Solid freebase forms of 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol for inhibiting NLRP3 and uses thereof

Abstract

To provide small molecules for modulating NLRP3 activity to treat various diseases and disorders.SOLUTION: The present disclosure relates to solid state forms of Compound 1 freebase. The present disclosure also relates to processes for the preparation of the solid state forms, pharmaceutical compositions comprising the forms, and the use thereof, e.g., in the treatment and prevention of disorders in which NLRP3 activity is implicated.SELECTED DRAWING: None

Description

Background Art

[0001] Innate immune responses are mediated by different types of receptors called pattern recognition receptors (PRRs). PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). When engaged, these receptors induce the activation of downstream inflammatory pathways that help resolve injury. However, in many cases, this activation is uncontrolled and can cause disease.

[0002] The inflammasome represents a class of PRRs that are important components of the innate immune response. Activation of the inflammasome induces a cascade of events that release IL-1β and IL-18 and promote an inflammatory form of cell death called pyroptosis, which is induced by the activation of Gasdermin. Pyroptosis is a distinct form of inflammatory cell death that causes the release of not only cytokines but also other intracellular components that promote a broader immune response in both the innate and adaptive immune systems. Thus, inflammasome activation is a major regulator of the inflammatory cascade.

[0003] NLRP3 is the most characterized inflammasome and has been shown to be important for innate immunity and the inflammatory response. While several other NLR complexes, such as NLRC4, are activated under very specific circumstances, NLRP3 can be activated by a number of stimuli and should be regarded as a sensor of intracellular homeostasis imbalance. Therefore, its exact function is indispensable. In addition to playing a role in host immune defense, dysregulation of NLRP3 has been linked to the etiology of many inflammatory disorders. These include genetic diseases such as cryopyrin-associated periodic syndrome (CAPS) caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, preclinical evidence has shown that overactivation of NLRP3 plays an important role in a variety of inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and many other autoinflammatory diseases. See, for example, Non-Patent Documents 1, 2, 3, and 4. Therefore, there is an unmet need in the art to develop small molecules to modulate NLRP3 activity for the treatment of various diseases and disorders.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

[0005] This disclosure provides a solid form of Compound 1 free base.

[0006] "Compound 1" is 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol and has the following structure.

Chemical formula

[0007] Compound 1 is an orally administrable and potent reversible small molecule inhibitor of NLRP3 that has been developed for the treatment of inflammatory diseases. Compound 1 is described as Compound 82 in Example 3 of PCT Application Publication No. WO2022 / 216971 and US11,319,319.

[0008] In some embodiments, the solid form of Compound 1 free base is an amorphous free base.

[0009] In some embodiments, the solid form of Compound 1 free base is a crystalline form.

[0010] In some embodiments, the solid form of Compound 1 free base is crystalline form V free base.

[0011] In some embodiments, the solid form of Compound 1 free base is crystalline form I free base.

[0012] In some embodiments, the solid form of Compound 1 free base is crystalline form II free base.

[0013] In some embodiments, the solid form of Compound 1 free base is crystalline form III free base.

[0014] In some embodiments, the solid form of Compound 1 free base is crystalline Form IV free base.

[0015] In some embodiments, a composition comprising a mixture of Compound 1 free base forms is provided. In some embodiments, the composition is a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0016] In some aspects, the present disclosure provides a pharmaceutical composition comprising a solid form of Compound 1 free base described herein and one or more pharmaceutically acceptable carriers.

[0017] In other aspects, a method of treating or preventing a disease or disorder is provided, comprising administering to a subject the forms described herein or the compositions described herein.

[0018] In some aspects, the present disclosure provides a method for preparing a solid form of Compound 1 free base. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

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MODE FOR CARRYING OUT THE INVENTION

[0020] Definitions Unless otherwise defined, the following terms used in this specification and the claims have the following meanings as described below.

[0021] Degree terms such as "about", "substantially similar", and "approximately" used in this specification mean a reasonable amount of deviation of the modified term such that the final result does not change significantly. These degree terms should be interpreted to include at least a ±5% deviation of the modified term if this deviation does not invalidate the meaning of the modified word.

[0022] "Form purity level" refers to the determination by solid-state NMR (ssNMR), vibrational (Raman) spectroscopy, and / or X-ray powder diffraction (XRPD) of the percentage purity level (w / w%) of a given form relative to other known solid forms (e.g., crystalline forms, amorphous forms) of the same compound. For methods of explaining the determination of purity levels, see, for example, Mingyue et al., TrAC Trends in Analytical Chemistry (2021) 135:116152 (ssNMR), Griffen et al., Journal of Pharmaceutical and Biomedical Analysis, (2016) 128:35-45 (Raman), and Dobelin, Powder Diffraction (2020) 35(4), 262-275 (XRPD). A "form purity level" of 95% or greater is considered to be "substantially free" of other known solid forms of the same compound.

[0023] "Pure phase" refers to the qualitative evaluation by XRPD of a given form using Cu K alpha radiation when measured at 25 °C, where characteristic non-overlapping signals associated with other crystalline forms of the same compound are not observed by XRPD. A "form purity level" of 100% of a given form determined by XRPD using Cu K alpha radiation when measured at 25 °C and the "pure phase" form of that given form are used interchangeably herein.

[0024] The term "stable" refers to a given form that maintains its form over a period of time, for example, at least one week under short-term stability test conditions (e.g., 40 °C ± 2 °C and 75% ± 5% relative humidity (RH)).

[0025] "Patient" or "subject" are used interchangeably herein and refer to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or macaque. In some embodiments, the patient or subject is a human.

[0026] "Effective amount" or "therapeutically effective amount" are used interchangeably herein and refer to an amount of the crystalline form of the compound 1 free base sufficient to provide a therapeutic benefit in the treatment of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder, in a subject in need thereof. An effective amount may include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effectiveness of another therapeutic agent. The effective amount of a compound may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0027] "Disease" or "disorder" are used interchangeably herein.

[0028] "Treating", "treat", or "treatment" describe the administration of the solid form of the compound 1 free base described herein to a subject in need thereof for the purpose of managing and caring for a disease or disorder in the subject, and includes alleviating the symptoms or complications of the disease or disorder, or eradicating the disease or disorder. The term "treating" may also include the treatment of cells in vitro, or of an animal model (in vivo). References to "treating" or "treatment" should be understood to include the alleviation of established symptoms of a disease or disorder in a subject in need thereof, and thus include: (1) delaying the appearance of at least one clinical or non-clinical symptom of a disease or disorder that develops in a subject afflicted with the disease or disorder, (2) arresting, halting, reducing, or delaying the continued development or recurrence of a disease in a subject (e.g., in the case of maintenance therapy), or at least one clinical or non-clinical symptom thereof, or (3) reducing or regressing a disease in a subject, i.e., causing regression of the disease or disorder, or at least one of its clinical or non-clinical symptoms.

[0029] As used herein, the terms "preventing", "prevent", or "protecting from" describe the management and care of a subject who may have or has a predisposition to a disease or disorder, but has not yet experienced or exhibited a clinical or non-clinical symptom of the disease or disorder, and who is in need of management and care for the purpose of preventing the occurrence of at least one clinical or non-clinical symptom of the disease or disorder in the subject, and includes the administration of a solid form of Compound 1 free base as described herein.

[0030] "Inhibiting", "inhibition", "inhibit", and "inhibitor" and the like refer to the ability of a solid form of Compound 1 free base to reduce, delay, stop, or prevent the activity of a specific biological process (e.g., NLRP3 activity) in cells relative to a vehicle.

[0031] The phrase "at least one" refers to one case or more than one case.

[0032] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article.

[0033] Unless otherwise indicated, the term "and / or" is used in the present disclosure to mean either "and" or "or".

[0034] "Solid form" refers to crystalline form and amorphous form.

[0035] The term "free base" of Compound 1 refers to the neutral non-ionized form of the compound. It is understood that the free base is not a salt.

[0036] The term "solvate" of Compound 1 refers to a crystalline form having at least one stoichiometric or non-stoichiometric amount of a solvent (non-water molecule) as part of the unit cell within the crystal lattice. "Non-solvated" and "not a solvate" are used interchangeably and refer to a form that does not contain solvent molecules.

[0037] The term "hydrate" of Compound 1 refers to a crystalline form having at least one stoichiometric or non-stoichiometric amount of water molecules as part of the unit cell within the crystal lattice. "Anhydrous" and "not a hydrate" are used interchangeably and refer to a form that does not contain water molecules.

[0038] "Slightly hygroscopic" means an increase in mass weight percentage of 0.2 wt% or more and less than 2 wt%, and "hygroscopic" means an increase in mass weight percentage of 2 wt% or more and less than 15 wt%, each related to an increase in water content determined by dynamic vapor sorption (DVS). "Deliquescent" means that sufficient water is absorbed to form a liquid. A mass weight percentage of less than 0.2 is considered "non-hygroscopic".

[0039] (i) Compound 1 free base This disclosure provides a solid form of Compound 1 free base.

[0040] As used herein, "Compound 1" refers to a compound having the structure shown below,

Chemical formula

[0041] In some embodiments, this solid form is a crystalline form of Compound 1 free base.

[0042] In some embodiments, the solid form is the amorphous form of Compound 1 free base.

[0043] In some embodiments, the solid form of Compound 1 is the crystalline Form V free base.

[0044] In some embodiments, the solid form of Compound 1 is the crystalline Form I free base.

[0045] In some embodiments, the solid form of Compound 1 is the crystalline Form II free base.

[0046] In some embodiments, the solid form of Compound 1 is the crystalline Form III free base.

[0047] In some embodiments, the solid form of Compound 1 is the crystalline Form IV free base.

[0048] In some embodiments, the solid form of Compound 1 is the crystalline Pattern A free base.

[0049] In some embodiments, the solid form of Compound 1 is the crystalline Pattern B free base.

[0050] In some embodiments, the solid form of Compound 1 is the crystalline Pattern C free base.

[0051] In some embodiments, Compound 1 is the amorphous Compound 1 free base.

[0052] In some embodiments, the solid form is a mixture of one or more solid forms of Compound 1 selected from amorphous free base, Form I free base, Form II free base, Form III free base, Form IV free base, and Form V free base.

[0053] In some embodiments, the solid form substantially does not contain amorphous Compound 1 free base.

[0054] In some embodiments, the solid form substantially does not contain the free base of crystal pattern A.

[0055] In some embodiments, the solid form substantially does not contain the free base of crystal pattern B.

[0056] In some embodiments, the solid form substantially does not contain the free base of crystal pattern C.

[0057] In some embodiments, the solid form is a stable form.

[0058] In some embodiments, the solid form is a pure phase form.

[0059] (a) X-ray powder diffraction (XRPD) characterization of the crystal form (i) Free base of crystal form V In some embodiments, the crystal form of compound 1 free base is the free base of crystal form V. In some embodiments, the free base of crystal form V is characterized by the XRPD pattern defined in section (a)(i) of this section.

[0060] In some embodiments, the crystal form of compound 1 free base, when measured at 25°C, is characterized by an XRPD pattern that includes a signal at 6.8 ± 0.2° 2θ using Cu K alpha radiation.

[0061] In some embodiments, the crystal form of compound 1 free base, when measured at 25°C, is characterized by an XRPD pattern that includes a signal at 11.7 ± 0.2° 2θ using Cu K alpha radiation.

[0062] In some embodiments, the crystal form of compound 1 free base, when measured at 25°C, is characterized by an XRPD pattern that includes signals at 6.8 ± 0.2 and 11.7 ± 0.2° 2θ using Cu K alpha radiation.

[0063] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern that includes signals at 6.8 ± 0.5, 18.9 ± 0.5, and 20.5 ± 0.5° 2θ (e.g., 6.8 ± 0.2, 18.9 ± 0.2, and 20.5 ± 0.2° 2θ (e.g., 6.8 ± 0.1, 18.9 ± 0.1, and 20.5 ± 0.1° 2θ (e.g., 6.8, 18.9, and 20.5° 2θ))) using Cu K alpha radiation.

[0064] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern that includes signals at 6.8 ± 0.5, 18.9 ± 0.5, and 22.9 ± 0.5° 2θ (e.g., 6.8 ± 0.2, 18.9 ± 0.2, and 22.9 ± 0.2° 2θ (e.g., 6.8 ± 0.1, 18.9 ± 0.1, and 22.9 ± 0.1° 2θ (e.g., 6.8, 18.9, and 22.9° 2θ)) using Cu K alpha radiation.

[0065] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern that includes signals at 6.8 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5° 2θ (e.g., 6.8 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2° 2θ (e.g., 6.8 ± 0.1, 20.5 ± 0.1, and 22.9 ± 0.1° 2θ (e.g., 6.8, 20.5, and 22.9° 2θ))) using Cu K alpha radiation.

[0066] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern that includes signals at 6.8 ± 0.5, 18.9 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5° 2θ, e.g., 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2° 2θ, e.g., 6.8 ± 0.1, 18.9 ± 0.1, 20.5 ± 0.1, and 22.9 ± 0.1° 2θ, e.g., 6.8, 18.9, 20.5, and 22.9° 2θ using Cu K alpha radiation.

[0067] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 11.7±0.5, 18.9±0.5, and 20.5±0.5° 2θ (e.g., 11.7±0.2, 18.9±0.2, and 20.5±0.2° 2θ (e.g., 11.7±0.1, 18.9±0.1, and 20.5±0.1° 2θ (e.g., 11.7, 18.9, and 20.5° 2θ))), when measured at 25 °C using Cu K alpha radiation.

[0068] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 11.7±0.5, 18.9±0.5, and 22.9±0.5° 2θ, e.g., 11.7±0.2, 18.9±0.2, and 22.9±0.2° 2θ, e.g., 11.7±0.1, 18.9±0.1, and 22.9±0.1° 2θ, e.g., 11.7, 18.9, and 22.9° 2θ, when measured at 25 °C using Cu K alpha radiation.

[0069] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 11.7±0.5, 20.5±0.5, and 22.9±0.5° 2θ (e.g., 11.7±0.2, 20.5±0.2, and 22.9±0.2° 2θ (e.g., 11.7±0.1, 20.5±0.1, and 22.9±0.1° 2θ (e.g., 11.7, 20.5, and 22.9° 2θ))), when measured at 25 °C using Cu K alpha radiation.

[0070] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 11.7±0.5, 18.9±0.5, 20.5±0.5, and 22.9±0.5° 2θ, e.g., 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ, e.g., 11.7±0.1, 18.9±0.1, 20.5±0.1, and 22.9±0.1° 2θ, e.g., 11.7, 18.9, 20.5, and 22.9° 2θ, when measured at 25 °C using Cu K alpha radiation.

[0071] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, and 22.9±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, and 22.9±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, and 22.9° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0072] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0073] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, 22.9±0.5, and 23.8±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, and 23.8±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, 22.9±0.1, and 23.8±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, 22.9, and 23.8° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0074] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, 22.9±0.5, and 26.5±0.5° 2θ, for example, 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, and 26.5±0.2° 2θ, for example, 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, 22.9±0.1, and 26.5±0.1° 2θ, for example, 6.8, 11.7, 18.9, 20.5, 22.9, and 26.5° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0075] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, 22.9±0.5, 23.8±0.5, and 26.5±0.5° 2θ (for example, 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ (for example, 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, 22.9±0.1, 23.8±0.1, and 26.5±0.1° 2θ (for example, 6.8, 11.7, 18.9, 20.5, 22.9, 23.8, and 26.5° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0076] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0077] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and further includes signals at one or more of 11.8±0.2, 13.7±0.2, 17.0±0.2, 19.6±0.2, 22.2±0.2, 22.5±0.2, 23.9±0.2, 25.4±0.2, 29.2±0.2, and 29.6±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0078] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 26.5±0.5° 2θ, such as 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and further includes signals at two or more of 11.8±0.2, 13.7±0.2, 17.0±0.2, 19.6±0.2, 22.2±0.2, 22.5±0.2, 23.9±0.2, 25.4±0.2, 29.2±0.2, and 29.6±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0079] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 26.5±0.5° 2θ, such as 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and further includes signals at three or more of 11.8±0.2, 13.7±0.2, 17.0±0.2, 19.6±0.2, 22.2±0.2, 22.5±0.2, 23.9±0.2, 25.4±0.2, 29.2±0.2, and 29.6±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0080] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 26.5±0.5° 2θ, for example, 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and further includes signals at four or more of 11.8±0.2, 13.7±0.2, 17.0±0.2, 19.6±0.2, 22.2±0.2, 22.5±0.2, 23.9±0.2, 25.4±0.2, 29.2±0.2, and 29.6±0.2° 2θ when measured at 25 °C using Cu K alpha radiation. 1 / 2

[0081] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, 22.9±0.5, 23.8±0.5, 23.9±0.5, and 26.5±0.5° 2θ (for example, 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, 23.9±0.2, and 26.5±0.2° 2θ (for example, 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, 22.9±0.1, 23.8±0.1, 23.9±0.1, and 26.5±0.1° 2θ (for example, 6.8, 11.7, 18.9, 20.5, 22.9, 23.8, 23.9, and 26.5° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0082] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 6.8 ± 0.5, 11.7 ± 0.5, 11.8 ± 0.5, 13.7 ± 0.5, 17.0 ± 0.5, 18.9 ± 0.5, 19.6 ± 0.5, 20.5 ± 0.5, 22.2 ± 0.5, 22.5 ± 0.5, 22.9 ± 0.5, 23.8 ± 0.5, 23.9 ± 0.5, 25.4 ± 0.5, 26.5 ± 0.5, 29.2 ± 0.5, and 29.6 ± 0.5 ° 2θ (e.g., 6.8 ± 0.2, 11.7 ± 0.2, 11.8 ± 0.2, 13.7 ± 0.2, 17.0 ± 0.2, 18.9 ± 0.2, 19.6 ± 0.2, 20.5 ± 0.2, 22.2 ± 0.2, 22.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, 23.9 ± 0.2, 25.4 ± 0.2, 26.5 ± 0.2, 29.2 ± 0.2, and 29.6 ± 0.2 ° 2θ (e.g., 6.8 ± 0.1, 11.7 ± 0.1, 11.8 ± 0.1, 13.7 ± 0.1, 17.0 ± 0.1, 18.9 ± 0.1, 19.6 ± 0.1, 20.5 ± 0.1, 22.2 ± 0.1, 22.5 ± 0.1, 22.9 ± 0.1, 23.8 ± 0.1, 23.9 ± 0.1, 25.4 ± 0.1, 26.5 ± 0.1, 29.2 ± 0.1, and 29.6 ± 0.1 ° 2θ (e.g., 6.8, 11.7, 11.8, 13.7, 17.0, 18.9, 19.6, 20.5, 22.2, 22.5, 22.9, 23.8, 23.9, 25.4, 26.5, 29.2, and 29.6 ° 2θ))) using Cu K alpha radiation.

[0083] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern having at least one signal selected from 6.8 ± 0.5, 18.9 ± 0.5, and 20.5 ± 0.5 ° 2θ (e.g., 6.8 ± 0.2, 18.9 ± 0.2, and 20.5 ± 0.2 ° 2θ (e.g., 6.8 ± 0.1, 18.9 ± 0.1, and 20.5 ± 0.1 ° 2θ (e.g., 6.8, 18.9, and 20.5 ° 2θ))) using Cu K alpha radiation.

[0084] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least one signal selected from 6.8±0.5, 20.5±0.5, and 22.9±0.5° 2θ (e.g., 6.8±0.2, 20.5±0.2, and 22.9±0.2° 2θ (e.g., 6.8±0.1, 20.5±0.1, and 22.9±0.1° 2θ (e.g., 6.8, 20.5, and 22.9° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0085] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least one signal selected from 11.7±0.5, 18.9±0.5, and 20.5±0.5° 2θ (e.g., 11.7±0.2, 18.9±0.2, and 20.5±0.2° 2θ (e.g., 11.7±0.1, 18.9±0.1, and 20.5±0.1° 2θ (e.g., 11.7, 18.9, and 20.5° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0086] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least one signal selected from 11.7±0.5, 20.5±0.5, and 22.9±0.5° 2θ (e.g., 11.7±0.2, 20.5±0.2, and 22.9±0.2° 2θ (e.g., 11.7±0.1, 20.5±0.1, and 22.9±0.1° 2θ (e.g., 11.7, 20.5, and 22.9° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0087] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least two signals selected from 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, and 22.9±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, and 22.9±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, and 22.9° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0088] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least three signals selected from 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, and 22.9±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, and 22.9±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, and 22.9° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0089] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least four signals selected from 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, and 22.9±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, and 22.9±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, and 22.9° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0090] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least five signals selected from 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, 22.9±0.5, and 23.8±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, and 23.8±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, 22.9±0.1, and 23.8±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, 22.9, and 23.8° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0091] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least five signals selected from 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, 22.9±0.5, 23.8±0.5, and 26.5±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, 22.9±0.1, 23.8±0.1, and 26.5±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, 22.9, 23.8, and 26.5° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0092] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25° C., has an XRPD pattern having at least five signals selected from 6.8±0.5, 11.7±0.5, 18.9±0.5, 20.5±0.5, 22.9±0.5, 23.8±0.5, 23.9±0.5, and 26.5±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, 23.9±0.2, and 26.5±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 18.9±0.1, 20.5±0.1, 22.9±0.1, 23.8±0.1, 23.9±0.1, and 26.5±0.1° 2θ (e.g., 6.8, 11.7, 18.9, 20.5, 22.9, 23.8, 23.9, and 26.5° 2θ))) using Cu K alpha radiation.

[0093] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.8±0.5, 11.7±0.5, 11.8±0.5, 13.7±0.5, 17.0±0.5, 18.9±0.5, 19.6±0.5, 20.5±0.5, 22.2±0.5, 22.5±0.5, 22.9±0.5, 23.8±0.5, 23.9±0.5, 25.4±0.5, 26.5±0.5, 29.2±0.5, and 29.6±0.5° 2θ (e.g., 6.8±0.2, 11.7±0.2, 11.8±0.2, 13.7±0.2, 17.0±0.2, 18.9±0.2, 19.6±0.2, 20.5±0.2, 22.2±0.2, 22.5±0.2, 22.9±0.2, 23.8±0.2, 23.9±0.2, 25.4±0.2, 26.5±0.2, 29.2±0.2, and 29.6±0.2° 2θ (e.g., 6.8±0.1, 11.7±0.1, 11.8±0.1, 13.7±0.1, 17.0±0.1, 18.9±0.1, 19.6±0.1, 20.5±0.1, 22.2±0.1, 22.5±0.1, 22.9±0.1, 23.8±0.1, 23.9±0.1, 25.4±0.1, 26.5±0.1, 29.2±0.1, and 29.6±0.1° 2θ (e.g., 6.8, 11.7, 11.8, 13.7, 17.0, 18.9, 19.6, 20.5, 22.2, 22.5, 22.9, 23.8, 23.9, 25.4, 26.5, 29.2, and 29.6° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0094] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.8±0.2, 11.7±0.2, 13.7±0.2, 17.0±0.2, 18.9±0.2, 19.6±0.2, 20.5±0.2, 22.2±0.2, 22.5±0.2, 22.9±0.2, 23.8±0.2, 23.9±0.2, 25.4±0.2, 26.5±0.2, 29.2±0.2, and 29.6±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0095] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 18.9±0.5, 20.5±0.5, and 22.9±0.5° 2θ, for example, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ, for example, 18.9±0.1, 20.5±0.1, and 22.9±0.1° 2θ, for example, 18.9, 20.5, and 22.9° 2θ, when measured at 25 °C using Cu K alpha radiation.

[0096] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 18.9±0.5, 20.5±0.5, 22.9±0.5, 23.8±0.5, 23.9±0.5, and 26.5±0.5° 2θ (for example, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, 23.9±0.2, and 26.5±0.2° 2θ (for example, 18.9±0.1, 20.5±0.1, 22.9±0.1, 23.8±0.1, 23.9±0.1, and 26.5±0.1° 2θ (for example, 6.8, 11.7, 18.9, 20.5, 22.9, 23.8, 23.9, and 26.5° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0097] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes one or more signals described in Table 1 below.

[0098] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes two or more signals described in Table 1 below.

[0099] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes three or more signals described in Table 1 below.

[0100] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes four or more signals described in Table 1 below.

[0101] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising five or more signals as set forth in Table 1 below.

[0102] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising six or more signals as set forth in Table 1 below.

[0103] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising seven or more signals as set forth in Table 1 below.

[0104] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising eight or more signals as set forth in Table 1 below.

[0105] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising nine or more signals as set forth in Table 1 below.

[0106] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising ten or more signals as set forth in Table 1 below.

[0107] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising eleven or more signals as set forth in Table 1 below. [Table 1]

[0108] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that is substantially similar to that shown in Figure 6A and / or Table 1. In some embodiments, the crystalline form of the free base of Compound 1 so characterized is the crystalline form V free base.

[0109] In some embodiments, the Form V free base is the pure phase Form V free base.

[0110] (ii) Crystalline Form I free base In some embodiments, the crystalline form of Compound 1 free base is the Crystalline Form I free base. In some embodiments, the Crystalline Free Base Form I is as defined in section (a)(ii) of this section.

[0111] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 11.2 ± 0.2° 2θ using Cu K alpha radiation.

[0112] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 12.0 ± 0.2° 2θ using Cu K alpha radiation.

[0113] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 11.2 ± 0.2° 2θ and 12.0 ± 0.2° 2θ using Cu K alpha radiation.

[0114] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 5.6 ± 0.5, 11.2 ± 0.5, and 12.0 ± 0.5° 2θ (e.g., 5.6 ± 0.2, 11.2 ± 0.2, and 12.0 ± 0.2° 2θ (e.g., 5.6 ± 0.1, 11.2 ± 0.1, and 12.0 ± 0.1° 2θ (e.g., 5.6, 11.2, and 12.0° 2θ))) using Cu K alpha radiation.

[0115] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 5.6±0.5, 11.2±0.5, 12.0±0.5, 21.3±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 21.3±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 21.3±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 21.3, and 28.3° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0116] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 5.6±0.5, 11.2±0.5, 12.0±0.5, 16.9±0.5, 21.3±0.5, 26.8±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 16.9±0.2, 21.3±0.2, 26.8±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 16.9±0.1, 21.3±0.1, 26.8±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 16.9, 21.3, 26.8, and 28.3° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0117] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 5.6±0.5, 11.2±0.5, 12.0±0.5, 13.1±0.5, 14.0±0.5, 15.4±0.5, 16.9±0.5, 21.3±0.5, 22.9±0.5, 24.0±0.5, 24.9±0.5, 26.8±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 13.1±0.2, 14.0±0.2, 15.4±0.2, 16.9±0.2, 21.3±0.2, 22.9±0.2, 24.0±0.2, 24.9±0.2, 26.8±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 13.1±0.1, 14.0±0.1, 15.4±0.1, 16.9±0.1, 21.3±0.1, 22.9±0.1, 24.0±0.1, 24.9±0.1, 26.8±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 13.1, 14.0, 15.4, 16.9, 21.3, 22.9, 24.0, 24.9, 26.8, and 28.3° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0118] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 5.6±0.5, 11.2±0.5, 12.0±0.5, 13.1±0.5, 14.0±0.5, 14.8±0.5, 15.4±0.5, 16.9±0.5, 17.1±0.5, 18.0±0.5, 18.4±0.5, 20.3±0.5, 21.3±0.5, 22.5±0.5, 22.9±0.5, 23.0±0.5, 23.6±0.5, 24.0±0.5, 24.9±0.5, 26.6±0.5, 26.8±0.5, 27.2±0.5, 28.3±0.5, 29.0±0.5, and 31.0±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 13.1±0.2, 14.0±0.2, 14.8±0.2, 15.4±0.2, 16.9±0.2, 17.1±0.2, 18.0±0.2, 18.4±0.2, 20.3±0.2, 21.3±0.2, 22.5±0.2, 22.9±0.2, 23.0±0.2, 23.6±0.2, 24.0±0.2, 24.9±0.2, 26.6±0.2, 26.8±0.2, 27.2±0.2, 28.3±0.2, 29.0±0.2, and 31.0±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 13.1±0.1, 14.0±0.1, 14.8±0.1, 15.4±0.1, 16.9±0.1, 17.1±0.1, 18.0±0.1, 18.4±0.1, 20.3±0.1, 21.3±0.1, 22.5±0.1, 22.9±0.1, 23.0±0.1, 23.6±0.1, 24.0±0.1, 24.9±0.1, 26.6±0.1, 26.8±0.1, 27.2±0.1, 28.3±0.1, 29.0±0.1, and 31.0±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 13.1, 14.0, 14.8, 15.4, 16.9, 17.1, 18.0, 18.4, 20.3, 21.3, 22.5, 22.9, 23.0, 23.6, 24.0, 24.9, 26.6, 26.8, 27.2, 28.3, 29.0, and 31.0° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0119] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by XRPD having at least one signal selected from 5.6±0.5, 11.2±0.5, and 12.0±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, and 12.0±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, and 12.0±0.1° 2θ (e.g., 5.6, 11.2, and 12.0° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0120] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least two signals selected from 5.6±0.5, 11.2±0.5, 12.0±0.5, 21.3±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 21.3±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 21.3±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 21.3, and 28.3° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0121] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least three signals selected from 5.6±0.5, 11.2±0.5, 12.0±0.5, 21.3±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 21.3±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 21.3±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 21.3, and 28.3° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0122] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least four signals selected from 5.6±0.5, 11.2±0.5, 12.0±0.5, 21.3±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 21.3±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 21.3±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 21.3, and 28.3° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0123] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least five signals selected from 5.6±0.5, 11.2±0.5, 12.0±0.5, 16.9±0.5, 21.3±0.5, 26.8±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 16.9±0.2, 21.3±0.2, 26.8±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 16.9±0.1, 21.3±0.1, 26.8±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 16.9, 21.3, 26.8, and 28.3° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0124] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least five signals selected from 5.6±0.5, 11.2±0.5, 12.0±0.5, 13.1±0.5, 14.0±0.5, 15.4±0.5, 16.9±0.5, 21.3±0.5, 22.9±0.5, 24.0±0.5, 24.9±0.5, 26.8±0.5, and 28.3±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 13.1±0.2, 14.0±0.2, 15.4±0.2, 16.9±0.2, 21.3±0.2, 22.9±0.2, 24.0±0.2, 24.9±0.2, 26.8±0.2, and 28.3±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 13.1±0.1, 14.0±0.1, 15.4±0.1, 16.9±0.1, 21.3±0.1, 22.9±0.1, 24.0±0.1, 24.9±0.1, 26.8±0.1, and 28.3±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 13.1, 14.0, 15.4, 16.9, 21.3, 22.9, 24.0, 24.9, 26.8, and 28.3° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0125] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 5.6±0.5, 11.2±0.5, 12.0±0.5, 13.1±0.5, 14.0±0.5, 14.8±0.5, 15.4±0.5, 16.9±0.5, 17.1±0.5, 18.0±0.5, 18.4±0.5, 20.3±0.5, 21.3±0.5, 22.5±0.5, 22.9±0.5, 23.0±0.5, 23.6±0.5, 24.0±0.5, 24.9±0.5, 26.6±0.5, 26.8±0.5, 27.2±0.5, 28.3±0.5, 29.0±0.5, and 31.0±0.5° 2θ (e.g., 5.6±0.2, 11.2±0.2, 12.0±0.2, 13.1±0.2, 14.0±0.2, 14.8±0.2, 15.4±0.2, 16.9±0.2, 17.1±0.2, 18.0±0.2, 18.4±0.2, 20.3±0.2, 21.3±0.2, 22.5±0.2, 22.9±0.2, 23.0±0.2, 23.6±0.2, 24.0±0.2, 24.9±0.2, 26.6±0.2, 26.8±0.2, 27.2±0.2, 28.3±0.2, 29.0±0.2, and 31.0±0.2° 2θ (e.g., 5.6±0.1, 11.2±0.1, 12.0±0.1, 13.1±0.1, 14.0±0.1, 14.8±0.1, 15.4±0.1, 16.9±0.1, 17.1±0.1, 18.0±0.1, 18.4±0.1, 20.3±0.1, 21.3±0.1, 22.5±0.1, 22.9±0.1, 23.0±0.1, 23.6±0.1, 24.0±0.1, 24.9±0.1, 26.6±0.1, 26.8±0.1, 27.2±0.1, 28.3±0.1, 29.0±0.1, and 31.0±0.1° 2θ (e.g., 5.6, 11.2, 12.0, 13.1, 14.0, 14.8, 15.4, 16.9, 17.1, 18.0, 18.4, 20.3, 21.3, 22.5, 22.9, 23.0, 23.6, 24.0, 24.9, 26.6, 26.8, 27.2, 28.3, 29.0, and 31.0° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0126] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 5.6±0.2, 11.2±0.2, 12.0±0.2, 13.1±0.2, 14.0±0.2, 14.8±0.2, 15.4±0.2, 16.9±0.2, 17.1±0.2, 18.0±0.2, 18.4±0.2, 20.3±0.2, 21.3±0.2, 22.5±0.2, 22.9±0.2, 23.0±0.2, 23.6±0.2, 24.0±0.2, 24.9±0.2, 26.6±0.2, 26.8±0.2, 27.2±0.2, 28.3±0.2, 29.0±0.2, and 31.0±0.2° 2θ when measured at 25°C using Cu K alpha radiation.

[0127] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising one or more signals set forth in Table 2 below.

[0128] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising two or more signals set forth in Table 2 below.

[0129] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising three or more signals set forth in Table 2 below.

[0130] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising four or more signals set forth in Table 2 below.

Table 2

[0131] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that is substantially similar to that shown in Figure 2A and / or Table 2. In some embodiments, the crystalline form of Compound 1 free base so characterized is Crystalline Form I free base.

[0132] In some embodiments, the Form I free base is the pure phase Form I free base.

[0133] (iii) Crystalline Form II free base In some embodiments, the crystalline form of Compound 1 free base is the Crystalline Form II free base. In some embodiments, the crystalline free base form II free base is as defined in section (a)(iii) of this section.

[0134] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1 ± 0.2° 2θ using Cu K alpha radiation, when measured at 25°C.

[0135] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 13.6 ± 0.2° 2θ using Cu K alpha radiation, when measured at 25°C.

[0136] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1 ± 0.2° 2θ and 13.6 ± 0.2° 2θ using Cu K alpha radiation, when measured at 25°C.

[0137] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1 ± 0.5, 12.1 ± 0.5, and 13.6 ± 0.5° 2θ (e.g., 11.1 ± 0.2, 12.1 ± 0.2, and 13.6 ± 0.2° 2θ (e.g., 11.1 ± 0.1, 12.1 ± 0.1, and 13.6 ± 0.1° 2θ (e.g., 11.1, 12.1, and 15.6° 2θ))) using Cu K alpha radiation, when measured at 25°C.

[0138] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1 ± 0.2, 12.1 ± 0.2, and 13.6 ± 0.2° 2θ using Cu K alpha radiation, when measured at 25°C.

[0139] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1 ± 0.5, 12.1 ± 0.5, 13.6 ± 0.5, 22.5 ± 0.5, and 26.3 ± 0.5° 2θ (e.g., 11.1 ± 0.2, 12.1 ± 0.2, 13.6 ± 0.2, 22.5 ± 0.2, and 26.3 ± 0.2° 2θ (e.g., 11.1 ± 0.1, 12.1 ± 0.1, 13.6 ± 0.1, 22.5 ± 0.1, and 26.3 ± 0.1° 2θ (e.g., 11.1, 12.1, 13.6, 22.5, and 26.3° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0140] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1 ± 0.2, 12.1 ± 0.2, 13.6 ± 0.2, 22.5 ± 0.2, and 26.3 ± 0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0141] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1 ± 0.5, 12.1 ± 0.5, 13.6 ± 0.5, 16.7 ± 0.5, 22.5 ± 0.5, 26.3 ± 0.5, and 28.0 ± 0.5° 2θ (e.g., 11.1 ± 0.2, 12.1 ± 0.2, 13.6 ± 0.2, 16.7 ± 0.2, 22.5 ± 0.2, 26.3 ± 0.2, and 28.0 ± 0.2° 2θ (e.g., 11.1 ± 0.1, 12.1 ± 0.1, 13.6 ± 0.1, 16.7 ± 0.1, 22.5 ± 0.1, 26.3 ± 0.1, and 28.0 ± 0.1° 2θ (e.g., 11.1, 12.1, 13.6, 16.7, 22.5, 26.3, and 28.0° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0142] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 11.1±0.2, 12.1±0.2, 13.6±0.2, 16.7±0.2, 22.5±0.2, 26.3±0.2, and 28.0±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0143] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 11.1±0.2, 12.1±0.2, 13.6±0.2, 16.7±0.2, 22.5±0.2, 26.3±0.2, and 28.0±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and further includes signals at one or more of 14.8±0.2, 15.5±0.2, 16.1±0.2, 18.2±0.2, 19.7±0.2, 19.9±0.2, 20.1±0.2, 20.4±0.2, 21.6±0.2, 24.4±0.2, 24.8±0.2, 27.0±0.2, and 28.0±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0144] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 11.1±0.2, 12.1±0.2, 13.6±0.2, 16.7±0.2, 22.5±0.2, 26.3±0.2, and 28.0±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and further includes signals at two or more of 14.8±0.2, 15.5±0.2, 16.1±0.2, 18.2±0.2, 19.7±0.2, 19.9±0.2, 20.1±0.2, 20.4±0.2, 21.6±0.2, 24.4±0.2, 24.8±0.2, 27.0±0.2, and 28.0±0.2° 2θ when measured at 25 °C using Cu K alpha radiation.

[0145] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that, when measured at 25 °C using Cu K alpha radiation, includes signals at 11.1 ± 0.2, 12.1 ± 0.2, 13.6 ± 0.2, 16.7 ± 0.2, 22.5 ± 0.2, 26.3 ± 0.2, and 28.0 ± 0.2 °2θ, and further includes signals at three or more of 14.8 ± 0.2, 15.5 ± 0.2, 16.1 ± 0.2, 18.2 ± 0.2, 19.7 ± 0.2, 19.9 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2, 21.6 ± 0.2, 24.4 ± 0.2, 24.8 ± 0.2, 27.0 ± 0.2, and 28.0 ± 0.2 °2θ when measured at 25 °C using Cu K alpha radiation.

[0146] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that, when measured at 25 °C using Cu K alpha radiation, includes signals at 11.1 ± 0.2, 12.1 ± 0.2, 13.6 ± 0.2, 16.7 ± 0.2, 22.5 ± 0.2, 26.3 ± 0.2, and 28.0 ± 0.2 °2θ, and further includes signals at four or more of 14.8 ± 0.2, 15.5 ± 0.2, 16.1 ± 0.2, 18.2 ± 0.2, 19.7 ± 0.2, 19.9 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2, 21.6 ± 0.2, 24.4 ± 0.2, 24.8 ± 0.2, 27.0 ± 0.2, and 28.0 ± 0.2 °2θ when measured at 25 °C using Cu K alpha radiation.

[0147] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 11.1±0.5, 12.1±0.5, 13.6±0.5, 14.8±0.5, 15.5±0.5, 16.1±0.5, 16.7±0.5, 18.2±0.5, 19.7±0.5, 19.9±0.5, 20.1±0.5, 20.4±0.5, 21.6±0.5, 22.5±0.5, 24.4±0.5, 24.8±0.5, 26.3±0.5, 27.0±0.5, 27.4±0.5, and 28.0±0.5° 2θ (e.g., 11.1±0.2, 12.1±0.2, 13.6±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.7±0.2, 18.2±0.2, 19.7±0.2, 19.9±0.2, 20.1±0.2, 20.4±0.2, 21.6±0.2, 22.5±0.2, 24.4±0.2, 24.8±0.2, 26.3±0.2, 27.0±0.2, 27.4±0.2, and 28.0±0.2° 2θ (e.g., 11.1±0.1, 12.1±0.1, 13.6±0.1, 14.8±0.1, 15.5±0.1, 16.1±0.1, 16.7±0.1, 18.2±0.1, 19.7±0.1, 19.9±0.1, 20.1±0.1, 20.4±0.1, 21.6±0.1, 22.5±0.1, 24.4±0.1, 24.8±0.1, 26.3±0.1, 27.0±0.1, 27.4±0.1, and 28.0±0.1° 2θ (e.g., 11.1, 12.1, 13.6, 14.8, 15.5, 16.1, 16.7, 18.2, 19.7, 19.9, 20.1, 20.4, 21.6, 22.5, 24.4, 24.8, 26.3, 27.0, 27.4, and 28.0° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0148] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25°C, using Cu K alpha radiation, has 5.6±0.5, 11.1±0.5, 12.1±0.5, 13.1±0.5, 13.6±0.5, 14.8±0.5, 15.5±0.5, 16.1±0.5, 16.7±0.5, 18.2±0.5, 19.7±0.5, 19.9±0.5, 20.1±0.5, 20.4±0.5, 21.6±0.5, 22.5±0.5, 24.4±0.5, 24.8±0.5, 26.3±0.5, 27.0±0.5, 27.4±0.5, 28.0±0.5, 29.4±0.5, 32.5±0.5, 33.6±0.5, 34.7±0.5, 38.0±0.5, and 39.6±0.5° 2θ (e.g., 5.6±0.2, 11.1±0.2, 12.1±0.2, 13.1±0.2, 13.6±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.7±0.2, 18.2±0.2, 19.7±0.2, 19.9±0.2, 20.1±0.2, 20.4±0.2, 21.6±0.2, 22.5±0.2, 24.4±0.2, 24.8±0.2, 26.3±0.2, 27.0±0.2, 27.4±0.2, 28.0±0.2, 29.4±0.2, 32.5±0.2, 33.6±0.2, 34.7±0.2, 38.0±0.2, and 39.6±0.2° 2θ (e.g., 5.6±0.1, 11.1±0.1, 12.1±0.1, 13.1±0.1, 13.6±0.1, 14.8±0.1, 15.5±0.1, 16.1±0.1, 16.7±0.1, 18.2±0.1, 19.7±0.1, 19.9±0.1, 20.1±0.1, 20.4±0.1, 21.6±0.1, 22.5±0.1, 24.4±0.1, 24.8±0.1, 26.3±0.1, 27.0±0.1, 27.4±0.1, 28.0±0.1, 29.4±0.1, 32.5±0.1, 33.6±0.1, 34.7±0.1, 38.0±0.1, and 39.6±0.1° 2θ (e.g., 5.6, 11.1, 12.1, 13.1, 13.6, 14.8, 15.5, 16.1, 16.7, 18.2, 19.7, 19.9, 20.1, 20.4, 21.6, 22.5, 24.4, 24.8, 26.3, 27.0, 27.4, 28.0, 29.4, 32.5, 33.6, 34.7, 38.0, and 39.It is characterized by an XRPD pattern containing signals at 6° 2θ).

[0149] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has an XRPD characterized by at least one signal selected from 11.1 ± 0.5, 12.1 ± 0.5, and 13.6 ± 0.5 ° 2θ (e.g., 11.1 ± 0.2, 12.1 ± 0.2, and 13.6 ± 0.2 ° 2θ (e.g., 11.1 ± 0.1, 12.1 ± 0.1, and 13.6 ± 0.1 ° 2θ (e.g., 11.1, 12.1, and 15.6 ° 2θ))).

[0150] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has an XRPD pattern characterized by at least two signals selected from 11.1 ± 0.5, 12.1 ± 0.5, 13.6 ± 0.5, 22.5 ± 0.5, and 26.3 ± 0.5 ° 2θ (e.g., 11.1 ± 0.2, 12.1 ± 0.2, 13.6 ± 0.2, 22.5 ± 0.2, and 26.3 ± 0.2 ° 2θ (e.g., 11.1 ± 0.1, 12.1 ± 0.1, 13.6 ± 0.1, 22.5 ± 0.1, and 26.3 ± 0.1 ° 2θ (e.g., 11.1, 12.1, 13.6, 22.5, and 26.3 ° 2θ))).

[0151] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has an XRPD pattern characterized by at least three signals selected from 11.1 ± 0.5, 12.1 ± 0.5, 13.6 ± 0.5, 22.5 ± 0.5, and 26.3 ± 0.5 ° 2θ (e.g., 11.1 ± 0.2, 12.1 ± 0.2, 13.6 ± 0.2, 22.5 ± 0.2, and 26.3 ± 0.2 ° 2θ (e.g., 11.1 ± 0.1, 12.1 ± 0.1, 13.6 ± 0.1, 22.5 ± 0.1, and 26.3 ± 0.1 ° 2θ (e.g., 11.1, 12.1, 13.6, 22.5, and 26.3 ° 2θ))).

[0152] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least four signals selected from 11.1±0.5, 12.1±0.5, 13.6±0.5, 22.5±0.5, and 26.3±0.5° 2θ (e.g., 11.1±0.2, 12.1±0.2, 13.6±0.2, 22.5±0.2, and 26.3±0.2° 2θ (e.g., 11.1±0.1, 12.1±0.1, 13.6±0.1, 22.5±0.1, and 26.3±0.1° 2θ (e.g., 11.1, 12.1, 13.6, 22.5, and 26.3° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0153] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least five signals selected from 11.1±0.5, 12.1±0.5, 13.6±0.5, 16.7±0.5, 22.5±0.5, 26.3±0.5, and 28.0±0.5° 2θ (e.g., 11.1±0.2, 12.1±0.2, 13.6±0.2, 16.7±0.2, 22.5±0.2, 26.3±0.2, and 28.0±0.2° 2θ (e.g., 11.1±0.1, 12.1±0.1, 13.6±0.1, 16.7±0.1, 22.5±0.1, 26.3±0.1, and 28.0±0.1° 2θ (e.g., 11.1, 12.1, 13.6, 16.7, 22.5, 26.3, and 28.0° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0154] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least five signals selected from 11.1±0.5, 12.1±0.5, 13.6±0.5, 14.8±0.5, 15.5±0.5, 16.1±0.5, 16.7±0.5, 18.2±0.5, 19.7±0.5, 19.9±0.5, 20.1±0.5, 20.4±0.5, 21.6±0.5, 22.5±0.5, 24.4±0.5, 24.8±0.5, 26.3±0.5, 27.0±0.5, 27.4±0.5, and 28.0±0.5° 2θ (e.g., 11.1±0.2, 12.1±0.2, 13.6±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.7±0.2, 18.2±0.2, 19.7±0.2, 19.9±0.2, 20.1±0.2, 20.4±0.2, 21.6±0.2, 22.5±0.2, 24.4±0.2, 24.8±0.2, 26.3±0.2, 27.0±0.2, 27.4±0.2, and 28.0±0.2° 2θ (e.g., 11.1±0.1, 12.1±0.1, 13.6±0.1, 14.8±0.1, 15.5±0.1, 16.1±0.1, 16.7±0.1, 18.2±0.1, 19.7±0.1, 19.9±0.1, 20.1±0.1, 20.4±0.1, 21.6±0.1, 22.5±0.1, 24.4±0.1, 24.8±0.1, 26.3±0.1, 27.0±0.1, 27.4±0.1, and 28.0±0.1° 2θ (e.g., 11.1, 12.1, 13.6, 14.8, 15.5, 16.1, 16.7, 18.2, 19.7, 19.9, 20.1, 20.4, 21.6, 22.5, 24.4, 24.8, 26.3, 27.0, 27.4, and 28.0° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0155] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has 5.6±0.5, 11.1±0.5, 12.1±0.5, 13.1±0.5, 13.6±0.5, 14.8±0.5, 15.5±0.5, 16.1±0.5, 16.7±0.5, 18.2±0.5, 19.7±0.5, 19.9±0.5, 20.1±0.5, 20.4±0.5, 21.6±0.5, 22.5±0.5, 24.4±0.5, 24.8±0.5, 26.3±0.5, 27.0±0.5, 27.4±0.5, 28.0±0.5, 29.4±0.5, 32.5±0.5, 33.6±0.5, 34.7±0.5, 38.0±0.5, and 39.6±0.5° 2θ (e.g., 5.6±0.2, 11.1±0.2, 12.1±0.2, 13.1±0.2, 13.6±0.2, 14.8±0.2, 15.5±0.2, 16.1±0.2, 16.7±0.2, 18.2±0.2, 19.7±0.2, 19.9±0.2, 20.1±0.2, 20.4±0.2, 21.6±0.2, 22.5±0.2, 24.4±0.2, 24.8±0.2, 26.3±0.2, 27.0±0.2, 27.4±0.2, 28.0±0.2, 29.4±0.2, 32.5±0.2, 33.6±0.2, 34.7±0.2, 38.0±0.2, and 39.6±0.2° 2θ (e.g., 5.6±0.1, 11.1±0.1, 12.1±0.1, 13.1±0.1, 13.6±0.1, 14.8±0.1, 15.5±0.1, 16.1±0.1, 16.7±0.1, 18.2±0.1, 19.7±0.1, 19.9±0.1, 20.1±0.1, 20.4±0.1, 21.6±0.1, 22.5±0.1, 24.4±0.1, 24.8±0.1, 26.3±0.1, 27.0±0.1, 27.4±0.1, 28.0±0.1, 29.4±0.1, 32.5±0.1, 33.6±0.1, 34.7±0.1, 38.0±0.1, and 39.6±0.1° 2θ (e.g., 5.6, 11.1, 12.1, 13.1, 13.6, 14.8, 15.5, 16.1, 16.7, 18.2, 19.7, 19.9, 20.1, 20.4, 21.6, 22.5, 24.4, 24.8, 26.3, 27.0, 27.4, 28.0, 29.4, 32.5, 33.6, 34.7, 38.0, and 39.It is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6° 2θ).

[0156] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has an XRPD pattern characterized by at least one X-ray powder diffraction signal at 5.6 ± 0.2, 11.1 ± 0.2, 12.1 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.8 ± 0.2, 15.5 ± 0.2, 16.1 ± 0.2, 16.7 ± 0.2, 18.2 ± 0.2, 19.7 ± 0.2, 19.9 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 24.4 ± 0.2, 24.8 ± 0.2, 26.3 ± 0.2, 27.0 ± 0.2, 27.4 ± 0.2, 28.0 ± 0.2, 29.4 ± 0.2, 32.5 ± 0.2, 33.6 ± 0.2, 34.7 ± 0.2, 38.0 ± 0.2, and 39.6 ± 0.2 ° 2θ.

[0157] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising one or more signals described in Table 3 below.

[0158] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising two or more signals described in Table 3 below.

[0159] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising three or more signals described in Table 3 below.

[0160] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising four or more signals described in Table 3 below. [Table 3]

[0161] In some embodiments, the crystalline form of the compound 1 free base is characterized by an XRPD pattern that is substantially similar to that shown in Figure 3A and / or Table 3. In some embodiments, the crystalline form of the compound 1 free base so characterized is the crystalline form II free base.

[0162] In some embodiments, the form II free base is the pure phase form II free base.

[0163] (iv) Crystalline form III free base In some embodiments, the crystalline form of the compound 1 free base is the crystalline form III free base. In some embodiments, the crystalline free base form III free base is as defined in section (a)(iv) of this section.

[0164] In some embodiments, the crystalline form of the compound 1 free base is characterized by an XRPD pattern that includes a signal at 6.4 ± 0.2° 2θ using Cu K alpha radiation when measured at 25°C.

[0165] In some embodiments, the crystalline form of the compound 1 free base is characterized by an XRPD pattern that includes signals at 6.4 ± 0.5, 10.2 ± 0.5, and 12.7 ± 0.5° 2θ (e.g., 6.4 ± 0.2, 10.2 ± 0.2, and 12.7 ± 0.2° 2θ (e.g., 6.4 ± 0.1, 10.2 ± 0.1, and 12.7 ± 0.1° 2θ (e.g., 6.4, 10.2, and 12.7° 2θ))) using Cu K alpha radiation when measured at 25°C.

[0166] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 6.4 ± 0.5, 10.2 ± 0.5, 12.7 ± 0.5, 17.8 ± 0.5, 18.1 ± 0.5, 20.7 ± 0.5, and 21.8 ± 0.5° 2θ (e.g., 6.4 ± 0.2, 10.2 ± 0.2, 12.7 ± 0.2, 17.8 ± 0.2, 18.1 ± 0.2, 20.7 ± 0.2, and 21.8 ± 0.2° 2θ (e.g., 6.4 ± 0.1, 10.2 ± 0.1, 12.7 ± 0.1, 17.8 ± 0.1, 18.1 ± 0.1, 20.7 ± 0.1, and 21.8 ± 0.1° 2θ (e.g., 6.4, 10.2, 12.7, 17.8, 18.1, 20.7, and 21.8° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0167] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has signals at 6.4 ± 0.5, 8.6 ± 0.5, 10.2 ± 0.5, 12.7 ± 0.5, 16.3 ± 0.5, 17.2 ± 0.5, 17.8 ± 0.5, 18.1 ± 0.5, 20.7 ± 0.5, 21.8 ± 0.5, 23.4 ± 0.5, 24.7 ± 0.5, 24.9 ± 0.5, 25.4 ± 0.5, 25.5 ± 0.5, 26.3 ± 0.5, and 26.6 ± 0.5 ° 2θ (e.g., 6.4 ± 0.2, 8.6 ± 0.2, 10.2 ± 0.2, 12.7 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, 17.8 ± 0.2, 18.1 ± 0.2, 20.7 ± 0.2, 21.8 ± 0.2, 23.4 ± 0.2, 24.7 ± 0.2, 24.9 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, 26.3 ± 0.2, and 26.6 ± 0.2 ° 2θ (e.g., 6.4 ± 0.1, 8.6 ± 0.1, 10.2 ± 0.1, 12.7 ± 0.1, 16.3 ± 0.1, 17.2 ± 0.1, 17.8 ± 0.1, 18.1 ± 0.1, 20.7 ± 0.1, 21.8 ± 0.1, 23.4 ± 0.1, 24.7 ± 0.1, 24.9 ± 0.1, 25.4 ± 0.1, 25.5 ± 0.1, 26.3 ± 0.1, and 26.6 ± 0.1 ° 2θ (e.g., 6.4, 8.6, 10.2, 12.7, 16.3, 17.2, 17.8, 18.1, 20.7, 21.8, 23.4, 24.7, 24.9, 25.4, 25.5, 26.3, and 26.6 ° 2θ))) and is characterized by an XRPD pattern containing these signals.

[0168] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 6.4±0.5, 8.6±0.5, 10.2±0.5, 12.7±0.5, 15.0±0.5, 16.3±0.5, 17.2±0.5, 17.8±0.5, 18.1±0.5, 19.5±0.5, 20.5±0.5, 20.7±0.5, 21.8±0.5, 22.2±0.5, 22.6±0.5, 23.4±0.5, 24.7±0.5, 24.9±0.5, 25.4±0.5, 25.5±0.5, 26.3±0.5, 26.6±0.5, 28.1±0.5, 29.2±0.5, 32.4±0.5, 33.5±0.5, and 37.9±0.5° 2θ (e.g., 6.4±0.2, 8.6±0.2, 10.2±0.2, 12.7±0.2, 15.0±0.2, 16.3±0.2, 17.2±0.2, 17.8±0.2, 18.1±0.2, 19.5±0.2, 20.5±0.2, 20.7±0.2, 21.8±0.2, 22.2±0.2, 22.6±0.2, 23.4±0.2, 24.7±0.2, 24.9±0.2, 25.4±0.2, 25.5±0.2, 26.3±0.2, 26.6±0.2, 28.1±0.2, 29.2±0.2, 32.4±0.2, 33.5±0.2, and 37.9±0.2° 2θ (e.g., 6.4±0.1, 8.6±0.1, 10.2±0.1, 12.7±0.1, 15.0±0.1, 16.3±0.1, 17.2±0.1, 17.8±0.1, 18.1±0.1, 19.5±0.1, 20.5±0.1, 20.7±0.1, 21.8±0.1, 22.2±0.1, 22.6±0.1, 23.4±0.1, 24.7±0.1, 24.9±0.1, 25.4±0.1, 25.5±0.1, 26.3±0.1, 26.6±0.1, 28.1±0.1, 29.2±0.1, 32.4±0.1, 33.5±0.1, and 37.9±0.1° 2θ (e.g., 6.4, 8.6, 10.2, 12.7, 15.0, 16.3, 17.2, 17.8, 18.1, 19.5, 20.5, 20.7, 21.8, 22.2, 22.6, 23.4, 24.7, 24.9, 25.4, 25.5, 26.3, 26.6, 28.1, 29.2, 32.4, 33.5, and 37.9° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0169] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by XRPD having at least one signal selected from 6.4±0.5, 10.2±0.5, and 12.7±0.5° 2θ (e.g., 6.4±0.2, 10.2±0.2, and 12.7±0.2° 2θ (e.g., 6.4±0.1, 10.2±0.1, and 12.7±0.1° 2θ (e.g., 6.4, 10.2, and 12.7° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0170] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least two signals selected from 6.4±0.5, 10.2±0.5, 12.7±0.5, 17.8±0.5, 18.1±0.5, 20.7±0.5, and 21.8±0.5° 2θ (e.g., 6.4±0.2, 10.2±0.2, 12.7±0.2, 17.8±0.2, 18.1±0.2, 20.7±0.2, and 21.8±0.2° 2θ (e.g., 6.4±0.1, 10.2±0.1, 12.7±0.1, 17.8±0.1, 18.1±0.1, 20.7±0.1, and 21.8±0.1° 2θ (e.g., 6.4, 10.2, 12.7, 17.8, 18.1, 20.7, and 21.8° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0171] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern having at least three signals selected from 6.4 ± 0.5, 10.2 ± 0.5, 12.7 ± 0.5, 17.8 ± 0.5, 18.1 ± 0.5, 20.7 ± 0.5, and 21.8 ± 0.5 ° 2θ (e.g., 6.4 ± 0.2, 10.2 ± 0.2, 12.7 ± 0.2, 17.8 ± 0.2, 18.1 ± 0.2, 20.7 ± 0.2, and 21.8 ± 0.2 ° 2θ (e.g., 6.4 ± 0.1, 10.2 ± 0.1, 12.7 ± 0.1, 17.8 ± 0.1, 18.1 ± 0.1, 20.7 ± 0.1, and 21.8 ± 0.1 ° 2θ (e.g., 6.4, 10.2, 12.7, 17.8, 18.1, 20.7, and 21.8 ° 2θ))) using Cu K alpha radiation.

[0172] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern having at least four signals selected from 6.4 ± 0.5, 10.2 ± 0.5, 12.7 ± 0.5, 17.8 ± 0.5, 18.1 ± 0.5, 20.7 ± 0.5, and 21.8 ± 0.5 ° 2θ (e.g., 6.4 ± 0.2, 10.2 ± 0.2, 12.7 ± 0.2, 17.8 ± 0.2, 18.1 ± 0.2, 20.7 ± 0.2, and 21.8 ± 0.2 ° 2θ (e.g., 6.4 ± 0.1, 10.2 ± 0.1, 12.7 ± 0.1, 17.8 ± 0.1, 18.1 ± 0.1, 20.7 ± 0.1, and 21.8 ± 0.1 ° 2θ (e.g., 6.4, 10.2, 12.7, 17.8, 18.1, 20.7, and 21.8 ° 2θ))) using Cu K alpha radiation.

[0173] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least five signals selected from 6.4±0.5, 10.2±0.5, 12.7±0.5, 17.8±0.5, 18.1±0.5, 20.7±0.5, and 21.8±0.5° 2θ (e.g., 6.4±0.2, 10.2±0.2, 12.7±0.2, 17.8±0.2, 18.1±0.2, 20.7±0.2, and 21.8±0.2° 2θ (e.g., 6.4±0.1, 10.2±0.1, 12.7±0.1, 17.8±0.1, 18.1±0.1, 20.7±0.1, and 21.8±0.1° 2θ (e.g., 6.4, 10.2, 12.7, 17.8, 18.1, 20.7, and 21.8° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0174] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has an XRPD pattern having at least five signals selected from 6.4 ± 0.5, 8.6 ± 0.5, 10.2 ± 0.5, 12.7 ± 0.5, 16.3 ± 0.5, 17.2 ± 0.5, 17.8 ± 0.5, 18.1 ± 0.5, 20.7 ± 0.5, 21.8 ± 0.5, 23.4 ± 0.5, 24.7 ± 0.5, 24.9 ± 0.5, 25.4 ± 0.5, 25.5 ± 0.5, 26.3 ± 0.5, and 26.6 ± 0.5 ° 2θ (e.g., 6.4 ± 0.2, 8.6 ± 0.2, 10.2 ± 0.2, 12.7 ± 0.2, 16.3 ± 0.2, 17.2 ± 0.2, 17.8 ± 0.2, 18.1 ± 0.2, 20.7 ± 0.2, 21.8 ± 0.2, 23.4 ± 0.2, 24.7 ± 0.2, 24.9 ± 0.2, 25.4 ± 0.2, 25.5 ± 0.2, 26.3 ± 0.2, and 26.6 ± 0.2 ° 2θ (e.g., 6.4 ± 0.1, 8.6 ± 0.1, 10.2 ± 0.1, 12.7 ± 0.1, 16.3 ± 0.1, 17.2 ± 0.1, 17.8 ± 0.1, 18.1 ± 0.1, 20.7 ± 0.1, 21.8 ± 0.1, 23.4 ± 0.1, 24.7 ± 0.1, 24.9 ± 0.1, 25.4 ± 0.1, 25.5 ± 0.1, 26.3 ± 0.1, and 26.6 ± 0.1 ° 2θ (e.g., 6.4, 8.6, 10.2, 12.7, 16.3, 17.2, 17.8, 18.1, 20.7, 21.8, 23.4, 24.7, 24.9, 25.4, 25.5, 26.3, and 26.6 ° 2θ))).

[0175] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least five signals selected from 6.4±0.5, 8.6±0.5, 10.2±0.5, 12.7±0.5, 15.0±0.5, 16.3±0.5, 17.2±0.5, 17.8±0.5, 18.1±0.5, 19.5±0.5, 20.5±0.5, 20.7±0.5, 21.8±0.5, 22.2±0.5, 22.6±0.5, 23.4±0.5, 24.7±0.5, 24.9±0.5, 25.4±0.5, 25.5±0.5, 26.3±0.5, 26.6±0.5, 28.1±0.5, 29.2±0.5, 32.4±0.5, 33.5±0.5, and 37.9±0.5° 2θ (e.g., 6.4±0.2, 8.6±0.2, 10.2±0.2, 12.7±0.2, 15.0±0.2, 16.3±0.2, 17.2±0.2, 17.8±0.2, 18.1±0.2, 19.5±0.2, 20.5±0.2, 20.7±0.2, 21.8±0.2, 22.2±0.2, 22.6±0.2, 23.4±0.2, 24.7±0.2, 24.9±0.2, 25.4±0.2, 25.5±0.2, 26.3±0.2, 26.6±0.2, 28.1±0.2, 29.2±0.2, 32.4±0.2, 33.5±0.2, and 37.9±0.2° 2θ (e.g., 6.4±0.1, 8.6±0.1, 10.2±0.1, 12.7±0.1, 15.0±0.1, 16.3±0.1, 17.2±0.1, 17.8±0.1, 18.1±0.1, 19.5±0.1, 20.5±0.1, 20.7±0.1, 21.8±0.1, 22.2±0.1, 22.6±0.1, 23.4±0.1, 24.7±0.1, 24.9±0.1, 25.4±0.1, 25.5±0.1, 26.3±0.1, 26.6±0.1, 28.1±0.1, 29.2±0.1, 32.4±0.1, 33.5±0.1, and 37.9±0.1° 2θ (e.g., 6.4, 8.6, 10.2, 12.7, 15.0, 16.3, 17.2, 17.8, 18.1, 19.5, 20.5, 20.7, 21.8, 22.2, 22.6, 23.4, 24.7, 24.9, 25.4, 25.5, 26.3, 26.6, 28.1, 29.2, 32.4, 33.5, and 37.9° 2θ)) when measured at 25°C using Cu K alpha radiation.

[0176] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.4±0.5, 8.6±0.5, 10.2±0.5, 12.7±0.5, 15.0±0.5, 16.3±0.5, 17.2±0.5, 17.8±0.5, 18.1±0.5, 19.5±0.5, 20.5±0.5, 20.7±0.5, 21.8±0.5, 22.2±0.5, 22.6±0.5, 23.4±0.5, 24.7±0.5, 24.9±0.5, 25.4±0.5, 25.5±0.5, 26.3±0.5, 26.6±0.5, 28.1±0.5, 29.2±0.5, 32.4±0.5, 33.5±0.5, and 37.9±0.5° 2θ (e.g., 6.4±0.2, 8.6±0.2, 10.2±0.2, 12.7±0.2, 15.0±0.2, 16.3±0.2, 17.2±0.2, 17.8±0.2, 18.1±0.2, 19.5±0.2, 20.5±0.2, 20.7±0.2, 21.8±0.2, 22.2±0.2, 22.6±0.2, 23.4±0.2, 24.7±0.2, 24.9±0.2, 25.4±0.2, 25.5±0.2, 26.3±0.2, 26.6±0.2, 28.1±0.2, 29.2±0.2, 32.4±0.2, 33.5±0.2, and 37.9±0.2° 2θ (e.g., 6.4±0.1, 8.6±0.1, 10.2±0.1, 12.7±0.1, 15.0±0.1, 16.3±0.1, 17.2±0.1, 17.8±0.1, 18.1±0.1, 19.5±0.1, 20.5±0.1, 20.7±0.1, 21.8±0.1, 22.2±0.1, 22.6±0.1, 23.4±0.1, 24.7±0.1, 24.9±0.1, 25.4±0.1, 25.5±0.1, 26.3±0.1, 26.6±0.1, 28.1±0.1, 29.2±0.1, 32.4±0.1, 33.5±0.1, and 37.9±0.1° 2θ (e.g., 6.4, 8.6, 10.2, 12.7, 15.0, 16.3, 17.2, 17.8, 18.1, 19.5, 20.5, 20.7, 21.8, 22.2, 22.6, 23.4, 24.7, 24.9, 25.4, 25.5, 26.3, 26.6, 28.1, 29.2, 32.4, 33.5, and 37.9° 2θ))) when measured at 25°C using Cu K alpha radiation.

[0177] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 6.4±0.2, 8.6±0.2, 10.2±0.2, 12.7±0.2, 15.0±0.2, 16.3±0.2, 17.2±0.2, 17.8±0.2, 18.1±0.2, 19.5±0.2, 20.5±0.2, 20.7±0.2, 21.8±0.2, 22.2±0.2, 22.6±0.2, 23.4±0.2, 24.7±0.2, 24.9±0.2, 25.4±0.2, 25.5±0.2, 26.3±0.2, 26.6±0.2, 28.1±0.2, 29.2±0.2, 32.4±0.2, 33.5±0.2, and 37.9±0.2° 2θ when measured at 25°C using Cu K alpha radiation.

[0178] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising one or more signals set forth in Table 4 below.

[0179] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising two or more signals set forth in Table 4 below.

[0180] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising three or more signals set forth in Table 4 below.

[0181] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising four or more signals set forth in Table 4 below. [Table 4]

[0182] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that is substantially similar to those shown in Figure 4A and / or Table 4. In some embodiments, the crystalline form of Compound 1 free base so characterized is the crystalline form III free base.

[0183] In some embodiments, Form III free base is the pure phase Form III free base.

[0184] (v) Crystalline Form IV Free Base In some embodiments, the crystalline form of Compound 1 free base is the crystalline form IV free base. In some embodiments, the crystalline free base form IV free base is as defined in section (a)(v) of this section.

[0185] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 16.0 ± 0.2° 2θ using Cu K alpha radiation, when measured at 25°C.

[0186] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 6.5 ± 0.5, 8.5 ± 0.5, and 16.0 ± 0.5° 2θ (e.g., 6.5 ± 0.2, 8.5 ± 0.2, and 16.0 ± 0.2° 2θ (e.g., 6.5 ± 0.1, 8.5 ± 0.1, and 16.0 ± 0.1° 2θ (e.g., 6.5, 8.5, and 16.0° 2θ)) using Cu K alpha radiation, when measured at 25°C.

[0187] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern that includes signals at 6.5 ± 0.5, 10.2 ± 0.5, and 16.0 ± 0.5° 2θ (e.g., 6.5 ± 0.2, 10.2 ± 0.2, and 16.0 ± 0.2° 2θ (e.g., 6.5 ± 0.1, 10.2 ± 0.1, and 16.0 ± 0.1° 2θ (e.g., 6.5, 10.2, and 16.0° 2θ)) using Cu K alpha radiation, when measured at 25°C.

[0188] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 8.5±0.5, 10.2±0.5, and 16.0±0.5° 2θ (e.g., 8.5±0.2, 10.2±0.2, and 16.0±0.2° 2θ (e.g., 8.5±0.1, 10.2±0.1, and 16.0±0.1° 2θ (e.g., 8.5, 10.2, and 16.0° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0189] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.5±0.5, 8.5±0.5, 10.2±0.5, and 16.0±0.5° 2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, and 16.0±0.2° 2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, and 16.0±0.1° 2θ (e.g., 6.5, 8.5, 10.2, and 16.0° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0190] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.5±0.5, 8.5±0.5, 10.2±0.5, 16.0±0.5, 18.0±0.5, 20.5±0.5, 21.0±0.5, and 22.0±0.5° 2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, 16.0±0.2, 18.0±0.2, 20.5±0.2, 21.0±0.2, and 22.0±0.2° 2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, 16.0±0.1, 18.0±0.1, 20.5±0.1, 21.0±0.1, and 22.0±0.1° 2θ (e.g., 6.5, 8.5, 10.2, 16.0, 18.0, 20.5, 21.0, and 22.0° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0191] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has an XRPD pattern characterized by signals at 6.5 ± 0.5, 8.5 ± 0.5, 10.2 ± 0.5, 16.0 ± 0.5, 16.9 ± 0.5, 18.0 ± 0.5, 20.4 ± 0.5, 20.5 ± 0.5, 21.0 ± 0.5, 22.0 ± 0.5, 22.6 ± 0.5, 23.4 ± 0.5, 24.4 ± 0.5, 25.1 ± 0.5, 26.0 ± 0.5, and 27.2 ± 0.5 ° 2θ (e.g., 6.5 ± 0.2, 8.5 ± 0.2, 10.2 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.0 ± 0.2, 20.4 ± 0.2, 20.5 ± 0.2, 21.0 ± 0.2, 22.0 ± 0.2, 22.6 ± 0.2, 23.4 ± 0.2, 24.4 ± 0.2, 25.1 ± 0.2, 26.0 ± 0.2, and 27.2 ± 0.2 ° 2θ (e.g., 6.5 ± 0.1, 8.5 ± 0.1, 10.2 ± 0.1, 16.0 ± 0.1, 16.9 ± 0.1, 18.0 ± 0.1, 20.4 ± 0.1, 20.5 ± 0.1, 21.0 ± 0.1, 22.0 ± 0.1, 22.6 ± 0.1, 23.4 ± 0.1, 24.4 ± 0.1, 25.1 ± 0.1, 26.0 ± 0.1, and 27.2 ± 0.1 ° 2θ (e.g., 6.5, 8.5, 10.2, 16.0, 16.9, 18.0, 20.4, 20.5, 21.0, 22.0, 22.6, 23.4, 24.4, 25.1, 26.0, and 27.2 ° 2θ))).

[0192] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has 6.5±0.5, 8.5±0.5, 10.2±0.5, 12.9±0.5, 15.1±0.5, 16.0±0.5, 16.9±0.5, 17.2±0.5, 18.0±0.5, 18.9±0.5, 20.4±0.5, 20.5±0.5, 21.0±0.5, 22.0±0.5, 22.6±0.5, 23.4±0.5, 24.4±0.5, 25.1±0.5, 24.8±0.5, 25.9±0.5, 26.0±0.5, 27.2±0.5, 28.2±0.5, 29.7±0.5, 30.7±0.5, 31.5±0.5, 33.5±0.5, 35.7±0.5, 37.4±0.5, and 39.5±0.5 °2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, 12.9±0.2, 15.1±0.2, 16.0±0.2, 16.9±0.2, 17.2±0.2, 18.0±0.2, 18.9±0.2, 20.4±0.2, 20.5±0.2, 21.0±0.2, 22.0±0.2, 22.6±0.2, 23.4±0.2, 24.4±0.2, 25.1±0.2, 24.8±0.2, 25.9±0.2, 26.0±0.2, 27.2±0.2, 28.2±0.2, 29.7±0.2, 30.7±0.2, 31.5±0.2, 33.5±0.2, 35.7±0.2, 37.4±0.2, and 39.5±0.2 °2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, 12.9±0.1, 15.1±0.1, 16.0±0.1, 16.9±0.1, 17.2±0.1, 18.0±0.1, 18.9±0.1, 20.4±0.1, 20.5±0.1, 21.0±0.1, 22.0±0.1, 22.6±0.1, 23.4±0.1, 24.4±0.1, 25.1±0.1, 24.8±0.1, 25.9±0.1, 26.0±0.1, 27.2±0.1, 28.2±0.1, 29.7±0.1, 30.7±0.1, 31.5±0.1, 33.5±0.1, 35.7±0.1, 37.4±0.1, and 39.5±0.1 °2θ (e.g., 6.5, 8.5, 10.2, 12.9, 15.1, 16.0, 16.9, 17.2, 18.0, 18.9, 20.4, 20.5, 21.0, 22.0, 22.6, 23.4, 24.4, 25.1, 24.8, 25.9, 26.0, 27.2, 28.Characterized by an XRPD pattern comprising signals at 2, 29.7, 30.7, 31.5, 33.5, 35.7, 37.4, and 39.5° 2θ).

[0193] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, is characterized by an XRPD pattern having at least one signal selected from 6.5 ± 0.5, 8.5 ± 0.5, and 16.0 ± 0.5° 2θ (e.g., 6.5 ± 0.2, 8.5 ± 0.2, and 16.0 ± 0.2° 2θ (e.g., 6.5 ± 0.1, 8.5 ± 0.1, and 16.0 ± 0.1° 2θ (e.g., 6.5, 8.5, and 16.0° 2θ))).

[0194] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, is characterized by an XRPD pattern having at least one signal selected from 6.5 ± 0.5, 10.2 ± 0.5, and 16.0 ± 0.5° 2θ (e.g., 6.5 ± 0.2, 10.2 ± 0.2, and 16.0 ± 0.2° 2θ (e.g., 6.5 ± 0.1, 10.2 ± 0.1, and 16.0 ± 0.1° 2θ (e.g., 6.5, 10.2, and 16.0° 2θ))).

[0195] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, is characterized by an XRPD pattern having at least one signal selected from 8.5 ± 0.5, 10.2 ± 0.5, and 16.0 ± 0.5° 2θ (e.g., 8.5 ± 0.2, 10.2 ± 0.2, and 16.0 ± 0.2° 2θ (e.g., 8.5 ± 0.1, 10.2 ± 0.1, and 16.0 ± 0.1° 2θ (e.g., 8.5, 10.2, and 16.0° 2θ))).

[0196] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least two signals selected from 6.5±0.5, 8.5±0.5, 10.2±0.5, and 16.0±0.5° 2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, and 16.0±0.2° 2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, and 16.0±0.1° 2θ (e.g., 6.5, 8.5, 10.2, and 16.0° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0197] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least three signals selected from 6.5±0.5, 8.5±0.5, 10.2±0.5, and 16.0±0.5° 2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, and 16.0±0.2° 2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, and 16.0±0.1° 2θ (e.g., 6.5, 8.5, 10.2, and 16.0° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0198] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern having at least four signals selected from 6.5±0.5, 8.5±0.5, 10.2±0.5, 16.0±0.5, 18.0±0.5, 20.5±0.5, 21.0±0.5, and 22.0±0.5° 2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, 16.0±0.2, 18.0±0.2, 20.5±0.2, 21.0±0.2, and 22.0±0.2° 2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, 16.0±0.1, 18.0±0.1, 20.5±0.1, 21.0±0.1, and 22.0±0.1° 2θ (e.g., 6.5, 8.5, 10.2, 16.0, 18.0, 20.5, 21.0, and 22.0° 2θ))) when measured at 25° C. using Cu K alpha radiation.

[0199] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25°C, has an XRPD pattern having at least five signals selected from 6.5±0.5, 8.5±0.5, 10.2±0.5, 16.0±0.5, 18.0±0.5, 20.5±0.5, 21.0±0.5, and 22.0±0.5° 2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, 16.0±0.2, 18.0±0.2, 20.5±0.2, 21.0±0.2, and 22.0±0.2° 2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, 16.0±0.1, 18.0±0.1, 20.5±0.1, 21.0±0.1, and 22.0±0.1° 2θ (e.g., 6.5, 8.5, 10.2, 16.0, 18.0, 20.5, 21.0, and 22.0° 2θ))) using Cu K alpha radiation.

[0200] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, has an XRPD pattern having at least five signals selected from 6.5 ± 0.5, 8.5 ± 0.5, 10.2 ± 0.5, 16.0 ± 0.5, 16.9 ± 0.5, 18.0 ± 0.5, 20.4 ± 0.5, 20.5 ± 0.5, 21.0 ± 0.5, 22.0 ± 0.5, 22.6 ± 0.5, 23.4 ± 0.5, 24.4 ± 0.5, 25.1 ± 0.5, 26.0 ± 0.5, and 27.2 ± 0.5 ° 2θ (e.g., 6.5 ± 0.2, 8.5 ± 0.2, 10.2 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 18.0 ± 0.2, 20.4 ± 0.2, 20.5 ± 0.2, 21.0 ± 0.2, 22.0 ± 0.2, 22.6 ± 0.2, 23.4 ± 0.2, 24.4 ± 0.2, 25.1 ± 0.2, 26.0 ± 0.2, and 27.2 ± 0.2 ° 2θ (e.g., 6.5 ± 0.1, 8.5 ± 0.1, 10.2 ± 0.1, 16.0 ± 0.1, 16.9 ± 0.1, 18.0 ± 0.1, 20.4 ± 0.1, 20.5 ± 0.1, 21.0 ± 0.1, 22.0 ± 0.1, 22.6 ± 0.1, 23.4 ± 0.1, 24.4 ± 0.1, 25.1 ± 0.1, 26.0 ± 0.1, and 27.2 ± 0.1 ° 2θ (e.g., 6.5, 8.5, 10.2, 16.0, 16.9, 18.0, 20.4, 20.5, 21.0, 22.0, 22.6, 23.4, 24.4, 25.1, 26.0, and 27.2 ° 2θ))).

[0201] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has 6.5 ± 0.5, 8.5 ± 0.5, 10.2 ± 0.5, 12.9 ± 0.5, 15.1 ± 0.5, 16.0 ± 0.5, 16.9 ± 0.5, 17.2 ± 0.5, 18.0 ± 0.5, 18.9 ± 0.5, 20.4 ± 0.5, 20.5 ± 0.5, 21.0 ± 0.5, 22.0 ± 0.5, 22.6 ± 0.5, 23.4 ± 0.5, 24.4 ± 0.5, 25.1 ± 0.5, 24.8 ± 0.5, 25.9 ± 0.5, 26.0 ± 0.5, 27.2 ± 0.5, 28.2 ± 0.5, 29.7 ± 0.5, 30.7 ± 0.5, 31.5 ± 0.5, 33.5 ± 0.5, 35.7 ± 0.5, 37.4 ± 0.5, and 39.5 ± 0.5 °2θ (e.g., 6.5 ± 0.2, 8.5 ± 0.2, 10.2 ± 0.2, 12.9 ± 0.2, 15.1 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 17.2 ± 0.2, 18.0 ± 0.2, 18.9 ± 0.2, 20.4 ± 0.2, 20.5 ± 0.2, 21.0 ± 0.2, 22.0 ± 0.2, 22.6 ± 0.2, 23.4 ± 0.2, 24.4 ± 0.2, 25.1 ± 0.2, 24.8 ± 0.2, 25.9 ± 0.2, 26.0 ± 0.2, 27.2 ± 0.2, 28.2 ± 0.2, 29.7 ± 0.2, 30.7 ± 0.2, 31.5 ± 0.2, 33.5 ± 0.2, 35.7 ± 0.2, 37.4 ± 0.2, and 39.5 ± 0.2 °2θ (e.g., 6.5 ± 0.1, 8.5 ± 0.1, 10.2 ± 0.1, 12.9 ± 0.1, 15.1 ± 0.1, 16.0 ± 0.1, 16.9 ± 0.1, 17.2 ± 0.1, 18.0 ± 0.1, 18.9 ± 0.1, 20.4 ± 0.1, 20.5 ± 0.1, 21.0 ± 0.1, 22.0 ± 0.1, 22.6 ± 0.1, 23.4 ± 0.1, 24.4 ± 0.1, 25.1 ± 0.1, 24.8 ± 0.1, 25.9 ± 0.1, 26.0 ± 0.1, 27.2 ± 0.1, 28.2 ± 0.1, 29.7 ± 0.1, 30.7 ± 0.1, 31.5 ± 0.1, 33.5 ± 0.1, 35.7 ± 0.1, 37.4 ± 0.1, and 39.5 ± 0.1 °2θ (e.g., 6.5, 8.5, 10.2, 12.9, 15.1, 16.0, 16.9, 17.2, 18.0, 18.9, 20.4, 20.5, 21.0, 22.0, 22.6, 23.4, 24.4, 25.1, 24.8, 25.9, 26.0, 27.2, 28.Characterized by an XRPD pattern having at least 5 signals selected from 2, 29.7, 30.7, 31.5, 33.5, 35.7, 37.4, and 39.5° 2θ).

[0202] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has 6.5±0.5, 8.5±0.5, 10.2±0.5, 12.9±0.5, 15.1±0.5, 16.0±0.5, 16.9±0.5, 17.2±0.5, 18.0±0.5, 18.9±0.5, 20.4±0.5, 20.5±0.5, 21.0±0.5, 22.0±0.5, 22.6±0.5, 23.4±0.5, 24.4±0.5, 25.1±0.5, 24.8±0.5, 25.9±0.5, 26.0±0.5, 27.2±0.5, 28.2±0.5, 29.7±0.5, 30.7±0.5, 31.5±0.5, 33.5±0.5, 35.7±0.5, 37.4±0.5, and 39.5±0.5 °2θ (e.g., 6.5±0.2, 8.5±0.2, 10.2±0.2, 12.9±0.2, 15.1±0.2, 16.0±0.2, 16.9±0.2, 17.2±0.2, 18.0±0.2, 18.9±0.2, 20.4±0.2, 20.5±0.2, 21.0±0.2, 22.0±0.2, 22.6±0.2, 23.4±0.2, 24.4±0.2, 25.1±0.2, 24.8±0.2, 25.9±0.2, 26.0±0.2, 27.2±0.2, 28.2±0.2, 29.7±0.2, 30.7±0.2, 31.5±0.2, 33.5±0.2, 35.7±0.2, 37.4±0.2, and 39.5±0.2 °2θ (e.g., 6.5±0.1, 8.5±0.1, 10.2±0.1, 12.9±0.1, 15.1±0.1, 16.0±0.1, 16.9±0.1, 17.2±0.1, 18.0±0.1, 18.9±0.1, 20.4±0.1, 20.5±0.1, 21.0±0.1, 22.0±0.1, 22.6±0.1, 23.4±0.1, 24.4±0.1, 25.1±0.1, 24.8±0.1, 25.9±0.1, 26.0±0.1, 27.2±0.1, 28.2±0.1, 29.7±0.1, 30.7±0.1, 31.5±0.1, 33.5±0.1, 35.7±0.1, 37.4±0.1, and 39.5±0.1 °2θ (e.g., 6.5, 8.5, 10.2, 12.9, 15.1, 16.0, 16.9, 17.2, 18.0, 18.9, 20.4, 20.5, 21.0, 22.0, 22.6, 23.4, 24.4, 25.1, 24.8, 25.9, 26.0, 27.2, 28.2. Characterized by an XRPD pattern having at least one X-ray powder diffraction signal at 2, 29.7, 30.7, 31.5, 33.5, 35.7, 37.4, and 39.5° 2θ).

[0203] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, using Cu K alpha radiation, has an XRPD pattern characterized by at least one X-ray powder diffraction signal at 6.5 ± 0.2, 8.5 ± 0.2, 10.2 ± 0.2, 12.9 ± 0.2, 15.1 ± 0.2, 16.0 ± 0.2, 16.9 ± 0.2, 17.2 ± 0.2, 18.0 ± 0.2, 18.9 ± 0.2, 20.4 ± 0.2, 20.5 ± 0.2, 21.0 ± 0.2, 22.0 ± 0.2, 22.6 ± 0.2, 23.4 ± 0.2, 24.4 ± 0.2, 25.1 ± 0.2, 24.8 ± 0.2, 25.9 ± 0.2, 26.0 ± 0.2, 27.2 ± 0.2, 28.2 ± 0.2, 29.7 ± 0.2, 30.7 ± 0.2, 31.5 ± 0.2, 33.5 ± 0.2, 35.7 ± 0.2, 37.4 ± 0.2, and 39.5 ± 0.2° 2θ.

[0204] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising one or more signals described in Table 5 below.

[0205] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising two or more signals described in Table 5 below.

[0206] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising three or more signals described in Table 5 below.

[0207] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising four or more signals described in Table 5 below. [Table 5]

[0208] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern substantially similar to those shown in FIG. 5A and / or Table 5. In some embodiments, the crystalline form of Compound 1 free base so characterized is the crystalline form IV free base.

[0209] In some embodiments, Form IV free base is the pure phase Form IV free base.

[0210] (vi) Crystalline Pattern A Free Base In some embodiments, the crystalline form of Compound 1 free base is the Crystalline Pattern A Free Base. In some embodiments, the Crystalline Pattern A Free Base is as defined in section (a)(vi) of this section.

[0211] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25°C, using Cu K alpha radiation, has X-ray powder diffraction signals at 11.9±0.5, 21.2±0.5, and 26.8±0.5° 2θ (e.g., 11.9±0.2, 21.2±0.2, and 26.8±0.2° 2θ (e.g., 11.9±0.1, 21.2±0.1, and 26.8±0.1° 2θ (e.g., 11.9, 21.2, and 26.8° 2θ))).

[0212] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising one or more signals described in Table 6 below.

[0213] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising two or more signals described in Table 6 below.

[0214] In some embodiments, the crystalline form of Compound 1 free base is characterized by an XRPD pattern comprising three or more signals described in Table 6 below.

[0215] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising four or more signals set forth in Table 6 below. [Table 6]

[0216] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that is substantially similar to that shown in FIG. 7A and / or Table 6. In some embodiments, the crystalline form of the free base of Compound 1 so characterized is the crystalline pattern A free base.

[0217] (vii) Crystalline pattern B free base In some embodiments, the crystalline form of the free base of Compound 1 is the crystalline pattern B free base. In some embodiments, the crystalline pattern B free base is as defined in section (a)(vii) of this section.

[0218] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25° C., has X-ray powder diffraction signals at 5.6±0.5, 16.9±0.5, and 22.6±0.5° 2θ (e.g., 5.6±0.2, 16.9±0.2, and 22.6±0.2° 2θ (e.g., 5.6±0.1, 16.9±0.1, and 22.6±0.1° 2θ (e.g., 5.6, 16.9, and 22.6° 2θ))) using Cu K alpha radiation.

[0219] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising one or more signals set forth in Table 7 below.

[0220] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising two or more signals set forth in Table 7 below.

[0221] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising three or more signals as set forth in Table 7 below.

[0222] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising four or more signals as set forth in Table 7 below. [Table 7]

[0223] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that is substantially similar to that shown in Figure 7C and / or Table 7. In some embodiments, the crystalline form of the free base of Compound 1 so characterized is the crystalline pattern B free base.

[0224] (viii) Crystalline pattern C free base In some embodiments, the crystalline form of the free base of Compound 1 is the crystalline pattern C free base. In some embodiments, the crystalline pattern C free base is as defined in section (a)(viii) of this section.

[0225] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, has X-ray powder diffraction signals at 4.5 ± 0.5 and 9.0 ± 0.5 °2θ (e.g., 4.5 ± 0.2 and 9.0 ± 0.2 °2θ (e.g., 4.5 ± 0.1 and 9.0 ± 0.1 °2θ (e.g., 4.5 and 9.0 °2θ))) using Cu K alpha radiation.

[0226] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by having X-ray powder diffraction signals at 4.5±0.5, 9.0±0.5, and 13.4±0.5° 2θ (e.g., 4.5±0.2, 9.0±0.2, and 13.4±0.2° 2θ (e.g., 4.5±0.1, 9.0±0.1, and 13.4±0.1° 2θ (e.g., 4.5, 9.0, and 13.4° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0227] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising one or more signals described in Table 8 below.

[0228] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising two or more signals described in Table 8 below.

[0229] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising three or more signals described in Table 8 below.

[0230] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern comprising four or more signals described in Table 8 below. [Table 8]

[0231] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that is substantially similar to that shown in Figure 7D and / or Table 8. In some embodiments, the crystalline form of the free base of Compound 1 so characterized is the crystalline pattern C free base.

[0232] (b) Differential Scanning Calorimetry (DSC) Characterization of the Crystalline Form In some embodiments, the crystalline form of Compound 1 free base has a differential scanning calorimetry (DSC) thermogram characterized by an endothermic event, onset temperature, and / or peak temperature measured by DSC.

[0233] In some embodiments, the DSC is performed using a TA Discovery DSC.

[0234] In some embodiments, the DSC is performed on a sample of 1 - 5 mg.

[0235] In some embodiments, the DSC is performed according to the lamp method.

[0236] In some embodiments, the DSC is performed at a heating rate of 10.0 °C / min.

[0237] In some embodiments, the DSC is performed in a temperature range of 30 - 300 °C.

[0238] In some embodiments, the DSC is performed using N 2 gas at 50.00 mL / min.

[0239] (i) Crystalline Form V Free Base In some embodiments, the crystalline form of Compound 1 free base is the crystalline form V free base. In some embodiments, the crystalline form V free base has a differential scanning calorimetry (DSC) thermogram characterized by an endothermic event, onset temperature, and / or peak temperature as defined in section (b)(i) of this section.

[0240] In some embodiments, the crystalline form of Compound 1 free base is characterized by an endothermic event of about 215 °C to about 230 °C as measured by DSC.

[0241] In some embodiments, the crystalline form of Compound 1 free base is characterized by a single endothermic event of about 215 °C to about 230 °C as measured by DSC.

[0242] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 215 ± 20 °C, 215 ± 15 °C, 215 ± 10 °C, or 215 ± 5 °C (e.g., about 215 °C) as measured by DSC.

[0243] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 230 ± 20 °C, 230 ± 15 °C, 230 ± 10 °C, or 230 ± 5 °C (e.g., about 230 °C) as measured by DSC.

[0244] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of about 227.5 °C to 227.7 °C as measured by DSC.

[0245] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of 227.5 ± 20 °C, 227.5 ± 15 °C, 227.5 ± 10 °C, or 227.5 ± 5 °C (e.g., about 227.5 °C) as measured by DSC.

[0246] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of 227.7 ± 20 °C, 227.7 ± 15 °C, 227.7 ± 10 °C, or 227.7 ± 5 °C (e.g., about 227.7 °C) as measured by DSC.

[0247] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of about 228.8 °C to 229.9 °C as measured by DSC.

[0248] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 228.8 ± 20 °C, 228.8 ± 15 °C, 228.8 ± 10 °C, or 228.8 ± 5 °C (e.g., about 228.8 °C) as measured by DSC.

[0249] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 229.9 ± 20 °C, 229.9 ± 15 °C, 229.9 ± 10 °C, or 229.9 ± 5 °C (e.g., about 229.9 °C) as measured by DSC.

[0250] In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the DSC scan is substantially similar to that shown in Figure 6E. In some embodiments, the crystalline form of the free base of Compound 1 is Form V free base.

[0251] In some embodiments, the DSC measurement is performed at a heating rate of 10.0 °C / min, using a TA Discovery DSC and / or on a sample of 1-5 mg.

[0252] In some embodiments, the crystalline form of the free base of Compound 1 is Form V, characterized in that the onset temperature is about 227.4 °C to 227.7 °C, e.g., about 227.5 °C to 227.7 °C, as measured by DSC performed at a heating rate of 10.0 °C / min, using a TA Discovery DSC and / or on a sample of 1-5 mg.

[0253] In some embodiments, the crystalline form of the free base of Compound 1 is Form V, characterized in that the peak temperature is about 228.8 °C to 229.9 °C, as measured by DSC performed at a heating rate of 10.0 °C / min, using a TA Discovery DSC and / or on a sample of 1-5 mg.

[0254] In some embodiments, the crystalline form of the free base of Compound 1 is Form V, characterized in that the onset temperature is about 227.5 °C to 227.7 °C and the peak temperature is about 228.8 °C to 229.9 °C, as measured by DSC performed at a heating rate of 10.0 °C / min, using a TA Discovery DSC and / or on a sample of 1-5 mg.

[0255] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, has an XRPD pattern containing signals at 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2 °2θ using Cu K alpha radiation, and when measured by DSC performed using a TA Discovery DSC at a heating rate of 10.0 °C / min and / or on a sample of 1 - 5 mg, has an onset temperature of about 227.5 °C to 227.7 °C and / or a peak temperature of about 228.8 °C to 229.9 °C, and is Crystal Form V.

[0256] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, has an XRPD pattern containing signals at 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, and 26.5 ± 0.2 °2θ using Cu K alpha radiation, and when measured by DSC performed using a TA Discovery DSC at a heating rate of 10.0 °C / min and / or on a sample of 1 - 5 mg, has an onset temperature of about 227.5 °C to 227.7 °C and / or a peak temperature of about 228.8 °C to 229.9 °C, and is Crystal Form V.

[0257] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, has an XRPD pattern containing signals at 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2, °2θ using Cu K alpha radiation, and when measured by DSC performed using a TA Discovery DSC at a heating rate of 10.0 °C / min and / or on a sample of 1 - 5 mg, has an onset temperature of about 227.5 °C to 227.7 °C and / or a peak temperature of about 228.8 °C to 229.9 °C, and is Crystal Form V.

[0258] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, has an XRPD pattern containing signals at 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2 °2θ using Cu K alpha radiation, and when measured by DSC using a heating rate of 10.0 °C / min and / or on a sample of 1 - 5 mg, has an onset temperature of about 227.5 °C to 227.7 °C and / or a peak temperature of about 228.8 °C to 229.9 °C, and is crystalline form V.

[0259] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, has an XRPD pattern containing signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2 °2θ using Cu K alpha radiation, and when measured by DSC using a heating rate of 10.0 °C / min and / or on a sample of 1 - 5 mg, has an onset temperature of about 227.5 °C to 227.7 °C and / or a peak temperature of about 228.8 °C to 229.9 °C, and is crystalline form V.

[0260] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, has an XRPD pattern containing signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2 °2θ using Cu K alpha radiation, and when measured by DSC using a heating rate of 10.0 °C / min and / or on a sample of 1 - 5 mg, has an onset temperature of about 227.5 °C to 227.7 °C and / or a peak temperature of about 228.8 °C to 229.9 °C, and is crystalline form V.

[0261] (ii) Crystalline form I free base In some embodiments, the crystalline form of the free base of Compound 1 is the crystalline form I free base. In some embodiments, the crystalline form I free base has a differential scanning calorimetry (DSC) thermogram characterized by an endothermic event, onset temperature, and / or peak temperature as defined in section (b)(ii) of this section.

[0262] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endotherm measured by DSC in the range of about 210°C to about 240°C.

[0263] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 210 ± 20°C, 210 ± 15°C, 210 ± 10°C, or 210 ± 5°C (e.g., about 210°C) as measured by DSC.

[0264] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 240 ± 20°C, 240 ± 15°C, 240 ± 10°C, or 240 ± 5°C (e.g., about 240°C) as measured by DSC.

[0265] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature measured by DSC in the range of about 225°C to 227°C.

[0266] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of 225 ± 20°C, 225 ± 15°C, 225 ± 10°C, or 225 ± 5°C (e.g., about 225°C) as measured by DSC.

[0267] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of 227 ± 20°C, 227 ± 15°C, 227 ± 10°C, or 227 ± 5°C (e.g., about 227°C) as measured by DSC.

[0268] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature measured by DSC in the range of about 227°C to 229°C.

[0269] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 227 ± 20 °C, 227 ± 15 °C, 227 ± 10 °C, or 227 ± 5 °C (e.g., about 227 °C) as measured by DSC.

[0270] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 229 ± 20 °C, 229 ± 15 °C, 229 ± 10 °C, or 229 ± 5 °C (e.g., about 229 °C) as measured by DSC.

[0271] In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the DSC scan is substantially similar to that shown in Figure 2D. In some embodiments, the crystalline form of the free base of Compound 1 is Form I free base.

[0272] (iii) Crystalline Form II Free Base In some embodiments, the crystalline form of the free base of Compound 1 is Crystalline Form II free base. In some embodiments, Crystalline Form II free base has a differential scanning calorimetry (DSC) thermogram characterized by an endothermic event, onset temperature, and / or peak temperature as defined in section (b)(iii) of this section.

[0273] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endotherm of about 221 °C to about 230 °C as measured by DSC.

[0274] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 221 ± 20 °C, 221 ± 15 °C, 221 ± 10 °C, or 221 ± 5 °C (e.g., about 221 °C) as measured by DSC.

[0275] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 230 ± 20 °C, 230 ± 15 °C, 230 ± 10 °C, or 230 ± 5 °C (e.g., about 230 °C) as measured by DSC.

[0276] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of about 221.5 °C to 221.9 °C as measured by DSC.

[0277] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of 221.5 ± 20 °C, 221.5 ± 15 °C, 221.5 ± 10 °C, or 221.5 ± 5 °C (e.g., about 221.5 °C) as measured by DSC.

[0278] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of 221.9 ± 20 °C, 221.9 ± 15 °C, 221.9 ± 10 °C, or 221.9 ± 5 °C (e.g., about 221.9 °C) as measured by DSC.

[0279] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of about 225 °C to 225.8 °C as measured by DSC.

[0280] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 225 ± 20 °C, 225 ± 15 °C, 225 ± 10 °C, or 225 ± 5 °C (e.g., about 225 °C) as measured by DSC.

[0281] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 225.8 ± 20 °C, 225.8 ± 15 °C, 225.8 ± 10 °C, or 225.8 ± 5 °C (e.g., about 225.8 °C) as measured by DSC.

[0282] In some embodiments, the DSC measurement is performed at a heating rate of 10.0 °C / min, using a TA Discovery DSC, and / or on a sample of 1 - 5 mg.

[0283] In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the DSC scan is substantially similar to that shown in Figure 3E. In some embodiments, the crystalline form of the free base of Compound 1 is Form II free base.

[0284] (iv) Crystalline Form III Free Base In some embodiments, the crystalline form of Compound 1 free base is Crystalline Form III Free Base. In some embodiments, the Crystalline Form III Free Base has a differential scanning calorimetry (DSC) thermogram characterized by an endothermic event, onset temperature, and / or peak temperature as defined in section (b)(iv) of this section.

[0285] In some embodiments, the crystalline form of Compound 1 free base is characterized by an endotherm at about 220 °C to about 245 °C as measured by DSC.

[0286] In some embodiments, the crystalline form of Compound 1 free base is characterized by an endothermic event at 220 ± 20 °C, 220 ± 15 °C, 220 ± 10 °C, or 220 ± 5 °C (e.g., about 220 °C) as measured by DSC.

[0287] In some embodiments, the crystalline form of Compound 1 free base is characterized by an endothermic event at 245 ± 20 °C, 245 ± 15 °C, 245 ± 10 °C, or 245 ± 5 °C (e.g., about 245 °C) as measured by DSC.

[0288] In some embodiments, the crystalline form of Compound 1 free base is characterized by an onset temperature of about 221.5 °C to 229.4 °C as measured by DSC.

[0289] In some embodiments, the crystalline form of Compound 1 free base is characterized by an onset temperature of 221.5 ± 20 °C, 221.5 ± 15 °C, 221.5 ± 10 °C, or 221.5 ± 5 °C (e.g., about 221.5 °C) as measured by DSC.

[0290] In some embodiments, the crystalline form of Compound 1 free base is characterized by an onset temperature of 229.4 ± 20 °C, 229.4 ± 15 °C, 229.4 ± 10 °C, or 229.4 ± 5 °C (e.g., about 229.4 °C) as measured by DSC.

[0291] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of about 230 °C to 231.5 °C as measured by DSC.

[0292] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 230 ± 20 °C, 230 ± 15 °C, 230 ± 10 °C, or 230 ± 5 °C (e.g., about 230 °C) as measured by DSC.

[0293] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of 231.5 ± 20 °C, 231.5 ± 15 °C, 231.5 ± 10 °C, or 231.5 ± 5 °C (e.g., about 231.5 °C) as measured by DSC.

[0294] In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the DSC scan is substantially similar to that shown in Figure 4E. In some embodiments, the crystalline form of the free base of Compound 1 is Form III free base.

[0295] (v) Crystalline Form IV Free Base In some embodiments, the crystalline form of the free base of Compound 1 is Crystalline Form IV free base. In some embodiments, Crystalline Form IV free base has a differential scanning calorimetry (DSC) thermogram characterized by an endothermic event, onset temperature, and / or peak temperature as defined in section (b)(v) of this section.

[0296] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an exothermic event from about 185 °C to 205 °C and an endothermic event from about 215 °C to about 240 °C as measured by DSC.

[0297] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an exothermic event from about 185 °C to 205 °C as measured by DSC.

[0298] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an exothermic event at 185 ± 20 °C, 185 ± 15 °C, 185 ± 10 °C, or 185 ± 5 °C (e.g., about 185 °C) as measured by DSC.

[0299] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an exothermic event at 205 ± 20 °C, 205 ± 15 °C, 205 ± 10 °C, or 205 ± 5 °C (e.g., about 205 °C) as measured by DSC.

[0300] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endotherm in the range of about 215 °C to about 240 °C as measured by DSC.

[0301] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 215 ± 20 °C, 215 ± 15 °C, 215 ± 10 °C, or 215 ± 5 °C (e.g., about 215 °C) as measured by DSC.

[0302] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an endothermic event at 240 ± 20 °C, 240 ± 15 °C, 240 ± 10 °C, or 240 ± 5 °C (e.g., about 240 °C) as measured by DSC.

[0303] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of an exothermic event in the range of about 192.2 °C to 195.1 °C as measured by DSC.

[0304] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of an exothermic event at 192.2 ± 20 °C, 192.2 ± 15 °C, 192.2 ± 10 °C, or 192.2 ± 5 °C (e.g., about 192.2 °C) as measured by DSC.

[0305] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of an exothermic event at 195.1 ± 20 °C, 195.1 ± 15 °C, 195.1 ± 10 °C, or 195.1 ± 5 °C (e.g., about 195.1 °C) as measured by DSC.

[0306] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of an endothermic event of about 226.7 °C to 227.6 °C as measured by DSC.

[0307] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of an endothermic event at 226.7 ± 20 °C, 226.7 ± 15 °C, 226.7 ± 10 °C, or 226.7 ± 5 °C (e.g., about 226.7 °C) as measured by DSC.

[0308] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an onset temperature of an endothermic event at 227.6 ± 20 °C, 227.6 ± 15 °C, 227.6 ± 10 °C, or 227.6 ± 5 °C (e.g., about 227.6 °C) as measured by DSC.

[0309] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature of about 229.6 °C to 229.8 °C as measured by DSC.

[0310] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature at 229.6 ± 20 °C, 229.6 ± 15 °C, 229.6 ± 10 °C, or 229.6 ± 5 °C (e.g., about 229.6 °C) as measured by DSC.

[0311] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a peak temperature at 229.8 ± 20 °C, 229.8 ± 15 °C, 229.8 ± 10 °C, or 229.8 ± 5 °C (e.g., about 229.8 °C) as measured by DSC.

[0312] In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the DSC scan is substantially similar to that shown in Figure 5E. In some embodiments, the crystalline form of the free base of Compound 1 is the free base of Form IV.

[0313] (c) Evaluation of the thermogravimetric analysis (TGA) characteristics of the crystalline form In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a mass loss of about 0.1% to 0.5% (e.g., 0.2%) as measured by TGA. In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the TGA scan is substantially similar to that shown in Figure 6D. In some embodiments, the crystalline form of the free base of Compound 1 is the free base of Form V.

[0314] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a mass loss of about 0.5 to 1% (e.g., 0.8%) as measured by TGA. In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the TGA scan is substantially similar to that shown in Figure 3D. In some embodiments, the crystalline form of the free base of Compound 1 is the free base of Form II.

[0315] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a mass loss of about 0.1% to 0.5% (e.g., 0.2%) as measured by TGA. In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the TGA scan is substantially similar to that shown in Figure 4D. In some embodiments, the crystalline form of the free base of Compound 1 is the free base of Form III.

[0316] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by a mass loss of about 0.3% to 0.8% (e.g., 0.5%) as measured by TGA. In some embodiments, the crystalline form of the free base of Compound 1 is characterized in that the TGA scan is substantially similar to that shown in Figure 5D. In some embodiments, the crystalline form of the free base of Compound 1 is the free base of Form IV.

[0317] (d) Other property evaluations of the crystal form In some embodiments, the crystal form of Compound 1 free base is an anhydrous crystal form.

[0318] In some embodiments, the crystal form of Compound 1 free base is not a solvate.

[0319] In some embodiments, the crystal form of Compound 1 free base has a shape including rhombohedral plates.

[0320] In some embodiments, the crystal form of Compound 1 free base has a shape including rectangular plates.

[0321] In some embodiments, the crystal form of Compound 1 free base has a shape including needles.

[0322] In some embodiments, the crystal form of Compound 1 free base had a water uptake with a weight increase of about 0.20% at 5 - 95% relative humidity (RH) as measured by dynamic vapor sorption (DVS).

[0323] In some embodiments, the crystal form of Compound 1 free base is Crystal Form V free base which is an anhydrous crystal form.

[0324] In some embodiments, the crystal form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern including signals at 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2 °2θ using Cu K alpha radiation, and is Crystal Form V free base which is characterized by being an anhydrous crystal form.

[0325] In some embodiments, the crystalline form of the free base of Compound 1 is a crystalline form V free base, characterized by an XRPD pattern comprising signals at 6.8±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25°C using Cu K alpha radiation, and is characterized by an anhydrous crystalline form.

[0326] In some embodiments, the crystalline form of the free base of Compound 1 is a crystalline form V free base, characterized by an XRPD pattern comprising signals at 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2,° 2θ when measured at 25°C using Cu K alpha radiation, and is characterized by an anhydrous crystalline form.

[0327] In some embodiments, the crystalline form of the free base of Compound 1 is a crystalline form V free base, characterized by an XRPD pattern comprising signals at 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25°C using Cu K alpha radiation, and is characterized by an anhydrous crystalline form.

[0328] In some embodiments, the crystalline form of the free base of Compound 1 is a crystalline form V free base, characterized by an XRPD pattern comprising signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ when measured at 25°C using Cu K alpha radiation, and is characterized by an anhydrous crystalline form.

[0329] In some embodiments, the crystalline form of the free base of Compound 1 is a crystalline form V free base, characterized by an XRPD pattern comprising signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25°C using Cu K alpha radiation, and is characterized by an anhydrous crystalline form.

[0330] In some embodiments, the crystalline form of the free base of Compound 1 is crystalline form V of the free base which is not a solvate.

[0331] In some embodiments, the crystalline form of the free base of Compound 1 is crystalline form V of the free base, which is characterized by an XRPD pattern comprising signals at 6.8±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is not a solvate.

[0332] In some embodiments, the crystalline form of the free base of Compound 1 is crystalline form V of the free base, which is characterized by an XRPD pattern comprising signals at 6.8±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is not a solvate.

[0333] In some embodiments, the crystalline form of the free base of Compound 1 is crystalline form V of the free base, which is characterized by an XRPD pattern comprising signals at 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2,° 2θ when measured at 25 °C using Cu K alpha radiation, and is not a solvate.

[0334] In some embodiments, the crystalline form of the free base of Compound 1 is crystalline form V of the free base, which is characterized by an XRPD pattern comprising signals at 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is not a solvate.

[0335] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8 ± 0.2, 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is a crystalline form V free base that is not a solvate.

[0336] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8 ± 0.2, 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, and 26.5 ± 0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is a crystalline form V free base that is not a solvate.

[0337] In some embodiments, the crystalline form of the free base of Compound 1 is a crystalline form V free base having a shape that includes rhombohedral plates, for example, rhombohedral plates having a diameter of about 5 microns to about 20 microns as measured by polarized light microscopy (PLM).

[0338] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2° 2θ when measured at 25 °C as the free base using Cu K alpha radiation, and is a crystalline form V free base characterized by a shape that includes rhombohedral plates, for example, rhombohedral plates having a diameter of about 5 microns to about 20 microns.

[0339] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, and 26.5 ± 0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is a crystalline form V free base characterized by a shape that includes rhombohedral plates, for example, rhombohedral plates having a diameter of about 5 microns to about 20 microns.

[0340] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2 °2θ using Cu K alpha radiation, and is a crystalline form V free base characterized by a shape comprising rhombohedral crystal plates, e.g., rhombohedral crystal plates having a diameter of about 5 microns to about 20 microns.

[0341] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, and 26.5 ± 0.2 °2θ using Cu K alpha radiation, and is a crystalline form V free base characterized by a shape comprising rhombohedral crystal plates, e.g., rhombohedral crystal plates having a diameter of about 5 microns to about 20 microns.

[0342] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 6.8 ± 0.2, 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2 °2θ using Cu K alpha radiation, and is a crystalline form V free base characterized by a shape comprising rhombohedral crystal plates, e.g., rhombohedral crystal plates having a diameter of about 5 microns to about 20 microns.

[0343] In some embodiments, the crystalline form of Compound 1 free base, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 6.8 ± 0.2, 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, and 26.5 ± 0.2 °2θ using Cu K alpha radiation, and is a crystalline form V free base characterized by a shape comprising rhombohedral crystal plates, e.g., rhombohedral crystal plates having a diameter of about 5 microns to about 20 microns.

[0344] In some embodiments, the crystalline form of the free base of Compound 1 is crystalline form V free base, which is characterized by water uptake with a weight increase of about 0.20% at 5 - 95% relative humidity (RH) as measured by dynamic vapor sorption (DVS).

[0345] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2 °2θ using Cu K alpha radiation, and is crystalline form V free base, which is characterized by water uptake with a weight increase of about 0.20% at 5 - 95% RH as measured by DVS.

[0346] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 6.8 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, and 26.5 ± 0.2 °2θ using Cu K alpha radiation, and is crystalline form V free base, which is characterized by water uptake with a weight increase of about 0.20% at 5 - 95% RH as measured by DVS.

[0347] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, and 22.9 ± 0.2, °2θ using Cu K alpha radiation, and is crystalline form V free base, which is characterized by water uptake with a weight increase of about 0.20% at 5 - 95% RH as measured by DVS.

[0348] In some embodiments, the crystalline form of the free base of Compound 1, when measured at 25 °C, is characterized by an XRPD pattern comprising signals at 11.7 ± 0.2, 18.9 ± 0.2, 20.5 ± 0.2, 22.9 ± 0.2, 23.8 ± 0.2, and 26.5 ± 0.2 °2θ using Cu K alpha radiation, and is crystalline form V free base, which is characterized by water uptake with a weight increase of about 0.20% at 5 - 95% RH as measured by DVS.

[0349] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, and 22.9±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is characterized by water uptake with a weight gain of about 0.20% at 5-95% RH as measured by DVS, and is the crystalline form V free base.

[0350] In some embodiments, the crystalline form of the free base of Compound 1 is characterized by an XRPD pattern that includes signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, and 26.5±0.2° 2θ when measured at 25 °C using Cu K alpha radiation, and is characterized by water uptake with a weight gain of about 0.20% at 5-95% RH as measured by DVS, and is the crystalline form V free base.

[0351] (e) Amorphous form In some embodiments, the free base of Compound 1 is the amorphous free base of Compound 1.

[0352] In some embodiments, the amorphous free base of Compound 1 is characterized by an XRPD pattern that includes a single broad halo signal at about 10 to about 32° 2θ when measured at 25 °C using Cu K alpha radiation.

[0353] In some embodiments, the amorphous free base of Compound 1 is characterized by an XRPD pattern that includes a single broad halo signal at 10±0.5 to 32±0.5° 2θ (e.g., 10±0.2 to 32±0.2° 2θ (e.g., 10±0.1 to 32±0.1° 2θ (e.g., 10 to 32° 2θ))) when measured at 25 °C using Cu K alpha radiation.

[0354] In some embodiments, the amorphous free base of Compound 1 is characterized by an XRPD pattern that is substantially similar to that shown in Figure 1A.

[0355] In some embodiments, the amorphous compound 1 free base is characterized by a peak temperature of about 198 °C as measured by DSC.

[0356] In some embodiments, the amorphous compound 1 free base is characterized by a peak temperature of 198 ± 20 °C, 198 ± 15 °C, 198 ± 10 °C, or 198 ± 5 °C (e.g., about 198 °C) as measured by DSC.

[0357] In some embodiments, the amorphous compound 1 free base is characterized in that the DSC scan is substantially similar to that shown in FIG. 1B.

[0358] In some embodiments, the amorphous compound 1 free base is characterized by a mass loss of about 5-10% (e.g., 7-8%) as measured by TGA.

[0359] In some embodiments, the amorphous compound 1 free base is characterized in that the TGA scan is substantially similar to that shown in FIG. 1B.

[0360] In some embodiments, the free base of amorphous compound 1 is converted to the free base of Form II of compound 1.

[0361] (ii) Composition Compositions comprising a pharmaceutical composition comprising crystalline and / or amorphous compound 1 free base are further contemplated herein.

[0362] In some embodiments, there is provided a composition comprising a mixture of solid forms of compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form I, Form II, Form III, Form IV, or Form V free base.

[0363] In some embodiments, there is provided a composition comprising a mixture of solid forms of compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form I free base.

[0364] In some embodiments, there is provided a composition comprising a mixture of solid forms of Compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form II free base.

[0365] In some embodiments, there is provided a composition comprising a mixture of solid forms of Compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form III free base.

[0366] In some embodiments, there is provided a composition comprising a mixture of solid forms of Compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form IV free base.

[0367] In some embodiments, there is provided a composition comprising a mixture of solid forms of Compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form V free base.

[0368] In some embodiments, the composition is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers.

[0369] In some embodiments, there is provided a pharmaceutical composition comprising a mixture of solid forms of Compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form I free base.

[0370] In some embodiments, there is provided a pharmaceutical composition comprising a mixture of solid forms of Compound 1 free base, wherein 75% (w / w%) of the mixture is crystalline Form II free base. In some embodiments, there is provided a pharmaceutical composition comprising a mixture of solid forms of Compound 1 free base, wherein at least 75% (w / w%) of the mixture is crystalline Form II free base. In some embodiments, there is provided a pharmaceutical composition comprising a mixture of solid forms of Compound 1 free base, wherein at least 80% (w / w%), at least 90% (w / w%), at least 95% (w / w%), at least 98% (w / w%), or at least 99% (w / w%) of the mixture is crystalline Form II free base.

[0371] In some embodiments, there is provided a pharmaceutical composition comprising a mixture of the free base form of Compound 1, wherein 75% (w / w%) of the mixture is the crystalline Form III free base.

[0372] In some embodiments, there is provided a pharmaceutical composition comprising a mixture of the free base form of Compound 1, wherein 75% (w / w%) of the mixture is the crystalline Form IV free base.

[0373] In some embodiments, there is provided a pharmaceutical composition comprising a mixture of the free base form of Compound 1, wherein 75% (w / w%) of the mixture is the crystalline Form V free base. In some embodiments, there is provided a pharmaceutical composition comprising a mixture of the free base form of Compound 1, wherein at least 75% (w / w%) of the mixture is the crystalline Form V free base. In some embodiments, there is provided a pharmaceutical composition comprising a mixture of the free base form of Compound 1, wherein at least 80% (w / w%), at least 90% (w / w%), at least 95% (w / w%), at least 98% (w / w%), or at least 99% (w / w%) of the mixture is the crystalline Form V free base.

[0374] In some embodiments, about 75% of the mixture of Compound 1 is the Form I free base of Compound 1.

[0375] In some embodiments, about 80% of the mixture of Compound 1 is the Form I free base of Compound 1.

[0376] In some embodiments, about 85% of the mixture of Compound 1 is the Form I free base of Compound 1.

[0377] In some embodiments, about 90% of the mixture of Compound 1 is the Form I free base of Compound 1.

[0378] In some embodiments, about 91% of the mixture of Compound 1 is the Form I free base of Compound 1.

[0379] In some embodiments, about 92% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0380] In some embodiments, about 93% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0381] In some embodiments, about 94% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0382] In some embodiments, about 95% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0383] In some embodiments, about 96% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0384] In some embodiments, about 97% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0385] In some embodiments, about 98% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0386] In some embodiments, about 99% of the mixture of Compound 1 is the free base of Form I of Compound 1.

[0387] In some embodiments, about 75% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0388] In some embodiments, about 80% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0389] In some embodiments, about 85% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0390] In some embodiments, about 90% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0391] In some embodiments, about 91% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0392] In some embodiments, about 92% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0393] In some embodiments, about 93% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0394] In some embodiments, about 94% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0395] In some embodiments, about 95% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0396] In some embodiments, about 96% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0397] In some embodiments, about 97% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0398] In some embodiments, about 98% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0399] In some embodiments, about 99% of the mixture of Compound 1 is the free base of Form II of Compound 1.

[0400] In some embodiments, about 75% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0401] In some embodiments, about 80% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0402] In some embodiments, about 85% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0403] In some embodiments, about 90% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0404] In some embodiments, about 91% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0405] In some embodiments, about 92% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0406] In some embodiments, about 93% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0407] In some embodiments, about 94% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0408] In some embodiments, about 95% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0409] In some embodiments, about 96% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0410] In some embodiments, about 97% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0411] In some embodiments, about 98% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0412] In some embodiments, about 99% of the mixture of Compound 1 is the free base of Form III of Compound 1.

[0413] In some embodiments, about 75% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0414] In some embodiments, about 80% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0415] In some embodiments, about 85% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0416] In some embodiments, about 90% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0417] In some embodiments, about 91% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0418] In some embodiments, about 92% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0419] In some embodiments, about 93% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0420] In some embodiments, about 94% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0421] In some embodiments, about 95% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0422] In some embodiments, about 96% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0423] In some embodiments, about 97% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0424] In some embodiments, about 98% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0425] In some embodiments, about 99% of the mixture of Compound 1 is the free base of Form IV of Compound 1.

[0426] In some embodiments, about 75% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0427] In some embodiments, about 80% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0428] In some embodiments, about 85% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0429] In some embodiments, about 90% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0430] In some embodiments, about 91% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0431] In some embodiments, about 92% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0432] In some embodiments, about 93% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0433] In some embodiments, about 94% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0434] In some embodiments, about 95% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0435] In some embodiments, about 96% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0436] In some embodiments, about 97% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0437] In some embodiments, about 98% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0438] In some embodiments, about 99% of the mixture of Compound 1 is the free base of Form V of Compound 1.

[0439] In some embodiments, a composition comprising the free base of Compound 1, wherein 100% (w / w%) of the free base of Compound 1 is in the crystalline pure phase Form I, Form II, Form III, Form IV, or Form V, i.e., 100% of Form I, Form II, Form III, Form IV, or Form V, is provided. In some embodiments, the present composition is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers.

[0440] Exemplary pharmaceutically acceptable carriers include diluents such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils such as EPA or DHA or esters or triglycerides thereof or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine.

[0441] Pharmaceutical compositions containing crystalline and / or amorphous free base of Compound 1 may be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, tablet coating, elutriation, emulsifying, encapsulating, entrapping, or lyophilization processes. The pharmaceutical composition may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and / or auxiliaries that facilitate processing the solid form of the free base of Compound 1 into a preparation that can be used pharmaceutically. The appropriate formulation depends on the chosen route of administration.

[0442] Administration of the composition to a subject can be achieved via any mode of administration, for example, oral administration, topical administration, or injection. Depending on the intended mode of administration, the pharmaceutical composition containing the solid form of the free base of Compound 1 can be a solid, a semi-solid, or a liquid dosage formulation.

[0443] The solid form of Compound 1 free base may be administered alone in a pharmaceutical composition as the sole therapeutic agent or in combination with another therapeutic agent. The combination therapy may be achieved by means of simultaneous administration (e.g., the two agents are administered simultaneously) or sequential administration (e.g., one agent is administered first and then the other). In the case of simultaneous administration, the solid form of Compound 1 free base may be administered in the same pharmaceutical composition as the other therapeutic agent or in separate pharmaceutical compositions. The choice of the other therapeutic agent is based on the diagnosis of the attending physician and the judgment of the condition of the subject and the appropriate treatment protocol.

[0444] (iii) Method of treatment The solid form of Compound 1 free base has been found to be useful as an inhibitor of NLRP3 activity.

[0445] In some embodiments, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the solid form of Compound 1 free base or a pharmaceutical composition thereof. In some embodiments, provided is a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the solid form of Compound 1 free base or a pharmaceutical composition thereof.

[0446] In some embodiments, provided is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the solid form of Compound 1 free base or a pharmaceutical composition thereof. In some embodiments, provided is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the solid form of Compound 1 free base or a pharmaceutical composition thereof.

[0447] In some embodiments, provided is the solid form of Compound 1 free base or a pharmaceutical composition thereof for use in treating or preventing a disease or disorder.

[0448] In some embodiments, a solid form of Compound 1 free base or a pharmaceutical composition thereof is provided for use in treating a disease or disorder.

[0449] In some embodiments, use of a solid form of Compound 1 free base in the manufacture of a medicament for the treatment or prevention of a disease or disorder is provided.

[0450] In some embodiments, use of a solid form of Compound 1 free base in the manufacture of a medicament for the treatment of a disease or disorder is provided.

[0451] In some embodiments, use of a solid form of Compound 1 free base for the treatment or prevention of a disease or disorder is provided.

[0452] In some embodiments, use of a solid form of Compound 1 free base for the treatment of a disease or disorder is provided.

[0453] In some embodiments, the disease or disorder is associated with abnormal NLRP3 activity, and the method comprises inhibiting the abnormal NLRP3 activity such that the subject is treated.

[0454] In some embodiments, the disease or disorder is a central nervous system (CNS) disease or disorder, a peripheral nervous system (PNS) disease or disorder, a primary nerve disease of muscle, an inflammatory disorder, an autoimmune disorder, cancer, an infectious disease, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ophthalmic disease, a skin disease, a lymphatic disease, a rheumatic disease, a mental disease, graft-versus-host disease, pain (including disorders related to pain management), or an NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3.

[0455] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system and / or peripheral nervous system (“PNS”), such as dementia, Alzheimer's disease (“AD”), epilepsy, traumatic brain injury (“TBI”), multiple sclerosis (“MS”), developmental disorders, acute disseminated encephalomyelitis, transverse myelitis, Parkinson's disease (“PD”), amyotrophic lateral sclerosis (“ALS”), Huntington's disease (“HD”), or spinal cord injury.

[0456] In some embodiments, the disease or disorder is a major nerve disease of the muscle, such as dystrophy or spinal muscular atrophy.

[0457] In some embodiments, the disease or disorder is an inflammatory disorder, such as gout or anemia due to inflammation.

[0458] In some embodiments, the disease or disorder is an autoimmune disease, such as ulcerative colitis.

[0459] In some embodiments, the disease or disorder is a cancer, such as skin cancer or colon cancer.

[0460] In some embodiments, the disease or disorder is an infectious disease, such as a nerve infection.

[0461] In some embodiments, the disease or disorder is a metabolic disease, such as diabetes, for example, type 2 diabetes.

[0462] In some embodiments, the disease or disorder is a cardiovascular disease, such as stroke.

[0463] In some embodiments, the disease or disorder is a respiratory disease, such as asthma (e.g., steroid-resistant asthma, severe steroid-resistant asthma) or chronic obstructive pulmonary disease (“COPD”).

[0464] In some embodiments, the disease or disorder is a kidney disease, such as acute kidney disease, chronic kidney disease, or rare kidney disease.

[0465] In some embodiments, the disease or disorder is a liver disease such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0466] In some embodiments, the disease or disorder is an ophthalmic disease such as optic neuritis or macular degeneration.

[0467] In some embodiments, the disease or disorder is a skin disease such as psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0468] In some embodiments, the disease or disorder is a lymphatic disease.

[0469] In some embodiments, the disease or disorder is a rheumatic disease such as osteoarthritis, dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0470] In some embodiments, the disease or disorder is a psychological disease such as a neuropsychiatric condition including depression, major depressive disorder, or treatment-resistant depression.

[0471] In some embodiments, the disease or disorder is graft-versus-host disease.

[0472] In some embodiments, the disease or disorder is pain (including disorders related to pain management) such as pain management dependence, osteoarthritis pain, or allodynia.

[0473] In some embodiments, the NLRP3-related disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3 is a cryopyrin-associated autoinflammatory syndrome. In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease (NOMID).

[0474] In some embodiments, the disease or disorder is dementia, Alzheimer's disease ("AD"), epilepsy, traumatic brain injury ("TBI"), multiple sclerosis ("MS"), developmental disorder, acute disseminated encephalitis, transverse myelitis, Parkinson's disease ("PD"), amyotrophic lateral sclerosis ("ALS"), spinal muscular atrophy, Huntington's disease ("HD"), spinal cord injury, dystrophy, neurological infection, pain management dependence, neuropsychiatric condition (e.g., depression, major depressive disorder, treatment-resistant depression), neonatal-onset multisystem inflammatory disease ("NOMID"), asthma, osteoarthritis, ulcerative colitis, gout, anemia due to inflammation, Still's disease, chronic obstructive pulmonary disease ("COPD"), osteoarthritis pain, or hidradenitis suppurativa.

[0475] (iv) Preparation method The solid form of Compound 1 free base can be prepared by any suitable technique known in the art. In some embodiments, the present disclosure provides a crystalline or amorphous Compound 1 free base that can be obtained by, or is obtained by, or is directly obtained by, the method for preparation described in the Examples. In some embodiments, the present disclosure provides a method for preparing the crystalline free base form of Compound 1 as described in the Examples.

[0476] In some embodiments, the prepared crystalline Compound 1 free base is substantially free of the amorphous Compound 1 free base, characterized by the X-ray powder diffraction pattern of Figure 1A.

[0477] In some embodiments, the prepared crystalline Compound 1 free base is substantially free of the crystalline Compound 1 free base, characterized by the X-ray powder diffraction pattern of Figure 7A. In some embodiments, the crystalline Compound 1 free base is substantially free of Pattern A.

[0478] In some embodiments, the prepared crystalline Compound 1 free base is substantially free of the crystalline Compound 1 free base, characterized by the X-ray powder diffraction pattern of Figure 7C. In some embodiments, the crystalline Compound 1 free base is substantially free of Pattern B.

[0479] In some embodiments, the prepared crystalline compound 1 free base substantially does not contain a crystalline isopropanol solvate in the form of the compound 1 free base, and when measured at 25°C, it is characterized by having X-ray powder diffraction signals at 4.5 ± 0.2° 2θ and 9.0 ± 0.2° 2θ using Cu K alpha radiation. In some embodiments, the crystalline compound 1 free base substantially does not contain a crystalline compound 1 free base as shown in the X-ray powder diffraction pattern of FIG. 7D. In some embodiments, the crystalline compound 1 free base substantially does not contain Pattern C.

Example

[0480] The following examples are presented to enable a more complete understanding of the present disclosure. Of course, these examples are for illustrative purposes only and should not be construed as limiting the present disclosure in any way.

Table 9

[0481] Analysis methods X-ray powder diffraction (XRPD) XRPD was performed using a Bruker D8 Advance equipped with a LYNXEYE detector in reflection mode (Bragg-Brentano configuration). Samples were prepared on a Si zero-backscatter wafer. All XRPD experiments were performed at room temperature (RT). The parameters of the XRPD method used are provided in Table A.

Table 10

[0482] Polarized light microscopy (PLM) Optical microscopy was performed using a Zeiss AxioScope A1 digital imaging microscope equipped with 2.5x, 10x, 20x, and 40x objective lenses and a polarizer. Images were captured through the built-in Axiocam105 digital camera and processed using ZEN2 (Blue Edition) software provided by Zeiss.

[0483] Simultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry (S-TGA / DSC) TGA and DSC were performed simultaneously on the same sample using a Mettler Toledo TGA / DSC 3+ The protective and purge gases were nitrogen at flow rates of 20 - 30 mL / min and 50 - 100 mL / min, respectively. The desired amount of sample (5 - 10 mg) was directly weighed into a sealed aluminum pan with a pinhole and analyzed according to the parameters provided in Table B.

Table 11

[0484] Differential Scanning Calorimetry (Standalone DSC) DSC was performed using a TA Discovery DSC. The sample (1 - 5 mg) was directly weighed into a 40 μL sealed aluminum pan with a pinhole and analyzed according to the following parameters: Method = Ramp, Sample Size = 1 - 5 mg, Heating Rate = 10.0 °C / min, Temperature Range = 30 - 300 °C, Method Gas = 50.00 mL / min of N 2 .

[0485] Dynamic Vapor Sorption (DVS) DVS was performed using a TA Instruments Q5000SA. The sample (5 - 15 mg) was loaded into a metal quartz sample pan, suspended from a microbalance, and exposed to a humidified nitrogen gas stream. The weight change was relative to a matching empty reference pan on the opposite side of the sample, suspended from the microbalance. The sample was held at each level for a minimum of 10 minutes and proceeded to the next humidity level only if there was a weight change of less than 0.002% (interval: 5 seconds) between measurements or 45 minutes had elapsed (for 5 - 65% RH) or 2 hours had elapsed (for 80 - 95% RH). The program used is provided in Table C. The mass change by DVS is related to hygroscopicity.

Table 12

[0486] Proton nuclear magnetic resonance ( 1 H NMR) spectroscopy 1 H NMR was performed on a Bruker Avance 300 MHz spectrometer. The solid was dissolved in 0.75 mL of deuterated solvent in a 4 mL vial and transferred to an NMR tube (Wilmad 5 mm thin wall 8” 200 MHz, 506-PP-8) and analyzed according to the parameters provided in Table D. [Table 13]

[0487] High performance liquid chromatography (HPLC) HPLC was performed using an Agilent 1220 Infinity LC. The flow rate range of the instrument is 0.2 - 5.0 mL / min, the operating pressure range is 0 - 600 bar, the temperature range is 5 °C higher than ambient temperature - 60 °C, and the wavelength range is 190 - 600 nm.

[0488] The HPLC conditions used are as follows. Mobile phase A = 5 mM ammonium bicarbonate in water, mobile phase B = acetonitrile, diluent = acetonitrile: water (1:1 vol), injection volume = 5 μL, monitoring wavelength = 254 nm, column = Zorbax Eclipse XDB-C18 Rapid Resolution, 4.6 × 100 mm, 3.5 μm, column temperature = 40 °C. The gradient method is provided in Table E. [Table 14]

[0489] Karl Fischer (KF) titration KF titration for moisture determination was carried out using a Mettler Toledo C20S Coulometric KF Titrator equipped with a current generator cell having a diaphragm and a double platinum pin electrode. The detection range of the instrument is 1 ppm to 5% water. Aquastar (trademark) CombiCoulomat fritless reagent was used in both the anode compartment and the cathode compartment. Approximately 0.03 - 0.10 g of the sample was dissolved in the anode compartment and titrated until the solution potential dropped below 100 mV. For verification before sample analysis, a Hydranal 1 wt% water standard was used. The detection limit is less than 0.04 wt%. BDL = below detection limit.

[0490] 0.50 wt% KF means approximately 0.10 molar equivalent of water. Based on the molecular weight of Compound 1 (344.8 g / mol), (i) the hemihydrate (0.5 molar equivalent of water) has approximately 2.55 wt% KF, (ii) the monohydrate (1.0 molar equivalent of water) has approximately 4.97 wt% KF, and (iii) the dihydrate (2.0 molar equivalent of water) has approximately 9.46 wt% KF.

[0491] Synthesis method Example 1 Amorphous free base After weighing approximately 250 mg of the Compound 1 free base into a 20 mL scintillation vial, 12 mL of tert-butyl alcohol:water (8:2 vol.) was added to dissolve the solid. The resulting solution was filtered through a 0.45 μm syringe filter to remove a small amount of undissolved solid. The vial was then frozen in liquid nitrogen for approximately 5 minutes and then lyophilized overnight. XRPD analysis of the solid produced by lyophilization confirmed the formation of the amorphous free base form. See Figure 1A which has a broad halo signal.

[0492] When the amorphous free base form was dried in vacuo at 50 °C overnight prior to S-TGA / DSC analysis, it showed a mass loss of approximately 7.26 wt% up to a maximum of about 170 °C, followed by a broad exotherm starting at 185.1 °C and peaking at 198.3 °C, after which it decomposed. See Figure 1B. The mass loss may be due to the loss of adsorbed water and / or residual solvent from the lyophilization process.

[0493] Heat treatment of the amorphous free base was carried out. 10 mg of amorphous Compound 1 free base was weighed into a 100 μL DSC pan. The pan was heated to 200 °C at a rate of 10 °C / min, held at 200 °C for 10 minutes, and then cooled to 25 °C at a rate of 20 °C / min. Data are omitted. The resulting solid was brittle and dark orange in color. Solids sampled for XRPD, NMR, and HPLC purity analysis showed that Compound 1 free base was neither converted to a crystalline form nor decomposed, but maintained its amorphous state.

[0494] Rapid conversion from the amorphous free base to Form I free base (Example 2) was observed upon addition of 5 vol. of acetone. In another similar experiment, rapid conversion from the amorphous free base to Form II free base (Example 3) was observed upon addition of toluene. Data are omitted.

[0495] Example 2. Form I Free Base Evaporation crystallization experiments were carried out, where solutions of Compound 1 free base were prepared at room temperature (RT) or 50 °C. All solutions were evaporated to dryness in open containers overnight under the atmosphere and then left at 50 °C under vacuum (-29 inHg) for 3 hours. If sufficient solid was available after evaporation and drying, it was analyzed by XRPD. The results are summarized in Table 2A. Dashed lines (--) indicate that no data are available.

[0496] When sufficient solid was available, the Form I free base was obtained from most of the samples. For the isopropanol (IPA): water (9:1 vol.) sample at room temperature, the extra peaks observed could later be assigned as Pattern C (Example 7). The Form II free base (Example 3) was identified from tetrahydrofuran (THF), and Pattern A (Example 7) was identified from trifluoroethanol (TFE).

Table 15

[0497] When cooling crystallization was carried out in the range of solvent systems, similar to the evaporation crystallization experiment, the Form I free base was obtained from most of the samples. Two cooling methods were used: slow cooling from 60 °C to 5 °C at 10 °C per hour and rapid cooling from 60 °C to 0 °C. For all experiments, 20 - 30 mg of Compound 1 free base was weighed into a 4 mL vial. Then, the solvent was gradually added at 60 °C until dissolution. In all experiments, the solid was completely dissolved before cooling.

[0498] For the slow cooling experiment, the solution was cooled to 5 °C at 10 °C per hour while mixing.

[0499] For rapid cooling, the solution was transferred to an ice - water bath close to 0 °C without mixing. After 15 minutes in the ice - water bath, mixing was resumed. If precipitation was observed, the slurry was immediately filtered.

[0500] If the solid did not precipitate from the solution at 5 °C overnight or at 0 °C for 1 hour, the solution was further cooled to - 20 °C by placing it in the freezer without mixing.

[0501] The results of high - speed and low - speed cooling crystallization are summarized in Table 2B. The dashed line (--) indicates that no data is available.

[0502] "Vol." or "volume" refers to the equivalent volume relative to the mass. The actual volume (in microliters) can be calculated by multiplying the equivalent volume by the mass (mg) of the sample. For example, the actual volume of a 23.6 mg test sample with a reported equivalent Vol. of 27 is 637 mL.

[0503] For rapid cooling crystallization, Form I free base was obtained from methanol (MeOH), MeOH: water (9:1 vol.), ethanol (EtOH): water (9:1 vol.), ethyl acetate (EtOAc): N,N-dimethylformamide (DMF) (9:1 vol.), and EtOH: tetrahydrofuran (THF) (3:7 vol.). Form II free base (Example 3) was obtained from THF and as a mixture with Form I free base from acetonitrile: dimethylformamide (DMF) (9:1 vol.). Pattern C (Example 7) was obtained from isopropanol (IPA): water (9:1 vol.) at -20 °C. Pattern C was converted to Pattern A after drying overnight at 50 °C.

[0504] For slow cooling crystallization, Form I free base was obtained from MeOH, IPA: water (9:1 vol.), EtOH: water (9:1 vol.), EtOAc: DMF (9:1 vol.), and acetonitrile: DMF (9:1 vol.). Form II free base (Example 3) was obtained as a mixture with Form I free base from MeOH: water (9:1 vol.) and toluene: DMF (9:1 vol.). Form II free base was also obtained from THF and EtOH: THF (3:7 vol.). Form III free base (Example 4) was obtained from acetone: water (7:3 vol.).

Table 16

[0505] Poor solvent crystallization was also completed in various solvent systems, and similar to the above-described crystallization experiments in Tables 2A - 2B, Form I free base was formed in most of the tested systems.

[0506] First, 20 - 25 mg of Compound 1 free base was dissolved in a solvent. Subsequently, poor solvent crystallization was carried out using either the direct addition method or the reverse addition method.

[0507] For direct poor solvent addition, a solvent with twice the volume was used as the poor solvent and added dropwise equally in four portions over 1 hour. For example, when the solid was dissolved in 0.5 mL of solvent, 1.0 mL of poor solvent was added over 1 hour. The solution / slurry was mixed while adding the poor solvent.

[0508] For reverse poor solvent addition, the solution was transferred all at once up to twice the volume of the poor solvent while stirring rapidly. For example, when the solid was dissolved in 0.5 mL of solvent, the solution was added all at once to 1.0 mL of poor solvent while stirring. Once the solid was formed, the slurry was filtered and the solid was collected for XRPD analysis.

[0509] The results of all poor solvent crystallizations are shown in Table 2C. The dashed line (--) indicates that data was not collected. The asterisk (*) indicates that the poor solvent was added at 50 °C. All other experiments were conducted at room temperature (20 - 24 °C).

[0510] Pattern B (Example 7) was obtained from dimethylacetamide (DMAc) / methyl isobutyl ketone (MIBK) after standing at -20 °C overnight. By drying Pattern B at 50 °C overnight, a conversion to Form I free base occurred, and several additional peaks were also present at 8.1° 2θ, 16.2° 2θ, and 24.4° 2θ. A mixture of Form III free base (Example 4) (main) and Form I free base (minor) was obtained by directly adding water to dimethyl sulfoxide (DMSO). The ratio of the two patterns remained unchanged after drying in vacuo at 50 °C for 4 hours. By reverse addition (DMSO / water), Form III free base (Example 4) was obtained alone without signs of Form I free base. By reverse poor solvent addition (dimethylacetamide (DMAc) / water or N-methylpyrrolidone (NMP) / water), Form IV free base (Example 5) was obtained.

[0511] In the poor solvent crystallization experiment carried out at 50 °C, the solvent system used was a water / alcohol mixture, and precipitation was not observed at 50 °C except when water was used as the poor solvent. After cooling these samples to 10 °C and stirring for a long time, the formation of a thin slurry was observed in most cases. Except for the addition of water to ethanol (EtOH): water (9:1 vol.) from which the Form III free base (Example 4) was obtained, the rest of the recovered solid was the Form I free base as determined by XRPD.

Table 17

[0512] The pure phase Form I free base was obtained via direct poor solvent crystallization in a solution of, for example, dimethylacetamide (DMAc) or N-methylpyrrolidone (NMP) (as the solvent) and water (as the poor solvent). In one representative experiment, 22.9 mg of Compound 1 free base was dissolved in 0.5 mL of dimethylacetamide (DMAc), and 1 mL of water was added dropwise at room temperature over 1 hour to obtain a clear orange solution. After standing at -20 °C overnight and stirring at room temperature for 2 days, an off-white solid was generated. The XRPD of the Form I free base is provided in Figure 2A, and the DSC thermogram is shown in Figure 2B. A signal list of the Form I free base is provided in Table 2D.

Table 18

[0513] The free base form I, obtained from the lyophilization of a solution of Compound 1 free base in 50% acetonitrile in water and containing a trace amount of an unknown metastable form (UnID.*) identified by XRPD, was also tested. See Figure 2B. By dynamic vapor sorption (DVS), it was shown that the free base form I had a water uptake with a weight gain of 0.5% at 5 - 95% relative humidity (RH), and a weight gain of 0.04% at 35 - 65% RH, but it was shown that all the adsorbed water was lost during the drying cycle, indicating that the free base form I is reversible but slightly hygroscopic. XRPD of the material after DVS analysis showed the absence of the signal at 5.9° 2θ due to the unknown metastable form (UnID.*), while the signal corresponding to the free base form I remained unchanged, supporting the view that form I is the stable crystalline form.

[0514] A polarized light microscopy (PLM) image of the free base form I crystals, present as rhombohedral plates with a diameter of about 20 microns to about 100 microns, is provided in Figure 2C.

[0515] The free base form I exhibited a single endotherm with an onset of about 226.8 °C and a peak of about 228.5 °C, as observed by an independent DSC experiment. See Figure 2B. The DSC of the free base form I showed no endothermic events at 30 - 170 °C, suggesting that form I is anhydrous and not hydrated or solvated.

[0516] KF analysis confirmed about 0.50 wt% water in the solid, further suggesting that this form is anhydrous (not hydrated). Data omitted.

[0517] 1 1H NMR analysis confirmed that the residual solvent in the free base form I was below the detection limit of the NMR instrument. Data omitted. Combining the above KF and S-TGA / DSC and independent DSC analyses of the free base form I, the results suggest that this form is anhydrous and no solvent or water is trapped in the crystal lattice.

[0518] Dry milling and solvent-drop milling of the pure form I free base were carried out using a ball mill with 1 / 4-inch stainless steel balls as the milling media. Approximately 30 - 35 mg of form I free base was weighed into the milling capsule, and one volume of solvent (solvent-drop) was added. Milling was carried out at 3500 rpm for 16 seconds. The results are summarized in Table 2E. Overall, no new patterns were identified from the dry milling and solvent-drop milling experiments. In most cases, the XRPD of the form I free base remained mostly unchanged except for some loss of crystallinity. The loss of crystallinity was most evident in the dry-milled samples, but the form I free base pattern was still easily distinguishable. [Table 19]

[0519] A summary of the results for the form I free base is provided in Table 2F. [Table 20]

[0520] Example 3. Form II Free Base As described in Example 2, the pure form II can be prepared by evaporation from tetrahydrofuran (THF). See Tables 2A and 2B. In a representative experiment, 208.5 mg of Compound 1 free base was weighed into a 20 mL vial. THF (9 mL) was added to the vial, and the sample was stirred at 50 °C until a thin slurry was formed. The thin slurry was syringe-filtered through a 0.45 μm syringe filter and then evaporated under air at 50 °C without stirring. The solid was then dried in vacuo (-29.5 inHg) at 50 °C for 3 hours to obtain the form II free base. The XRPD of the form II free base is provided in Figure 3A, and the corresponding signal list is provided in Table 3A. [Table 21]

[0521] By dynamic vapor sorption (DVS), the form II free base had a water uptake of about 1.03% weight gain at 5 - 95% relative humidity (RH), but it was shown that all adsorbed water was lost during the drying cycle, indicating that form II is reversible but slightly hygroscopic and more hygroscopic than form I free base. A comparison of XRPD before and after DVS is provided in Figure 3B, showing that the form II free base remains unchanged before and after DVS, supporting the view that the form II free base is a stable crystalline form.

[0522] A polarized light microscopy (PLM) image of form II free base crystals present as rhombohedral crystal plates with a diameter of about 5 microns to about 40 microns is provided in Figure 3C.

[0523] The form II free base exhibited a single endotherm with onset at about 221.5 °C (Figure 3E) and about 221.9 °C (Figure 3D), and peak at about 225.0 °C (Figure 3E) and about 225.8 °C (Figure 3D) as observed by S-TGA / DSC experiments and stand-alone DSC experiments. The mass loss up to the endotherm observed in the TGA scan was about 0.78 wt%. See Figure 3D. No significant weight loss was observed between 20 - 150 °C via TGA, suggesting that the form II free base is anhydrous and not solvated or hydrated. The DSC of the form II free base showed no endothermic events between 30 - 170 °C, further suggesting that form II is anhydrous and not solvated or hydrated.

[0524] KF analysis confirmed that there was no water in the solid (below the detection limit, BDL), indicating that this form is anhydrous (not hydrated). Data omitted.

[0525] 1 1H NMR analysis confirmed that the form II free base contains approximately 0.65 wt% tetrahydrofuran (THF). Data omitted. Combining the above S-TGA / DSC, stand-alone DSC, and KF analysis of the form II free base, the results suggest that THF is the residual solvent, the form II free base is anhydrous, and neither the residual solvent nor water is trapped in the crystal lattice.

[0526] Table 3B provides a summary of the results for the Form II free base. [Table 22]

[0527] Example 4. Form III Free Base As described in Example 2, a mixture of Form III free base (main) and Form I free base (minor) was obtained by directly adding water (poor solvent) to a solution of 22.4 mg of Compound 1 free base in dimethyl sulfoxide (DMSO) (5V). See Table 2B of Example 2. The ratio of the two patterns remained essentially unchanged after drying in vacuo at 50 °C for 4 hours. By reverse addition (DMSO / water), Form III was obtained alone without signs of Form I. See Table 2B of Example 2.

[0528] The pure phase Form III free base was also prepared by seeding from ethanol (EtOH) / water poor solvent crystallization. In a representative experiment, 205.0 mg of Compound 1 free base was weighed into a 20 mL vial. EtOH:water (9:1 vol., 30 vol., 6.15 mL) was added to the vial and stirred at 50 °C until dissolved. Water was added dropwise in two 15 volumes with a 15 - 20 minute interval between additions. Then, approximately 1 mg of Form III free base was seeded into the solution to obtain a slurry of light tan solid. The slurry was stirred for 1 hour and then another 15V of water was added. Stirring was continued at 50 °C for 1 hour. Then, the slurry was cooled to 10 °C at a rate of 10 °C / hour and held at 10 °C overnight. The solid was isolated by vacuum filtration and dried in vacuo at 50 °C for 3 hours.

[0529] The XRPD of the Form III free base is provided in Figure 4A and the corresponding signal list is provided in Table 4A. [Table 23]

[0530] By dynamic vapor sorption (DVS), the Form III free base had a water uptake with a weight gain of approximately 0.24% at 5 - 95% relative humidity (RH), but it was shown that all the adsorbed water was lost during the drying cycle, indicating that Form III is reversible but slightly hygroscopic and less hygroscopic than either Form I or Form II free base. A comparison of XRPD before and after DVS is provided in Figure 4B, showing that the Form III free base remains unchanged before and after DVS, supporting the view that the Form III free base is a stable crystalline form.

[0531] A polarized light microscopy (PLM) image of the Form III free base crystals present as rectangular plates with a diameter of about 5 microns to about 20 microns is provided in Figure 4C.

[0532] The Form III free base exhibited endotherms with onset at approximately 227.8 °C (Figure 4D) and approximately 229.4 °C (Figure 4E), and peaks at approximately 230.0 °C (Figure 4D) and approximately 231.5 °C (Figure 4E) as observed by S - TGA / DSC experiments and stand - alone DSC experiments. The mass loss up to the endotherm observed in the TGA scan was approximately 0.16 wt%. See Figure 4D. No significant weight loss was observed between 20 - 150 °C via TGA, suggesting that the Form III free base is anhydrous and not solvated. The DSC of the Form III free base showed no endothermic events between 30 - 170 °C, further suggesting that the Form III free base is anhydrous and not hydrated or solvated.

[0533] KF analysis confirmed that there was no water in the solid (below the detection limit, BDL), indicating that this form is anhydrous (not hydrated). Data is omitted.

[0534] 1 1H NMR analysis confirmed that the residual solvent in the Form III free base was below the detection limit of the NMR instrument. Data is omitted. When combined with the above KF, stand - alone DSC, and S - TGA / DSC analyses of the Form III free base, the results suggest that this form is anhydrous and no solvent or water is trapped in the crystal lattice.

[0535] The heat treatment of Form III free base at 210 °C was carried out. Approximately 5 mg of Form III free base was weighed into a DSC pan. The sample was heated from 30 °C to 210 °C at a rate of 10 °C / min, held at 210 °C for 10 minutes, and then cooled from 210 °C to 30 °C at a rate of 20 °C / min. The recovered solid was yellow, and when analyzed by XRPD, it showed a conversion to Form I free base (Example 2) with extra side peaks at 14.7° 2θ, 16.2° 2θ, 20.1° 2θ, and 22.4° 2θ. Data is omitted. The peaks at 16.2° 2θ and 20.1° 2θ may have been due to trace amounts of Form II free base (Example 3).

[0536] A summary of the results of Form III free base is provided in Table 4B. [Table 24]

[0537] Example 5. Form IV Free Base As described in Example 2, pure phase Form IV free base was obtained by inverse anti-solvent addition using dimethylacetamide (DMAc) / water or N-methylpyrrolidone (NMP) / water. See Table 2B of Example 2. In a representative experiment, 64.6 mg of Compound 1 free base was weighed into a 2 mL vial. Dimethylacetamide (DMAc) (5 vol.) was added to the vial and stirred at room temperature until dissolved. Water (10 vol.) was added to a 4 mL vial containing a 10 mm stirring bar and stirred at room temperature. While stirring the water vial, the entire solution of DMAc was added. A tan / yellow slurry immediately precipitated. After 30 minutes, a white solid immobile slurry was observed. Another 5 V of water was added to the slurry, which was then stirred at room temperature overnight. The slurry was filtered, washed with 2 × 2 vol. of water, and then dried in vacuo at 50 °C for 3 hours to obtain the free base of Form IV. The XRPD of Form IV free base is provided in Figure 5A, and the corresponding signal list is provided in Table 5A. [Table 25]

[0538] By dynamic vapor sorption (DVS), it was shown that the Form IV free base had a water uptake with a weight gain of about 1.59% at 5 - 95% relative humidity (RH), but all the adsorbed water was lost during the drying cycle, indicating that Form IV is reversible, slightly hygroscopic, and more hygroscopic than any of Forms I - III free bases. A comparison of XRPD before and after DVS is provided in Figure 5B, showing that the Form IV free base remains unchanged before and after DVS, supporting the view that the Form IV free base is a stable crystalline form.

[0539] A polarized light microscopy (PLM) image of Form IV free base crystals present as needles with a length of about 5 microns to about 50 microns is provided in Figure 5C.

[0540] The Form IV free base, as observed by S - TGA / DSC and stand - alone DSC experiments, exhibited exotherms at 192.2 °C (Figure 5D) and about 195.1 °C (Figure 5E) with onset at about 226.7 °C (Figure 5D) and about 227.6 °C (Figure 5E), and peak at about 229.6 °C (Figure 5D) and about 229.8 °C (Figure 5E). The mass loss up to the endotherm observed in the TGA scan was about 0.54 wt%. See Figure 5D. The samples tested were high in residual solvent, but not at a level suggesting that the Form IV free base is a solvate. Further, no significant weight loss was observed between 20 - 150 °C via TGA, suggesting that the Form IV free base is anhydrous and not solvated or hydrated. The DSC of Form IV showed no endothermic events between 30 - 170 °C, further suggesting that Form IV is anhydrous and not solvated or hydrated.

[0541] KF analysis confirmed about 0.29 wt% water in the solid, further suggesting that this form is anhydrous (not hydrated).

[0542] 1By \(^1H\) NMR analysis, it was confirmed that the Form IV free base contains approximately 0.74 wt% of dimethylacetamide (DMAc). Data are omitted. When combined with the KF, independent DSC, and S-TGA / DSC analyses of the above Form IV free base, the results suggest that DMAc is the residual solvent, the Form IV free base is anhydrous, and neither the residual solvent nor water is trapped in the crystal lattice.

[0543] Heat treatment of the Form IV free base was carried out at 210 °C. Approximately 5 mg of the Form IV free base was weighed into a DSC pan. The sample was heated from 30 °C to 210 °C at a rate of 10 °C / min, held at 210 °C for 10 minutes, and then cooled from 210 °C to 30 °C at a rate of 20 °C / min. The recovered solid was orange in color, and when analyzed by XRPD, conversion to the Form I free base was indicated (having two minor peaks at 14.7° 2θ and 16.2° 2θ).

[0544] A summary of the results for the Form IV free base is provided in Table 5C.

Table 26

[0545] Example 6. Competitive slurry experiments and discovery of the Form V free base Competitive slurry experiments were carried out using the Form I-IV free bases in five solvents / solvent systems at two temperatures, room temperature (RT) and 50 °C. First, saturated solutions of the Form I free base (Example 2) were prepared in each solvent system at each temperature. To prepare the saturated solution, the Form I free base was added to 2 mL of the solvent that was already stirring at the desired temperature, either at room temperature (RT) or 50 °C. If a thin slurry was observed, the sample was equilibrated overnight. After stirring overnight, the stir bar was removed to precipitate the solid, and the supernatant was pipetted into a clean 4 mL vial containing a 10 mm stir bar.

[0546] Subsequently, the supernatant was further stirred for 15 minutes, after which the following pattern of seeds (approximately 5 mg per form, pre-weighed) was added: Form I free base (Example 2), Form II free base (Example 3), Form III free base (Example 4), and Form IV free base (Example 5). Samples of the slurry were plated for XRPD analysis immediately after seeding. Subsequently, the slurry was sampled again after 2 days and 7 days at each temperature.

[0547] The overview of the competing slurries is shown in Table 6A. In all experiments, no signs of Form III free base or Form IV free base were observed after 2 days, either at room temperature or 50 °C. In methanol (MeOH), Form II free base was favored, and Form I free base was present only in trace amounts at room temperature and was not present at 50 °C after 2 days. Form II free base was also favored in tetrahydrofuran (THF) at 50 °C after 2 days. In the remaining experiments, little change in the ratio of Form I free base and Form II free base was observed after 2 days, either at room temperature or 50 °C.

[0548] After 7 days, Form II free base was favored in most solvent systems.

[0549] In the case of isopropanol (IPA): water (9:1 vol.), a significant conversion to a new pattern, Form V free base, was observed at 50 °C after 7 days. Signs of Form V free base were not seen in any other solvent system.

[0550] These initial competing slurry experiments demonstrated the relative stability of Forms I-IV free bases. Forms III and IV free bases were rapidly converted, while Forms I and II free bases were more stable. Form II free base was favored over Form I free base in all solvent systems (except acetone: water (7:3 vol.) where neither form was clearly dominant over the other).

Table 27

[0551] To evaluate the relative stability of Form V free base with respect to Form I free base and Form II free base, a second set of competitive slurry experiments was set up at three solvent systems and two temperatures. Since Form II free base is favored in most solvent systems, seeding of Form I free base was carried out only in the acetone:water (7:3 vol.) system. An overview of the second set of competitive slurries is shown in Table 6B. In all samples, an input seed pattern was observed in less than 1 minute after addition. After 3 days at the corresponding temperature, Form V free base was the only form observed in all experiments (except in acetonitrile at room temperature where a large amount of Form II free base still remained). After 7 days, the amount of Form II free base remaining in the room temperature acetonitrile sample decreased significantly, but Form II free base still remained in trace amounts.

[0552] The second set of slurry experiments showed that Form V free base was favored over both Form I free base and Form II free base in various solvent systems including methanol (MeOH) and acetone:water (7:3 vol.). [Table 28]

[0553] Solid form stability tests for Forms I - V free base forms were carried out by weighing approximately 10 - 15 mg of crystalline material into 4 mL vials and covering them with a laboratory grade task wipe (Kimwipe). These vials were placed in a stability chamber set at 40 °C ± 2 °C and 75% ± 5% relative humidity (RH) for 1 week (exactly 7 days). The recovered material was then analyzed by XRPD and HPLC. The results are summarized in Table 6C. In all cases, the initial material and the tested material were identical by XRPD, except for Form I free base where an extra peak at 5.8° 2θ in the initial material was not present after the stability test. The HPLC purity of the tested material did not change substantially from the purity of the initial material. [Table 29]

[0554] The additional preparation of the pure polymorphic form V free base was carried out by (i) slurrying 96.0 mg of the compound 1 free base in 20 vol. of isopropanol:water (9:1 vol.) at 50 °C and (ii) seeding with a mixture of form II free base and form V free base obtained from a competitive slurry experiment. After stirring at 50 °C for approximately 24 hours, complete conversion to form V free base was observed. The slurry was cooled to room temperature, filtered, and washed with 2 × 1 vol. of isopropanol:water (9:1 vol). The resulting solid was dried in vacuo at 50 °C for 3 hours. The XRPD of form V free base is provided in Figure 6A, and the corresponding signal list is provided in Table 6D.

Table 30

[0555] By dynamic vapor sorption (DVS), it was shown that form V free base had a water uptake with a weight gain of approximately 0.20% at 5 - 95% relative humidity (RH), but all the adsorbed water was lost during the drying cycle, indicating that form V is reversible but slightly hygroscopic and less hygroscopic than any of forms I - IV free bases. A comparison of XRPD before and after DVS is provided in Figure 6B, showing that form V free base remains unchanged before and after DVS, supporting the view that form V free base is a stable crystalline form.

[0556] A polarized light microscopy (PLM) image of form V free base crystals present as rhombohedral crystal plates with a diameter of approximately 5 microns to approximately 20 microns is provided in Figure 6C.

[0557] The free base of Form V was observed by S-TGA / DSC experiments and stand-alone DSC experiments, showing a single endotherm with onset at 227.5 °C (Figure 6D) and 227.7 °C (Figure 6E), and peak at 228.8 °C (Figure 6E) and 229.9 °C (Figure 6D). The weight loss up to the endotherm observed in the TGA scan was 0.16 wt%. See Figure 6D. No significant weight loss was observed between 20 - 150 °C via TGA, suggesting that the free base of Form V is anhydrous and not solvated. The DSC of Form V showed no endothermic events between 30 - 170 °C, further suggesting that Form V is anhydrous and not solvated.

[0558] KF analysis confirmed the absence of water in the solid (below the detection limit, BDL), indicating that this form is anhydrous (not hydrated). Data not shown.

[0559] 1 H NMR analysis confirmed that the residual solvent in the free base of Form V is below the detection limit of the NMR instrument. Data not shown. When combined with the above KF, stand-alone DSC, and S-TGA / DSC analyses of the free base of Form V, the results suggest that this form is anhydrous and that neither solvent nor water is trapped in the crystal lattice.

[0560] A summary of the results for the free base of Form V is provided in Table 6E.

Table 31

[0561] Polymorph V free base was tested by DVS and had the lowest hygroscopicity of the polymorphs, and by DSC had a relatively high melting onset temperature (which is an indicator of desirable stability), appeared to be the most thermodynamically stable polymorph tested (determined by the second set of competitive slurry experiments), and exhibited good solid form and chemical stability at high RH (observed by no polymorph change or purity decrease after 1 week at 75% RH and 40 °C). For this reason, polymorph V free base was considered a suitable form for manufacturability and clinical purposes based on its good physicochemical properties and demonstrated thermodynamic stability.

[0562] Single crystals of polymorph V free base were grown by temperature cycling a slurry of Compound 1 polymorph V free base (50 mg) in 90% v / v isopropanol / water (500 μL). The slurry was temperature cycled from 0 to 50 °C using Profile 1 (overhead stirring at 200 rpm) [(1) ramp to 50 °C at 2 °C / min, (2) isothermal hold for 2 min, (3) ramp to 0 °C at 0.1 °C / min, (4) isothermal hold for 20 min, (5) total of 50 cycles] to allow complete conversion to polymorph V, and then, for crystal growth, using Profile 2 (no stirring) [(1) ramp to 40 °C at 5 °C / min, (2) isothermal hold for 1 min, (3) ramp to 0 °C at 0.05 °C / min, (4) isothermal hold for 20 min, (5) total of 10 cycles, (6) ramp to 30 °C at 5 °C / min, (7) isothermal hold for 1 min, (8) ramp to 0 °C at 0.05 °C / min, (9) isothermal hold for 20 min, (10) total of 30 cycles]. Block-like crystals with a length of approximately 140 μm were obtained and analyzed by PLM.

[0563] The structure of polymorph V free base was solved and refined in the monoclinic space group P2 1 / c. See Table 6F.

Table 32

[0564] The asymmetric unit contains one molecule of the compound 1 free base, and there are four asymmetric units within the unit cell. Solvent molecules were not refined in the asymmetric unit, and there were no regions of unrefined electron density in the Fourier map. Void spaces accessible to the solvent were not observed along the a-axis (Figure 6F), the b-axis (Figure 6G), or the c-axis (Figure 6H). Investigation of the packing of the form V free base in a form that has both the b-axis (Figure 6G) and the c-axis lowered showed the presence of a slip plane. The slip plane along the c-axis is indicated by the dashed line in Figure 6H. These crystal lattice features enable the crystal to deform plastically, which can lead to easier grindability and the possibility of high tableting performance. See, for example, Pallipurath et al., “Sulfamerazine: Understanding the Influence of Slip Planes in the Polymorphic Phase Transformation through X-Ray Crystallographic Studies and ab Initio Lattice Dynamics.”, Molecular Pharmaceutics (2015) 12(10):3735 - 3748, and Wahyudi et al., “The Crystal Packing and Slip Plane Analysis in Mechanical Properties Improvement of Mefenamic Acid by Crystallization with Nicotinamide Conformer.” Communications in Science and Technology (2020) 5(2)93 - 97. Both of these show that the slip surface improved the mechanical properties of the tested crystal forms.

[0565] The simulated (100K) XRPD of the superimposed single crystal and the experimental (≈293K) XRPD diffractogram of form V free base are provided in Figure 6I. Some shift of the diffraction peaks is expected due to the thermal expansion effect caused by the temperature difference between the two measurements.

[0566] Example 7. Patterns A - C The Pattern A free base was identified from trifluoroethanol (TFE) (see Example 2, Table 2A), and it was determined to be the low - crystalline version of the Form I free base. The XRPD of the Pattern A free base is provided in Figure 7A, and the corresponding signal list is provided in Table 7A. A comparison of the XRPD of the Pattern A free base and the Form I free base is provided in Figure 7B. [Table 33]

[0567] The Pattern B free base was obtained from dimethylacetamide (DMAc) / methyl isobutyl ketone (MIBK) after standing overnight at - 20 °C. See Example 2, Table 2B. When the Pattern B free base was dried at 50 °C overnight, conversion to the Form I free base occurred, but some strong extra peaks were also present at 8.1° 2θ, 16.2° 2θ, and 24.4° 2θ. The XRPD of the Pattern B free base taken before drying is provided in Figure 7C, and the corresponding signal list is provided in Table 7B. [Table 34]

[0568] The Pattern C free base was obtained from isopropanol (IPA): water (9:1 vol.) at - 20 °C. See Table 2B of Example 2. The Pattern C free base was converted to the low - crystalline version of the Form I free base (Pattern A free base) after drying at 50 °C overnight, and since neither the peaks at 4.5° 2θ nor 8.9° 2θ were present or were significantly reduced in the dried sample, it was suggested that the Pattern C free base is an isopropanol solvate. The XRPD of the Pattern C free base is provided in Figure 7D, and the corresponding signal list is provided in Table 7C. [Table 35]

[0569] Example 8: Method for Preparing the Form V Free Base Compound 1 Form II free base (40 mg / mL) was stirred in a mixture of water / THF (1:19 v / v, 25 volumes) at 32 °C until a turbid solution was obtained. After cooling to 20 °C and filtering, the solution was concentrated under reduced pressure to a concentration of 133 mg / mL (7.5 vol) at 40 - 50 °C. The solution was then maintained at 45 °C, and to this solution, seeds of Form V free base (0.4 wt / wt%) were added. Subsequently, the temperature was adjusted to 40 °C and maintained at this temperature for 58 minutes. The resulting suspension was then cooled to 22 °C over 160 minutes, then cooled to 20 °C and maintained at this temperature for 10 hours. The slurry was concentrated under reduced pressure to a concentration of 200 mg / mL (5 vol) at 40 - 50 °C, then the slurry was maintained at 41 °C for 42 minutes, then cooled to 21 °C over 57 minutes and further maintained at this temperature for 40 minutes. Acetone (10 vol) was added over 63 minutes, the suspension was heated to 40 °C and maintained at this temperature for 72 minutes, then cooled to 20 °C over 90 minutes and further maintained at this temperature for 13.5 hours. The suspension was filtered and washed first with a mixture of acetone / THF (3:1 v / v, 4 vol) and then with acetone (4 vol). Finally, Compound 1 Form V free base was dried at 40 °C under reduced pressure and nitrogen sweep.

[0570] Exemplary Embodiments Embodiment 1. Crystalline free base form of Compound 1:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0571] Other embodiments This application references various patents and publications, each of which is hereby incorporated by reference herein. Above, non-limiting embodiments of the present disclosure have been described. Those skilled in the art will understand that various changes and modifications to this specification can be made without departing from the spirit or scope of the present disclosure as defined in the following claims.

Claims

1. Compound 1: 【Chemistry 1】 The crystalline free base form of.

2. 2. The crystalline form of claim 1 having an X-ray powder diffraction signal at 6.8±0.2 or 11.7±0.2 degrees 2θ, and at least one additional signal at 18.9±0.2, 20.5±0.2, or 22.9±0.2 degrees 2θ, using Cu K alpha radiation, when measured at 25° C.

3. (a) 6.8±0.2, 18.9±0.2, and 20.5±0.2 degrees 2θ using Cu K alpha radiation when measured at 25° C.; (b) 6.8±0.2, 20.5±0.2, and 22.9±0.2 degrees 2θ using Cu K alpha radiation when measured at 25° C.; (c) 11.7±0.2, 18.9±0.2, and 20.5±0.2 degrees 2θ using Cu K alpha radiation when measured at 25° C.; or (d) the crystalline form of claim 1 or 2 having X-ray powder diffraction signals at 11.7±0.2, 20.5±0.2, and 22.9±0.2 degrees 2θ using Cu K alpha radiation when measured at 25° C.

4. 4. The crystalline form of any one of embodiments 1-3, having X-ray powder diffraction signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, 23.9±0.2, and 26.5±0.2 degrees 2θ using Cu K alpha radiation when measured at 25°C.

5. 5. The crystalline form of any one of claims 1 to 4, characterized by a single endothermic event at about 215°C to about 230°C as measured by differential scanning calorimetry (DSC).

6. 6. The crystalline form of claim 5, characterized by an onset temperature of about 227.5 to about 227.7 as measured by DSC, and / or a peak temperature of about 228.8 to about 229.9 as measured by DSC.

7. 7. The crystalline form of any one of claims 1 to 6, characterized by a mass loss of about 0.1% to 0.5% as measured by thermogravimetric analysis (TGA).

8. 8. The crystalline form of any one of claims 1 to 7, characterized in that it has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 6A.

9. 9. The crystalline form of any one of claims 1 to 8, characterized in that it has a thermogravimetric analysis (TGA) scan substantially similar to that shown in Figure 6D.

10. 10. The crystalline form of any one of claims 1 to 9, characterized in that it has a differential scanning calorimetry (DSC) scan substantially similar to that shown in Figure 6E.

11. 2. The crystalline form of claim 1, characterized in that it has an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in FIG. 3A.

12. Compound 1: 【Chemistry 2】 1. A crystalline free base form of Compound 1 having X-ray powder diffraction signals at 6.8±0.2, 11.7±0.2, 18.9±0.2, 20.5±0.2, 22.9±0.2, 23.8±0.2, 23.9±0.2, and 26.5±0.2 degrees 2θ using Cu K alpha radiation when measured at 25° C. and characterized by a single endothermic event at about 215° C. to about 230° C. as measured by differential scanning calorimetry (DSC), with an onset temperature of about 227.5 to about 227.7° C. and a peak temperature of about 228.8 to about 229.9° C. as measured by DSC, wherein said crystalline form is anhydrous.

13. Amorphous Compound 1 Free Base: 【Chemistry 3】 2. Amorphous Compound 1 free base having a single broad halo signal from about 10 to about 32 degrees 2θ using Cu K alpha radiation when measured at 25°C.

14. 14. The amorphous free base of claim 13, characterized in that it has an X-ray powder diffraction pattern substantially similar to that shown in FIG. 1A.

15. 15. A composition comprising a mixture of Compound 1 free base forms, wherein 75% of said mixture is the crystalline form of any one of claims 1 to 14.

16. 17. The crystalline form of any one of claims 1-12, or the amorphous form of claims 13 or 14, or the composition of claim 15, for use in a method of treating a disease or disorder of the central nervous system (CNS), a disease or disorder of the peripheral nervous system (PNS), a primary neurological disease of muscle, an inflammatory disorder, an autoimmune disorder, cancer, an infectious disease, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a hepatic disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychiatric disease, graft versus host disease, pain (including disorders related to pain management), or an NLRP3-associated disease in a subject determined to carry a germline or somatic non-silent mutation in NLRP3.

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