used for analysis was a change of less than 0.0100 wt% within 5 minutes with a maximum equilibrium time of 3 hours. TIFF2025522079000024.tif57165

[0245] Example 2 - Anhydrous Crystal Form of the Compound of Formula (I) (i) Preparation of anhydrous crystalline form The anhydrous crystal 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 and placed in a pre - heated (60 °C) vial. The vial was capped and the sample was placed in a freezer at - 15 to - 25 °C. Solids were precipitated from the solution and isolated by syringe filtration.

[0246] Single crystals of the 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 placed at ambient temperature for cooling. Suitable single crystals were then harvested and analyzed.

[0247] (ii) Characterization of anhydrous crystalline form The XRPD pattern of the anhydrous crystalline form of the compound of formula (I) is provided in Figure 1. The tabular characteristics of the XRPD pattern in Figure 1 are provided in Table 9, which lists the diffraction angle 2θ, d-spacing [Å], and relative intensity (expressed as a percentage relative to the strongest peak).

[0248] The anhydrous crystalline form of the compound of formula (I) dissolved in dimethylsulfoxide-d6 containing trimethylsilane 1 The 1H NMR spectrum is provided in Figure 3. 1 The 1H NMR spectrum was consistent with the structure of the compound of formula (I).

[0249] The DSC thermogram of the anhydrous crystalline form of the compound of formula (I) is provided in Figure 4. The DSC thermogram showed an endothermic event with an onset value of about 175.5 °C and a peak maximum value of about 178.2 °C.

[0250] The TGA thermogram of the anhydrous crystalline form of the compound of formula (I) is provided in Figure 4. Very little weight loss was observed (less than 0.1 wt%), indicating that the crystalline form is anhydrous.

[0251] 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 showed a 0.4% weight increase or 0.1 mol of water per mol of API at relative humidities (RH) from 5% to 95%. The increased weight decreased upon desorption, and the hysteresis was very small. TIFF2025522079000025.tif241165TIFF2025522079000026.tif230165TIFF2025522079000027.tif46165

[0252] A suitable single crystal of the anhydrous crystalline form of the compound of formula (I) was selected and analyzed by single crystal X-ray diffraction. The approximate dimensions were 0.27×0.04×0.03 mm 3 The pale orange needles of were attached in a random orientation to a polymer loop. The unit cell parameters of the anhydrous crystalline form, as well as the data collection method and structure refinement method, are shown in Table 10.

[0253] The quality of the obtained structure is high, as indicated by a fit residual R of 0.0456 (4.56%). R-factors in the range of 2% - 6% are cited as being the most reliably determined structures (Glusker, Jenny Pickworth; Trueblood, Kenneth N. Crystal Structure Analysis: A Primer, 3 rd ed.; Oxford University press: New York, 2010; p.97.). An atomic displacement ellipsoid diagram of the anhydrous crystalline form is 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 overlay of the XRPD pattern of the anhydrous crystalline form calculated from the single crystal XRD data and the experimental XRPD pattern is located in Figure 30. The experimental XRPD pattern and the calculated XRPD pattern are in good agreement. TIFF2025522079000028.tif236165TIFF2025522079000029.tif31165

[0254] (iii) Solubility determination An aliquot of various solvents was added to the anhydrous crystalline form of the compound of formula (I) in the measured amount, at various temperatures, with sonication or while stirring. Solubility was calculated based on the total amount of solvent used to obtain the solution, and the actual solubility may be higher due to the volume of the solvent portion utilized or the slowness of the dissolution rate. If no dissolution occurred as determined by visual evaluation, the value was reported as "<". If dissolution occurred with the first aliquot, the value was reported as ">".

[0255] Table 11 shows the solubility of the anhydrous crystalline form in various solvents. TIFF2025522079000030.tif238165

[0256] Example 3 - Crystalline Acetone Solvate of the Compound of Formula (I) (i) Preparation of crystalline acetone solvate 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.

[0257] (ii) Characterization of crystalline acetone solvate The XRPD pattern of the crystalline acetone solvate of the compound of formula (I) is provided in Figure 6. The tabular form characteristics of the XRPD pattern in Figure 6 are provided in Table 12, which lists the diffraction angle 2θ, d-spacing [Å], and relative intensity (expressed as a percentage relative to the strongest peak).

[0258] The 1 1H NMR spectrum of the crystalline acetone solvate of the compound of formula (I) dissolved in dimethyl sulfoxide - d6 containing trimethylsilane is provided in Figure 8. 1 The 1H NMR spectrum was consistent with the structure of the compound of formula (I) and contained approximately 1 mole of acetone.

[0259] The DSC thermogram of the crystalline acetone solvate of the compound of formula (I) is provided in Figure 9. The DSC thermogram showed two endothermic events: (1) an endothermic event with an onset value of about 89.9 °C and a peak maximum value of about 100.1 °C, and (2) an endothermic event with a peak maximum value of about 173.1 °C.

[0260] The TGA thermogram of the crystalline acetone solvate of the compound of formula (I) is provided in Figure 9. The data showed a 5.3% weight loss from 61 °C to 121 °C, which corresponded to approximately 0.5 moles of acetone. TIFF2025522079000031.tif240165TIFF2025522079000032.tif239165TIFF2025522079000033.tif94165

[0261] The XRPD pattern of the crystalline acetone solvate of the compound of formula (I) was successfully indexed (Figure 7). The volume from the unit cell was shown to be large enough to contain 1 mole of acetone per molecule of the compound of formula (I) (Table 13). TIFF2025522079000034.tif95165

[0262] Example 4 - Crystalline p-dioxane solvate of the compound of formula (I) (i) Preparation of crystalline p-dioxane solvate 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 at 55 °C in a mixture of heptane (0.5 ml) and p-dioxane (0.5 ml). The resulting suspension was stirred at ambient temperature for 6 days. The solid was isolated by syringe filtration.

[0263] 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 and placed into a pre-heated (60 °C) vial. The vial was capped and the sample was cooled to ambient temperature at 6 °C / hour. The solid was isolated by syringe filtration.

[0264] (ii) Characterization of crystalline p-dioxane solvate The XRPD pattern of the crystalline p-dioxane solvate of the compound of formula (I) is provided in Figure 10. The tabular characteristics of the XRPD pattern in Figure 10 are provided in Table 14, which lists the diffraction angle 2θ, d-spacing [Å], and relative intensity (expressed as a percentage relative to the strongest peak).

[0265] The 1 H NMR spectrum of the crystalline p-dioxane solvate of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is provided in Figure 12. 1H The NMR spectrum was consistent with the structure of the compound of formula (I) and contained approximately 0.9 mol of p-dioxane.

[0266] The DSC thermogram of the crystalline p-dioxane solvate of the compound of formula (I) is provided in Figure 13. The DSC thermogram showed a single endothermic event with an onset value of approximately 94.2 °C and a peak maximum value of approximately 106.3 °C.

[0267] The TGA thermogram of the crystalline p-dioxane solvate of the compound of formula (I) is provided in Figure 13. The data showed a 3.9% weight loss from 51 °C to 120 °C, corresponding to 0.2 mol of p-dioxane. TIFF2025522079000035.tif240165TIFF2025522079000036.tif222165TIFF2025522079000037.tif47165

[0268] The XRPD pattern of the crystalline p-dioxane solvate of the compound of formula (I) was successfully indexed (Figure 11). The volume from the unit cell indicated that it could contain 1 mol of p-dioxane per mol of the compound of formula (I) (Table 15). TIFF2025522079000038.tif95165

[0269] Example 5 - Crystalline THF Solvate of the Compound of Formula (I) (i) Preparation of crystalline THF solvate 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.

[0270] 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 and placed in a pre-heated (60 °C) vial. The sample was then cooled to ambient temperature at 6 °C / hour. The solid was isolated by syringe filtration.

[0271] (ii) Characterization of crystalline THF solvate The XRPD pattern of the crystalline THF solvate of the compound of formula (I) is provided in Figure 14. The tabular form characteristics of the XRPD pattern in Figure 14 are provided in Table 16, which lists the diffraction angle 2θ, d-spacing [Å], and relative intensity (expressed as a percentage relative to the strongest peak).

[0272] The 1 1H NMR spectrum of the crystalline THF solvate of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane is provided in Figure 16. 1H The 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.

[0273] The DSC thermogram of the crystalline THF solvate of the compound of formula (I) is provided in Figure 17. The DSC thermogram showed a single endothermic event with an onset value of approximately 84.8 °C and a peak maximum value of approximately 97.5 °C.

[0274] The TGA thermogram of the crystalline THF solvate of the compound of formula (I) is provided in Figure 17. The data showed a 4.5% weight loss or 0.4 moles of THF from 56 °C to 112 °C. TIFF2025522079000039.tif240165TIFF2025522079000040.tif211165

[0275] The XRPD pattern of the crystalline THF solvate of the compound of formula (I) was successfully indexed (Figure 15). The volume from the unit cell indicated that it may contain 1 mole of THF per mole of the compound of formula (I) (Table 17). TIFF2025522079000041.tif95165

[0276] Example 6 - Acetone Solvate Crystal Citrate of the Compound of Formula (I) (i) Preparation of acetone solvated crystalline citrate The acetone solvate crystal citrate of the compound of formula (I) was prepared as follows: The amorphous form of the compound of formula (I) was prepared by column chromatography of the compound of (I) followed by evaporation. Then, 71 mg of the amorphous solid of the compound of formula (I) and 1 molar equivalent of citric acid (25 mg) were stirred in acetone (0.5 ml) at ambient temperature for 1 day. A thick slurry was obtained and additional acetone (0.5 ml) was added. The mixture was stirred at ambient temperature for an additional 3 days. The solid was isolated by syringe filtration using a Swinnex filtration assembly.

[0277] (ii) Characterization of acetone solvated crystalline citrate The XRPD pattern of the acetone solvate crystal citrate of the compound of formula (I) is provided in Figure 18. The tabular characteristics of the XRPD pattern in Figure 18 are provided in Table 18, which lists the diffraction angle 2θ, d-spacing [Å], and relative intensity (expressed as a percentage relative to the strongest peak).

[0278] 1H NMR spectrum of the acetone solvate crystal citrate of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 is provided in Figure 20. 1HThe NMR spectrum was consistent with the structure of the compound of formula (I), and approximately 1 mol of citric acid. Approximately 2 mol of acetone was also observed in the spectrum, but it should be noted that overlap of the peaks of acetone and the compound of formula (I) was observed, and the actual amount of acetone could be less than 2 mol.

[0279] The DSC thermogram of the acetone solvate crystal citrate of the compound of formula (I) is provided in Figure 21. The DSC thermogram showed a single endothermic event with an onset value of about 109.8 °C and a peak maximum value of about 117.4 °C.

[0280] The TGA thermogram of the acetone solvate crystal citrate of the compound of formula (I) is provided in Figure 21. The data showed a 7.0% weight loss from 46 °C to 131 °C, which is considered to be due to acetone (0.9 mol). TIFF2025522079000042.tif240165TIFF2025522079000043.tif228165TIFF2025522079000044.tif47165

[0281] The XRPD pattern of the acetone solvate crystal citrate of the compound of formula (I) was successfully indexed (Figure 19). The volume from the unit cell indicated a solvate monocitrate. (Table 19). TIFF2025522079000045.tif95165

[0282] Example 7 - ACN Solvate Crystal Citrate of the Compound of Formula (I) (i) Preparation of ACN solvated crystalline citrate The ACN solvate crystal citrate 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 approximately 2 weeks. The solid was isolated by syringe filtration using a Swinnex filtration assembly.

[0283] (ii) Characterization of ACN solvated crystalline citrate The XRPD pattern of the ACN solvate crystal citrate salt of the compound of formula (I) is provided in Figure 22. The tabular characteristics of the XRPD pattern of Figure 22 are provided in Table 20, which lists the diffraction angle 2θ, d-spacing [Å], and relative intensity (expressed as a percentage relative to the strongest peak). TIFF2025522079000046.tif240165TIFF2025522079000047.tif239165TIFF2025522079000048.tif135165

[0284] The XRPD pattern of the ACN solvate crystal citrate salt of the compound of formula (I) was successfully indexed (Figure 23). The volume from the unit cell indicated a solvate monocitrate salt. (Table 21). TIFF2025522079000049.tif95165

[0285] Example 8 - Anhydrous Crystal Citrate Salt of the Compound of Formula (I) (i) Preparation of anhydrous crystalline citrate The anhydrous crystal citrate salt of the compound of formula (I) was prepared as follows: The ACN solvate crystal citrate salt of the compound of formula (I) (see Example 7) was placed in a vial and capped with pierced aluminum foil. The sample was then placed in a vacuum oven at ambient temperature for 1 day.

[0286] Alternative method: The ACN solvate crystal citrate salt of the compound of formula (I) (see Example 7) was placed in a vial and capped with pierced aluminum foil. The sample was then placed in a vacuum oven at 44 °C for 1 day.

[0287] (ii) Characterization of anhydrous crystalline citrate The XRPD pattern of the anhydrous crystal citrate salt of the compound of formula (I) is provided in Figure 24. The tabular characteristics of the XRPD pattern of Figure 24 are provided in Table 22, which lists the diffraction angle 2θ, d-spacing [Å], and relative intensity (expressed as a percentage relative to the strongest peak).

[0288] The anhydrous crystalline form of the compound of formula (I) dissolved in dimethyl sulfoxide-d6 containing trimethylsilane 1 The 1H NMR spectrum is provided in Figure 26. 1H The NMR spectrum was consistent with the structure of the compound of formula (I) with approximately 1 mole of citric acid.

[0289] The DSC thermogram of the anhydrous crystalline form of the compound of formula (I) is provided in Figure 28. The DSC thermogram showed an endothermic event with a peak maximum at about 131.5 °C. A second endotherm was observed immediately after this event, which is thought to be due to decomposition.

[0290] The TGA thermogram of the anhydrous crystalline form of the compound of formula (I) is provided in Figure 27. A very small weight loss was observed (less than 0.1 wt%), indicating that the crystalline form is anhydrous.

[0291] The water adsorption isotherm of the anhydrous crystalline form of the compound of formula (I) is provided in Figure 29. The isotherm showed a weight increase of 1.2 wt% at RH from 5% to 74% and 14.6 wt% at RH from 75% to 96%. Significant hysteresis was observed upon desorption, and the sample showed signs of partial deliquescence. XRPD analysis of the sample after DVS showed that the material was amorphous (Figure 31). TIFF2025522079000050.tif240165TIFF2025522079000051.tif164165

[0292] The XRPD pattern of the anhydrous crystalline citrate of the compound of formula (I) was successfully indexed (Figure 25). The volume from the unit cell was consistent with the anhydrous monocitrate (Table 23). TIFF2025522079000052.tif95165

[0293] (iii) Water solubility of anhydrous crystalline citrate The water solubility of the anhydrous crystalline citrate of the compound of formula (I) at 25 °C was determined to be greater than 111 mg / ml by addition of solvent (the same solubility determination method as described in Example 2).

[0294] Incorporation by reference All disclosures of each of the patent documents and scientific papers referred to in this specification are incorporated by reference for all purposes.

[0295] Equivalents The present disclosure can be embodied in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments are not intended to limit the present disclosure described herein, but should be regarded as illustrative in all respects. Accordingly, the scope of the present disclosure is indicated by the appended claims rather than the foregoing description, and all modifications within the meaning and scope of equivalents of the claims are intended to be included herein.

Claims

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

2. The crystalline form according to claim 1, which is a crystalline salt.

3. The crystalline form according to claim 1 or 2, which is a non-solvated crystalline form.

4. The crystalline form according to claim 1 or 2, which is a crystalline solvate.

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

6. The crystalline form according to claim 5, wherein 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.

7. The crystalline form according to claim 5 or 6, wherein the XRPD pattern further comprises one or more peaks selected from 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°, 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 according to any one of claims 5 to 7, characterized by an XRPD pattern substantially the same as that shown in Figure 1.

9. Existing in the orthorhombic system, P2 １ 2 １ 2 １ The crystal form according to any one of claims 5 to 8, having a space group.

10. The following crystallographic unit cell parameters: The crystalline form according to claim 9, characterized thereby.

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

12. The crystalline form according to any one of claims 5 to 11, which is an anhydrous crystalline form.

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

14. The crystalline solvate according to claim 13, which is an acetone solvate, a p-dioxane solvate, or a tetrahydrofuran solvate.

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

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

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

18. The crystalline acetone solvate according to claim 17, wherein the XRPD pattern further comprises one or more peaks selected from 2θ 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°.

19. The crystalline acetone solvate according to claim 17 or 18, wherein the XRPD pattern further comprises one or more peaks selected from 2θ 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°, 24.0° ± 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°.

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

21. Existing in the orthorhombic system, P2 １ 2 １ 2 １ The crystalline acetone solvate according to any one of claims 15 to 20, having a space group.

22. The following crystallographic unit cell parameters: Characterized by, the crystalline acetone solvate according to claim 21.

23. The crystalline acetone solvate according to any one of claims 15 to 22, characterized by one or more endotherms having peak maxima selected from about 100 °C, about 107 °C, and about 173 °C when determined by differential scanning calorimetry. **Claim 24** A compound of formula (I): The crystalline p-dioxane solvate of **Claim 25** The crystalline p-dioxane solvate according to claim 24, wherein the p-dioxane solvate is a monop-dioxane solvate. **Claim 26** The crystalline p-dioxane solvate according to claim 24 or 25, characterized by an X-ray powder diffraction (XRPD) pattern comprising one or more peaks selected from 2θ of 6.3° ± 0.2°, 16.0° ± 0.2°, 17.0° ± 0.2°, and 21.8° ± 0.2°. **Claim 27** The crystalline p-dioxane solvate according to claim 26, wherein the XRPD pattern further comprises one or more peaks selected from 2θ of 11.8° ± 0.2°, 14.2° ± 0.2°, 17.5° ± 0.2°, 20.0° ± 0.2°, and 21.6° ± 0.2°. **Claim 28** The crystalline p-dioxane solvate according to claim 26 or 27, wherein the XRPD pattern further comprises one or more peaks selected from 2θ 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°, 21.0° ± 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°. **Claim 29** The crystalline p-dioxane solvate according to any one of claims 26 to 28, characterized by an XRPD pattern substantially the same as that shown in Figure 10. **Claim 30** Existing in the orthorhombic system, P2 １ 2 １ 2 １ The crystalline p-dioxane solvate according to any one of claims 24 to 29, having a space group. **Claim 31** The following crystallographic unit cell parameters: The crystalline p-dioxane solvate according to claim 30, characterized by **Claim 32** The crystalline p-dioxane solvate according to any one of claims 24 to 31, characterized by an endotherm having a peak onset of about 94 °C as determined by differential scanning calorimetry.

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

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

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

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

37. The crystalline tetrahydrofuran solvate according to claim 35 or 36, wherein the XRPD pattern further comprises one or more peaks selected from 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 according to any one of claims 35 to 37, characterized by an XRPD pattern substantially the same as that shown in Figure 14.

39. Existing in the orthorhombic system, P2 １ 2 １ 2 １ The crystalline tetrahydrofuran solvate according to any one of claims 33 to 38, having a space group.

40. The following crystallographic unit cell parameters: The crystalline tetrahydrofuran solvate according to claim 39, characterized thereby.

41. The crystalline tetrahydrofuran solvate according to any one of claims 33 to 40, characterized by an endotherm having a peak onset of about 85 °C when determined by differential scanning calorimetry.

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

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

44. The crystalline citrate salt according to claim 43, wherein 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.

45. The crystalline citrate salt according to claim 43 or 44, wherein the XRPD pattern further comprises one or more peaks selected from 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 according to any one of claims 43 to 45, characterized by an XRPD pattern substantially the same as that shown in Figure 18.

47. Existing in the orthorhombic system, P2 １ 2 １ 2 １ The crystalline citrate according to any one of claims 42 to 46, having a space group.

48. The following crystallographic unit cell parameters: The crystalline citrate salt according to claim 47, characterized thereby.

49. The crystalline citrate salt according to any one of claims 42 to 48, characterized by an endotherm having a peak onset of about 110 °C when determined by differential scanning calorimetry.

50. The crystalline citrate salt according to any one of claims 42 to 49, which is an acetone solvate crystalline citrate salt.

51. The crystalline citrate according to claim 42, characterized by an XRPD pattern comprising one or more peaks selected from 2θ of 5.1 ± 0.2°, 6.9 ± 0.2°, 17.8 ± 0.2°, and 18.7 ± 0.2°.

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

53. The crystalline citrate according to claim 51 or 52, wherein the XRPD pattern further comprises one or more peaks selected from 2θ 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°.

54. The crystalline citrate according to any one of claims 51 to 53, characterized by an XRPD pattern substantially the same as that shown in Figure 22.

55. It exists in the orthorhombic system and has the space group P2 １ 2 １ 2 １ The crystalline citrate according to any one of claims 42 and 51 to 54.

56. The following crystallographic unit cell parameters: The crystalline citrate according to claim 55, characterized by the above.

57. The crystalline citrate according to any one of claims 42 and 51 to 56, which is an acetonitrile solvate crystalline citrate.

58. The crystalline citrate according to claim 42, characterized by an XRPD pattern comprising one or more peaks selected from 2θ of 5.3 ± 0.2°, 6.4 ± 0.2°, 17.6 ± 0.2°, and 23.0 ± 0.2°.

59. The crystalline citrate according to claim 58, wherein 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.

60. The crystalline citrate according to claim 58 or 59, wherein 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.

61. The crystalline citrate according to any one of claims 58 to 60, characterized by an XRPD pattern substantially the same as that shown in Figure 24.

62. It exists in the orthorhombic system and has the space group P2 １ 2 １ 2 １ The crystalline citrate according to any one of claims 42 and 58 to 61.

63. The following crystallographic unit cell parameters: The crystalline citrate according to claim 62, characterized by the above.

64. The crystalline citrate according to any one of claims 42 and 58 to 63, characterized by an endotherm having a peak maximum of about 131 °C as determined by differential scanning calorimetry.

65. The crystalline citrate according to any one of claims 42 and 58 to 64, which is an anhydrous citrate.

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

67. A crystalline form according to any one of claims 1 to 12, a crystalline solvate according to any one of claims 13 to 41, or a crystalline citrate according to any one of claims 42 to 66, and a pharmaceutically acceptable excipient comprising a pharmaceutical composition.

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

69. The method according to claim 68, wherein the disease or condition associated with cell proliferation is hyperplasia or cancer.

70. The method according to claim 69, wherein the cancer is a blood cancer.

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

72. The method according to claim 69, wherein the cancer is a non-blood cancer.

73. The method according to claim 72, wherein the non-blood cancer is a sarcoma or a carcinoma.

74. The subject has one or more of an increase in T cell activation, an increase in T cell proliferation, a decrease in T cell exhaustion, a decrease in T cell anergy, and a decrease in T cell tolerance after administration of the crystalline form according to any one of claims 1 to 12, the crystalline solvate according to any one of claims 13 to 41, the crystalline citrate according to any one of claims 42 to 66, or the pharmaceutical composition according to claim 67. The method according to any one of claims 68 to 73.

75. The method according to claim 74, wherein the increase in T cell activation includes an increase in cytokine production.

76. The method according to any one of claims 68 to 73, wherein the subject has an increase in NK cell activation.

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