Crystalline forms of a glp-1 receptor modulator

Abstract

The present disclosure relates to solid forms of a GLP-1R agonist, Compound 1. The present disclosure also relates to amorphous or crystalline forms of Compound 1 as characterized herein. The disclosure further relates to pharmaceutical compositions comprising the amorphous or crystalline forms of Compound 1 as characterized herein. The disclosure further relates to methods of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of GLP-1R using the amorphous or crystalline forms of Compound 1 as characterized herein.

Description

CRYSTALLINE FORMS OF A GLP-1 RECEPTOR MODULATORCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application is a PCT International Application, claiming the benefit of International Application No. PCT / CN2023 / 137919, filed on December 11, 2023, the entire content of which is herein incorporated by reference.TECHNICAL FIELD

[0002] The present disclosure relates to solid forms (e.g., crystalline and / or amorphous forms) of a GLP-1 receptor modulator, 2-(((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)pyrimidin-4- yl)oxy)-2-methylpiperidin-l-yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6- carboxylic acid. The disclosure also relates to processes for preparation; pharmaceutical compositions; and uses thereof in treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a GLP-1 receptor.BACKGROUND

[0003] Diabetes is a serious chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Complications of diabetes include damage to the heart, blood vessels, eyes, kidneys, and nerves. Diabetes can increase risk of heart disease, and stroke. The results include serious effects on quality of life, health, and mortality. WHO Global Report on Diabetes, 2016, World Health Organization. As of 2017, approximately 462 million individuals worldwide, about 6.28% of the population was affected by type 2 diabetes, and this prevalence was increasing measurably. Khan et al., 2020, J. Epidemiol. Glob. Health 10(1): 107-111. The global economic burden of diabetes in 2015 was estimated to be $1.3T and estimated to increase to $2. IT by 2030. Bommer et al., 2018, Diabetes Care 41(5):963-970. Approximately 90-95% of all diabetes cases are type 2 diabetes. Tripathi & Srivastava, 2016, Med. Sci. Monit. 12(7):RA130-147.

[0004] The glucagon-like peptide-1 receptor (GLP-1 receptor, or GLP-1R) has emerged as a potential target for treating type 2 diabetes. Its ligand, glucagon-like peptide-1 (GLP-1) enhances glucose-induced insulin secretion and increases insulin synthesis among many other effects. Doyle and Egan, 2007, Pharmacol. Ther. 113 (3) :546-593. GLP-1 is known to delay gastric emptying, suppress food intake, increase satiety, and reduce weight in humans. Shah and Vella,2014, Rev Endocr Metab Disord. 15(3): 181-187. Activating the GLP-1 receptor has been shown to have beneficial effects on insulin secretion and the maintenance of beta cell glucose sensing, transcription, synthesis, proliferation, and survival. Doyle and Egan, 2007, supra. While the GLP-1 receptor is a promising therapeutic target, only a handful of GLP-1 receptor drugs have been approved to date, and most, or all of these are peptide, or polypeptide drugs.

[0005] There is a need for additional therapies for treating metabolic diseases, and conditions, like type 2 diabetes. Small molecules targeting GLP-1 receptor should provide safe, stable, and easy to administer therapeutics for metabolic diseases, and conditions such as type 2 diabetes. Suitable forms of these small compounds that have favorable properties related to processing, manufacturing, storage stability, and / or usefulness as a drug are consistently sought and remain vital to drug development.SUMMARY

[0006] The present disclosure provides crystalline and amorphous forms of Compound 1, 2- (((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)pyrimidin-4-yl)oxy)-2-methylpiperidin-l- yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid, which has the structure.Compound 1

[0007] Compound 1 is disclosed as Compound 485 in PCT Application No. PCT / US2022 / 014156, published as WO 2022165076.

[0008] Specific crystalline forms of an active pharmaceutical ingredient (API) can have advantages over other crystalline or amorphous forms, such as ease of preparation, increased stability during storage or processing, more favorable solubility, ease of formulation, ease of handling, and increased bioavailability. Because of the potential advantages associated with one pure crystalline form, it is also desirable to prevent or minimize polymorphic conversion (i.e., conversion of one crystal form to another; or conversion between one crystal form andamorphous form) when two or more solid forms of the API can exist. The stability during both the preparation of formulations containing a solid form (e.g., a crystalline form), and during storage of a pharmaceutical dosage form containing a solid form (e.g., a crystalline form) is an important determinant for drug development. The novel solid forms (e.g., crystalline and / or amorphous forms) of Compound 1 described herein are directed toward this and other important ends.

[0009] In one aspect, the disclosure provides a crystalline form of Compound 1 or solvates, hydrates, or anhydrates thereof, wherein the crystalline form is selected from the group consisting of Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, Compound 1 Form D, and Compound 1 Form E.

[0010] In one aspect, the disclosure provides an amorphous form of Compound 1.

[0011] In one aspect, the disclosure provides a pharmaceutical composition comprising a crystalline form or amorphous form as described herein and a pharmaceutically acceptable excipient.

[0012] In another aspect, the disclosure provides a method of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of GLP-1R, comprising administering to a subject in need thereof a crystalline form, an amorphous form, or pharmaceutical composition as described herein.

[0013] In one embodiment of this aspect, the disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of GLP-1R is a metabolic disease.

[0014] Also provided herein is the use of a crystalline or amorphous form of Compound 1 as described herein, and compositions thereof, for the treatment of a metabolic disease or condition. Also provided herein is the use of the crystalline or amorphous form described herein, and compositions thereof, for the treatment of type 2 diabetes, obesity with or without type 2 diabetes, and / or hyperglycemia.BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1 is an XRPD pattern of amorphous Compound 1.

[0016] FIG. 2 is an mDSC thermogram of amorphous Compound 1.

[0017] FIG. 3 is a TGA thermogram of amorphous Compound 1.

[0018] FIG. 4 is a 'H NAIR spectrum of amorphous Compound 1 in d6-DMSO.

[0019] FIG. 5A is an XRPD pattern of Compound 1 Form A in reflection geometry.

[0020] FIG. 5B is an XRPD pattern of Compound 1 Form A in transmission geometry.

[0021] FIG. 6 is a DSC thermogram of Compound 1 Form A.

[0022] FIG. 7 is a TGA thermogram of Compound 1 Form A.

[0023] FIG. 8 is a1H NMR spectrum of Compound 1 Form A in d6-DMSO.

[0024] FIG. 9A is a DVS thermogram of Compound 1 Form A, showing the change of the relative sample weight and relative humidity as a function of time.

[0025] FIG. 9B is a DVS thermogram of Compound 1 Form A, showing the change of the relative sample weight as a function of relative humidity.

[0026] FIG. 10 is an FT-IR spectrum of Compound 1 Form A.

[0027] FIG. 11 is a SEM microphotograph of Compound 1 Form A.

[0028] FIG. 12 is an XRPD pattern of Compound 1 Form B.

[0029] FIG. 13 is a DSC thermogram of Compound 1 Form B.

[0030] FIG. 14 is a TGA thermogram of Compound 1 Form B.

[0031] FIG. 15 is a 'H NMR spectrum of Compound 1 Form B in d6-DMSO.

[0032] FIG. 16 is an XRPD pattern of Compound 1 Form C.

[0033] FIG. 17 is a DSC thermogram of Compound 1 Form C.

[0034] FIG. 18 is a TGA thermogram of Compound 1 Form C.

[0035] FIG. 19 is a 'H NMR spectrum of Compound 1 Form C in d6-DMSO.

[0036] FIG. 20 is an XRPD pattern of Compound 1 Form D.

[0037] FIG. 21 is a DSC thermogram of Compound 1 Form D.

[0038] FIG. 22 is a TGA thermogram of Compound 1 Form D.

[0039] spectrum of Compound 1 Form D in DMSO.

[0040] FIG. 24 shows the interconversion relationship of Compound 1 polymorphs.

[0041] FIG. 25 is an XRPD pattern of Compound 1 Form E.

[0042] FIG. 26 is a TGA thermogram of Compound 1 Form E.

[0043] FIG. 27 is a DSC thermogram of Compound 1 Form E.

[0044] FIG. 28 shows the Ortep image of single crystal structure of Compound 1 Form A.DETAILED DESCRIPTIONDEFINITIONS, ABBREVIATIONS AND ACRONYMS

[0045] As used herein, the following definitions shall apply unless otherwise indicated.

[0046] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry,” 2ndEd., Thomas Sorrell, University Science Books, Sausalito: 2006, and "March’s Advanced Organic Chemistry,” 7th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are hereby incorporated by reference.

[0047] As used herein, the term “about” or “approximate” or “approximately” includes (anddescribes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” or “approximate” or “approximately” includes the indicated amount ± 10%. In other embodiments, the term “about” approximate” or “approximately” includes the indicated amount ± 5%. In certain other embodiments, the term “about” approximate” or “approximately” includes the indicated amount ± 1%.

[0048] As used herein, the term “crystalline” refers to compounds in a solid state having a periodic and repeating three-dimensional internal arrangement of atoms, ions or molecules characteristic of crystals, for example, arranged in fixed geometric patterns or lattices that have rigid long-range order. The term crystalline does not necessarily mean that the compound exists as crystals, but that it has a crystal-like internal structural arrangement.

[0049] As used herein, the term “amorphous” refers to a material having diffuse scattering pattern present, but no evidence for Bragg peaks in the XRPD pattern, as well as to noncrystalline solid in which the atoms and molecules are not organized in a definite lattice pattern.

[0050] “Patient” for the purposes of the present disclosure includes humans and any other animals, particularly mammals. Thus, the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment, the patient is a mammal, and in a most preferred embodiment, the patient is human. Examples of the preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and primates.

[0051] “Therapeutically effective amount” is an amount of a crystalline form or amorphous form of the present disclosure that, when administered to a patient, ameliorates a symptom of the disease. The amount of a crystalline form of the present disclosure which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

[0052] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit risk ratio. In addition, guidelines forimpurities and residual solvents levels in crystalline and amorphous pharmaceuticals are provided by ICH in “Impurities: Guidelines for Residual Solvents Q3C(R6)” posted at https: / / database.ich.org / sites / default / fdes / Q3C-R6_Guideline_ErrorCorrection_2019 _0410_0.pdf (last visited December 01, 2023).

[0053] As used herein, the phrase “pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid fdler, diluent, solvent, or encapsulating material. Excipients are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0054] The terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The terms contemplate administering a therapeutically effective amount of a compound of the present disclosure to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be achieved over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

[0055] The terms “prevent,” “preventing,” and “prevention” refer to a method of preventing the onset of a disease or condition and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent,” “preventing,” and “prevention” also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms “prevent,” “preventing” and “prevention” may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the diseaseor condition.

[0056] In general, the nomenclature used in this application is based on naming conventions adopted by the international union of pure and applied chemistry (IUPAC). Chemical structures shown herein were prepared using CHEMDRAW®. Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0057] Unless otherwise stated, all XRPD peaks are reported on a 2 Theta (29) scale, measured in degrees. The XRPD pattern of Compound 1 Form A was recorded in both reflection geometry and transmission geometry. The XRPD patterns of Compound 1 Form B, Form C, and Form D were recorded in reflection geometry. The XRPD pattern of Compound 1 Form E was recorded in transmission geometry.EMBODIMENTS

[0058] In one aspect, the disclosure relates to an amorphous or crystalline form of Compound 1, also known as 2-(((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)pyrimidin-4-yl)oxy)-2- methylpiperidin- 1 -yl)methyl)- 1 -(((S)-oxetan-2-yl)methyl)- lH-benzo[d]imidazole-6-carboxylic acid. Compound 1 has the structure depicted below.Compound 1

[0059] In one embodiment, the disclosure relates to solvates, hydrates, and anhydrates of crystalline Compound 1 or amorphous Compound 1.

[0060] In another embodiment, the disclosure relates to crystalline Compound 1 characterized as Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, Compound 1 Form D, or Compound Form E.

[0061] In another embodiment, the disclosure relates to mixtures of the solids disclosed herein.Compound 1

[0062] As noted above, this disclosure relates to amorphous and crystalline forms of Compound1. A number of methods can be used to prepare Compound 1, for example, see Example 485 of PCT Application No. PCT / US2022 / 014156, published as WO 2022165076. Compound 1 prepared according to the procedure in WO 2022165076 is isolated as an amorphous material. Amorphous Compound 1 can also be prepared by evaporation from THF or DCM, or by fast evaporation from MeOH, THF, EA, DCM, or 2-MeTHF.

[0063] Amorphous Compound 1 was used as the starting material to make the crystalline forms of the present disclosure.

[0064] FIG. 1 is an XRPD pattern of amorphous Compound 1.

[0065] FIG. 2 is an mDSC thermogram of amorphous Compound 1 indicating a glass transition temperature of 78.2 °C.

[0066] FIG. 3 is a TGA thermogram of amorphous Compound 1.

[0067] FIG. 4 is a ’H NMR spectrum of amorphous Compound 1 in DMSO showing 1 percent residual DCM solvent.

[0068] In one aspect, the disclosure relates to a crystalline form of Compound 1 or an anhydrate, a hydrate, or a solvate thereof.

[0069] In one embodiment of this aspect, the crystalline form of Compound 1 is characterized as Form A, Form B, Form C, Form D, or Form E.Compound 1 Form A

[0070] In one embodiment, the crystalline form is characterized as Compound 1 Form A.

[0071] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

[0072] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.200, comprising one or more peaks selected from 6.049, 9.530, 10.831, 11.952, 12.799, 12.878, 13.269, 14.243, 15.028, 15.713, 17.510, 18.004, 18.547, 19.509, 19.999, 20.565, 21.103, 21.504, 22.079, 22.463, 23.638, 23.813, 24.548, 25.216, 25.434, 27.074, 27.971, 28.525, 29.188, 29.644, 29.964, 31.629, 32.584, 34.443, 35.093, and 35.541.

[0073] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

[0074] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising five or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

[0075] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising ten or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

[0076] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising a peak at 20.57.

[0077] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.53, 20.57, and 23.81.

[0078] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.53, 10.83, 14.24, 20.57, and 23.81.

[0079] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.53, 10.83, 14.24, 20.57, 21.10, 22.46, and 23.81.

[0080] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.53, 10.83, 14.24, 15.71, 19.51, 20.57, 21.10, 22.08, 22.46, and 23.81.

[0081] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.200, comprising a peak at 20.565.

[0082] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern inreflection geometry on a 2 Theta scale, ± 0.200, comprising peaks at 9.530, 20.565, and 23.813.

[0083] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.200, comprising peaks at 9.530, 10.831, 14.243, 20.565, and 23.813.

[0084] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.200, comprising peaks at 9.530, 10.831, 14.243, 20.565, 21.103, 22.463, and 23.813.

[0085] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.200, comprising peaks at 9.530, 10.831, 14.243, 15.713, 19.509, 20.565, 21.103, 22.079, 22.463, and 23.813.

[0086] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising all of the peaks 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

[0087] In another embodiment, Compound 1 Form A is characterized by the XRPD pattern substantially in accordance with FIG. 5A.

[0088] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 5.86, 9.35, 9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46.

[0089] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 5.86, 9.35, 9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46.

[0090] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising five or more peaks selected from5.86, 9.35, 9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35,23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46.

[0091] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising a peak at 20.42.

[0092] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.35, 20.42, and 23.66.

[0093] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.35, 14.07, 20.42, 22.31, and 23.66.

[0094] In another embodiment, Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising all of the peaks 5.86, 9.35, 9.61,10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37,18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01,25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84,33.31, 33.73, 34.34, 34.94, 35.29, and 35.46.

[0095] In another embodiment, Compound 1 Form A is characterized by the XRPD pattern substantially in accordance with FIG. 5B.

[0096] In another embodiment, Compound 1 Form A is characterized by a DSC thermogram substantially in accordance with FIG. 6.

[0097] In another embodiment, Compound 1 Form A is characterized by a DSC thermogram with a melting peak onset temperature about 178 °C - 182 °C and a melting peak temperature about 180 °C - 184 °C.

[0098] In another embodiment, Compound 1 Form A is characterized by a DSC thermogram showing a melting peak onset temperature of about 180.0 °C and a melting peak temperature of about 181.6 °C.

[0099] In another embodiment, Compound 1 Form A is characterized by a TGA thermogram substantially in accordance with FIG. 7.

[0100] In another embodiment, Compound 1 Form A is characterized by a TGA thermogram showing about 0.1-0.3 percent weight loss at 150 °C.

[0101] In another embodiment, Compound 1 Form A is characterized by a TGA thermogram showing about 0.2 percent weight loss at 150 °C.

[0102] In another embodiment, Compound 1 Form A is characterized by the 'H NMR spectrum in d6-DMSO substantially in accordance with FIG. 8 indicating no detectable residual solvent.

[0103] In another embodiment, Compound 1 Form A is characterized by the DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B.

[0104] In another embodiment, Compound 1 Form A is characterized by the FT-IR spectrum substantially in accordance with FIG. 10.

[0105] In another embodiment, Compound 1 Form A is characterized by the SEM microphotograph substantially in accordance with FIG. 11.

[0106] In another embodiment, Compound 1 Form A is characterized by at least one of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46 in transmission geometry;(2) an endotherm with an onset temperature of about 180.0 °C in a DSC thermogram;(3) a 0.2 percent weight loss at about 150 °C in a TGA thermogram;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0107] In another embodiment, Compound 1 Form A is characterized by at least one of the following:(1) an XRPD pattern substantially in accordance with FIG. 5A or FIG. 5B;(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0108] In another embodiment, Compound 1 Form A is characterized by at least two of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07,27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94,21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82,28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and35.46 in transmission geometry;(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0109] In another embodiment, Compound 1 Form A is characterized by at least three of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07,27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94,21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82,28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and35.46 in transmission geometry;(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0110] In another embodiment, Compound 1 Form A is characterized by at least four of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07,27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94,21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82,28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and35.46 in transmission geometry;(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0111] In another embodiment, Compound 1 Form A is characterized by at least five of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07,27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94,21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82,28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and35.46 in transmission geometry;(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9 A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0112] In another embodiment, Compound 1 Form A is characterized by all of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46 in transmission geometry;(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0113] In another embodiment, Compound 1 Form A is characterized by (1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46 in transmission geometry; and at least one of the following:(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0114] In another embodiment, Compound 1 Form A is characterized by (1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46 in transmission geometry; and at least two of the following:(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0115] In another embodiment, Compound 1 Form A is characterized by (1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46 in transmission geometry; and at least three of the following:(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0116] In another embodiment, Compound 1 Form A is characterized by (1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54 in reflection geometry, or one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46 in transmission geometry; and at least four of the following:(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and / or(6) an SEM microphotograph substantially in accordance with FIG. 11.

[0117] In another embodiment, Compound 1 Form A is characterized by (1) an XRPD pattern substantially in accordance with FIG. 5A or FIG. 5B and all of the following:(2) a DSC thermogram substantially in accordance with FIG. 6;(3) a TGA thermogram substantially in accordance with FIG. 7;(4) a DVS isotherm substantially in accordance with FIG. 9A and / or Fig. 9B;(5) an FT-IR spectrum substantially in accordance with FIG. 10; and(6) an SEM microphotograph substantially in accordance with FIG. 11.Compound 1 Form B

[0118] In one embodiment, the crystalline form is characterized as Compound 1 Form B.

[0119] The XRPD pattern of Compound 1 Form B was recorded in reflection geometry.

[0120] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.67, 10.42, 11.40, 13.32,13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74,22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93, 25.43, 26.01, 26.42, 26.61, 26.81, 27.34,28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36, 31.50, 32.21, 32.88, 33.44, 34.08, 35.21,35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.84.

[0121] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.200, comprising one or more peaks selected from 9.674, 10.415, 11.397, 13.317, 13.795, 14.817, 15.633, 16.795, 17.674, 17.995, 18.769, 19.103, 19.365, 19.799, 20.489, 21.030,21.187, 21.742, 22.220, 22.569, 22.806, 22.931, 23.858, 24.211, 24.502, 24.932, 25.432, 26.006,26.419, 26.608, 26.807, 27.337, 28.005, 28.468, 28.719, 29.030, 29.249, 29.825, 30.521, 31.361,31.499, 32.207, 32.884, 33.439, 34.078, 35.206, 35.606, 36.448, 36.966, 37.448, 39.097, 39.572, and 39.840.

[0122] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 9.67, 10.42, 11.40, 13.32,13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74,22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93, 25.43, 26.01, 26.42, 26.61, 26.81, 27.34,28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36, 31.50, 32.21, 32.88, 33.44, 34.08, 35.21,35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.84.

[0123] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising five or more peaks selected from 9.67, 10.42, 11.40, 13.32,13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74,22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93, 25.43, 26.01, 26.42, 26.61, 26.81, 27.34,28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36, 31.50, 32.21, 32.88, 33.44, 34.08, 35.21,35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.84.

[0124] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising ten or more peaks selected from 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22,22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93, 25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01,28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36, 31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61,36.45, 36.97, 37.45, 39.10, 39.57, and 39.84.

[0125] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising a peak at 19.37.

[0126] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 19.37, 22.81, and 26.01.

[0127] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 10.42, 13.32, and 19.37.

[0128] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 13.32, 19.37, 21.19, 22.81, and 26.01.

[0129] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 10.42, 13.32, 17.67, 19.37, and 26.01.

[0130] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 10.42, 13.32, 17.67, 19.37, 21.03, 21.19, 22.81, 23.86, 26.01, and 29.83.

[0131] In another embodiment, Compound 1 Form B is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising all of the peaks 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63,16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22, 22.57, 22.81,22.93, 23.86, 24.21, 24.50, 24.93, 25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01, 28.47, 28.72,29.03, 29.25, 29.83, 30.52, 31.36, 31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61, 36.45, 36.97,37.45, 39.10, 39.57, and 39.84.

[0132] In another embodiment, Compound 1 Form B is characterized by the XRPD pattern substantially in accordance with FIG. 12.

[0133] In another embodiment, Compound 1 Form B is characterized by a DSC thermogram substantially in accordance with FIG. 13.

[0134] In another embodiment, Compound 1 Form B is characterized by a DSC thermogram indicating a melting peak onset temperature about 148°C - 153 °C.

[0135] In another embodiment, Compound 1 Form B is characterized by a DSC thermogram indicating high crystallinity and a melting peak onset temperature about 150.4 °C.

[0136] In another embodiment, Compound 1 Form B is characterized by the TGA thermogram substantially in accordance with FIG. 14.

[0137] In another embodiment, Compound 1 Form B is characterized by the TGA thermogram showing about 0.05-0.15 percent weight loss from 25 °C to 100 °C.

[0138] In another embodiment, Compound 1 Form B is characterized by the TGA thermogram showing about 0.1 percent weight loss from 25 °C to 100 °C.

[0139] In another embodiment, Compound 1 Form B is characterized by the 'H NMR spectrum in d6-DMSO substantially in accordance with FIG. 15 indicating no detectable residual solvent.

[0140] In another embodiment, Compound 1 Form B is characterized by at least one of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10,19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93,25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36,31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.84;(2) a DSC thermogram substantially in accordance with FIG. 13; and / or(3) a TGA thermogram substantially in accordance with FIG. 14.

[0141] In another embodiment, Compound 1 Form B is characterized by at least one of the following:(1) an XRPD pattern substantially in accordance with FIG. 12;(2) a DSC thermogram substantially in accordance with FIG. 13; and / or(3) a TGA thermogram substantially in accordance with FIG. 14.

[0142] In another embodiment, Compound 1 Form B is characterized by at least two of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10,19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93,25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36,31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.84;(2) a DSC thermogram substantially in accordance with FIG. 13; and / or(3) a TGA thermogram substantially in accordance with FIG. 14.

[0143] In another embodiment, Compound 1 Form B is characterized by all of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10,19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93,25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36,31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.84;(2) a DSC thermogram substantially in accordance with FIG. 13; and / or(3) a TGA thermogram substantially in accordance with FIG. 14.

[0144] In another embodiment, Compound 1 Form B is characterized by (1) an XRPD pattern substantially in accordance with FIG. 12 and at least one of the following:(2) a DSC thermogram substantially in accordance with FIG. 13; and / or(3) a TGA thermogram substantially in accordance with FIG. 14.

[0145] In another embodiment, Compound 1 Form B is characterized by (1) an XRPD pattern substantially in accordance with FIG. 12 and both of the following:(2) a DSC thermogram substantially in accordance with FIG. 13; and / or(3) a TGA thermogram substantially in accordance with FIG. 14.Compound 1 Form C

[0146] In one embodiment, the crystalline form is characterized as Compound 1 Form C.

[0147] The XRPD pattern of Compound 1 Form C was recorded in reflection geometry.

[0148] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07,19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66,27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77.

[0149] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.200, comprising one or more peaks selected from 5.893, 8.609, 9.663, 9.899, 10.382, 10.564, 11.338, 11.780, 12.544, 13.292, 13.848, 14.786, 15.314, 16.346, 16.759, 17.225,17.689, 18.808, 19.074, 19.345, 19.846, 20.470, 21.107, 21.732, 21.905, 22.254, 22.507, 22.967,23.682, 24.328, 24.926, 25.974, 26.660, 27.346, 28.484, 28.928, 29.715, 30.106, 30.625, 30.840,31.840, 33.075, 34.266, 34.798, 35.590, and 35.768.

[0150] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07,19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66,27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77.

[0151] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2Theta scale, ± 0.20, comprising five or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07,19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66,27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77.

[0152] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising ten or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07,19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66,27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77.

[0153] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 13.29, 17.69, and 19.85.

[0154] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 13.29, 17.69, 19.85, 24.33, and 25.97.

[0155] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 9.90, 11.78, 13.29, 17.69, 19.35, 19.85, 22.97, 23.68, 24.33, and 25.97.

[0156] In another embodiment, Compound 1 Form C is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising all of the peaks 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63,16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22, 22.57, 22.81,22.93, 23.86, 24.21, 24.50, 24.93, 25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01, 28.47, 28.72,29.03, 29.25, 29.83, 30.52, 31.36, 31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61, 36.45, 36.97,37.45, 39.10, 39.57, and 39.84.

[0157] In another embodiment, Compound 1 Form C is characterized by the XRPD pattern substantially in accordance with FIG. 16.

[0158] In another embodiment, Compound 1 Form C is characterized by a DSC thermogram substantially in accordance with FIG. 17.

[0159] In another embodiment, Compound 1 Form C is characterized by a DSC thermogram indicating a first melting peak onset temperature about 138 °C - 142 °C, a second melting peak onset about 146 °C - 151 °C, and third melting peak onset about 174 °C - 178 °C.

[0160] In another embodiment, Compound 1 Form C is characterized by a DSC thermogram indicating high crystallinity and a first melting peak onset temperature of about 140.2 °C, asecond melting peak onset of about 149.4 °C, and third melting peak onset at about 176.2 °C.

[0161] In another embodiment, Compound 1 Form C is characterized by a TGA thermogram substantially in accordance with FIG. 18.

[0162] In another embodiment, Compound 1 Form C is characterized by a TGA thermogram showing about 0.05-0.15 percent weight loss from 25 °C to 100 °C.

[0163] In another embodiment, Compound 1 Form C is characterized by a TGA thermogram showing about 0.1 percent weight loss from 25 °C to 100 °C.

[0164] In another embodiment, Compound 1 Form C is characterized by the 'H NMR spectrum in d6-DMSO substantially in accordance with FIG. 19 indicating no detectable residual solvent.

[0165] In another embodiment, Compound 1 Form C is characterized by at least one of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07, 19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66, 27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77;(2) a DSC thermogram substantially in accordance with FIG. 17; and / or(3) a TGA thermogram substantially in accordance with FIG. 18.

[0166] In another embodiment, Compound 1 Form C is characterized by at least one of the following:(1) an XRPD pattern substantially in accordance with FIG. 16;(2) a DSC thermogram substantially in accordance with FIG. 17; and / or(3) a TGA thermogram substantially in accordance with FIG. 18.

[0167] In another embodiment, Compound 1 Form C is characterized by at least two of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07, 19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66, 27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77;(2) a DSC thermogram substantially in accordance with FIG. 17; and / or(3) a TGA thermogram substantially in accordance with FIG. 18.

[0168] In another embodiment, Compound 1 Form C is characterized by all of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07, 19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66, 27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77;(2) a DSC thermogram substantially in accordance with FIG. 17; and / or(3) a TGA thermogram substantially in accordance with FIG. 18.

[0169] In another embodiment, Compound 1 Form C is characterized by (1) an XRPD pattern substantially in accordance with FIG. 16 and at least one of the following:(2) a DSC thermogram substantially in accordance with FIG. 17; and / or(3) a TGA thermogram substantially in accordance with FIG. 18.

[0170] In another embodiment, Compound 1 Form C is characterized by (1) an XRPD pattern substantially in accordance with FIG. 16 and both of the following:(2) a DSC thermogram substantially in accordance with FIG. 17; and / or(3) a TGA thermogram substantially in accordance with FIG. 18.Compound 1 Form D

[0171] In one embodiment, the crystalline form is characterized as Compound 1 Form D.

[0172] The XRPD pattern of Compound 1 Form D was recorded in reflection geometry.

[0173] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09, 22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

[0174] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.200, comprising one or more peaks selected from 9.659, 10.432, 11.313, 12.813, 13.326, 14.835, 16.805, 17.731, 17.949, 19.371, 20.410, 21.094, 22.239, 22.644, 22.862, 23.868, 24.448, 25.986, 28.015, 29.832, and 35.628.

[0175] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 9.66, 10.43, 11.31, 12.81,13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09, 22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

[0176] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising five or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09, 22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

[0177] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising ten or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09, 22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

[0178] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 9.66, 19.37, and 25.99.

[0179] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 9.66, 13.33, 19.37, 22.86, and 25.99.

[0180] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 9.66, 10.43, 13.33, 17.73, 17.95, 19.37, 22.64, 22.86, 23.87, and 25.99.

[0181] In another embodiment, Compound 1 Form D is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising all of the peaks 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09, 22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

[0182] In another embodiment, Compound 1 Form D is characterized by the XRPD pattern substantially in accordance with FIG. 20.

[0183] In another embodiment, Compound 1 Form D is characterized by a DSC thermogram substantially in accordance with FIG. 21.

[0184] In another embodiment, Compound 1 Form D is characterized by a DSC thermogram indicating a melting peak onset temperature about 141°C - 145 °C.

[0185] In another embodiment, Compound 1 Form D is characterized by a DSC thermogram indicating medium crystallinity and a melting peak onset temperature of about 142.9 °C.

[0186] In another embodiment, Compound 1 Form D is characterized by a TGA thermogram substantially in accordance with FIG. 22.

[0187] In another embodiment, Compound 1 Form D is characterized by a TGA thermogram showing about 0. 1-0.3 percent weight loss from 25 °C to 100 °C.

[0188] In another embodiment, Compound 1 Form D is characterized by a TGA thermogram showing 0.2 percent weight loss from 25 °C to 100 °C.

[0189] In another embodiment, Compound 1 Form D is characterized by the ’H N R spectrum in d6-DMSO substantially in accordance with FIG. 23 indicating 0.1 percent by weight of residual solvent.

[0190] In another embodiment, Compound 1 Form D is characterized by at least one of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09,22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63;(2) a DSC thermogram substantially in accordance with FIG. 21; and / or(3) a TGA thermogram substantially in accordance with FIG. 22.

[0191] In another embodiment, Compound 1 Form D is characterized by at least one of the following:(1) an XRPD pattern substantially in accordance with FIG. 20;(2) a DSC thermogram substantially in accordance with FIG. 21; and / or(3) a TGA thermogram substantially in accordance with FIG. 22.

[0192] In another embodiment, Compound 1 Form D is characterized by at least two of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09,22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63;(2) a DSC thermogram substantially in accordance with FIG. 21; and / or(3) a TGA thermogram substantially in accordance with FIG. 22.

[0193] In another embodiment, Compound 1 Form D is characterized by all of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09,22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63;(2) a DSC thermogram substantially in accordance with FIG. 21; and / or(3) a TGA thermogram substantially in accordance with FIG. 22.

[0194] In another embodiment, Compound 1 Form D is characterized by (1) an XRPD pattern substantially in accordance with FIG 20 and at least one of the following:(2) a DSC thermogram substantially in accordance with FIG. 21; and / or(3) a TGA thermogram substantially in accordance with FIG. 22.

[0195] In another embodiment, Compound 1 Form D is characterized by (1) an XRPD pattern substantially in accordance with FIG. 20 and both of the following:(2) a DSC thermogram substantially in accordance with FIG. 21; and / or(3) a TGA thermogram substantially in accordance with FIG. 22.Compound 1 Form E

[0196] In one embodiment, the crystalline form is characterized as Compound 1 Form E.

[0197] The XRPD pattern of Compound 1 Form E was recorded in transmission geometry.

[0198] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05,12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90.

[0199] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90.

[0200] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising five or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05,12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90.

[0201] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising ten or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05,12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94,23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90.

[0202] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising a peak at 21.22.

[0203] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 15.02, 18.81, and 21.22.

[0204] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 9.36, 13.63, 15.02, 18.81, and 21.22.

[0205] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising peaks at 9.04, 9.36, 13.63, 15.02, 18.15, 18.81, 20.27, 21.22, 22.94, and 25.89.

[0206] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern on a 2 Theta scale, ± 0.20, comprising all of the peaks 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90.

[0207] In another embodiment, Compound 1 Form E is characterized by an XRPD pattern substantially in accordance with FIG. 25.

[0208] In another embodiment, Compound 1 Form E is characterized by a TG-FTIR thermogram substantially in accordance with FIG. 26.

[0209] In another embodiment, Compound 1 Form E is characterized by the DSC thermogram substantially in accordance with FIG. 27.

[0210] In another embodiment, Compound 1 Form E is characterized by at least one of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90;(2) a TG-FTIR thermogram substantially in accordance with FIG. 26; and / or(3) a DSC thermogram substantially in accordance with FIG. 27.

[0211] In another embodiment, Compound 1 Form E is characterized by at least one of thefollowing:(1) an XRPD pattern substantially in accordance with FIG. 25;(2) a TG-FTIR thermogram substantially in accordance with FIG. 26; and / or(3) a DSC thermogram substantially in accordance with FIG. 27.

[0212] In another embodiment, Compound 1 Form E is characterized by at least two of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90;(2) a TG-FTIR thermogram substantially in accordance with FIG. 26; and / or(3) a DSC thermogram substantially in accordance with FIG. 27.

[0213] In another embodiment, Compound 1 Form E is characterized by all of the following:(1) an XRPD pattern on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90;(2) a TG-FTIR thermogram substantially in accordance with FIG. 26; and / or(3) a DSC thermogram substantially in accordance with FIG. 27.

[0214] In another embodiment, Compound 1 Form D is characterized by (1) an XRPD pattern substantially in accordance with FIG 25 and at least one of the following:(2) a TG-FTIR thermogram substantially in accordance with FIG. 26; and / or(3) a DSC thermogram substantially in accordance with FIG. 27.

[0215] In another embodiment, Compound 1 Form E is characterized by (1) an XRPD pattern substantially in accordance with FIG. 25 and both of the following:(2) a TG-FTIR thermogram substantially in accordance with FIG. 26; and / or(3) a DSC thermogram substantially in accordance with FIG. 27.General Administration

[0216] Administration of the amorphous or crystalline forms of the present disclosure, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intraci stemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, and the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

[0217] The compositions will include a conventional pharmaceutical excipient and an amorphous or crystalline form of the present disclosure as the / an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, excipients, adjuvants, and so on. Compositions of the disclosure may be used in combination with anti cancer or other agents that are generally administered to a patient being treated for cancer. Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate, and gelatin.

[0218] If desired, a pharmaceutical composition of the disclosure may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan, monolaurate, triethanolamine oleate, butylated hydroxytoluene, and so on.

[0219] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous excipients, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0220] One preferable route of administration is oral, using a convenient daily dosage regimenthat can be adjusted according to the degree of severity of the disease-state to be treated.

[0221] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient such as sodium citrate or dicalcium phosphate or (a) fdlers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate, and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0222] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0223] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, and so on., crystalline forms of Compound 1, and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, and dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

[0224] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

[0225] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the crystalline forms of Compound 1 with for example suitable non-irritating excipients such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt while in a suitable body cavity and release the active component therein.

[0226] Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable excipient and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this disclosure.

[0227] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a crystalline form of Compound 1, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a crystalline form of Compound 1, with the rest being suitable pharmaceutical excipients.

[0228] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 21stEd., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006). The composition to be administered will, in any event, contain a therapeutically effective amount of a crystalline form of Compound 1 for treatment of a disease-state in accordance with the teachings of this disclosure.

[0229] The crystalline forms of Compound 1, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of Compound 1, the metabolic stability and length of action of Compound 1, the age, body weight, general health, sex, diet, mode, and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The crystalline forms of Compound 1 can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms,a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.Pharmaceutical Compositions, Treatment Methods, and Uses

[0230] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the solid forms provided herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.

[0231] The methods provided herein encompass administering pharmaceutical compositions comprising at least one solid form provided herein and one or more compatible and pharmaceutically acceptable carriers. The term “carrier” includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils including petroleum, animal, vegetable, or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions, aqueous dextrose, and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, E.W., Remington 's Pharmaceutical Sciences.

[0232] In clinical practice the pharmaceutical compositions, or compounds provided herein may be administered by any route known in the art. Exemplary routes of administration include, but are not limited to, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, a pharmaceutical composition or compound provided herein is administered parenterally.

[0233] The compositions for parenteral administration can be emulsions or sterile solutions. Parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions can also contain wetting, isotonizing, emulsifying, dispersing, and stabilizing agents. Sterilization can becarried out in several ways, for example, using a bacteriological filter, via radiation, or via heating. Parenteral compositions can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water, or any other injectable sterile medium.

[0234] In some embodiments, a composition provided herein is a pharmaceutical composition, or a single unit dosage form. Pharmaceutical compositions, and single unit dosage forms provided herein comprise a prophylactically, or therapeutically effective amount of one, or more prophylactic, or therapeutic compounds.

[0235] The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, wherein a person of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition, or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific compound in the dosage form. The composition, or single unit dosage form, if desired, can also contain minor amounts of wetting, or emulsifying agents, or pH buffering agents. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference herein in its entirety.

[0236] In some embodiments, the pharmaceutical composition comprises an anti-foaming agent. Any suitable anti-foaming agent may be used. In some aspects, the anti-foaming agent is selected from an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof. In some aspects, the anti-foaming agent is selected from a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long-chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycolpolypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0237] In some embodiments, the pharmaceutical composition comprises a co-solvent.Illustrative examples of co-solvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0238] In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0239] In some embodiments, the pharmaceutical composition comprises a carrier, or filler. Illustrative examples of carriers, or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0240] In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants, include -alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxy stearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E poly ethyl ene(gly col) succinate.

[0241] In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.

[0242] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), The Pharmaceutical Press, incorporated by reference herein in its entirety.

[0243] In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is saline solution, such as a sterile isotonic saline solution, or dextrose solution. In some aspects, the solvent is water for injection.

[0244] In some embodiments, the pharmaceutical compositions are in a particulate form, such as a microparticle or a nanoparticle. Microparticles, and nanoparticles may be formed from anysuitable material, such as a polymer, or a lipid. In some aspects, the microparticles, or nanoparticles are micelles, liposomes, or polymersomes.

[0245] Further provided herein are anhydrous pharmaceutical compositions, and dosage forms comprising a compound, since, in some embodiments, water can facilitate the degradation of some compounds.

[0246] Anhydrous pharmaceutical compositions, and dosage forms provided herein can be prepared using anhydrous, or low moisture containing ingredients, and low moisture, or low humidity conditions. Pharmaceutical compositions, and dosage forms that comprise lactose, and at least one active ingredient that comprises a primary, or secondary amine can be anhydrous if substantial contact with moisture, and / or humidity during manufacturing, packaging, and / or storage is expected.

[0247] An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0248] Lactose-free compositions provided herein can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopeia (USP) SP (XXI) / NF (XVI). In general, lactose-free compositions comprise an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible, and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.

[0249] Also provided are pharmaceutical compositions, and dosage forms that comprise one, or more excipients that reduce the rate by which a compound will decompose. Such excipients, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.Parenteral Dosage Forms

[0250] In certain embodiments, provided are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because theiradministration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically sterile, or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0251] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose, and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0252] Excipients that increase the solubility of one, or more of the antibodies disclosed herein can also be incorporated into the parenteral dosage forms.Dosage and Unit Dosage Forms

[0253] In human therapeutics, the doctor will determine the posology which he considers most appropriate according to a preventive, or curative treatment, and according to the age, weight, condition, and other factors specific to the subject to be treated.

[0254] In certain embodiments, a composition provided herein is a pharmaceutical composition, or a single unit dosage form. Pharmaceutical compositions, and single unit dosage forms provided herein comprise a prophylactically, or therapeutically effective amount of one, or more prophylactic, or therapeutic antibodies, or antigen binding fragments thereof.

[0255] The amount of the compound, or composition which will be effective in the prevention, or treatment of a disorder, or one, or more symptoms thereof will vary with the nature, and severity of the disease, or condition, and the route by which the compound is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro, or animal model test systems.

[0256] In certain embodiments, exemplary doses of a composition include milligram, or microgram amounts of the compound per kilogram of subject, or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). In certain embodiments, the dosage of the compound provided herein, based on weight of the compound, administered to prevent, treat, manage, or ameliorate a disorder, or one, or more symptoms thereof in a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of a subject’s body weight.

[0257] In another embodiment, the dosage of the composition, or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one, or more symptoms thereof in a subject is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0258] The dose can be administered according to a suitable schedule, for example, once, two times, three times, or four times weekly. It may be necessary to use dosages of the compound outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician, or treating physician will know how, and when to interrupt, adjust, or terminate therapy in conjunction with subject response.

[0259] Different therapeutically effective amounts may be applicable for different diseases, and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat, or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the antibodies, or antigen binding fragments thereof provided herein are also encompassed by the described dosage amounts, and dose frequency schedules herein. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic, or therapeutic effect of the composition, or it may be decreased to reduce one, or more side effects that a particular subject is experiencing.

[0260] In certain embodiments, treatment, or prevention can be initiated with one, or more loading doses of a compound, or composition provided herein followed by one, or more maintenance doses.

[0261] In certain embodiments, a dose of a compound, or composition provided herein can be administered to achieve a steady-state concentration of the compound in blood, or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight, and age.

[0262] In certain embodiments, administration of the same composition may be repeated, and the administrations may be separated by at least one day, two days, three days, five days, ten days, fifteen days, thirty days, forty-five days, two months, seventy-five days, three months, or six months. In other embodiments, administration of the same prophylactic, or therapeutic agent may be repeated, and the administration may be separated by at least one day, two days, three days, five days, ten days, fifteen days, thirty days, forty-five days, two months, seventy-five days, three months, or six months.Therapeutic Applications

[0263] For therapeutic applications, the compounds are administered to a mammal, in certain embodiments, a human, in a pharmaceutically acceptable dosage suitable for administration form such as those known in the art, and those discussed herein, intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intra-cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, or intratumoral routes. The compounds also are suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects. In certain embodiments, the compounds are administered to a mammal, in certain embodiments, a human, in a pharmaceutically acceptable dosage suitable for oral administration form such as those known in the art, and those discussed herein. For example, the compounds of this disclosure may be administered orally to a human as a liquid, or solid form. Solid dosage forms include capsules, tablets, pills, powders, and granules.

[0264] In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b)binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0265] The compounds provided herein may be useful for the treatment of any disease or condition described herein (e.g., a metabolic disease or condition). In certain embodiments, the disease, or condition is any disease, or condition that benefits from modulation of GLP-1 receptor activity. In certain embodiments, the disease, or condition is any disease, or condition that benefits from agonizing GLP-1 receptor activity. In certain embodiments, the methods reduce blood glucose levels. In certain embodiments, the methods promote insulin synthesis, stimulate insulin secretion, increase the mass of P-cells, modulate gastric acid secretion, modulate gastric emptying, and / or decrease glucagon production. In certain embodiments, the disease, or condition is type 2 diabetes.

[0266] In certain embodiments, the disease, or condition is obesity, or one, or more diseases, or conditions associated with obesity. Non-limiting examples of obesity, and obesity related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal adiposity). Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, or -blocker-induced obesity). In certain embodiments, the disease or condition is obesity with diabetes. In certain embodiments, the disease or condition is obesity without diabetes.

[0267] Examples of such diseases, and conditions associated with obesity include, withoutlimitation, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism abnormality, hyperlipidemia, hypertension, cardiac failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., brain thrombosis, transient cerebral ischemic attack), bone, or articular disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorder (e.g., abnormal menstrual cycle, abnormality of menstrual flow and cycle, amenorrhea, abnormal catamenial symptom), visceral obesity syndrome, and metabolic syndrome. In certain embodiments, the compounds described herein can be used to treat subjects exhibiting symptoms of both obesity, and insulin deficiency.

[0268] In some embodiments, the disease, or condition is diabetes. Non-limiting examples of diabetes include, type 1 diabetes, type 2 diabetes (e.g., diet-treated type 2-diabetes, sulfonylurea- treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin-treated type 2- diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline type diabetes.

[0269] In some embodiments, the disease or condition is associated with diabetes (e.g., a complication of diabetes). Non-limiting examples of disorders associated with diabetes include, obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, diabetic cachexia, delayed wound healing, diabetic dyslipidemia peripheral blood circulation disorder, cardiovascular risk factors, (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to unmanaged cholesterol, and / or lipid levels, and / or inflammation), NASH, bone fracture, and cognitive dysfunction

[0270] Other non-limiting examples of diseases, or conditions related to diabetes include, prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL- cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), metabolic syndrome(e.g., metabolic disorder where activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0271] In some embodiments, the disease, or condition is diabetes, and obesity (diabesity). In certain embodiments, the compounds described herein are useful in improving the therapeutic effectiveness of metformin.

[0272] In some embodiments, the disease or condition is a disorder of a metabolically important tissue.

[0273] In some embodiments, the disease, or condition is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty acid liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) , steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, Abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, Wolmans disease, acute fatty liver of pregnancy, and lipodystrophy.

[0274] Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease occurring in the absence of alcohol abuse, and is typically characterized by the presence of steatosis (fat in the liver). NAFLDis believed to be linked to a variety of conditions, e.g., metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia), and insulin resistance. It can cause liver disease in adults and children, and may ultimately lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from the relatively benign isolated predominantly macrovesicular steatosis (i.e., nonalcoholic fatty liver orNAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 SuppkS 186-90). In certain embodiments, the subject is a pediatric subject (e.g., 6-16 years old; or 6-12 years old; or 6-10 years old). In certain embodiments, the subject is an adult subject.

[0275] Other non-limiting examples of diseases, or conditions in metabolically important tissues include, joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g. in the liver); gall stones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorder characterized by altered bone metabolism, such as osteoporosis, including postmenopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastasisin cancer patients, osteodystrophy in liver disease, and the altered bone metabolism caused by renal failure, or hemodialysis, bone fracture, bone surgery, aging, pregnancy, protection against bone fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pectoris, acute, or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndrome. In certain embodiments, the chemical entities described herein can be used for treating surgical trauma by improving recovery after surgery, and / or by preventing the catabolic reaction caused by surgical trauma.

[0276] In some embodiments, the disease, or condition is a cardiovascular disease. Non-limiting examples of cardiovascular disease include, congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, or peripheral artery disease, stroke, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, cardiac failure, cerebrovascular disorder (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130 / 85 mm Hg or higher), and prothrombotic state (exemplified by high fibrinogen, or plasminogen activator inhibitor in the blood).

[0277] In some embodiments, the disease, or condition is a neurological disorder (e.g., neurodegenerative disorder), or a psychiatric disorder. Non-limiting examples of neurological disorders include, brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson, steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve trauma, brain trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), chronic wasting syndrome).

[0278] Non-limiting examples of psychiatric disorders include drug dependence / addiction (narcotics, amphetamines, and attention deficit / hyperactivity disorder (ADHD). The chemical entities described herein can be useful in improving behavioral response to addictive drugs, decreasing drug dependence, prevention drug abuse relapse, and relieving anxiety caused by the absence of a given addictive substance.

[0279] In certain embodiments, the chemical entities described herein are useful in improving learning, and memory by enhancing neuronal plasticity, and facilitation of cellular differentiation, and also in preserving dopamine neurons, and motor function in Morbus Parkinson.

[0280] In some embodiments, the disease, or condition is impaired fasting glucose (IFG), impaired fasting glycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids, or glycerol, a hypoglycemic condition, insulin resistant syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesteremia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperuric acidemia, hypoglycemia (e.g., nighttime hypoglycemia), and concomitant comatose endpoint associated with insulin.

[0281] In certain embodiments, the compounds described herein can reduce, or slow down the progression of borderline type, impaired fasting glucose, or impaired fasting glycemia into diabetes.

[0282] In some embodiments, the disease, or condition is an autoimmune disorder. Non-limiting examples of autoimmune disorders include, multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder is associated with immune rejection, graft versus host disease, uveitis, optic neuropathies, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves’ disease.

[0283] In some embodiments, the disease, or condition is a stomach, or intestine related disorder. Non-limiting examples of these disorders include, ulcers of any etiology (e.g. peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers related to infections, or other pathogens), digestion disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel diseases (Crohn’s disease, and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy, and / or radiation therapy-induced mucositis, and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancerous cachexia, tuberculous cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious disease, cachexiacaused by acquired immunodeficiency syndrome).

[0284] In some embodiments, the compounds described herein can be used to reduce body weight (e.g., excess body weight), prevent body weight gain, induce weight loss, decrease body fat, or reduce food intake in a subject (e.g., a subject in need thereof). In certain embodiments, the weight increase in a subject may be attributed to excessive ingestion of food, or unbalanced diets, or may be weight increase derived from a concomitant drug (e.g., insulin sensitizers having a PPARy agonist-like action, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, and the like). Alternatively, the weight increase may be weight increase before reaching obesity, or may be weight increase in an obese subject. The weight increase may also be medication-induced weight gain, or weight gain subsequent to cessation of smoking. In some embodiments, the compounds described herein can be used to maintain body weight following weight loss, In certain embodiments, the weight loss is caused by injectable medications. In certain embodiments, the injectable medication is selected from the group consisting of CT-388, CT-868, Mounjaro®, Zepbound®, Wegovy®, Ozempic®, Zepbound®, and Saxenda®, as well as others.

[0285] In some embodiments, the condition, disease, or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, or compulsive eating.

[0286] In some embodiments, the disease, or condition is an inflammatory disorder. Nonlimiting examples of inflammatory disorders include, chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, lumbago, gout, post-operational or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory large bowel disease), inflammation in metabolically important tissues including liver, fat, pancreas, kidney, and gut, and a proinflammatory state (e.g., elevated levels of proinflammatory cytokines or, markers of inflammation-like C-reactive protein in the blood).

[0287] In some embodiments, the disease, or condition is cancer. Suitable examples of cancer include, breast cancer (e.g., invasive ductal breast cancer, noninvasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone- independent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small-cell lung cancer, malignant mesothelioma), coloncancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestinal cancer (e.g., non-Hodgkin's lymphoma, gastrointestinal stromal tumor), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharynx cancer, hypopharyngeal cancer), salivary gland cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), neurilemmoma, liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer), renal cancer (e.g., renal cell cancer, transitional cell cancer of the renal pelvis and ureter), bile duct cancer, endometrial cancer, uterine cervical cancer, ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor of low malignant potential), bladder cancer, urethral cancer, skin cancer (e.g., intraocular (ocular) melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid cancer), parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumor (e.g., osteosarcoma, Ewing tumor, uterine sarcoma, soft tissue sarcoma), angiofibroma, sarcoma of the retina, penis cancer, testicular tumor, pediatric solid tumor (e.g., Wilms’ tumor, childhood kidney tumor), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, tumor of maxillary sinus, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0288] In certain embodiments, provided herein are methods for the treatment that include the administration of an effective amount of compounds provided herein. In certain embodiments, the methods encompass the step of administering to the subject in need thereof an amount of a compound described herein effective for the treatment of disease, or condition in combination with a second agent effective for the treatment, or prevention of the disease, or condition. In certain embodiments, the compound is in the form of a pharmaceutical composition, or dosage form, as described elsewhere herein.

[0289] In certain embodiments, the subject is a treatment naive subject. In further embodiments, the subject has previously received therapy. For instance, in certain embodiments, the subject has not responded to a single agent treatment regimen. In some embodiments, the subject has received a prior incretin treatment. In some embodiments, the incretin treatment is selected from exenatide (Byetta®, Bydureon®), liraglutide (Victoza®), sitagliptin (Januvia®, Janumet®, Janumet® XR, Juvisync®), saxagliptin (Onglyza®, Kombiglyze® XR), alogliptin (Nesina®,Kazano®, Oseni®), linagliptin (Tradjenta®, Jentadueto®), semaglutide, Wegovy®, Mounjaro®, and Rybelsus®, as well as others.

[0290] In certain embodiments, the subject is a subject that discontinued some other therapy because of one or more adverse events associated with the other therapy. In certain embodiments, the subject has received some other therapy and discontinued that therapy prior to administration of a method provided herein. In further embodiments, the subject has received therapy and continues to receive that therapy along with administration of a compound provided herein. The compounds described herein can be co-administered with other therapy for treatment of the disease or condition according to the judgment of one of skill in the art. In certain embodiments, the methods or compositions provided herein can be co-administered with a reduced dose of the other therapy for the treatment of the disease or condition.Kits

[0291] In some embodiments, a compound provided herein is provided in the form of a kit (i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure). In some embodiments, the procedure is a diagnostic assay. In certain embodiments, the procedure is a therapeutic procedure.

[0292] In some embodiments, the kit further comprises a solvent for the reconstitution of the compound. In some embodiments, the compound is provided in the form of a pharmaceutical composition.

[0293] In some embodiments, the kits can include a compound, or composition provided herein, an optional second agent, or composition, and instructions providing information to a health care provider regarding usage for treating the disorder. Instructions may be provided in printed form, or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a compound, or a composition provided herein, or a second agent, or composition, can include a dosage such that when administered to a subject, a therapeutically, or prophylactically effective plasma level of the compound, or composition can be maintained in the subject for at least one day. In some embodiments, a compound, or composition can be included as a sterile aqueous pharmaceutical composition, or dry powder (e g., lyophilized) composition.

[0294] In some embodiments, suitable packaging is provided. As used herein, “packaging”includes a solid matrix, or material customarily used in a system, and capable of holding within fixed limits a compound provided herein, and / or a second agent suitable for administration to a subject. Such materials include glass, and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, plastic-foil laminated envelopes, and the like. If e- beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.Labeled Compounds and Assay Methods

[0295] Another aspect relates to labeled crystalline forms of the present disclosure (radio- labeled, fluorescent-labeled, and so on) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo.

[0296] The present disclosure further includes isotopically-labeled crystalline forms of the present disclosure. An “isotopically” or “radio-labeled” compound is a crystalline form of the present disclosure where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (that is, naturally occurring). Suitable radionuclides that may be incorporated in crystalline forms of the present disclosure include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),UC,13C,14C,13N,15N,15O,17O,18O,18F,35S,36C1,82Br,75Br,76Br,77Br,123I,124I,125I, and131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro metalloprotease labeling and competition assays, compounds that incorporate3H,14C,82Br,125I,131I, or35S will generally be most useful. For radio-imaging applicationsnC,18F,125I,123I,124I,131I,75Br,76Br, or77Br will generally be most useful. In some embodiments, the crystalline forms described herein in which one or more hydrogens is / are replaced by deuterium, such as hydrogen bonded to a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. They can also be useful as tools for pharmacokinetic studies.

[0297] It is understood that a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of3H,14C,1251,35S, and82Br.

[0298] The present disclosure can further include synthetic methods for incorporating radioisotopes into crystalline forms of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and a person of ordinary skill in the art will readily recognize the methods applicable for the compounds of disclosure.

[0299] A labeled compound of the disclosure can be used in a screening assay to identify / evaluate compounds. For example, a newly synthesized or identified compound (that is, test compound) which is labeled can be evaluated. Conversely, in some other screening assays, the standard compound is labeled, and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.EXAMPLESInstrumental Techniques

[0300] X-Ray Powder Diffraction (XRPD)

[0301] XRPD Method 1

[0302] XRPD Method 2

[0303] XRPD Method 3

[0304] X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu Kai radiation, primary Ge-monochromator, Mythen IK silicon strip detector, angular range 3° to 42° 2Theta, 0.02° 2Theta step size, 20 seconds measurement time per step). The samples were prepared and analyzed without further processing (e.g., grinding or sieving) of the substance.

[0305] Measurement and evaluation of the X-ray diffraction data was done using WinXPOW software (STOE & Cie GmbH, Darmstadt, Germany).

[0306] Compound 1 Form A was recorded in reflection geometry (Method 1 and Method 2) and this transmission geometry (Method 3).

[0307] XRPD Method 4

[0308] The Compound 1 Form E X-ray diffraction pattern was recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu Kai radiation, primary Ge-monochromator, Mythen IK silicon strip detector, angular range 1.5° to 50.5° 2Theta, 0.02° 2Theta step size, 12 seconds measurement time per step).

[0309] Differential Scanning Calorimetry (DSC)

[0310] Modulated Differential Scanning Calorimetry (mDSC)

[0311] Thermal Gravimetric Analysis (TGA)

[0312] Dynamic Vapor Sorption (DVS)

[0313] Scanning Electron Microscopy (SEM)

[0314] Nuclear Magnetic Resonance (NMR)

[0315] Fourier Transform Infrared Spectroscopy (FT-IR)

[0316] High Performance Liquid Chromatography (HPLC) (For Solubility)

[0317] High Performance Liquid Chromatography (Except for Solubility)

[0318] Singel Crystal X-ray DiffractometerInstrument: Bruker D8 VentureMethod:Example 1: Polymorph StudiesEquilibration with solvents at 25°C for 2 weeks

[0319] About 50 mg of Compound 1 was equilibrated in 0.1-0.5 m of a solvent or solvent mixture selected from water, methanol, ethanol, acetone, acetonitrile, THF, ethyl acetate, isopropyl acetate, DCM, MEK, MTBE, n-heptane, 2-MeTHF, toluene, 1,4-dioxane, DMSO, THF / Heptane (50:50 v:v), DCM.MTBE (50:50 v:v), water / ethanol (50:50 v:v)(a.w.= 0.9; water activity calculated by the UNIFAC method), and water / THF (50:50 v:v)(a.w.= 0.9; water activity calculated by the UNIFAC method) at 25°C for 2 weeks with a stirring bar on a magnetic stirring plate at a rate of 400 rotations per minute (rpm). Obtained suspensions were filtered through a 0.45pm nylon membrane filter by centrifugation.

[0320] Compound 1 Form A was obtained from the following solvents or solvent mixtures: water, methanol, ethanol, acetone, acetonitrile, THF, ethyl acetate, dichloromethane (DCM), MEK, MTBE, 2-Me THF, 1,4-dioxane, DMSO, THFZ / / -heptane (50:50,v:v), DCM / MTBE (50:50, v:v), Water / Ethanol (50:50, v:v), and Water / THF (50:50, v:v).

[0321] Form D was obtained from w-heptane.Equilibration with solvents at 50°C for one week

[0322] About 100 mg of Compound 1 was equilibrated in 0.1-0.5 m of a solvent or solvent mixture selected from water, methanol, ethanol, acetone, acetonitrile, THF, ethyl acetate, isopropyl acetate, DCM, MEK, MTBE, heptane, 2-MeTHF, toluene, 1,4-dioxane, DMSO, THF / Heptane (50:50 v:v), DCM.MTBE (50:50 v:v), water / ethanol (50:50 v:v)(a.w.= 0.9; water activity calculated by the UNIFAC method), and water / THF (50:50 v:v)(a.w.= 0.9; water activity calculated by the UNIFAC method)at 50°C for one week with a stirring bar on a magnetic stirring plate at a rate of 400 rpm. Obtained suspensions were filtered through a 0.45 pm nylon membrane filter by centrifugation at 14,000 rpm.

[0323] Compound 1 Form A was obtained from the following solvents or solvent mixtures: water, methanol, ethanol, acetone, acetonitrile, THF, ethyl acetate, MEK, MTBE, 2-Me THF, toluene, 1,4-dioxane, DMSO, THF / heptane (50:50, v:v), water / ethanol (50:50, v:v), and water / THF (50:50, v:v).Equilibration under a temperature cycle

[0324] About 50 mg of Compound 1 was equilibrated in 0.1-0.5 m of a solvent or solvent mixture selected from water, methanol, ethanol, acetone, acetonitrile, THF, ethyl acetate, isopropyl acetate, DCM, MEK, MTBE, heptane, 2-MeTHF, toluene, 1,4-dioxane, DMSO, THF / Heptane (50:50 v:v), DCM.MTBE (50:50 v:v), water / ethanol (50:50 v:v), and water / THF (50:50 v:v) under a temperature cycle between 5°C to 50°C at a heating / cooling rate of 0.1°C / min for 10 cycles. The equilibration was executed with a stirring bar on a magnetic stirring plate at a rate of 400 rpm. Obtained suspensions were filtered through a 0.45 pm nylon membrane filter by centrifugation at 14,000 rpm.

[0325] Form A was obtained from the following solvents or solvent mixtures: water, methanol, ethanol, acetone, acetonitrile, THF, ethyl acetate, MEK, MTBE, 2-Me THF, toluene, 1,4- dioxane, DMSO, THF / heptane (50:50, v:v), water / ethanol (50:50, v:v), and water / THF (50:50, v:v).Crystallization at room temperature by slow evaporation

[0326] About 50 mg of Compound 1 was dissolved in 1.0-2.0 mL of a solvent or solvent mixture selected from methanol, ethanol, acetone, THF, ethyl acetate, DCM, MEK, and 2 -Me THF. Obtained solutions were filtered through a 0.45 pm syringe nylon membrane filter. The clear solutions were slowly evaporated in ambient condition (about 25°C, 60-80% RH).

[0327] Compound 1 Form A was obtained from acetone, ethyl acetate, MEK, and 2-Me THF.

[0328] The amorphous form was obtained from THF and DCM.Crystallization at room temperature by fast evaporation

[0329] About 50 mg of Compound 1 was dissolved in 1.0-2.0 mL of solvents. Obtained solutions were filtered through a 0.45pm syringe nylon membrane filter. The clear solutions were fast evaporated at room temperature (about 25°C) under a dry nitrogen flow.

[0330] Compound 1 Form A was obtained in solvents including ethanol, acetone, and MEK.

[0331] The amorphous form was obtained from methanol, THF, ethyl acetate, DCM, and 2-Me THF.Crystallization from hot saturated solutions by slow cooling

[0332] About 50 mg of Compound 1 was dissolved in the minimal amount of selected solvents at 50°C. Obtained solutions were filtered through a 0.45pm syringe membrane filter. The clear solutions were cooled to 5°C at 0.1°C / min. Mixtures without precipitates at 5°C were further cooled to -20°C. Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000 rpm.

[0333] Form A was obtained from methanol and 1, 4-di oxane.

[0334] Form C was obtained from ethanol

[0335] Form D was obtained from acetonitrile.Crystallization from hot saturated solutions by fast cooling

[0336] About 50 mg of Compound 1 was dissolved in the minimal amount of selected solvents at 50 °C. Obtained solutions were filtered through a 0.45 pm syringe membrane filter. The clear solutions were put into a 0 °C ice bath and agitated. Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000 rpm.

[0337] Form A was obtained from ethanol, MEK, 2-Me THF, and 1,4-di oxane.

[0338] Form B was obtained from methanol.

[0339] Form D was obtained from acetonitrile.Crystallization by addition of anti-solvent

[0340] About 50 mg of Compound 1 was dissolved in the minimal amount of selected good solvents at ambient temperature (about 25 °C). Obtained solutions were filtered through a 0.45 pm syringe membrane filter. 1-4 folds of anti-solvent were added into the clear solutions slowly until a large amount of solids precipitated out. Precipitates were collected by centrifugation filtration through a 0.45 pm nylon membrane filter at 14,000 rpm.

[0341] Form A was obtained from acetone / water (solvent / anti-solvent) and DMSO / water.

[0342] Form B was obtained from acetone / MTBE.Crystallization by reverse addition of anti-solvent

[0343] About 50 mg of Compound 1 was dissolved in the minimal amount of selected good solvents at ambient temperature (about 25 °C). Obtained solutions were filtered through a 0.45 pm syringe membrane filter. The clear solutions were added into 4 folds of anti-solvent quickly. Precipitates were collected by centrifugation filtration through a 0.45 pm nylon membrane filter at 14,000 rpm.

[0344] Form A was obtained from acetone / water (solvent / anti-solvent) and DMSO / water.

[0345] Form B was obtained from acetone / MTBE.Example 2: Scale up of Compound 1 Form A

[0346] Compound 1 (0.3 g) was weighed into an 8 mL glass vial. 2 mL of MeOH was added into the vial under stirring at 25 °C for about 5 min and 2.0 mg of Compound 1 Form A seeds were added to the clear solution and kept stirring at 25 °C for about 1 day to afford a suspension. The suspension was then stirring at 5 °C for about 12 hours. Solids were collected by centrifugation and investigated by XRPD. Compound 1 Form A was obtained as an off-white solid (200 mg, 66% yield). Compound 1 Form A is an anhydrate. The XRPD pattern for Compound 1 Form A was recorded in both reflection geometry and transmission geometry, and is provided in Fig. 5A and Fig. 5B, respectively. The lists of the peaks from the XRPD in reflection and transmissiongeometry are provided in Table 1 below.Table 1. XRPD Peaks of Compound 1 Form A

[0347] Single crystals of Compound 1 were obtained by slow evaporation from ethanol. The crystal structure was determined from the obtained single crystals. Based on single crystal data, the single crystal is crystallized in Orthorhombic system, P2i2i2i space group with Rint= 5.1%, the final R1 = [I>2o(I)] = 0.039 at 170K and Flack parameter = 0.09. No solvent molecule was contained in the single crystal. The Ortep image (FIG. 28) obtained from the single crystal data confirms the structure and absolute configuration of Compound 1. The simulated XRPD pattern based on the single crystal data is in accordance with the powder XRD of Form A (Fig. 5A). Therefore, the single crystal structure corresponds to the structure of Compound 1 Form A. The single crystal data is shown below.

[0348] The behavior of Compound 1 Form A was also investigated in the presence of variable water vapor pressure at 25°C using DVS. Fig 9A and Fig. 9B show the change of the relative sample weight as a function of time and function of relative humidity, respectively. The relative sample weight was calculated from the mass change of the sample during the DVS measurement. By decreasing the relative humidity to 0%, the sample lost approx. 0.2% of weight. Then, a massuptake of 0.5% was observed when the relative humidity was increased to 95% and equilibrated for 5 hours. The sample lost 0.5% of mass by decreasing the relative humidity again to 0%. At 85% relative humidity, the mass change was 0.13% above the initial mass. Thus, Compound 1 Form A is considered as non-hygroscopic according to the European Pharmacopoeia.

[0349] After the DVS measurement, the sample was recovered and submitted for XRPD analysis. The obtained XRPD pattern is identical to the starting Compound 1 Form A, meaning no irreversible form conversion was observed during the DVS measurement.Example 3: Scale up of Compound 1 Form B

[0350] Compound 1 (0.1 g) was weighed into 20 mL glass vial. 3.0 mL of acetone was added into the vial under stirring at 25 °C for about 5 min to obtain a solution. The obtained solution was filtered through a 0.45 gm syringe membrane filter to afford a clear solution. Compound 1 Form B seeds (2.0 mg) and 12mL of methyl tert-butyl ether (MTBE) were added into the clear solution and stirred at 25°C for about 3 days to afford a suspension. Solids were collected by centrifugation and investigated by XRPD in reflection geometry. Compound 1 Form B was obtained as an off-white solid (40 mg, 40% yield). Compound 1 Form B is an anhydrate. The XRPD pattern for Compound 1 Form A is provided in Fig. 12, and a list of the peaks from the XRPD is provided in Table 2 below.Table 2. XRPD Peaks of Compound 1 Form BExample 4: Compound 1 Form C

[0351] Compound 1 Form C was obtained from EtOH by slow cooling as provided in Example1. Form C is an anhydrate. DSC shows a first melting peak at Tonset of 140.2 °C, a second melting peak at Tonsct of 149.4 °C, and a third melting peak at Tonset of 176.2 °C. TGA shows about 0.1% weight loss at about 100 °C. 'H-NMR shows no detectable residual solvent. The XRPD pattern for Compound 1 Form C in reflection geometry is provided in Fig. 16, and a list of the peaksfrom the XRPD is provided in Table 3 below.Table 3. XRPD Peaks of Compound 1 Form CExample 5: Scale up of Compound 1 Form D

[0352] Compound 1 (0.1 g) was weighed into an 8 mL glass vial. 5.0 mL of ACN was added into the vial under stirring at 50 °C for about 5min to obtain a solution. Obtained solution was filtered through a 0.45 pm syringe membrane filter to afford a clear solution. Compound 1 Form D seeds (2.0 mg) were added into the clear solution. Then the clear solution was put into a 0 °C ice bath and agitated for one day to afford a suspension. Solids were collected by centrifugation and investigated by XRPD in reflection geometry. Compound 1 Form D was obtained as an off- white solid (50 mg, 50% yield). Compound 1 Form D is an anhydrate. The XRPD pattern for Compound 1 Form D is provided in Fig. 20, and a list of the peaks from the XRPD is provided in Table 4 below.Table 4. XRPD Peaks of Compound 1 Form DExample 6: Relative Stability Testing

[0353] Compound 1 Form A, Form B, and Form D competitive equilibration experiments wereconducted in different solvent systems. About 3 mg each of Form A, Form B, and Form D were added to 0.5 mL saturated solutions of a solvent selected from methanol, ethanol, and acetonitrile. Obtained suspensions were stirred at 5 °C, at 25 °C and at 50 °C for 4 days, respectively. Solid parts (wet cakes) were isolated by centrifugation fdtration and investigated by XRPD. Table 5 below show the results of the relative stability testing.Table 5. Results of Competitive Equilibration Testing

[0354] Table 5 shows that in all the solvent systems tested, and at low, ambient, and high temperatures, only Form A was obtained. Thus, based on the relative stability testing that was performed, Form A appears to be the most thermodynamically stable crystalline form of Compound 1.

[0355] Fig. 24 shows the inter conversion relationship between the Crystalline Forms A, B, C, and D of Compound 1, and indicates that under the testing conditions, Form B, Form C, and Form D and the amorphous form all convert to Form A.Example 7: Bulk Stability of Compound 1 Form A

[0356] Compound 1 Form A and Form D were each placed at 25°C / 92.5% RH in an open container, at 40°C / 75% RH in an open container, and at 60°C in a closed container for 1 week, respectively. The samples after the stress were characterized by XRPD and HPLC and inspected for color change. Table 6 shows the test results.Table 6. Results of Competitive 1 Form A and Form D Bulk StabilityExample 8: Solubility of Compound 1 Form A and Form D

[0357] Compound 1 Form A (10 mg) was weighed into a 20 mL glass vial. 5 mL of solubility medium as listed in Table 7 below was added. The obtained suspensions were stirred at 37°C at 400 rpm and sampled at 2 hours and at 24 hours. The samples were centrifuged at 37°C at 14,000 rpm for 5min. Supernatants were analyzed by HPLC for solubility. Residual solids (wet cakes) from the 24-hour samples were also characterized by XRPD, and were found to be Compound 1 Form A.

[0358] Compound 1 Form D (8 mg) was weighed into an 8 mL glass vial. 4mL of solubility medium as listed in Table 7 below was added. The obtained suspensions were stirred at 37°C at 600 rpm and sampled at 2 hours and at 24 hours. The suspensions were filtered, and the filtrates were analyzed by HPLC for solubility. The collected solids (wet cakes) from the 24 hours samples were also characterized by XRPD to show that the solid form remained as Form D.Table 7. Results of Compound 1 Form A and Form D Solubility TestingExample 9: Compound 1 Form A Compression Simulation Testing

[0359] Compound 1 Form A (10 mg) was compressed for 5 minutes under 2 MPa, 5 MPa and 10 MPa with a hydraulic press. Potential form change and degree of crystallinity were evaluated by XRPD. Table 4 shows the test results.Table 8. Results of Compound 1 Form A Compression Simulation Testing

[0360] Example 10: Compound 1 Form A Wet Granulation Simulation Testing

[0361] Water was added drop wise to about 10 mg of Compound 1 Form A until the sample was wetted sufficiently. The wet sample was ground gently in a mortar and a pestle for 5 min. The post granulation sample was dried under ambient condition for 10 min and evaluated by XRPD. Form A showed good tolerance to compression with no form change and no obvious crystallinity decrease.

[0362] Example 11: Compound 1 Form E

[0363] Compound 1 amorphous material was dissolved in methanol at room temperature. After 10 minutes of stirring, a precipitate was observed, which was crystalline and designated as Compound 1 Form E. Compound 1 Form E was also obtained from spontaneous precipitation of the amorphous material in a methanol / water 4 : 1 (v / v) mixture. Compound 1 Form E is anhydrous and also solvent-free. The XRPD pattern for Compound 1 Form E in transmission geometry is provided in Fig. 25, and a list of the peaks from the XRPD is provided in Table 9 below.Table 9. XRPD Peaks of Compound 1 Form E

[0364] Compound 1 Form E was characterized by TG-FTIR, and the obtained thermogram is depicted in Fig. 26. Only 0.18% of water loss was observed from 23°C to 220°C. No methanol was detected. This result suggests that the new form is a polymorph rather than a solvated form.

[0365] Form E was also investigated by DSC with a heating rate of 10°C / min using a sample pan with hermetic lid, and the DSC thermogram is shown in Fig. 27. DSC revealed a melting peak at 178.1°C with an onset at 176.6°C and an enthalpy of 78.53 J / g.

[0366] Example 12: Competitive Slurry Experiment Between Form A and Form E

[0367] The relative stability of Form A and Form E was evaluated in competitive slurry experiments at three different temperatures using various solvent systems. For all the conducted experiments, Form A was first equilibrated in the selected solvent and at the desired temperature for at least 10 minutes. Form E (2 mg - 20 mg) was then added to the resulting suspension. Theobtained suspensions were then equilibrated under magnetic stirring for two weeks at room temperature or 5°C and for 6 days at 65°C. The materials were then isolated by filter centrifugation, and the wet cakes were submitted for XRPD analysis. The obtained results are summarized in Table 10 below.Table 10. Competitive Slurry Experiment Between Form A and Form E

[0368] Form A was obtained in all the experiments, suggesting that Form A is more stable than Form E, over at least temperature range 5°C to 65°C.Other Embodiments

[0369] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The disclosure has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the disclosure. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive.

[0370] The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

CLAIMS1. A crystalline form of Compound 1Compound 1 wherein the crystalline form of Compound 1 is selected from Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, Compound 1 Form D, Compound 1 Form E, and mixtures thereof.

2. The crystalline form of claim 1, wherein the crystalline form of Compound 1 is selected from Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, Compound 1 Form D, and Compound 1 Form E.

3. The crystalline form of claim 1 or 2, which is a solvate, hydrate, or anhydrate of Compound 1.

4. The crystalline form of any one of claims 1-3, characterized as Compound 1 Form A.

5. The crystalline form of any one of claims 1-4, wherein Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

6. The crystalline form of any one of claims 1-5, wherein Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising a peak at 20.57.

7. The crystalline form of any one of claims 1-6, wherein Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

8. The crystalline form of any one of claims 1-7, wherein Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.53, 20.57, and 23.81.

9. The crystalline form of any one of claims 1-8, wherein Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising five or more peaks selected from 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

10. The crystalline form of any one of claims 1-9, wherein Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.53, 10.83, 14.24, 20.57, and 23.81.

11. The crystalline form of any one of claims 1-10, wherein Compound 1 Form A is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising all of the peaks at 6.05, 9.53, 10.83, 11.95, 12.80, 12.88, 13.27, 14.24, 15.03, 15.71, 17.51, 18.00, 18.55, 19.51, 20.00, 20.57, 21.10, 21.50, 22.08, 22.46, 23.64, 23.81, 24.55, 25.22, 25.43, 27.07, 27.97, 28.53, 29.19, 29.64, 29.96, 31.63, 32.58, 34.44, 35.09, and 35.54.

12. The crystalline form of any one of claims 1-4, wherein Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42,20.94, 21.30, 21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18,27.82, 28.41, 29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46.

13. The crystalline form of any one of claims 1-4 or 12, wherein Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising a peak at 20.42.

14. The crystalline form of any one of claims 1-4 or 12, wherein Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.35, 20.42, and 23.66.

15. The crystalline form of any one of claims 1-4 or 12, wherein Compound 1 Form A is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.35, 14.07, 20.42, 22.31, and 23.66.

16. The crystalline form of any one of claims 1-4 or 12, wherein Compound 1 Form A is characterized by an XRPD in transmission geometry pattern on a 2 Theta scale, ± 0.20, comprising all of the peaks at 5.86, 9.35,9.61, 10.66, 11.77, 12.54, 12.75, 13.10, 14.07, 14.78, 14.94, 15.55, 17.24, 17.40, 17.83, 18.07, 18.37, 18.61, 19.31, 19.55, 19.85, 20.42, 20.94, 21.30,21.43, 21.91, 22.31, 23.35, 23.66, 24.40, 25.01, 25.31, 25.64, 26.41, 26.91, 27.18, 27.82, 28.41,29.00, 29.45, 29.83, 31.26, 31.56, 32.49, 32.84, 33.31, 33.73, 34.34, 34.94, 35.29, and 35.46.

17. The crystalline form of any one of the preceding claims, wherein Compound 1 Form A is characterized by an XRPD pattern substantially in accordance with FIG. 5A or FIG. 5B.

18. The crystalline form of any one of the preceding claims, wherein Compound 1 Form A is characterized by a DSC thermogram substantially in accordance with FIG. 6.

19. The crystalline form of any one of the preceding claims, wherein Compound 1 Form A is characterized by an endotherm with an onset temperature of about 180.0 °C and / or a peaktemperature of about 182 °C in a DSC thermogram.

20. The crystalline form of any one of the preceding claims, wherein the Compound 1 Form A is characterized by a TGA thermogram substantially in accordance with FIG. 7.

21. The crystalline form of any one of claims 1-3, characterized as Compound 1 Form B.

22. The crystalline form of claim 21, wherein Compound 1 Form B is characterized by anXRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93,25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36,31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.8423. The crystalline form of claim 22, wherein Compound 1 Form B is characterized by anXRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising a peak at 19.37.

24. The crystalline form of claim 21, wherein Compound 1 Form B is characterized by anXRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49, 21.03, 21.19, 21.74, 22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93,25.43, 26.01, 26.42, 26.61, 26.81, 27.34, 28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36,31.50, 32.21, 32.88, 33.44, 34.08, 35.21, 35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.8425. The crystalline form of claim 24, wherein Compound 1 Form B is characterized by anXRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 10.42, 13.32, and 19.37.

26. The crystalline form of claim 24, wherein Compound 1 Form B is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising peaks at 10.42, 13.32, 17.67, 19.37, and 26.01.

27. The crystalline form of claim 21, wherein Compound 1 Form B is characterized by anXRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising all of the peaks 9.67, 10.42, 11.40, 13.32, 13.80, 14.82, 15.63, 16.80, 17.67, 18.00, 18.77, 19.10, 19.37, 19.80, 20.49,21.03, 21.19, 21.74, 22.22, 22.57, 22.81, 22.93, 23.86, 24.21, 24.50, 24.93, 25.43, 26.01, 26.42,26.61, 26.81, 27.34, 28.01, 28.47, 28.72, 29.03, 29.25, 29.83, 30.52, 31.36, 31.50, 32.21, 32.88,33.44, 34.08, 35.21, 35.61, 36.45, 36.97, 37.45, 39.10, 39.57, and 39.8428. The crystalline form of claim 21, wherein Compound 1 Form B is characterized by an XRPD pattern substantially in accordance with FIG. 12.

29. The crystalline form of any one of claims 21-28, wherein Compound 1 Form B is characterized by a DSC thermogram substantially in accordance with FIG. 13.

30. The crystalline form of any one of claims 21-29, wherein the Compound 1 Form B is characterized by a TGA thermogram substantially in accordance with FIG. 14.

31. The crystalline form of any one of claims 1-3, characterized as Compound 1 Form C.

32. The crystalline form of claim 31, wherein Compound 1 Form C is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07, 19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66, 27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77.

33. The crystalline form of claim 31, wherein Compound 1 Form C is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76, 17.23, 17.69, 18.81, 19.07, 19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66, 27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77.

34. The crystalline form of claim 31, wherein Compound 1 Form C is characterized by anXRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising all of the peaks 5.89, 8.61, 9.66, 9.90, 10.38, 10.56, 11.34, 11.78, 12.54, 13.29, 13.85, 14.79, 15.31, 16.35, 16.76,17.23, 17.69, 18.81, 19.07, 19.35, 19.85, 20.47, 21.11, 21.73, 21.91, 22.25, 22.51, 22.97, 23.68, 24.33, 24.93, 25.97, 26.66, 27.35, 28.48, 28.93, 29.72, 30.11, 30.63, 30.84, 31.84, 33.08, 34.27, 34.80, 35.59, and 35.77.

35. The crystalline form of any one of claims 31-34, wherein Compound 1 Form C is characterized by an XRPD pattern substantially in accordance with FIG. 16.

36. The crystalline form of any one of claims 31-35, wherein Compound 1 Form C is characterized by a DSC thermogram substantially in accordance with FIG. 17.

37. The crystalline form of any one of claims 31-36, wherein the Compound 1 Form C is characterized by a TGA thermogram substantially in accordance with FIG. 18.

38. The crystalline form of any one of claims 1-3, characterized as Compound 1 Form D.

39. The crystalline form of claim 38, wherein Compound 1 Form D is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09,22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

40. The crystalline form of claim 38, wherein Compound 1 Form D is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09,22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

41. The crystalline form of claim 38, wherein Compound 1 Form D is characterized by an XRPD pattern in reflection geometry on a 2 Theta scale, ± 0.20, comprising all the peaks 9.66, 10.43, 11.31, 12.81, 13.33, 14.84, 16.81, 17.73, 17.95, 19.37, 20.41, 21.09, 22.24, 22.64, 22.86, 23.87, 24.45, 25.99, 28.02, 29.83, and 35.63.

42. The crystalline form of any one of claims 38-41, wherein Compound 1 Form D is characterized by an XRPD pattern substantially in accordance with FIG. 20.

43. The crystalline form of any one of claims 38-42, wherein Compound 1 Form D is characterized by a DSC thermogram substantially in accordance with FIG. 21.

44. The crystalline form of any one of claims 38-43, wherein the Compound 1 Form D is characterized by a TGA thermogram substantially in accordance with FIG. 22.

45. The crystalline form of any one of claims 1-3, characterized as Compound 1 Form E.

46. The crystalline form of claim 45, wherein Compound 1 Form E is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising one or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15,18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and34.90.

47. The crystalline form of claim 46, wherein Compound 1 Form E is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising a peak at 21.22.

48. The crystalline form of claim 45, wherein Compound 1 Form E is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising three or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15,18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and34.90.

49. The crystalline form of claim 48, wherein Compound 1 Form E is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising peaks at 15.02,18.81, and 21.22.

50. The crystalline form of claim 45, wherein Compound 1 Form E is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising five or more peaks selected from 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90.

51. The crystalline form of claim 50, wherein Compound 1 Form E is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising peaks at 9.36, 13.63, 15.02, 18.81, and 21.22.

52. The crystalline form of claim 45, wherein Compound 1 Form E is characterized by an XRPD pattern in transmission geometry on a 2 Theta scale, ± 0.20, comprising all the peaks 9.04, 9.36, 10.27, 11.23, 12.05, 12.41, 13.63, 15.02, 16.50, 17.25, 18.15, 18.81, 18.99, 20.27, 21.03, 21.22, 21.67, 22.54, 22.94, 23.39, 24.10, 24.23, 24.47, 25.89, 26.24, 27.20, 27.70, 28.42, 28.86, 29.38, 29.85, 30.32, 30.66, 31.07, 31.85, 32.07, 32.51, 32.88, and 34.90.

53. The crystalline form of any one of claims 45-52, wherein Compound 1 Form E is characterized by an XRPD pattern substantially in accordance with FIG. 25.

54. The crystalline form of any one of claims 45-53, wherein Compound 1 Form E is characterized by an TG-FTIR thermogram substantially in accordance with FIG. 26.

55. The crystalline form of any one of claims 45-54, wherein Compound 1 Form E is characterized by an DSC thermogram substantially in accordance with FIG. 27.

56. A pharmaceutical composition comprising a crystalline form of Compound 1 of any one of the preceding claims and one or more pharmaceutically acceptable excipient.

57. A method of treating a metabolic disease or disorder, comprising administering to a subject in need thereof a crystalline form of Compound 1 of any one of claims 1-55, or a'llpharmaceutical composition of claim 56.

58. A crystalline form of Compound 1 of any one of claims 1-55, or the pharmaceutical composition of claim 56 for use in therapy.

59. A crystalline form of Compound 1 of any one of claims 1-55, or the pharmaceutical composition of claim 56, for use in the treatment of a metabolic disease, or disorder.

60. Use of a crystalline form of Compound 1 of any one of claims 1-55, or a pharmaceutical composition of claim 56 for treating a metabolic disease or disorder.

61. Use of a crystalline form of Compound 1 of any one of claims 1-55, or a pharmaceutical composition of claim 56 for the manufacture of a medicament for treating a metabolic disease or disorder.

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