Crystalline forms of compounds for targeted degradation of estrogen receptors

Abstract

The present disclosure relates to polymorphic forms of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound A), methods of making these polymorphic forms, and compositions comprising these polymorphic forms. These polymorphic forms are useful in treating various diseases, including, for example, breast cancer. (A)

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180070126.4, filed on September 13, 2021, entitled "Crystal Form of a Compound for Targeting Degradation of Estrogen Receptors".

[0002] Cross-referencing related applications

[0003] This application claims priority and benefit to 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. Background Technology

[0004] Most small molecule drugs bind to enzymes or receptors in a tight and well-defined pocket. In contrast, protein-protein interactions are notoriously difficult to target with small molecules because they involve large contact surfaces and often involve shallow grooves or flat interfaces. E3 ubiquitin ligases confer substrate specificity against ubiquitination and are attractive therapeutic targets due to their specificity for certain protein substrates. The development of E3 ligase ligands has proven challenging, partly because they must disrupt protein-protein interactions. However, recent developments have yielded 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.

[0005] One E3 ligase with special therapeutic potential is cereblon, a protein synthesized in the human body by... CRBN Genetically encoded proteins. CRBN orthologs are highly conserved from plants to humans, indicating their physiological importance. CRBNs form an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and the regulator of cullin 1 (ROC1). This complex ubiquitinates several other proteins. Through a mechanism not yet fully elucidated, ubiquitination of target proteins with CRBNs leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates several developmental processes, such as the formation of limbs and auditory vesicles. Ultimately, this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of CRBNs, DDB1 forms a complex with DDB2 that acts as a DNA damage-binding protein.

[0006] Thalidomide, already approved for the treatment of many immunological indications, has also been approved for the treatment of certain proliferative diseases, including multiple myeloma. Furthermore, thalidomide and several of its analogues are currently under investigation for the treatment of various other types of cancer. Although the exact mechanism of thalidomide's antitumor activity is still emerging, it is known to inhibit angiogenesis. Recent literature discussing imide biology includes Lu et al., *Science* 343, 305 (2014) and Kroenke et al., *Science* 343, 301 (2014).

[0007] It is noteworthy that thalidomide and its analogues (such as pomalidomide and lenalidomide) are known to bind to cerebrosides and alter the specificity of the complex to induce ubiquitination and degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for the growth of multiple myeloma. In fact, higher expression of cerebrosides has been associated with increased efficacy of imide drugs in the treatment of multiple myeloma.

[0008] The estrogen receptor (ER) is a member of the nuclear hormone receptor family and acts as a transcription factor involved in the upregulation and downregulation of gene expression through ligand activation. The natural hormone of ER is 17-β-estradiol (E2) and closely associated metabolites. The binding of estradiol to ER causes dimerization of the receptor and the dimer, which in turn binds to estrogen response elements (EREs) on DNA. The ER-DNA complex recruits other transcription factors responsible for transcribing downstream DNA into mRNA, which is ultimately translated into protein. Alternatively, the interaction of ER with DNA can be indirect, most notably through the intermediates of fos and jun. Because the expression of a large number of genes is regulated by ER, and because ER is expressed in many cell types, regulation of ER through the binding of natural hormones or synthetic ER ligands can have profound implications for the physiology and pathophysiology of organisms.

[0009] The etiology and / or pathology of many diseases are mediated by estrogen. These diseases are collectively referred to as estrogen-dependent diseases. Estrogen is essential for female sexual development. Furthermore, estrogen plays a crucial role in maintaining bone density, regulating blood lipid levels, and appears to have neuroprotective effects. Therefore, the reduction in estrogen production in postmenopausal women is associated with many diseases, such as osteoporosis, atherosclerosis, depression, and cognitive impairment. Conversely, certain types of proliferative diseases, such as breast cancer and uterine cancer, as well as endometriosis, are stimulated by estrogen and are therefore anti-estrogenic. (Right now Estrogen antagonists can be used to prevent and treat these types of conditions.

[0010] ER has two different forms, commonly referred to as α and β, each generated by a separate gene (respectively). ESR1 and ESR2 ) Encoding. Both ERs are widely expressed in different tissue types, but there are some significant differences in their expression patterns. ERα It has been found in the endometrium, breast cancer cells, ovarian stromal cells, and hypothalamus. In men, it has been found in the epithelium of the efferent ducts. ERα protein. ERβ The expression of the protein in the kidneys, brain, bones, heart, lungs, intestinal mucosa, prostate, and endothelial cells has been confirmed. Therefore, the development of selective ligands targeting one form or another could preserve the beneficial aspects of estrogen.

[0011] Breast cancer is the most common malignant tumor affecting women, and its incidence is increasing worldwide. Specifically, estrogen acts as the endocrine growth factor in at least one-third of breast cancers, and depriving the tumor of this stimulation is the accepted treatment for advanced disease in premenopausal women. This is achieved through surgical, radiation, or medical procedures to eliminate ovarian function, and in postmenopausal women, through the use of aromatase inhibitors.

[0012] An alternative to discontinuing estrogen is to antagonize estrogen with anti-estrogens. These are drugs that 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 efficacy is often limited by the partial agonist activity they exhibit, resulting in incomplete blocking of estrogen-mediated activity. In the treatment of estrogen-dependent disorders, specific or “pure” anti-estrogens with high affinity for the ER and no agonist effect can have advantages over conventional nonsteroidal anti-estrogens. Fulvestrant is the first in a new class of potent pure anti-estrogens and is completely free of the partial agonist estrogen-like activity associated with currently available anti-estrogens such as tamoxifen.

[0013] Therefore, other methods are needed to antagonize ER. One approach is to develop selective ER downregulators or degraders that reduce ER expression at the transcript or protein level. Summary of the Invention

[0014] 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-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A), with the molecular formula C 45H 49 N5O4, and has the following structural formula:

[0015]

[0016] Compound A is being developed as a PROTAC® protein degrader targeting the estrogen receptor (ER) for potential breast cancer treatment. Compound A has been shown to be a useful regulator of protein ubiquitination and degradation via the ubiquitin-proteasome pathway.

[0017] This disclosure provides several crystalline (polymorphic) and amorphous forms of compound A.

[0018] On one hand, this disclosure provides a polymorph of compound A (“Form I”), characterized by an X-ray powder diffraction pattern obtained using Cu Kα radiation at an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern containing peaks at approximately 13.9°2θ, approximately 16.4°2θ and approximately 17.9°2θ.

[0019] On one hand, this disclosure provides a polymorph of compound A (“Form II”), characterized by an X-ray powder diffraction pattern obtained using Cu Kα radiation at an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern containing peaks at approximately 10.0°2θ, approximately 16.3°2θ and approximately 17.5°2θ.

[0020] On one hand, this disclosure provides a polymorph of compound A (“Form III”), characterized by an X-ray powder diffraction pattern obtained using Cu Kα radiation at an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern containing peaks at approximately 8.8°2θ, approximately 10.7°2θ, and 18.2°2θ.

[0021] On one hand, this disclosure provides a polymorph of compound A (“form IV”), characterized by an X-ray powder diffraction pattern with an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern containing peaks at about 10.5°2θ, about 14.5°2θ and about 16.9°2θ.

[0022] On the other hand, this disclosure provides a method for treating a disease or condition in a subject in need, the method comprising administering to the subject 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, intrinsic 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 intrinsic 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.

[0023] In some embodiments, the disease or condition is a cancer or neoplasia associated with ER activity, excessive activity, inherent 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.

[0024] On the other hand, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a polymorph and / or amorphous form of compound A, wherein the composition is effective in treating or improving at least one symptom of the disease or condition. In some embodiments, the disease or condition is causally related to ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia causally related to ER activity, excessive activity, inherent 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] On the other hand, 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).

[0026] In some embodiments, the polymorphs of the present invention are preferred forms for bulk storage of compound A prior to conversion to 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 of compound A disclosed herein (e.g., polymorphs or amorphous forms). In some embodiments, the form for bulk storage of compound A is a mixture of form I and amorphous forms. 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.

[0027] On the other hand, this disclosure provides the use of polymorphs and / or amorphous forms of compound A in the preparation of medicaments for treating diseases or conditions. In some embodiments, the disease or condition is associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia associated with ER activity, excessive activity, inherent 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.

[0028] On the other hand, this disclosure provides polymorphs and / or amorphous forms of compound A for use in medicine.

[0029] On the other hand, this disclosure provides polymorphic and / or amorphous forms of compound A for treating diseases or conditions. In some embodiments, the disease or condition is associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia associated with ER activity, excessive activity, inherent 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.

[0030] On the other hand, this disclosure provides a method for preparing a polymorph of compound A in form I, the method 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.

[0031] On the other hand, this disclosure provides a method for preparing a form II polymorph of compound A, the method comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is dichloromethane or a mixture of acetone and water.

[0032] On the other hand, this disclosure provides a method for preparing a form III polymorph of compound A, the method comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is acetonitrile.

[0033] On the other hand, this disclosure provides a method for preparing a polymorph of compound A in form IV, the method comprising rapidly cooling compound A from a solvent. In some embodiments, the solvent is a mixture of dichloromethane and methanol.

[0034] On the other hand, this disclosure provides a method for preparing a polymorph of compound A in form IV, the method comprising adding an antisolvent to a solution of compound A from a solvent. In some embodiments, the solvent comprises a mixture of dichloromethane and methanol. In some embodiments, the antisolvent is methyl tert-butyl ether. Attached Figure Description

[0035] Figure 1A The XRPD spectrum of a sample of polymorph I of compound A is shown. The diffraction pattern is from material recovered from methyl ethyl ketone.

[0036] Figure 1B The TG / DT plots of a sample of polymorph I of compound A are shown. The TG plot begins at the top left, and the DT plot begins at the bottom left.

[0037] Figure 1C A PLM image of polymorph I of compound A is shown. The sample in this image was recovered from methanol.

[0038] Figure 2A The XRPD spectrum of a sample of compound A in form II is shown. The diffraction pattern is from material recovered from dichloromethane.

[0039] Figure 2B The TG / DT plots of a sample of polymorph II of compound A are shown. The TG plot begins at the top left, and the DT plot begins at the bottom left.

[0040] Figure 2C A PLM image of polymorph II of compound A is shown. The sample in this image was recovered from dichloromethane.

[0041] Figure 3A The XRPD spectrum of a sample of polymorph III of compound A is shown. The diffraction pattern is from the material recovered from acetonitrile.

[0042] Figure 3B The TG / DT plots of a sample of polymorph III of compound A are shown. The TG plot begins at the top left, and the DT plot begins at the bottom left.

[0043] Figure 3C A PLM image of polymorph III of compound A is shown. The sample in this image was recovered from acetonitrile.

[0044] Figure 4A The XRPD spectrum of a sample of polymorph IV of compound A is shown. The diffraction pattern is from the material recovered from dichloromethane:methanol (25:75 v / v) after rapid cooling.

[0045] Figure 4B The TG / DT plots of the sample showing the form IV polymorph of compound A are shown. The TG plot starts at the top left, and the DT plot starts at the bottom left.

[0046] Figure 4C PLM images of polymorph IV of compound A are shown. The sample in this image was recovered from dichloromethane:methanol (25:75 v / v). Detailed Implementation

[0047] This application relates to: U.S. Patent Application Serial No. 15 / 829,541, published as U.S. Patent No. 10,647,698; U.S. Patent Application Serial No. 16 / 744,414, published as U.S. Patent No. 10,899,742; and U.S. Patent Application Serial No. 17 / 001,519. For all purposes, each of these U.S. patent applications is incorporated herein by reference in its entirety.

[0048] The following detailed description is provided to assist those skilled in the art in implementing this disclosure. Modifications and alterations can be made to the embodiments described herein without departing from the spirit or scope of this disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated herein by reference in their entirety for all purposes.

[0049] 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 describing particular embodiments only and is not intended to limit this disclosure.

[0050] Where a range of values ​​is provided, it should be understood that every intermediate value between the upper and lower limits of the range (to one-tenth of the lower limit, unless the context clearly indicates otherwise) (such as in the case of a group containing many carbon atoms, in which case the number of carbon atoms falling within the range is provided), as well as any other stated values ​​or intermediate values ​​within the range, are included within this disclosure. The upper and lower limits of these smaller ranges may be independently included within a smaller range, subject to any specific exclusions within the stated range. Where a stated range includes one or both of the included limits, the range excluding any one or both of the included limits is also included within this disclosure.

[0051] definition

[0052] The following terms are used to describe this disclosure. Where no particular term is specifically defined herein, it is to be assumed by one of ordinary skill in the art to have a meaning recognized by that skill, and to be used in the context of its use in describing the content of this disclosure.

[0053] As defined herein, “XRPD” or “XPD” should be understood to mean X-ray powder diffraction. Unless otherwise specified, all XRPD peaks and plots are given in °2θ using Cu Kα1 radiation at a wavelength of 1.5406 Å.

[0054] The abbreviations "TG" and "TGA" should be understood as referring to thermogravimetry / thermogravimetric analysis. The abbreviations "DT" or "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.

[0055] The term "PLM" should be understood as referring to polarized light microscopy.

[0056] As used herein, the term "about" means approximately, within a range, substantially, or around. When used in conjunction with a numerical range, the term modifies the range by extending the boundaries above and below the stated numerical value. The term "about" is generally used herein to refer to a numerical value modified by 20% above and below the value. When used in the context of XRPD peaks (i.e., the location of the XRPD peak along the x-axis of the diffraction pattern), 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 exactly at the disclosed peak value.

[0057] As used herein, 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%).

[0058] As used herein, the term "substantially similar" for analytical spectra (such as XRPD plots) means that the spectra are substantially similar to a reference spectrum in both peak positions and their relative intensities. For example, two spectra can be considered "substantially similar" when they share defining features sufficient to distinguish them from spectra obtained for different solid forms. In some embodiments, spectra or characterization data substantially similar to those of a reference crystalline form, amorphous form, or mixture thereof are understood by those skilled in the art to correspond to the same crystalline form, amorphous form, or mixture thereof as a particular reference. In determining whether analytical spectra or characterization data are substantially similar, those skilled in the art will understand that specific characterization data points can vary reasonably well due to, for example, experimental errors and routine sample-to-sample analysis, while still describing a given solid form.

[0059] The articles “a” and “an” as used herein and in the appended claims refer to one or more (i.e., at least one) grammatical objects of the article, unless the context clearly indicates otherwise. For example, “element” means one or more elements.

[0060] 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, i.e., the elements are combined in some cases and separate in others. Multiple elements listed with “and / or” should be interpreted in the same way, i.e., “one or more” of the elements so combined. Other elements may optionally be present, whether related to or unrelated to those specifically identified by the “and / or” clause. Thus, 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 (optionally including elements other than B); in another embodiment, it may refer only to B (optionally including elements other than A); in yet another embodiment, it may refer to both A and B (optionally including other elements); and so on.

[0061] As used herein in this specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when items in a list are separated, “or” or “and / or” should be interpreted as inclusive, i.e., including a plurality of elements or at least one element in a list of elements, but also including more than one element and optionally other items not listed. Only explicitly indicating the opposite terms, such as “only one of…” or “exact one of…” or, when used in the claims, “consisting of…” will refer to including a plurality of elements or exactly one element in a list of elements. In general, when preceded by an exclusive term, such as “any one,” “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”).

[0062] In the claims and the specification, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “accommodating,” “constituting,” “made of,” etc., should be understood as open-ended, meaning that they include but are not limited to. As described in Section 2111.03 of the U.S. Patent Examination Procedure Manual, only the transitional phrases “composed of” and “substantially composed of” should be closed or semi-closed transitional phrases, respectively.

[0063] As used herein in the specification and claims, the phrase "at least one" relating 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 at least one of each element specifically listed in the list of elements and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase "at least one," whether or not they are related to those specifically identified elements. Thus, 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") in one embodiment may refer to at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment may refer to at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment may refer to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0064] It should also be understood that, unless the context explicitly indicates otherwise, in some methods described herein that involve more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are described.

[0065] The terms "crystalline form," "crystalline form," and "polymorph" are each understood to mean any solid having short-range or long-range ordered molecules, atoms, or ions in a fixed lattice arrangement. The crystals of the present invention can be in single-crystal form. Therefore, the crystals of the present invention can be, for example, triclinic, monoclinic, orthorhombic, tetragonal, rhombic, hexagonal, or cubic forms, or mixtures thereof. In another specific embodiment, the crystals of the present invention are substantially free of other forms, for example, amorphous or other crystalline forms.

[0066] The term "amorphous" refers to a solid in which molecules are arranged in a disordered manner and do not have a discernible crystal lattice.

[0067] The terms "co-administration" and "co-administering" or "combination therapy" refer to simultaneous administration (the simultaneous administration of two or more therapeutic agents) and time-varying administration (the administration of one or more therapeutic agents at a different time than the administration of another one or more therapeutic agents), provided that the therapeutic agents are present in the patient to a certain extent, preferably in an effective amount. In some preferred aspects, one or more compounds of the present invention described herein are co-administered in combination with at least one additional bioactive agent (particularly a bioactive pharmaceutical agent comprising an anticancer agent). In a particularly preferred aspect, the co-administration activity of the compounds produces improved or synergistic activity and / or therapy, including anticancer activity.

[0068] Unless otherwise specified, as used herein, the term "compound" means any particular chemical compound disclosed herein, including its deuterated form as applicable in the context. A contemplated deuterated small molecule is one in which one or more hydrogen atoms in a drug molecule have been replaced by deuterium. Unless the context otherwise indicates, the term "compound" refers to compound A.

[0069] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, thereby targeting and degrading those proteins. For example, cerebroside is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugate, causes ubiquitin to be linked to a lysine residue on a target protein. Therefore, E3 ubiquitin ligases, alone or in combination with an E2 ubiquitin conjugate, are responsible for transferring ubiquitin to the target protein. Typically, ubiquitin ligases participate in polyubiquitination, causing a second ubiquitin to link to the first; a third ubiquitin to the second, and so on. This polyubiquitination labels the target protein for degradation via the proteasome.

[0070] Throughout this specification, the terms "patient" or "subject" are used to describe animals, preferably humans or domesticated animals, to which treatment, including prophylactic treatment, is administered using the compositions according to this disclosure. For treatments of infections, symptoms, or disease states that are specific to a particular animal (such as a human patient), the term "patient" refers to that particular animal, including domesticated 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 from the context of its use.

[0071] The term "effective" is used to describe the amount of a compound, composition, or component that, when used in the context of its intended use, can achieve the desired results. The term "effective" includes all other effective amount or effective concentration terms otherwise described or used in this application.

[0072] The term "therapeuticly effective amount," as used herein, refers to the amount required to be administered to a patient or the patient's cells, tissues, or organs to achieve a therapeutic effect (such as improvement or alternative cure). A therapeutically effective amount is sufficient to elicit a biological or medical response in cells, tissues, systems, animals, or humans sought by researchers, veterinarians, physicians, or clinicians. The determination of an appropriate therapeutically effective amount is within the level of conventional skill in the art.

[0073] Polymorphs

[0074] 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. Polymorphs of form I of compound A can be prepared by crystallization from a variety of solvents. For example, form I can be recovered from solvents such as 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) by temperature cycling for 72 hours between ambient temperature (approximately 22°C) and 40°C for 4 hours. The XRPD spectrum of form I recovered from methyl ethyl ketone is shown in [data missing]. Figure 1A As shown, the XRPD spectrum was obtained using Cu Kα radiation.

[0075] In some embodiments, this application provides a method for preparing polymorphic form I as disclosed herein, the method 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.

[0076] In some embodiments, form I can be... Figure 1AThe XRPD peaks shown are used to characterize it. For example, in some embodiments, the characteristic of Form I may be an XRPD peak at about 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, the characteristic of Form I may further be an XRPD peak at about 13.9°2θ and / or about 16.4°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ, or ± 0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form I may further be an XRPD peak at about 16.2°2θ, about 18.5°2θ, about 16.8°2θ, about 14.5°2θ, and / or about 13.5°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ, or ± 0.0°2θ; Cu Kα radiation).

[0077] In some embodiments, Form I may be 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 may be 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 may be 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).

[0078] In some embodiments, Form I may be 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 may be 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 may be 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 may be 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 may be 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 may be 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).

[0079] In some embodiments, Form I may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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 may be 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, the characteristic of Form I may be the 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, the characteristic of Form I may be approximately...

[0080] XRPD peaks at approximately 13.9°2θ, about 16.2°2θ, about 16.8°2θ, and about 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, about 16.2°2θ, about 16.8°2θ, and about 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, about 16.2°2θ, about 16.4°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 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 may be 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, the characteristic of Form I may be the XRPD peaks at about 13.9°2θ, about 16.2°2θ, about 16.4°2θ, and about 16.8°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0081] 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: 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 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).

[0082] 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.

[0083] Table 1: Representative XRPD peaks of Form I

[0084]

[0085]

[0086] Figure 1BThis is the TG / DT plot of the sample of Form I. TG shows approximately 1% weight loss at approximately 250°C until melting. This is followed by a 0.6% weight loss during melting, and a final weight loss of up to approximately 0.4% can be seen at up to approximately 350°C. An endothermic event is noted in the DT trace, which begins at approximately 259°C and peaks at approximately 266°C. In some embodiments, Form I is characterized by approximately 1% weight loss between approximately 25°C and approximately 250°C. In some embodiments, Form I is characterized by an endothermic event as measured by DT, which begins at approximately 259°C. In some embodiments, Form I is characterized by an endothermic event as measured by DT, which peaks at approximately 166°C. In some embodiments, Form I is characterized by an endothermic event as measured by DT, which begins at approximately 259°C and peaks at approximately 266°C. In some embodiments, the weight loss is determined by thermogravimetric analysis. In some embodiments, the thermogravimetric analysis is performed substantially as shown in Example 1. In some embodiments, endothermic events are calculated using 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.

[0087] Figure 1C A PLM image of Form I recovered from methanol is shown. The PLM indicates that the material is birefringent and has an irregular lath-like morphology. In some embodiments, Form I is characterized by a birefringent material with an irregular lath-like morphology.

[0088] Form II of compound A can be prepared by crystallization from a variety of solvents. For example, form II was recovered from dichloromethane and also from acetone:water (90:10 v / v) by temperature cycling for 72 hours between ambient (approximately 22°C) and 40°C for 4 hours. The XRPD spectrum of form II recovered from dichloromethane is shown in [data missing]. Figure 2A As shown, the XRPD spectrum was obtained using Cu Kα radiation.

[0089] In some embodiments, this application provides a method for preparing form II of compound A as disclosed herein, the method 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 ratio of acetone to water is between about 85:15 (v / v) and about 95:5 (v / v). In some embodiments, the ratio of acetone to water is between 85:15 (v / v) and 95:5 (v / v). In some embodiments, the ratio of acetone to water is about 90:10 (v / v). In some embodiments, the water is deionized water.

[0090] In some embodiments, form II can be... Figure 2A The XRPD peaks shown are used to characterize it. For example, the characteristic of Form II may be an XRPD peak at about 17.5°2θ (e.g., 17.5 ± 0.2°2θ, 17.5 ± 0.1°2θ, or 17.5 ± 0.0°2θ). In some embodiments, the characteristic of Form II may further be an XRPD peak at about 9.2°2θ, about 10.0°2θ, about 16.3°2θ, and / or about 18.1°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ, or ± 0.0°2θ; Cu Kα radiation). In some embodiments, the feature of Form II may further be the XRPD peaks at about 12.5°2θ, about 14.1°2θ, about 15.7°2θ, about 16.9°2θ, about 19.1°2θ and / or about 19.6°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ or ± 0.0°2θ; Cu Kα radiation).

[0091] In some embodiments, the characteristic of Form II may be an XRPD peak at about 9.2°2θ and about 17.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form II may be an XRPD peak at about 10.0°2θ and about 17.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form II may be an XRPD peak at about 16.3°2θ and about 17.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form II may be an XRPD peak at about 18.1°2θ and about 17.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form II may be an XRPD peak at about 12.5°2θ and about 17.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form II may be an XRPD peak at about 14.1°2θ and about 17.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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).

[0092] In some embodiments, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the characteristics of Form II may be 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, the characteristics of Form II may be 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, the characteristics of Form II may be 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, the characteristics of Form II may be 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, the characteristics of Form II may be 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, the characteristics of Form II may be 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, the feature of Form II may be the XRPD peak at about 9.2°2θ, about 10.0°2θ, about 16.3°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0093] In some embodiments, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the characteristic of Form II may be an XRPD peak 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, the feature of Form II may be the XRPD peak at about 9.2°2θ, about 10.0°2θ, about 16.3°2θ, and about 17.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0094] 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: 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 five 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 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: 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 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, and so on.

[0095] 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; CuKα 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: 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; CuKα 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).

[0096] 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.

[0097] Table 2: Representative XRPD peaks of Form II

[0098]

[0099] Figure 2B This is the TG / DT plot of the sample of Form II. TG shows approximately 11% weight loss at up to about 85°C and an additional 2.4% weight loss at up to about 325°C. Potential endothermic events can be seen in the DT trace, which peak at about 212°C. In some embodiments, Form II is characterized by approximately 11% weight loss between about 25°C and about 85°C. In some embodiments, Form II is characterized by endothermic events as measured by DT, which peak at about 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 events are 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 2CA PLM image of Form II recovered from dichloromethane is shown. 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.

[0101] Form III of compound A can be prepared by crystallization from a variety of solvents. For example, form III can be recovered from acetonitrile by temperature cycling for 72 hours between ambient (approximately 22°C) and 40°C for 4 hours. The XRPD spectrum of form III recovered from acetonitrile is shown in [data missing]. Figure 3A As shown, the XRPD spectrum was obtained using Cu Kα radiation.

[0102] In some embodiments, this application provides a method for preparing form III of compound A as disclosed herein, the method comprising recrystallizing compound A from a solvent. In some embodiments, the solvent is acetonitrile.

[0103] In some embodiments, form III can be... Figure 3A The XRPD peaks shown are used to characterize it. For example, in some embodiments, the characteristic of Form III may be an XRPD peak at about 10.7°2θ (e.g., 10.7 ± 0.2°2θ, 10.7 ± 0.1°2θ, 10.7 ± 0.0°2θ). In some embodiments, the characteristic of Form III may further be an XRPD peak at about 8.8°2θ, about 11.2°2θ, about 16.5°2θ and / or about 18.2°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ or ± 0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form III may further be an XRPD peak at about 15.0°2θ and / or about 17.8°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ or ± 0.0°2θ; Cu Kα radiation). In some embodiments, the features of Form III may further include 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).

[0104] In some embodiments, the characteristic of Form III may be an XRPD peak at about 8.8°2θ and about 10.7°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form III may be an XRPD peak at about 11.2°2θ and about 10.7°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form III may be an XRPD peak at about 16.5°2θ and about 10.7°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form III may be an XRPD peak at about 18.2°2θ and about 10.7°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of Form III may be an XRPD peak at about 8.8°2θ, about 11.2°2θ, about 16.5°2θ, about 18.2°2θ, and about 10.7°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0105] In some embodiments, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the features of Form III may be the XRPD peaks at about 10.7°2θ, about 18.2°2θ, and about 8.8°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0106] In some embodiments, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristics of Form III may be 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, the characteristic of Form III may be an XRPD peak 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, the characteristic of Form III may be an XRPD peak 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).

[0107] In some embodiments, the characteristic of form III may be an XRPD peak 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, the characteristic of form III may be an XRPD peak 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, the feature of Form III may be the XRPD peaks at about 8.8°2θ, about 11.2°2θ, about 16.5°2θ, about 18.2°2θ, about 10.7°2θ, about 17.8°2θ, and about 15.0°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; CuKα radiation).

[0108] In some embodiments, the characteristic of Form III may be an XRPD peak 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, the characteristic of Form III may be an XRPD peak 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, the characteristic of Form III may be an XRPD peak 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, the characteristic of Form III may be an XRPD peak 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, the characteristic of Form III may be an XRPD peak 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, the characteristic of Form III may be an XRPD peak 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, the characteristic of form III may be the 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).

[0109] In some embodiments, the characteristic of Form III may be 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: 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 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).

[0110] 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.

[0111] Table 3: Representative XRPD peaks of Form III

[0112]

[0113] Figure 3BThis is the TG / DT plot of the sample of Form III. TG shows approximately 3.7% weight loss at up to about 75°C, an additional 4.7% weight loss at up to about 160°C, and a final weight loss of 0.6% at up to 350°C. Small, widespread endothermic events are noted in DT, starting at about 196°C and peaking at about 204°C. In some embodiments, Form III is characterized by approximately 3.7% weight loss between about 25°C and about 75°C. In some embodiments, Form III is further characterized by approximately 4.7% weight loss between about 75°C and about 160°C. In some embodiments, Form III is further characterized by approximately 0.6% weight loss between about 160°C and about 350°C. In some embodiments, Form III is characterized by endothermic events as measured by DT, starting at about 196°C. In some embodiments, Form III is characterized by endothermic events as measured by DT, peaking at about 204°C. In some embodiments, Form III is characterized by an endothermic event as measured by DT, the endothermic event starting at approximately 196°C and having a peak at approximately 204°C. In some embodiments, weight loss is determined by thermogravimetric analysis. In some embodiments, the 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, the differential thermal analysis is performed substantially as shown in Example 1. In some embodiments, thermogravimetric analysis and differential thermal analysis are performed simultaneously.

[0114] Figure 3C A PLM image of Form III recovered from acetonitrile is shown. The PLM indicates that the material is birefringent and has an irregular lath-like morphology. In some embodiments, Form III is characterized by being a birefringent material with an irregular lath-like morphology.

[0115] Form IV of compound A can be prepared by crystallization under various conditions. For example, form IV was recovered from dichloromethane / methanol (25:75 v / v) after the addition of methyl tert-butyl ether to the antisolvent, and further recovered from dichloromethane / methanol (25:75 v / v) after rapid cooling at 2–8 °C. The XRPD spectrum of form IV recovered from dichloromethane / methanol (25:75) after rapid cooling is shown in [data missing]. Figure 4A As shown, the XRPD spectrum was obtained using Cu Kα radiation.

[0116] In some embodiments, this application provides a method for preparing form IV of compound A as disclosed herein, the method 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, the method comprising adding an antisolvent to a solution of compound A from a solvent. In some embodiments, the solvent comprises a mixture of dichloromethane and methanol. In some embodiments, the antisolvent is methyl tert-butyl ether.

[0117] In some embodiments, form IV can be... Figure 4A The XRPD peaks shown are used to characterize it. For example, in some embodiments, the form IV may be characterized by an XRPD peak at about 10.5°2θ (e.g., 10.5 ± 0.2°2θ, 10.5 ± 0.1°2θ, 10.5 ± 0.0°2θ). In some embodiments, the form IV may be further characterized by an XRPD peak at about 14.5°2θ and / or about 16.9°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ, or ± 0.0°2θ; Cu Kα radiation). In some embodiments, the form IV may be further characterized by an XRPD peak at about 11.5°2θ, about 14.2°2θ, and / or about 16.3°2θ (e.g., ± 0.2°2θ, ± 0.1°2θ, or ± 0.0°2θ; Cu Kα radiation).

[0118] In some embodiments, the characteristic of form IV may be an XRPD peak at about 14.5°2θ and about 10.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of form IV may be an XRPD peak at about 16.9°2θ and about 10.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation). In some embodiments, the characteristic of form IV may be an XRPD peak at about 14.5°2θ, about 16.9°2θ, and about 10.5°2θ (e.g., ±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα radiation).

[0119] In some embodiments, the characteristic of form IV may be an XRPD peak 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, the characteristic of form IV may be an XRPD peak 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, the characteristic of form IV may be an XRPD peak 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, the characteristic of form IV may be an XRPD peak 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).

[0120] 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 one 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: 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 three 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 four 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 five 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 six 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 seven 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).

[0121] In some embodiments, form IV may have one, two, three, four, five, six, seven or more peaks as listed in Table 4.

[0122] Table 4: Representative XRPD peaks of Form IV

[0123]

[0124] Figure 4B This is the TG / DT plot of the sample of form IV. TG shows a weight loss of approximately 3.1% at up to approximately 350°C. Small, widespread endothermic events are noted in DT, which begin at approximately 196°C and peak 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 endothermic events as measured by DT, which begin at approximately 196°C. In some embodiments, form IV is characterized by endothermic events as measured by DT, which peak at approximately 213°C. In some embodiments, form IV is characterized by endothermic events as measured by DT, which begin at approximately 196°C and peak at approximately 213°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, endothermic events are 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.

[0125] Figure 4C A PLM image of form IV recovered from dichloromethane:methanol (25:75 v / v) is shown. The PLM indicates that the material is birefringent and has an irregular lath-like morphology. In some embodiments, form III is characterized by a birefringent material having an irregular lath-like morphology.

[0126] The polymorphs of the present invention can be used in various ways. In some embodiments, the polymorph of compound A serves as a convenient storage (e.g., bulk storage) form for preparing the amorphous form of compound A. In some embodiments, the polymorph of compound A can be further used to prepare pharmaceutical compositions or final dosage forms of the present disclosure, comprising, for example, tablets or capsules. In some embodiments, the amorphous form of compound A can be further used to prepare pharmaceutical compositions or final dosage forms of the present disclosure, comprising, for example, tablets or capsules.

[0127] In some embodiments, compound A is stored in bulk as a polymorph of form I.

[0128] In some embodiments, compound A is stored in bulk as a polymorph of form II.

[0129] In some embodiments, compound A is stored in bulk as a polymorph of form III.

[0130] In some embodiments, compound A is stored in bulk primarily as a polymorph of form IV.

[0131] amorphous form

[0132] This application further provides an amorphous form of compound A.

[0133] In some embodiments, the bulk storage form of compound A is essentially the amorphous form of compound A.

[0134] 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, comprising compound A.

[0135] Therapeutic Composition

[0136] This application further provides pharmaceutical compositions 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 pharmaceutical compositions 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).

[0137] According to this disclosure, compound A of the present invention, which is substantially crystalline or amorphous as described herein, can be administered to a patient or subject in a pharmaceutical composition in a single dose or multiple doses. The pharmaceutical composition can be administered orally, parenterally, by inhalation, topically, rectally, nasally, orally, vaginally, percutaneously, sublingually, via suppository, or via an implantable receptacle. As used herein, the term "parenterical" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion. Preferably, the pharmaceutical composition is administered orally.

[0138] 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 specific crystalline and / or amorphous form chosen, as well as the severity of the disease and / or condition being treated in the patient. Compound A according to this disclosure can be used as a spray, nebulizer, or aerosol for intranasal, intratracheal, intraocular, or pulmonary administration. Therefore, this disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of the crystalline and / or amorphous form or a combination thereof of compound A as described herein, combined 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 preferably administered orally, but can alternatively be administered as suppositories, transdermal, or other topical forms. For example, intramuscular injection in liposome form can be used to control (e.g., maintain) the release of compound A at the injection site.

[0139] The pharmaceutical compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can also be administered in the form of controlled-release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of glycerides of saturated vegetable fatty acids, 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.

[0140] The sterile injectable form of the pharmaceutical compositions described herein can be an aqueous or oily suspension. In view of this disclosure, these suspensions can be formulated according to techniques known in the art, using appropriate dispersants or wetting agents and suspending agents. The sterile injectable form can be a sterile injectable solution or suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution, etc. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides, etc. Fatty acids such as oleic acid and their glyceride derivatives can be used to prepare injectables, as can natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethyleneized forms. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0141] 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, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension for oral administration is required, the active ingredient can be combined with one or more emulsifiers and suspending agents. Certain buffers, sweeteners, flavoring agents, and / or coloring agents may also be added, if desired.

[0142] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories or enemas for rectal administration, for local application to the lower intestine, or for systemic absorption and treatment. In view of this disclosure, such suppositories can be prepared by mixing compound A 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 temperatures, thereby melting in the rectum to release the drug. Such excipients may comprise cocoa butter, beeswax, polyethylene glycol, and combinations thereof.

[0143] 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 said pharmaceutical formulation is suitable for topical application, such as as an ointment, cream, lotion, lotion, or topical liquid.

[0144] For topical application, the pharmaceutical composition may be formulated in a suitable ointment containing an active ingredient (i.e., compound A) suspended or dissolved in one or more carriers. Carriers for topical application include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water.

[0145] Alternatively, the pharmaceutical composition may be formulated in 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, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0146] Alternatively, the pharmaceutical formulation of the present invention can be delivered via a transdermal patch, which is to be worn 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-type patch. In another embodiment, the transdermal patch will be an adhesive-coated medicated patch. The transdermal patch according to the present invention may also include one or more absorption enhancers.

[0147] 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 petrolatum.

[0148] The pharmaceutical compositions described herein can also be administered via nasal aerosol or inhalation. In view of this disclosure, such compositions are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0149] The amount of the compound in the pharmaceutical composition of the present invention can be combined with a carrier or excipient material to produce a single dosage form, the amount of which will vary depending on the host and disease being treated and the specific method of administration. Preferably, the single dosage form will be formulated to contain, alone or in combination with at least one other therapeutically active compound, about 0.05 mg to 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. 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, comprising, but not limited to, containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of about 25-250 mg may be a convenient dosage.

[0150] 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 symptom being treated, the activity and bioavailability of compound A in a specific dosage form, the patient's age, weight, health and sex, the metabolism and excretion rate of the active compound or its metabolites, and the judgment of the treating physician, etc.

[0151] Patients or subjects who require therapy using the pharmaceutical composition according to the methods described herein can be treated by administering a therapeutically effective amount of the composition to the patient (subject).

[0152] The active compound is included in the pharmaceutical composition in an amount sufficient to deliver a therapeutically effective amount for the desired indication to the patient without causing undue adverse effects in the treated patient. In some embodiments, for all the conditions mentioned herein, the dose of the active compound ranges from about 10 ng / kg to 300 mg / kg daily, preferably from 0.1 to 100 mg / kg, and more generally from 0.5 to about 25 mg per kilogram of recipient / patient body weight.

[0153] Preferably, the active ingredient is administered to achieve a peak plasma concentration of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by oral administration of tablets or capsules, or by intravenous injection of a solution or formulation of the active ingredient.

[0154] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage values ​​will also vary depending on the severity of the symptom to be alleviated. It should be further understood that, for any given subject, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges set forth herein are merely exemplary and not intended to limit the scope and practice of the desired compositions. The active ingredient may be administered all at once or divided into many smaller doses administered at selected time intervals.

[0155] Oral compositions will typically contain 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 be incorporated with excipients and used in tablet, lozenge, or capsule form. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition.

[0156] Tablets, pills, capsules, lozenges, etc., 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 alginate, Primogel, or corn starch; buffers; lubricants, such as magnesium stearate; glidants, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavorings, such as peppermint, methyl salicylate, or orange flavorings. When the dosage unit is in capsule form, in addition to the materials of the above types, it may also contain a liquid carrier, such as fatty oil. Furthermore, the dosage unit form may contain various other materials that alter the physical form of the dosage unit, such as coatings of sugar, shellac, or enteric solvents.

[0157] The active polymorph and / or amorphous form of compound A, or combinations thereof, may be applied as a component of elixirs, suspensions, syrups, tablets, chewing gum, etc. In addition to the active compound, syrups may also contain sweeteners (such as sucrose) as well as certain preservatives, dyes, colorants, and flavorings.

[0158] 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, etc.). In some aspects of this disclosure, one or more compounds, polymorphs, and / or amorphous forms according to this disclosure may be co-administered with another bioactive agent, such as another anticancer agent or wound healing agent.

[0159] Solutions or suspensions intended for parenteral, intradermal, subcutaneous, or topical application may contain the following components: sterile diluents, such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial 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 dextran. Parenteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0160] If administered intravenously, the carrier may contain physiological saline or phosphate-buffered saline (PBS).

[0161] In one embodiment, the active compound, polymorph, and / or amorphous form are prepared together with a carrier (such as a controlled-release formulation, comprising an implant or microencapsulated delivery system) that protects the compound from rapid elimination from the body. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0162] Treatment

[0163] In another aspect, this specification provides therapeutic compositions comprising a therapeutically effective amount of a polymorph and / or amorphous form of compound A as described herein, or a pharmaceutical composition thereof, and a pharmaceutically acceptable carrier. The therapeutic compositions of the present invention modulate protein degradation in patients or subjects, such as humans or other animals, and can be used to treat or improve disease states or symptoms causally related to the protein to be degraded.

[0164] As used herein, the terms “treat,” “treating,” and “treatment,” etc., refer to any action that provides benefit to a patient by administering an active compound, polymorph, and / or amorphous form, encompassing treatment of any disease state or symptom causally related to (e.g., modulating) ER (including one or more of its symptoms). The foregoing describes disease states or symptoms that can be treated with compounds, polymorphs, amorphous forms, and / or pharmaceutical compositions according to this disclosure, including breast cancer, uterine cancer, ovarian cancer, and / or endometriosis.

[0165] This specification provides therapeutic pharmaceutical compositions as described herein for achieving ER degradation to treat or improve diseases (e.g., cancer). In some additional embodiments, the disease is breast cancer, uterine cancer, ovarian cancer, endometrial cancer, or endometriosis. Therefore, in another aspect, this specification provides methods for ubiquitinizing / degrading ER in cells. In some embodiments, the method includes administering a bifunctional compound A, or a polymorph and / or amorphous form thereof, as described herein, such that ubiquitination of ER occurs upon placement in the vicinity of a ubiquitin ligase, leading to ubiquitination and subsequent degradation of the target protein 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, symptoms, or signs causally related to ER by reducing ER levels in cells within a patient. In some embodiments, the method includes administering a therapeutically effective amount of compound A as described herein, optionally comprising one or more pharmaceutically acceptable excipients (e.g., dispersants, carriers, lubricants), optionally comprising another bioactive agent and combinations thereof.

[0166] In another embodiment, this specification provides a method for treating or improving a disease, condition, or symptom in a subject or patient (e.g., an animal such as a human), the method comprising administering a composition to a subject in need, the 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), another bioactive agent, or a combination thereof, wherein the composition is effective in treating or improving the subject's disease, condition, or symptom.

[0167] In another embodiment, this disclosure relates to a method for treating a human patient in need of a disease state, symptom, or condition causally related to the ER protein, wherein degradation of the ER protein produces a therapeutic effect in the patient, the method comprising administering to the patient in need a therapeutically effective amount of compound A according to this disclosure, optionally in combination with another bioactive agent. The disease state, symptom, or condition may be caused by the expression or overexpression of the ER protein.

[0168] The term "disease state, symptom, or condition" is used to describe any disease state, symptom, or condition that is causally related to protein activity, excessive activity, expression, or overexpression (e.g., elevated levels of ER expressed in a patient), where targeted degradation of the protein in the patient provides a beneficial treatment or relief of the disease state, symptom, or condition. In some cases, the disease state or symptom may decrease, lessen, or improve. In other cases, the disease state, symptom, or condition may be reversed or cured.

[0169] As used herein, the terms "tumor" or "cancer" refer to the pathological processes that lead to the formation and growth of cancerous or malignant tumors; that is, abnormal tissue that grows through cell proliferation, typically growing faster than normal tissue and continuing to grow after a stimulus that causes new growth to cease. Malignant tumors are characterized by a partial or complete lack of structural organization and function in coordination with normal tissue and largely invading surrounding tissues, metastasize to several sites, and may recur after attempted removal, leading to patient death unless appropriate treatment is administered. As used herein, the term tumor is used to describe any and all cancerous disease states and includes or encompasses 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 stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, and Kaposi's sarcoma. Sarcoma, liposarcoma, myoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, medullary 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 according to this disclosure include, for example, acute T-cell lymphoblastic leukemia (T-ALL), T-cell 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.

[0170] Protein level control

[0171] This disclosure also provides methods for controlling (e.g., reducing) intracellular protein levels. This is based on the use of compound A, as described herein, or its polymorphic or amorphous form, which induces targeted ubiquitination of the ER protein and its proteasome degradation, thereby controlling (i.e. reducing) the amount of the ER protein in the cells of a biological system or a subject or patient, for example, to obtain a specific therapeutic benefit.

[0172] Example:

[0173] Various aspects of this disclosure are further described with reference to the following numbered embodiments:

[0174] 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)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0175] (Compound A)

[0176] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 13.9°2θ and approximately 17.9°2θ.

[0177] 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)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0178] (Compound A)

[0179] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 13.9°2θ, approximately 16.4°2θ, and approximately 17.9°2θ.

[0180] 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)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0181] (Compound A)

[0182] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 13.9°2θ, approximately 16.2°2θ, and approximately 17.9°2θ.

[0183] 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)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0184] (Compound A)

[0185] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 13.9°2θ, approximately 17.9°2θ, and approximately 20.9°2θ.

[0186] Example 5. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A) (designated as form I).

[0187] (Compound A)

[0188] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 13.9°2θ and approximately 17.9°2θ.

[0189] Example 6. The polymorph according to Example 1 is further characterized by an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing a peak at approximately 16.4°2θ.

[0190] Example 7. The polymorph according to Example 1 is further characterized by using an X-ray powder diffraction pattern of Cu Kα radiation, the X-ray powder diffraction pattern containing at least one peak selected from about 16.2°2θ, about 16.4°2θ, about 18.5°2θ and about 20.9°2θ.

[0191] Example 8. The polymorph according to Example 1 is further characterized by using an X-ray powder diffraction pattern of Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 16.2°2θ, approximately 16.4°2θ, approximately 18.5°2θ and approximately 20.9°2θ.

[0192] Example 9. The polymorph according to any one of Examples 1 to 8, further characterized by using an X-ray powder diffraction pattern of CuKα radiation, the X-ray powder diffraction pattern containing at least one peak selected from about 13.5°2θ, about 14.3°2θ, about 14.5°2θ, and about 16.8°2θ.

[0193] Example 10. The polymorph according to any one of Examples 1 to 9, further characterized by using an X-ray powder diffraction pattern of CuKα radiation, the X-ray powder diffraction pattern containing peaks at about 13.5°2θ, about 14.3°2θ, about 14.5°2θ, and about 16.8°2θ.

[0194] Example 11. The polymorph according to any one of Examples 1 to 10, characterized in that it is compatible with... Figure 1A The X-ray powder diffraction pattern shown is essentially the same as the X-ray powder diffraction pattern.

[0195] Example 12. The polymorph according to any one of Examples 1 to 11, further characterized by an endothermic event as measured by DT, said endothermic event starting at about 259°C and having a peak at about 266°C.

[0196] Example 13. The polymorph according to any one of Examples 1 to 12, further characterized by a weight loss of about 1% between about 25°C and about 250°C, as measured by TG.

[0197] Example 14. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0198] (Compound A)

[0199] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 10.0°2θ and approximately 17.5°2θ.

[0200] Example 15. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0201] (Compound A)

[0202] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 10.0°2θ, approximately 16.3°2θ, and approximately 17.5°2θ.

[0203] 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)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0204] (Compound A)

[0205] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 9.2°2θ, approximately 16.3°2θ, and approximately 17.5°2θ.

[0206] Example 17. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0207] (Compound A)

[0208] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 16.3°2θ, approximately 17.5°2θ, and approximately 18.1°2θ.

[0209] Example 18. A polymorph (designated as form II) of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0210] (Compound A)

[0211] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 10.0°2θ and approximately 17.5°2θ.

[0212] Example 19. The polymorph according to Example 14 or 18 is further characterized by an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing a peak at approximately 16.3°2θ.

[0213] Example 20. The polymorph according to any one of Examples 14 to 19, further characterized by an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing at least one peak selected from about 9.2°2θ, about 16.3°2θ and about 18.1°2θ.

[0214] Example 21. The polymorph according to any one of Examples 14 to 20, further characterized by an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at about 9.2°2θ, about 16.3°2θ and about 18.1°2θ.

[0215] Example 22. The polymorph according to any one of Examples 14 to 21, characterized in that it is compatible with... Figure 2A The X-ray powder diffraction pattern shown is essentially the same as the X-ray powder diffraction pattern.

[0216] Example 23. The polymorph according to any one of Examples 14 to 22, further characterized in that the endothermic event, as measured by DT, has a peak at about 212°C.

[0217] Example 24. The polymorph according to any one 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.

[0218] Example 25. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0219] (Compound A)

[0220] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 10.7°2θ and 18.2°2θ.

[0221] Example 26. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0222] (Compound A)

[0223] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 8.8°2θ, approximately 10.7°2θ, and approximately 18.2°2θ.

[0224] Example 27. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0225] (Compound A)

[0226] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 10.7°2θ, approximately 11.2°2θ, and 18.2°2θ.

[0227] Example 28. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0228] (Compound A)

[0229] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 10.7°2θ, approximately 16.5°2θ, and approximately 18.2°2θ.

[0230] Example 29. A polymorph (designated as form III) of (S)-3-(5-(4-((1-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0231] (Compound A)

[0232] The feature is an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at approximately 10.7°2θ and 18.2°2θ.

[0233] Example 30. The polymorph according to any one of Examples 25 or 27 to 29, further characterized by an X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing a peak at approximately 8.8°2θ.

[0234] Example 31. The polymorph according to any one of Examples 25 to 30, further characterized by using an X-ray powder diffraction pattern of Cu Kα radiation, the X-ray powder diffraction pattern containing 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.

[0235] Example 32. The polymorph according to any one of Examples 25 to 31, further characterized by using an X-ray powder diffraction pattern of Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at about 8.8°2θ, about 11.2°2θ, about 15.0°2θ, about 16.5°2θ and about 17.8°2θ.

[0236] Example 33. The polymorph according to any one of Examples 25 to 32, characterized in that it is further characterized by... Figure 3A The X-ray powder diffraction pattern shown is essentially the same as the X-ray powder diffraction pattern.

[0237] Example 34. The polymorph according to any one of Examples 25 to 33, further characterized by an endothermic event as measured by DT, said endothermic event starting at about 196°C and having a peak at about 204°C.

[0238] Example 35. The polymorph according to any one 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.

[0239] Example 36. The polymorph according to 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.

[0240] Example 37. The polymorph according to 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.

[0241] Example 38. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A)

[0242] (Compound A)

[0243] The feature is an X-ray powder diffraction pattern containing peaks at approximately 10.5°2θ, approximately 14.5°2θ, and approximately 16.9°2θ.

[0244] Example 39. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A) (designated as form IV)

[0245] (Compound A)

[0246] The feature is an X-ray powder diffraction pattern containing peaks at approximately 10.5°2θ, approximately 14.5°2θ, and approximately 16.9°2θ.

[0247] Example 40. The polymorph according to Example 38 or 39, further characterized by using an X-ray powder diffraction pattern of Cu Kα radiation, the X-ray powder diffraction pattern containing at least one peak selected from about 11.5°2θ, about 14.2°2θ, about 16.3°2θ and about 17.8°2θ.

[0248] Example 41. The polymorph according to any one of Examples 38 to 40, further characterized by using an X-ray powder diffraction pattern of Cu Kα radiation, the X-ray powder diffraction pattern containing peaks at about 11.5°2θ, about 14.2°2θ, about 16.3°2θ and about 17.8°2θ.

[0249] Example 42. The polymorph according to any one of Examples 38 to 41, characterized in that it is compatible with... Figure 4A The X-ray powder diffraction pattern shown is essentially the same as the X-ray powder diffraction pattern.

[0250] Example 43. The polymorph according to any one of Examples 38 to 42, further characterized by an endothermic event as measured by DT, said endothermic event starting at about 196°C and having a peak at about 213°C.

[0251] Example 44. The polymorph according to any one of Examples 38 to 43, further characterized by a weight loss of about 3.1% between about 25°C and about 350°C, as measured by TG.

[0252] Example 45. A method for treating a disease or condition in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the polymorph according to any one of Examples 1 to 44.

[0253] Example 46. The method according to Example 45, wherein the disease or condition is associated with estrogen receptor (ER) activity, excessive activity, intrinsic activity, expression, overexpression, or accumulation and aggregation.

[0254] Example 47. The method according to Example 45 or 46, wherein the disease or condition is a cancer or neoplasia associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation.

[0255] Example 48. The method according to any one of Examples 45 to 47, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

[0256] Example 49. A pharmaceutical composition comprising a therapeutically effective amount of a polymorph according to any one of Examples 1 to 44 and a pharmaceutically acceptable carrier, wherein the composition is effective in treating or improving at least one symptom of the disease or condition.

[0257] Example 50. The composition according to Example 49, wherein the disease or condition is associated with excessive activity, inherent activity, or ER accumulation and aggregation.

[0258] Example 51. The composition according to Example 49 or 50, wherein the disease or condition is a cancer or neoplasm associated with ER accumulation and aggregation or ER activity or hyperactivity.

[0259] Example 52. The composition according to any one of Examples 49 to 51, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

[0260] Example 53. A pharmaceutical composition comprising a therapeutically effective amount of the amorphous form of compound A.

[0261] (Compound A)

[0262] And pharmaceutically acceptable dispersants.

[0263] Example 54. The composition according to Example 53 further comprises pharmaceutically acceptable additives.

[0264] Example 55. The composition according to Example 53 or 54, wherein the pharmaceutically acceptable additive is HPMC.

[0265] Example 56. The composition according to Example 53 or 54, wherein the pharmaceutically acceptable additive is TPGS.

[0266] Example 57. The composition according to any one of Examples 53 to 56, wherein the composition is effective in treating or improving at least one symptom of the disease or condition.

[0267] Example 58. The composition according to Example 57, wherein the disease or condition is associated with excessive activity, inherent activity, or ER accumulation and aggregation.

[0268] Example 59. The composition according to Example 57 or 58, wherein the disease or condition is a cancer or neoplasm associated with ER accumulation and aggregation or ER activity or hyperactivity.

[0269] Example 60. The composition according to any one of Examples 57 to 59, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

[0270] Example 61. Use of a polymorph according to any one of Examples 1 to 44 in the preparation of a medicament for treating a disease or condition.

[0271] Example 62. The use according to Example 61, wherein the disease or condition is associated with ER accumulation and aggregation or ER activity or excessive activity.

[0272] Example 63. The use according to Example 61 or 62, wherein the disease or condition is a cancer or neoplasm associated with ER accumulation and aggregation or ER activity or hyperactivity.

[0273] Example 64. Use according to any one of Examples 61 to 63, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

[0274] Example 65. The polymorph according to any one of Examples 1 to 44, which is used in medicine.

[0275] Example 66. A polymorph according to any one of Examples 1 to 44, 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.

[0276] Example 67. The polymorph for use according to Example 66, wherein the disease or condition is cancer or neoplasia associated with ER accumulation and aggregation or ER activity or hyperactivity.

[0277] Example 68. A polymorph for use according to Example 66 or 67, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

[0278] Example 69. A method for preparing a polymorph of compound A according to any one of Examples 1 to 13, the method comprising recrystallizing compound A from a solvent.

[0279] Example 70. The method according to 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 a mixture of ethanol and water.

[0280] Example 71. The method according to Example 69, wherein the solvent is 1-butanol.

[0281] Example 72. The method according to Example 69, wherein the solvent is methyl ethyl ketone.

[0282] Example 73. A method for preparing a polymorph of compound A according to any one of Examples 14 to 24, the method comprising recrystallizing compound A from a solvent.

[0283] Example 74. The method according to Example 73, wherein the solvent is selected from a mixture of dichloromethane and acetone / water.

[0284] Example 75. A method for preparing a polymorph of compound A according to any one of Examples 25 to 37, the method comprising recrystallizing compound A from a solvent.

[0285] Example 76. The method according to Example 75, wherein the solvent is acetonitrile.

[0286] Example 77. A method for preparing a polymorph of compound A according to any one of Examples 38 to 44, the method comprising rapidly cooling a solution of compound A in a solvent.

[0287] Example 78. A method for preparing a polymorph of compound A according to any one of Examples 38 to 44, the method comprising adding an antisolvent to a solution of compound A in a solvent.

[0288] Example 79. The method according to Example 77 or 78, wherein the solvent is a mixture of dichloromethane and methanol.

[0289] Example 80. The method according to Example 79, wherein the ratio of dichloromethane to methanol is about 25:75 (v / v).

[0290] Example 81. The method according to any one of Examples 78 to 80, wherein the antisolvent is methyl tert-butyl ether.

[0291] Example

[0292] 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 aid in the description of this disclosure and should not be construed as limiting this disclosure in any way.

[0293] Example 1: Analysis Method

[0294] Unless otherwise specified, all characterization data were obtained using the following procedure:

[0295] X-ray powder diffraction (XRPD):

[0296] XRPD analysis was performed on a PANalytical X'pert pro, scanning the sample between 3° and 35°2θ. The material was gently ground to release any agglomerates and loaded onto a porous plate with a Mylar polymer membrane 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) with a 40 kV / 40 mA generator setting, operating in transmission mode (step size 0.0130°2θ).

[0297] Polarized light microscopy (PLM)

[0298] The presence of crystallinity (birefringence) was determined using an Olympus BX50 polarization microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded using a 20× objective lens unless otherwise specified.

[0299] Thermogravimetric analysis (TGA) and differential thermal analysis (DTA)

[0300] Approximately 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analysis (TG / DTA) instrument and 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 was used as the purge gas at a flow rate of 300 cm³ / min.

[0301] Differential scanning calorimetry (DSC)

[0302] Approximately 5 mg of material was weighed into an aluminum DSC pan and non-airtightly 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. Once a stable thermal flux response 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 response was monitored. Nitrogen was used as the purge gas at a flow rate of 50 cm³ / min.

[0303] Example 2: Screening of Polymorphs

[0304] Add an appropriate solvent to a vial containing approximately 30 mg of compound A to suspend the material. Then, cycle the experiment at ambient temperature (approximately 22°C) and 40°C for 72 hours in a 4-hour cycle.

[0305] 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.

[0306] Table 5: Temperature Cycling Results

[0307]

[0308] The filtered saturated solution of compound A was then divided into three equal aliquots and used in subsequent polymorph screening experiments, as detailed below:

[0309] evaporation: A saturated solution of compound A was transferred to 2 mL vials; these 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.

[0310] Table 6: Evaporation Results

[0311]

[0312] Rapid cooling:A saturated solution of compound A was stored at 2–8 °C for 24–72 hours. Any recovered material was analyzed by XRPD during this time, and the experiment was then stored at -20 °C for 24–72 hours. Afterward, any recovered material was analyzed by XRPD. The results are shown in Tables 7 and 8 below.

[0313] Table 7: Results of rapid cooling (2-8℃)

[0314]

[0315] Table 8: Results of rapid cooling (-20℃)

[0316]

[0317] Antisolvent addition at ambient temperature: Up to 1 mL of antisolvent was added dropwise to a stirred, saturated solution of compound A. The lid was then opened and allowed to evaporate at ambient temperature. All recovered solids were analyzed by XRPD. The results are shown in Table 9 below.

[0318] Table 9: Results of Antisolvent Addition

[0319]

[0320] Example 3: Form I

[0321] Approximately 30 mg of the amorphous compound A, a free base, was suspended in 1.0 mL of methyl ethyl ketone. The experiment was temperature-cycled between ambient temperature (approximately 22°C) and 40°C for 72 hours in 4-hour cycles. After 72 hours, the solid was separated by centrifugation and dried at 40°C for 18 hours before analysis.

[0322] Form I was found to be a thermodynamically stable, non-solventized 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 forms identified, form I was determined to be the most stable. A summary of the relevant properties of form I is shown in Table 10 below:

[0323] Table 10: Characteristics of Form I

[0324]

[0325] Alternatively, form I can be isolated from polyethylene glycol.

[0326] Amorphous or partially amorphous solids were slurried in PEG-400 and cycled overnight at RT and 40°C. The solids were separated from the supernatant, first washed with ethanol, then with methyl ethyl ketone, and dried in a vacuum oven to produce flat, plate-like crystals.

[0327] Example 4: Form II

[0328] Approximately 30 mg of the amorphous compound A, a free base, was suspended in 0.5 mL of dichloromethane. The experiment was cyclical between ambient temperature (approximately 22 °C) and 40 °C for 72 hours, in 4-hour cycles. After 72 hours, the solid was separated by centrifugation and dried at 40 °C for 18 hours before analysis.

[0329] Form II appears to be the kinetic form of crystallization. It appears to be unsolvated and possibly hydrated. It has a very small particle size and a needle-like rod morphology.

[0330] Example 5: Form III

[0331] Approximately 30 mg of the amorphous compound A, a free base, was suspended in 1.0 mL of acetonitrile. The experiment was cyclical between ambient temperature (approximately 22 °C) and 40 °C for 72 hours, in 4-hour cycles. After 72 hours, the solid was separated by centrifugation and dried at 40 °C for 18 hours before analysis.

[0332] Form III appears to be the kinetic form of crystallization. It has a high melting temperature (starting at 196 °C) after dehydration. It appears to be unsolvated and possibly hydrated. It shows some loss of crystallinity upon dehydration.

[0333] Example 6: Form IV

[0334] Approximately 30 mg of the amorphous compound A (free base) was suspended in 1.0 mL of dichloromethane:methanol (25:75 v / v). The experiment was cycled at ambient temperature (approximately 22°C) to 40°C for 72 hours in a 4-hour cycle. After 72 hours, the sample was filtered through a 0.22 μm nylon filter, and the supernatant was retained. The supernatant was cooled to between 2 and 8°C in a refrigerator and maintained for 72 hours. After 72 hours, the resulting solid was separated by centrifugation and analyzed as a wet powder.

[0335] Form IV was found to be partially crystallized.

Claims

1. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A) (Compound A) Its features The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the pattern contained peaks at approximately 13.9°2θ, approximately 16.4°2θ, and approximately 17.9°2θ.

2. The polymorph according to claim 1, further characterized in that... The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the X-ray powder diffraction pattern contained at least one peak selected from about 16.2°2θ, about 18.5°2θ, and about 20.9°2θ.

3. The polymorph according to claim 1, further characterized in that... An X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing at least two peaks selected from about 16.2°2θ, about 18.5°2θ, and about 20.9°2θ.

4. The polymorph according to any one of claims 1 to 3, characterized in that... The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the X-ray powder diffraction pattern contained at least one peak selected from about 13.5°2θ, about 14.3°2θ, about 14.5°2θ, and about 16.8°2θ.

5. The polymorph according to any one of claims 1 to 4, characterized in that... An X-ray powder diffraction pattern that is substantially similar to the X-ray powder diffraction pattern shown in Figure 1A.

6. The polymorph according to any one of claims 1 to 5, further characterized by an endothermic event as measured by DT, said endothermic event initiating at about 259°C and having a peak at about 266°C.

7. The polymorph according to any one of claims 1 to 6, further characterized by a weight loss of about 1% between about 25°C and about 250°C, as measured by TG.

8. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A) (Compound A) Its features The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the pattern contained peaks at approximately 10.0°2θ, approximately 16.3°2θ, and approximately 17.5°2θ.

9. The polymorph according to claim 8, further characterized in that... The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the pattern contained peaks at approximately 9.2°2θ and approximately 18.1°2θ.

10. The polymorph according to claim 8, further characterized in that... The X-ray powder diffraction pattern using Cu Kα radiation contains peaks at approximately 9.2°2θ and approximately 18.1°2θ.

11. The polymorph according to any one of claims 8 to 10, characterized in that... An X-ray powder diffraction pattern that is substantially similar to the X-ray powder diffraction pattern shown in Figure 2A.

12. The polymorph according to any one of claims 8 to 11, further characterized in that the endothermic event, as measured by DT, has a peak at about 212°C.

13. The polymorph according to any one of claims 8 to 12, further characterized by a weight loss of about 11% between about 25°C and about 85°C, as measured by TG.

14. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A) (Compound A) Its features The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the pattern contained peaks at approximately 8.8°2θ, approximately 10.7°2θ, and 18.2°2θ.

15. The polymorph according to claim 14, further characterized in that... The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the X-ray powder diffraction pattern contained at least one peak selected from about 11.2°2θ, about 15.0°2θ, about 16.5°2θ, and about 17.8°2θ.

16. The polymorph according to claim 14, further characterized in that... An X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing at least two peaks selected from about 11.2°2θ, about 15.0°2θ, about 16.5°2θ, and about 17.8°2θ.

17. The polymorph according to any one of claims 14 to 16, further characterized in that it has an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern shown in FIG. 3A.

18. The polymorph according to any one of claims 14 to 17, further characterized by an endothermic event as measured by DT, said endothermic event initiating at about 196°C and having a peak at about 204°C.

19. The polymorph according to any one of claims 14 to 18, further characterized by a weight loss of about 3.7% between about 25°C and about 75°C, as measured by TG.

20. The polymorph according to claim 19, further characterized by a weight loss of about 4.7% between about 75°C and about 160°C, as measured by TG.

21. The polymorph according to claim 20, further characterized by a weight loss of about 0.6% between about 160°C and about 350°C, as measured by TG.

22. A polymorph of (S)-3-(5-(4-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (compound A) (Compound A) Its features An X-ray powder diffraction pattern with an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern containing peaks at approximately 10.5°2θ, approximately 14.5°2θ, and approximately 16.9°2θ.

23. The polymorph according to claim 22, further characterized in that... The X-ray powder diffraction pattern was obtained using Cu Kα radiation at a wavelength of 1.5406 Å, and the X-ray powder diffraction pattern contained at least one peak selected from about 11.5°2θ, about 14.2°2θ, about 16.3°2θ, and about 17.8°2θ.

24. The polymorph according to claim 22, further characterized in that... An X-ray powder diffraction pattern using Cu Kα radiation, the X-ray powder diffraction pattern containing at least two peaks selected from about 11.5°2θ, about 14.2°2θ, about 16.3°2θ, and about 17.8°2θ.

25. The polymorph according to any one of claims 22 to 24, characterized in that... An X-ray powder diffraction pattern that is substantially similar to the X-ray powder diffraction pattern shown in Figure 4A.

26. The polymorph according to any one of claims 22 to 25, further characterized by an endothermic event as measured by DT, said endothermic event initiating at about 196°C and having a peak at about 213°C.

27. The polymorph according to any one of claims 22 to 26, further characterized by a weight loss of about 3.1% between about 25°C and about 350°C, as measured by TG.

28. A method of treating a disease or condition in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the polymorph according to any one of claims 1 to 27.

29. The method of claim 28, wherein the disease or condition is associated with estrogen receptor (ER) activity, excessive activity, intrinsic activity, expression, overexpression, or accumulation and aggregation.

30. The method of claim 28 or 29, wherein the disease or condition is cancer or neoplasia associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation.

31. The method according to any one of claims 28 to 30, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

32. A pharmaceutical composition comprising a therapeutically effective amount of the polymorph according to any one of claims 1 to 27 and a pharmaceutically acceptable carrier, wherein the composition is effective in treating or improving at least one symptom of the disease or condition.

33. The composition of claim 32, wherein the disease or condition is associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation.

34. The composition of claim 32 or 33, wherein the disease or condition is cancer or neoplasia associated with ER accumulation and aggregation or ER activity or hyperactivity.

35. The composition according to any one of claims 32 to 34, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

36. Use of a polymorph according to any one of claims 1 to 27 in the preparation of a medicament for treating a disease or ailment.

37. The use according to claim 36, wherein the disease or condition is associated with ER accumulation and aggregation or ER activity or excessive activity.

38. The use according to claim 36 or 37, wherein the disease or condition is a cancer or neoplasm associated with ER accumulation and aggregation or ER activity or hyperactivity.

39. The use according to any one of claims 36 to 38, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

40. The polymorph according to any one of claims 1 to 27, for use in medicine.

41. The polymorph according to any one of claims 1 to 27, for treating a disease or condition, wherein the disease or condition is associated with ER accumulation and aggregation or ER activity or excessive activity.

42. The polymorph for use according to claim 41, wherein the disease or condition is cancer or neoplasia associated with ER accumulation and aggregation or ER activity or hyperactivity.

43. The polymorph for use according to claim 41 or 42, wherein the disease or condition is breast cancer, uterine cancer, or endometriosis.

44. A method for preparing a polymorph of compound A according to any one of claims 1 to 7, the method comprising recrystallizing compound A from a solvent.

45. The method of claim 44, 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 mixtures of ethanol and water.

46. ​​The method of claim 44, wherein the solvent comprises 1-butanol.

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

48. A method for preparing a polymorph of compound A according to any one of claims 8 to 13, the method comprising recrystallizing compound A from a solvent.

49. The method of claim 48, wherein the solvent is selected from a mixture of dichloromethane and acetone / water.

50. A method for preparing a polymorph of compound A according to any one of claims 14 to 21, the method comprising recrystallizing compound A from a solvent.

51. The method of claim 50, wherein the solvent is acetonitrile.

52. A method for preparing a polymorph of compound A according to any one of claims 22 to 27, the method comprising rapidly cooling a solution of compound A in a solvent.

53. A method for preparing a polymorph of compound A according to any one of claims 22 to 27, the method comprising adding an antisolvent to a solution of compound A in a solvent.

54. The method according to claim 52 or 53, wherein the solvent is a mixture of dichloromethane and methanol.

55. The method of claim 54, wherein the ratio of dichloromethane to methanol is about 25:75 (v / v).

56. The method according to any one of claims 53 to 55, wherein the antisolvent is methyl tert-butyl ether.

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