Crystalline and amorphous forms of a compound for the targeted degradation of estrogen receptor

Abstract

This disclosure relates to polymorphic forms of (S)-3-(5-(4-((1-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione, methods for preparing such polymorphic forms, and compositions comprising such polymorphic forms. These polymorphic forms can be used to treat various diseases, including, for example, breast cancer.

Description

Technical Field

[0001] This disclosure concerns (S)-3-(5-(4-((1-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindolin-2-yl)hexahydropyridin-2,6-dione The polymorphic forms, methods for preparing the polymorphic forms, and compositions comprising the polymorphic forms are disclosed. These polymorphic forms can be used to treat various diseases, including, for example, breast cancer. Prior Technology

[0002] Most small molecule drugs bind to enzymes or receptors in tight, well-defined pockets. In contrast, it is well known that targeting protein-protein interactions with small molecules is difficult due to their larger contact surfaces, which often involve shallow grooves or flat interfaces. E3 ubiquitin ligases confer specificity for receptor ubiquitination and are therefore attractive therapeutic targets due to their specificity for certain protein receptors. Developing ligands for E3 ligases has proven challenging, partly because they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutlin, other compounds targeting E3 ligases have been reported.

[0003] One E3 ligase with specific therapeutic potential is cereblon, a protein encoded by the CRBN gene in humans. CRBN heterologs are highly conserved from plant to human, indicating its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damage-binding protein 1 (DDB1), Cullin-4A (CUL4A), and cullin regulatory protein 1 (ROC1). This complex ubiquitinates several other proteins. Through a mechanism not yet fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates several developmental processes, such as limb and auditory sac formation. Ultimately, this ubiquitin ligase complex is crucial for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 (which acts as a DNA damage-binding protein).

[0004] Thalidomide, already approved for the treatment of various immunotherapies, is also approved for the treatment of certain neoplastic diseases, including multiple myeloma. Furthermore, thalidomide and several analogues are currently being investigated for the treatment of various other types of cancer. Although the exact mechanism of thalidomide's antitumor activity is still being understood, its inhibition of angiogenesis is known. Recent literature discussing amide biology includes Lu et al., Science 343, 305 (2014) and Kroenke et al., Science 343, 301 (2014).

[0005] It is noteworthy that thalidomide and its analogues (such as pomalidomide and lenalidomide) are known to bind to cereblon and alter the specificity of the complex in inducing ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for the growth of multiple myeloma. In fact, higher cereblon expression is associated with increased efficacy of aceimide drugs in the treatment of multiple myeloma.

[0006] The estrogen receptor (ER) is a member of the nuclear hormone receptor family and acts as a ligand-activated transcription factor involved in the upregulation and downregulation of gene expression. The natural hormone of ER is 17-β-estradiol (E2) and its closely related metabolites. The binding of estradiol to ER causes receptor dimerization, and the dimer then binds to the estrogen response element (ERE) on DNA. The ER-DNA complex recruits other transcription factors responsible for transcribing downstream DNA of the ERE into mRNA, which is ultimately translated into protein. Alternatively, the interaction between ER and DNA can be indirect via other transcription factors, most notably fos and jun. Because the expression of a large number of genes is regulated by ER and because ER is present in many cell types, regulation of ER through binding to natural hormones or synthetic ER ligands can have significant physiological and pathophysiological effects on organisms.

[0007] Estrogen-dependent diseases are mediated by ER in the etiology and / or pathogenesis of many conditions. These diseases are collectively referred to as estrogen-dependent diseases. Estrogen is crucial for female sexual development. In addition, estrogen plays an important role in maintaining bone density, regulating blood lipid levels, and appears to have neuroprotective effects. Therefore, in postmenopausal women, decreased estrogen production is associated with a variety of diseases, such as osteoporosis, atherosclerosis, depression, and cognitive impairment. Conversely, estrogen stimulates certain types of proliferative diseases, such as breast cancer, uterine cancer, and endometriosis, and therefore anti-estrogens (i.e., estrogen antagonists) can be used to prevent and treat these types of conditions.

[0008] There are two distinct forms of ER, commonly referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Both ERs are widely expressed in different tissue types, but their expression patterns differ significantly. ERα has been found in the endometrium, breast cancer cells, ovarian stromal cells, and hypothalamus. In men, ERα protein is found in the epithelium of the efferent ducts. ERβ protein expression has been documented in the kidneys, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells. Therefore, developing selective ligands of one or the other form could preserve the beneficial properties of estrogen.

[0009] Breast cancer is the most common malignant disease affecting women, and its incidence is increasing worldwide. Specifically, estrogen acts as an endocrine growth factor in at least one-third of breast cancers, and depriving the tumor of this stimulation is a recognized treatment for advanced disease in premenopausal women. This treatment is achieved through surgery, radiation therapy, or medical procedures to ablate ovarian function, and in postmenopausal women, it is achieved by using aromatase inhibitors.

[0010] Alternative methods for estrogen withdrawal involve using anti-estrogens to antagonize estrogen. These anti-estrogens bind to and compete with the estrogen receptor (ER) present in estrogen-responsive tissues. Conventional nonsteroidal anti-estrogens (such as tamoxifen) effectively compete for ER binding, but their effectiveness is often limited by their partial agonist effect, resulting in incomplete blocking of estrogen-mediated activity. In the treatment of estrogen-dependent diseases, specific or "pure" anti-estrogens with high affinity for the ER and no agonist effect may have advantages over conventional nonsteroidal anti-estrogens. Fulvestrant is the first novel, potent, pure anti-estrogen that is completely free of the partial agonist estrogen-like activity associated with currently available anti-estrogens (such as tamoxifen).

[0011] Therefore, the industry needs other methods to antagonize ER. One approach would be to develop selective ER downregulators or degraders that reduce ER performance at the transcript or protein level. Summary of the Invention

[0012] The compound prepared and used according to the present invention is (S)-3-(5-(4-((1-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), with the molecular formula C 45H 49N 5O 4 and the following structural formula:

[0013] Compound A is being developed as a PROTAC® protein degrader targeting the estrogen receptor (ER) for potential treatment of breast cancer. Compound A has been shown to be a potential modulator of protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0014] This disclosure provides several crystalline forms (polymorphs) and one amorphous form of compound A.

[0015] In one embodiment, this disclosure provides a polymorph of compound A (“Form I”), characterized by using Cu Kα radiation with an X-ray wavelength of 1.5406 Å, wherein the X-ray powder diffraction pattern includes peaks at approximately 13.9 °2θ, approximately 16.4 °2θ, and approximately 17.9 °2θ.

[0016] In one embodiment, this disclosure provides a polymorph of compound A (“Form II”), characterized by using Cu Kα radiation with an X-ray wavelength of 1.5406 Å, wherein the X-ray powder diffraction pattern includes peaks at approximately 10.0 °2θ, approximately 16.3 °2θ, and approximately 17.5 °2θ.

[0017] In one embodiment, this disclosure provides a polymorph of compound A (“Form III”), characterized by using Cu Kα radiation with an X-ray wavelength of 1.5406 Å, wherein the X-ray powder diffraction pattern includes peaks at approximately 8.8 °2θ, approximately 10.7 °2θ, and 18.2 °2θ.

[0018] In one state sample, this disclosure provides a polymorph of compound A (“Form IV”), characterized in that the X-ray powder diffraction pattern at an X-ray wavelength of 1.5406 Å includes peaks at approximately 10.5 °2θ, approximately 14.5 °2θ and approximately 16.9 °2θ.

[0019] In another embodiment, this disclosure provides a method for treating a disease or condition in an individual in need, comprising administering to the individual a therapeutically effective amount of a polymorph and / or amorphous form of compound A. In some embodiments, the disease or condition is associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is associated with ER activity. In some embodiments, the disease or condition is associated with excessive ER activity. In some embodiments, the disease or condition is associated with constitutive ER activity. In some embodiments, the disease or condition is associated with ER expression. In some embodiments, the disease or condition is associated with ER overexpression. In some embodiments, the disease or condition is associated with ER accumulation and aggregation.

[0020] In some embodiments, the disease or condition is cancer or neoplasm formation associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is endometriosis.

[0021] In another embodiment, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a polycrystalline and / or amorphous form of compound A, wherein the composition effectively treats or improves at least one symptom of a disease or condition. In some embodiments, the disease or condition is etiologically associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia etiologically associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is endometriosis.

[0022] In another embodiment, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of compound A and a pharmaceutically acceptable dispersant. In some embodiments, the pharmaceutically acceptable dispersant further comprises a pharmaceutically acceptable additive. In some embodiments, the pharmaceutically acceptable dispersant is hydroxypropyl methylcellulose (HPMC). In some embodiments, the pharmaceutically acceptable additive is D-α-tocopherol polyethylene glycol succinate (vitamin E TPGS or TPGS).

[0023] In some embodiments, the polymorph of the present invention is a preferred form for bulk storage of compound A before conversion into an amorphous compound A. In some embodiments, the polymorph of compound A is form I. In some embodiments, the polymorph of compound A is form II. In some embodiments, the polymorph of compound A is form III. In some embodiments, the polymorph of compound A is form IV. In some embodiments, the form for bulk storage of compound A is a mixture of one or more solid forms (e.g., polymorphs or amorphous forms) of compound A disclosed herein. In some embodiments, the form for bulk storage of compound A is a mixture of form I and an amorphous form. In some embodiments, the form for bulk storage of compound A is a mixture of form I and form II. In some embodiments, the form for bulk storage of compound A is a mixture of form I and form III. In some embodiments, the preferred form for bulk storage of compound A is a mixture of form I and form IV.

[0024] In another embodiment, this disclosure provides the use of compound A in its polycrystalline and / or amorphous forms for the manufacture of pharmaceutical agents for treating diseases or conditions. In some embodiments, the disease or condition is associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is endometriosis.

[0025] In another embodiment, this disclosure provides polymorphic and / or amorphous forms of compound A for use in medicine.

[0026] In another embodiment, this disclosure provides polymorphic and / or amorphous forms of compound A for the treatment of diseases or conditions. In some embodiments, the disease or condition is associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is endometriosis.

[0027] In another embodiment, this disclosure provides a method for preparing a polymorph of compound A in form I, comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is acetone, 1-butanol, 2-ethoxyethanol, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, 1-propanol, 2-propanol, or a mixture of ethanol and water.

[0028] In another embodiment, this disclosure provides a method for preparing a form II polymorph of compound A, comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is a mixture of dichloromethane or acetone and water.

[0029] In another embodiment, this disclosure provides a method for preparing a form III polymorph of compound A, comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is acetonitrile.

[0030] In another embodiment, this disclosure provides a method for preparing a polymorph of compound A in form IV, comprising rapidly cooling compound A from a solvent. In some embodiments, the solvent is a mixture of dichloromethane and methanol.

[0031] In another embodiment, this disclosure provides a method for preparing polymorph IV of compound A, comprising adding an antisolvent to a solution of compound A in a solvent. In some embodiments, the solvent comprises a mixture of dichloromethane and methanol. In some embodiments, the antisolvent is tert-butylmethyl ether. Simple Explanation of the Diagram

[0032] [Figure 1A] shows the XRPD spectrum of a polymorph sample of compound A in form I. The diffraction pattern is from material recovered from methyl ethyl ketone. [Figure 1B] shows the TG / DT plots of the polymorph sample of compound A in form I. The TG plots start from the upper left, and the DT plots start from the lower left. [Figure 1C] shows a PLM image of polymorph I of compound A. The sample in this image was recovered from methanol. [Figure 2A] shows the XRPD spectrum of the form II sample of compound A. The diffraction pattern is from the material recovered from dichloromethane. [Figure 2B] shows the TG / DT plots of the polymorph sample of compound A in form II. The TG plots start from the upper left, and the DT plots start from the lower left. [Figure 2C] shows a PLM image of polymorph II of compound A. The sample in this image was recovered from dichloromethane. [Figure 3A] shows the XRPD spectrum of a polymorph sample of compound A in form III. The diffraction pattern is from material recovered from acetonitrile. [Figure 3B] shows the TG / DT plots of the polymorph sample of form III of compound A. The TG plot starts from the upper left, and the DT plot starts from the lower left. [Figure 3C] shows a PLM image of polymorph III of compound A. The sample in this image was recovered from acetonitrile. [Figure 4A] shows the XRPD spectrum of a polymorph sample of compound A in form IV. The diffraction pattern is from the material recovered from dichloromethane:methanol (25:75 v / v) after rapid cooling. [Figure 4B] shows the TG / DT plots of the polymorph sample of compound A in form IV. The TG plot starts from the upper left and the DT plot starts from the lower left. [Figure 4C] shows a PLM image of polymorph IV of compound A. The sample in this figure was recovered from dichloromethane:methanol (25:75 v / v). Implementation

[0033] Cross-reference to related applications

[0034] This application claims priority and interest in U.S. Provisional Application No. 63 / 078,225, filed on September 14, 2020, the contents of which are incorporated herein by reference in their entirety.

[0035] This application relates to U.S. Patent Application No. 15 / 829,541, issued as U.S. Patent No. 10,647,698; U.S. Patent Application No. 16 / 744,414, issued as U.S. Patent No. 10,899,742; and U.S. Patent Application No. 17 / 001,519. Each of these patent applications is incorporated herein by reference in its entirety for all purposes.

[0036] The following is a detailed description provided to assist those skilled in the art in practicing this disclosure. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of this disclosure. All publications, patent applications, patents, figures, and other references mentioned herein are expressly incorporated herein by reference in their entirety for all purposes.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the scope of this disclosure.

[0038] If a range of values ​​is provided, it should be understood that this disclosure covers every intermediate value between the upper and lower limits of that range, and any other specified value or intermediate value within that range, accurate to one-tenth of the lower limit unit, unless the context explicitly indicates otherwise (such as in the case of a group containing multiple carbon atoms, in which case the number of each carbon atom falling within the range is provided). The upper and lower limits of such smaller ranges may be independently included within the smaller range, subject to any explicitly excluded limits within the specified range. If a specified range includes one or both of the limits, this disclosure also includes ranges excluding any or both of the included limits. [definition]

[0039] The following terms are used to describe this disclosure. Where a term is not explicitly defined herein, it is given a meaning generally accepted in the art, and those skilled in the art shall use the term in the context of its use to describe this disclosure.

[0040] As defined herein, "XRPD" or "XPD" should be understood as referring to X-ray powder diffraction. Unless otherwise specified, all XRPD peaks and patterns are given in °2θ using Cu Kα1 radiation at a wavelength of 1.5406 Å.

[0041] The abbreviations "TG" and "TGA" should be understood as referring to thermogravimetric analysis. The abbreviations "DT" and "DTA" should be understood as referring to differential thermal analysis. The abbreviations "TG / DT" and "TG / DTA" should be understood as referring to thermogravimetric analysis / differential thermal analysis.

[0042] The term "PLM" should be understood as referring to polarized light microscopy.

[0043] The term "about" is used herein to mean approximately, around, roughly, or approximately. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries to values ​​above and below the stated values. Generally, the term "about" is used herein to modify values ​​above and below specified values ​​with a variance of 20%. When used in the context of XRPD peaks (i.e., the location of the XRPD peak along the x-axis of the diffraction plot), the term "about" may indicate a peak value ±0.20; ±0.15; ±0.10; ±0.05; or ±0.01 °2θ. In some embodiments, when used in the context of XRPD peaks, "about" may indicate a peak value located exactly at the disclosed peak value.

[0044] As used in this article, the term "substantially" means greater than 85% (i.e., greater than 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%).

[0045] As used herein with respect to analytical spectra (such as XRPD patterns), the term "substantially similar" means that the spectra are substantially similar to the reference spectrum in both peak positions and their relative intensities. For example, two spectra can be considered "substantially similar" when they share defining characteristics sufficient to distinguish them from spectra obtained for different solid forms. In some embodiments, those skilled in the art understand that spectra or characterization data substantially similar to a reference crystalline form, amorphous form, or mixture thereof correspond to the same crystalline form, amorphous form, or mixture thereof as that particular reference. In determining whether analytical spectra or characterization data are substantially similar, those skilled in the art understand that, due to, for example, experimental errors and routine intersample analysis, specific characterization data points can vary to a reasonable degree while still describing a given solid form.

[0046] Unless the context clearly indicates otherwise, the article "a (and an)" as used herein and in the claims of the appended patent application is used herein to refer to one or more (i.e., at least one) grammatical objects of that article. For example, "element" means one or more elements.

[0047] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "any one or both" of the elements so combined, that is, elements that exist in combination in some cases and separately in others. Multiple elements listed with "and / or" should be interpreted in the same way, that is, "one or more" of the elements so combined. Other elements may exist, whether related to or unrelated to the explicitly identified elements, in addition to those explicitly identified by the "and / or" clause. Therefore, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" may in one embodiment refer only to A (including elements other than B, as appropriate); in another embodiment, refer only to B (including elements other than A, as appropriate); in yet another embodiment, refer to both A and B (including other elements, as appropriate); and so on.

[0048] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, that is, including multiple elements or at least one of the elements in the list (and also including more than one) and, where applicable, other items not listed. Only when the term explicitly indicates the opposite, such as "only one of..." or "exact one of..." or when used in the claims, "consisting of..." will mean including multiple elements or exactly one of the elements in the list. Generally, when preceded by an exclusive term (such as "any", "one of", "only one of", or "exact one of"), the term "or" as used herein should be interpreted only as indicating an exclusive alternative (i.e., "one or the other but not both").

[0049] In the scope of the patent application and the specification, all transitional phrases such as "comprising," "including," "with," "having," "containing," "involving," "holding," "constituting of," and the like should be understood as open-ended, that is, meaning including but not limited to. As stated in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedures, only the transitional phrases "constituting of" and "substantially consisting of" should be closed or semi-closed transitional phrases, respectively.

[0050] As used herein in the specification and claims, the phrase "at least one" in relation to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include each and at least one of each element expressly listed in the list of elements, nor excludes any combination of elements in the list of elements. This definition also allows for the presence, as appropriate, of elements other than those expressly identified in the list of elements referred to by the phrase "at least one," whether related to or unrelated to those expressly identified elements. Therefore, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently, "at least one of A and / or B") may in one embodiment refer to at least one (as the case includes more than one) A without B (and, as the case includes elements other than B); in another embodiment, it refers to at least one (as the case includes more than one) B without A (and, as the case includes elements other than A); in yet another embodiment, it refers to at least one (as the case includes more than one) A and at least one (as the case includes more than one) B (and, as the case includes other elements); and so on.

[0051] It should also be understood that in some methods described herein that include more than one step or action, unless the context otherwise indicates, the order of the steps or actions of the method is not necessarily limited to the order of the steps or actions listed in the method.

[0052] The terms "crystalline form," "crystalline shape," and "polymorph" are each understood to mean any solid having short-range or long-range molecular, atomic, or ionic order in a fixed lattice arrangement. The crystals of the present invention may be in single-crystal form. Therefore, the crystals of the present invention may be, for example, triclinic, monoclinic, orthorhombic, tetragonal, rhombic, hexagonal, or cubic crystal forms, or mixtures thereof. In another specific embodiment, the crystals of the present invention substantially do not contain other forms, such as amorphous or other crystalline forms.

[0053] The term "amorphous" refers to a solid in which molecules are arranged in a disordered manner and do not have a distinguishable crystal lattice.

[0054] The terms "co-administration" or "combination therapy" refer to both concurrent administration (simultaneous administration of two or more therapeutic agents) and variable administration (administration of one or more therapeutic agents at times different from administration of one or more other therapeutic agents), provided that the therapeutic agents are simultaneously present in the patient to a certain extent, preferably in an effective amount. In some preferred embodiments, one or more of the compounds of the invention described herein are co-administered in combination with at least one other bioactive agent (particularly including anticancer agents). In particularly preferred embodiments, the co-administration of the compounds results in improved activity or synergistic activity and / or therapeutic effects, including anticancer activity.

[0055] As used herein, unless otherwise indicated, the term "compound" means any specific compound disclosed herein, including its deuterated form (where applicable in the context). Deuterated small molecules under consideration are those small molecules in which one or more hydrogen atoms in a drug molecule have been deuterated. Unless otherwise indicated in the context, the term "compound" refers to compound A.

[0056] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific receptor proteins, thereby targeting and degrading those proteins. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugate, causes ubiquitin to attach to a lysine residue on a target protein. Therefore, an E3 ubiquitin ligase, alone or in combination with an E2 ubiquitin conjugate, leads to the transfer of ubiquitin to the target protein. Generally, ubiquitin ligases participate in polyubiquitination, causing a second ubiquitin to attach to a first ubiquitin; a third ubiquitin to the second ubiquitin, and so on. This polyubiquitination marks the target protein for proteasome degradation.

[0057] The terms "patient" or "individual" are used throughout this specification to describe an animal, preferably a human or domestic animal, to whom the composition of this disclosure is administered, including for preventative treatment. For the treatment of an infection, ailment, or disease state specific to a particular animal (such as a human patient), the term "patient" refers to that particular animal, including domestic animals such as dogs or cats, or farm animals such as horses, cattle, sheep, etc. Generally, in this disclosure, the term "patient" refers to a human patient unless otherwise stated or implied in the context of its use.

[0058] The term "effective" is used to describe the amount of a compound, composition, or component that produces the intended results when used in its intended context. The term "effective" includes all other effective amount or effective concentration terms otherwise described or used in this application.

[0059] As used herein, the phrase "therapeutic effective dose" and similar instructions refer to the amount administered to a patient or to the patient's cells, tissues, or organs to achieve a therapeutic effect (such as an ameliorative or alternative curative effect). A therapeutic effective dose is sufficient to elicit the biological or medical response in cells, tissues, systems, animals, or humans sought by the researcher, veterinarian, physician, or clinician. Determining an appropriate therapeutic effective dose is within the usual competence of someone skilled in this technique. [Polymorphic materials]

[0060] Compound A can be prepared according to the method disclosed in U.S. Patent No. 10,647,698, which is incorporated herein by reference for all purposes. The polymorph of form I of compound A can be prepared by crystallization from a variety of solvents. For example, form I can be recovered from each of the following solvents by cycling for 4 hours at temperatures between ambient temperature (approximately 22°C) and 40°C for 72 hours: acetone, 1-butanol, 2-ethoxyethanol, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, 1-propanol, 2-propanol, and ethanol:water (90:10 v / v). The XRPD spectrum of form I recovered from methyl ethyl ketone is shown in Figure 1A, obtained using Cu Kα radiation.

[0061] In some embodiments, this application provides a method for preparing polymorphic form I as disclosed herein, comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is acetone, 1-butanol, 2-ethoxyethanol, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, 1-propanol, 2-propanol, or a mixture of ethanol and water. In some embodiments, the solvent is acetone. In some embodiments, the solvent is 1-butanol. In some embodiments, the solvent is 2-ethoxyethanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is isopropyl acetate. In some embodiments, the solvent is methanol. In some embodiments, the solvent is methyl ethyl ketone. In some embodiments, the solvent is 1-propanol. In some embodiments, the solvent is 2-propanol. In some embodiments, the solvent is an ethanol / water mixture. In some embodiments, the ethanol to water ratio is between about 85:15 (v / v) and about 95:5 (v / v). In some embodiments, the ethanol to water ratio is between 85:15 (v / v) and 95:5 (v / v). In some embodiments, the ratio of ethanol to water is approximately 90:10 (v / v). In some embodiments, the water is deionized water.

[0062] In some embodiments, Form I may be characterized by the XRPD peak shown in FIG. 1A. For example, in some embodiments, Form I may be characterized by an XRPD peak at approximately 17.9 °2θ (e.g., 17.9 ± 0.2 °2θ, 17.9 ± 0.1 °2θ, or 17.9 ± 0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may further be characterized by an XRPD peak at approximately 13.9 °2θ and / or approximately 16.4 °2θ (e.g., ± 0.2 °2θ, ± 0.1 °2θ, or ± 0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may further be characterized by XRPD peaks at approximately 16.2 °2θ, approximately 18.5 °2θ, approximately 16.8 °2θ, approximately 14.5 °2θ and / or approximately 13.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ or ±0.0 °2θ; Cu Kα radiation).

[0063] In some embodiments, Form I is characterized by an XRPD peak at approximately 17.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I is characterized by an XRPD peak at approximately 13.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at both approximately 17.9°2θ and approximately 13.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0064] In some embodiments, Form I is characterized by XRPD peaks at approximately 13.5 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 14.3 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 14.5 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.4 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.8 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 18.5 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 18.9 °2θ, approximately 17.9 °2θ, and approximately 13.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0065] In some embodiments, Form I is characterized by XRPD peaks at approximately 16.4 °2θ, approximately 16.8 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.4 °2θ, approximately 16.8 °2θ, approximately 17.9 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.4 °2θ, approximately 16.8 °2θ, approximately 17.9 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 17.9 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.8 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.8 °2θ, approximately 17.9 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.8 °2θ, approximately 17.9 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.4 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.4 °2θ, approximately 17.9 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.4 °2θ, approximately 17.9 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.4 °2θ, approximately 16.8 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.4 °2θ, approximately 16.8 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 16.2 °2θ, approximately 16.4 °2θ, approximately 16.8 °2θ, and approximately 17.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 17.9 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.8 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.8 °2θ, approximately 17.9 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.8 °2θ, approximately 17.9 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.4 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.4 °2θ, approximately 17.9 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.4 °2θ, approximately 17.9 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.4 °2θ, approximately 16.8 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.4 °2θ, approximately 16.8 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.4 °2θ, approximately 16.8 °2θ, and approximately 17.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 17.9 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 17.9 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 16.8 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 16.8 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 16.8 °2θ, and approximately 17.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 16.4 °2θ, and approximately 20.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 16.4 °2θ, and approximately 18.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 16.4 °2θ, and approximately 17.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form I is characterized by XRPD peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, approximately 16.4 °2θ, and approximately 16.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). .

[0066] In some embodiments, Form I may be characterized by one or more XRPD peaks selected from the following: about 17.9°2θ, about 13.9°2θ, about 13.5°2θ, about 14.3°2θ, about 14.5°2θ, about 16.2°2θ, about 16.4°2θ, about 16.8°2θ, about 18.5°2θ, about 18.9°2θ, and about 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by an XRPD peak selected from the following: about 17.9°2θ, about 13.9°2θ, about 13.5°2θ, about 14.3°2θ, about 14.5°2θ, about 16.2°2θ, about 16.4°2θ, about 16.8°2θ, about 18.5°2θ, about 18.9°2θ, and about 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by two XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by three XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by four XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).In some embodiments, Form I may be characterized by five XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by six XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by seven XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by eight XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by nine XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).In some embodiments, Form I may be characterized by ten XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, Form I may be characterized by eleven XRPD peaks selected from the following: approximately 17.9°2θ, approximately 13.9°2θ, approximately 13.5°2θ, approximately 14.3°2θ, approximately 14.5°2θ, approximately 16.2°2θ, approximately 16.4°2θ, approximately 16.8°2θ, approximately 18.5°2θ, approximately 18.9°2θ, and approximately 20.9°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0067] In some embodiments, Form I may have one, two, three, four, five, six, seven, eight, nine, ten, eleven or more peaks as listed in Table 1.

[0068] Figure 1B shows the TG / DT plot of the Form I sample. TG indicates a weight loss of approximately 1% up to melting at approximately 250°C. Thereafter, the weight loss is 0.6% during melting, with a final weight loss of 0.4% observed up to approximately 350°C. An endothermic event is noted in the DT trace, starting at approximately 259°C and peaking at approximately 266°C. In some embodiments, Form I is characterized by a weight loss of approximately 1% between approximately 25°C and approximately 250°C. In some embodiments, Form I is characterized by an endothermic event starting at approximately 259°C as measured by DT. In some embodiments, Form I is characterized by an endothermic event peaking at approximately 166°C as measured by DT. In some embodiments, Form I is characterized by an endothermic event starting at approximately 259°C and peaking at approximately 266°C as measured by DT. In some embodiments, the weight loss is determined by thermogravimetric analysis. In some embodiments, thermogravimetric analysis is performed substantially as shown in Example 1. In some embodiments, the endothermic event is calculated by differential thermal analysis. In some embodiments, differential thermal analysis is performed substantially as shown in Example 1. In some embodiments, thermogravimetric analysis and differential thermal analysis are performed simultaneously.

[0069] Figure 1C shows a PLM image of Form I recovered from methanol. The PLM indicates that the material is birefringent and has an irregular, plate-like morphology. In some embodiments, Form I is characterized by being a birefringent material with an irregular, plate-like morphology.

[0070] Form II of compound A can be prepared by crystallization from various solvents. For example, form II was recovered from dichloromethane and from acetone:water (90:10 v / v) by cycling at ambient (approximately 22°C) and 40°C for 72 hours for 4 hours. The XRPD spectrum of form II recovered from dichloromethane is shown in Figure 2A, obtained using Cu Kα radiation.

[0071] In some embodiments, this application provides a method for preparing compound A, form II, as disclosed herein, comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is selected from dichloromethane and mixtures of acetone and water. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is a mixture of acetone and water. In some embodiments, the acetone-to-water ratio is between about 85:15 (v / v) and about 95:5 (v / v). In some embodiments, the acetone-to-water ratio is between 85:15 (v / v) and 95:5 (v / v). In some embodiments, the acetone-to-water ratio is about 90:10 (v / v). In some embodiments, the water is deionized water.

[0072] In some embodiments, Form II may be characterized by the XRPD peak shown in Figure 2A. For example, Form II may be characterized by an XRPD peak at approximately 17.5°2θ (e.g., 17.5 ±0.2 °2θ, 17.5 ±0.1 °2θ, or 17.5 ±0.0 °2θ). In some embodiments, Form II may further be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, and / or approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may further be characterized by XRPD peaks at approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ and / or approximately 19.6 °2θ (e.g. ±0.2 °2θ, ±0.1 °2θ or ±0.0 °2θ; Cu Kα radiation).

[0073] In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 10.0 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 16.3 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 18.1 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 12.5 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 14.1 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 15.7 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 16.9 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 19.1 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 19.6 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 18.1 °2θ and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0074] In some embodiments, Form II may be characterized by XRPD peaks at approximately 16.3 °2θ, approximately 17.5 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 10.0 °2θ, approximately 17.5 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 10.0 °2θ, approximately 16.3 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 10.0 °2θ, approximately 16.3 °2θ, and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 17.5 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 16.3 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 16.3 °2θ, and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 10.0 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 10.0 °2θ, and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 10.0 °2θ, and approximately 16.3 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0075] In some embodiments, Form II may be characterized by XRPD peaks at approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 17.5 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 16.3 °2θ, approximately 17.5 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 17.5 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, and approximately 18.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by XRPD peaks at approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, and approximately 17.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0076] In some embodiments, Form II may be characterized by one or more XRPD peaks selected from the following: about 17.5 °2θ, about 9.2 °2θ, about 10.0 °2θ, about 16.3 °2θ, about 18.1 °2θ, about 12.5 °2θ, about 14.1 °2θ, about 15.7 °2θ, about 16.9 °2θ, about 19.1 °2θ, about 19.6 °2θ, about 21.1 °2θ, about 21.9 °2θ, about 22.4 °2θ, and about 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by an XRPD peak selected from the following: about 17.5 °2θ, about 9.2 °2θ, about 10.0 °2θ, about 16.3 °2θ, about 18.1 °2θ, about 12.5 °2θ, about 14.1 °2θ, about 15.7 °2θ, about 16.9 °2θ, about 19.1 °2θ, about 19.6 °2θ, about 21.1 °2θ, about 21.9 °2θ, about 22.4 °2θ, and about 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by two XRPD peaks selected from the following: about 17.5 °2θ, about 9.2 °2θ, about 10.0 °2θ, about 16.3 °2θ, about 18.1 °2θ, about 12.5 °2θ, about 14.1 °2θ, about 15.7 °2θ, about 16.9 °2θ, about 19.1 °2θ, about 19.6 °2θ, about 21.1 °2θ, about 21.9 °2θ, about 22.4 °2θ, and about 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by three XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form II may be characterized by four XRPD peaks selected from the following: about 17.5 °2θ, about 9.2 °2θ, about 10.0 °2θ, about 16.3 °2θ, about 18.1 °2θ, about 12.5 °2θ, about 14.1 °2θ, about 15.7 °2θ, about 16.9 °2θ, about 19.1 °2θ, about 19.6 °2θ, about 21.1 °2θ, about 21.9 °2θ, about 22.4 °2θ, and about 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by five XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by six XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by seven XRPD peaks selected from the following: about 17.5 °2θ, about 9.2 °2θ, about 10.0 °2θ, about 16.3 °2θ, about 18.1 °2θ, about 12.5 °2θ, about 14.1 °2θ, about 15.7 °2θ, about 16.9 °2θ, about 19.1 °2θ, about 19.6 °2θ, about 21.1 °2θ, about 21.9 °2θ, about 22.4 °2θ, and about 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form II may be characterized by eight XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by nine XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by ten XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by eleven XRPD peaks selected from the following: about 17.5 °2θ, about 9.2 °2θ, about 10.0 °2θ, about 16.3 °2θ, about 18.1 °2θ, about 12.5 °2θ, about 14.1 °2θ, about 15.7 °2θ, about 16.9 °2θ, about 19.1 °2θ, about 19.6 °2θ, about 21.1 °2θ, about 21.9 °2θ, about 22.4 °2θ, and about 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form II may be characterized by twelve XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by thirteen XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by fourteen XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form II may be characterized by fifteen XRPD peaks selected from the following: approximately 17.5 °2θ, approximately 9.2 °2θ, approximately 10.0 °2θ, approximately 16.3 °2θ, approximately 18.1 °2θ, approximately 12.5 °2θ, approximately 14.1 °2θ, approximately 15.7 °2θ, approximately 16.9 °2θ, approximately 19.1 °2θ, approximately 19.6 °2θ, approximately 21.1 °2θ, approximately 21.9 °2θ, approximately 22.4 °2θ, and approximately 25.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0077] In some embodiments, Form II may have one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more peaks as listed in Table 2.

[0078] Figure 2B shows the TG / DT plot of the Form II sample. TG indicates a weight loss of approximately 11% up to approximately 85°C, and a further weight loss of 2.4% up to approximately 325°C. A potential endothermic event is observed in the DT trace, peaking at approximately 212°C. In some embodiments, Form II is characterized by a weight loss of approximately 11% between approximately 25°C and approximately 85°C. In some embodiments, Form II is characterized by an endothermic event, as measured by DT, peaking at approximately 212°C. In some embodiments, the weight loss is determined by thermogravimetric analysis (TGA). In some embodiments, TGA is performed substantially as shown in Example 1. In some embodiments, the endothermic event is calculated by differential thermal analysis (DTA). In some embodiments, DTA is performed substantially as shown in Example 1. In some embodiments, TGA and DTA are performed simultaneously.

[0079] Figure 2C shows a PLM image of Form II recovered from dichloromethane. The PLM indicates that the material is birefringent and has an irregular, needle-like morphology. In some embodiments, Form II is characterized by being a birefringent material with an irregular, needle-like morphology.

[0080] Form III of compound A can be prepared by crystallization from various solvents. For example, form III can be recovered from acetonitrile by cycling at ambient (approximately 22°C) for 4 hours and at a temperature between 40°C and 42 hours. The XRPD spectrum of form III recovered from acetonitrile is shown in Figure 3A, obtained using Cu Kα radiation.

[0081] In some embodiments, this application provides a method for preparing compound A, form III, as disclosed herein, comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is acetonitrile.

[0082] In some embodiments, Form III may be characterized by the XRPD peak shown in FIG. 3A. For example, in some embodiments, Form III may be characterized by an XRPD peak at approximately 10.7 °2θ (e.g., 10.7 ±0.2 °2θ, 10.7 ±0.1 °2θ, 10.7 ±0.0 °2θ). In some embodiments, Form III may further be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, and / or approximately 18.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may further be characterized by XRPD peaks at approximately 15.0 °2θ and / or approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may further be characterized by XRPD peaks at approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ and / or approximately 19.6 °2θ (e.g. ±0.2 °2θ, ±0.1 °2θ or ±0.0 °2θ; Cu Kα radiation).

[0083] In some embodiments, Form III may be characterized by XRPD peaks at approximately 8.8 °2θ and approximately 10.7 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 11.2 °2θ and approximately 10.7 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 16.5 °2θ and approximately 10.7 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 18.2 °2θ and approximately 10.7 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, and approximately 10.7 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0084] In some embodiments, Form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 16.5 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 18.2 °2θ, approximately 16.5 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 18.2 °2θ, approximately 8.8 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 18.2 °2θ, approximately 8.8 °2θ, and approximately 16.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 16.5 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 8.8 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 8.8 °2θ, and approximately 16.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 18.2 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 18.2 °2θ, and approximately 16.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 18.2 °2θ, and approximately 8.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0085] In some embodiments, Form III may be characterized by XRPD peaks at approximately 18.2 °2θ, approximately 8.8 °2θ, approximately 16.5 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 8.8 °2θ, approximately 16.5 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 18.2 °2θ, approximately 16.5 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 18.2 °2θ, approximately 8.8 °2θ, and approximately 11.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 10.7 °2θ, approximately 18.2 °2θ, approximately 8.8 °2θ, and approximately 16.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0086] In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, and approximately 15.0 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, and approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, and approximately 15.0 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0087] In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, and approximately 12.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, and approximately 12.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, and approximately 16.1 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, and approximately 18.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, and approximately 19.0 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, form III may be characterized by XRPD peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0088] In some embodiments, Form III may be characterized by one or more XRPD peaks selected from the following: about 8.8 °2θ, about 11.2 °2θ, about 16.5 °2θ, about 18.2 °2θ, about 10.7 °2θ, about 17.8 °2θ, about 15.0 °2θ, about 12.2 °2θ, about 12.8 °2θ, about 16.1 °2θ, about 18.6 °2θ, about 19.0 °2θ, and about 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by an XRPD peak selected from the following: about 8.8 °2θ, about 11.2 °2θ, about 16.5 °2θ, about 18.2 °2θ, about 10.7 °2θ, about 17.8 °2θ, about 15.0 °2θ, about 12.2 °2θ, about 12.8 °2θ, about 16.1 °2θ, about 18.6 °2θ, about 19.0 °2θ, and about 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by two XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by three XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form III may be characterized by four XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by five XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by six XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by seven XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by eight XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form III may be characterized by nine XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by ten XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by eleven XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, Form III may be characterized by twelve XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, Form III may be characterized by thirteen XRPD peaks selected from the following: approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 16.5 °2θ, approximately 18.2 °2θ, approximately 10.7 °2θ, approximately 17.8 °2θ, approximately 15.0 °2θ, approximately 12.2 °2θ, approximately 12.8 °2θ, approximately 16.1 °2θ, approximately 18.6 °2θ, approximately 19.0 °2θ, and approximately 19.6 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0089] In some embodiments, Form III may have one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or more peaks as listed in Table 3.

[0090] Figure 3B shows the TG / DT plots of the Form III sample. TG indicates a weight loss of approximately 3.7% up to approximately 75°C, a further weight loss of 4.7% up to approximately 160°C, and a final weight loss of 0.6% up to 350°C. DT shows a small and broad endothermic event that begins at approximately 196°C and peaks at approximately 204°C. In some embodiments, Form III is characterized by a weight loss of approximately 3.7% between approximately 25°C and approximately 75°C. In some embodiments, Form III is further characterized by a weight loss of approximately 4.7% between approximately 75°C and approximately 160°C. In some embodiments, Form III is further characterized by a weight loss of approximately 0.6% between approximately 160°C and approximately 350°C. In some embodiments, Form III is characterized by an endothermic event beginning at approximately 196°C as measured by DT. In some embodiments, Form III is characterized by an endothermic event peaking at approximately 204°C as measured by DT. In some embodiments, Form III is characterized by an endothermic event, as measured by DT, starting at approximately 196°C and peaking at approximately 204°C. In some embodiments, weight loss is determined by thermogravimetric analysis (TGA). In some embodiments, TGA is performed substantially as shown in Example 1. In some embodiments, the endothermic event is calculated by differential thermal analysis (DTA). In some embodiments, DTA is performed substantially as shown in Example 1. In some embodiments, TGA and DTA are performed simultaneously.

[0091] Figure 3C shows a PLM image of Form III recovered from acetonitrile. The PLM indicates that the material is birefringent and has an irregular, plate-like morphology. In some embodiments, Form III is characterized by being a birefringent material with an irregular, plate-like morphology.

[0092] Form IV of compound A can be prepared by crystallization under various conditions. For example, form IV is recovered from dichloromethane / methanol (25:75 v / v) with the addition of the antisolvent tributylmethyl ether, and further recovered from dichloromethane / methanol (25:75 v / v) upon rapid cooling at 2°C–8°C. The XRPD spectrum of form IV recovered from dichloromethane / methanol (25:75) after rapid cooling is shown in Figure 4A, obtained using Cu Kα radiation.

[0093] In some embodiments, this application provides a method for preparing form IV of compound A as disclosed herein, comprising rapidly cooling compound A from a solvent. In some embodiments, the solvent is a mixture of dichloromethane and methanol. In some embodiments, this disclosure provides a method for preparing a polymorph of form IV of compound A, comprising adding an antisolvent to a solution of compound A in a solvent. In some embodiments, the solvent comprises a mixture of dichloromethane and methanol. In some embodiments, the antisolvent is tert-butylmethyl ether.

[0094] In some embodiments, form IV may be characterized by the XRPD peak shown in FIG. 4A. For example, in some embodiments, form IV may be characterized by an XRPD peak at approximately 10.5 °2θ (e.g., 10.5 ±0.2 °2θ, 10.5 ±0.1 °2θ, 10.5 ±0.0 °2θ). In some embodiments, form IV may further be characterized by an XRPD peak at approximately 14.5 °2θ and / or approximately 16.9 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may further be characterized by XRPD peaks at approximately 11.5 °2θ, approximately 14.2 °2θ, and / or approximately 16.3 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0095] In some embodiments, form IV may be characterized by XRPD peaks at approximately 14.5 °2θ and approximately 10.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by XRPD peaks at approximately 16.9 °2θ and approximately 10.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by XRPD peaks at approximately 14.5 °2θ, approximately 16.9 °2θ, and approximately 10.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0096] In some embodiments, form IV may be characterized by XRPD peaks at approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, and approximately 11.5 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by XRPD peaks at approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, and approximately 14.2 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by XRPD peaks at approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, and approximately 16.3 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by XRPD peaks at approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, approximately 11.5 °2θ, approximately 14.2 °2θ, and approximately 16.3 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0097] In some embodiments, form IV may be characterized by one or more XRPD peaks selected from the following: about 14.5 °2θ, about 16.9 °2θ, about 10.5 °2θ, about 11.5 °2θ, about 14.2 °2θ, about 16.3 °2θ, and about 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by an XRPD peak selected from the following: about 14.5 °2θ, about 16.9 °2θ, about 10.5 °2θ, about 11.5 °2θ, about 14.2 °2θ, about 16.3 °2θ, and about 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by two XRPD peaks selected from the following: approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, approximately 11.5 °2θ, approximately 14.2 °2θ, approximately 16.3 °2θ, and approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by three XRPD peaks selected from the following: approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, approximately 11.5 °2θ, approximately 14.2 °2θ, approximately 16.3 °2θ, and approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by four XRPD peaks selected from the following: approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, approximately 11.5 °2θ, approximately 14.2 °2θ, approximately 16.3 °2θ, and approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by five XRPD peaks selected from the following: approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, approximately 11.5 °2θ, approximately 14.2 °2θ, approximately 16.3 °2θ, and approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation). In some embodiments, form IV may be characterized by six XRPD peaks selected from the following: approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, approximately 11.5 °2θ, approximately 14.2 °2θ, approximately 16.3 °2θ, and approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).In some embodiments, form IV may be characterized by seven XRPD peaks selected from the following: approximately 14.5 °2θ, approximately 16.9 °2θ, approximately 10.5 °2θ, approximately 11.5 °2θ, approximately 14.2 °2θ, approximately 16.3 °2θ, and approximately 17.8 °2θ (e.g., ±0.2 °2θ, ±0.1 °2θ, or ±0.0 °2θ; Cu Kα radiation).

[0098] In some embodiments, form IV may have one, two, three, four, five, six, seven or more peaks as listed in Table 4.

[0099] Figure 4B shows the TG / DT plots for Form IV samples. TG indicates a weight loss of approximately 3.1% up to approximately 350°C. DT notes a small, broad endothermic event that begins at approximately 196°C and peaks at approximately 213°C. In some embodiments, Form IV is characterized by a weight loss of approximately 3.1% between approximately 25°C and approximately 350°C. In some embodiments, Form IV is characterized by an endothermic event beginning at approximately 196°C as measured by DT. In some embodiments, Form IV is characterized by an endothermic event peaking at approximately 213°C as measured by DT. In some embodiments, Form IV is characterized by an endothermic event beginning at approximately 196°C and peaking at approximately 213°C as measured by DT. In some embodiments, the weight loss is determined by thermogravimetric analysis (TGA). In some embodiments, TGA is performed substantially as shown in Example 1. In some embodiments, the endothermic event is calculated by differential thermal analysis (DTA). In some embodiments, DTA is performed substantially as shown in Example 1. In some embodiments, TGA and DTA are performed simultaneously.

[0100] Figure 4C shows a PLM image of Form IV recovered from dichloromethane:methanol (25:75 v / v). The PLM indicates that the material is birefringent and has an irregular, plate-like morphology. In some embodiments, Form III is characterized by being a birefringent material with an irregular, plate-like morphology.

[0101] The polymorphs of this invention can be used in various ways. In some embodiments, the polymorph of compound A is used as a convenient storage (e.g., bulk storage) form that can be used to prepare the amorphous form of compound A. In some embodiments, the polymorph of compound A can be further used to prepare the pharmaceutical compositions or final dosage forms of this disclosure, including, for example, tablets or capsules. In some embodiments, the amorphous form of compound A can be further used to prepare the pharmaceutical compositions or final dosage forms of this disclosure, including, for example, tablets or capsules.

[0102] In some embodiments, compound A is stored in bulk as a polymorph of form I.

[0103] In some embodiments, compound A is stored in bulk as a polymorph of form II.

[0104] In some embodiments, compound A is stored in bulk as a polymorph of form III.

[0105] In some embodiments, compound A is stored in bulk as a polymorph of form IV. [Amorphous form]

[0106] This application further provides an amorphous form of compound A.

[0107] In some embodiments, compound A is stored in bulk in essentially its amorphous form.

[0108] In some embodiments, the amorphous form of compound A prepared as described herein is used to prepare one or more pharmaceutical compositions or dosage forms of the present invention, such as tablets or capsules containing compound A. [Therapeutic Composition]

[0109] This application further provides a pharmaceutical composition comprising a therapeutically effective amount of at least one crystalline and / or amorphous form of compound A as described herein, combined with a dispersant, carrier, additive, or other pharmaceutical excipient, or a combination thereof. This application further provides a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of compound A as described herein, combined with a dispersant, carrier, additive, or other pharmaceutical excipient, or a combination thereof. In some embodiments, the dispersant is hydroxypropyl methylcellulose (HPMC). In some embodiments, the additive is D-α-tocopherol polyethylene glycol succinate (vitamin E TPGS or TPGS).

[0110] According to this disclosure, compound A, whether substantially in the crystalline or amorphous form as described herein, can be administered to a patient or individual in single or separate doses as a pharmaceutical composition. The pharmaceutical composition can be administered orally, enterically, by inhalation, topically, rectally, nasally, buccally, vaginally, percutaneously, sublingually, via suppository, or via an implanted reservoir. As used herein, "entrantly" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion. Preferably, the pharmaceutical composition is administered orally.

[0111] Enteric-coated oral tablets can be used to enhance the bioavailability of compounds administered orally. The most effective dosage form will depend on the pharmacokinetics of the chosen specific crystalline and / or amorphous form, as well as the severity of the disease and / or condition being treated in the patient. Compound A according to this disclosure can be administered as a spray, aerosol, or aerosol for intranasal, intratracheal, intraocular, or transpulmonary administration. Therefore, this disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of crystalline and / or amorphous forms of compound A as described herein, or a combination thereof, in combination with a pharmaceutically acceptable carrier, additive, or excipient. Compound A can be administered in an immediate-release, sustained-release, or controlled-release form. Sustained-release or controlled-release forms are preferred orally, but can be alternatively administered as suppositories, transdermal, or other topical forms. Intramuscular injection (e.g., in liposome form) can be used to control (e.g., maintain) the release of compound A at the injection site.

[0112] The pharmaceutical compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and the formulation can be administered in a controlled manner. Pharmaceutically acceptable carriers that can be used in such pharmaceutical compositions include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in glycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0113] The sterile injectable form of the pharmaceutical compositions described herein can be an aqueous or oily suspension. According to this disclosure, such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in this art. The sterile injectable form can be a sterile injectable solution or suspension in a non-toxic, non-enteric-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are often used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Like pharmaceutically acceptable natural oils (such as olive oil or castor oil, especially in their polyoxyethylated forms), fatty acids (such as oleic acid and its glyceride derivatives) can also be used to prepare injectable formulations. Such oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0114] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including (but not limited to) capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, diluents include lactose and dry corn starch. When an aqueous suspension is required for oral administration, the active ingredient can be combined with one or more emulsifiers and suspending agents. Buffers, sweeteners, flavoring agents, and / or coloring agents may also be added if desired.

[0115] Alternatively, the pharmaceutical compositions described herein can be administered rectally as suppositories or enemas for local administration to the lower intestine or for systemic absorption and treatment. According to this disclosure, such suppositories can be prepared by mixing compound A, which is in a substantially crystalline or substantially amorphous form, with a suitable non-irritating excipient that is solid or semi-solid at room temperature but liquid at rectal temperature, thereby melting in the rectum to release the drug. Such excipients may include cocoa butter, beeswax, polyethylene glycol, and combinations thereof.

[0116] The pharmaceutical compositions described herein can be applied topically as an alternative. For example, in one embodiment, the present invention provides a pharmaceutical formulation comprising compound A in a crystalline form (such as form I, form II, form III or form IV) or in an amorphous form, and suitable for topical application, such as as an ointment, cream, lotion, lotion or topical liquid.

[0117] For external application, a pharmaceutical composition may be formulated into a suitable ointment containing an active ingredient (i.e., compound A) suspended or dissolved in one or more carriers. Carriers used for external application include (but are not limited to) mineral oil, liquid paraffin, leucocele, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water.

[0118] Alternatively, the pharmaceutical composition may be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oil, sorbitan monostearate, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0119] Alternatively, the pharmaceutical formulation of the present invention can be delivered via a transdermal patch for application for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In one embodiment, the transdermal patch will be a reservoir patch. In another embodiment, the transdermal patch will be a drug adhesive dispersion patch. The transdermal patch of the present invention may also contain one or more absorption enhancers.

[0120] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, with or without preservatives (such as benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment (such as paraffin).

[0121] The pharmaceutical compositions described herein can also be administered via nasal aerosol or inhalation. According to this disclosure, these compositions are prepared according to techniques known in pharmaceutical formulation and can be prepared into solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers (to enhance bioavailability), fluorocarbons and / or other conventional solubilizers or dispersants.

[0122] The amount of the compound in the pharmaceutical composition of the present invention may be combined with a carrier or excipient material to produce a single dosage form, which will vary depending on the host and disease being treated, and the specific mode of administration. Preferably, the single dosage form is formulated to contain between about 0.05 mg and about 750 mg, more preferably about 1 mg to about 600 mg, and even more preferably about 10 mg to about 500 mg of the active ingredient, which may be alone or in combination with at least one other therapeutically active compound. In some embodiments, the other therapeutically active compound is an anticancer agent. The polymorph (crystalline form) and / or amorphous form of compound A, or its pharmaceutical composition, may be conveniently administered in any suitable unit dosage form, including (but not limited to) containing less than 1 mg, 1 mg to 3000 mg, and preferably 5 mg to 500 mg of the active ingredient per unit dosage form. An oral dose of about 25-250 mg may be a convenient dosage.

[0123] It should be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the severity of the specific disease or ailment being treated, the activity and bioavailability of compound A in the specific dosage form, the patient's age, weight, health status and sex, the rate of metabolism and excretion of the active compound or its metabolites, the judgment of the treating physician, and other factors.

[0124] Patients or individuals who require treatment using the pharmaceutical composition according to the methods described herein may be treated by administering a therapeutically effective amount of the composition to the patient (individual).

[0125] The amount of active compound included in the pharmaceutical composition is sufficient to deliver to a patient a therapeutically effective amount for the desired indication without causing undue adverse effects in the treated patient. In some embodiments, the dose of the active compound for all the diseases mentioned herein is in the range of about 10 ng / kg to 300 mg / kg, preferably from 0.1 mg / kg to 100 mg / kg daily, and more typically from 0.5 mg to about 25 mg per kilogram of recipient / patient body weight daily.

[0126] Preferably, the active ingredient is administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, more preferably about 0.1-30 μM. This concentration can be achieved, for example, by oral administration of a tablet or capsule of the active ingredient or by intravenous injection of a solution or formulation of the active ingredient.

[0127] The concentration of the active compound in a pharmaceutical composition will depend on the rate of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the disease to be alleviated. It should be further understood that, for any given individual, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the composition, and the concentration ranges stated herein are merely illustrative and not intended to limit the scope or practice of the proposed compositions. The active ingredient may be administered in one dose or divided into multiple smaller doses administered at selected time intervals.

[0128] Oral compositions typically include an inert diluent or an edible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may contain excipients and be used in tablet, sugar tablet, or capsule form. Pharmaceutically compatible binders and / or adjuvant materials may be incorporated as part of the composition.

[0129] Tablets, pills, capsules, sugar tablets, and the like may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; dispersants, such as alginic acid, Primogel, or corn starch; buffers; lubricants, such as magnesium stearate; glidants, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit is in capsule form, it may also contain liquid carriers such as fatty oils in addition to the above types of materials. Furthermore, the dosage unit form may contain other materials that alter the physical form of the dosage unit, such as sugar coatings, shellac, or enteric absorbents.

[0130] The active polymorph and / or amorphous form of compound A, or combinations thereof, may be administered as elixirs, suspensions, syrups, rice paper capsules, chewing gum, or similar components. In addition to the active compound, syrups may also contain sweeteners (such as sucrose) and certain preservatives, dyes and colorants, and flavorings.

[0131] The active polymorph and / or amorphous form of compound A, or a combination thereof, may also be mixed with other active materials that do not impair the desired effect, or with materials that complement the desired effect (such as another anticancer agent). In some embodiments of this disclosure, one or more compounds, polymorphs and / or amorphous forms of this disclosure are co-administered with another bioactive agent (such as another anticancer agent or wound healing agent).

[0132] Solutions or suspensions intended for non-enteral, intradermal, subcutaneous, or topical application may include the following components: sterile diluents, such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and agents for adjusting osmotic pressure, such as sodium chloride or dextrose. Non-enteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0133] If administered intravenously, the carrier may include normal saline or phosphate-buffered saline (PBS).

[0134] In one embodiment, an active compound, a polymorph, and / or amorphous form, is prepared together with a carrier that protects the compound from rapid elimination from the body, such as a controlled-release formulation, including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene / vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. [Treatment methods]

[0135] In another embodiment, this specification provides therapeutic compositions comprising a therapeutically effective amount of a polymorph and / or amorphous form of compound A, or its pharmaceutical composition as described herein, and a pharmaceutically acceptable carrier. The therapeutic compositions of this invention regulate protein degradation in patients or individuals (e.g., animals, such as humans) and can be used to treat or improve disease states or conditions causally related to the degradation of the protein.

[0136] As used herein, the terms "treat," "treating," and "treatment" refer to any action that provides benefit to a patient by administering an active compound, polymorph, and / or amorphous form, including treatment of any disease state or condition (including one or more symptoms) that is causally related to (e.g., modulation) ER. Disease states or conditions that can be treated with the compounds, polymorphs, amorphous forms, and / or pharmaceutical compositions disclosed herein, including breast cancer, uterine cancer, ovarian cancer, and / or endometriosis, are stated above.

[0137] This specification provides therapeutic pharmaceutical compositions, as described herein, for achieving the degradation of ER to treat or improve diseases (e.g., cancer). In some other embodiments, the disease is breast cancer, uterine cancer, ovarian cancer, endometrial cancer, or endometriosis. Therefore, in another embodiment, this specification provides a method for ubiquitinizing / degrading ER in cells. In some embodiments, the method includes administration of a bifunctional compound (i.e., compound A) or its polymorph and / or amorphous form as described herein, such that ER is ubiquitinated in the vicinity of a ubiquitin ligase, leading to ubiquitination of the target protein and subsequent degradation via the proteasome pathway, thereby providing control (i.e., reduction) of ER protein levels. The control of ER levels provided by the invention of this disclosure provides treatment for disease states, conditions, or symptoms causally related to ER by reducing ER levels in patient cells. In some embodiments, the method includes administering a therapeutically effective amount of compound A as described herein, which may include one or more pharmaceutically acceptable excipients (e.g., dispersants, carriers, lubricants), and may include another bioactive agent and combinations thereof.

[0138] In other embodiments, this specification provides a method for treating or improving a disease, condition, or symptom of an individual or patient (e.g., an animal, such as a human), comprising administering to an individual in need a composition comprising a therapeutically effective amount (e.g., a therapeutically effective amount) of compound A as described herein and a pharmaceutically acceptable excipient (e.g., a dispersant, carrier, lubricant), other bioactive agent, or a combination thereof, wherein the composition effectively treats or improves the individual's disease or condition or symptom.

[0139] In another embodiment, this disclosure relates to a method for treating a disease state, ailment, or symptom causally related to the ER protein in a human patient in need, wherein the degradation of the ER protein produces a therapeutic effect in the patient. The method includes administering a therapeutically effective amount of compound A of this disclosure to the patient in need, which, if applicable, is combined with another bioactive agent. The disease state, ailment, or symptom may be caused by the expression or overexpression of the ER protein.

[0140] The term "disease state, disorder, or symptom" is used to describe any disease state, disorder, or symptom causally related to protein activity, excessive activity, expression, or overexpression (e.g., elevated levels of ER expression in a patient), wherein targeted degradation of the protein in the patient provides a beneficial treatment or relief for the disease state, disorder, or symptom. In some cases, the disease state or disorder may be reduced, alleviated, or improved. In other cases, the disease state, disorder, or symptom may be reversible or curable.

[0141] As used in this specification, the terms "tumor formation" and "cancer" refer to the pathological processes that lead to the formation and growth of a cancerous or malignant tumor, which is an abnormal tissue that grows through cell proliferation, typically faster than normal and continuing to grow after the initial stimulus for new growth has ceased. Malignant tumors are characterized by a partial or complete lack of structural tissue and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted resection, and cause patient death unless adequately treated. As used herein, the term tumor formation is used to describe any and all cancerous disease states and encompasses or covers the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated alone or in combination with at least one other anticancer agent by the polymorphic and / or amorphous forms of the compounds of the present invention include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, colorectal cancer, breast cancer, cervical cancer, endometrial cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer; leukemia; benign and malignant lymphomas, specifically Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, and Kaposi's sarcoma. Sarcoma, liposarcoma, myoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendritic glioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma. Other cancers that can be treated with the compounds disclosed herein include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML. In some embodiments, cancers that can be treated alone or in combination with at least one other anticancer agent by the compounds, polymorphs, and / or amorphous forms of the present invention include breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. [Protein Level Control]

[0142] This disclosure also provides a method for controlling (e.g., reducing) intracellular protein levels. This method is based on the use of compound A, as described herein, or its polymorphic or amorphous form, which leads to targeted ubiquitination and proteasome degradation of the ER protein, thereby controlling (i.e. reducing) the amount of the ER protein in the cells of a biological system, individual, or patient, for example, to obtain specific therapeutic benefits. [Example:]

[0143] The form of this disclosure is further illustrated by referring to the following numbered embodiments: Example 1. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 13.9 °2θ and approximately 17.9 °2θ. Example 2. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The feature is that it uses Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at about 13.9 °2θ, about 16.4 °2θ and about 17.9 °2θ. Example 3. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 13.9 °2θ, approximately 16.2 °2θ, and approximately 17.9 °2θ. Example 4. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The feature is that it uses Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 13.9 °2θ, approximately 17.9 °2θ, and approximately 20.9 °2θ. Example 5. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A) (named Form I), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 13.9 °2θ and approximately 17.9 °2θ. Example 6. A polymorph as in Example 1, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes a peak at approximately 16.4 °2θ. Example 7. The polymorph of Example 1 is further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes at least one peak selected from about 16.2 °2θ, about 16.4 °2θ, about 18.5 °2θ and about 20.9 °2θ. Example 8. A polymorph as in Example 1, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes peaks at approximately 16.2 °2θ, approximately 16.4 °2θ, approximately 18.5 °2θ, and approximately 20.9 °2θ. Example 9. A polymorph of any of Examples 1 to 8, characterized in that Cu Kα radiation is used and the X-ray powder diffraction pattern includes at least one peak selected from about 13.5 °2θ, about 14.3 °2θ, about 14.5 °2θ, and about 16.8 °2θ. Example 10. A polymorph of any of Examples 1 to 9, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes peaks at approximately 13.5 °2θ, approximately 14.3 °2θ, approximately 14.5 °2θ, and approximately 16.8 °2θ. Example 11. A polymorph of any of Examples 1 to 10, characterized in that the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in FIG1A. Example 12. A polymorph of any of Examples 1 to 11, further characterized by an endothermic event, as measured by DT, starting at about 259°C and peaking at about 266°C. Example 13. A polymorph of any of Examples 1 to 12, characterized further by a weight loss of about 1% between about 25°C and about 250°C, as measured by TG. Example 14. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 10.0 °2θ and approximately 17.5 °2θ. Example 15. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The feature is that it uses Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at about 10.0 °2θ, about 16.3 °2θ and about 17.5 °2θ. Example 16. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 9.2 °2θ, approximately 16.3 °2θ, and approximately 17.5 °2θ. Example 17. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The feature is that it uses Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at about 16.3 °2θ, about 17.5 °2θ and about 18.1 °2θ. Example 18. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A) (named Form II), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 10.0 °2θ and approximately 17.5 °2θ. Example 19. A polymorph as in Examples 14 or 18, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes a peak at approximately 16.3 °2θ. Example 20. A polymorph of any of Examples 14 to 19, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes at least one peak selected from about 9.2 °2θ, about 16.3 °2θ and about 18.1 °2θ. Example 21. A polymorph of any of Examples 14 to 20, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes peaks at approximately 9.2 °2θ, approximately 16.3 °2θ, and approximately 18.1 °2θ. Example 22. A polymorph of any of Examples 14 to 21, characterized in that the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in FIG. 2A. Example 23. A polymorph of any of Examples 14 to 22, further characterized by an endothermic event with a peak value of about 212°C as measured by DT. Example 24. A polymorph of any of Examples 14 to 23, further characterized by a weight loss of about 11% between about 25°C and about 85°C, as measured by TG. Example 25. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The feature is that it uses Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 10.7 °2θ and 18.2 °2θ. Example 26. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 8.8 °2θ, approximately 10.7 °2θ, and approximately 18.2 °2θ. Example 27. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The invention is characterized by using Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 10.7 °2θ, approximately 11.2 °2θ, and 18.2 °2θ. Example 28. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The feature is that it uses Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at about 10.7 °2θ, about 16.5 °2θ and about 18.2 °2θ. Example 29. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A) (designated as form III), (Compound A) The feature is that it uses Cu Kα radiation, and the X-ray powder diffraction pattern includes peaks at approximately 10.7 °2θ and 18.2 °2θ. Example 30. A polymorph of any of Examples 25 or 27 to 29, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes a peak at approximately 8.8 °2θ. Example 31. A polymorph of any of Examples 25 to 30, characterized in that Cu Kα radiation is used and the X-ray powder diffraction pattern includes at least one peak selected from about 8.8 °2θ, about 11.2 °2θ, about 15.0 °2θ, about 16.5 °2θ and about 17.8 °2θ. Example 32. A polymorph of any of Examples 25 to 31, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes peaks at approximately 8.8 °2θ, approximately 11.2 °2θ, approximately 15.0 °2θ, approximately 16.5 °2θ, and approximately 17.8 °2θ. Example 33. A polymorph of any of Examples 25 to 32, further characterized in that the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in 3A. Example 34. Polymorphs 25 to 33 of any of the examples are further characterized by an endothermic event, as measured by DT, starting at about 196°C and peaking at about 204°C. Example 35. A polymorph of any of Examples 25 to 34, further characterized by a weight loss of about 3.7% between about 25°C and about 75°C, as measured by TG. Example 36. The polymorph of Example 35 is further characterized by a weight loss of about 4.7% between about 75°C and about 160°C, as measured by TG. Example 37. The polymorph of Example 36 is further characterized by a weight loss of about 0.6% between about 160°C and about 350°C, as measured by TG. Example 38. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A), (Compound A) The feature is that the X-ray powder diffraction pattern includes peaks at approximately 10.5 °2θ, approximately 14.5 °2θ, and approximately 16.9 °2θ. Example 39. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione (compound A) (named form IV), (Compound A) The feature is that the X-ray powder diffraction pattern includes peaks at approximately 10.5 °2θ, approximately 14.5 °2θ, and approximately 16.9 °2θ. Example 40. A polymorph as in Example 38 or 39, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes at least one peak selected from about 11.5 °2θ, about 14.2 °2θ, about 16.3 °2θ and about 17.8 °2θ. Example 41. A polymorph of any of Examples 38 to 40, further characterized by the use of Cu Kα radiation, wherein the X-ray powder diffraction pattern includes peaks at approximately 11.5 °2θ, approximately 14.2 °2θ, approximately 16.3 °2θ, and approximately 17.8 °2θ. Example 42. A polymorph of any of Examples 38 to 41, characterized in that the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in FIG4A. Example 43. A polymorph of any of Examples 38 to 42, further characterized by an endothermic event, as measured by DT, starting at about 196°C and peaking at about 213°C. Example 44. A polymorph of any of Examples 38 to 43, characterized further by a weight loss of about 3.1% between about 25°C and about 350°C, as measured by TG. Example 45. A method of treating a disease or ailment of an individual in need, comprising administering to the individual a therapeutically effective amount of a polymorph of any of the examples 1 to 44. Example 46. The method of Example 45, wherein the disease or condition is associated with estrogen receptor (ER) activity, excessive activity, constitutive activity, expression, overexpression or accumulation and aggregation. Example 47. The method of Example 45 or 46, wherein the disease or condition is cancer or neoplasm formation associated with ER activity, excessive activity, constitutive activity, expression, overexpression or accumulation and aggregation. Example 48. The method of any of Examples 45 to 47, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis. Example 49. A pharmaceutical composition comprising a therapeutically effective amount of a polymorph of any of Examples 1 to 44 and a pharmaceutically acceptable carrier, wherein the composition effectively treats or improves at least one symptom of a disease or condition. Example 50. A composition as in Example 49, wherein the disease or condition is associated with excessive activity, constitutive activity, or ER accumulation and aggregation. Example 51. A composition as in Example 49 or 50, wherein the disease or condition is cancer or neoplasm formation associated with ER accumulation and aggregation or ER activity or hyperactivity. Example 52. A composition of any of Examples 49 to 51, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis. Example 53. A pharmaceutical composition comprising a therapeutically effective amount of compound A in its amorphous form. (Compound A) And medically acceptable dispersants. Example 54. The composition of Example 53 further comprises a pharmaceutically acceptable additive. Example 55. A composition as in Example 53 or 54, wherein the pharmaceutically acceptable additive is HPMC. Example 56. A composition as in Example 53 or 54, wherein the pharmaceutically acceptable additive is TPGS. Example 57. A composition as described in any of Examples 53 to 56, wherein the composition is effective in treating or improving at least one symptom of a disease or condition. Example 58. A composition as in Example 57, wherein the disease or condition is associated with excessive activity, constitutive activity, or ER accumulation and aggregation. Example 59. A composition as in Example 57 or 58, wherein the disease or condition is cancer or neoplasm formation associated with ER accumulation and aggregation or ER activity or hyperactivity. Example 60. A composition of any of Examples 57 to 59, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis. Example 61. Use of a polymorph as described in any of Examples 1 to 44 for manufacturing a medicament for treating diseases or conditions. Example 62. As used in Example 61, wherein the disease or condition is associated with ER accumulation and aggregation or ER activity or excessive activity. Example 63. As used in Example 61 or 62, wherein the disease or condition is cancer or neoplasm formation associated with ER accumulation and aggregation or ER activity or hyperactivity. Example 64. Used as in any of Examples 61 to 63, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis. Example 65. A polymorph of any of Examples 1 to 44, used in medicine. Example 66. A polymorph of any of Examples 1 to 44, used to treat a disease or condition associated with ER accumulation and aggregation or ER activity or excessive activity. Example 67. A polymorph for use as in Example 66, wherein the disease or condition is cancer or neoplasm formation associated with ER accumulation and aggregation or ER activity or hyperactivity. Example 68. A polymorph for use as in Example 66 or 67, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis. Example 69. A method for preparing a polymorph of compound A as described in any of Examples 1 to 13, comprising recrystallizing compound A from a solvent. Example 70. The method of Example 69, wherein the solvent is selected from the group consisting of: acetone, 1-butanol, 2-ethoxyethanol, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, 1-propanol, 2-propanol, polyethylene glycol, and ethanol / water mixtures. Example 71. The method of Example 69, wherein the solvent is 1-butanol. Example 72. The method as in Example 69, wherein the solvent is methyl ethyl ketone. Example 73. A method for preparing a polymorph of compound A as described in any of Examples 14 to 24, comprising recrystallizing compound A from a solvent. Example 74. The method of Example 73, wherein the solvent is selected from dichloromethane and an acetone / water mixture. Example 75. A method for preparing a polymorph of compound A as described in any of Examples 25 to 37, comprising recrystallizing compound A from a solvent. Example 76. The method of Example 75, wherein the solvent is acetonitrile. Example 77. A method for preparing a polymorph of compound A as described in any of Examples 38 to 44, comprising rapidly cooling a solution of compound A in a solvent. Example 78. A method for preparing a polymorph of compound A as described in any of Examples 38 to 44, comprising adding an antisolvent to a solution of compound A in a solvent. Example 79. The method of Example 77 or 78, wherein the solvent is a mixture of dichloromethane and methanol. Example 80. The method of Example 79, wherein the ratio of dichloromethane to methanol is about 25:75 (v / v). Example 81. The method of any of Examples 78 to 80, wherein the antisolvent is third butyl methyl ether. Example

[0144] Compound A can be prepared according to the method disclosed in U.S. Patent No. 10,647,698, which is incorporated herein for all purposes. The following examples are used to help describe this disclosure, but should not be construed as limiting this disclosure in any way. [Example] [1] [Analysis Methods]

[0145] Unless otherwise specified, all characterization data were obtained using the following procedure: [X] [Powder diffraction] [(XRPD)]

[0146] XRPD analysis was performed on a PANalytical X'pert pro, scanning the sample between 3° 2θ and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous plate with a Mylar polymer film for sample support. The porous plate was then placed in a diffractometer and analyzed using Cu K radiation (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1 : α2 ratio = 0.5) in transmission mode (step size 0.0130° 2θ). Polarizing microscopy [(PLM)]

[0147] The presence of crystallinity (birefringence) was determined using an Olympus BX50 polarizing microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). Unless otherwise stated, all images were recorded using a 20× objective lens. [Thermogravimetric Analysis] [(TGA)] [and differential thermal analysis] [(DTA)]

[0148] Approximately 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analysis (TG / DTA) instrument, which was then kept at room temperature. The sample was then heated from 20 °C to 400 °C at a rate of 10 °C / min, during which the change in sample weight and any differential thermal events (DTA) were recorded. Nitrogen gas was used as the purge gas at a flow rate of 300 cm³ / min. Differential scanning calorimetry [(DSC)]

[0149] Approximately 5 mg of material was weighed into an aluminum DSC pan and non-hermetically sealed with a perforated aluminum cap. The sample pan was then loaded into a Seiko DSC6200 (equipped with a cooler) that was cooled and maintained at 20°C. After a stable thermal flux was obtained, the sample and reference were heated to the desired temperature at a scan rate of 10°C / min, and the resulting thermal flux was monitored. Nitrogen was used as the purge gas at a flow rate of 50 cm³ / min. [Example] [2] [Polymorph Screening]

[0150] Add an appropriate solvent to a vial containing approximately 30 mg of compound A to suspend the material. Then, cycle the experiment for 4 hours at a temperature between ambient temperature (approximately 22°C) and 40°C for 72 hours.

[0151] All solids were separated by centrifugation and analyzed by XRPD. Any new forms were further analyzed by TG / DT and PLM. The results of this step are shown in Table 5 below.

[0152] The filtered saturated solution of compound A was then divided into three equal portions, which were used in subsequent polymorph screening experiments, as detailed below: Evaporation: A saturated solution of compound A was transferred to 2 mL vials; the vials were then opened and allowed to evaporate at ambient temperature to recover the material. All recovered solids were analyzed by XRPD. The results are shown in Table 6 below.

[0153] Rapid cooling: The saturated solution of compound A was stored at 2°C–8°C for 24–72 h. Any recovered material was analyzed by XRPD during this period. The experiment was then stored at -20°C for 24–72 h. Subsequently, any recovered material was analyzed by XRPD. The results are shown in Tables 7 and 8 below. []

[0154] Add the antisolvent at ambient temperature: Add up to 1 mL of antisolvent dropwise to the stirred saturated solution of compound A. Then open the lid of the experiment and allow it to evaporate at ambient temperature. Analyze all recovered solids by XRPD. The results are shown in Table 9 below. [Example] [3] [:form] [I]

[0155] Approximately 30 mg of the free base of amorphous compound A was suspended in 1.0 mL of methyl ethyl ketone. The experiment was cycled for 4 hours between ambient temperature (approximately 22°C) and 40°C for 72 hours. After 72 hours, the solid was separated by centrifugation and filtration, and dried at 40°C for 18 hours before analysis.

[0156] Form I was found to be a thermodynamically stable, non-solventizable form with a high melting point (259°C). This form exhibits excellent stability, good solubility in process-related solvents, improved solubility at lower biorelevant pH levels, and low hygroscopicity (1.7 wt.%) at 90% RH. Of the four identified forms, form I was determined to be the most stable. A summary of the relevant characteristics of form I is shown in Table 10 below: Form I: Alternative Separation from Polyethylene Glycol

[0157] Amorphous or partially amorphous solids were pulped in PEG-400 and cyclically heated overnight between room temperature and 40°C. The solids were separated from the supernatant, washed first with ethanol and then with methyl ethyl ketone, and dried in a vacuum oven to produce flat, plate-like crystals. [Example] [4] [:form] [II]

[0158] Approximately 30 mg of the free base of amorphous compound A was suspended in 0.5 mL of dichloromethane. The experiment was cycled for 4 hours at ambient temperature (approximately 22°C) and 40°C for 72 hours. After 72 hours, the solid was separated by centrifugation and filtration, and dried at 40°C for 18 hours before analysis.

[0159] Form II appears to be a crystallization kinetic form. It appears to be unsolvable and possibly hydrated. Its particle size is extremely small and it has a needle-like or rod-like morphology. [Example] [5] [:form] [III]

[0160] Approximately 30 mg of the free base of amorphous compound A was suspended in 1.0 mL of acetonitrile. The experiment was cycled for 4 hours at ambient temperature (approximately 22°C) and 40°C for 72 hours. After 72 hours, the solid was separated by centrifugation and filtration, and dried at 40°C for 18 hours before analysis.

[0161] Form III appears to be a crystallization-kinetic form. It exhibits a high melting temperature (starting at 196 °C) after dehydration. It appears to be non-solventized and potentially hydrated. It shows a loss of crystallinity upon dehydration. [Example] [6] [:form] [IV]

[0162] Approximately 30 mg of amorphous compound A (free base) was suspended in 1.0 mL of dichloromethane:methanol (25:75 v / v). The experiment was cycled for 4 hours at ambient temperature (approximately 22°C) to 40°C for 72 hours. After 72 hours, the sample was filtered through a 0.22 μm Nylon filter, and the supernatant was retained. The supernatant was cooled in a refrigerator to between 2°C and 8°C and maintained for 72 hours. After 72 hours, the resulting solid was separated by centrifugation and analyzed as a wet powder.

[0163] Form IV was found to be partially crystalline.

Claims

1. A crystalline compound A(S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione, 1. Characterized by using Cu Kα radiation with an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern has peaks at 13.9 °2θ±0.20 °2θ, 16.4 °2θ±0.20 °2θ and 17.9 °2θ±0.20 °2θ.

2. The crystalline compound A of claim 1, wherein Cu Kα radiation with an X-ray wavelength of 1.5406 Å is used, and the X-ray powder diffraction pattern includes one or more peaks at 16.2 °2θ±0.20 °2θ, 18.5 °2θ±0.20 °2θ, and 20.9 °2θ±0.20 °2θ.

3. The crystalline compound A of claim 1, wherein the X-ray powder diffraction pattern, when using Cu Kα radiation, comprises one or more peaks at 16.2 °2θ±0.20 °2θ, 18.5 °2θ±0.20 °2θ, and 20.9 °2θ±0.20 °2θ.

4. The crystalline compound A of any one of claims 1 to 3, wherein Cu Kα radiation at an X-ray wavelength of 1.5406 Å is used, and the X-ray powder diffraction pattern includes one or more peaks at 13.5 °2θ ± 0.20 °2θ, 14.3 °2θ ± 0.20 °2θ, 14.5 °2θ ± 0.20 °2θ, and 16.8 °2θ ± 0.20 °2θ.

5. The crystalline compound A of any one of claims 1 to 3, wherein the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in Figure 1A.

6. The crystalline compound A of any one of claims 1 to 3, wherein the endothermic event, measured by DT, begins at 259°C and peaks at 266°C.

7. The crystalline compound A of any one of claims 1 to 3, wherein the weight loss is 1% between 25°C and 250°C as measured by TG.

8. A crystalline compound A(S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione, 8. Cu Kα radiation with an X-ray wavelength of 1.5406 Å was used, and the X-ray powder diffraction pattern had peaks at 10.0 °2θ±0.20 °2θ, 16.3 °2θ±0.20 °2θ and 17.5 °2θ±0.20 °2θ.

9. The crystalline compound A of claim 8, wherein Cu Kα radiation at an X-ray wavelength of 1.5406 Å is used, and the X-ray powder diffraction pattern comprises one or two peaks at 9.2 °2θ ± 0.20 °2θ and 18.1 °2θ ± 0.20 °2θ.

10. The crystalline compound A of claim 8, wherein the X-ray powder diffraction pattern, when irradiated with Cu Kα, comprises one or two peaks at 9.2 °2θ ± 0.20 °2θ and 18.1 °2θ ± 0.20 °2θ.

11. The crystalline compound A of any one of claims 8 to 10, wherein the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in Figure 2A.

12. The crystalline compound A of any one of claims 8 to 10, wherein the endothermic event is such that the peak value measured by DT is at 212°C.

13. The crystalline compound A of any one of claims 8 to 10, wherein the weight loss is 11% between 25°C and 85°C as measured by TG.

14. A crystalline compound A(S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione, 14. Cu Kα radiation with an X-ray wavelength of 1.5406 Å was used, and the X-ray powder diffraction pattern had peaks at 8.8 °2θ±0.20 °2θ, 10.7 °2θ±0.20 °2θ and 18.2 °2θ±0.20 °2θ.

15. The crystalline compound A of claim 14, wherein Cu Kα radiation at an X-ray wavelength of 1.5406 Å is used, and the X-ray powder diffraction pattern comprises one or more peaks at 11.2 °2θ ± 0.20 °2θ, 15.0 °2θ ± 0.20 °2θ, 16.5 °2θ ± 0.20 °2θ, and 17.8 °2θ ± 0.20 °2θ.

16. The crystalline compound A of claim 14, wherein Cu Kα radiation is used and the X-ray powder diffraction pattern includes one or more peaks at 11.2 °2θ ± 0.20 °2θ, 15.0 °2θ ± 0.20 °2θ, 16.5 °2θ ± 0.20 °2θ and 17.8 °2θ ± 0.20 °2θ.

17. The crystalline compound A of any one of claims 14 to 16, wherein the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in Figure 3A.

18. The crystalline compound A of any one of claims 14 to 16, wherein the endothermic event, measured by DT, begins at 196°C and peaks at 204°C.

19. The crystalline compound A of any one of claims 14 to 16, wherein the weight loss is 3.7% between 25°C and 75°C as measured by TG.

20. The crystalline compound A of claim 19, wherein the weight loss is 4.7% between 75°C and 160°C, as measured by TG.

21. The crystalline compound A of claim 20, wherein the weight loss is 0.6% between 160°C and 350°C, as measured by TG.

22. A crystalline compound A(S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)hexahydropyridin-4-yl)methyl)hexahydropyrazin-1-yl)-1-sideoxyisoindoline-2-yl)hexahydropyridin-2,6-dione, 22. Characterized by having peaks at 10.5 °2θ±0.20 °2θ, 14.5 °2θ±0.20 °2θ and 16.9 °2θ±0.20 °2θ at an X-ray wavelength of 1.5406 Å.

23. The crystalline compound A of claim 22, wherein Cu Kα radiation at an X-ray wavelength of 1.5406 Å is used, and the X-ray powder diffraction pattern comprises one or more peaks at 11.5 °2θ ± 0.20 °2θ, 14.2 °2θ ± 0.20 °2θ, 16.3 °2θ ± 0.20 °2θ, and 17.8 °2θ ± 0.20 °2θ.

24. The crystalline compound A of claim 22, wherein the X-ray powder diffraction pattern, when irradiated with Cu Kα, comprises one or more peaks at 11.5 °2θ ± 0.20 °2θ, 14.2 °2θ ± 0.20 °2θ, 16.3 °2θ ± 0.20 °2θ, and 17.8 °2θ ± 0.20 °2θ.

25. The crystalline compound A of any one of claims 22 to 24, wherein the X-ray powder diffraction pattern is substantially similar to the X-ray powder diffraction pattern shown in Figure 4A.

26. The crystalline compound A of any one of claims 22 to 24, wherein the endothermic event, measured by DT, begins at 196°C and peaks at 213°C.

27. The crystalline compound A of any one of claims 22 to 24, wherein the weight loss is 3.1% between 25°C and 350°C as measured by TG.

28. The crystalline compound A of any one of claims 1 to 3, 8 to 10, 14 to 16 and 22 to 24, wherein the crystalline compound A is substantially anhydrous.

29. The crystalline compound A of any one of claims 1 to 3, 8 to 10, 14 to 16 and 22 to 24, wherein the crystalline compound A is substantially non-solventized.

30. The crystalline compound A of any one of claims 1 to 3, 8 to 10, 14 to 16 and 22 to 24, wherein the crystalline compound A is substantially anhydrous and substantially non-solventized.

31. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 30 of a crystalline compound A and a pharmaceutically acceptable carrier, wherein the composition effectively treats or improves at least one symptom of a disease or condition, wherein the disease or condition is associated with ER activity, excessive activity, constitutive activity, expression, overexpression, or accumulation and aggregation.

32. The composition of claim 31, wherein the disease or condition is cancer or neoplasm formation associated with ER accumulation and aggregation or ER activity or hyperactivity.

33. The composition of claim 31, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

34. Use of a crystalline compound A as claimed in any one of claims 1 to 30, for the manufacture of a medicament for treating a disease or condition, wherein the disease or condition is associated with ER accumulation and aggregation or ER activity or excessive activity.

35. As claimed in claim 34, wherein the disease or condition is a cancer or neoplasm formation associated with ER accumulation and aggregation or ER activity or hyperactivity.

36. As requested in claim 34, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

37. The crystalline compound A of any one of claims 1 to 3, 8 to 10, 14 to 16 and 22 to 24, used in medicine.

38. The crystalline compound A of any one of claims 1 to 3, 8 to 10, 14 to 16 and 22 to 24, used to treat a disease or condition, wherein the disease or condition is associated with ER accumulation and aggregation or ER activity or excessive activity.

39. The crystalline compound A for use as claimed in claim 38, wherein the disease or condition is cancer or neoplasm formation associated with ER accumulation and aggregation or ER activity or hyperactivity.

40. The crystalline compound A for use as claimed in claim 38, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

41. A method for preparing a crystalline compound A as claimed in any one of claims 1 to 7, comprising recrystallizing compound A from a solvent.

42. The method of claim 41, wherein the solvent is selected from the group consisting of acetone, 1-butanol, 2-ethoxyethanol, ethanol, ethyl acetate, isopropyl acetate, methanol, methyl ethyl ketone, 1-propanol, 2-propanol, polyethylene glycol, and ethanol / water mixtures.

43. The method of claim 41, wherein the solvent comprises 1-butanol.

44. The method of claim 41, wherein the solvent comprises methyl ethyl ketone.

45. A method for preparing a crystalline compound A as claimed in any one of claims 8 to 13, comprising recrystallizing compound A from a solvent.

46. ​​The method of claim 45, wherein the solvent is selected from dichloromethane and an acetone / water mixture.

47. A method for preparing a crystalline compound A as claimed in any one of claims 14 to 21, comprising recrystallizing compound A from a solvent.

48. The method of claim 47, wherein the solvent is acetonitrile.

49. A method for preparing a crystalline compound A as claimed in any one of claims 22 to 24, comprising rapidly cooling a solution of compound A in a solvent.

50. A method for preparing a crystalline compound A as claimed in any one of claims 22 to 24, comprising adding an antisolvent to a solution of compound A in a solvent.

51. The method of claim 49 or 50, wherein the solvent is a mixture of dichloromethane and methanol.

52. The method of claim 51, wherein the ratio of dichloromethane to methanol is 25:75 (v / v).

53. The method of claim 50, wherein the antisolvent is a third butyl methyl ether.

54. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 30 of a crystalline compound A and a pharmaceutically acceptable carrier.

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