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WO2025079036A1 - Formes solides comprenant un inhibiteur de dimère de kinase b-raf, procédés de préparation et leurs utilisations - Google Patents

Formes solides comprenant un inhibiteur de dimère de kinase b-raf, procédés de préparation et leurs utilisations Download PDF

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Publication number
WO2025079036A1
WO2025079036A1 PCT/IB2024/059987 IB2024059987W WO2025079036A1 WO 2025079036 A1 WO2025079036 A1 WO 2025079036A1 IB 2024059987 W IB2024059987 W IB 2024059987W WO 2025079036 A1 WO2025079036 A1 WO 2025079036A1
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Prior art keywords
solid form
compound
braf
approximately
ray powder
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Guoliang Zhang
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BeiGene Switzerland GmbH
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BeiGene Switzerland GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • Figure 1 depicts a schematic diagram of interconversion relationship of polymorphs.
  • Figure 2 depicts an XRPD pattern of Compound A Form I.
  • Figure 3 depicts a DSC thermogram of Compound A free base Form I.
  • Figure 4 depicts a TGA thermogram of Compound A free base Form I.
  • Figure 5 depicts a PLM photograph of Compound A free base Form I.
  • Figure 6 depicts an XRPD pattern of free base Form II.
  • Figure 7 depicts a DSC thermogram of free base Form II.
  • Figure 8 depicts a TGA thermogram of free base Form II.
  • Figure 9 depicts a PLM photograph of free base Form II.
  • Figure 10 depicts a DVS isotherm plot of free base Form II.
  • Figure 11 depicts an XRPD overlay of free base Form II before and after DVS test.
  • Figure 12 depicts an XRPD pattern of Compound A free base Form III.
  • Figure 13 depicts a DSC thermogram of Form III.
  • Figure 14 depicts a TGA thermogram of Form III.
  • Figure 15 depicts a PLM photograph of Form III.
  • Figure 16 depicts an XRPD pattern of Compound A free base Form IV.
  • Figure 17 depicts a DSC thermogram of Compound A free base Form IV.
  • Figure 18 depicts a TGA thermogram of Compound A free base Form IV.
  • Figure 19 depicts a PLM photograph of Compound A free base Form IV.
  • Figure 20 depicts an XRPD pattern of Compound A free base Form V.
  • Figure 21 depicts a TGA and DSC overlay profile of Form V
  • Figure 22 depicts an XRPD pattern of Compound A free base Form VI.
  • Figure 23 depicts an XRPD pattern of Compound A free base Form VII.
  • Figure 24 depicts an XRPD pattern of free base Form VIII.
  • Figure 25 depicts a DSC thermogram of free base Form VIII.
  • Figure 26 depicts a TGA thermogram of free base Form VIII.
  • Figure 27 depicts a PLM photograph of free base Form VIII.
  • Figure 28 depicts an XRPD pattern of Compound A free base Form IX.
  • Figure 29 depicts a DSC thermogram of Compound A free base Form IX.
  • Figure 30 depicts a TGA thermogram of Compound A free base Form IX.
  • Figure 31 depicts a PLM photograph of Compound A free base Form IX.
  • Figure 32 depicts an XRPD pattern of Compound A free base Form X.
  • Figure 33 depicts a DSC thermogram of Compound A free base Form X.
  • Figure 34 depicts a TGA thermogram of Compound A free base Form X.
  • Figure 35 depicts a PLM photograph of Compound A free base Form X.
  • Figure 36 depicts an XRPD pattern of Compound A free base Form XL
  • Figure 37 depicts an XRPD pattern of Compound A free base Form XII.
  • Figure 38 depicts a DSC thermogram of Compound A free base Form XII.
  • Figure 39 depicts a TGA thermogram of Compound A free base Form XII.
  • Figure 40 depicts a PLM photograph of Compound A free base Form XII.
  • Figure 41 depicts an XRPD pattern of Compound A free base Form XIII.
  • Figure 42 depicts a DSC thermogram of Compound A free base Form XIII.
  • Figure 43 depicts a TGA thermogram of Compound A free base Form XIII.
  • Figure 44 depicts a PLM photograph of Compound A free base Form XIII.
  • Figure 45 depicts an XRPD pattern of Compound A free base Form XIV.
  • Figure 46 depicts a DSC thermogram of Compound A free base Form XIV.
  • Figure 47 depicts a TGA thermogram of Compound A free base Form XIV.
  • Figure 48 depicts an XRPD overlay of Forms I-VII.
  • Figure 49 depicts an XRPD overlay of Forms VIII-XIV.
  • 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.
  • TGA thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffractometry
  • solubility studies 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.
  • 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.
  • the value of an XRPD peak position may vary by up to ⁇ 0.2 degrees two theta while still describing the particular XRPD peak.
  • a crystalline that is “pure,” z.e., substantially free of other crystalline or amorphous forms, contains less than about 10% by weight of one or 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.
  • a crystal form or an amorphous form of a compound means a crystal form or an oxyphous 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.
  • 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.
  • 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.
  • 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.
  • a solid form that is “substantially physically pure” is substantially free from other solid forms.
  • 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.
  • a solid form that is “substantially chemically pure” is substantially free from other chemical compounds i.e., chemical impurities).
  • 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.
  • methods of chemical analysis such as, e.g., mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and/or chromatographic analysis.
  • 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.
  • solvate refers to a solid form of a substance which contains solvent.
  • 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.
  • polymorphs of hydrates refer to the existence of more than one solid form for a particular hydrate composition.
  • desolvated solvate refers to a solid form of a substance which can be made by removing the solvent from a solvate.
  • solvate and “solvated,” as used herein, can also refer to a solvate of a salt, cocrystal, or molecular complex.
  • hydrate and “hydrated,” as used herein, can also refer to a hydrate of a salt, cocrystal, or molecular complex.
  • 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:
  • 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).
  • 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.
  • solid form refers to a physical form which is not predominantly in a liquid or a gaseous state.
  • 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.
  • a solid form may be an amorphous form.
  • the term “a solid form comprising Compound A” includes a crystal form comprising Compound A.
  • the solid form is Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV.
  • 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, 23 rd ed., 1843-1844 (1995).
  • crystal form or “crystalline form” refers to a solid form that is crystalline.
  • crystal forms include salts.
  • a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms.
  • 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.
  • a crystal form of a substance may be physically and/or chemically pure.
  • 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.
  • polymorph refers 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).
  • 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
  • mechanical changes e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically a more stable polymorph
  • both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
  • 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).
  • amorphous or amorphous form means that the substance, component, or product in question is not substantially crystalline as determined by X-ray diffraction.
  • amorphous form describes a disordered solid form, i.e., a solid form lacking long range crystalline order.
  • an amorphous form of a substance may be substantially free of other amorphous forms and/or crystal forms.
  • 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.
  • an amorphous form of a substance may be physically and/or chemically pure.
  • 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.
  • Treating 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.
  • Preventing 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.
  • an effective amount of 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.
  • 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.
  • the kinase is a BRAF kinase.
  • the kinase is a BRAF kinase dimer. In one embodiment the kinase is a BRAF kinase monomer.
  • 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.
  • 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 the effective 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.
  • a different disorder e.g., cancer or a metabolic disorder.
  • “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.
  • the patient or subject is a human.
  • 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, [ 18 F]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.
  • IWC International Workshop Criteria
  • 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
  • PD progressive disease.
  • complete response is the disappearance of all target lesions
  • partial response 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 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
  • stable disease 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.
  • complete response is the disappearance of all non-target lesions and normalization of tumor marker level
  • incomplete response/stable disease is the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits
  • progressive disease is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FLAIR fluid-attenuated inversion recovery
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a time point response will be determined for target lesions, non-target lesions, and new lesion. 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.
  • prevention or chemoprevention 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.
  • 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.
  • certain solid forms are characterized by physical properties, e.g., stability, solubility, and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms.
  • certain solid forms 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, spectros
  • the solid form crystals provided herein 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), and thermogravimetric analysis coupled with mass spectroscopy (TGA
  • 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).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • MS mass spectrometry
  • Solid Form I comprising Compound A.
  • Form I is a crystal form.
  • Form I is a hydrate.
  • Form I is substantially crystalline.
  • Form I is a solvated form comprising Compound A.
  • Form I is a hydrate form comprising Compound A.
  • Form I is crystalline.
  • Form I is a metastable form.
  • Form I is converted to Form II.
  • Form I is converted to Form III.
  • 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.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form I has an X-ray powder diffraction pattern substantially as shown in Figure 2.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 56.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 33.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 91.7 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 177.6 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with an onset temperature at approximately 170.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 17.2 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 228.4 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 219.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 120 J/g.
  • Form I having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 4.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form I of Compound A is substantially pure.
  • the substantially pure Form I of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • 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.
  • the solution may be seeded.
  • the solvent is a mixture of acetone and water.
  • the ratio of acetone and water is 1: 1 by volume.
  • 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.
  • 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.
  • Solid Form II comprising Compound A.
  • Form II is a crystal form.
  • Form II is an anhydrous form.
  • Form II is crystalline.
  • Form II is substantially crystalline.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form II has an X-ray powder diffraction pattern substantially as shown in Figure 6.
  • Form II has 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 229.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 220.7 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 129.9 J/g.
  • Form II having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 8.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form II of Compound A is substantially pure.
  • the substantially pure Form II of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • 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).
  • the solution may be seeded.
  • the solvent is a mixture of methanol and acetone.
  • the ratio of methanol to acetone is 1: 1 by volume.
  • the starting material is Form III.
  • the resulting solid is Form II.
  • the seed is Form II.
  • the slurry is stirred at about 50 °C. In one embodiment, the slurry is stirred for about 5 days.
  • Solid Form III comprising Compound A.
  • Form III is a crystal form.
  • Form III is a hydrate.
  • Form III is substantially crystalline.
  • 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.
  • 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.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form III has an X-ray powder diffraction pattern substantially as shown in Figure 12.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 211.6 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 202.4 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 18.1 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 164.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with an onset temperature at approximately 157.6 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 42.9 J/g.
  • Form III having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 14.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form III of Compound A is substantially pure.
  • the substantially pure Form III of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • 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).
  • the solution may be seeded.
  • the solvent is water.
  • the resulting solid is Form III.
  • the seed is Form III.
  • the slurry is stirred at about 50 °C.
  • the slurry is stirred for about 4 days.
  • the solvent is a mixture of DMSO and water (0.5% HC1).
  • the ratio of DMSO and water (0.5% HC1) is 1: 1 by volume.
  • Form IV comprising Compound A.
  • Form IV is a crystal form.
  • Form IV is a hydrate.
  • Form IV is substantially crystalline.
  • 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.
  • 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.
  • a solid form provided herein, e.g., Form IV is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form IV has an X-ray powder diffraction pattern substantially as shown in Figure 16.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 55.3 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 17.4 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 28.0 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 147.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 128.7 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 23.0 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 160.0 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with onset temperature at about 156.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 20.9 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 215.3 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 205.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 27.6 J/g.
  • Form IV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 18.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form IV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 18.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form IV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 18.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form IV of Compound A is substantially pure.
  • the substantially pure Form IV of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • 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).
  • the solution may be seeded.
  • the solvent is isopropyl acetate.
  • the starting material is Form III.
  • the resulting solid is Form IV.
  • the seed is Form IV.
  • the slurry is stirred at about 50 °C. In one embodiment, the slurry is stirred for about 5 days.
  • Form IV is prepared from multiple solvents by an equilibration experiment.
  • Form IV is prepared from MEK/IPAc (50:50, v:v) by slow cooling experiment.
  • Form IV is prepared from THF/water or THF/heptane by an antisolvent addition experiment.
  • Form IV is prepared from THF/water, THF/MTBE or THF/heptane by a reverse antisolvent addition experiment.
  • Form V comprising Compound A.
  • Form V is a crystal form.
  • Form V is an anhydrous form.
  • Form V is crystalline.
  • Form V is substantially crystalline.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form V has an X-ray powder diffraction pattern substantially as shown in Figure 20.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 218.7 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 216 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 83.9 J/g.
  • Form V having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 21.
  • TGA thermogravimetric
  • 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.
  • 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.
  • 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.
  • Form VI comprising Compound A.
  • Form VI is a crystal form.
  • Form VI is an anhydrous form.
  • Form VI is a crystal form.
  • Form VI is an anhydrous form.
  • Form VI is crystalline. In one embodiment, Form VI is substantially crystalline.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form VI has an X-ray powder diffraction pattern substantially as shown in Figure 22.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the starting solid form is Form I.
  • the resulting solid is Form VI.
  • the temperature is about 200 °C.
  • the solid is heated for about 1 hour.
  • the solid is heated under vacuum.
  • Solid Form VII comprising Compound A.
  • Form VII comprising Compound A.
  • Form VII 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. [00150] 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, Form
  • Form VII 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the solution may be seeded.
  • the solvent is a mixture of methanol and acetone.
  • the solvent is a mixture of method and water.
  • 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.
  • 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.
  • Form VIII comprising Compound A.
  • Form VIII comprising Compound A.
  • Form VIII is a crystal form. In one embodiment, Form VIII is a hydrate. In one embodiment, Form VIII is substantially crystalline.
  • Form VIII is a solvated form comprising Compound A.
  • Form VIII is a hydrate form comprising Compound A.
  • Form VIII is crystalline.
  • Form VIII is a metastable form.
  • Form VIII is converted to Form II.
  • 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.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form VIII has an X-ray powder diffraction pattern substantially as shown in Figure 24.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 127.0 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 103.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 32.6 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 165.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 151.5 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 3.3 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 176.7 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with onset temperature at about 172.6 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with enthalpy (normalized) of about 15.6 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 222.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with onset temperature at about 209.5 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 59.2 J/g.
  • Form VIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 26.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form VIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 26.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form VIII of Compound A is substantially pure.
  • the substantially pure Form VIII of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • 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).
  • the solution may be seeded.
  • the solvent is a mixture of methanol and water.
  • the ratio of methanol to water is 2:3 by volume.
  • the starting material is Form III.
  • the resulting solid is Form VIII.
  • the seed is Form VIII.
  • the slurry is stirred at about 25 °C. In one embodiment, the slurry is stirred for about 5 days.
  • Form VIII is prepared from acetone/water (60:40, v:v) or MeOH/water (40:60, v:v) by an equilibration experiment.
  • Form VIII is prepared from acetone/water by an antisolvent addition experiment.
  • Form VIII is prepared from acetone/water or MEK/water by a reverse antisolvent addition experiment.
  • Form IX comprising Compound A.
  • Form IX is a crystal form.
  • Form IX is a hydrate.
  • Form IX is substantially crystalline.
  • 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.
  • 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.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form IX has an X-ray powder diffraction pattern substantially as shown in Figure 28.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 55.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 16.1 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 9.6 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 173.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 163.7 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 51.2 J/g.
  • Form IX having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 30.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form IX having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 30.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form IX of Compound A is substantially pure.
  • the substantially pure Form IX of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • 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.
  • the solution may be seeded.
  • the solvent is a mixture of methyl ethyl ketone and 2-methyl-tetrahydrofuran.
  • the ratio of methyl ethyl ketone and 2- methyl-tetrahydrofuran is 1: 1 by volume.
  • the starting material is Form III.
  • the resulting solid is Form IX.
  • the seed is Form IX.
  • 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.
  • Form X comprising Compound A.
  • Form X is a crystal form.
  • Form X is a DMSO solvate.
  • Form X is substantially crystalline.
  • 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.
  • 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.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form X has an X-ray powder diffraction pattern substantially as shown in Figure 32.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 164.4 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 131.5 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 51.3 J/g.
  • Form X having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 33 comprising an endothermic event with a maximum at about 226.2 °C with onset temperature at about 213.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 226.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 213.2 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 34.2 J/g.
  • Form X having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 33 comprising an endothermic event with a maximum at about
  • 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.
  • Form X having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 34.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form X of Compound A is substantially pure.
  • the substantially pure Form X of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • Form X is prepared from DMSO/EtOH (50:50, v:v) by an equilibration experiment at 25 °C or 50°C.
  • Form XI comprising Compound A.
  • Form XI is a crystal form.
  • Form XI is crystalline.
  • Form XI is substantially crystalline.
  • Form XI is a metastable form.
  • Form XI is converted to Form I.
  • a solid form provided herein is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form XI has an X-ray powder diffraction pattern substantially as shown in Figure 36.
  • Form XI has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.1,
  • 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.
  • 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.
  • 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.
  • 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.
  • Form XI is prepared from methanol by an equilibration experiment at 25°C.
  • Form XII comprising Compound A.
  • Form XII is a crystal form.
  • Form XII is a DMAc solvate.
  • Form XII is substantially crystalline.
  • 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.
  • 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.
  • a solid form provided herein e.g., Form XII
  • Form XII is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form XII has an X-ray powder diffraction pattern substantially as shown in Figure 37.
  • Form XII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately
  • 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.
  • 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.
  • 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.
  • 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.
  • Form XII having a differential scanning calorimetry (DSC) thermogram as depicted in Figure 38 comprising an endothermic event with a maximum at about 154.9 °C with onset temperature at about 144.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 154.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 144.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 101.9 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with a maximum at about 162.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an exothermic event with an onset temperature at approximately 161.1 °C .
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 164.0 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 162.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 14.0 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 219.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 212.0 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 36.2 J/g.
  • Form XII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 39.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form XII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 39.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form XII of Compound A is substantially pure.
  • the substantially pure Form XII of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • Form XII is prepared from DMAc by an equilibration experiment at 25°C.
  • Form XIII comprising Compound A.
  • Form XIII is a crystal form.
  • Form XIII is an anhydrous form.
  • Form XIII is an anhydrate.
  • Form XIII is substantially crystalline.
  • Form XIII is crystalline.
  • Form XIII is a metastable form.
  • Form XIII is converted to Form II.
  • a solid form provided herein e.g., Form XIII
  • Form XIII is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form XIII has an X-ray powder diffraction pattern substantially as shown in Figure 41.
  • Form XIII has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 173.9 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 164.8 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 55.5 J/g.
  • Form XIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 43.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form XIII having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 43.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form XIII of Compound A is substantially pure.
  • the substantially pure Form XIII of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • 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.
  • the starting solid form is Form IX.
  • the resulting solid is Form XIII.
  • the temperature is about 120 °C.
  • the solid is heated for about 1 hour.
  • the solid is heated under vacuum.
  • Form XIV comprising Compound A.
  • Form XIV is a crystal form.
  • Form XIV is a DMSO solvate.
  • Form XIV is substantially crystalline.
  • 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.
  • 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.
  • a solid form provided herein, e.g., Form XIV is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements.
  • Form XIV has an X-ray powder diffraction pattern substantially as shown in Figure 45.
  • 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).
  • 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.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 143.5 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 143. 1 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 41.4 J/g.
  • 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.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with a maximum at about 236. 1 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with an onset temperature at approximately 230.0 °C.
  • the crystal form has a differential scanning calorimetry thermogram comprising an endothermic event with enthalpy (normalized) of about 80.9 J/g.
  • Form XIV having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in Figure 47.
  • TGA thermogravimetric
  • 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.
  • 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.
  • TGA thermogravimetric
  • 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.
  • 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.
  • Form XIV of Compound A is substantially pure.
  • the substantially pure Form XIV of Compound A is substantially free of other solid forms, e.g., amorphous form.
  • 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.
  • Form XIV is prepared from crystallization from DMSO/IPA/H2O (5v/16v/0.4v) mixture.
  • 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.
  • kits 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.
  • 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.
  • 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.
  • 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.
  • the cancer is characterized by a mutation in a gene selected from the group consisting of NRAS, KRAS, BRAF, and their combination thereof.
  • the cancer is characterized by:
  • 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.
  • 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.
  • 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.
  • 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.
  • the cancer is characterized by other MAPK pathway genomic aberration.
  • the cancer is melanoma.
  • the melanoma is cutaneous melanoma.
  • the melanoma is metastatic melanoma.
  • the cancer is non-small cell lung cancer.
  • the cancer is colorectal cancer.
  • the cancer is ovarian cancer.
  • the solid form is administered one to three times a day.
  • the solid form is administered once a day.
  • the solid form is administered twice a day.
  • the solid form is administered three times a day.
  • the solid form is administered from about 5 mg to about 600 mg per day.
  • 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.
  • the solid form is administered at about 25 mg, about 40 mg or about 60 mg per day.
  • the solid form is administered at about 25 mg per day.
  • the solid form is administered at about 40 mg per day.
  • the solid form is administered at about 60 mg per day.
  • the method provides a plasma Compound A AUC8h between about
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the subject achieves a stable disease, a partial response, or a complete response.
  • the subject achieves a partial response or a complete response.
  • the subject achieves a complete response.
  • the subject does not experience a progressive disease.
  • the subject achieves a stable disease.
  • the subject achieves a partial response.
  • 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.
  • 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.
  • NCI-WG CLL National Cancer Institute-Sponsored Working Group on Chronic Lymphocytic Leukemia
  • 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.
  • PCWG2 Prostate Cancer Working Group 2
  • 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.
  • IURC International Uniform Response Criteria
  • 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.
  • kits for treating a cancer 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.
  • 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 disease progression, increased Time To Progression (TTP), increased Progression Free Survival (PFS), and/or increased Overall Survival (OS), among others.
  • TTP Time To Progression
  • PFS Progression Free Survival
  • OS Overall Survival
  • 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, sonic
  • 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.
  • crystallization conditions such as, e.g., the rate of crystallization and/or the crystallization solvent system
  • particle-size reduction techniques e.g., grinding, milling, micronizing, or sonication.
  • 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).
  • 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.
  • the solution may be seeded.
  • 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.
  • the solution may be seeded.
  • equilibrium crystallization is a process where crystals form from a 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.
  • 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.
  • 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.
  • the solution may be seeded.
  • 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).
  • the solution may be seeded.
  • 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.
  • 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.
  • the pharmaceutical compositions described herein are suitable for oral, parenteral, mucosal, transdermal, or topical administration.
  • 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). [00273] 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.
  • the pharmaceutically acceptable excipients and carriers are selected from binders, diluents, disintegrants and lubricants.
  • 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.
  • 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.
  • Compound A free base shows complicated polymorphic behaviors.
  • 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.
  • Form I was prepared using the procedure below.
  • 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. [00293] Figure 1 describes the XRPD pattern of Compound A free base Form I.
  • Form II was prepared using the procedure below.
  • 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.
  • Figure 2 describes the XRPD pattern of Compound A free base Form II.
  • DMSO 81 mL
  • 0.5% hydrochloric acid 270 mL
  • the filter cake was washed with purified water (20 mL).
  • DMSO 81 mL
  • 0.5% hydrochloric acid 270 mL
  • the filter cake was washed with purified water (20 mL).
  • Figure 3 describes the XRPD pattern of Form III
  • 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.
  • Form IV was prepared using the procedure below.
  • 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.
  • Figure 4 describes the XRPD pattern of Compound A free base Form IV.
  • Figure 5 describes the XRPD pattern of Compound A free base Form V
  • 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.
  • Figure 7 describes the XRPD pattern of Compound A free base Form VII
  • Form VIII was prepared using the procedure below.
  • Form VIII was obtained as a white solid.
  • 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.
  • Figure 8 describes the XRPD pattern of Compound A free base Form VIII
  • Form IX was prepared using the procedure below.
  • 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.
  • Figure 9 describes the XRPD pattern of Compound A free base Form IX
  • 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.
  • Figure 10 describes the XRPD pattern of Compound A free base Form X
  • 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.
  • Figure 11 describes the XRPD pattern of Compound A free base Form XI
  • 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.
  • Figure 12 describes the XRPD pattern of Compound A free base Form XII
  • Form XIII was prepared using the procedure below.
  • 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.
  • Figure 13 describes the XRPD pattern of Compound A free base Form XIII
  • 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.
  • Figure 14 describes the XRPD pattern of Compound A free base Form XIV
  • Form II is the thermodynamically stable form across a wide water activity, from 0 to 1.0 at 25 °C and 50°C.
  • Table 28 Crystallization at room temperature by slow evaporation
  • Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD.
  • Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD.
  • Precipitates were collected by centrifugation filtration through a 0.45pm nylon membrane filter at 14,000rpm. Solid parts (wet cakes) were investigated by XRPD.
  • Compound A free base Form II is physically and chemically stable under these conditions. [00424] 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.
  • 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.
  • Compound A free base Form II 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.
  • Compound A free base Form II was the most stable polymorph identified. It showed good chemical and physical stability and was slightly hygroscopic.

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Abstract

L'invention concerne des formes solides, des procédés d'utilisation et des procédés se rapportant à la 1-((1S,1aS,6bS)-5-((7- oxo-5,6,7,8-tétrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3- (2,4,5-trifluorophényl)) urée.
PCT/IB2024/059987 2023-10-12 2024-10-11 Formes solides comprenant un inhibiteur de dimère de kinase b-raf, procédés de préparation et leurs utilisations Pending WO2025079036A1 (fr)

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