Solid forms comprising a b-RAF kinase dimer inhibitor, methods of preparation, and uses therefor

Abstract

Provided herein are solid forms, methods of use, and processes relating to 1-((1S,1aS,6bS)-5-((7- oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3- (2,4,5-trifluorophenyl) urea.

Description

SOLID FORMS COMPRISING A B-RAF KINASE DIMER INHIBITOR, METHODS OF PREPARATION, AND USES THEREFOR1. FIELD

[0001] Provided herein are solid forms comprising l-((lS,laS,6bS)-5-((7-oxo-5,6,7,8- tetrahydro- 1 ,8-naphthyridin-4-yl)oxy)- la,6b-dihydro- lH-cyclopropa[b] benzofuran- 1 -yl) -3 - (2,4,5- trifluorophenyl) urea. Pharmaceutical compositions comprising such solid forms, and methods of use for treating, preventing, and managing various disorders are also provided herein.2. BACKGROUND

[0002] Whether crystalline or amorphous, potential solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Variety among single -component crystalline materials may potentially arise from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound (see, e.g., S. R. Bym et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The importance of discovering polymorphs was underscored by the case of Ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the product was launched, the unanticipated precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more consistent formulation could be developed (see S. R. Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417).

[0003] Additional diversity among the potential solid forms of a pharmaceutical compound may arise from the possibility of multiple-component solids. Crystalline solids comprising two or more ionic species are termed salts (see, e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types of multiple-component solids that may potentially offer other property improvements for a pharmaceutical compound or salt thereof include, e.g., hydrates, solvates, cocrystals and clathrates, among others (see, e.g., S. R. Bym et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Moreover, multiple -component crystal forms may potentially be susceptible to polymorphism, wherein a given multiple -component composition may exist in more than one three-dimensional crystalline arrangement. The discovery of solid forms is of great importance in the development of a safe, effective, stable, and marketable pharmaceutical compound.

[0004] Notably, it is not possible to predict a priori if crystalline forms of a compound even exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun. 3635-3645 (with respect to crystal engineering, if instructions are not very precise and / or if other external factors affect the process, the result can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An EmergingApproach to Physical Property Enhancement,” MRS Bulletin 31 : 875-879 (At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules); Price, 2004, “The computational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Review s 56:301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and Polymorphism,” ACA Transactions 39: 14-23 (a great deal still needs to be learned and done before one can state with any degree of confidence the ability to predict a crystal structure, much less polymorphic forms)).

[0005] There is a great need for solid forms of Compound A, which shows good bioavailability and has chemical and physical stability during formulation and storage of this drug. There is also a need for solid forms of Compound A (e.g., a crystalline form or an amorphous form) which has stable physicochemical properties and is suitable for pharmaceutical manufacture.

[0006] Citation or identification of any reference in Section 2 of this application is not to be construed as an admission that the reference is prior art to the present application.3. SUMMARY

[0007] Provided herein are solid forms comprising Compound A:Compound A, having the name l-((lS,laS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4- yl)oxy)-la,6b-dihydro-lH-cyclopropa[b]benzofuran-l-yl)-3- (2,4,5 -trifluorophenyl) urea, including tautomers thereof. Also provided are methods of preparing, isolating, and characterizing the solid forms.

[0008] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.4. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 depicts a schematic diagram of interconversion relationship of polymorphs.

[0010] Figure 2 depicts an XRPD pattern of Compound A Form I.

[0011] Figure 3 depicts a DSC thermogram of Compound A free base Form I.

[0012] Figure 4 depicts a TGA thermogram of Compound A free base Form I.

[0013] Figure 5 depicts a PLM photograph of Compound A free base Form I.

[0014] Figure 6 depicts an XRPD pattern of free base Form II.

[0015] Figure 7 depicts a DSC thermogram of free base Form II.

[0016] Figure 8 depicts a TGA thermogram of free base Form II.

[0017] Figure 9 depicts a PLM photograph of free base Form II.

[0018] Figure 10 depicts a DVS isotherm plot of free base Form II.

[0019] Figure 11 depicts an XRPD overlay of free base Form II before and after DVS test.

[0020] Figure 12 depicts an XRPD pattern of Compound A free base Form III.

[0021] Figure 13 depicts a DSC thermogram of Form III.

[0022] Figure 14 depicts a TGA thermogram of Form III.

[0023] Figure 15 depicts a PLM photograph of Form III.

[0024] Figure 16 depicts an XRPD pattern of Compound A free base Form IV.

[0025] Figure 17 depicts a DSC thermogram of Compound A free base Form IV.

[0026] Figure 18 depicts a TGA thermogram of Compound A free base Form IV.

[0027] Figure 19 depicts a PLM photograph of Compound A free base Form IV.

[0028] Figure 20 depicts an XRPD pattern of Compound A free base Form V.

[0029] Figure 21 depicts a TGA and DSC overlay profile of Form V

[0030] Figure 22 depicts an XRPD pattern of Compound A free base Form VI.

[0031] Figure 23 depicts an XRPD pattern of Compound A free base Form VII.

[0032] Figure 24 depicts an XRPD pattern of free base Form VIII.

[0033] Figure 25 depicts a DSC thermogram of free base Form VIII.

[0034] Figure 26 depicts a TGA thermogram of free base Form VIII.

[0035] Figure 27 depicts a PLM photograph of free base Form VIII.

[0036] Figure 28 depicts an XRPD pattern of Compound A free base Form IX.

[0037] Figure 29 depicts a DSC thermogram of Compound A free base Form IX.

[0038] Figure 30 depicts a TGA thermogram of Compound A free base Form IX.

[0039] Figure 31 depicts a PLM photograph of Compound A free base Form IX.

[0040] Figure 32 depicts an XRPD pattern of Compound A free base Form X.

[0041] Figure 33 depicts a DSC thermogram of Compound A free base Form X.

[0042] Figure 34 depicts a TGA thermogram of Compound A free base Form X.

[0043] Figure 35 depicts a PLM photograph of Compound A free base Form X.

[0044] Figure 36 depicts an XRPD pattern of Compound A free base Form XL

[0045] Figure 37 depicts an XRPD pattern of Compound A free base Form XII.

[0046] Figure 38 depicts a DSC thermogram of Compound A free base Form XII.

[0047] Figure 39 depicts a TGA thermogram of Compound A free base Form XII.

[0048] Figure 40 depicts a PLM photograph of Compound A free base Form XII.

[0049] Figure 41 depicts an XRPD pattern of Compound A free base Form XIII.

[0050] Figure 42 depicts a DSC thermogram of Compound A free base Form XIII.

[0051] Figure 43 depicts a TGA thermogram of Compound A free base Form XIII.

[0052] Figure 44 depicts a PLM photograph of Compound A free base Form XIII.

[0053] Figure 45 depicts an XRPD pattern of Compound A free base Form XIV.

[0054] Figure 46 depicts a DSC thermogram of Compound A free base Form XIV.

[0055] Figure 47 depicts a TGA thermogram of Compound A free base Form XIV.

[0056] Figure 48 depicts an XRPD overlay of Forms I-VII.

[0057] Figure 49 depicts an XRPD overlay of Forms VIII-XIV.5. DETAILED DESCRIPTION DEFINITIONS

[0058] As used herein, and in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” include plural as well as single referents, unless the context clearly indicates otherwise.

[0059] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percents of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.

[0060] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, for example, that describes a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), singlecrystal X-ray diffractometry, and solubility studies. In certain embodiments, the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position may vary by up to ±0.2 degrees two theta while still describing the particular XRPD peak.

[0061] As used herein, and unless otherwise specified, a crystalline that is “pure,” z.e., substantially free of other crystalline or amorphous forms, contains less than about 10% by weight of oneor more other crystalline or amorphous forms, less than about 5% by weight of one or more other crystalline or amorphous forms, less than about 3% by weight of one or more other crystalline or amorphous forms, or less than about 1% by weight of one or more other crystalline or amorphous forms.

[0062] As used herein and unless otherwise indicated, the term “substantially pure” when used to describe a polymorph of a compound, i.e. a crystal form or an amorphous form of a compound, means a crystal form or an amourphous form of the compound that comprises that crystal form or amorphous form and is substantially free of other polymorphs of the compound. A substantially pure crystal form is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. In certain embodiments, a form that is substantially pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other polymorphs on a weight basis.

[0063] As used herein and unless otherwise indicated, the term “substantially crystalline” when used to describe a polymorph of a compound, i.e. a crystal form of a compound, means a crystal form of the compound that comprises that crystal form and is substantially free of other polymorphs of the compound. A substantially crystalline crystal form is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. In certain embodiments, a form that is substantially crystalline contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other polymorphs or amorphous form on a weight basis.

[0064] As used herein, and unless otherwise specified, a solid form that is “substantially physically pure” is substantially free from other solid forms. In certain embodiments, a crystal form that is substantially physically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other solid forms on a weight basis. The detection of other solid forms can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis and / or spectroscopic analysis.

[0065] As used herein, and unless otherwise specified, a solid form that is “substantially chemically pure” is substantially free from other chemical compounds i.e., chemical impurities). In certain embodiments, a solid form that is substantially chemically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other chemical compounds on a weight basis. The detection of other chemical compounds can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, methods of chemical analysis, such as, e.g., mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and / or chromatographic analysis.

[0066] As used herein, and unless otherwise indicated, a chemical compound, solid form, or composition that is “substantially free” of another chemical compound, solid form, or composition means that the compound, solid form, or composition contains, in certain embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% 0.1%, 0.05%, or 0.01% by weight of the other compound, solid form, or composition.

[0067] Unless otherwise specified, the terms “solvate” and “solvated,” as used herein, refer to a solid form of a substance which contains solvent. The terms “hydrate” and “hydrated” refer to a solvate wherein the solvent is water. “Polymorphs of solvates” refer to the existence of more than one solid form for a particular solvate composition. Similarly, “polymorphs of hydrates” refer to the existence of more than one solid form for a particular hydrate composition. The term “desolvated solvate,” as used herein, refers to a solid form of a substance which can be made by removing the solvent from a solvate. The terms “solvate” and “solvated,” as used herein, can also refer to a solvate of a salt, cocrystal, or molecular complex. The terms “hydrate” and “hydrated,” as used herein, can also refer to a hydrate of a salt, cocrystal, or molecular complex.

[0068] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0069] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of Compound A are within the scope of the present invention.

[0070] Unless otherwise specified, the term “composition” as used herein is intended to encompass a product comprising the specified ingredient(s) (and in the specified amount(s), if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredient(s) in the specified amount(s). By “pharmaceutically acceptable,” it is meant a diluent, excipient, or carrier in a formulation must be compatible with the other ingredient(s) of the formulation and not deleterious to the recipient thereof.

[0071] The term “solid form” refers to a physical form which is not predominantly in a liquid or a gaseous state. As used herein and unless otherwise specified, the term “solid form” refers to a physical form comprising Compound A which is not predominantly in a liquid or a gaseous state. A solid form may be a crystalline form or a mixture thereof. In certain embodiments, a solid form may be an amorphous form. In certain embodiments, the term “a solid form comprising Compound A” includes acrystal form comprising Compound A. In one embodiment, the solid form is Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV.

[0072] As used herein and unless otherwise specified, the term “crystalline” when used to describe a compound, substance, modification, material, component, or product, unless otherwise specified, means that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rded., 1843-1844 (1995).

[0073] The term “crystal form” or “crystalline form” refers to a solid form that is crystalline. In certain embodiments, crystal forms include salts. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and / or other crystal forms. In certain embodiments, a crystal form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more amorphous forms and / or other crystal forms. In certain embodiments, a crystal form of a substance may be physically and / or chemically pure. In certain embodiments, a crystal form of a substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0074] Unless otherwise specified, the terms “polymorph,” “polymorphic form,” “polymorphs,” “polymorphic forms,” and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules or ions. Different polymorphs may have different physical properties, such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates, and / or vibrational spectra as a result of a different arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically a more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility / dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g., particle shape and size distribution might be different between polymorphs).

[0075] Unless otherwise specified, the term “amorphous” or “amorphous form” means that the substance, component, or product in question is not substantially crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous forms and / or crystal forms. In certain embodiments, an amorphous form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more other amorphous forms and / or crystal forms on a weight basis. In certain embodiments, an amorphous form of a substance may be physically and / or chemically pure. In certain embodiments, an amorphous form of a substance be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0076] “Treating” as used herein, means an alleviation, in whole or in part, of the disease or disorder, or symptoms associated with the disease or disorder, or slowing, or halting of further progression or worsening of the disease or disorder, or symptoms associated with the disease or disorder.

[0077] “Preventing” as used herein, means prevention of the onset, recurrence, or spread of the disease or disorder, or symptoms associated with the disorder or disease, in a patient at risk for developing the disease or disorder.

[0078] The term “effective amount” in connection with a solid form of Compound A means, in one embodiment, an amount capable of alleviating, in whole or in part, symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or, in another embodiment, an amount capable of preventing or providing prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder as disclosed herein, such as cancer. In one embodiment, an effective amount of a solid form of Compound A is an amount that inhibits a kinase in a cell, such as, for example, in vitro or in vivo. In one embodiment the kinase is a BRAF kinase. In one embodiment the kinase is a BRAF kinase dimer. In one embodiment the kinase is a BRAF kinase monomer. In some embodiments, the effective amount of a solid form of Compound A inhibits the kinase in a cell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the activity of the kinase in an untreated cell. The effective amount of a solid form of Compound A, for example in a pharmaceutical composition, may be at a level that will exercise the desired effect; for example, about 0.005 mg / kg of a subject’s body weight to about 100 mg / kg of a patient’s body weight in unit dosage for both oral and parenteral administration. As will be apparent to those skilled in the art, it is to be expected that the effective amount of a solid form of Compound A disclosed herein may vary depending on the indication being treated, e.g., the effective amount of a solid form of Compound A would likely be different for treating patients suffering from, or at risk for, inflammatory conditions relative to theeffective amount of a solid form of Compound A for treating patients suffering from, or at risk of, a different disorder, e.g., cancer or a metabolic disorder.

[0079] “Patient” or “subject” is defined herein to include animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quails, or guinea pigs and the like. In specific embodiments, the patient or subject is a human.

[0080] In certain embodiments, the treatment of lymphoma may be assessed by the International Workshop Criteria (IWC) for non-Hodgkin lymphoma (NHL) (see Cheson BD, Pfistner B, Juweid, ME, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586), using the response and endpoint definitions shown below:

[0081] Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease.

[0082] In certain embodiments, the treatment of a cancer may be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1. 1) (see Thereasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for all possible combinations of tumor responses in target and non-target lesions with our without the appearance of new lesions are as follows:CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease.

[0083] With respect to the evaluation of target lesions, complete response (CR) is the disappearance of all target lesions, partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, progressive disease (PD) is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions and stable disease (SD) is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.

[0084] With respect to the evaluation of non-target lesions, complete response (CR) is the disappearance of all non-target lesions and normalization of tumor marker level; incomplete response / stable disease (SD) is the persistence of one or more non-target lesion(s) and / or the maintenance of tumor marker level above the normal limits, and progressive disease (PD) is the appearance of one or more new lesions and / or unequivocal progression of existing non-target lesions.

[0085] The procedures, conventions, and definitions described below provide guidance for implementing the recommendations from the Response Assessment for Neuro-Oncology (RANG) Working Group regarding response criteria for high-grade gliomas (Wen P., Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria for highgrade gliomas: Response assessment in neurooncology working group. J Clin Oncol 2010; 28: 1963-1972). Primary modifications to the RANG criteria for Criteria for Time Point Responses (TPR) can include the addition of operational conventions for defining changes in glucocorticoid dose, and the removal of subjects’ clinical deterioration component to focus on objective radiologic assessments. The baseline MRI scan is defined as the assessment performed at the end of the post-surgery rest period, prior to re-initiating compound treatment. The baseline MRI is used as the reference for assessing complete response (CR) and partial response (PR).Whereas, the smallest SPD (sum of the products of perpendicular diameters) obtained either at baseline or at subsequent assessments will be designated the nadir assessment and utilized as the reference for determining progression. For the 5 days preceding any protocol-defined MRI scan, subjects receive either no glucocorticoids or are on a stable dose of glucocorticoids. A stable dose is defined as the same daily dose for the 5 consecutive days preceding the MRI scan. If the prescribed glucocorticoid dose is changed in the 5 days before the baseline scan, a new baseline scan is required with glucocorticoid use meeting the criteria described above. The following definitions will be used.

[0086] Measurable Lesions: Measurable lesions are contrast-enhancing lesions that can be measured bidimensionally. A measurement is made of the maximal enhancing tumor diameter (also known as the longest diameter, LD). The greatest perpendicular diameter is measured on the same image.The cross hairs of bidimensional measurements should cross and the product of these diameters will be calculated.

[0087] Minimal Diameter: T1 -weighted image in which the sections are 5 mm with 1 mm skip. The minimal LD of a measurable lesion is set as 5 mm by 5 mm. Larger diameters may be required for inclusion and / or designation as target lesions. After baseline, target lesions that become smaller than the minimum requirement for measurement or become no longer amenable to bidimensional measurement will be recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that disappear will be recorded as 0 mm by 0 mm.

[0088] Multicentric Lesions: Lesions that are considered multicentric (as opposed to continuous) are lesions where there is normal intervening brain tissue between the two (or more) lesions. For multicentric lesions that are discrete foci of enhancement, the approach is to separately measure each enhancing lesion that meets the inclusion criteria. If there is no normal brain tissue between two (or more) lesions, they will be considered the same lesion.

[0089] Nonmeasurable Lesions: All lesions that do not meet the criteria for measurable disease as defined above will be considered non-measurable lesions, as well as all nonenhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include foci of enhancement that are less than the specified smallest diameter (ie., less than 5 mm by 5 mm), nonenhancing lesions (eg., as seen on Tl- weighted post-contrast, T2 -weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumor. Hemorrhagic lesions often have intrinsic T1 -weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this reason, the pre-contrast T1 -weighted image may be examined to exclude baseline or interval subacute hemorrhage.

[0090] At baseline, lesions will be classified as follows: Target lesions: Up to 5 measurable lesions can be selected as target lesions with each measuring at least 10 mm by 5 mm, representative of the subject’s disease; non-target lesions: All other lesions, including all nonmeasurable lesions (including mass effects and T2 / FLAIR findings) and any measurable lesion not selected as a target lesion. At baseline, target lesions are to be measured as described in the definition for measurable lesions and the SPD of all target lesions is to be determined. The presence of all other lesions is to be documented. At all post-treatment evaluations, the baseline classification of lesions as target and non-target lesions will be maintained and lesions will be documented and described in a consistent fashion over time (eg., recorded in the same order on source documents and eCRFs). All measurable and nonmeasurable lesions must be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner or at least with the same magnet strength) for the duration of the study to reduce difficulties in interpreting changes. At each evaluation, target lesions will be measured and the SPD calculated. Non- target lesions will be assessed qualitatively and new lesions, if any, will be documented separately. At each evaluation, a time point response will be determined for target lesions, non-target lesions, and newlesion. Tumor progression can be established even if only a subset of lesions is assessed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are assessed.

[0091] Confirmation assessments for overall time point responses of CR and PR will be performed at the next scheduled assessment, but confirmation may not occur if scans have an interval of < 28 days. Best response, incorporating confirmation requirements, will be derived from the series of time points.

[0092] In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term “prevention” includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of a cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer.

[0093] Unless otherwise specified, to the extent that there is a discrepancy between a depicted chemical structure of a compound provided herein and a chemical name of a compound provided herein, the chemical structure shall control. COMPOUND A

[0094] As used herein, “Compound A” refers to the compound having the name of l-((lS,laS,6bS)- 5-((7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-4-yl)oxy)-la,6b-dihydro-lH-cyclopropa[b]benzofuran-l- yl)-3- (2,4,5 -trifluorophenyl) urea, or the structure of formula (I):or a tautomer thereof. Compound A is disclosed and claimed, along with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of BRAF activity, particularly in treatment of cancer, in WO2014206343 and W02020151756, the entire disclosure of which are incorporated herein by reference. Compound A is compound 1.49 in WO2014206343 and Compound 1 in WO2020151756. Compound A can be prepared as described in WO2014206343 and WO2020151756. SQUID FORMS OF COMPOUND 1

[0095] While not intending to be bound by any particular theory, certain solid forms (e.g., crystals) are characterized by physical properties, e.g., stability, solubility, and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be boundby any particular theory, certain solid forms (e.g., crystals) are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, fdtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms (e.g., crystals) suitable for the manufacture of a solid dosage form. Such properties can be determined using particular analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein and known in the art.

[0096] The solid form crystals provided herein (e.g, Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, and XIV) may be characterized using a number of methods known to a person having ordinary skill in the art, including, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and hot-stage microscopy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), single differential thermal analysis (SDTA), high performance liquid chromatography coupled with mass spectroscopy (HPLC-MS), thermogravimetrical analysis coupled with single differential thermal analysis (TGA- SDTA), and thermogravimetric analysis coupled with mass spectroscopy (TGA-MS). The particle size and size distribution of the solid form provided herein may be determined by conventional methods, such as laser light scattering technique.

[0097] The purity of the solid forms provided herein may be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS).

[0098] It should be understood that the numerical values of the peaks of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute, but with an allowable variability, such as ±0.2 degrees two theta (°20) (see United State Pharmacopoeia, page 2228 (2003)). Unless instructed otherwise, the X-ray powder diffraction provided herein is obtained by Cu / K-Alphal (Z= l .5406A) according to "6.8 Instrumental methods".5.3.1 Form I

[0099] Provided herein is solid Form I, comprising Compound A. In one embodiment, Form I is a crystal form. In one embodiment, Form I is a hydrate. In one embodiment, Form I is substantially crystalline.

[0100] In one embodiment, Form I is a solvated form comprising Compound A. In one embodiment, Form I is a hydrate form comprising Compound A. In another embodiment, Form I iscrystalline. In another embodiment, Form I is a metastable form. In another embodiment, Form I is converted to Form II. In another embodiment, Form I is converted to Form III.

[0101] In one embodiment, the molar ratio of water to Compound A of Form I is 1.0 ± 0.1, 1.0 ± 0.05, 1.0 ± 0.01, or about 1.0.

[0102] In certain embodiments, a solid form provided herein, e.g., Form I, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form I has an X-ray powder diffraction pattern substantially as shown in Figure 2. In one embodiment, Form I has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.4, 14.0, or 18.7 degrees (see Table 5). In another embodiment, Form I has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.4, 14.0, 18.7, 21.1, 24.3, or 29.0 degrees. In another embodiment, Form I of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.4, 14.0, 14.8, 18.7, 21.1, 24.3, 24.7, 25.1, or 29.0 degrees.In another embodiment, Form I of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 5. In another embodiment, Form I has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 2.

[0103] In one embodiment, provided herein is Form I having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 3 comprising an endothermic event with a maximum at about 56.9 °C with onset temperature at about 33.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 56.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 33.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 91.7 J / g.

[0104] In one embodiment, provided herein is Form I having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 3 comprising an exothermic event with a maximum at about 177.6 °C with onset temperature at about 170.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 177.6 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with an onset temperature at approximately 170.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 17.2 J / g.

[0105] In one embodiment, provided herein is Form I having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 3 comprising an endothermic event with a maximum at about 228.4 °C with onset temperature at about 219.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 228.4 °C.In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 219.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 120 J / g.

[0106] In one embodiment, provided herein is Form I having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 4. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 3.7 % of the total mass of the sample between approximately 35.4 °C and approximately 100.0 °C. Thus, in certain embodiments, the crystalline form loses about 3.7 % of the total mass of the crystal form when heated from about 35 °C to about 100 °C.

[0107] In still another embodiment, Form I of Compound A is substantially pure. In certain embodiments, the substantially pure Form I of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form I of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0108] In certain embodiments, provided herein are slow evaporation methods for making a solid form of Compound A, comprising 1) obtaining a close-to saturated or saturated solution of Compound A in a solvent; 2) slowly evaporating the solution at a temperature (e.g. , about 22 °C to about 26 °C) for a period of time (e.g., about 5 days); 3) fdtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded. In certain embodiments, the solvent is a mixture of acetone and water. In one embodiment, the ratio of acetone and water is 1: 1 by volume. In certain embodiments, the solvent is a mixture of DMSO and water (0.5% HC1). In one embodiment, the ratio of DMSO and water (0.5% HC1) is 1: 1 by volume. In one embodiment, the starting material is Form III. In one embodiment, the resulting solid is Form I. In one embodiment, the seed is Form I. In one embodiment, the solution is stirred at about 22 °C to about 26 °C. In one embodiment, the solution is stirred at about 25 %RH to about 65 %RH. In one embodiment, the solution is stirred for about 13 days.5.3.2 Form II

[0109] Provided herein is solid Form II, comprising Compound A. In one embodiment, Form II is a crystal form. In one embodiment, Form II is an anhydrous form. In another embodiment, Form II is crystalline. In one embodiment, Form II is substantially crystalline.

[0110] In certain embodiments, a solid form provided herein, e.g., Form II, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form II has an X-ray powder diffraction pattern substantially as shown in Figure 6. In one embodiment, Form IIhas one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 16.1, 17.4, or 24.5 degrees (see Table 7). In another embodiment, Form II has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 15.1, 16.1, 17.4, 21.2, 24.1, or 24.5 degrees. In another embodiment, Form II of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 14.9, 15.1, 16.1, 17.4, 21.2, 24.1, 24.5, 25.1, or 26.8 degrees. In another embodiment, Form II of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at atwo-theta angle selected from the peaks listed in Table 7. In another embodiment, Form II has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 6.

[0111] In one embodiment, provided herein is Form II having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 7 comprising an endothermic event with a maximum at about 229.2 °C with onset temperature at about 220.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 229.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 220.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 129.9 J / g.

[0112] In one embodiment, provided herein is Form II having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 8. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 0.9 % of the total mass of the sample between approximately 36.5 °C and approximately 190.0 °C. Thus, in certain embodiments, the crystalline form loses about 0.9 % of the total mass of the crystal form when heated from about 36.5 °C to about 190 °C.

[0113] In still another embodiment, Form II of Compound A is substantially pure. In certain embodiments, the substantially pure Form II of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form II of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0114] In certain embodiments, provided herein are slurry methods for making a solid form of Compound A, comprising 1) obtaining a slurry of Compound A in a solvent; 2) stirring the slurry for a period of time; 3) collecting a solid from the slurry by filtration (e.g., centrifuge filtration). In one embodiment, the solution may be seeded. In certain embodiments, the solvent is a mixture of methanol and acetone. In one embodiment, the ratio of methanol to acetone is 1: 1 by volume. In one embodiment, the starting material is Form III. In one embodiment, the resulting solid is Form II. In one embodiment, the seed is Form II. In one embodiment, the slurry is stirred at about 50 °C. In one embodiment, theslurry is stirred for about 5 days.5.3.3 Form III

[0115] Provided herein is solid Form III, comprising Compound A. In one embodiment, Form III is a crystal form. In one embodiment, Form III is a hydrate. In one embodiment, Form III is substantially crystalline.

[0116] In one embodiment, Form III is a solvated form comprising Compound A. In one embodiment, Form III is a hydrate form comprising Compound A. In another embodiment, Form III is crystalline. In another embodiment, Form III is a metastable form. In another embodiment, Form III is converted to Form II. In another embodiment, Form III is converted to Form I.

[0117] In one embodiment, the molar ratio of water to Compound A of Form III is 0.8 ± 0.1, 0.8 ± 0.05, 0.8 ± 0.01, or about 0.8.

[0118] In certain embodiments, a solid form provided herein, e.g., Form III, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form III has an X-ray powder diffraction pattern substantially as shown in Figure 12. In one embodiment, Form III has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.5, 14.2, or 15.5 degrees (see Table 8). In another embodiment, Form III has one or more characteristic X- ray powder diffraction peaks at a two-theta angle of approximately 9.5, 14.2, 15.5, 18.9, 20.7, or 24.2 degrees. In another embodiment, Form III of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.5, 14.2, 15.5, 18.9, 20.7, 24.2, 24.2, 25.2, or 29.6 degrees. In another embodiment, Form III of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 8. In another embodiment, Form III has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 12.

[0119] In one embodiment, provided herein is Form III having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 13 comprising an endothermic event with a maximum at about 211.6 °C with onset temperature at about 202.4 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 211.6 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 202.4 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 18.1 J / g.

[0120] In one embodiment, provided herein is Form III having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 13 comprising an exothermic event with a maximum at about 164.9 °C with onset temperature at about 157.6 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with amaximum at about 164.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with an onset temperature at approximately 157.6 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 42.9 J / g.

[0121] In one embodiment, provided herein is Form III having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 14. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 3.0 % of the total mass of the sample between approximately 34.7 °C and approximately 150.0 °C. Thus, in certain embodiments, the crystalline form loses about 3.0 % of the total mass of the crystal form when heated from about 35 °C to about 150 °C.

[0122] In still another embodiment, Form III of Compound A is substantially pure. In certain embodiments, the substantially pure Form III of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form III of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0123] In certain embodiments, provided herein are slurry methods for making a solid form of Compound A, comprising 1) obtaining a slurry of Compound A in a solvent; 2) stirring the slurry for a period of time; 3) collecting a solid from the slurry by filtration (e.g., centrifuge filtration). In one embodiment, the solution may be seeded. In certain embodiments, the solvent is water. In one embodiment, the resulting solid is Form III. In one embodiment, the seed is Form III. In one embodiment, the slurry is stirred at about 50 °C. In one embodiment, the slurry is stirred for about 4 days. In certain embodiments, the solvent is a mixture of DMSO and water (0.5% HC1). In one embodiment, the ratio of DMSO and water (0.5% HC1) is 1: 1 by volume.5.3.4 Form IV

[0124] Provided herein is solid Form IV, comprising Compound A. In one embodiment, Form IV is a crystal form. In one embodiment, Form IV is a hydrate. In one embodiment, Form IV is substantially crystalline.

[0125] In one embodiment, Form IV is a solvated form comprising Compound A. In one embodiment, Form IV is a hydrate form comprising Compound A. In another embodiment, Form IV is crystalline. In another embodiment, Form IV is a metastable form. In another embodiment, Form IV is converted to Form II.

[0126] In one embodiment, the molar ratio of water to Compound A of Form IV is 1.0 ± 0.1, 1.0 ± 0.05, 1.0 ± 0.01, or about 1.0.

[0127] In certain embodiments, a solid form provided herein, e.g., Form IV, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form IV has an X-ray powder diffraction pattern substantially as shown in Figure 16. In one embodiment, Form IV has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.5, 17.6, or 21.7 degrees (see Table 10). In another embodiment, Form IV has one or more characteristic X- ray powder diffraction peaks at a two-theta angle of approximately 7.5, 7.7, 17.6, 20.1, 21.7, or 23.3 degrees. In another embodiment, Form IV of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.5, 7.7, 12.3, 17.6, 19.2, 20.1, 20.6, 21.7, or 23.3 degrees. In another embodiment, Form IV of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at atwo-theta angle selected from the peaks listed in Table 10. In another embodiment, Form IV has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 16.

[0128] In one embodiment, provided herein is Form IV having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 17 comprising an endothermic event with a maximum at about 55.3 °C with onset temperature at about 17.4 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 55.3 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 17.4 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 28.0 J / g.

[0129] In one embodiment, provided herein is Form IV having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 17 comprising an endothermic event with a maximum at about 147.2 °C with onset temperature at about 128.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 147.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 128.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 23.0 J / g.

[0130] In one embodiment, provided herein is Form IV having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 17 comprising an exothermic event with a maximum at about 160.0 °C with onset temperature at about 156.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 160.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with onset temperature at about 156.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 20.9 J / g.

[0131] In one embodiment, provided herein is Form IV having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 17 comprising an endothermic event with a maximum at about 215.3 °C with onset temperature at about 205.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 215.3 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 205.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 27.6 J / g.

[0132] In one embodiment, provided herein is Form IV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 18. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 1.7 % of the total mass of the sample between approximately 26.2 °C and approximately 100.0 °C. Thus, in certain embodiments, the crystalline form loses about 1.7 % of the total mass of the crystal form when heated from about 25 °C to about 100 °C.

[0133] In one embodiment, provided herein is Form IV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 18. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 2.5 % of the total mass of the sample between approximately 100.0 °C and approximately 140.0 °C. Thus, in certain embodiments, the crystalline form loses about 2.5 % of the total mass of the crystal form when heated from about 100 °C to about 140 °C.

[0134] In one embodiment, provided herein is Form IV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 18. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 2.0 % of the total mass of the sample between approximately 140.0 °C and approximately 160.0 °C. Thus, in certain embodiments, the crystalline form loses about 2.0 % of the total mass of the crystal form when heated from about 140 °C to about 160 °C.

[0135] In still another embodiment, Form IV of Compound A is substantially pure. In certain embodiments, the substantially pure Form IV of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form IV of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0136] In certain embodiments, provided herein are slurry methods for making a solid form of Compound A, comprising 1) obtaining a slurry of Compound A in a solvent; 2) stirring the slurry for a period of time; 3) collecting a solid from the slurry by filtration (e.g., centrifuge filtration). In one embodiment, the solution may be seeded. In certain embodiments, the solvent is isopropyl acetate. In oneembodiment, the starting material is Form III. In one embodiment, the resulting solid is Form IV. In one embodiment, the seed is Form IV. In one embodiment, the slurry is stirred at about 50 °C. In one embodiment, the slurry is stirred for about 5 days.

[0137] In one embodiment, Form IV is prepared from multiple solvents by an equilibration experiment.

[0138] In one embodiment, Form IV is prepared from MEK / IPAc (50:50, v:v) by slow cooling experiment.

[0139] In one embodiment, Form IV is prepared from THF / water or THF / heptane by an antisolvent addition experiment.

[0140] In one embodiment, Form IV is prepared from THF / water, THF / MTBE or THF / heptane by a reverse antisolvent addition experiment.5.3.5 Form V

[0141] Provided herein is solid Form V, comprising Compound A. In one embodiment, Form V is a crystal form. In one embodiment, Form V is an anhydrous form. In another embodiment, Form V is crystalline. In one embodiment, Form V is substantially crystalline.

[0142] In certain embodiments, a solid form provided herein, e.g., Form V, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form V has an X-ray powder diffraction pattern substantially as shown in Figure 20. In one embodiment, Form V has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 13.3, 15.3, or 17.6 degrees (see Table 11). In another embodiment, Form V has one or more characteristic X- ray powder diffraction peaks at a two-theta angle of approximately 13.3, 13.9, 15.3, 17.6, 18.7, or 21.6 degrees. In another embodiment, Form V of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 13.3, 13.9, 15.3, 17.6, 18.7, 20.3, 21.6, 24.9, or 26.3 degrees.In another embodiment, Form V of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 11. In another embodiment, Form V has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 20.

[0143] In one embodiment, provided herein is Form V having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 21 comprising an endothermic event with a maximum at about 218.67 °C with onset temperature at about 215.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 218.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 216 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 83.9 J / g.

[0144] In one embodiment, provided herein is Form V having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 21. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 1.34 % of the total mass of the sample between approximately 15 °C and approximately 185.0 °C. Thus, in certain embodiments, the crystalline form loses about 1.3 % of the total mass of the crystal form when heated from about 15 °C to about 185 °C.

[0145] In one embodiment, Form V is prepared from 2-butanone by an equilibration experiment. In one embodiment, Form V is prepared from 2-butanone by an equilibration experiment with Form I as the starting material.5.3.6 Form VI

[0146] Provided herein is solid Form VI, comprising Compound A. In one embodiment, Form VI is a crystal form. In one embodiment, Form VI is an anhydrous form. In another embodiment, FormVI is crystalline. In one embodiment, Form VI is substantially crystalline.

[0147] In certain embodiments, a solid form provided herein, e.g., Form VI, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 22. In one embodiment, Form VI has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 12.8, 14.4, or 22.8 degrees (see Table 12). In another embodiment, Form VI has one or more characteristic X- ray powder diffraction peaks at a two-theta angle of approximately 12.8, 14.4, 17.2, 19.5, 22.8, or 24.4 degrees. In another embodiment, Form VI of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 12.8, 14.4, 15.9, 17.2, 19.5, 19.9, 20.8, 22.8, or 24.4 degrees.In another embodiment, Form VI of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 12. In another embodiment, Form VI has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 22.

[0148] In certain embodiments, provided herein are thermo conversion methods for making a solid form of Compound A, comprising heating a starting solid form of Compound A to a temperature for a period of time. In one embodiment, the starting solid form is Form I. In one embodiment, the resulting solid is Form VI. In one embodiment, the temperature is about 200 °C. In one embodiment, the solid is heated for about 1 hour. In one embodiment, the solid is heated under vacuum.5.3.7 Form VII

[0149] Provided herein is solid Form VII, comprising Compound A. In one embodiment, FormVII is a crystal form. In one embodiment, Form VII is an anhydrous form. In another embodiment, Form VII is crystalline. In one embodiment, Form VII is substantially crystalline.

[0150] In certain embodiments, a solid form provided herein, e.g., Form VII, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form VII has an X-ray powder diffraction pattern substantially as shown in Figure 23. In one embodiment, FormVII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 14.0, 15.4, or 19.4 degrees (see Table 13). In another embodiment, Form VII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 14.0, 15.4, 19.4, 21.0, 21.8, or 23.5 degrees. In another embodiment, Form VII of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 13.2, 14.0, 15.4, 17.4, 19.4, 21.0, 21.8, 23.5, or 27.6 degrees.In another embodiment, Form VII of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 13. In another embodiment, Form VII has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 23.

[0151] In certain embodiments, provided herein are slow evaporation methods for making a solid form of Compound A, comprising 1) obtaining a close-to saturated or saturated solution of Compound A in a solvent; 2) slowly evaporating the solution at a temperature (e.g. , about 22 °C to about 26 °C) for a period of time (e.g., about 5 days); 3) filtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded. In certain embodiments, the solvent is a mixture of methanol and acetone. In certain embodiments, the solvent is a mixture of method and water. In one embodiment, the ratio of method and water is 1: 1 by volume. In one embodiment, the ratio of MeOH and acetone is 1: 1 by volume. In one embodiment, the starting material is Form III. In one embodiment, the starting material is Form I. In one embodiment, the resulting solid is Form VII. In one embodiment, the seed is Form VII. In one embodiment, the solution is stirred at about 22 °C to about 26 °C. In one embodiment, the solution is stirred at about 25 %RH to about 65 %RH. In one embodiment, the solution is stirred for about 13 days.5.3.8 Form VIII

[0152] Provided herein is solid Form VIII, comprising Compound A. In one embodiment, FormVIII is a crystal form. In one embodiment, Form VIII is a hydrate. In one embodiment, Form VIII is substantially crystalline.

[0153] In one embodiment, Form VIII is a solvated form comprising Compound A. In one embodiment, Form VIII is a hydrate form comprising Compound A. In another embodiment, Form VIII is crystalline. In another embodiment, Form VIII is a metastable form. In another embodiment, Form VIII is converted to Form II.

[0154] In one embodiment, the molar ratio of water to Compound A of Form VIII is 0.7 ± 0.1, 0.74 ± 0.05, 0.74 ± 0.01, or about 0.74.

[0155] In certain embodiments, a solid form provided herein, e.g., Form VIII, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form VIII has an X-ray powder diffraction pattern substantially as shown in Figure 24. In one embodiment, Form VIII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 20.0, 21.9, or 24.1 degrees (see Table 15). In another embodiment, Form VIII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 13.3, 16.2, 20.0, 21.9, 22.4, or 24.1 degrees. In another embodiment, Form VIII of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 13.3, 15.7, 16.2, 20.0, 21.9, 22.4, 24.1, 24.9, or 26.9 degrees.In another embodiment, Form VIII of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 15. In another embodiment, Form VIII has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 24.

[0156] In one embodiment, provided herein is Form VIII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 25 comprising an endothermic event with a maximum at about 127.0 °C with onset temperature at about 103.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 127.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 103.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 32.6 J / g.

[0157] In one embodiment, provided herein is Form VIII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 25 comprising an endothermic event with a maximum at about 165.9 °C with onset temperature at about 151.5 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 165.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 151.5 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 3.3 J / g.

[0158] In one embodiment, provided herein is Form VIII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 25 comprising an exothermic event with a maximum at about 176.7 °C with onset temperature at about 172.6 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 176.7 °C. In one embodiment, the crystal form has a differential scanning calorimetrythermogram comprising an exothermic event with onset temperature at about 172.6 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 15.6 J / g.

[0159] In one embodiment, provided herein is Form VIII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 25 comprising an endothermic event with a maximum at about 222.2 °C with onset temperature at about 209.5 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 222.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 209.5 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 59.2 J / g.

[0160] In one embodiment, provided herein is Form VIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 26. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 1.6 % of the total mass of the sample between approximately 85.0 °C and approximately 120.0 °C. Thus, in certain embodiments, the crystalline form loses about 1.6 % of the total mass of the crystal form when heated from about 85 °C to about 120 °C.

[0161] In one embodiment, provided herein is Form VIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 26. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 0.3 % of the total mass of the sample between approximately 36.0 °C and approximately 85.0 °C. Thus, in certain embodiments, the crystalline form loses about 0.3 % of the total mass of the crystal form when heated from about 35 °C to about 85 °C.

[0162] In still another embodiment, Form VIII of Compound A is substantially pure. In certain embodiments, the substantially pure Form VIII of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form VIII of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0163] In certain embodiments, provided herein are slurry methods for making a solid form of Compound A, comprising 1) obtaining a slurry of Compound A in a solvent; 2) stirring the slurry for a period of time; 3) collecting a solid from the slurry by filtration (e.g., centrifuge filtration). In one embodiment, the solution may be seeded. In certain embodiments, the solvent is a mixture of methanol and water. In one embodiment, the ratio of methanol to water is 2:3 by volume. In one embodiment, the starting material is Form III. In one embodiment, the resulting solid is Form VIII. In one embodiment, the seed is Form VIII. In one embodiment, the slurry is stirred at about 25 °C. In one embodiment, theslurry is stirred for about 5 days.

[0164] In one embodiment, Form VIII is prepared from acetone / water (60:40, v:v) or MeOH / water (40:60, v:v) by an equilibration experiment.

[0165] In one embodiment, Form VIII is prepared from acetone / water by an antisolvent addition experiment.

[0166] In one embodiment, Form VIII is prepared from acetone / water or MEK / water by a reverse antisolvent addition experiment.5.3.9 Form IX

[0167] Provided herein is solid Form IX, comprising Compound A. In one embodiment, Form IX is a crystal form. In one embodiment, Form IX is a hydrate. In one embodiment, Form IX is substantially crystalline.

[0168] In one embodiment, Form IX is a solvated form comprising Compound A. In one embodiment, Form IX is a hydrate form comprising Compound A. In another embodiment, Form IX is crystalline. In another embodiment, Form IX is a metastable form. In another embodiment, Form IX is converted to Form II. In another embodiment, Form IX is converted to Form XIII.

[0169] In one embodiment, the molar ratio of water to Compound A of Form IX is 0.3 ± 0.1, 0.30 ± 0.05, 0.30 ± 0.01, or about 0.30.

[0170] In certain embodiments, a solid form provided herein, e.g., Form IX, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form IX has an X-ray powder diffraction pattern substantially as shown in Figure 28. In one embodiment, Form IX has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.4, 14.9, or 18.6 degrees (see Table 17). In another embodiment, Form IX has one or more characteristic X- ray powder diffraction peaks at a two-theta angle of approximately 7.4, 14.9, 16.4, 17.6, 18.6, or 30.0 degrees. In another embodiment, Form IX of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.4, 7.7, 14.9, 16.4, 17.6, 18.6, 22.4, 23.4, or 30.0 degrees. In another embodiment, Form IX of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 17. In another embodiment, Form IX has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 28.

[0171] In one embodiment, provided herein is Form IX having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 29 comprising an endothermic event with a maximum at about 55.8 °C with onset temperature at about 16.1 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 55.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 16.1 °C. In oneembodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 9.6 J / g.

[0172] In one embodiment, provided herein is Form IX having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 29 comprising an endothermic event with a maximum at about 173.8 °C with onset temperature at about 163.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 173.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 163.7 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 51.2 J / g.

[0173] In one embodiment, provided herein is Form IX having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 30. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 2.6 % of the total mass of the sample between approximately 33.5 °C and approximately 145.0 °C. Thus, in certain embodiments, the crystalline form loses about 2.6 % of the total mass of the crystal form when heated from about 34 °C to about 145 °C.

[0174] In one embodiment, provided herein is Form IX having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 30. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 6.5 % of the total mass of the sample between approximately 145.0 °C and approximately 170.0 °C. Thus, in certain embodiments, the crystalline form loses about 6.5 % of the total mass of the crystal form when heated from about 145 °C to about 170 °C.

[0175] In still another embodiment, Form IX of Compound A is substantially pure. In certain embodiments, the substantially pure Form IX of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form IX of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0176] In certain embodiments, provided herein are slow evaporation methods for making a solid form of Compound A, comprising 1) obtaining a close-to saturated or saturated solution of Compound A in a solvent; 2) slowly evaporating the solution at a temperature (e.g. , about 22 °C to about 26 °C) for a period of time (e.g., about 5 days); 3) fdtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded. In certain embodiments, the solvent is a mixture of methyl ethyl ketone and 2-methyl-tetrahydrofuran. In one embodiment, the ratio of methyl ethyl ketone and 2- methyl-tetrahydrofuran is 1: 1 by volume. In one embodiment, the starting material is Form III. In oneembodiment, the resulting solid is Form IX. In one embodiment, the seed is Form IX. In one embodiment, the solution is stirred at about 22 °C to about 26 °C. In one embodiment, the solution is stirred at about 25 %RH to about 65 %RH. In one embodiment, the solution is stirred for about 5 days.5.3. 10 Form X

[0177] Provided herein is solid Form X, comprising Compound A. In one embodiment, Form X is a crystal form. In one embodiment, Form X is a DMSO solvate. In one embodiment, Form X is substantially crystalline.

[0178] In one embodiment, Form X is a solvated form comprising Compound A. In one embodiment, Form X is a DMSO solvated form comprising Compound A. In another embodiment, Form X is crystalline. In another embodiment, Form X is a metastable form. In another embodiment, Form X is converted to Form II.

[0179] In one embodiment, the molar ratio of DMSO to Compound A of Form X is 2.0 ± 0.1, 2.00 ± 0.05, 2.00 ± 0.01, or about 2.

[0180] In certain embodiments, a solid form provided herein, e.g., Form X, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form X has an X-ray powder diffraction pattern substantially as shown in Figure 32. In one embodiment, Form X has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 8.0, 21.3, or 24.1 degrees (see Table 18). In another embodiment, Form X has one or more characteristic X- ray powder diffraction peaks at a two-theta angle of approximately 8.0, 18.1, 21.3, 24.1, 24.7, or 28.4 degrees. In another embodiment, Form X of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 4.0, 8.0, 18.1, 20.0, 21.3, 24.1, 24.7, 25.2, or 28.4 degrees. In another embodiment, Form X of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 18. In another embodiment, Form X has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 32.

[0181] In one embodiment, provided herein is Form X having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 33 comprising an endothermic event with a maximum at about 164.4 °C with onset temperature at about 131.5 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 164.4 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 131.5 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 51.3 J / g.

[0182] In one embodiment, provided herein is Form X having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 33 comprising an endothermic event with a maximum at about226.2 °C with onset temperature at about 213.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 226.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 213.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 34.2 J / g.

[0183] In one embodiment, provided herein is Form X having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 33 comprising an endothermic event with a maximum at about91.2 °C with onset temperature at about 76.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 91.2 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 76.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 302.3 J / g.

[0184] In one embodiment, provided herein is Form X having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 34. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 14.6 % of the total mass of the sample between approximately 32.8 °C and approximately 100.0 °C. Thus, in certain embodiments, the crystalline form loses about 14.6 % of the total mass of the crystal form when heated from about 33 °C to about 100 °C.

[0185] In still another embodiment, Form X of Compound A is substantially pure. In certain embodiments, the substantially pure Form X of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form X of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0186] In one embodiment, Form X is prepared from DMSO / EtOH (50:50, v:v) by an equilibration experiment at 25 °C or 50°C.5.3. 11 Form XI

[0187] Provided herein is solid Form XI, comprising Compound A. In one embodiment, Form XI is a crystal form. In another embodiment, Form XI is crystalline. In one embodiment, Form XI is substantially crystalline. In another embodiment, Form XI is a metastable form. In another embodiment, Form XI is converted to Form I.

[0188] In certain embodiments, a solid form provided herein, e.g., Form XI, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form XIhas an X-ray powder diffraction pattern substantially as shown in Figure 36. In one embodiment, Form XI has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.1,14.2, or 24.6 degrees (see Table 19). In another embodiment, Form XI has one or more characteristic X- ray powder diffraction peaks at a two-theta angle of approximately 9.1, 13.7, 14.2, 21.0, 24.6, or 29.0 degrees. In another embodiment, Form XI of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.1, 13.7, 14.2, 16.3, 21.0, 24.2, 24.6, 25.2, or 29.0 degrees.In another embodiment, Form XI of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at atwo-theta angle selected from the peaks listed in Table 19. In another embodiment, Form XI has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 36.

[0189] In one embodiment, Form XI is prepared from methanol by an equilibration experiment at 25°C.5.3.12 Form XII

[0190] Provided herein is solid Form XII, comprising Compound A. In one embodiment, Form XII is a crystal form. In one embodiment, Form XII is a DMAc solvate. In one embodiment, Form XII is substantially crystalline.

[0191] In one embodiment, Form XII is a solvated form comprising Compound A. In one embodiment, Form XII is a DMAc solvated form comprising Compound A. In another embodiment, Form XII is crystalline.

[0192] In one embodiment, the molar ratio of DMAc to Compound A of Form XII is 0.65 ± 0.1, 0.65 ± 0.05, 0.65 ± 0.01, or about 0.65.

[0193] In certain embodiments, a solid form provided herein, e.g., Form XII, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form XII has an X-ray powder diffraction pattern substantially as shown in Figure 37. In one embodiment, Form XII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately5.2, 15.7, or 26.0 degrees (see Table 20). In another embodiment, Form XII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 5.2, 14.1, 15.7, 19.7, 26.0, or 28.4 degrees. In another embodiment, Form XII of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 5.2, 14.1, 15.7, 17.5, 19.7, 24.9, 26.0, 26.9, or 28.4 degrees. In another embodiment, Form XII of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 20. In another embodiment, Form XII has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 37.

[0194] In one embodiment, provided herein is Form XII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 38 comprising an endothermic event with amaximum at about 154.9 °C with onset temperature at about 144.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 154.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 144.9 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 101.9 J / g.

[0195] In one embodiment, provided herein is Form XII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 38 comprising an exothermic event with a maximum at about 162.8 °C with onset temperature at about 161.1 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 162.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with an onset temperature at approximately 161.1 °C .

[0196] In one embodiment, provided herein is Form XII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 38 comprising an endothermic event with a maximum at about 164.0 °C with onset temperature at about 162.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 164.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 162.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 14.0 J / g.

[0197] In one embodiment, provided herein is Form XII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 38 comprising an endothermic event with a maximum at about 219.8 °C with onset temperature at about 212.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 219.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 212.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 36.2 J / g.

[0198] In one embodiment, provided herein is Form XII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 39. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 0.8 % of the total mass of the sample between approximately 26.1 °C and approximately 120.0 °C. Thus, in certain embodiments, the crystalline form loses about 0.8 % of the total mass of the crystal form when heated from about 26 °C to about 120 °C.

[0199] In one embodiment, provided herein is Form XII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 39.In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 9.4 % of the total mass of the sample between approximately 120.0 °C and approximately 155.0 °C. Thus, in certain embodiments, the crystalline form loses about 9.4 % of the total mass of the crystal form when heated from about 120 °C to about 155 °C.

[0200] In still another embodiment, Form XII of Compound A is substantially pure. In certain embodiments, the substantially pure Form XII of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form XII of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0201] In one embodiment, Form XII is prepared from DMAc by an equilibration experiment at 25°C.5.3.13 Form XIII

[0202] Provided herein is solid Form XIII, comprising Compound A. In one embodiment, Form XIII is a crystal form. In one embodiment, Form XIII is an anhydrous form. In one embodiment, Form XIII is an anhydrate. In one embodiment, Form XIII is substantially crystalline. In another embodiment, Form XIII is crystalline. In another embodiment, Form XIII is a metastable form. In another embodiment, Form XIII is converted to Form II.

[0203] In certain embodiments, a solid form provided herein, e.g., Form XIII, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form XIII has an X-ray powder diffraction pattern substantially as shown in Figure 41. In one embodiment, Form XIII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately7.4, 14.9, or 18.6 degrees (see Table 22). In another embodiment, Form XIII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.4, 7.7, 14.9, 17.6, 18.6, or 23.4 degrees. In another embodiment, Form XIII of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.4, 7.7, 14.9, 16.4, 17.6, 18.6, 19.1,23.4, or 30.0 degrees. In another embodiment, Form XIII of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 22. In another embodiment, Form XIII has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 41.

[0204] In one embodiment, provided herein is Form XIII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 42 comprising an endothermic event with a maximum at about 173.9 °C with onset temperature at about 164.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 173.9 °C. In one embodiment, the crystal form has a differential scanning calorimetrythermogram comprising an endothermic event with an onset temperature at approximately 164.8 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 55.5 J / g.

[0205] In one embodiment, provided herein is Form XIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 43. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 2.2 % of the total mass of the sample between approximately 35.4 °C and approximately 150.0 °C. Thus, in certain embodiments, the crystalline form loses about 2.2 % of the total mass of the crystal form when heated from about 35 °C to about 150 °C.

[0206] In one embodiment, provided herein is Form XIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 43. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 5.8 % of the total mass of the sample between approximately 150.0 °C and approximately 180.0 °C. Thus, in certain embodiments, the crystalline form loses about 5.8 % of the total mass of the crystal form when heated from about 150 °C to about 180 °C.

[0207] In still another embodiment, Form XIII of Compound A is substantially pure. In certain embodiments, the substantially pure Form XIII of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form XIII of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0208] In certain embodiments, provided herein are thermo conversion methods for making a solid form of Compound A, comprising heating a starting solid form of Compound A to a temperature for a period of time. In one embodiment, the starting solid form is Form IX. In one embodiment, the resulting solid is Form XIII. In one embodiment, the temperature is about 120 °C. In one embodiment, the solid is heated for about 1 hour. In one embodiment, the solid is heated under vacuum.5.3.14 Form XIV

[0209] Provided herein is solid Form XIV, comprising Compound A. In one embodiment, Form XIV is a crystal form. In one embodiment, Form XIV is a DMSO solvate. In one embodiment, Form XIV is substantially crystalline.

[0210] In one embodiment, Form XIV is a solvated form comprising Compound A. In one embodiment, Form XIV is a DMSO solvated form comprising Compound A. In another embodiment, Form XIV is crystalline.

[0211] In one embodiment, the molar ratio of DMSO to Compound A of Form XIV is 1.0 ± 0. 1, 1.00 ± 0.05, 1.00 ± 0.01, or about 1.

[0212] In certain embodiments, a solid form provided herein, e.g., Form XIV, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form XIV has an X-ray powder diffraction pattern substantially as shown in Figure 45. In one embodiment, Form XIV has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 11.4, 17.2, or 23.0 degrees (see Table 23). In another embodiment, Form XIV has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 5.7, 11.4, 17.2, 19.1, 22.0, or 23.0 degrees. In another embodiment, Form XIV of Compound A has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 5.7, 11.4, 13.3, 17.2, 18.5, 19.1, 22.0, 23.0, or 23.4 degrees. In another embodiment, Form XIV of Compound A has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks at a two-theta angle selected from the peaks listed in Table 23. In another embodiment, Form XIV has one, two, three, four, five, six, seven, eight, nine, or more characteristic X-ray powder diffraction peaks as set forth in Figure 45.

[0213] In one embodiment, provided herein is Form XIV having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 46 comprising an endothermic event with a maximum at about 143.5 °C with onset temperature at about 143.1 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 143.5 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 143. 1 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 41.4 J / g.

[0214] In one embodiment, provided herein is Form XIV having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 46 comprising an endothermic event with a maximum at about 236. 1 °C with onset temperature at about 230.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 236. 1 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 230.0 °C. In one embodiment, the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 80.9 J / g.

[0215] In one embodiment, provided herein is Form XIV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 47. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 2.3 % of the total mass of the sample between approximately 28.0 °C and approximately 130.0 °C. Thus, in certain embodiments, the crystalline form loses about 2.3 % of the total mass of the crystal form when heated from about 28 °C to about 130 °C.

[0216] In one embodiment, provided herein is Form XIV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 47. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 12.5 % of the total mass of the sample between approximately 130.0 °C and approximately 200.0 °C. Thus, in certain embodiments, the crystalline form loses about 12.5 % of the total mass of the crystal form when heated from about 130 °C to about 200 °C.

[0217] In still another embodiment, Form XIV of Compound A is substantially pure. In certain embodiments, the substantially pure Form XIV of Compound A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form XIV of Compound A is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure.

[0218] In one embodiment, Form XIV is prepared from crystallization from DMSO / IPA / H2O (5v / 16v / 0.4v) mixture. METHODS OF USE

[0219] The solid forms and the pharmaceutical compositions provided herein can be used in all the methods provided herein. The solid forms and the pharmaceutical compositions thereof can be used in the treatment of all diseases, disorders or conditions provided herein.

[0220] Provided herein are methods for treating or preventing a cancer, comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to a patient having a cancer.

[0221] In some embodiments, the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, thyroid tumor, and their complications; preferably melanoma, and non-small cell lung cancer.

[0222] In some embodiments, the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and their combination thereof.

[0223] In some embodiments, the cancer is characterized by a mutation in a gene selected from the group consisting of RAS, NRAS, KRAS, RAF, BRAF, and their combination thereof.

[0224] In some embodiments, the cancer is characterized by a mutation in a gene selected from the group consisting of NRAS, KRAS, BRAF, and their combination thereof.

[0225] In some embodiments, the cancer is characterized by:(i) a mutation in a gene selected from the group consisting of ARAF, BRAF, RAFI, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, and their combination thereof;(ii) a mutation selected from the group consisting of BRAF N20T, BRAF A33T, BRAF S36A, BRAF V47_G393del, BRAF V47_G327del, BRAF V47_D380del, BRAF V47_M438del, BRAF N49I, BRAF M53I, BRAF L64I, BRAF G69S, BRAF A81_D380del, BRAF A81_M438del, BRAF G104E, BRAF T119S, BRAF P141L, BRAF S151A, BRAF P162S, BRAF V169_G327del, BRAF V169_D380del, BRAF R188T, BRAF Q201H, BRAF G203_G393del, BRAF K205Q, BRAF V226L, BRAF E228V, BRAF R239Q, BRAF T241P, BRAF T241M, BRAF L245F, BRAF A246P, BRAF F247L, BRAF Q257R, BRAF Q257H, BRAF G258V, BRAF F259L, BRAF Q262R, BRAF H269Y, BRAF R271H, BRAF E275K, BRAF D287H, BRAF F294L, BRAF T310I, BRAF A320T, BRAF I326V, BRAF P341S, BRAF R347*, BRAF P348T, BRAF S363F, BRAF S364L, BRAF P367S, BRAF P367R, BRAF P367L, BRAF D380H, BRAF R389C, BRAF T401I, BRAF A404Cfs*9, BRAF P407L, BRAF S419Y, BRAF G421V, BRAF R444W, BRAF D448Y, BRAF D449Y, BRAF W450*, BRAF W450L, BRAF E451K, BRAF E451Q, BRAF P453T, BRAF V459L, BRAF R462E, BRAF R462K, BRAF R462I, BRAF I463T, BRAF 1463 S, BRAF G464I, BRAF G464R, BRAF G464E, BRAF G464A, BRAF G464V, BRAF S465D, BRAF S465E, BRAF S465A, BRAF G466R, BRAF G466E, BRAF G466A, BRAF G466V, BRAF S467A, BRAF S467L, BRAF F468C, BRAF G469L, BRAF G469del, BRAF G469S, BRAF G469R, BRAF G469E, BRAF G469A, BRAF G469V, BRAF T470K, BRAF V471I, BRAF V471F, BRAF Y472dup, BRAF Y472S, BRAF Y472C, BRAF G478C, BRAF K483E, BRAF K483M, BRAF L485_P490del, BRAF L485Y, BRAF L485_P490delinsY, BRAF L485S, BRAF L485W, BRAF L485F, BRAF L485_P490delinsF, BRAF N486_Q494del, BRAF N486del, BRAF N486_T488del, BRAF N486_T491del, BRAF N486_L495del, BRAF N486D, BRAF N486_V487del, BRAF N486_P490del, BRAF N486_A489delinsK, BRAF N486_T491delinsK, BRAF V487_P490del, BRAF V487_P492delinsA, BRAF T488_P492del, BRAF T488_Q493delinsK, BRAF A489_P490del, BRAF P490del, BRAF P490_Q494del, BRAF K499E, BRAF K499N, BRAF E501K, BRAF E501G, BRAF V504_R506dup, BRAF V504I, BRAF L505F, BRAF L505H, BRAF R509G, BRAF R509H, BRAF L514V, BRAF M517I, BRAF Q524L, BRAF L525R, BRAF T529M, BRAF T529N, BRAF T529I, BRAF W531C, BRAF G534D, BRAF Y538H, BRAF R558Q, BRAF G563D, BRAF H568D, BRAF H574N, BRAF H574Y, BRAF H574Q, BRAF N581 D, BRAF N581 Y, BRAF N581 T, BRAF N581 S, BRAF N581I, BRAF N581K, BRAF I582M, BRAF F583C, BRAF L584F, BRAF H585Y, BRAF E586K, BRAF D587A, BRAF D587G, BRAF D587E, BRAF V590I, BRAF V590G, BRAF I592V, BRAF I592M, BRAF G593D, BRAF D594N, BRAF D594H, BRAF D594Y, BRAF D594_T599dup, BRAF D594A, BRAF D594G, BRAF D594V, BRAF D594E, BRAF F595L, BRAF F595S, BRAF G596S, BRAF G596R, BRAF G596C, BRAF G596D, BRAF G596V, BRAF L597S, BRAF L597V, BRAF L597Q, BRAF L597P, BRAF L597R, BRAF A598T, BRAF A598S, BRAF A598V, BRAF A598_T599insARC, BRAF A598_T599insV, BRAF T599dup, BRAF T599A, BRAF T599K, BRAF T599R, BRAF T599I, BRAF T599_V600insTT, BRAF T599_V600insS, BRAF T599_V600insETT, BRAF T599_V600insEAT, BRAF V600_K601delinsEN, BRAF V600_S605delinsEISRWR, BRAF V600K, BRAF V600R, BRAF V600Q, BRAF V600dup, BRAF V600delinsYM, BRAF V600M, BRAFV600L, BRAF V600D, BRAF V600_K601delinsE, BRAF V600E, BRAF V600A, BRAF V600G, BRAF K601del, BRAF K601Q, BRAF K601E, BRAF K601_W604del, BRAF K601T, BRAF K601I, BRAF K601_S602delinsNT, BRAF K601N, BRAF S602T, BRAF S602Y, BRAF S602F, BRAF R603*, BRAF W604del, BRAF W604R, BRAF W604G, BRAF S605A, BRAF S605F, BRAF S605E, BRAF S605G, BRAF S605N, BRAF S605I, BRAF G606W, BRAF G606E, BRAF G606A, BRAF G606V, BRAF S607P, BRAF S607F, BRAF H608R, BRAF Q609E, BRAF Q609L, BRAF Q609H, BRAF E61 ID, BRAF L613F, BRAF G615R, BRAF L618F, BRAF W619R, BRAF S637*, BRAF V639I, BRAF E648Q, BRAF Y656D, BRAF R671Q, BRAF P676S, BRAF L678I, BRAF V681I, BRAF E695K, BRAF K698R, BRAF L71 IF, BRAF A712T, BRAF R719S, BRAF H725Y, BRAF A728V, BRAF P73 IT, BRAF P73 IS, BRAF P73 IL, BRAF A762E, BRAF A762V, and their combination thereof;(iii) a mutation selected from the group consisting of KIAA1549-BRAF fusion, BCAS1- BRAF fusion, CCDC6-BRAF fusion, CDC42BPB-BRAF fusion, FAM131B-BRAF fusion, FXR1-BRAF fusion, GIT2-BRAF fusion, KLHL7-BRAF fusion, RNF130-BRAF fusion, TMEM106B-BRAF fusion, MKRN1-BRAF fusion, AGAP3-BRAF fusion, AGK-BRAF fusion, AKAP9-BRAF fusion, ARMC10- BRAF fusion, CUL1-BRAF fusion, GTF2I-BRAF fusion, PAPSS1-BRAF fusion, PCBP2-BRAF fusion, PPFIBP2-BRAF fusion, SND1-BRAF fusion, TRIM24-BRAF fusion, ZKSCAN1-BRAF fusion, SEPT3- BRAF fusion, and their combination thereof; or(iv) a mutation selected from the group consisting ofNRAS G12A, NRAS G12C, NRAS G12D, NRAS G12N, NRAS G12P, NRAS G12R, NRAS G12S, NRAS G12V, NRAS G12Y, NRAS G13A, NRAS G13C, NRAS G13D, NRAS G13E, NRAS G13N, NRAS GI3R. NRAS G13S, NRAS G13V, NRAS A18T, NRAS I24N, NRAS P34L, NRAS Y40*, NRAS Q43*, NRAS T50I, NRAS T58I, NRAS A59G, NRAS A59D, NRAS A59T, NRAS G60E, NRAS G60R, NRAS Q61E, NRAS Q61H, NRAS Q61H, NRAS Q61K, NRAS Q61L, NRAS Q61L, NRAS Q61P, NRAS Q61R, NRAS Q61R, NRAS Q61R, NRAS Q61*, NRAS E63K, NRAS Y64D, NRAS S65C, NRAS R68S, NRAS S89A, NRAS G115Efs*46, NRAS E132K, NRAS K135N, NRAS A146P, NRAS A146T, NRAS A146V, NRAS El 62*, and their combination thereof.

[0226] In some embodiments, the cancer is characterized by a mutation selected from the group consisting ofNRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof.

[0227] In some embodiments, the cancer is characterized by a mutation selected from the group consisting ofNRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and their combination thereof.

[0228] In some embodiments, the cancer is characterized by a mutation selected from the group consisting ofNRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and their combination thereof.

[0229] In some embodiments, the cancer is characterized by other MAPK pathway genomic aberration.

[0230] In some embodiments, the cancer is melanoma.

[0231] In one embodiment, the melanoma is cutaneous melanoma.

[0232] In one embodiment, the melanoma is metastatic melanoma.

[0233] In one embodiment, the cancer is non-small cell lung cancer.

[0234] In one embodiment, the cancer is colorectal cancer.

[0235] In one embodiment, the cancer is ovarian cancer.

[0236] In one embodiment, the solid form is administered one to three times a day.

[0237] In one embodiment, the solid form is administered once a day.

[0238] In one embodiment, the solid form is administered twice a day.

[0239] In one embodiment, the solid form is administered three times a day.

[0240] In one embodiment, the solid form is administered from about 5 mg to about 600 mg per day.

[0241] In one embodiment, the solid form is administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 115 mg, or about 120 mg per day.

[0242] In one embodiment, the solid form is administered at about 25 mg, about 40 mg or about 60 mg per day.

[0243] In one embodiment, the solid form is administered at about 25 mg per day.

[0244] In one embodiment, the solid form is administered at about 40 mg per day.

[0245] In one embodiment, the solid form is administered at about 60 mg per day.

[0246] In one embodiment, the method provides a plasma Compound A AUC8h between about2,128 ng*h / ml and about 3,192 ng*h / ml in the subject.

[0247] In one embodiment, the method provides a plasma Compound A AUC8h between about 4,576 ng*h / ml and about 6,864 ng*h / ml in the subject.

[0248] In one embodiment, the method provides a plasma Compound A AUC8h between about 7,944 ng*h / ml and about 11,916 ng*h / ml in the subject.

[0249] In one embodiment, the method provides a plasma Compound A AUC8h between about 9,840 ng*h / ml and about 14,760 ng*h / ml in the subject.

[0250] In one embodiment, the method provides a plasma Compound A AUC8h between about 12,640 ng*h / ml and about 18,960 ng*h / ml in the subject.

[0251] In one embodiment, the method provides a plasma Compound A AUC8h between about 30,000 ng*h / ml and about 45,000 ng*h / ml in the subject.

[0252] In one embodiment, the subject achieves a stable disease, a partial response, or a complete response.

[0253] In one embodiment, the subject achieves a partial response or a complete response.

[0254] In one embodiment, the subject achieves a complete response.

[0255] In one embodiment, the subject does not experience a progressive disease.

[0256] In one embodiment, the subject achieves a stable disease.

[0257] In one embodiment, the subject achieves a partial response.

[0258] In certain embodiments, provided herein are methods for achieving a Response Evaluation Criteria in Solid Tumors (for example, RECIST 1.1) of complete response, partial response or stable disease in a patient having a solid tumor, comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to said patient. In certain embodiments, provided herein are methods for achieving a National Cancer Institute-Sponsored Working Group on Chronic Lymphocytic Leukemia (NCI-WG CLL) of complete response, partial response or stable disease in a patient having leukemia, comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to said patient. In certain embodiments, provided herein are methods for achieving a Prostate Cancer Working Group 2 (PCWG2) Criteria of complete response, partial response or stable disease in a patient having prostate cancer, comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to said patient. In certain embodiments, provided herein are methods for achieving an International Workshop Criteria (IWC) for non-Hodgkin’s lymphoma of complete response, partial response or stable disease in a patient having non-Hodgkin’s lymphoma, comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to said patient. In certain embodiments, provided herein are methods for achieving an International Uniform Response Criteria (IURC) for multiple myeloma of complete response, partial response or stable disease in a patient having multiple myeloma, comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to said patient.

[0259] In certain embodiments, provided herein are methods for increasing survival without disease progression of a patient having a cancer, comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to said patient.

[0260] In certain embodiments, provided herein are methods for treating a cancer, the methods comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to a patient having a cancer, wherein the treatment results in prevention or retarding of clinical progression, such as cancer-related cachexia or increased pain.

[0261] In some embodiments, provided herein are methods for treating a cancer, the methods comprising administering a solid form of Compound A provided herein or a pharmaceutical composition thereof to a patient having a cancer, wherein the treatment results in one or more of inhibition of diseaseprogression, increased Time To Progression (TTP), increased Progression Free Survival (PFS), and / or increased Overall Survival (OS), among others. METHODS OF MAKING

[0262] The solid forms provided herein can be prepared by the methods described herein, or by techniques, including, but not limited to, heating, cooling, freeze drying, spray drying, lyophilization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, solvent recrystallization, antisolvent addition, slurry recrystallization, crystallization from the melt, desolvation, recrystallization in confined spaces, such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., salt counter-molecules, cocrystal counter-molecules, desolvation, dehydration, rapid cooling, slow cooling, exposure to solvent and / or water, drying, including, e.g., vacuum drying, vapor diffusion, sublimation, grinding (including, e.g., cryo-grinding and solvent-drop grinding), microwave-induced precipitation, sonication-induced precipitation, laser-induced precipitation, and precipitation from a supercritical fluid. The particle size of the resulting solid forms, which can vary (e.g., from nanometer dimensions to millimeter dimensions), can be controlled, e.g., by varying crystallization conditions, such as, e.g., the rate of crystallization and / or the crystallization solvent system, or by particle-size reduction techniques, e.g., grinding, milling, micronizing, or sonication.

[0263] In certain embodiments, reverse antisolvent addition crystallization is a process that involves the addition of an antisolvent to a solution containing the solute. The controlled addition of antisolvent reduces solubility in the mixture and triggers recrystallization. Two common ways of operation are either antisolvent addition to product solution or product solution addition to antisolvent (reverse addition).

[0264] In certain embodiments, provided herein are antisolvent addition methods for making a solid form of Compound A, comprising 1) obtaining a close-to saturated or saturated solution of Compound A in a polar solvent; 2) slowly adding a non-polar solvent into the solution at a temperature (e.g., about 22 °C to about 26 °C) for a period of time (e.g., about 5 days); 3) filtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded.

[0265] In certain embodiments, provided herein are reverse antisolvent addition methods for making a solid form of Compound A, comprising 1) obtaining a close-to saturated or saturated solution of Compound A in a polar solvent; 2) slowly adding the solution into a non-polar solvent at a temperature (e.g., about 22 °C to about 26 °C) for a period of time (e.g., about 5 days); 3) filtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded.

[0266] In certain embodiments, equilibrium crystallization is a process where crystals form froma cooling melt in a closed system. Chemical equilibrium is maintained until the melt has completely crystallized. Crystal growth is a dynamic process occurring in equilibrium where solute molecules or atoms precipitate out of solution, and dissolve back into solution. A system in which crystallization and dissolution occur at the same rate is in dynamic equilibrium.

[0267] In certain embodiments, crystallization is a natural process that happens when the materials solidify from a liquid, it can also occur when a solid precipitates from a liquid or gas. The crystallization process occurs resulting in a change in the physical property of the liquid, such as the change in temperature, change in its acidity. The three major stages in the process of Crystallization are: 1) Supersaturation of Solution: It can be done in three ways: Heating the solution, Cooling the solution, and Salting it out. 2) Nucleation: This takes place in several steps. During their random motion, the atoms / molecules / ions will come closer to one another, and form aggregates called Clusters. 3) Crystal Growth: Once the crystals are formed, nuclei formation stops, and crystal growth begins.

[0268] In certain embodiments, provided herein are slow evaporation methods for making a solid form of Compound A, comprising 1) obtaining a close-to saturated or saturated solution of Compound A in a solvent; 2) slowly evaporating the solution at a temperature (e.g. , about 22 °C to about 26 °C) for a period of time (e.g., about 5 days); 3) fdtering the solution to yield a solid if there is precipitation; and 4) evaporating the solvent to collect a solid if there is no precipitation after step 2. In one embodiment, the solution may be seeded.

[0269] In certain embodiments, provided herein are slurry methods for making a solid form of Compound A, comprising 1) obtaining a slurry of Compound A in a solvent; 2) stirring the slurry for a period of time; 3) collecting a solid from the slurry by filtration (e.g., centrifuge filtration). In one embodiment, the solution may be seeded.

[0270] In certain embodiments, provided herein are thermo conversion methods for making a solid form of Compound A, comprising heating a starting solid form of Compound A to a temperature for a period of time. PHARMACEUTICAL COMPOSITIONS

[0271] Solid forms of Compound A provided herein are useful for the preparation of pharmaceutical compositions, comprising an effective amount of a solid form of Compound A and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutical compositions described herein are suitable for oral, parenteral, mucosal, transdermal, or topical administration.

[0272] In certain embodiments, provided herein are compositions comprising one or more solid forms of Compound A. Also provided herein are compositions comprising: (i) one or more solid forms of Compound A provided herein, and (ii) other active or inactive ingredient(s).

[0273] In one embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound A and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise one of the solid forms provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0274] In one embodiment, the pharmaceutically acceptable excipients and carriers are selected from binders, diluents, disintegrants and lubricants.

[0275] In certain embodiments, the pharmaceutical compositions provided herein comprise Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV of Compound A.6. EXAMPLES

[0276] The following Examples are presented by way of illustration, not limitation. Polymorph Screening Summary

[0277] The objective of this polymorph study was to identify potential polymorphs and pseudopolymorphs of the Compound A free base and select an optimal polymorph in terms of stability, hygroscopicity and feasibility for downstream development. Polymorph Screening

[0278] Compound A free base Form III was used as starting material in the polymorph screening. Polymorphic behaviors of Compound A were investigated by equilibration, slow evaporation, slow cooling, antisolvent addition and reverse antisolvent addition experiments.

[0279] Compound A free base shows complicated polymorphic behaviors. In total, 14 crystalline forms were identified to be polymorphs or pseudo-polymorphs of the free base, including 2 anhydrates, named as Form II and Form XIII, 5 hydrates, named as Form I, Form III, Form IV, Form VIII and Form IX, 3 solvates, named as Form X, XII and XIV and 1 metastable form, named as Form XI.

[0280] Table 1 : Summary of polymorphs

[0281] Explanation Form V (anhydrate), Form VI (anhydrate), Form VII (anhydrate) were identified.

[0282] “**”: Form I and Form XIV were identified.

[0283] Table 2: Summary of characterization of polymorphs and pseudo-polymorphs

[0284] ExplanationNo comments.

[0285] Table 3 : Summary of characterization of polymorphs and pseudo-polymorphsFree base polymorphs6.3.1 Form I

[0286] Preparation of Compound A free base Form I (hydrate):

[0287] Form I was prepared using the procedure below.

[0288] About 300mg of Compound A free base Form III was added in 55mL of acetone / water(50:50, v / v). Obtained solutions were fdtered through a 0.45pm syringe membrane fdter. The clear solutions were slowly evaporated in ambient condition, (about 22-26°C, 25-65%RH)

[0289] About lOmg free base Form I seeds were added into above clear solution.

[0290] After slowly evaporated in ambient condition for about 13 days, solids were analyzed byXRPD. A physical mixture of Form I and Form VIII was obtained.

[0291] Table 4 Characterization of Compound A free base

[0292] Form I is a hydrate. It was crystallized from DMSO / water system. Form I is of high crystallinity. It contains about 1.06 equiv. (3.8% by weight) of water according to KF result. DSC showed a dehydration peak at Tonset of 33.8°C with an enthalpy of 92J / g, an exothermic peak at Tonset of 170.2°C and a melting peak at Tonset of 219.2°C. Decomposition occurred upon melting. TGA showed about 3.7% weight loss at about 100°C. 1H-NMR showed no detectable residual solvent. Form I is a metastable form. It converted to anhydrate Form II in water activity from 0 to 1 at 25°C and 50°C.

[0293] Figure 1 describes the XRPD pattern of Compound A free base Form I.

[0294] Table 5 XRPD peaks table of Compound A free base Form I6.3.2 Form II

[0295] Preparation of Compound A free base Form II (anhydrate):

[0296] Form II was prepared using the procedure below.

[0297] About 1. 1g of Compound A free base Form III was weighed into a 20mL glass vial. 22mL of MeOH / acetone (50:50, v / v) was added into the vial under stirring at 50°C. (suspension)

[0298] About lOmg of free base Form II seeds were added into above suspension, (suspension)

[0299] After stirring at 50°C for about 5 days, solids were filtrated through a 0.45pm nylon membrane filter at 4,000rpm. Solids were air dried at ambient condition for about 16hours.

[0300] 965.6mg of the Form II was obtained as a white solid in 86% yield.

[0301] Table 6 Characterization of Compound A free base Form II

[0302] Form II is an anhydrate. It was obtained from most of solvents by equilibration, slow evaporation, slow cooling experiments and from MEK / water by addition of antisolvent experiments. Form II is of high crystallinity. DSC showed a melting peak at Tonset of 220.7°C. Decomposition occured upon melting. TGA showed about 0.9% weight loss at about 190°C. 1H-NMR showed 0.2% acetone residue by weight. Water activity experiments showed that Form II was stable across a wide activity from 0 to 1.0 at 25°C and 50°C. Interrelationship of polymorphs was summarized in Section 6.4.

[0303] Figure 2 describes the XRPD pattern of Compound A free base Form II.

[0304] Table 7 XRPD peaks table of Compound A free base Form II6.3.3 Form III

[0305] Syntheses of Form III of Compound A

[0306] INTQ-18 and INTQ-19 were prepared according to the synthetic processes in paragraphs

[0179] -

[0215] ofWO2020151756 which is incorporated herein by reference.

[0307] The reactor was vacuumed to < -0.08 MPa and then charged with inert nitrogen to atmosphere. DMSO (81 mL), INTQ-18 (10g) and N-methyl morpholine (2.95g, 1 eq) were charged to the reactor. The mixture was stirred for at least 0.5 hour at 20±5°C. INTQ-19 (7.02g, 0.9eq) was charged to the reactor at 20±5°C. The mixture was stirred for 4 hours at 20±5°C.

[0308] 0.5% hydrochloric acid (270 mL) was charged into the reactor slowly at 20±5°C, and the mixture was stirred for 17 hours at 20±5°C, and then fdtered. The fdter cake was washed with purified water (20 mL).

[0309] DMSO (81 mL), 0.5% hydrochloric acid (270 mL) and the filter cake were charged to a reactor, and the mixture was stirred for at least 4 hours at 20±5°C, and then filtered. The filter cake was washed with purified water (20 mL).

[0310] DMSO (81 mL), 0.5% hydrochloric acid (270 mL) and the filter cake were charged to a reactor, and the mixture was stirred for at least 14 hours at 20±5°C, and then filtered. The filter cake was washed with purified water (20 mL).

[0311] Purified water (400 mL) and the filter cake were charged to a reactor, and the mixture was stirred for at least 4 hours at 20±5°C, and then filtered. The filter cake was washed with purified water (20 mL).

[0312] The cake was then dried under vacuum at 50±5°C for 48 hours. 13.10 g solid was collected (98.45 % purity and 83.99 % yield).

[0313] Figure 3 describes the XRPD pattern of Form III

[0314] Table 8. XRPD peaks table of Form III

[0315] Form III is a hydrate. It was the starting material for polymorph screening. Form III is of low crystallinity. It contains about 0.8 equiv. (2.9% by weight) of water according to KF result. DSC showed an exothermic peak at Tonset of 157.6°C with an enthalpy of about 43J / g and a melting peak at Tonset of 202.4°C. Decomposition occurred upon melting. TGA showed about 3.0% weight loss at about 150°C. 1H-NMR showed no detectable residual solvent. Form III is a metastable form. It converted to anhydrate Form II in water activity from 0 to 1 at 25°C and 50°C.6.3.4 Form IV

[0316] Preparation of Compound A free base Form IV (hydrate):

[0317] Form IV was prepared using the procedure below.

[0318] About 300mg of Compound A free base Form III was weighed into an 8mL glass vial.3mL of IP Ac was added into the vial under stirring at 50°C. (suspension)

[0319] About lOmg of free base Form IV seeds were added into above suspension, (suspension)

[0320] After stirring at 50°C for about 5 days, solids were filtrated through a 0.45pm nylon membrane filter at 4,000rpm. Solids were air dried at ambient condition for about 16 hours.

[0321] 308. Omg of the Form IV was obtained as a white solid in 90% yield.

[0322] Table 9 Characterization of Compound A free base Form IV

[0323] Form IV is a hydrate. It was obtained from multiple solvents by equilibration experiments, from MEK / IPAc (50:50, v:v) by slow cooling experiment, from THF / water and THF / heptane by antisolvent addition experiments and from THF / water, THF / MTBE and THF / heptane by reverse antisolvent addition experiments. Form IV is of high crystallinity. DSC showed two endothermic peaks at Tonset of 17.4°C with an enthalpy of about 28J / g and at Tonset of 128.7°C with an enthalpy of about 23J / g. Then an exothermic peak at Tonset of 156.9°C and a melting peak at Tonset of 205.8°C appear. Decomposition occurred upon melting. TGA showed about 1.7% weight loss at about 100°C, about 2.5% weight loss from about 100°C to about 140°C and about 2.0% weight loss at about 140°C to about 160°C. 1H-NMR showed 1.0% (0.05 equiv.) IP Ac residue. Form IV is a metastable form. It converted to anhydrate Form II in water activity from 0 to 1 at 25°C and 50°C.

[0324] Figure 4 describes the XRPD pattern of Compound A free base Form IV.

[0325] Table 10 XRPD peaks table of Compound A free base Form IV6.3.5 Form V

[0326] Figure 5 describes the XRPD pattern of Compound A free base Form V

[0327] Form V was obtained through slurried in 2-butanone. The sample was then performed thermal analysis (Figure 21). TGA result showed that about 1.34% of weight loss was observed. DSC profde showed that an endothermic peak was observed with onset and peak temperatures of 215.73 °C and 218.67 °C and the enthalpy was 83.93 J / g. No residual solvent peak was detected by NMR. It was presumed that the weight loss in TGA might due to water loss.

[0328] Table 11 XRPD peaks table of Compound A free base Form V6.3.6 Form VI

[0329] Figure 6 describes the XRPD pattern of Compound A free base Form VI

[0330] Table 12 XRPD peaks table of Compound A free base Form VI6.3.7 Form VII

[0331] Figure 7 describes the XRPD pattern of Compound A free base Form VII

[0332] Table 13 XRPD peaks table of Compound A free base Form VII6.3.8 Form VIII

[0333] Preparation of Compound A free base Form VIII (hydrate):

[0334] Form VIII was prepared using the procedure below.

[0335] About 300mg of Compound A free base Form III was weighed into an 8mL glass vial.2mL of MeOH / water (40:60, v / v) was added into the vial under stirring at 25°C. (suspension)

[0336] About lOmg of free base Form VIII seeds were added into above suspension, (suspension)

[0337] After stirring at 25 °C for about 5 days, solids were filtrated through a 0.45pm nylon membrane filter at 4,000rpm. Solids were air dried in ambient condition for about 16 hours.

[0338] Form VIII was obtained as a white solid.

[0339] Table 14 Characterization of Compound A free base Form VIII

[0340] Form VIII is a hydrate. It was obtained from acetone / water (60:40, v:v) and from MeOH / water (40:60, v:v) by equilibration experiments at 25°C, from acetone / water by antisolvent addition and from acetone / water and MEK / water by reverse antisolvent addition experiments. Form VIII is of high crystallinity. It contains about 0.74 equiv. (2.7% by weight) of water according to KF result. DSC showed a dehydration peak at Tonset of 103.8°C with an enthalpy of about 33 J / g, an endothermic peak at Tonset of 151.5°C, an exothermic peak at Tonset of 172.6°C and a melting peak at Tonset of 209.5°C. Decomposition occurred upon melting. TGA showed about 0.3% weight loss at about 85°C and about 1.6% weight loss from about 85°C to about 120°C. 1H-NMR showed no detectable residual solvent. Form VIII only appeared in solvent / water systems with high water activity. Form VIII is a metastable form. It converted to anhydrate Form II in water activity from 0 to 1 at 25°C and 50°C.

[0341] Figure 8 describes the XRPD pattern of Compound A free base Form VIII

[0342] Table 15 XRPD peaks table of Compound A free base Form VIII6.3.9 Form IX

[0343] Preparation of Compound A free base Form IX (hydrate):

[0344] Form IX was prepared using the procedure below.

[0345] About 600mg of Compound A free base Form III was added in 50mL of MEK / 2-MeTHF(50:50, v / v). Obtained solutions were fdtered through a 0.45pm syringe membrane fdter. The clear solutions were slowly evaporated in ambient condition (about 22-26°C, 25-65%RH).

[0346] About lOmg free base Form IX seeds were added into above clear solution.

[0347] After slowly evaporated in ambient condition for about 5 days, 409. Img of the Form IX was obtained as a white solid in 68% yield.

[0348] Table 16 Characterization of Compound A free base Form IX

[0349] Form IX is a hydrate. It was obtained from MEK / 2-MeTHF by slow evaporation experiment. Form IX is of high crystallinity. DSC showed a dehydration peak at Tonset of 16.1°C with an enthalpy of about lOJ / g and a melting peak at Tonset of 163.7°C with an enthalpy of about 5 IJ / g. TGA showed about 2.6% weight loss at about 145°C. 1H-NMR showed 1.5% (0.1 equiv.) MEK and 3.4% (0.2 equiv.) 2-MeTHF residue. Form IX is a metastable form. It converted to anhydrate Form II in water activity from 0 to 1 at 25°C and 50°C. After dehydration, Form IX converted to anhydrate Form XIII.

[0350] Figure 9 describes the XRPD pattern of Compound A free base Form IX

[0351] Table 17 XRPD peaks table of Compound A free base Form IX6.3.10 Form X

[0352] Form X is a DMSO solvate. It was obtained from DMSO / EtOH (50:50, v:v) by equilibration experiment at 25°C. Form X is of high crystallinity. DSC showed two desolvation peaks at Tonset of 76.0°C and 131.5°C. After desolvation, a melting peak at Tonset of 213.2°C appeared.Decomposition occurred upon melting. TGA showed about 14.6% weight loss at about 100°C. 1H-NMR showed 24.8% DMSO residue (2.0 equiv. by molar ratio) by weight. After heating to 185°C by TGA, Form X converted to anhydrate Form II.

[0353] Figure 10 describes the XRPD pattern of Compound A free base Form X

[0354] Table 18 XRPD peaks table of Compound A free base Form X6.3.11 Form XI

[0355] Form XI is a metastable form. It was captured from methanol. Form XI is of high crystallinity. It was unstable in bulk and converted to Form I in ambient condition.

[0356] Figure 11 describes the XRPD pattern of Compound A free base Form XI

[0357] Table 19 XRPD peaks table of Compound A free base Form XI6.3.12 Form XII

[0358] Form XII is a DMAc solvate. It was obtained from DMAc by equilibration experiment at 25°C. Form XII is of high crystallinity. DSC showed a desolvation peak at Tonset of 144.9°C, an exothermic peak at Tonset of 161.1°C and two melting peaks at Tonset of 162.8°C and at Tonset of 212.0°C. Decomposition occurred upon melting. TGA showed about 0.8% weight loss at about 120°C and about 9.4% weight loss from about 120°C to 155°C. 1H-NMR showed 10.5% DMAc residue (0.65 equiv. by molar ratio) by weight.

[0359] Figure 12 describes the XRPD pattern of Compound A free base Form XII

[0360] Table 20 XRPD peaks table of Compound A free base Form XII6.3.13 Form XIII

[0361] Preparation of Compound A free base Form XIII (anhydrate):

[0362] Form XIII was prepared using the procedure below.

[0363] About 200mg of Compound A Form IX was dried at 120°C under vacuum for about 1 hour.

[0364] About 196.5mg of the Form XIII was obtained as a white solid in 90% yield.

[0365] Table 21 Characterization of Compound A free base Form XIII

[0366] Form XIII is an anhydrate. It was obtained by heating Form IX to 120°C. Form XIII is of high crystallinity. DSC showed a melting peak at Tonset of 164.8°C with an enthalpy of about 55 J / g. TGA showed about 2.2% weight loss at about 150°C and about 5.8% weight loss from about 150°C to 180°C. 1H-NMR showed 1.2% (0.08 equiv. by molar ratio) MEK and 3.6% (0.21 equiv. by molar ratio) 2-MeTHF residue by weight. Form XIII is a metastable form. It converted to anhydrate Form II in water activity from 0 to 1 at 25 °C and 50°C.

[0367] Figure 13 describes the XRPD pattern of Compound A free base Form XIII

[0368] Table 22 XRPD peaks table of Compound A free base Form XIII6.3.14 Form XIV

[0369] Form XIV is a DMSO solvate. It was obtained from DMSO / IPA / H2O (5: 16:0.4) by crystallization experiment. Form XIV is of high crystallinity. DSC showed a desolvation peak at Tonset of 143.1°C with an enthalpy of about 41 J / g and a melting peak at Tonset of 230.0°C. Decomposition occurred upon melting. TGA showed about 2.3% weight loss at about 130°C and about 12.5% weight loss from about 130°C to 200°C. 1H-NMR showed 14.1% DMSO residue (1.0 equiv. by molar ratio) by weight.

[0370] Figure 14 describes the XRPD pattern of Compound A free base Form XIV

[0371] Table 23 XRPD peaks table of Compound A free base Form XIVInterrelationship of polymorphs

[0372] Relative stability of the hydrate Form I, the anhydrate Form II, the hydrate Form III, the hydrate Form IV, the hydrate Form VIII, the hydrate Form IX and the anhydrate Form XIII was investigated by water activity experiments.

[0373] After equilibration for 10-29 days, all forms converted to Form II in water activity from 0 to 1.0 at 25°C and 50°C.

[0374] Based on above results, Form II is the thermodynamically stable form across a wide water activity, from 0 to 1.0 at 25 °C and 50°C. Polymorph screening6.5.1 Approximate solubility at 25 °C and at 50°C

[0375] About 5mg of Compound A free base Form III was weighed to a 2mL glass vial. 20pL aliquots of each solvent were added to dissolve the drug substance at 25°C and 50°C.

[0376] Vortex and sonication were applied to assist dissolution. Max. volume of each solvent added was ImL. Approximate solubility was determined by visual observation.

[0377] Table 24: Approximate solubility at 25 °C and at 50°C6.5.2 Equilibration with solvents at 25 °C for 10 weeks

[0378] Based on approximate solubility results, about 50mg of Compound A free base Form III was equilibrated in 0. 1-0.3mL of solvents at 25°C for 10 weeks with a stirring bar on a magnetic stirring plate at a rate of 400 rpm.

[0379] Obtained suspensions were fdtered through a 0.45pm nylon membrane fdter by centrifugation at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD. For samples with different XRPD patterns, additional analysis including DSC, TGA and 1H-NMR was performed.

[0380] Table 25: Equilibration with solvents at 25 °C for 10 weeks

[0381] Explanation: “ / / ”: Not carried out. “-”:No comments. Water activity is calculated byUNIFAC method.6.5.3 Equilibration with solvents at 50°C for 12 days

[0382] Based on approximate solubility results, about 50mg of Compound A free base Form III was equilibrated in 0. 1-0.3mL of solvents at 50°C for 12 days with a stirring bar on a magnetic stirring plate at a rate of 400 rpm.

[0383] Obtained suspensions were fdtered through a 0.45pm nylon membrane fdter by centrifugation at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD. For samples with different XRPD patterns, additional analysis including DSC, TGA and 1H-NMR was performed.

[0384] Table 26: Equilibration with solvents at 50°C for 12 days

[0385] Explanation “ / / ”: Not carried out.No comments. Water activity is calculated by UNIFAC method.6.5.4 Equilibration under a temperature cycle

[0386] Based on approximate solubility results, about 50mg of Compound A free base Form III was equilibrated in 0.3mL of solvents 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.

[0387] Obtained suspensions were fdtered through a 0.45pm nylon membrane fdter by centrifugation at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD. For the sample with different XRPD pattern, DSC analysis was performed.

[0388] Table 27 : Equilibration under a temperature cycle

[0389] ExplanationNot carried out. “-”:No comments.6.5.5 Crystallization at room temperature by slow evaporation

[0390] Based on approximate solubility results, about 50mg of Compound A free base Form III was dissolved in 0.3- 0.7mL of solvents. Obtained solutions were fdtered through a 0.45pm syringe membrane fdter. The clear solutions were slowly evaporated in ambient condition (about 20-26°C, 20- 60%RH).

[0391] Solid residues were investigated by XRPD. For samples with different XRPD patterns, additional analysis including DSC, TGA and 1H-NMR was performed.

[0392] Table 28: Crystallization at room temperature by slow evaporation6.5.6 Crystallization from hot saturated solutions by slow cooling

[0394] Based on approximate solubility results, about 50mg of Compound A free base Form III was dissolved in the minimal amount of selected solvents at 50°C. Obtained solutions were fdtered through a 0.45pm syringe membrane filter. The clear solutions were cooled to 5°C at 0. 1°C / min.

[0395] Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD.

[0396] Table 29: Crystallization from hot saturated solutions by slow cooling

[0397] Explanation: “ / / ”: Not carried out. “-”:No comments.6.5.7 Crystallization by addition of antisolvent

[0398] Based on approximate solubility results, about 50mg of Compound A free base Form III was dissolved in the minimal amount of selected good solvents at ambient temperature (about 23-28°C). Obtained solutions were filtered through a 0.45pm syringe membrane filter. 1-5 folds of antisolvent was added into the clear solutions slowly.

[0399] Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD.

[0400] Table 30: Crystallization by addition of antisolvent

[0401] Explanation:Not carried out.No comments.6.5.8 Crystallization by reverse addition of antisolvent

[0402] Based on approximate solubility results, about 50mg of Compound A free base Form III was dissolved in the minimal amount of selected good solvents at ambient temperature (about 20-25 °C).Obtained solutions were filtered through a 0.45pm syringe membrane filter. The clear solutions were added into 4 folds of antisolvent quickly.

[0403] Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD.

[0404] Table 31 : Crystallization by reverse addition of antisolvent

[0405] Explanation: Not carried out.No comments.6.6 Interrelationship investigation of polymorphs6.6.1 Water activity experiments

[0406] The water activity experiments were conducted at 25 °C and 50°C in acetone / water system to determine critical water activity between Compound A Form I, Form II, Form III, Form IV, Form VIII, Form IX and Form XIII.

[0407] About 5mg of Compound A free base Form II, 5mg of Compound A free base Form III, 5mg of Compound A free base Form IV, 5mg of Compound A free base Form VIII, and 5mg of Compound A free base Form XIII were added to 0.4mL saturated solutions (prepared with Compound A free base Form II) of the acetone / water system.

[0408] Obtained suspensions were stirred at 25°C and 50°C for 3 days, respectively. Half number of suspensions were fdtered by centrifugation. Solid parts (wet cakes) were investigated by XRPD.

[0409] After stirring at 25 °C and 50°C for 5 days, about 5mg of Compound A free base Form IX, was added into the suspensions.

[0410] After stirring at 25 °C and 50°C for 7 days, about 5mg of Compound A free base Form I was added into the suspensions.

[0411] Obtained suspensions were stirred at 25°C and 50°C for another 3 days, respectively.Solid parts (wet cakes) were isolated by centrifugation fdtration and investigated by XRPD.

[0412] Table 32: Water activity experiments

[0413] Note: water activity is calculated by UNIFAC method.

[0414] Explanation Form I was provided.6.6.2 Water activity experiments

[0415] The water activity experiments were conducted at 25 °C and 50°C in acetone / water system to determine critical water activity between Compound A Form I, Form II and Form VIII.

[0416] About 5mg of Compound A free base Form I, 5mg of Compound A free base Form II, and 5mg of Compound A free base Form VIII were added to 0.4mL saturated solutions (prepared with Compound A free base Form XIII) of the acetone / water system.

[0417] Obtained suspensions were stirred at 25°C and 50°C for 14 days, respectively. Half number of suspensions were fdtered by centrifugation. Solid parts (wet cakes) were investigated by XRPD.

[0418] Obtained suspensions were stirred at 25°C and 50°C for another 15 days, respectively. Solid parts (wet cakes) were isolated by centrifugation fdtration and investigated by XRPD.

[0419] Table 33: Water activity experiments

[0420] Note: water activity is calculated by UNIFAC method.

[0421] Explanation “ / / ”: Not carried out.6.7 Evaluation of Compound A free base Form II6.7.1 Physicochemical characteristics

[0422] Table 34 Physicochemical characteristics6.7.2 Bulk stability

[0423] Bulk stability of Compound A free base Form II was evaluated 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 tight container over 1 week.Compound A free base Form II is physically and chemically stable under these conditions.

[0424] Compound A free base Form II was 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 Iweek. Samples after the stress were characterized by XRPD and HPLC and inspected for color change.

[0425] Table 35 Bulk stability6.7.3 Water sorption and desorption experiments

[0426] Hygroscopicity of Compound A free base Form II was evaluated by dynamic vapor sorption (DVS) test at 25°C. Compound A free base Form II is slightly hygroscopic. It absorbed about 0.5% water at 80%RH at 25°C. After the DVS test, obtained sample was still Form II.

[0427] Water sorption and desorption behavior of Compound A free base Form II was investigated by DVS at 25°C with a cycle of 40-0-95-0-40%RH, dm / dt 0.002% / min. equilibration time 60min and max. equilibration time 360min. XRPD was measured after the DVS test to determine form change.

[0428] Table 36 Water sorption and desorption experiments

[0429] Explanation “N / A”: Not applicable.6.7.4 Mechanical properties

[0430] Mechanical properties for Compound A free base Form II were evaluated by compression, grinding, granulation simulation experiments. Compound A free base Form II showed good tolerance to compression and wet granulation simulation with no form change and no obvious decrease in crystallinity or only slight decrease in crystallinity. Upon dry grinding manually, the Form II showed no form change, but its crystallinity decreased significantly.6.7.5 Compression simulation experiments

[0431] About lOmg of Compound A free base Form II was compressed for 5min under 2MPa, 5MPa and lOMPa with a hydraulic press. Potential form change and degree of crystallinity were evaluated by XRPD.

[0432] Table 37 Compression simulation experiments6.7.6 Dry grinding simulation experiments

[0433] About 30mg of Compound A free base Form II was ground manually with a mortar and a pestle for 3min. Potential form change and degree of crystallinity were evaluated by XRPD.

[0434] Table 38 Dry grinding simulation experiments

[0435] Wet granulation simulation experiments

[0436] Water or ethanol was added drop wise to about 20mg of Compound A free base Form II, until the sample was wetted sufficiently. Wet sample was ground gently with in a mortar and a pestle. Post granulation sample was dried under ambient condition for 10 min. Potential form change and degree of crystallinity were evaluated by XRPD.

[0437] Table 39 Wet granulation simulation experiments

[0438] Compound A free base Form II was the most stable polymorph identified. It showed good chemical and physical stability and was slightly hygroscopic.6.8 Instrumental methods

[0439] The embodiments disclosed herein are not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the disclosed embodiments and any embodiments that are functionally equivalent are encompassed by the present disclosure. Indeed, various modifications of the embodiments disclosed herein are in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0440] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

Claims

What is claimed is:

1. A solid form comprising Compound A, which is substantially crystalline.

2. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 16.1, 17.4, and 24.5 °20.

3. The solid form of claim 2, which has an X-ray powder diffraction pattern further comprising peaks at approximately 15.1, 21.2, and 24.1 °20.

4. The solid form of claim 3, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 229.2 °C with onset temperature at about 220.7 °C.

5. The solid form of claim 4, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 0.9 % of the total mass of the crystal form when heated from about 36.5 °C to about 190 °C.

6. The solid form of claim 5, which is anhydrous.

7. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 13.3, 15.3, and 17.6 °20.

8. The solid form of claim 7, which has an X-ray powder diffraction pattern further comprising peaks at approximately 13.9, 18.7, and 21.6 °20.

9. The solid form of claim 8, which is anhydrous.

10. The solid form of claim 8, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 218.67 with onset temperature at about 215.7 °C.

11. The solid form of claim 8, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 1.34 % of the total mass of the crystal form when heated from about 15 °C to about 185 °C.

12. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 12.8, 14.4, and 22.8 °20.

13. The solid form of claim 12, which has an X-ray powder diffraction pattern further comprising peaks at approximately 17.2, 19.5, and 24.4 °20.

14. The solid form of claim 13, which is anhydrous.

15. The solid form of claim 1, which has an X-ray powder diffraction patern comprising peaks at approximately 14.0, 15.4, and 19.4 °20.

16. The solid form of claim 15, which has an X-ray powder diffraction patern further comprising peaks at approximately 21.0, 21.8, and 23.5°20.

17. The solid form of claim 16, which is anhydrous.

18. The solid form of claim 1, which has an X-ray powder diffraction patern comprising peaks at approximately 20.0, 21.9, and 24.1 °20.

19. The solid form of claim 18, which has an X-ray powder diffraction patern further comprising peaks at approximately 13.3, 16.2, and 22.4, °20.

20. The solid form of claim 19, which is a hydrate.

21. The solid form of claim 20, where the molar ratio of water to Compound A is 0.7 ± 0.1 , 0.74 ± 0.05, 0.74 ± 0.01, or about 0.74.

22. The solid form of claim 19, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 127.0 °C with onset temperature at about 103.8 °C, an endothermic event with a maximum at about 165.9 °C with onset temperature at about 151.5 °C, an exothermic event with a maximum at about 176.7 °C with onset temperature at about 172.6 °C, or an endothermic event with a maximum at about 222.2 °C with onset temperature at about 209.5 °C.

23. The solid form of claim 19, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 1.6 % of the total mass of the crystal form when heated from about 85 °C to about 120 °C.

24. The solid form of claim 19, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 0.3 % of the total mass of the crystal form when heated from about 35 °C to about 85 °C.

25. The solid form of claim 1, which has an X-ray powder diffraction patern comprising peaks at approximately 7.4, 14.9, and 18.6 °20.

26. The solid form of claim 25, which has an X-ray powder diffraction patern further comprising peaks at approximately 16.4, 17.6, and 30.0 °20.

27. The solid form of claim 26, which is a hydrate.

28. The solid form of claim 27, where the molar ratio of water to Compound A is 0.3 ± 0.1, 0.30 ± 0.05, 0.30 ± 0.01, or about 0.30.

29. The solid form of claim 26, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 55.8 °C with onset temperature at about 16.1 °C, or an endothermic event with a maximum at about 173.8 °C with onset temperature at about 163.7 °C.

30. The solid form of claim 26, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 2.6 % of the total mass of the crystal form when heated from about 34 °C to about 145 °C.

31. The solid form of claim 26, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 6.5 % of the total mass of the crystal form when heated from about 145 °C to about 170 °C.

32. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 8.0, 21.3, and 24.1 °20.

33. The solid form of claim 32, which has an X-ray powder diffraction pattern further comprising peaks at approximately 18.1, 24.7, and 28.4 °20.

34. The solid form of claim 33, which is a DMSO solvate.

35. The solid form of claim 34, where the molar ratio of DMSO to Compound A is 2.0 ± 0. 1, 2.00 ± 0.05, 2.00 ± 0.01, or about 2.

36. The solid form of claim 33, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 164.4 °C with onset temperature at about 131.5 °C, an endothermic event with a maximum at about 226.2 °C with onset temperature at about 213.2 °C, or an endothermic event with a maximum at about 91.2 °C with onset temperature at about 76.0 °C.

37. The solid form of claim 33, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 14.6 % of the total mass of the crystal form when heated from about 33 °C to about 100 °C.

38. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 9.1, 14.2, and 24.6 °20.

39. The solid form of claim 38, which has an X-ray powder diffraction pattern further comprising peaks at approximately 13.7, 21.0, and 29.0 °20.

40. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 5.2, 15.7, and 26.0 °20.

41. The solid form of claim 40, which has an X-ray powder diffraction pattern further comprising peaks at approximately 14.1, 19.7, and 28.4 °20.

42. The solid form of claim 41, which is a DMAc solvate.

43. The solid form of claim 42, where the molar ratio of DMAc to Compound A is 0.65 ± 0.1, 0.65 ± 0.05, 0.65 ± 0.01, or about 0.65.

44. The solid form of claim 41, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 154.9 °C with onset temperature at about 144.9 °C, an exothermic event with a maximum at about 162.8 °C with onset temperature at about 161.1 °C, an endothermic event with a maximum at about 164.0 °C with onset temperature at about 162.8 °C, or an endothermic event with a maximum at about 219.8 °C with onset temperature at about 212.0 °C.

45. The solid form of claim 41, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 0.8 % of the total mass of the crystal form when heated from about 26 °C to about 120 °C.

46. The solid form of claim 41, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 9.4 % of the total mass of the crystal form when heated from about 120 °C to about 155 °C.

47. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 7.4, 14.9, and 18.6 °20.

48. The solid form of claim 47, which has an X-ray powder diffraction pattern further comprising peaks at approximately 7.7, 17.6, and 23.4 °20.

49. The solid form of claim 48, which is anhydrous.

50. The solid form of claim 48, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 173.9 °C with onset temperature at about 164.8 °C.

51. The solid form of claim 48, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 2.2 % of the total mass of the crystal form when heated from about 35 °C to about 150 °C.

52. The solid form of claim 48, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 5.8 % of the total mass of the crystal form when heated from about 150 °C to about 180 °C.

53. The solid form of claim 1, which has an X-ray powder diffraction pattern comprising peaks at approximately 11.4, 17.2, and 23.0 °20.

54. The solid form of claim 53, which has an X-ray powder diffraction pattern further comprising peaks at approximately 5.7, 19.1, and 22.0 °20.

55. The solid form of claim 54, which is a DMSO solvate.

56. The solid form of claim 55, where the molar ratio of DMSO to Compound A is 1.0 ± 0. 1, 1.00 ± 0.05, 1.00 ± 0.01, or about 1.

57. The solid form of claim 54, which has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 143.5 °C with onset temperature at about 143.1 °C, or an endothermic event with a maximum at about 236.1 °C with onset temperature at about 230.0 °C.

58. The solid form of claim 54, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 2.3 % of the total mass of the crystal form when heated from about 28 °C to about 130 °C.

59. The solid form of claim 54, which has a thermogravimetric analysis thermogram comprising a total mass loss of about 12.5 % of the total mass of the crystal form when heated from about 130 °C to about 200 °C.

60. A method of treating a cancer in a subject in need thereof, comprising administering to the subject a solid form of any one of claims 1-59.

61. The method of claim 60, wherein the cancer is colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, or thyroid tumor.

62. The method of claim 61, wherein the solid form is administered at about 25 mg, about 40 mg or about 60 mg per day.

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