Salts and forms of wee1 inhibitor

Abstract

To provide a compound, salts and salt forms which are WEE1 inhibitors, and methods of using them for treating diseases or conditions characterized by excessive cellular proliferation, such as cancer.SOLUTION: Provided herein is the use of salts, such as adipate salt Form A, and / or forms and free base forms of Compound A which is a WEE1 inhibitor, as well as pharmaceutically acceptable salts and compositions thereof, in the treatment of diseases or conditions, including conditions characterized by excessive cellular proliferation, such as breast cancer.SELECTED DRAWING: Figure 24

Description

[Technical Field]

[0001] Incorporation by reference of any priority application Any and all applications for which a claim of foreign or domestic priority is identified in an Application Data Sheet filed with this application are incorporated herein by reference pursuant to 37 CFR § 1.57, including U.S. Provisional Patent Application No. 63 / 049996, filed July 9, 2020.

[0002] This application relates to compounds, salts and salt forms that are WEE1 inhibitors and methods of using them to treat conditions characterized by excessive cell proliferation, such as cancer. [Background technology]

[0003] WEE1 kinase plays a role in arrest at the G2-M cell cycle checkpoint for DNA repair before the onset of mitosis. Normal cells repair damaged DNA during G1 arrest. Cancer cells often lack the G1-S checkpoint and rely on a functional G2-M checkpoint for DNA repair. WEE1 is overexpressed in various cancer types. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2019 / 173082 [Non-patent literature]

[0005] [Non-Patent Document 1] Remington's Pharmaceutical Sciences,20thed., Lippincott Williams & Wilkins,Philadelphia Pa.,173(2000) [Non-patent document 2] The United States Pharmacopeia,37thed.,503-509(2014) Summary of the Invention

[0006] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, which can be a salt selected from the adipate salt of Compound A, the HCl salt of Compound A, the sulfate salt of Compound A, the mesylate salt of Compound A, the maleate salt of Compound A, the phosphate salt of Compound A, the tartrate salt of Compound A, the tosylate salt of Compound A, the mucate salt of Compound A, and the hippurate salt of Compound A. In some embodiments, the pharmaceutically acceptable salt can be a salt of Compound A selected from the adipate salt Form A of Compound A, the HCl salt Form A of Compound A, the sulfate salt Form A of Compound A, the mesylate salt Form A of Compound A, the maleate salt Form A of Compound A, the phosphate salt Form A of Compound A, the tartrate salt Form A of Compound A, the tosylate salt Form A of Compound A, the mucate salt Form A of Compound A, and the hippurate salt Form A of Compound A. In other embodiments, the pharmaceutically acceptable salt can be the HCl salt Form B of Compound A and / or the sulfate salt Form B of Compound A. Other embodiments disclosed herein relate to a free base form of Compound A selected from free base form A of Compound A, free base form B of Compound A, free base form C of Compound A, free base form D of Compound A, free base form E of Compound A, free base form F of Compound A, free base form G of Compound A, free base form H of Compound A, free base form I of Compound A, and free base form J of Compound A.

[0007] Other embodiments disclosed herein include administering to a subject a compound of formula (I) or (II) an effective amount of a pharmaceutically acceptable salt of Compound A, such as those described herein, and / or a free base of Compound A, including those described herein. It relates to pharmaceutical compositions that may include the base form and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0008] Still other embodiments disclosed herein relate to methods for ameliorating or treating malignant growths or tumors, comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable salt of Compound A, such as those described herein, and / or the free base of Compound A, such as those described herein, or a pharmaceutical composition that may include an effective amount of a pharmaceutically acceptable salt of Compound A (including those described herein) and / or the free base of Compound A, such as those described herein. Some embodiments disclosed herein relate to the use of a pharmaceutically acceptable salt of Compound A (such as those described herein) and / or the free base of Compound A (such as those described herein), or a pharmaceutical composition that may include an effective amount of a pharmaceutically acceptable salt of Compound A (including those described herein) and / or the free base of Compound A (including those described herein), for use in the amelioration or treatment of malignant growths or tumors.

[0009] Other embodiments disclosed herein relate to the use of a pharmaceutical salt of Compound A (e.g., Compound A adipate, Compound A HCl, Compound A sulfate, Compound A mesylate, Compound A maleate, Compound A phosphate, Compound A tartrate, Compound A tosylate, Compound A mucate, and / or Compound A hippurate) and / or the free base of Compound A (e.g., Compound A free base Form A, Compound A free base Form B, Compound A free base Form C, Compound A free base Form D, Compound A free base Form E, Compound A free base Form F, Compound A free base Form G, Compound A free base Form H, Compound A free base Form I, and / or Compound A free base Form J), or a pharmaceutical composition that may include an effective amount of a pharmaceutical salt of Compound A described herein and / or Compound A free base described herein, for use in the manufacture of a medicament for ameliorating or treating a malignant growth or tumor.

[0010] In some embodiments, the malignant growth or tumor may be caused by a cancer selected from breast cancer, cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, vulvar cancer, brain cancer, cervicocerebral cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, lung cancer, gastric cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal carcinoma, Wilms' carcinoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0011] These and other embodiments are described in more detail below. [Brief explanation of the drawings]

[0012] [Figure 1A] 1 provides a representative XRPD pattern of adipate salt Form A. [Figure 1B] 1 provides a representative XRPD pattern of adipate salt Form A. [Figure 2] 1 provides representative DSC and TGA thermograms of adipate salt Form A. [Figure 3] 1 provides representative XRPD patterns of HCl salt Form A and HCl salt Form B. [Figure 4] 1 provides representative DSC and TGA thermograms of HCl salt Form A. [Figure 5] 1 provides representative DSC and TGA thermograms of HCl salt Form B. [Figure 6] 1 provides a representative XRPD pattern of Sulfate Salt Form A. [Figure 7] 1 provides a representative XRPD pattern of Sulfate Salt Form B. [Figure 8] 1 provides a representative DSC thermogram of Sulfate Salt Form A. [Figure 9]1 provides representative DSC and TGA thermograms of Sulfate Salt Form B. [Figure 10] 1 provides a representative XRPD pattern of mesylate Form A. [Figure 11] 1 provides representative DSC and TGA thermograms of mesylate salt Form A. [Figure 12] 1 provides a representative XRPD pattern of maleate salt Form A. [Figure 13] 1 provides a representative DSC thermogram of maleate salt form A. [Figure 14] 1 provides a representative XRPD pattern of Phosphate Salt Form A. [Figure 15] 1 provides a representative DSC thermogram of Phosphate Form A. [Figure 16] 1 provides a representative XRPD pattern of tartrate salt Form A. [Figure 17] 1 provides representative DSC and TGA thermograms of tartrate salt Form A. [Figure 18] 1 provides a representative XRPD pattern of tosylate salt Form A. [Figure 19] 1 provides representative DSC and TGA thermograms of tosylate salt Form A. [Figure 20] 1 provides a representative XRPD pattern of mucate salt Form A. [Figure 21] 1 provides representative DSC and TGA thermograms of mucate salt Form A. [Figure 22] 1 provides a representative XRPD pattern of hippurate salt Form A. [Figure 23] 1 provides representative DSC and TGA thermograms of hippurate salt Form A. [Figure 24] 1 provides a representative XRPD pattern of Compound A free base Form A. [Figure 25] 1 provides representative DSC and TGA thermograms of Compound A free base Form A. [Figure 26] 1 provides a representative XRPD pattern of free base Form B of Compound A. [Figure 27] 1 provides a representative XRPD pattern of Compound A free base Form C. [Figure 28] 1 provides representative DSC and TGA thermograms of Compound A free base Form C. [Figure 29] 1 provides a representative XRPD pattern of free base Form D of Compound A. [Figure 30] 1 provides representative DSC and TGA thermograms of the free base form D of Compound A. [Figure 31] 1 provides a representative XRPD pattern of the free base form E of Compound A. [Figure 32] 1 provides representative DSC and TGA thermograms of Compound A free base Form E. [Figure 33] 1 provides a representative XRPD pattern of the free base form F of Compound A. [Figure 34] 1 provides representative DSC and TGA thermograms of Compound A free base form F. [Figure 35] 1 provides a representative XRPD pattern of the free base form G of Compound A. [Figure 36] 1 provides representative DSC and TGA thermograms of Compound A free base form G. [Figure 37] 1 provides a representative XRPD pattern of the free base form H of Compound A. [Figure 38] 1 provides representative DSC and TGA thermograms of Compound A free base Form H. [Figure 39] 1 provides a representative XRPD pattern of free base Form I of Compound A. [Figure 40] 1 provides a representative XRPD pattern of the free base form J of Compound A. [Figure 41] 1 provides a representative DVS plot of adipate salt Form A. [Figure 42] 1 provides representative XRPD overlays of adipate salt Form A before and after DVS. [Figure 43] 1 provides a representative DVS plot of the free base form E of Compound A. [Figure 44] 1 provides representative XRPD overlays of the free base form E of Compound A before and after DVS. [Figure 45] 1 provides a representative XRPD overlay of residual solids from a solubility study of adipate salt Form A. [Figure 46] 1 provides a representative XRPD overlay of residual solids from a solubility study of Compound A free base Form E. DETAILED DESCRIPTION OF THE INVENTION

[0013] WEE1 is a tyrosine kinase that is a key component of the ATR-mediated G2 cell cycle checkpoint, which blocks the initiation of mitosis in response to cellular DNA damage. ATR phosphorylates and activates CHK1, which then activates WEE1, leading to the selective phosphorylation of cyclin-dependent kinase 1 (CDK1) at Tyr15, thereby stabilizing the CDK1-cyclin B complex and arresting cell cycle progression. This process confers a survival advantage by allowing tumor cells time to repair damaged DNA before the onset of mitosis. Inhibition of WEE1 inhibits the G2 checkpoint, causing cancer cells with DNA damage to enter unscheduled mitosis and undergo cell death by mitotic apoptosis. Therefore, inhibition of WEE1 has the potential to sensitize tumors to DNA-damaging agents such as cisplatin and induce tumor cell death.

[0014] definition 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. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0015] Unless otherwise specified, as used herein, the term "crystalline" and related terms, when used to describe a substance, component, product, or form, means that the substance, component, product, or form is substantially crystalline, for example, as determined by X-ray diffraction (see, e.g., J. Chem. Soc. 1999, 144:111-112; J. Chem. Soc. 1999, 144:111-112).

[0016] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, refer to a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art as providing an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. In some embodiments, the terms "about" and "approximately," as used in this context, contemplate a dose, amount, or weight percent that is within 30%, 20%, 15%, 10%, or 5% of the specified dose, amount, or weight percent.

[0017] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or range of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range (e.g., those describing melting, dehydration, desolvation, or glass transition temperatures), mass change (e.g., mass change as a function of temperature or humidity), solvent or water content (e.g., mass or percentage), or peak position (e.g., in analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​may be deviated from to an extent that would be reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR), Raman spectroscopy), solid state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In some embodiments, the terms "about" and "approximately," when used in this context, indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. In the context of molar ratios, "about" and "approximately" indicate that a numerical value or range of values ​​may vary within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. Because the numerical values ​​of peaks in X-ray powder diffraction patterns can vary from instrument to instrument or sample to sample, quoted numerical values ​​should not be construed as absolute, and it is understood that there is an acceptable variability, such as ±0.2 degrees two-theta (°2θ) or more. For example, in some embodiments, XRPD peak position values ​​can vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak.

[0018] As used herein, unless otherwise specified, a solid form that is "substantially physically pure" is substantially free of other solid forms. In some embodiments, a substantially physically pure crystalline form contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other solid forms. Detection of other solid forms can be achieved by any method apparent to one of skill in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopy.

[0019] As used herein, unless otherwise specified, a solid form that is "substantially chemically pure" is substantially free of other chemical compounds (i.e., chemical impurities). In some embodiments, a solid form that is substantially chemically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of one or more other chemical compounds. Detection of other chemical compounds can be achieved by any method apparent to one of skill in the art, including, but not limited to, methods of chemical analysis such as mass spectrometry, spectroscopic analysis, thermal analysis, elemental combustion analysis, and / or chromatographic analysis.

[0020] As used herein, unless otherwise indicated, a chemical compound, solid form, or composition that is "substantially free" of other chemical compounds, solid forms, or compositions means that the compound, solid form, or composition contains, in some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% by weight of other compounds, solid forms, or compositions.

[0021] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0022] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0023] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0024] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," etc. As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended, not excluding additional, unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood to imply that a particular feature is critical, essential, or even important to its structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is intended to be synonymous with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0025] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope thereof.

[0026] compound As used herein, (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one is compound A having the following structure:

[0027] [ka]

[0028] Compound A is also referred to herein as "Compound A free base." In the event that the name of Compound A and the structure of Compound A provided herein are inconsistent, the structure of Compound A in this paragraph is the one intended for Compound A.

[0029] Various polymorphs of Compound A can be obtained. Some embodiments disclosed herein relate to free base form A of Compound A. Some embodiments disclosed herein relate to free base form B of Compound A. Other embodiments disclosed herein relate to free base form C of Compound A. Still other embodiments disclosed herein relate to free base form D of Compound A. Still other embodiments disclosed herein relate to free base form E of Compound A. Some embodiments disclosed herein relate to free base form F of Compound A. Other embodiments disclosed herein relate to free base form G of Compound A. Still other embodiments disclosed herein relate to free base form H of Compound A. Still other embodiments disclosed herein relate to free base form I of Compound A. Some embodiments disclosed herein relate to free base form J of Compound A.

[0030] In some embodiments, the free bases described herein can further comprise one or more other polymorphic forms. For example, free base form A may further comprise free base form F and / or one of more of the other free base forms. In some embodiments, free base form C may further comprise free base form F and / or one of more of the other free base forms. In some embodiments, free base form D may further comprise free base form F and / or one of more of the other free base forms. In some embodiments, free base form G may further comprise free base form F and / or one of more of the other free base forms. In some embodiments, free base form H may further comprise free base form F and / or one of more of the other free base forms. In some embodiments, free base form B may further comprise free base form E and / or one of more of the other free base forms. In some embodiments, free base form E may further comprise free base form J and / or one of more of the other free base forms. In some embodiments, free base form J may further comprise free base form E and / or one or more other free base forms. In some embodiments, free base form B may further comprise free base form J and / or one or more other free base forms.

[0031] The free base form of Compound A may be present in various amounts. For example, the amount of free base of Compound A that may be present in Form E may be in the range of about 90% to about 100%. In some embodiments, the amount of free base of Compound A that may be present in Form E may be in the range of about 95% to about 100%. In other embodiments, the amount of free base of Compound A that may be present in Form E may be in the range of about 98% to about 100%. In still other embodiments, the amount of free base of Compound A that may be present in Form E may be in the range of about 95% to about 98%. In some embodiments, the amount of free base of Compound A that may be present in Form E may be 90% or greater. In other embodiments, the amount of free base of Compound A that may be present in Form E may be 95% or greater. In still other embodiments, the amount of free base of Compound A that may be present in Form E may be 90% or greater. The amount of Compound A free base that may be present in Form J may be 98% or greater. In some embodiments, the amount of Compound A free base that may be present in Form J may be in the range of about 90% to about 100%. In some embodiments, the amount of Compound A free base that may be present in Form J may be in the range of about 95% to about 100%. In other embodiments, the amount of Compound A free base that may be present in Form J may be in the range of about 98% to about 100%. In still other embodiments, the amount of Compound A free base that may be present in Form J may be in the range of about 95% to about 98%. In some embodiments, the amount of Compound A free base that may be present in Form J may be 90% or greater. In other embodiments, the amount of Compound A free base that may be present in Form J may be 95% or greater. In still other embodiments, the amount of Compound A free base that may be present in Form J may be 98% or greater. When less than 100% of the free base forms described herein (such as Forms E and J) are the free base of Compound A, one or more components selected from (1) compounds that are the result of decomposition of the free base of Compound A and (2) impurities from the synthesis of the free base of Compound A may be present in the free base forms (such as Forms E and J).

[0032] Various salts of Compound A were obtained. Additionally, various salt forms of Compound A are provided herein. For example, some embodiments disclosed herein relate to the adipic acid salt form A of Compound A. Other embodiments disclosed herein relate to the HCl salt form A of Compound A. Still other embodiments disclosed herein relate to the sulfate salt form A of Compound A. Still other embodiments disclosed herein relate to the mesylate salt form A of Compound A. Some embodiments disclosed herein relate to the maleate salt form A of Compound A. Other embodiments disclosed herein relate to the phosphate salt form A of Compound A. Still other embodiments disclosed herein relate to the tartrate salt form A of Compound A. Still other embodiments disclosed herein relate to the tosylate salt form A of Compound A. Some embodiments disclosed herein relate to the mucate salt form A of Compound A. Still other embodiments disclosed herein relate to the hippurate salt form A of Compound A. Some embodiments disclosed herein relate to the HCl salt form B of Compound A. Other embodiments disclosed herein relate to sulfate Form B of Compound A.

[0033] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, which can be an adipate salt. One of ordinary skill in the art will appreciate that an adipate salt of Compound A has one molecule of Compound A per molecule of adipate. In some embodiments, the molar ratio of adipic acid to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0034] Various adipate forms of Compound A can be obtained. In some embodiments, the adipate form can be adipate form A. In some embodiments, the adipate forms described herein can further comprise the free base form of Compound A. For example, adipate form A can further comprise a small amount of the free base of Compound A. In some embodiments, the adipate forms described herein can further comprise a small amount of one or more other adipate forms (such as those described herein).

[0035] In salt forms of Compound A, varying amounts of the adipate form of Compound A may be present. For example, in some embodiments, the amount of adipate of Compound A that may be present in adipate Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of adipate of Compound A that may be present in adipate Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of adipate of Compound A that may be present in adipate Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of adipate of Compound A that may be present in adipate Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of adipate of Compound A that may be present in adipate Form A may be 90% or greater. In other embodiments, the amount of adipate of Compound A that may be present in adipate Form A may be greater than 90%. The amount of adipate salt of Compound A obtained may be 95% or greater. In yet other embodiments, the amount of adipate salt of Compound A that may be present in adipate Form A may be 98% or greater. When less than 100% of the salt forms described herein are the adipate form of Compound A, one or more components selected from (1) the free base of Compound A (such as those described herein), (2) compounds that are the result of decomposition of the adipate form of Compound A and / or decomposition of the free base of Compound A, and (3) impurities from the synthesis of the adipate form of Compound A and / or the synthesis of the free base of Compound A may be present in the adipate form of Compound A (such as adipate Form A of Compound A).

[0036] Various methods can be used to characterize the forms and salts of Compound A described herein, for example, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), 1 H NMR and 13 C NMR. All XRPD peaks and spectra provided herein are measured in degrees two-theta scale (2θ).

[0037] In some embodiments, adipate Form A can be characterized by one or more peaks in an XRPD pattern, and the one or more peaks can be selected from a peak in the range of about 12.2 degrees to about 12.5 degrees, a peak in the range of about 14.9 degrees to about 15.2 degrees, a peak in the range of about 15.3 degrees to about 15.6 degrees, a peak in the range of about 16.4 degrees to about 16.7 degrees, a peak in the range of about 22.0 degrees to about 22.3 degrees, and a peak in the range of about 22.7 degrees to about 23.0 degrees. In some embodiments, adipate Form A can be characterized by one or more peaks in an XRPD pattern selected from a peak in the range of about 5.0 degrees to about 5.3 degrees, a peak in the range of about 9.0 degrees to about 9.3 degrees, a peak in the range of about 11.2 degrees to about 11.5 degrees, a peak in the range of about 12.2 degrees to about 12.5 degrees, a peak in the range of about 14.9 degrees to about 15.2 degrees, a peak in the range of about 15.3 degrees to about 15.6 degrees, a peak in the range of about 16.4 degrees to about 16.7 degrees, a peak in the range of about 18.4 degrees to about 18.7 degrees, a peak in the range of about 19.0 degrees to about 19.3 degrees, a peak in the range of about 22.0 degrees to about 22.3 degrees, a peak in the range of about 22.7 degrees to about 23.0 degrees, and a peak in the range of about 24.8 degrees to about 25.1 degrees.

[0038] In some embodiments, adipate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 12.38 degrees, about 15.09 degrees, about 15.40 degrees, about 16.58 degrees, about 22.12 degrees, and about 22.88 degrees. In some embodiments, adipate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 11.36 degrees, about 12.38 degrees, about 15.09 degrees, about 15.40 degrees, about 16.58 degrees, about 18.57 degrees, about 19.17 degrees, about 22.12 degrees, and about 22.88 degrees. In some embodiments, adipate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 5.14 degrees, about 9.11 degrees, about 11.36 degrees, about 12.38 degrees, about 15.09 degrees, about 15.40 degrees, about 16.58 degrees, about 18.57 degrees, about 19.17 degrees, about 22.12 degrees, about 22.88 degrees, and about 24.92 degrees.

[0039] In some embodiments, adipate Form A can exhibit an XRPD pattern as shown in Figures 1A and 1B.

[0040] In some embodiments, adipate Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0041] [Table 1]

[0042] Adipic acid salt Form A can also be characterized by DSC and / or thermogravimetric analysis thermograms (TGA). In some embodiments, adipate form A can be characterized by the DSC and / or TGA thermograms of Figure 2. In some embodiments, adipate form A can be characterized by a weight loss of about 2.3% when heated from about 29°C to about 150°C. In some embodiments, adipate form A can be characterized by an endotherm in the range of about 175°C to about 183°C. In some embodiments, adipate form A can be characterized by an endotherm in the range of about 177°C to about 182°C. In some embodiments, adipate form A can be characterized by an endotherm at about 178.7°C.

[0043] In some embodiments, adipate Form A can be obtained by solution crystallization and can be characterized by an endotherm at about 179.9° C. The purity of such a compound is about 98.9%. In some embodiments, adipate Form A can be anhydrous.

[0044] Some embodiments disclosed herein relate to pharmaceutically acceptable salts of Compound A, which may be an HCl salt. Various HCl salt forms of Compound A can be obtained. In some embodiments, the HCl salt form may be HCl salt Form A. In some embodiments, the HCl salt form may be HCl salt Form B. In some embodiments, the HCl salt forms described herein may further comprise a free base form of Compound A. For example, HCl salt Form A may further comprise a small amount of free base Form A. In some embodiments, the HCl salt forms described herein may further comprise a small amount of one or more other HCl salt forms (such as those described herein). For example, HCl salt Form A may further comprise a small amount of HCl salt Form B.

[0045] In some embodiments, HCl salt Form A can be obtained via slurrying about 1 equivalent of Compound A with about 1 equivalent of HCl. In some embodiments, HCl salt Form B can be obtained via slurrying about 1 equivalent of Compound A with about 2 equivalents of HCl. In some embodiments, the molar ratio of HCl to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1. In some embodiments, the molar ratio of HCl to Compound A can be about 1.2 to about 2.8, about 1.6 to about 2.4, about 1.8 to about 2.2, or about 2.

[0046] In the salt form of Compound A, varying amounts of the HCl salt form of Compound A may be present. The amount of the HCl salt of Compound A that may be present in HCl Salt Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of the HCl salt of Compound A that may be present in HCl Salt Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of the HCl salt of Compound A that may be present in HCl Salt Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of the HCl salt of Compound A that may be present in HCl Salt Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of the HCl salt of Compound A that may be present in HCl Salt Form A may be 90% or greater. In other embodiments, the amount of the HCl salt of Compound A that may be present in HCl Salt Form A may be 95% or greater. In still other embodiments, the amount of the HCl salt of Compound A that may be present in HCl Salt Form A may be 98% or greater. When less than 100% of the salt forms described herein are the HCl salt form of Compound A, one or more components selected from: (1) the free base of Compound A (such as those described herein), (2) compounds that are the result of decomposition of the HCl salt form of Compound A and / or the decomposition of the free base of Compound A, and (3) impurities from the synthesis of the HCl salt form of Compound A and / or the synthesis of the free base of Compound A may be present in the HCl salt form of Compound A (such as HCl salt Form A of Compound A).

[0047] In some embodiments, HCl salt Form A can be characterized by one or more peaks in an XRPD pattern, and the one or more peaks can be selected from a peak in the range of about 3.4 degrees to about 3.8 degrees, a peak in the range of about 6.1 degrees to about 6.5 degrees, a peak in the range of about 8.5 degrees to about 8.9 degrees, a peak in the range of about 10.5 degrees to about 10.9 degrees, a peak in the range of about 12 degrees to about 12.4 degrees, and a peak in the range of about 17.6 degrees to about 18 degrees. In some embodiments, HCl salt Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 3.4 degrees to about 3.8 degrees, a peak in the range of about 6.1 degrees to about 6.5 degrees, a peak in the range of about 8.5 degrees to about 8.9 degrees, a peak in the range of about 9 degrees to about 9.4 degrees, a peak in the range of about 9.8 degrees to about 10.2 degrees, a peak in the range of about 10.5 degrees to about 10.9 degrees, a peak in the range of about 11.1 degrees to about 11.5 degrees, a peak in the range of about 11.7 degrees to about 12.1 degrees, a peak in the range of about 12 degrees to about 12.4 degrees, a peak in the range of about 12.2 degrees to about 12.6 degrees, a peak in the range of about 13 degrees to about 13.4 degrees, or a peak in the range of about 14.2 degrees to about 14.6 degrees. A peak in the range of about 15.5 degrees to about 15.9 degrees, a peak in the range of about 15.9 degrees to about 16.3 degrees, a peak in the range of about 16.9 degrees to about 17.3 degrees, a peak in the range of about 17.6 degrees to about 18 degrees, a peak in the range of about 18.9 degrees to about 19.3 degrees, a peak in the range of about 19.3 degrees to about 19.7 degrees, a peak in the range of about 20.2 degrees to about 20.6 degrees, a peak in the range of about 21.6 degrees to about 22 degrees, a peak in the range of about 22.6 degrees to about 23 degrees, a peak in the range of about 23.4 degrees to about 23.8 degrees, a peak in the range of about 24.1 degrees to about 24.5 degrees, a peak in the range of about 24.8 degrees to about 25.2 degrees, a peak in the range of about 25.8 degrees to about 26.2 degrees, and a peak in the range of about 26.3 degrees to about 26.7 degrees.

[0048] In some embodiments, the HCl salt Form A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 3.61 degrees, about 6.25 degrees, about 8.69 degrees, about 10.65 degrees, about 12.16 degrees, and about 17.81 degrees. In some embodiments, HCl salt Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 3.61 degrees, about 6.25 degrees, about 8.69 degrees, about 9.23 degrees, about 9.98 degrees, about 10.65 degrees, about 11.30 degrees, about 11.87 degrees, about 12.16 degrees, about 12.41 degrees, about 13.21 degrees, about 14.35 degrees, about 15.68 degrees, about 16.05 degrees, about 17.08 degrees, about 17.81 degrees, about 19.06 degrees, about 19.49 degrees, about 20.37 degrees, about 21.77 degrees, about 22.82 degrees, about 23.59 degrees, about 24.30 degrees, about 24.99 degrees, about 25.97 degrees, and about 26.47 degrees.

[0049] In some embodiments, the HCl salt Form A has an XRPD pattern selected from: The chromaticity can be characterized by one or more peaks in the

[0050] [Table 2]

[0051] In some embodiments, HCl salt Form B can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 3.1 degrees to about 3.5 degrees, a peak in the range of about 5.7 degrees to about 6.1 degrees, a peak in the range of about 6.9 degrees to about 7.3 degrees, a peak in the range of about 8.0 degrees to about 8.4 degrees, a peak in the range of about 10.6 degrees to about 11.0 degrees, a peak in the range of about 14.1 degrees to about 14.5 degrees, a peak in the range of about 18.8 degrees to about 19.2 degrees, a peak in the range of about 25.5 degrees to about 25.9 degrees, and a peak in the range of about 26.5 degrees to about 26.9 degrees. In some embodiments, HCl salt Form B can be characterized by one or more peaks in an XRPD pattern selected from a peak in the range of about 3.1 degrees to about 3.5 degrees, a peak in the range of about 5.7 degrees to about 6.1 degrees, a peak in the range of about 6.9 degrees to about 7.3 degrees, a peak in the range of about 8.0 degrees to about 8.4 degrees, a peak in the range of about 10.6 degrees to about 11.0 degrees, a peak in the range of about 13.6 degrees to about 14.0 degrees, a peak in the range of about 14.1 degrees to about 14.5 degrees, a peak in the range of about 16.0 degrees to about 16.4 degrees, a peak in the range of about 17.1 degrees to about 17.5 degrees, a peak in the range of about 18.8 degrees to about 19.2 degrees, a peak in the range of about 25.5 degrees to about 25.9 degrees, and a peak in the range of about 26.5 degrees to about 26.9 degrees.

[0052] In some embodiments, HCl salt Form B can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 3.30 degrees, about 5.87 degrees, about 7.14 degrees, about 8.19 degrees, about 10.80 degrees, about 14.33 degrees, about 18.99 degrees, about 25.66 degrees, and about 26.69 degrees. In some embodiments, HCl salt Form B can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 3.30 degrees, about 5.87 degrees, about 7.14 degrees, about 8.19 degrees, about 10.80 degrees, about 13.78 degrees, about 14.33 degrees, about 16.16 degrees, about 17.25 degrees, about 18.99 degrees, about 25.66 degrees, and about 26.69 degrees.

[0053] In some embodiments, HCl salt Form B can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0054] [Table 3]

[0055] In some embodiments, HCl salt Form A and HCl salt Form B can exhibit XRPD patterns as shown in FIG.

[0056] HCl salt Form A can be characterized by DSC and / or TGA. In some embodiments, HCl salt Form A can be characterized by the DSC and / or TGA thermograms of Figure 4. In some embodiments, HCl salt Form A can be characterized by a weight loss of about 9.0% when heated from about 29°C to about 150°C. In some embodiments, HCl salt Form A can be characterized by a first endotherm in the range of about 114°C to about 122°C and a second endotherm in the range of about 156°C to about 164°C. In some embodiments, HCl salt Form A can be characterized by a first endotherm in the range of about 115°C to about 121°C and a second endotherm in the range of about 157°C to about 163°C. In some embodiments, HCl salt Form A can be characterized by a first endotherm at about 117.7°C and a second endotherm at about 159.5°C.

[0057] HCl salt Form B can also be characterized by DSC and / or TGA. In some embodiments, HCl salt Form B can be characterized by the DSC and / or TGA thermograms of Figure 5. In some embodiments, HCl salt Form B can be characterized by a weight loss of about 12.0% when heated from about 29°C to about 150°C. In some embodiments, HCl salt Form B can be characterized by a first endotherm in the range of about 73°C to about 81°C and a second endotherm in the range of about 204°C to about 212°C ... and a second endotherm in the range of about 205° C. to about 211° C. In some embodiments, HCl salt Form B can be characterized by a first endotherm at about 77.0° C. and a second endotherm at about 207.9° C.

[0058] Some embodiments disclosed herein relate to pharmaceutically acceptable salts of Compound A, which may be sulfate salts. Various sulfate salt forms of Compound A can be obtained. In some embodiments, the sulfate salt form may be sulfate Form A. In some embodiments, the sulfate salt form may be sulfate Form B. In some embodiments, the sulfate salt forms described herein may further comprise the free base form of Compound A. For example, sulfate Form A may further comprise a small amount of free base Form A. In some embodiments, the sulfate salt forms described herein may further comprise a small amount of one or more other sulfate salt forms (such as those described herein). For example, sulfate Form A may further comprise a small amount of sulfate Form B. In some embodiments, the molar ratio of sulfate to Compound A may be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0059] In the salt form of Compound A, varying amounts of the sulfate salt form of Compound A may be present. For example, the amount of sulfate salt of Compound A that may be present in sulfate salt Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of sulfate salt of Compound A that may be present in sulfate salt Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of sulfate salt of Compound A that may be present in sulfate salt Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of sulfate salt of Compound A that may be present in sulfate salt Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of sulfate salt of Compound A that may be present in sulfate salt Form A may be 90% or greater. In other embodiments, the amount of sulfate salt of Compound A that may be present in sulfate salt Form A may be 95% or greater. In still other embodiments, the amount of sulfate salt of Compound A that may be present in sulfate salt Form A may be 98% or greater. When less than 100% of the salt forms described herein are the sulfate salt form of Compound A, one or more components selected from: (1) the free base of Compound A (such as those described herein); (2) compounds that are the result of decomposition of the sulfate salt form of Compound A and / or decomposition of the free base of Compound A; and (3) impurities from the synthesis of the sulfate salt form of Compound A and / or the synthesis of the free base of Compound A may be present in the sulfate salt form of Compound A (such as sulfate Form A of Compound A).

[0060] In some embodiments, Sulfate Salt Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 7.9 degrees to about 8.3 degrees, a peak in the range of about 11.2 degrees to about 11.6 degrees, a peak in the range of about 15.9 degrees to about 16.3 degrees, a peak in the range of about 16.1 degrees to about 16.5 degrees, a peak in the range of about 17.7 degrees to about 18.1 degrees, and a peak in the range of about 23.7 degrees to about 24.1 degrees. In some embodiments, Sulfate Salt Form A can be characterized by one or more peaks in an XRPD pattern selected from a peak in the range of about 7.9 degrees to about 8.3 degrees, a peak in the range of about 8.6 degrees to about 9 degrees, a peak in the range of about 11.2 degrees to about 11.6 degrees, a peak in the range of about 15.9 degrees to about 16.3 degrees, a peak in the range of about 16.1 degrees to about 16.5 degrees, a peak in the range of about 17.7 degrees to about 18.1 degrees, a peak in the range of about 19.9 degrees to about 20.3 degrees, a peak in the range of about 23.7 degrees to about 24.1 degrees, a peak in the range of about 24 degrees to about 24.4 degrees, and a peak in the range of about 24.9 degrees to about 25.3 degrees.

[0061] In some embodiments, Sulfate Salt Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks can be selected from about 8.07 degrees, about 11.37 degrees, about 16.11 degrees, about 16.33 degrees, about 17.92 degrees, and about 23.87 degrees. In some embodiments, Sulfate Salt Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks can be selected from about 8.07 degrees, about 8.84 degrees, about 11.37 degrees, about 16.11 degrees, about 16.33 degrees, about 17.92 degrees, and about 23.87 degrees. The angle is selected from the group consisting of approximately 8 degrees, approximately 23.87 degrees, approximately 24.24 degrees, and approximately 25.13 degrees.

[0062] In some embodiments, Sulfate Salt Form A can exhibit an XRPD pattern as shown in FIG.

[0063] In some embodiments, Sulfate Salt Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0064] [Table 4]

[0065] In some embodiments, Sulfate Salt Form B can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 4.3 degrees to about 4.7 degrees, a peak in the range of about 7.7 degrees to about 8.1 degrees, a peak in the range of about 8.8 degrees to about 9.2 degrees, a peak in the range of about 11.3 degrees to about 11.7 degrees, a peak in the range of about 11.8 degrees to about 12.2 degrees, a peak in the range of about 13.3 degrees to about 13.7 degrees, a peak in the range of about 15.5 degrees to about 15.9 degrees, a peak in the range of about 16 degrees to about 16.4 degrees, a peak in the range of about 16.3 degrees to about 16.7 degrees, a peak in the range of about 18.1 degrees to about 18.5 degrees, a peak in the range of about 20.7 degrees to about 21.1 degrees, a peak in the range of about 23.7 degrees to about 24.1 degrees, and a peak in the range of about 24.1 degrees to about 24.5 degrees. In some embodiments, Sulfate Salt Form B can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 4.3 degrees to about 4.7 degrees, a peak in the range of about 7.7 degrees to about 8.1 degrees, a peak in the range of about 8.2 degrees to about 8.6 degrees, a peak in the range of about 8.8 degrees to about 9.2 degrees, a peak in the range of about 11.3 degrees to about 11.7 degrees, a peak in the range of about 11.8 degrees to about 12.2 degrees, a peak in the range of about 13.3 degrees to about 13.7 degrees, a peak in the range of about 15.5 degrees to about 15.9 degrees, a peak in the range of about 16 degrees to about 16.4 degrees, a peak in the range of about 16.3 degrees to about 16.7 degrees, a peak in the range of about 18.1 degrees to about 18.5 degrees, a peak in the range of about 20.7 degrees to about 21.1 degrees, a peak in the range of about 22.2 degrees to about 22.6 degrees, a peak in the range of about 23.7 degrees to about The peak is selected from a peak in the range of 24.1 degrees, a peak in the range of about 24.1 degrees to about 24.5 degrees, a peak in the range of about 26.2 degrees to about 26.6 degrees, and a peak in the range of about 27.2 degrees to about 27.6 degrees.

[0066] In some embodiments, Sulfate Salt Form B can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 4.51 degrees, about 7.93 degrees, about 8.98 degrees, about 11.45 degrees, about 12.00 degrees, about 13.52 degrees, about 15.66 degrees, about 16.22 degrees, about 16.46 degrees, about 18.25 degrees, about 20.88 degrees, about 23.92 degrees, and about 24.29 degrees. In some embodiments, Sulfate Salt Form B can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 4.51 degrees, about 7.93 degrees, about 8.43 degrees, about 8.98 degrees, about 11.45 degrees, about 12.00 degrees, about 13.52 degrees, about 15.66 degrees, about 16.22 degrees, about 16.46 degrees, about 18.25 degrees, about 20.88 degrees, about 22.37 degrees, about 23.92 degrees, about 24.29 degrees, about 26.39 degrees, and about 27.42 degrees.

[0067] In some embodiments, Sulfate Salt Form B can exhibit an XRPD pattern as shown in FIG.

[0068] In some embodiments, Sulfate Salt Form B can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0069] [Table 5]

[0070] Sulfate Form A can also be characterized by DSC. In some embodiments, sulfate Form A can be characterized by the DSC thermogram of Figure 8. In some embodiments, sulfate Form A can be characterized by a first endotherm in the range of about 54°C to about 62°C, a second endotherm in the range of about 83°C to about 91°C, and a third endotherm in the range of about 179°C to about 187°C. In some embodiments, sulfate Form A can be characterized by a first endotherm in the range of about 56°C to about 60°C, a second endotherm in the range of about 85°C to about 89°C, and a third endotherm in the range of about 181°C to about 185°C. In some embodiments, sulfate Form A can be characterized by a first endotherm at about 58.2°C, a second endotherm at about 87.3°C, and a third endotherm at about 179°C to about 187°C. It can be characterized by a second endotherm and a third endotherm at about 182.9°C.

[0071] Sulfate Form B can also be characterized by DSC and / or TGA. In some embodiments, sulfate Form B can be characterized by the DSC and / or TGA thermograms of FIG. 9. In some embodiments, sulfate Form B can be characterized by a weight loss of about 4.2% when heated from about 29°C to about 150°C. In some embodiments, sulfate Form B can be characterized by a first endotherm in the range of about 98°C to about 106°C and a second endotherm in the range of about 178°C to about 186°C. In some embodiments, sulfate Form B can be characterized by a first endotherm in the range of about 100°C to about 104°C and a second endotherm in the range of about 180°C to about 184°C. In some embodiments, sulfate Form A can be characterized by a first endotherm at about 101.8°C and a second endotherm at about 182.2°C.

[0072] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, which can be a mesylate salt. In some embodiments, the mesylate form can be mesylate Form A. In some embodiments, the molar ratio of mesylate to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0073] Various mesylate forms of Compound A can be obtained. In some embodiments, the mesylate forms described herein can further comprise a free base of Compound A (such as those described herein). For example, mesylate Form A can further comprise a small amount of the free base of Compound A. In some embodiments, the mesylate forms described herein can further comprise a small amount of one or more other mesylate forms (such as those described herein).

[0074] In salt forms of Compound A, varying amounts of the mesylate form of Compound A may be present. For example, the amount of Compound A mesylate that may be present in mesylate Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of Compound A mesylate that may be present in mesylate Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of Compound A mesylate that may be present in mesylate Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of Compound A mesylate that may be present in mesylate Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of Compound A mesylate that may be present in mesylate Form A may be 90% or greater. In other embodiments, the amount of Compound A mesylate that may be present in mesylate Form A may be 95% or greater. In still other embodiments, the amount of Compound A mesylate that may be present in mesylate Form A may be 98% or greater. When less than 100% of the salt forms described herein are mesylate salts from Compound A, one or more components selected from: (1) the free base of Compound A (including those described herein), (2) compounds that are the result of decomposition of the mesylate form of Compound A and / or the free base of Compound A, and (3) impurities from the synthesis of the mesylate form of Compound A and / or the synthesis of the free base of Compound A may be present in the mesylate form of Compound A (such as mesylate Form A of Compound A).

[0075] In some embodiments, mesylate Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 4.5 degrees to about 4.9 degrees, a peak in the range of about 9.2 degrees to about 9.6 degrees, a peak in the range of about 18.6 degrees to about 19 degrees, a peak in the range of about 18.9 degrees to about 19.3 degrees, a peak in the range of about 19.7 degrees to about 20.1 degrees, a peak in the range of about 21 degrees to about 21.4 degrees, and a peak in the range of about 23.1 degrees to about 23.5 degrees. In some embodiments, mesylate Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 4.5 degrees to about 4.9 degrees, a peak in the range of about 9.2 degrees to about 9.6 degrees, Peaks in the range of about 9.7 degrees to about 10.1 degrees, peaks in the range of about 13.1 degrees to about 13.5 degrees, peaks in the range of about 14.3 degrees to about 14.7 degrees, peaks in the range of about 15.1 degrees to about 15.5 degrees, peaks in the range of about 15.6 degrees to about 16 degrees, peaks in the range of about 17.1 degrees to about 17.5 degrees, peaks in the range of about 17.8 degrees to about 18.2 degrees, peaks in the range of about 18.6 degrees to about 19 degrees, peaks in the range of about 18.9 degrees to about 19.3 degrees, peaks in the range of about 19.7 degrees to about 20. The angle is selected from a peak in the range of about 21 degrees to about 21.1 degrees, a peak in the range of about 21 degrees to about 21.4 degrees, a peak in the range of about 21.5 degrees to about 21.9 degrees, a peak in the range of about 23.1 degrees to about 23.5 degrees, a peak in the range of about 23.4 degrees to about 23.8 degrees, a peak in the range of about 24.6 degrees to about 25 degrees, a peak in the range of about 26 degrees to about 26.4 degrees, a peak in the range of about 26.4 degrees to about 26.8 degrees, a peak in the range of about 28.7 degrees to about 29.1 degrees, and a peak in the range of about 33 degrees to about 33.4 degrees.

[0076] In some embodiments, mesylate Form A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 4.66 degrees, about 9.36 degrees, about 18.8 degrees, about 19.12 degrees, about 19.9 degrees, about 21.17 degrees, and about 23.34 degrees. In some embodiments, mesylate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 4.66 degrees, about 9.36 degrees, about 9.89 degrees, about 13.29 degrees, about 14.45 degrees, about 15.26 degrees, about 15.82 degrees, about 17.32 degrees, about 17.98 degrees, about 18.8 degrees, about 19.12 degrees, about 19.9 degrees, about 21.17 degrees, about 21.72 degrees, about 23.34 degrees, about 23.55 degrees, about 24.83 degrees, about 26.18 degrees, about 26.55 degrees, about 28.92 degrees, and about 33.2 degrees.

[0077] In some embodiments, mesylate Form A can exhibit an XRPD pattern as shown in FIG.

[0078] In some embodiments, mesylate Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0079] [Table 6]

[0080] Mesylate Form A can also be characterized by DSC and / or TGA. In some embodiments, mesylate Form A can be characterized by the DSC and / or TGA thermograms of Figure 11. In some embodiments, mesylate Form A can be characterized by a weight loss of about 5.2% when heated from about 22°C to about 150°C. In some embodiments, mesylate Form A can be characterized by an endotherm in the range of about 126°C to about 134°C. In some embodiments, mesylate Form A can be characterized by an endotherm in the range of about 128°C to about 132°C. In some embodiments, mesylate Form A can be characterized by an endotherm at about 130.1°C.

[0081] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, which can be a maleate salt. In some embodiments, the maleate salt form can be maleate Form A. In some embodiments, the molar ratio of maleic acid to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0082] Various maleate salt forms of Compound A can be obtained. In some embodiments, the maleate salt forms described herein are the same as the free base of Compound A (as described herein). For example, maleate Form A may further comprise a small amount of free base Form A. In some embodiments, the maleate forms described herein may further comprise small amounts of one or more other maleate forms (such as those described herein).

[0083] Varying amounts of the maleate form of Compound A may be present in the salt form of Compound A. For example, the amount of maleate of Compound A that may be present in maleate form A may be in the range of about 90% to about 100%. In some embodiments, the amount of maleate of Compound A that may be present in maleate form A may be in the range of about 95% to about 100%. In other embodiments, the amount of maleate of Compound A that may be present in maleate form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of maleate of Compound A that may be present in maleate form A may be in the range of about 95% to about 98%. In some embodiments, the amount of maleate of Compound A that may be present in maleate form A may be 90% or greater. In other embodiments, the amount of maleate of Compound A that may be present in maleate form A may be 95% or greater. In still other embodiments, the amount of maleate of Compound A that may be present in maleate form A may be 98% or greater. When less than 100% of the salt forms described herein are maleate salts from Compound A, one or more components selected from: (1) the free base of Compound A (including those described herein), (2) compounds that are the result of decomposition of the maleate form of Compound A and / or the free base of Compound A, and (3) impurities from the synthesis of the maleate form of Compound A and / or the synthesis of the free base of Compound A may be present in the maleate form of Compound A (such as maleate Form A of Compound A).

[0084] In some embodiments, maleate salt Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 3 degrees to about 3.4 degrees, a peak in the range of about 4.8 degrees to about 5.2 degrees, a peak in the range of about 5 degrees to about 5.4 degrees, a peak in the range of about 10.1 degrees to about 10.5 degrees, a peak in the range of about 15.2 degrees to about 15.6 degrees, a peak in the range of about 15.8 degrees to about 16.2 degrees, a peak in the range of about 16.3 degrees to about 16.7 degrees, and a peak in the range of about 21.8 degrees to about 22.2 degrees. In some embodiments, maleate salt Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being in the range of about 3 degrees to about 3.4 degrees, about 4.8 degrees to about 5.2 degrees, about 5 degrees to about 5.4 degrees, about 8.9 degrees to about 9.3 degrees, about 10.1 degrees to about 10.5 degrees, about 11.2 degrees to about 11.6 degrees, about 13.8 degrees to about 14.2 degrees, about 14.9 degrees to about 15.3 degrees, or about 16.2 degrees to about 17.2 degrees. The angle is selected from a peak in the range of about 15.2 degrees to about 15.6 degrees, a peak in the range of about 15.8 degrees to about 16.2 degrees, a peak in the range of about 16.3 degrees to about 16.7 degrees, a peak in the range of about 16.7 degrees to about 17.1 degrees, a peak in the range of about 17.8 degrees to about 18.2 degrees, a peak in the range of about 18.8 degrees to about 19.2 degrees, a peak in the range of about 20.4 degrees to about 20.8 degrees, a peak in the range of about 21.8 degrees to about 22.2 degrees, a peak in the range of about 22.9 degrees to about 23.3 degrees, and a peak in the range of about 23.4 degrees to about 23.8 degrees.

[0085] In some embodiments, maleate salt Form A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 3.16 degrees, about 4.99 degrees, about 5.17 degrees, about 10.27 degrees, about 15.41 degrees, about 16.03 degrees, about 16.46 degrees, and about 22.02 degrees. In some embodiments, maleate salt Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 3.16 degrees, about 4.99 degrees, about 5.17 degrees, about 9.05 degrees, about 10.27 degrees, about 11.43 degrees, about 13.97 degrees, about 15.1 degrees, about 15.41 degrees, about 16.03 degrees, about 16.46 degrees, about 16.87 degrees, about 17.95 degrees, about 18.99 degrees, about 20.56 degrees, about 22.02 degrees, about 23.09 degrees, and about 23.55 degrees.

[0086] In some embodiments, maleate salt Form A can exhibit an XRPD pattern as shown in FIG.

[0087] In some embodiments, maleate salt Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0088] [Table 7]

[0089] Maleate Form A can also be characterized by DSC. In some embodiments, maleate Form A can be characterized by the DSC thermogram of Figure 13. In some embodiments, maleate Form A can be characterized by a first endotherm in the range of about 62°C to about 70°C, a second endotherm in the range of about 135°C to about 143°C, and a third endotherm in the range of about 154°C to about 162°C. In some embodiments, maleate Form A can be characterized by a first endotherm in the range of about 64°C to about 68°C, a second endotherm in the range of about 137°C to about 141°C, and a third endotherm in the range of about 156°C to about 160°C. In some embodiments, maleate Form A can be characterized by a first endotherm at about 65.6°C, a second endotherm at about 138.9°C, and a third endotherm at about 157.9°C.

[0090] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, which can be a phosphate salt. In some embodiments, the phosphate salt form can be phosphate Form A. In some embodiments, the molar ratio of phosphoric acid to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0091] Various phosphate forms of Compound A can be obtained. In some embodiments, The phosphate salt forms described herein may further comprise a free base of Compound A (such as those described herein). For example, phosphate Form A may further comprise a small amount of free base Form A. In some embodiments, the phosphate salt forms described herein may further comprise a small amount of one or more other phosphate salt forms (such as those described herein).

[0092] In the salt form of Compound A, varying amounts of the phosphate form of Compound A may be present. For example, the amount of phosphate of Compound A that may be present in phosphate Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of phosphate of Compound A that may be present in phosphate Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of phosphate of Compound A that may be present in phosphate Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of phosphate of Compound A that may be present in phosphate Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of phosphate of Compound A that may be present in phosphate Form A may be 90% or greater. In other embodiments, the amount of phosphate of Compound A that may be present in phosphate Form A may be 95% or greater. In still other embodiments, the amount of phosphate of Compound A that may be present in phosphate Form A may be 98% or greater. When less than 100% of the salt forms described herein are phosphate forms of Compound A, one or more components selected from: (1) the free base of Compound A (such as those described herein); (2) compounds that are the result of decomposition of the phosphate form of Compound A and / or the free base of Compound A; and (3) impurities from the synthesis of the phosphate form of Compound A and / or the synthesis of the free base of Compound A may be present in the phosphate form of Compound A (such as phosphate Form A of Compound A).

[0093] In some embodiments, phosphate Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 9.3 degrees to about 9.7 degrees, a peak in the range of about 10.9 degrees to about 11.3 degrees, a peak in the range of about 17.4 degrees to about 17.8 degrees, a peak in the range of about 18.8 degrees to about 19.2 degrees, a peak in the range of about 21.7 degrees to about 22.1 degrees, and a peak in the range of about 23.4 degrees to about 23.8 degrees. In some embodiments, phosphate Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 4.6 degrees to about 5 degrees, a peak in the range of about 9.3 degrees to about 9.7 degrees, a peak in the range of about 9.7 degrees to about 10.1 degrees, a peak in the range of about 10.9 degrees to about 11.3 degrees, a peak in the range of about 13.2 degrees to about 13.6 degrees, a peak in the range of about 14.1 degrees to about 14.5 degrees, or the like. a peak in the range of about 15.6 degrees to about 16 degrees, a peak in the range of about 17.4 degrees to about 17.8 degrees, a peak in the range of about 18.8 degrees to about 19.2 degrees, a peak in the range of about 19.9 degrees to about 20.3 degrees, a peak in the range of about 21.7 degrees to about 22.1 degrees, a peak in the range of about 23.4 degrees to about 23.8 degrees, a peak in the range of about 25.5 degrees to about 25.9 degrees, and a peak in the range of about 27.4 degrees to about 27.8 degrees.

[0094] In some embodiments, phosphate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 9.49 degrees, about 11.1 degrees, about 17.57 degrees, about 19.03 degrees, about 21.89 degrees, and about 23.62 degrees. In some embodiments, phosphate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 4.77 degrees, about 9.49 degrees, about 9.94 degrees, about 11.1 degrees, about 13.43 degrees, about 14.3 degrees, about 15.77 degrees, about 17.57 degrees, about 19.03 degrees, about 20.12 degrees, about 21.89 degrees, about 23.62 degrees, about 25.72 degrees, and about 27.59 degrees.

[0095] In some embodiments, Phosphate Form A can exhibit an XRPD pattern as shown in FIG.

[0096] In some embodiments, phosphate Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0097] [Table 8]

[0098] Phosphate Form A can also be characterized by DSC. In some embodiments, phosphate Form A can be characterized by the DSC thermogram of Figure 15. In some embodiments, phosphate Form A can be characterized by a first endotherm in the range of about 57°C to about 65°C, a second endotherm in the range of about 140°C to about 148°C, and a third endotherm in the range of about 217°C to about 225°C. In some embodiments, phosphate Form A can be characterized by a first endotherm in the range of about 59°C to about 63°C, a second endotherm in the range of about 142°C to about 146°C, and a third endotherm in the range of about 219°C to about 223°C. In some embodiments, phosphate Form A can be characterized by a first endotherm at about 60.9°C, a second endotherm at about 144.2°C, and a third endotherm at about 221.1°C.

[0099] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, where the pharmaceutically acceptable salt can be a tartrate salt. In some embodiments, the tartrate salt form can be tartrate Form A. In some embodiments, the molar ratio of tartaric acid to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0100] Various tartrate salt forms of Compound A can be obtained. In some embodiments, the tartrate salt forms described herein can further comprise a free base of Compound A (including those described herein). For example, tartrate salt Form A can further comprise a small amount of free base Form A. In some embodiments, the tartrate salt forms described herein can further comprise a small amount of one or more other tartrate salt forms (such as those described herein).

[0101] In the salt form of Compound A, varying amounts of the tartrate form of Compound A may be present. For example, the amount of tartrate of Compound A that may be present in tartrate Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of tartrate of Compound A that may be present in tartrate Form A may be in the range of about 90% to about 100%. The amount of tartrate of Compound A that may be present in tartrate salt Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of tartrate of Compound A that may be present in tartrate salt Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of tartrate of Compound A that may be present in tartrate salt Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of tartrate of Compound A that may be present in tartrate salt Form A may be 90% or greater. In other embodiments, the amount of tartrate of Compound A that may be present in tartrate salt Form A may be 95% or greater. In still other embodiments, the amount of tartrate of Compound A that may be present in tartrate salt Form A may be 98% or greater. When less than 100% of the salt forms described herein are the tartrate salt form of Compound A, one or more components selected from: (1) the free base of Compound A (such as those described herein); (2) compounds that are the result of decomposition of the tartrate salt form of Compound A and / or the decomposition of the free base of Compound A; and (3) impurities from the synthesis of the tartrate salt form of Compound A and / or the synthesis of the free base of Compound A may be present in the tartrate salt form of Compound A (such as tartrate Form A of Compound A).

[0102] In some embodiments, the tartrate salt Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 4.1 degrees to about 4.5 degrees, a peak in the range of about 8.3 degrees to about 8.7 degrees, a peak in the range of about 9 degrees to about 9.4 degrees, a peak in the range of about 11.9 degrees to about 12.3 degrees, a peak in the range of about 12.5 degrees to about 12.9 degrees, a peak in the range of about 15.3 degrees to about 15.7 degrees, a peak in the range of about 15.5 degrees to about 15.9 degrees, or a peak in the range of about 15.5 degrees to about 15.9 degrees. a peak in the range of about 17.8 degrees to about 18.2 degrees, a peak in the range of about 18.3 degrees to about 18.7 degrees, a peak in the range of about 19.5 degrees to about 19.9 degrees, a peak in the range of about 21.1 degrees to about 21.5 degrees, a peak in the range of about 21.9 degrees to about 22.3 degrees, a peak in the range of about 23.2 degrees to about 23.6 degrees, a peak in the range of about 24.2 degrees to about 24.6 degrees, a peak in the range of about 25.3 degrees to about 25.7 degrees, and a peak in the range of about 26.9 degrees to about 27.3 degrees. In some embodiments, tartrate salt Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being in the range of about 4.1 degrees to about 4.5 degrees, about 8.3 degrees to about 8.7 degrees, about 9 degrees to about 9.4 degrees, about 11.9 degrees to about 12.3 degrees, about 12.5 degrees to about 12.9 degrees, about 14.1 degrees to about 14.5 degrees, about 14.5 degrees to about 14.9 degrees, about 15.3 degrees to about 15.7 degrees, about 15.5 degrees to about 15.9 degrees, or about 17.8 degrees to about 18.2 degrees. a peak in the range of about 18.3 degrees to about 18.7 degrees, a peak in the range of about 19.5 degrees to about 19.9 degrees, a peak in the range of about 21.1 degrees to about 21.5 degrees, a peak in the range of about 21.9 degrees to about 22.3 degrees, a peak in the range of about 22.7 degrees to about 23.1 degrees, a peak in the range of about 23.2 degrees to about 23.6 degrees, a peak in the range of about 24.2 degrees to about 24.6 degrees, a peak in the range of about 24.9 degrees to about 25.3 degrees, a peak in the range of about 25.3 degrees to about 25.7 degrees, a peak in the range of about 26.2 degrees to about 26.6 degrees, a peak in the range of about 26.9 degrees to about 27.3 degrees, and a peak in the range of about 29.9 degrees to about 30.3 degrees.

[0103] In some embodiments, the tartrate salt Form A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 4.27 degrees, about 8.48 degrees, about 9.21 degrees, about 12.05 degrees, about 12.71 degrees, about 15.54 degrees, about 15.74 degrees, about 17.98 degrees, about 18.46 degrees, about 19.72 degrees, about 21.25 degrees, about 22.11 degrees, about 23.37 degrees, about 24.37 degrees, about 25.54 degrees, and about 27.12 degrees. In some embodiments, the tartrate salt Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being at about 4.27 degrees, about 8.48 degrees, about 9.21 degrees, about 12.05 degrees, about 12.71 degrees, about 14.25 degrees, about 14.74 degrees, about 15.54 degrees, about 15.74 degrees, about 17.98 degrees, about 18.46 degrees, about 19.72 degrees, about 21.25 degrees, about 22.11 degrees, about 22.86 degrees, about 23.37 degrees, about 24.37 degrees, about 25.09 degrees, about 25.54 degrees, about 26.4 degrees, about 27.12 degrees, and about 30.1 degrees. There are two degrees to choose from.

[0104] In some embodiments, tartrate salt Form A can exhibit an XRPD pattern as shown in FIG.

[0105] In some embodiments, tartrate salt Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0106] [Table 9]

[0107] Tartrate salt Form A can also be characterized by DSC and / or TGA. In some embodiments, tartrate salt Form A can be characterized by the DSC and / or TGA thermograms of Figure 17. In some embodiments, tartrate salt Form A can be characterized by a weight loss of about 8.2% when heated from about 26°C to about 150°C. In some embodiments, tartrate salt Form A can be characterized by a weight loss of about 8.2% when heated from about 100°C to about 108°C. 102.1°C、115.2°C、116.2°C、117.1°C、118.8°C、123.2°C、124.2°C、125.2°C、130.2°C、135.2°C、140.2°C、145.2°C、150.2°C、155.2°C、161.2°C、177.2°C、185.2°C、190.2°C、195.2°C、196.2°C、197.2°C、198.2°C、199.2°C、200.2°C、210.2°C、211.2°C、212.2°C、220.2°C、230.2°C、231.2°C、240.2°C、250.2°C、261.2°C、270.2°C、280.2°C、29 ...

[0108] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, wherein the pharmaceutically acceptable salt can be a tosylate salt. In some embodiments, the tosylate salt form can be tosylate Form A. In some embodiments, the molar ratio of tosylate to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0109] Various tosylate salt forms of Compound A can be obtained. In some embodiments, the tosylate salt forms described herein can further comprise the free base form of Compound A. For example, tosylate Form A can further comprise a small amount of free base Form A. In some embodiments, the tosylate salt forms described herein can further comprise a small amount of one or more other tosylate salt forms (such as those described herein).

[0110] In salt forms of Compound A, varying amounts of the tosylate form of Compound A may be present. For example, the amount of tosylate of Compound A that may be present in tosylate Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of tosylate of Compound A that may be present in tosylate Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of tosylate of Compound A that may be present in tosylate Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of tosylate of Compound A that may be present in tosylate Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of tosylate of Compound A that may be present in tosylate Form A may be 90% or greater. In other embodiments, the amount of tosylate of Compound A that may be present in tosylate Form A may be 95% or greater. In still other embodiments, the amount of tosylate of Compound A that may be present in tosylate Form A may be 98% or greater. When less than 100% of the salt forms described herein are tosylate salt forms from Compound A, one or more components selected from: (1) the free base of Compound A (including those described herein), (2) compounds that are the result of decomposition of the tosylate salt form of Compound A and / or decomposition of the free base of Compound A, and (3) impurities from the synthesis of the tosylate salt form of Compound A and / or the synthesis of the free base of Compound A may be present in the tosylate salt form of Compound A (such as tosylate Form A of Compound A).

[0111] In some embodiments, tosylate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks can be selected from a peak in the range of about 7.9 degrees to about 8.3 degrees, a peak in the range of about 10.7 degrees to about 11.1 degrees, a peak in the range of about 14.5 degrees to about 14.9 degrees, a peak in the range of about 15.9 degrees to about 16.3 degrees, a peak in the range of about 16.9 degrees to about 17.3 degrees, a peak in the range of about 18 degrees to about 18.4 degrees, a peak in the range of about 19.5 degrees to about 19.9 degrees, a peak in the range of about 20 degrees to about 20.4 degrees, a peak in the range of about 21.1 degrees to about 21.5 degrees, a peak in the range of about 22.5 degrees to about 22.9 degrees, a peak in the range of about 24.8 degrees to about 25.2 degrees, and a peak in the range of about 27.7 degrees to about 28.1 degrees. In some embodiments, tosylate Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 7.9 degrees to about 8.3 degrees, a peak in the range of about 10.7 degrees to about 11.1 degrees, a peak in the range of about 12.6 degrees to about 13 degrees, a peak in the range of about 14.5 degrees to about 14.9 degrees, a peak in the range of about 15.9 degrees, ~16.3 degrees, ~16.9 degrees ~17.3 degrees, ~18 degrees ~18.4 degrees, ~19 degrees ~19.4 degrees, ~19.5 degrees ~19.9 degrees, ~20 degrees ~20.4 degrees, ~21.1 degrees ~21.5 degrees, ~22.5 degrees ~22.9 degrees, ~23.3 degrees ~ The peak is selected from a peak in the range of 23.7 degrees, a peak in the range of about 24.3 degrees to about 24.7 degrees, a peak in the range of about 24.8 degrees to about 25.2 degrees, a peak in the range of about 25.6 degrees to about 26 degrees, a peak in the range of about 27 degrees to about 27.4 degrees, a peak in the range of about 27.7 degrees to about 28.1 degrees, a peak in the range of about 28.3 degrees to about 28.7 degrees, and a peak in the range of about 30.5 degrees to about 30.9 degrees.

[0112] In some embodiments, tosylate Form A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 8.06 degrees, about 10.87 degrees, about 14.67 degrees, about 16.13 degrees, about 17.11 degrees, about 18.22 degrees, about 19.66 degrees, about 20.17 degrees, about 21.29 degrees, about 22.71 degrees, about 25.04 degrees, and about 27.94 degrees. In some embodiments, tosylate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 8.06 degrees, about 10.87 degrees, about 12.79 degrees, about 14.67 degrees, about 16.13 degrees, about 17.11 degrees, about 18.22 degrees, about 19.2 degrees, about 19.66 degrees, about 20.17 degrees, about 21.29 degrees, about 22.71 degrees, about 23.46 degrees, about 24.5 degrees, about 25.04 degrees, about 25.82 degrees, about 27.19 degrees, about 27.94 degrees, about 28.5 degrees, and about 30.73 degrees.

[0113] In some embodiments, tosylate salt Form A can exhibit an XRPD pattern as shown in FIG.

[0114] In some embodiments, tosylate Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0115] [Table 10]

[0116] Tosylate Form A can also be characterized by DSC and / or TGA. In some embodiments, tosylate Form A can be characterized by the DSC and / or TGA thermograms of Figure 19. In some embodiments, tosylate Form A can be characterized by a weight loss of about 6.6% when heated from about 27°C to about 150°C. In some embodiments, tosylate Form A can be characterized by a first endotherm in the range of about 50°C to about 58°C, a second endotherm in the range of about 109°C to about 117°C, and a third endotherm in the range of about 189°C to about 197°C. In some embodiments, tosylate Form A can be characterized by a first endotherm in the range of about 52°C to about 56°C, a second endotherm in the range of about 111°C to about 115°C, and a third endotherm in the range of about 191°C to about 195°C. In some embodiments, tosylate Form A can be characterized by a first endotherm at about 53.6°C, a second endotherm at about 113.1°C, and a third endotherm at about 193.4°C.

[0117] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, wherein the pharmaceutically acceptable salt can be a mucate salt. In some embodiments, the mucate salt form can be mucate Form A. In some embodiments, the molar ratio of mucate to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0118] Various mucate forms of Compound A can be obtained. In some embodiments, the mucate forms described herein can further comprise the free base form of Compound A. For example, mucate Form A can further comprise a small amount of free base Form A. In some embodiments, the mucate forms described herein can further comprise a small amount of one or more other mucate forms (such as those described herein).

[0119] In the salt form of Compound A, varying amounts of the mucate salt form of Compound A may be present. For example, The amount of mucate of Compound A that may be present in mucate Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of mucate of Compound A that may be present in mucate Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of mucate of Compound A that may be present in mucate Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of mucate of Compound A that may be present in mucate Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of mucate of Compound A that may be present in mucate Form A may be 90% or greater. In other embodiments, the amount of mucate of Compound A that may be present in mucate Form A may be 95% or greater. In still other embodiments, the amount of mucate of Compound A that may be present in mucate Form A may be 98% or greater. When less than 100% of the salt forms described herein are mucate salt forms of Compound A, one or more components selected from: (1) the free base of Compound A (such as those described herein), (2) compounds that are the result of decomposition of the mucate salt form of Compound A and / or decomposition of the free base of Compound A, and (3) impurities from the synthesis of the mucate salt form of Compound A and / or the synthesis of the free base of Compound A may be present in the mucate salt form of Compound A (such as mucate salt Form A of Compound A).

[0120] In some embodiments, mucate Form A may be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks may be selected from a peak in the range of about 8.3 degrees to about 8.7 degrees, a peak in the range of about 9.4 degrees to about 9.8 degrees, a peak in the range of about 12.6 degrees to about 13 degrees, a peak in the range of about 13.9 degrees to about 14.3 degrees, a peak in the range of about 16.9 degrees to about 17.3 degrees, a peak in the range of about 19.1 degrees to about 19.5 degrees, a peak in the range of about 19.5 degrees to about 19.9 degrees, a peak in the range of about 21.2 degrees to about 21.6 degrees, and a peak in the range of about 25.5 degrees to about 25.9 degrees. In some embodiments, mucate Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 4.1 degrees to about 4.5 degrees, a peak in the range of about 6.8 degrees to about 7.2 degrees, a peak in the range of about 8.3 degrees to about 8.7 degrees, a peak in the range of about 9.4 degrees to about 9.8 degrees, a peak in the range of about 9.9 degrees to about 10.3 degrees, a peak in the range of about 10.3 degrees to about 10.7 degrees, a peak in the range of about 11.1 degrees to about 11.5 degrees, a peak in the range of about 12.6 degrees to about 13 degrees, a peak in the range of about 13.9 degrees to about 14.3 degrees, or the like. The angle is selected from a peak in the range of about 16.9 degrees to about 17.3 degrees, a peak in the range of about 17.4 degrees to about 17.8 degrees, a peak in the range of about 18.6 degrees to about 19 degrees, a peak in the range of about 19.1 degrees to about 19.5 degrees, a peak in the range of about 19.5 degrees to about 19.9 degrees, a peak in the range of about 20.6 degrees to about 21 degrees, a peak in the range of about 21.2 degrees to about 21.6 degrees, a peak in the range of about 22.5 degrees to about 22.9 degrees, a peak in the range of about 25.5 degrees to about 25.9 degrees, a peak in the range of about 26.7 degrees to about 27.1 degrees, and a peak in the range of about 30.6 degrees to about 31 degrees.

[0121] In some embodiments, mucate Form A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 8.52 degrees, about 9.62 degrees, about 12.78 degrees, about 14.06 degrees, about 17.06 degrees, about 19.3 degrees, about 19.67 degrees, about 21.36 degrees, and about 25.69 degrees. In some embodiments, mucate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 4.28 degrees, about 7.04 degrees, about 8.52 degrees, about 9.62 degrees, about 10.1 degrees, about 10.53 degrees, about 11.28 degrees, about 12.78 degrees, about 14.06 degrees, about 17.06 degrees, about 17.57 degrees, about 18.78 degrees, about 19.3 degrees, about 19.67 degrees, about 20.75 degrees, about 21.36 degrees, about 22.73 degrees, about 25.69 degrees, about 26.87 degrees, and about 30.79 degrees.

[0122] In some embodiments, mucate Form A can exhibit an XRPD pattern as shown in FIG.

[0123] In some embodiments, mucate Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0124] [Table 11]

[0125] Mucate Form A can also be characterized by DSC and / or TGA. In some embodiments, mucate Form A can be characterized by the DSC and / or TGA thermograms of Figure 21. In some embodiments, mucate Form A can be characterized by a weight loss of about 7.5% when heated from about 26°C to about 150°C. In some embodiments, mucate Form A can be characterized by a first endotherm in the range of about 72°C to about 80°C, a second endotherm in the range of about 148°C to about 156°C, a third endotherm in the range of about 160°C to about 168°C, and a fourth endotherm in the range of about 167°C to about 175°C. In some embodiments, mucate Form A can be characterized by a first endotherm in the range of about 74° C. to about 78° C., a second endotherm in the range of about 150° C. to about 154° C., a third endotherm in the range of about 162° C. to about 166° C., and a fourth endotherm in the range of about 169° C. to about 173° C. ... It can be characterized by a first endotherm at about 76.2°C, a second endotherm at about 152.0°C, a third endotherm at about 163.6°C, and a fourth endotherm at about 170.8°C.

[0126] Some embodiments disclosed herein relate to a pharmaceutically acceptable salt of Compound A, wherein the pharmaceutically acceptable salt can be a hippurate salt. In some embodiments, the hippurate salt form can be hippurate form A. In some embodiments, the molar ratio of hippuric acid to Compound A can be about 0.6 to about 1.4, about 0.8 to about 1.2, about 0.9 to about 1.1, or about 1.

[0127] Various hippurate forms of Compound A can be obtained. In some embodiments, the hippurate forms described herein can further comprise the free base form of Compound A. For example, hippurate Form A can further comprise a small amount of free base Form A. In some embodiments, the hippurate forms described herein can further comprise a small amount of one or more other hippurate forms (such as those described herein).

[0128] In the salt form of Compound A, varying amounts of the hippurate form of Compound A may be present. For example, the amount of hippurate salt of Compound A that may be present in hippurate salt Form A may be in the range of about 90% to about 100%. In some embodiments, the amount of hippurate salt of Compound A that may be present in hippurate salt Form A may be in the range of about 95% to about 100%. In other embodiments, the amount of hippurate salt of Compound A that may be present in hippurate salt Form A may be in the range of about 98% to about 100%. In still other embodiments, the amount of hippurate salt of Compound A that may be present in hippurate salt Form A may be in the range of about 95% to about 98%. In some embodiments, the amount of hippurate salt of Compound A that may be present in hippurate salt Form A may be 90% or greater. In other embodiments, the amount of hippurate salt of Compound A that may be present in hippurate salt Form A may be 95% or greater. In still other embodiments, the amount of hippurate salt of Compound A that may be present in hippurate salt Form A may be 98% or greater. When less than 100% of the salt forms described herein are hippurate salts from Compound A, one or more components selected from (1) the free base of Compound A (including those described herein), (2) compounds that are the result of decomposition of the hippurate salt form of Compound A and / or the free base of Compound A, and (3) impurities from the synthesis of the hippurate salt form of Compound A and / or the synthesis of the free base of Compound A may be present in the hippurate salt form of Compound A (such as Hippurate Form A of Compound A).

[0129] In some embodiments, hippurate Form A can be characterized by one or more peaks in an XRPD pattern, and the one or more peaks can be selected from a peak in the range of about 5.5 degrees to about 5.9 degrees, a peak in the range of about 6.7 degrees to about 7.1 degrees, a peak in the range of about 7.9 degrees to about 8.3 degrees, a peak in the range of about 9.5 degrees to about 9.9 degrees, a peak in the range of about 15.9 degrees to about 16.3 degrees, a peak in the range of about 16.9 degrees to about 17.3 degrees, a peak in the range of about 18.3 degrees to about 18.7 degrees, and a peak in the range of about 22.4 degrees to about 22.8 degrees. In some embodiments, hippurate Form A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 5.5 degrees to about 5.9 degrees, a peak in the range of about 6.7 degrees to about 7.1 degrees, a peak in the range of about 7.9 degrees to about 8.3 degrees, a peak in the range of about 9.5 degrees to about 9.9 degrees, a peak in the range of about 11.2 degrees to about 11.6 degrees, a peak in the range of about 14.6 degrees to about 15 degrees, a peak in the range of about 15.9 degrees to about 16.3 degrees, a peak in the range of about 16.9 degrees to about 17.3 degrees, or the like. a peak in the range of about 18.3 degrees to about 18.7 degrees, a peak in the range of about 20.4 degrees to about 20.8 degrees, a peak in the range of about 21.2 degrees to about 21.6 degrees, a peak in the range of about 21.7 degrees to about 22.1 degrees, a peak in the range of about 22.4 degrees to about 22.8 degrees, a peak in the range of about 22.7 degrees to about 23.1 degrees, a peak in the range of about 23 degrees to about 23.4 degrees, a peak in the range of about 23.2 degrees to about 23.6 degrees, a peak in the range of about 23.6 degrees to about 24 degrees, and a peak in the range of about 24.1 degrees to about 24.5 degrees.

[0130] In some embodiments, hippurate Form A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 5.69 degrees, about 6.85 degrees, about 8.05 degrees, about 9.69 degrees, about 16.12 degrees, about 17.1 degrees, about 18.53 degrees, and about 22.6 degrees. In some embodiments, hippurate Form A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks are selected from about 5.69 degrees, about 6.85 degrees, about 8.05 degrees, about 9.69 degrees, about 11.38 degrees, about 14.83 degrees, about 16.12 degrees, about 17.1 degrees, about 18.53 degrees, about 20.64 degrees, about 21.35 degrees, about 21.87 degrees, about 22.6 degrees, about 22.85 degrees, about 23.22 degrees, about 23.39 degrees, about 23.81 degrees, and about 24.27 degrees.

[0131] In some embodiments, hippurate Form A can exhibit an XRPD pattern as shown in FIG.

[0132] In some embodiments, hippurate Form A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0133] [Table 12]

[0134] Hippurate Form A can also be characterized by DSC and / or TGA. In some embodiments, hippurate Form A can be characterized by the DSC and / or TGA thermograms of Figure 23. In some embodiments, hippurate Form A can be characterized by a weight loss of about 7.7% when heated from about 29°C to about 150°C. In some embodiments, hippurate Form A can be characterized by a weight loss of about 7.7% when heated from about 99°C to about 107°C. and a second endotherm in the range of about 127°C to about 135°C. In some embodiments, hippurate Form A can be characterized by a first endotherm in the range of about 101°C to about 105°C and a second endotherm in the range of about 129°C to about 161°C. In some embodiments, hippurate Form A can be characterized by a first endotherm at about 103.0°C and a second endotherm at about 130.9°C.

[0135] Free base Form A of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, free base Form A of Compound A can be characterized by one or more peaks in an XRPD pattern, where the one or more peaks can be selected from a peak in the range of about 4.7 degrees to about 5.1 degrees, a peak in the range of about 5 degrees to about 5.4 degrees, and a peak in the range of about 5.3 degrees to about 5.7 degrees. In some embodiments, free base Form A of Compound A can be characterized by one or more peaks in an XRPD pattern, where the one or more peaks can be selected from a peak in the range of about 4.7 degrees to about 5.1 degrees, a peak in the range of about 5 degrees to about 5.4 degrees, a peak in the range of about 5.3 degrees to about 5.7 degrees, and a peak in the range of about 10.3 degrees to about 10.7 degrees.

[0136] In some embodiments, the free base Form A of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 4.92 degrees, about 5.24 degrees, and about 5.51 degrees. In some embodiments, the free base Form A of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 4.92 degrees, about 5.24 degrees, about 5.51 degrees, and about 10.45 degrees.

[0137] In some embodiments, the free base Form A of Compound A can exhibit an XRPD pattern as shown in Figure 24. In some embodiments, the free base Form A of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0138] [Table 13]

[0139] In some embodiments, the free base Form A of Compound A can be characterized by a DSC and / or TGA thermogram. In some embodiments, the free base Form A of Compound A can be characterized by a weight loss of about 2.4% when heated from about 30° C. to about 150° C. In some embodiments, the free base Form A of Compound A can exhibit a first endotherm in the range of about 116° C. to about 124° C. and a second endotherm in the range of about 162° C. to about 170° C. In some embodiments, free base Form A of Compound A can be characterized by a first endotherm in the range of about 118°C to about 122°C and a second endotherm in the range of about 164°C to about 168°C. In some embodiments, free base Form A of Compound A can be characterized by a first endotherm at about 120.0°C and a second endotherm at about 165.9°C. In some embodiments, free base Form A of Compound A can have the DSC and / or TGA thermogram of Figure 25.

[0140] The free base form B of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, the free base form B of Compound A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks can be selected from a peak in the range of about 5.2 degrees to about 5.6 degrees, a peak in the range of about 9.3 degrees to about 9.7 degrees, a peak in the range of about 11.5 degrees to about 11.9 degrees, a peak in the range of about 12 degrees to about 12.4 degrees, a peak in the range of about 14 degrees to about 14.4 degrees, a peak in the range of about 16.2 degrees to about 16.6 degrees, a peak in the range of about 16.9 degrees to about 17.3 degrees, a peak in the range of about 17.9 degrees to about 18.3 degrees, a peak in the range of about 19.8 degrees to about 20.2 degrees, a peak in the range of about 20.9 degrees to about 21.3 degrees, a peak in the range of about 24.2 degrees to about 24.6 degrees, and a peak in the range of about 24.7 degrees to about 25.1 degrees. In some embodiments, the free base form B of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being selected from the group consisting of a peak in the range of about 5.2 degrees to about 5.6 degrees, a peak in the range of about 9.3 degrees to about 9.7 degrees, a peak in the range of about 10.5 degrees to about 10.9 degrees, a peak in the range of about 11.1 degrees to about 11.5 degrees, a peak in the range of about 11.5 degrees to about 11.9 degrees, a peak in the range of about 12 degrees to about 12.4 degrees, a peak in the range of about 13.5 degrees to about 13.9 degrees, a peak in the range of about 14 degrees to about 14.4 degrees, a peak in the range of about 14.8 degrees to about 15.2 degrees, and a peak in the range of about 16.2 degrees to about 16.6 degrees. The angle can be selected from a peak in the range of about 16.9 degrees to about 17.3 degrees, a peak in the range of about 17.9 degrees to about 18.3 degrees, a peak in the range of about 18.5 degrees to about 18.9 degrees, a peak in the range of about 18.9 degrees to about 19.3 degrees, a peak in the range of about 19.3 degrees to about 19.7 degrees, a peak in the range of about 19.8 degrees to about 20.2 degrees, a peak in the range of about 20.9 degrees to about 21.3 degrees, a peak in the range of about 21.8 degrees to about 22.2 degrees, a peak in the range of about 23.6 degrees to about 24 degrees, a peak in the range of about 24.2 degrees to about 24.6 degrees, a peak in the range of about 24.7 degrees to about 25.1 degrees, and a peak in the range of about 26.5 degrees to about 26.9 degrees.

[0141] In some embodiments, the free base form B of Compound A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 5.44 degrees, about 9.52 degrees, about 11.72 degrees, about 12.23 degrees, about 14.17 degrees, about 16.42 degrees, about 17.1 degrees, about 18.14 degrees, about 20.02 degrees, about 21.09 degrees, about 24.39 degrees, and about 24.86 degrees. In some embodiments, the free base form B of compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 5.44 degrees, about 9.52 degrees, about 10.73 degrees, about 11.28 degrees, about 11.72 degrees, about 12.23 degrees, about 13.65 degrees, about 14.17 degrees, about 15 degrees, about 16.42 degrees, about 17.1 degrees, about 18.14 degrees, about 18.66 degrees, about 19.14 degrees, about 19.52 degrees, about 20.02 degrees, about 21.09 degrees, about 21.97 degrees, about 23.84 degrees, about 24.39 degrees, about 24.86 degrees, and about 26.65 degrees.

[0142] In some embodiments, the free base form B of Compound A can exhibit an XRPD pattern as shown in Figure 26. In some embodiments, the free base form B of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0143] [Table 14]

[0144] Free base Form C of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, free base Form C of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 4.8 degrees to about 5.2 degrees, a peak in the range of about 10.1 degrees to about 10.5 degrees, a peak in the range of about 11.1 degrees to about 11.5 degrees, a peak in the range of about 11.6 degrees to about 12 degrees, a peak in the range of about 12.3 degrees to about 12.7 degrees, a peak in the range of about 13.5 degrees to about 13.9 degrees, or a peak in the range of about 14.8 degrees to about 14.9 degrees. The angle can be selected from a peak in the range of about 14.4 degrees to about 14.8 degrees, a peak in the range of about 14.7 degrees to about 15.1 degrees, a peak in the range of about 15.7 degrees to about 16.1 degrees, a peak in the range of about 16.2 degrees to about 16.6 degrees, a peak in the range of about 17.9 degrees to about 18.3 degrees, a peak in the range of about 18.7 degrees to about 19.1 degrees, a peak in the range of about 21.1 degrees to about 21.5 degrees, and a peak in the range of about 21.5 degrees to about 21.9 degrees. In some embodiments, the free base Form C of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 4.8 degrees to about 5.2 degrees, a peak in the range of about 6.1 degrees to about 6.5 degrees, a peak in the range of about 7.7 degrees to about 8.1 degrees, a peak in the range of about 8.6 degrees to about 9 degrees, a peak in the range of about 10.1 degrees to about 10.5 degrees, a peak in the range of about 11.1 degrees to about 11.5 degrees, a peak in the range of about 11.6 degrees to about 12 degrees, or the like. , a peak in the range of about 11.9 degrees to about 12.3 degrees, a peak in the range of about 12.3 degrees to about 12.7 degrees, a peak in the range of about 12.6 degrees to about 13 degrees, a peak in the range of about 13.5 degrees to about 13.9 degrees, a peak in the range of about 14.4 degrees to about 14.8 degrees, a peak in the range of about 14.7 degrees to about 15.1 degrees, a peak in the range of about 15.7 degrees to about 16.1 degrees, a peak in the range of about 16.2 degrees to about 16.6 degrees, a peak in the range of about 17.5 degrees to about 17.9 degrees, a peak in the range of about 17.9 degrees to about 18.3 degrees The angle can be selected from a peak in the range of about 18.7 degrees to about 19.1 degrees, a peak in the range of about 19.5 degrees to about 19.9 degrees, a peak in the range of about 19.7 degrees to about 20.1 degrees, a peak in the range of about 20.6 degrees to about 21 degrees, a peak in the range of about 21.1 degrees to about 21.5 degrees, a peak in the range of about 21.5 degrees to about 21.9 degrees, a peak in the range of about 24.3 degrees to about 24.7 degrees, a peak in the range of about 25.4 degrees to about 25.8 degrees, and a peak in the range of about 26.9 degrees to about 27.3 degrees.

[0145] In some embodiments, the free base Form C of Compound A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 5.01 degrees, about 10.32 degrees, about 11.25 degrees, about 11.83 degrees, about 12.46 degrees, about 13.73 degrees, about 14.57 degrees, about 14.92 degrees, about 15.87 degrees, about 16.37 degrees, about 18.06 degrees, about 18.87 degrees, about 21.25 degrees, and about 21.65 degrees. In some embodiments, the free base Form C of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 5.01 degrees, about 6.28 degrees, about 7.92 degrees, about 8.81 degrees, about 10.32 degrees, about 11.25 degrees, about 11.83 degrees, about 12.09 degrees, about 12.46 degrees, about 12.75 degrees, about 13.73 degrees, about 14.57 degrees, about 14.92 degrees, about 15.87 degrees, about 16.37 degrees, about 17.67 degrees, about 18.06 degrees, about 18.87 degrees, about 19.68 degrees, about 19.91 degrees, about 20.82 degrees, about 21.25 degrees, about 21.65 degrees, about 24.5 degrees, about 25.62 degrees, and about 27.11 degrees.

[0146] In some embodiments, the free base form C of Compound A can exhibit an XRPD pattern as shown in Figure 27. In some embodiments, the free base form C of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0147] [Table 15]

[0148] In some embodiments, the free base form C of Compound A can be characterized by a DSC and / or TGA thermogram. In some embodiments, the free base form C of Compound A can be characterized by a weight loss of about 3.7% when heated from about 28°C to about 150°C. In some embodiments, the free base form C of Compound A can be characterized by a first endotherm in the range of about 149°C to about 157°C and a second endotherm in the range of about 162°C to about 170°C. In some embodiments, the free base form C of Compound A can be characterized by a first endotherm in the range of about 151°C to about 155°C and a second endotherm in the range of about 164°C to about 168°C. In some embodiments, the free base form C of Compound A can be characterized by a first endotherm at about 153.1°C and a second endotherm at about 165.9°C.

[0149] In other embodiments, the free base form C of Compound A can be characterized by a first endotherm in the range of about 147°C to about 155°C and a second endotherm in the range of about 161°C to about 169°C. In some embodiments, the free base form C of Compound A can be characterized by a first endotherm in the range of about 149°C to about 153°C and a second endotherm in the range of about 163°C to about 166°C. In some embodiments, the free base form C of Compound A can be characterized by a first endotherm at about 150.9°C and a second endotherm at about 164.6°C. In some embodiments, the free base form C of Compound A can be characterized by the DSC and / or NMR spectra of Figure 28. Or it may have a TGA thermogram.

[0150] Free base Form D of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, free base Form D of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 4.2 degrees to about 4.6 degrees, a peak in the range of about 4.4 degrees to about 4.8 degrees, a peak in the range of about 4.7 degrees to about 5.1 degrees, a peak in the range of about 8.5 degrees to about 8.9 degrees, a peak in the range of about 9 degrees to about 9.4 degrees, a peak in the range of about 9.7 degrees to about 10.1 degrees, a peak in the range of about 10.2 degrees to about 10.6 degrees, or a peak in the range of about 11.2 degrees to about 11.6 degrees. The angle can be selected from a peak in the range of about 11.5 degrees to about 11.9 degrees, a peak in the range of about 12 degrees to about 12.4 degrees, a peak in the range of about 14.8 degrees to about 15.2 degrees, a peak in the range of about 15.6 degrees to about 16 degrees, a peak in the range of about 16.3 degrees to about 16.7 degrees, a peak in the range of about 17.3 degrees to about 17.7 degrees, a peak in the range of about 17.6 degrees to about 18 degrees, a peak in the range of about 18.4 degrees to about 18.8 degrees, and a peak in the range of about 20 degrees to about 20.4 degrees. In some embodiments, the free base form D of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 3.8 degrees to about 4.2 degrees, a peak in the range of about 4.2 degrees to about 4.6 degrees, a peak in the range of about 4.4 degrees to about 4.8 degrees, a peak in the range of about 4.7 degrees to about 5.1 degrees, a peak in the range of about 5.5 degrees to about 5.9 degrees, a peak in the range of about 6.5 degrees to about 6.9 degrees, a peak in the range of about 8.5 degrees to about 8.9 degrees, a peak in the range of about 9 degrees to about 9.4 degrees, a peak in the range of about 9.7 degrees to about 10.1 degrees, a peak in the range of about 10.2 degrees to about 10.3 degrees, a peak in the range of about 10.4 degrees to about 10.5 degrees, a peak in the range of about 10.6 degrees to about 10.7 degrees, a peak in the range of about 10.8 degrees to about 10.9 degrees, a peak in the range of about 10.9 degrees to about 11.1 degrees, a peak in the range of about 11.5 degrees to about 11.6 degrees, a peak in the range of about 11.7 degrees to about 11.8 degrees, a peak in the range of about 11.8 degrees to about 11.9 degrees, a peak in the range of about 11.9 degrees to about 12.1 degrees, a peak in the range of about 12.1 degrees to about 12.2 degrees, a peak in the range of about 12.2 degrees to about 12.3 degrees, a peak in the range of about 12.3 degrees to about 12.4 degrees, a peak in the range of about 12.5 degrees to about 12.6 degrees, a peak in the range of about 12. The angle can be selected from a peak in the range of about 10.6 degrees to about 10.6 degrees, a peak in the range of about 11.5 degrees to about 11.9 degrees, a peak in the range of about 12 degrees to about 12.4 degrees, a peak in the range of about 13.2 degrees to about 13.6 degrees, a peak in the range of about 14.3 degrees to about 14.7 degrees, a peak in the range of about 14.8 degrees to about 15.2 degrees, a peak in the range of about 15.6 degrees to about 16 degrees, a peak in the range of about 16.3 degrees to about 16.7 degrees, a peak in the range of about 17.3 degrees to about 17.7 degrees, a peak in the range of about 17.6 degrees to about 18 degrees, a peak in the range of about 18.4 degrees to about 18.8 degrees, and a peak in the range of about 20 degrees to about 20.4 degrees.

[0151] In some embodiments, the free base form D of compound A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 4.37 degrees, about 4.57 degrees, about 4.93 degrees, about 8.65 degrees, about 9.21 degrees, about 9.94 degrees, about 10.35 degrees, about 11.71 degrees, about 12.2 degrees, about 14.96 degrees, about 15.75 degrees, about 16.45 degrees, about 17.46 degrees, about 17.8 degrees, about 18.62 degrees, and about 20.21 degrees. In some embodiments, the free base form D of compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 4.02 degrees, about 4.37 degrees, about 4.57 degrees, about 4.93 degrees, about 5.74 degrees, about 6.67 degrees, about 8.65 degrees, about 9.21 degrees, about 9.94 degrees, about 10.35 degrees, about 11.71 degrees, about 12.2 degrees, about 13.4 degrees, about 14.5 degrees, about 14.96 degrees, about 15.75 degrees, about 16.45 degrees, about 17.46 degrees, about 17.8 degrees, about 18.62 degrees, and about 20.21 degrees.

[0152] In some embodiments, the free base form D of Compound A can exhibit an XRPD pattern as shown in Figure 29. In some embodiments, the free base form D of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0153] [Table 16]

[0154] In some embodiments, Compound A free base Form D can be characterized by a DSC and / or TGA thermogram. In some embodiments, Compound A free base Form D can be characterized by a weight loss of about 5.8% when heated from about 28° C. to about 150° C. In some embodiments, Compound A free base Form D can be characterized by a first endotherm in the range of about 118° C. to about 126° C. and a second endotherm in the range of about 161° C. to about 169° C. In some embodiments, Compound A free base Form D can be characterized by a first endotherm in the range of about 120° C. to about 124° C. and a second endotherm in the range of about 163° C. to about 167° C. In some embodiments, Compound A free base Form D can be characterized by a first endotherm at about 121.6° C. and a second endotherm at about 165.1° C. In some embodiments, Compound A free base Form D can have the DSC and / or TGA thermogram of FIG. 30.

[0155] Free base Form E of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, free base Form E of Compound A can be characterized by one or more peaks in an XRPD pattern, where the one or more peaks can be selected from a peak in the range of about 6.0 degrees to about 6.3 degrees, a peak in the range of about 10.5 degrees to about 10.8 degrees, a peak in the range of about 12.0 degrees to about 12.3 degrees, a peak in the range of about 12.2 degrees to about 12.5 degrees, a peak in the range of about 15.1 degrees to about 15.4 degrees, a peak in the range of about 18.8 degrees to about 19.1 degrees, a peak in the range of about 21.5 degrees to about 21.8 degrees, a peak in the range of about 22.5 degrees to about 22.8 degrees, and a peak in the range of about 27.3 degrees to about 27.6 degrees ... The one or more peaks may be characterized by one or more peaks in the range of about 6.0 degrees to about 6.3 degrees, a peak in the range of about 9.8 degrees to about 10.1 degrees, a peak in the range of about 10.5 degrees to about 10.8 degrees, a peak in the range of about 11.1 degrees to about 11.4 degrees, a peak in the range of about 12.0 degrees to about 12.3 degrees, a peak in the range of about 12.2 degrees to about 12.5 degrees, a peak in the range of about 13.0 degrees to about 13.1 degrees, a peak in the range of about 14.0 degrees to about 14.2 degrees, a peak in the range of about 15.0 degrees to about 15.3 degrees, a peak in the range of about 16.0 degrees to about 16.3 degrees, a peak in the range of about 17.0 degrees to about 17.4 degrees, a peak in the range of about 18.0 degrees to about 18.5 degrees, a peak in the range of about 19.0 degrees to about 20.0 degrees, a peak in the range of about 21.0 degrees to about 21.1 degrees, a peak in the range of about 22.0 degrees to about 22.3 degrees, a peak in the range of about 23.0 degrees to about 23.1 degrees, a peak in the range of about 24.0 degrees to about 24.2 degrees, a peak in the range of about 25.0 degrees to about 26.0 degrees, a peak in the range of about 26.0 degrees to about 27.0 degrees, a peak in the range of about 27.0 degrees to about 28.0 degrees, a peak in the range of about 28.0 degrees to about 29.0 degrees, a peak in the range of about 29.0 degrees to about 30.0 degrees, a peak in the range of about 30.0 degrees to about 3 Peaks in the range of 3.8 degrees to approximately 14.1 degrees, peaks in the range of approximately 15.1 degrees to approximately 15.4 degrees, peaks in the range of approximately 16.3 degrees to approximately 16.6 degrees, peaks in the range of approximately 17.0 degrees to approximately 17.3 degrees, peaks in the range of approximately 18.0 degrees to approximately 18.3 degrees, peaks in the range of approximately 18.3 degrees to approximately 18.6 degrees, peaks in the range of approximately 18.8 degrees to approximately 19.1 degrees, peaks in the range of approximately 19.2 degrees to approximately 19.5 degrees Peaks in the range of about 19.6 degrees to about 19.9 degrees, peaks in the range of about 20.2 degrees to about 20.5 degrees, peaks in the range of about 21.5 degrees to about 21.8 degrees, peaks in the range of about 21.9 degrees to about 22.2 degrees, peaks in the range of about 22.5 degrees to about 22.8 degrees, peaks in the range of about 23.6 degrees to about 23.9 degrees, peaks in the range of about 24.5 degrees to about 24.8 degrees, peaks in the range of about 25.1 degrees to about 25.4 degrees The angle can be selected from a peak in the range of about 25.5 degrees to about 25.8 degrees, a peak in the range of about 27.3 degrees to about 27.6 degrees, a peak in the range of about 29.1 degrees to about 29.4 degrees, a peak in the range of about 29.7 degrees to about 30.0 degrees, a peak in the range of about 30.0 degrees to about 30.3 degrees, a peak in the range of about 30.5 degrees to about 30.8 degrees, and a peak in the range of about 31.4 degrees to about 31.7 degrees.

[0156] In some embodiments, the free base form E of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 6.20 degrees, about 10.63 degrees, about 12.17 degrees, about 12.40 degrees, about 15.22 degrees, about 18.96 degrees, about 21.63 degrees, about 22.62 degrees, and about 27.43 degrees. In some embodiments, the free base form E of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 6.20 degrees, about 9.94 degrees, about 10.63 degrees, about 11.26 degrees, about 12.17 degrees, about 12.40 degrees, about 13.92 degrees, about 15.22 degrees, about 16.41 degrees, about 17.19 degrees, about 18. You can choose from 19 degrees, approximately 18.39, approximately 18.96 degrees, approximately 19.32 degrees, approximately 19.76 degrees, approximately 20.38 degrees, approximately 21.63 degrees, approximately 22.09 degrees, approximately 22.62 degrees, approximately 23.75 degrees, approximately 24.66 degrees, approximately 25.30 degrees, approximately 25.59 degrees, approximately 27.43 degrees, approximately 29.22 degrees, approximately 29.89 degrees, approximately 30.17 degrees, approximately 30.69 degrees and approximately 31.53 degrees.

[0157] In some embodiments, the free base form E of Compound A can exhibit an XRPD pattern as shown in Figure 31. In some embodiments, the free base form E of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0158] [Table 17]

[0159] In some embodiments, the free base form E of Compound A can be characterized by a DSC and / or TGA thermogram. In some embodiments, the free base form E of Compound A can be characterized by a weight loss of about 3.8% when heated from about 28°C to about 150°C. In some embodiments, the free base form E of Compound A can be characterized by an endotherm in the range of about 105°C to about 125°C. In some embodiments, the free base form E of Compound A can be characterized by an endotherm in the range of about 110°C to about 118°C. In some embodiments, the free base form E of Compound A can be characterized by an endotherm at about 115.2°C. In some embodiments, the free base form E of Compound A can have the DSC and / or TGA thermogram of Figure 32.

[0160] In some embodiments, the free base form E of Compound A can be obtained by solution crystallization and can be characterized by an endotherm at about 114.3° C. The purity of such a compound is about 99.6%. In some embodiments, the free base form E of Compound A can be a hydrate.

[0161] The free base form F of Compound A can also be prepared by various methods, such as those described herein. In some embodiments, the free base form F of Compound A can be characterized by one or more peaks in an XRPD pattern, wherein the one or more peaks can be selected from a peak in the range of about 4.9 degrees to about 5.3 degrees, a peak in the range of about 6 degrees to about 6.4 degrees, a peak in the range of about 10 degrees to about 10.4 degrees, a peak in the range of about 12.2 degrees to about 12.6 degrees, and a peak in the range of about 19 degrees to about 19.4 degrees. In some embodiments, the free base form F of Compound A can be characterized by one or more peaks in an XRPD pattern, and the one or more peaks can be selected from a peak in the range of about 4.9 degrees to about 5.3 degrees, a peak in the range of about 6 degrees to about 6.4 degrees, a peak in the range of about 10 degrees to about 10.4 degrees, a peak in the range of about 12.2 degrees to about 12.6 degrees, a peak in the range of about 12.9 degrees to about 13.3 degrees, a peak in the range of about 16.4 degrees to about 16.8 degrees, and a peak in the range of about 19 degrees to about 19.4 degrees.

[0162] In some embodiments, the free base form F of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 5.14 degrees, about 6.24 degrees, about 10.19 degrees, about 12.4 degrees, and about 19.15 degrees. In some embodiments, the free base form F of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 5.14 degrees, about 6.24 degrees, about 10.19 degrees, about 12.4 degrees, about 13.11 degrees, about 16.58 degrees, and about 19.15 degrees.

[0163] In some embodiments, the free base form F of Compound A can exhibit an XRPD pattern as shown in Figure 33. In some embodiments, the free base form F of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0164] [Table 18]

[0165] In some embodiments, the free base form F of Compound A can be characterized by a DSC and / or TGA thermogram. In some embodiments, the free base form F of Compound A can be characterized by a weight loss of about 0.9% when heated from about 22° C. to about 150° C. In some embodiments, the free base form F of Compound A can be characterized by an endotherm in the range of about 163° C. to about 171° C. In some embodiments, the free base form F of Compound A can be characterized by an endotherm in the range of about 165° C. to about 169° C. In some embodiments, the free base form F of Compound A can be characterized by an endotherm at about 166.5° C. In some embodiments, the free base form F of Compound A can have the DSC and / or TGA thermogram of FIG. 34.

[0166] Free base Form G of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, free base Form G of Compound A can be characterized by one or more peaks in an XRPD pattern, and the one or more peaks can be selected from a peak in the range of about 3.1 degrees to about 3.5 degrees, a peak in the range of about 5 degrees to about 5.4 degrees, a peak in the range of about 11.2 degrees to about 11.6 degrees, and a peak in the range of about 16.3 degrees to about 16.7 degrees. In some embodiments, the free base form G of Compound A can be characterized by one or more peaks in an XRPD pattern, and the one or more peaks can be selected from a peak in the range of about 3.1 degrees to about 3.5 degrees, a peak in the range of about 5 degrees to about 5.4 degrees, a peak in the range of about 9.3 degrees to about 9.7 degrees, a peak in the range of about 11.2 degrees to about 11.6 degrees, a peak in the range of about 12 degrees to about 12.4 degrees, a peak in the range of about 14.6 degrees to about 15 degrees, a peak in the range of about 14.9 degrees to about 15.3 degrees, a peak in the range of about 15.2 degrees to about 15.6 degrees, a peak in the range of about 16.3 degrees to about 16.7 degrees, a peak in the range of about 18.7 degrees to about 19.1 degrees, and a peak in the range of about 22.2 degrees to about 22.6 degrees.

[0167] In some embodiments, the free base form G of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 3.32 degrees, about 5.17 degrees, about 11.35 degrees, and about 16.46 degrees. In some embodiments, the free base form G of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 3.32 degrees, about 5.17 degrees, about 9.46 degrees, about 11.35 degrees, about 12.22 degrees, about 14.83 degrees, about 15.09 degrees, about 15.36 degrees, about 16.46 degrees, about 18.88 degrees, and about 22.43 degrees.

[0168] In some embodiments, the free base form G of Compound A can exhibit an XRPD pattern as shown in Figure 35. In some embodiments, the free base form G of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0169] [Table 19]

[0170] In some embodiments, the free base form G of Compound A can be characterized by a DSC and / or TGA thermogram. In some embodiments, the free base form G of Compound A can be characterized by a weight loss of about 6.7% when heated from about 29°C to about 150°C. In some embodiments, the free base form G of Compound A can be characterized by a first endotherm in the range of about 64°C to about 72°C, a second endotherm in the range of about 87°C to about 95°C, a third endotherm in the range of about 101°C to about 109°C, and a fourth endotherm in the range of about 164°C to about 171°C. In some embodiments, the free base form G of Compound A can be characterized by a first endotherm in the range of about 66°C to about 70°C, a second endotherm in the range of about 89°C to about 93°C, a third endotherm in the range of about 103°C to about 107°C, and a fourth endotherm in the range of about 166°C to about 169°C. In some embodiments, the free base form G of Compound A can be characterized by a first endotherm at about 67.7° C., a second endotherm at about 91.0° C., a third endotherm at about 104.6° C., and a fourth endotherm at about 167.6° C. In some embodiments, the free base form G of Compound A can have the DSC and / or TGA thermogram of FIG.

[0171] In other embodiments, the free base form G of Compound A can be characterized by a first endotherm in the range of about 59° C. to about 67° C., a second endotherm in the range of about 104° C. to about 112° C., a third endotherm in the range of about 117° C. to about 125° C., and a fourth endotherm in the range of about 164° C. to about 171° C. In some embodiments, the free base form G of Compound A can be characterized by a first endotherm in the range of about 61° C. to about 65° C., a second endotherm in the range of about 106° C. to about 110° C., a third endotherm in the range of about 119° C. to about 123° C., and a fourth endotherm in the range of about 166° C. to about 169° C. In some embodiments, the free base form G of Compound A can be characterized by a first endotherm at about 63.2°C, a second endotherm at about 108.0°C, a third endotherm at about 120.7°C, and a fourth endotherm at about 167.6°C.

[0172] The free base form H of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, the free base form H of Compound A can be characterized by one or more peaks in an XRPD pattern, and one The above peaks can be selected from a peak in the range of about 4.6 degrees to about 5 degrees, a peak in the range of about 5 degrees to about 5.4 degrees, a peak in the range of about 10.2 degrees to about 10.6 degrees, a peak in the range of about 10.7 degrees to about 11.1 degrees, and a peak in the range of about 17.5 degrees to about 17.9 degrees.

[0173] In some embodiments, the free base form H of Compound A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 4.84 degrees, about 5.24 degrees, about 10.4 degrees, about 10.87 degrees, and about 17.73 degrees.

[0174] In some embodiments, the free base form H of Compound A can exhibit an XRPD pattern as shown in Figure 37. In some embodiments, the free base form H of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following:

[0175] [Table 20]

[0176] In some embodiments, the free base form H of Compound A can be characterized by a DSC and / or TGA thermogram. In some embodiments, the free base form H of Compound A can be characterized by a weight loss of about 0.9% when heated from about 29°C to about 150°C. In some embodiments, the free base form H of Compound A can be characterized by a first endotherm in the range of about 134°C to about 142°C, a second endotherm in the range of about 157°C to about 165°C, and a third endotherm in the range of about 164°C to about 172°C. In some embodiments, the free base form H of Compound A can be characterized by a first endotherm in the range of about 136°C to about 140°C, a second endotherm in the range of about 159°C to about 163°C, and a third endotherm in the range of about 166°C to about 170°C. In some embodiments, the free base form H of Compound A can be characterized by a first endotherm at about 137.5° C., a second endotherm at about 161.4° C., and a third endotherm at about 167.5° C. In some embodiments, the free base form H of Compound A can have the DSC and / or TGA thermogram of FIG.

[0177] In other embodiments, the free base form H of Compound A can be characterized by a first endotherm in the range of about 133° C. to about 141° C., a second endotherm in the range of about 155° C. to about 163° C., and a third endotherm in the range of about 162° C. to about 170° C. In some embodiments, the free base form H of Compound A can be characterized by a first endotherm in the range of about 135° C. to about 139° C., a second endotherm in the range of about 157° C. to about 161° C., and a third endotherm in the range of about 164° C. to about 168° C. In some embodiments, the free base form H of Compound A can be characterized by a first endotherm at about 137.2°C, a second endotherm at about 158.9°C, and a third endotherm at about 166.2°C.

[0178] Free base Form I of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, free base Form I of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 6.5 degrees to about 6.9 degrees, a peak in the range of about 10.4 degrees to about 10.8 degrees, a peak in the range of about 10.7 degrees to about 11.1 degrees, a peak in the range of about 13.3 degrees to about 13.7 degrees, a peak in the range of about 13.8 degrees to about 14.2 degrees, a peak in the range of about 14.6 degrees to about 15 degrees, or the like. The angle can be selected from a peak in the range of about 15.2 degrees to about 15.6 degrees, a peak in the range of about 15.4 degrees to about 15.8 degrees, a peak in the range of about 16.8 degrees to about 17.2 degrees, a peak in the range of about 19.1 degrees to about 19.5 degrees, a peak in the range of about 20 degrees to about 20.4 degrees, a peak in the range of about 21.3 degrees to about 21.7 degrees, a peak in the range of about 21.6 degrees to about 22 degrees, a peak in the range of about 24.9 degrees to about 25.3 degrees, and a peak in the range of about 28 degrees to about 28.4 degrees.In some embodiments, the free base Form I of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being selected from the group consisting of a peak in the range of about 4.8 degrees to about 5.2 degrees, a peak in the range of about 6.5 degrees to about 6.9 degrees, a peak in the range of about 9.6 degrees to about 10 degrees, a peak in the range of about 10.4 degrees to about 10.8 degrees, a peak in the range of about 10.7 degrees to about 11.1 degrees, a peak in the range of about 13.3 degrees to about 13.7 degrees, a peak in the range of about 13.8 degrees to about 14.2 degrees, a peak in the range of about 14.6 degrees to about 15 degrees, a peak in the range of about 15.2 degrees to about 15.6 degrees, a peak in the range of about 15.4 degrees to about 15.8 degrees, a peak in the range of about 16.8 degrees to 17.2 degrees, a peak in the range of about 19.1 degrees to 19.5 degrees, a peak in the range of about 19.6 degrees to 20 degrees, and the like. Peaks in the range of about 20 degrees to 20.4 degrees, peaks in the range of about 20.7 degrees to 21.1 degrees, peaks in the range of about 21.3 degrees to 21.7 degrees, peaks in the range of about 21.6 degrees to 22 degrees, peaks in the range of about 23.5 degrees to 23.9 degrees, peaks in the range of about 24.5 degrees to 24.9 degrees, peaks in the range of about 24.9 degrees to 25.3 degrees, peaks in the range of about 25.4 degrees to 25. The angle can be selected from a peak in the range of about 25.8 degrees to about 26.2 degrees, a peak in the range of about 27.4 degrees to about 27.8 degrees, a peak in the range of about 28 degrees to about 28.4 degrees, a peak in the range of about 28.5 degrees to about 28.9 degrees, a peak in the range of about 29.6 degrees to about 30 degrees, a peak in the range of about 30.8 degrees to about 31.2 degrees, and a peak in the range of about 33.2 degrees to about 33.6 degrees.

[0179] In some embodiments, the free base Form I of Compound A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 6.73 degrees, about 10.59 degrees, about 10.85 degrees, about 13.46 degrees, about 13.98 degrees, about 14.77 degrees, about 15.44 degrees, about 15.56 degrees, about 17.01 degrees, about 19.26 degrees, about 20.22 degrees, about 21.47 degrees, about 21.76 degrees, about 25.11 degrees, and about 28.16 degrees. In some embodiments, the free base Form I of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks are at about 4.95 degrees, about 6.73 degrees, about 9.84 degrees, about 10.59 degrees, about 10.85 degrees, about 13.46 degrees, about 13.98 degrees, about 14.77 degrees, about 15.44 degrees, about 15.56 degrees, or about 16.99 degrees. , approximately 17.01 degrees, approximately 19.26 degrees, approximately 19.8 degrees, approximately 20.22 degrees, approximately 20.92 degrees, approximately 21.47 degrees, approximately 21.76 degrees, approximately 23.7 degrees, approximately 24.73 degrees, approximately 25.11 degrees, approximately 25.62 degrees, approximately 25.95 degrees, approximately 27.6 degrees, approximately 28.16 degrees, approximately 28.71 degrees, approximately 29.77 degrees, approximately 30.99 degrees and approximately 33.37 degrees.

[0180] In some embodiments, the free base Form I of Compound A can exhibit an XRPD pattern as shown in Figure 39. In some embodiments, the free base Form I of Compound A can be characterized by one or more peaks in an XRPD pattern selected from the following: It is possible.

[0181] [Table 21]

[0182] Free base Form J of Compound A can also be characterized by various methods, such as those described herein. In some embodiments, free base Form J of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks can be selected from a peak in the range of about 5.9 degrees to about 6.2 degrees, a peak in the range of about 10.4 degrees to about 10.7 degrees, a peak in the range of about 11.5 degrees to about 11.8 degrees, a peak in the range of about 15.1 degrees to about 15.4 degrees, a peak in the range of about 19.3 degrees to about 19.6 degrees, a peak in the range of about 21.8 degrees to about 22.1 degrees, a peak in the range of about 23.1 degrees to about 23.4 degrees, and a peak in the range of about 25.3 degrees to about 25.6 degrees. In some embodiments, the free base form J of Compound A can be characterized by one or more peaks in an XRPD pattern, the one or more peaks being a peak in the range of about 5.9 degrees to about 6.2 degrees, a peak in the range of about 9.5 degrees to about 9.8 degrees, a peak in the range of about 10.4 degrees to about 10.7 degrees, a peak in the range of about 11.0 degrees to about 11.3 degrees, a peak in the range of about 11.5 degrees to about 11.8 degrees, a peak in the range of about 12.1 degrees to about 12.4 degrees, a peak in the range of about 12.5 degrees to about 12.8 degrees, or a peak in the range of about Peaks in the range of 15.1 degrees to approximately 15.4 degrees, peaks in the range of approximately 17.0 degrees to approximately 17.3 degrees, peaks in the range of approximately 17.8 degrees to approximately 18.1 degrees, peaks in the range of approximately 18.1 degrees to approximately 18.4 degrees, peaks in the range of approximately 18.7 degrees to approximately 19.0 degrees, peaks in the range of approximately 19.3 degrees to approximately 19.6 degrees, peaks in the range of approximately 20.3 degrees to approximately 20.6 degrees, peaks in the range of approximately 21.8 degrees to approximately 22.1 degrees, peaks in the range of approximately 22.2 degrees The angle can be selected from a peak in the range of about 22.5 degrees to about 22.5 degrees, a peak in the range of about 23.1 degrees to about 23.4 degrees, a peak in the range of about 24.5 degrees to about 24.8 degrees, a peak in the range of about 25.3 degrees to about 25.6 degrees, a peak in the range of about 25.9 degrees to about 26.2 degrees, a peak in the range of about 27.8 degrees to about 28.1 degrees, a peak in the range of about 29.8 degrees to about 30.1 degrees, and a peak in the range of about 30.8 degrees to about 31.1 degrees.

[0183] In some embodiments, the free base form J of Compound A can be characterized by one or more peaks in an XPRD pattern, and the one or more peaks can be selected from about 6.08 degrees, about 10.58 degrees, about 11.64 degrees, about 15.27 degrees, about 19.42 degrees, about 21.93 degrees, about 23.23 degrees, and about 25.49 degrees. In some embodiments, the free base form J of Compound A can be characterized by one or more peaks in an XPRD pattern, wherein the one or more peaks can be selected from about 6.08 degrees, about 9.63 degrees, about 10.58 degrees, about 11.19 degrees, about 11.64 degrees, about 12.23 degrees, about 12.62 degrees, about 15.27 degrees, about 17.13 degrees, about 17.96 degrees, about 18.28 degrees, about 18.82 degrees, about 19.42 degrees, about 20.48 degrees, about 21.93 degrees, about 22.33 degrees, about 23.23 degrees, about 24.63 degrees, about 25.49 degrees, about 26.08 degrees, about 27.95 degrees, about 29.97 degrees, and about 30.98 degrees.

[0184] In some embodiments, the free base form J of Compound A may exhibit an XRPD pattern as shown in Figure 40. In some embodiments, the free base form J of Compound A may be characterized by one or more peaks in an XRPD pattern selected from the following:

[0185] [Table 22]

[0186] Pharmaceutical Composition Some embodiments described herein relate to pharmaceutical compositions that can include an effective amount of a salt and / or salt form of Compound A described herein (e.g., adipic acid salt Form A of Compound A) and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0187] Some embodiments described herein relate to pharmaceutical compositions, which can include an effective amount of a free base form of Compound A (e.g., Free Base Form E or Free Base Form J) and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0188] The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein, such as the compounds, salts, and / or salt forms described herein, with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of compounds, such as the compounds, salts, and / or salt forms described herein, to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific route of administration intended.

[0189] The term "physiologically acceptable" defines a carrier, diluent, or excipient that does not neutralize the biological activity and properties of a compound, such as a compound, salt, and / or salt form described herein, or cause substantial damage or injury to an animal to which the composition is intended to be delivered.

[0190] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound, such as a compound, salt, and / or salt form described herein, into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0191] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0192] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0193] The pharmaceutical compositions described herein can be administered to human patients either by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof. The appropriate formulation depends on the selected route of administration. Techniques for formulating and administering the compounds, salts, salt forms, and / or compositions described herein are known to those skilled in the art.

[0194] The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping, or tabletting processes, and additionally, the active ingredient is contained in an amount effective to achieve its intended purpose.

[0195] Multiple techniques exist in the art for administering compounds (including free base forms), salts, salt forms, and / or compositions, including, but not limited to, oral, rectal, intrapulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection.

[0196] The compounds, salts, salt forms, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compounds, salts, salt forms, and / or compositions directly into the affected area, often as a depot or sustained-release formulation. Additionally, the compounds, salts, salt forms, and / or compositions can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or intrapulmonary delivery may be desirable to target respiratory diseases or conditions.

[0197] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a format prescribed by a governmental agency regulating the manufacture, use, or sale of drugs, the notice reflecting approval by the agency of the drug form for human or animal administration. Such notice may, for example, be in accordance with the U.S. Food and Drug Administration's (FDA) 2004 / 01010604. The labeling may be labeling approved by the Food and Drug Administration or an approved product insert. Compositions that may include the compounds, salts, and / or salt forms described herein formulated with a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0198] Uses and Treatment Methods Some embodiments described herein relate to methods for ameliorating and / or treating a cancer described herein, which may include administering to a subject having a cancer described herein an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and / or treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), for ameliorating and / or treating a cancer described herein.

[0199] Some embodiments described herein relate to methods for inhibiting malignant growth or tumor replication, which may include contacting the malignant growth or tumor with an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor results from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting malignant growth or tumor replication, wherein the malignant growth or tumor results from a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), for inhibiting malignant growth or replication of a tumor, wherein the malignant growth or tumor results from a cancer described herein.

[0200] Some embodiments described herein relate to methods for ameliorating or treating a cancer described herein, which may include contacting a malignant growth or tumor in a subject having a cancer described herein with an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating or treating cancer, which may include contacting a malignant growth or tumor with a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is caused by a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), for ameliorating or treating cancer, which can include contacting with a malignant growth or tumor, wherein the malignant growth or tumor is caused by a cancer described herein.

[0201] Some embodiments described herein relate to methods for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells), which may include providing an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), to cancer cells derived from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Still other embodiments described herein relate to an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells).Some embodiments described herein relate to methods for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells), which may include providing an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), to cancer cells derived from a cancer described herein. Other embodiments described herein relate to methods for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells), which may include inhibiting the activity of WEE1 by contacting cancer cells derived from a cancer described herein with an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof).

[0202] Some embodiments described herein are methods for ameliorating or treating cancer according to the present invention, comprising inhibiting the activity of WEE1 (e.g., in TP53 mutant cells) using an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating or treating a cancer described in the present invention by inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells). Still other embodiments described herein relate to an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), for ameliorating or treating a cancer described in the present invention by inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and / or reducing overexpression of WEE1 in cells).Some embodiments described herein relate to methods for ameliorating or treating cancer as described herein, which may include contacting cancer cells with an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of WEE1 (e.g., inhibits the activity of WEE1 in TP53 mutant cells, inhibits the activity of WEE1 in TP53 wild-type cells, inhibits WEE1 activity in p53-deficient cells, and / or reduces overexpression of WEE1 in the cells).

[0203] Some embodiments disclosed herein relate to a method for inhibiting the activity of WEE1, which may include providing an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), to a subject having a cancer described herein, or cancer cells derived from a cancer described herein. Other embodiments disclosed herein relate to the use of an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for inhibiting the activity of WEE1. Still other embodiments disclosed herein relate to a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof), for inhibiting the activity of WEE1.

[0204] Examples of suitable cancers include, but are not limited to, brain cancer, brain and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell carcinoma, breast cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), stomach cancer, gallbladder / bile duct cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine cancer, cervical cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, polycythemia vera, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

[0205] As described herein, cancers may become resistant to one or more anti-cancer agents. In some embodiments, a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof) can be used to treat and / or ameliorate cancers that have become resistant to one or more anti-cancer agents (e.g., one or more WEE1 inhibitors). Examples of anti-cancer agents to which a subject may become resistant include, but are not limited to, WEE1 inhibitors (e.g., AZD1775 or adavosertib). In some embodiments, the cancer that has become resistant to one or more anti-cancer agents may be a cancer described herein.

[0206] Some known WEE1 inhibitors may cause one or more undesirable side effects in treated subjects. Examples of undesirable side effects include, but are not limited to, thrombocytopenia, neutropenia, anemia, diarrhea, vomiting, nausea, abdominal pain, and constipation. In some embodiments, the compounds described herein (e.g., the free base form or salt form of Compound A, or a pharmaceutically acceptable salt thereof) can reduce the number and / or severity of one or more side effects associated with known WEE1 inhibitors. In some embodiments, the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof, may result in a severity of a side effect (such as one of those described herein) that is less than 25% of the severity of the same side effect experienced by a subject administered a known WEE1 inhibitor (e.g., AZD1775, formally known as MK1775 (CAS Number: 955365-80-7, 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1,2-dihydropyrazolo[3,4-d]pyrimidin-3-one)). In some embodiments, the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof, may result in a number of side effects that is less than 25% of the number of side effects experienced by a subject administered a known WEE1 inhibitor (e.g., AZD1775). In some embodiments, the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof, results in a side effect (e.g., one of those described herein) that is about 10% to about 30% less severe than the severity of the same side effect experienced by a subject receiving a known WEE1 inhibitor (e.g., AZD1775). In some embodiments, the free base or salt form of Compound A, or a pharmaceutically acceptable salt thereof, results in a number of side effects that is about 10% to about 30% less severe than the number of side effects experienced by a subject receiving a known WEE1 inhibitor (e.g., AZD1775).

[0207] One or more free base forms or one or more salt forms of Compound A, or pharmaceutically acceptable salts thereof, which may be used to treat, ameliorate, and / or inhibit the growth of cancers in which inhibition of WEE1 activity is beneficial, are provided in any of the embodiments described in paragraphs

[0069] to

[0076] under the heading "Compound."

[0208] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant, such as a child or infant with a fever. In other embodiments, the subject may be an adult.

[0209] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily imply a complete cure or elimination of a disease or condition. Any alleviation, to any extent, of any undesirable signs or symptoms of a disease or condition can be considered treatment and / or therapy. Furthermore, treatment can include actions that may worsen a subject's overall feeling of health or appearance.

[0210] The terms "therapeutically effective amount" and "effective amount" are used to refer to the amount of an active compound or pharmaceutical agent that elicits a described biological or medical response. For example, a therapeutically effective amount of a compound, salt, or composition may be the amount necessary to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The therapeutically effective amount of a compound disclosed herein required as a dose will depend on the route of administration, the type of animal, such as a human, being treated, and the physical characteristics of the particular animal under consideration. Dosage can be adjusted to achieve the desired effect and will depend on factors such as body weight, diet, concurrent medications, and other factors that one of ordinary skill in the medical field would recognize.

[0211] For example, an effective amount of a compound or radiation is an amount that results in (a) relief, alleviation, or elimination of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) tumor elimination, and / or (d) long-term disease stabilization (growth arrest) of the tumor. In the treatment of lung cancer (e.g., non-small cell lung cancer), a therapeutically effective amount is an amount that reduces or eliminates cough, shortness of breath, and / or pain. As another example, an effective amount, or therapeutically effective amount, of a WEE1 inhibitor is an amount that results in reduced WEE1 activity and / or phosphorylation (e.g., CDC2 phosphorylation). Reductions in WEE1 activity are known to those skilled in the art and can be determined by analyzing WEE1 endogenous kinase activity and phosphorylation of downstream substrates.

[0212] The amount of Compound A free base or salt form, or its pharmaceutically acceptable salt, required for therapeutic use will vary depending not only on the particular compound or salt selected, but also on the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges set forth herein to effectively and aggressively treat, particularly, progressive diseases or conditions.

[0213] Generally, however, suitable doses will often be within the range of about 0.05 mg / kg to about 10 mg / kg. For example, suitable doses may be within the range of about 0.10 mg to about 7.5 mg per kg of body weight per day, e.g., about 0.15 mg to about 5.0 mg per kg of recipient body weight per day, about 0.2 mg to 4.0 mg per kg of recipient body weight per day, or any amount therebetween. The compound may be administered in unit dosage form, which may contain, for example, 1 to 500 mg, 10 to 100 mg, 5 to 50 mg, or any amount therebetween of active ingredient per unit dosage form.

[0214] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day The sub-dose itself may be further divided, for example, into a number of discrete loosely spaced administrations.

[0215] As will be readily apparent to one skilled in the art, the useful in vivo dosage and the particular method of administration will vary depending on the age, weight, severity of the affliction, mammalian species being treated, the particular compound being used, and the The activity of the compound will vary depending on the specific application for which it is used, and the specific application for which it is used. The determination of effective dosage levels, i.e., the dosage levels necessary to achieve the desired result, can be accomplished by one of ordinary skill in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. The determination of effective dosage levels, i.e., the dosage levels necessary to achieve the desired result, can be accomplished by one of ordinary skill in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of the free base form or salt form of Compound A, or a pharmaceutically acceptable salt thereof, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparisons can be made by comparison with established drugs, such as cisplatin and / or gemcitabine.

[0216] Dosage amount and interval may be adjusted individually to provide plasma concentrations sufficient to maintain the active moiety's modulatory effect or minimal effective concentration (MEC). The MEC varies for each compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to measure plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma concentrations above the MEC for 10-90% of the time, preferably 30-90%, and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of a drug may not be related to plasma concentration.

[0217] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and the route of administration. The severity of the disease or condition may, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose, and perhaps the frequency of administration, will also vary with the age, weight, and response of the individual patient. Programs comparable to those discussed above may be used in veterinary medicine.

[0218] The compounds, salts, and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing a particular chemical moiety can be established by evaluating in vitro toxicity on cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or particularly humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, dog, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model for determining efficacy, those skilled in the art can rely on the state of the art to guide them in selecting the appropriate model, dose, route of administration, and / or regimen. [Example]

[0219] Further embodiments, which in no way limit the scope of the claims, are disclosed in more detail in the examples below.

[0220] The free base of Compound A can be prepared as described in U.S. Patent No. 6,279,999, which is incorporated herein by reference in its entirety. As described in U.S. Patent No. 6,279,999, the free base of Compound A is a WEE1 inhibitor.

[0221] Preparation of Adipate Salt Form A Adipate Form A was obtained by slurrying equimolar amounts of free base Form A and adipic acid in methyl tert-butyl ether (MTBE) at 1000 rpm at room temperature (rt) for 4 days, and the resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0222] Solution crystallization: To a 20 mL vial was added Compound A free base (approximately 1 g), followed by ethyl acetate (10 mL) to dissolve the solid. To a 100 mL reactor, 1.05 equimolar adipic acid (approximately 291 mg) was added, followed by EtOAc (40 mL) to dissolve the solid. Adipate Form A seeds (approximately 20 mg) were added to the acid solution (the seeds did not dissolve). The free base solution was added to the acid solution over 4 hours with stirring at 300 rpm at 25°C, followed by stirring at 300 rpm at 25°C for 16 hours. The solution was vacuum filtered, and the solid was washed with EtOAc (2 x 10 mL) and dried under vacuum at room temperature for 17 hours.

[0223] Preparation of HCl Salt Form A Equimolar amounts of free base Form A and HCl acid were slurried in EtOAc:n-heptane (1:1, v:v) at 1000 rpm at room temperature for 4 days to obtain HCl salt Form A. The resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0224] Preparation of HCl Salt Form B HCl salt Form B was obtained by slurrying 1 equivalent of free base Form B with 2 equivalents of HCl acid in EtOAc:n-heptane (1:1, v / v) at 1000 rpm at room temperature for 4 days, and the resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0225] Preparation of sulfate salt form A Sulfate salt Form A was obtained by slurrying equimolar amounts of free base Form A and sulfuric acid in acetone:HO (1:3, v:v) at 1000 rpm at room temperature for 4 days. The resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0226] Preparation of Mesylate Form A Mesylate Form A was obtained by slurrying equimolar amounts of free base Form A and methanesulfonic acid in EtOAc:n-heptane (1:1, v:v) at 1000 rpm at room temperature for 4 days, and the resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0227] Preparation of Maleate Salt Form A Equimolar amounts of free base Form A and maleic acid were slurried in EtOAc:n-heptane (1:1, v:v) at 1000 rpm at room temperature for 4 days to obtain maleate salt Form A. The resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0228] Preparation of Phosphate Form A Phosphate Form A was obtained by slurrying equimolar amounts of free base Form A and phosphoric acid in acetone:HO (1:3, v:v) at 1000 rpm at room temperature for 4 days, and the resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0229] Preparation of Tartrate Salt Form A Tartrate salt Form A was obtained by slurrying equimolar amounts of free base Form A and L-tartaric acid in acetone:HO (1:3, v:v) at 1000 rpm at room temperature for 4 days, and the resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0230] Preparation of Tosylate Salt Form A. Equimolar amounts of free base Form A and p-toluenesulfonic acid were slurried in EtOAc:n-heptane (1:1, v:v) at 1000 rpm at room temperature for 4 days to obtain tosylate Form A. The resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0231] Preparation of Mucate Form A Mucate salt Form A was obtained by slurrying equimolar amounts of free base Form A and mucic acid in acetone:HO (1:3, v:v) at 1000 rpm at room temperature for 4 days, and the resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0232] Preparation of Hippurate Form A Hippurate Form A was obtained by slurrying equimolar amounts of free base Form A and hippuric acid in acetone:HO (1:3, v:v) at 1000 rpm at room temperature for 4 days, and the resulting suspension was centrifuged at 10,000 rpm for 2 minutes to collect the solid.

[0233] Preparation of Free Base Form A of Compound A The free base Form A of Compound A was obtained by slurrying the amorphous free base of Compound A in MTBE at room temperature for 4 days.

[0234] Preparation of Free Base Form B of Compound A The free base form B of Compound A was obtained by slurrying the amorphous free base of Compound A in acetone:H2O (1:3, v:v) at 1000 rpm at room temperature for 4 days.

[0235] Preparation of Free Base Form C of Compound A The free base form C of Compound A was obtained by slurrying the amorphous free base of Compound A in EtOAc:n-heptane (1:1, v:v) at 1000 rpm at room temperature for 4 days.

[0236] Preparation of Free Base Form D of Compound A Compound A free base Form D was obtained by slurrying the amorphous free base of Compound A in IPAc at room temperature for 4 days.

[0237] Preparation of Free Base Form E of Compound A Compound A free base Form E was obtained by slurrying the amorphous free base of Compound A in acetone:H2O (1:3, v:v) on a 50 mg scale at room temperature for 4 days.

[0238] Solution Crystallization: Compound A free base (approximately 1 g) was added to a 20 mL vial, followed by acetone (5 mL) to dissolve the solid. Anti-solvent HO (5 mL) was added to the solution with stirring at 1000 rpm at room temperature (no precipitation was observed). Free base Form E seeds (approximately 20 mg) were added to the solution (the seeds did not dissolve). HO (10 mL) was added to the sample (a gel was observed after the addition of 5 mL of HO), which converted to a suspension after 15 minutes of slurrying), and the solution was stirred at 1000 rpm at room temperature for 2 minutes. The solution was slurried for 2.5 hours, the solution was vacuum filtered, and the solid was washed with H2O (2 x 10 mL) and dried in vacuo at room temperature for 17 hours.

[0239] Preparation of the Free Base Form F of Compound A Compound A free base Form F was obtained by heating any of Compound A free base Forms A, C, D, or G. Compound A free base Form F was also obtained by heating Compound A free base Form H to 160° C. followed by cooling to room temperature.

[0240] Preparation of the free base form G of compound A Compound A free base Form G was obtained by anti-solvent addition by dissolving 15 mg of amorphous free base of Compound A in approximately 0.4-1.0 mL of IPA, followed by the addition of n-heptane until a precipitant appeared or the total volume of anti-solvent reached 15.0 mL.

[0241] Preparation of the Free Base Form H of Compound A Compound A free base Form H was obtained by antisolvent addition by dissolving 15 mg of amorphous free base of Compound A in approximately 0.4-1.0 mL of CHCl, followed by the addition of n-heptane until a precipitant appeared or the total volume of antisolvent reached 15.0 mL.

[0242] Preparation of Free Base Form I of Compound A Compound A free base Form H was obtained by antisolvent addition by dissolving 15 mg of amorphous free base of Compound A in approximately 0.4-1.0 mL of DMSO, followed by the addition of 15.0 mL of HO. The sample was then transferred to a slurry at 5 °C for 4 days.

[0243] Preparation of the Free Base Form J of Compound A Compound A free base form J was obtained during XRPD characterization of Compound A free base form E. Compound A free base form J was assumed to be anhydrous because it was obtained only by heating Compound A free base form E to 60° C. under a N purge.

[0244] Free base polymorph interconversion Polymorphic conversion relationships were obtained between free base forms A, C, D, E, F, G, and H of Compound A. Approximately 20 mg of amorphous free base starting material was added to separate high-performance liquid chromatography (HPLC) vials, followed by 1.0 mL of the corresponding solvent. The samples were slurried at 1000 rpm at room temperature for approximately 2 to 5 hours. The samples were then filtered through 0.45 μm polytetrafluoroethylene (PTFE) into separate HPLC vials containing approximately 5 mg of each form. For XRPD characterization, the samples were slurried at 1000 rpm at room temperature. The results are shown in Table 1. Free base form E was obtained in all solvent systems except in MTBE. Free base form F is an anhydrous form with a DSC endotherm at a higher temperature than form E, and form F was obtained only by heating. Form E could be obtained in all solvent systems in the competitive slurry experiments.

[0245] [Table 23]

[0246] Adipate Form A was stable in its solid state for 4 weeks at 25°C / 60% relative humidity (RH) and 40°C / 75% RH, 2 weeks at 60°C, and 3 days at 80°C. It decomposed only slightly after 2 weeks at 60°C and after 3 days at 80°C. As shown in Table 2, after 4 weeks at 60°C and 7 days at 80°C, adipate Form A decomposed by 0.9% and 0.6%, respectively. There was no change in form under all test conditions.

[0247] [Table 24]

[0248] Free base Form E was stable in its solid state for 4 weeks at 25° C. / 60% RH, 40° C. / 75% RH, and 60° C., and for 7 days at 80° C., as shown in Table 3. There was no change in form under all test conditions.

[0249] [Table 25]

[0250] Samples of Compound A adipic acid salt Form A and free base Form E obtained from solution crystallization were ground for approximately 5 minutes and then dried under vacuum for 15 hours or 58.5 hours at 50° C. The samples were characterized after drying and the results are summarized in Table 4.

[0251] [Table 26]

[0252] Hygroscopic The hygroscopicity of adipate salt Form A and free base Form E of Compound A was evaluated by collecting DVS isotherm plots from 0% RH to 95% RH at 25°C. XRPD characterization was performed on adipate salt Form A and free base Form E of Compound A after DVS testing. Figure 41 shows the DVS plot of adipate salt Form A, and Figure 42 shows the XRPD overlay of adipate salt Form A before and after DVS. Based on the results, adipate salt Form A exhibited a water uptake of 2.2% at 25°C / 80% RH. Figure 43 shows the DVS plot of free base Form E of Compound A, and Figure 44 shows the XRPD overlay of free base Form E of Compound A before and after DVS. Based on the results, free base Form E of Compound A exhibited a water uptake of 0.6% at 25°C / 80% RH. For both forms, no morphological changes were observed after DVS testing.

[0253] equilibrium solubility The equilibrium solubility of adipate salt Form A and free base Form E of Compound A was evaluated in SGF, HO, FaSSIF, and FeSSIF. Approximately 10-50 mg of each sample was weighed into 1.0 mL of each medium followed by slurry at 37°C for 24 hours. The samples were centrifuged and filtered using a 0.45 μm PTFE filter. The solids were tested by XRPD and the supernatants were tested by HPLC and pH. The results are summarized in Table 5. Figure 45 shows an XRPD overlay of the residual solids from the solubility study of adipate salt Form A. Figure 46 shows the equilibrium solubility of Compound A. 1 shows an XRPD overlay of the residual solids from a solubility study of free base Form E. Based on the results, adipate salt Form A exhibited greater solubility than free base Form E of Compound A.

[0254] [Table 27]

[0255] The TGA curve for the amorphous free base of Compound A showed a substantial and gradual weight loss beginning at 30° C. and continuing up to 150° C., a total loss of approximately 17%. In comparison, adipate salt Form A and free base Form E of Compound A showed significantly less weight loss when heated to 150° C. Adipate salt Form A and free base Forms E and J of Compound A are thermodynamically more stable than the amorphous free base and also have better processability.

[0256] Characterization Method XRPD For XRPD analysis, a PANalytical Empyrean and X'Pert3 X-ray powder diffractometer were used.

[0257] [Table 28]

[0258] TGA and DSC TGA data was collected using a TA Instruments TA Q5000 / Discovery 5500 TGA. DSC was performed using a TA Instruments TA Q2000 / Discovery 2500 DSC.

[0259] [Table 29]

[0260] DVS DVS data were measured by an SMS (Surface Measurement Systems) DVS Intrinsic. Relative humidity at 25 °C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl.

[0261] [Table 30]

[0262] Moreover, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made thereto without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present invention.

Claims

[Claim 1] (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (Compound A), 【Chemistry 1】 Compound A is in crystalline free base form or a pharmaceutically acceptable salt form; Compound A.

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