Solid forms of {5-cyclopropyl-2-[2-(3,6-difluoro-pyridin-2-ylamino)-pyridin-4-yl]-pyrido[3,4-d]pyrimidin-4-yl}-((S)-3,3-dimethyl-piperidin-4-yl)-amine

Abstract

Disclosed herein are solid forms (e.g., crystalline forms) of 4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole (Compound 1), as well as compositions, pharmaceutical compositions, kits, methods, and uses thereof. The compounds disclosed herein are inhibitors of atypical protein kinase C (aPKC), and therefore, their solid forms are useful for treating and / or preventing basal cell carcinoma.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 387,200, filed December 13, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Polymorphic forms of a particular compound occur when the same compound crystallizes in different lattice configurations. The resulting polymorphs may have unique thermodynamic properties and stability. Furthermore, crystalline polymorphic forms may affect solubility, storage stability, ease of preparation and formulation, and in vivo pharmacological action. Therefore, when two or more polymorphic forms can be produced, it is desirable to obtain each in a substantially pure form. There is a continuing need for new or purer polymorphic forms of therapeutically active compounds to obtain improved physical properties and bioavailability. Summary of the Invention

[0003] Crystalline forms of Compound 1 are disclosed herein. [ka]

[0004] In one aspect, the present disclosure provides crystalline Form II of Compound 1: [ka]

[0005] In another aspect, the present disclosure provides a composition comprising crystalline Form II of Compound 1, wherein the composition comprises 90% or more by weight of crystalline Form II of Compound 1.

[0006] In another aspect, the disclosure provides a composition comprising crystalline Form II of Compound 1, wherein the molar ratio of the amount of Form II to the sum of the amounts of other forms of Compound 1 in the composition is 90:10 or greater.

[0007] In another embodiment, the present disclosure provides crystalline Form III of Compound 1: [ka]

[0008] In another aspect, the present disclosure provides a composition comprising crystalline Form III of Compound 1, wherein the composition comprises 90% or more by weight of crystalline Form III of Compound 1.

[0009] In another aspect, the disclosure provides a composition comprising crystalline Form III of Compound 1, wherein the molar ratio of the amount of Form III to the sum of the amounts of other forms of Compound 1 in the composition is 90:10 or greater.

[0010] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form provided herein, or a composition provided herein, and a pharmaceutically acceptable excipient.

[0011] In another aspect, the disclosure provides a method for preparing crystalline Form II of Compound 1 or a composition thereof, comprising: (1) providing a solution of Compound 1 in one or more solvents; (2) precipitating crystalline Form II of Compound 1 from a solution of Compound 1; and (3) isolating crystalline form II of compound 1 The present invention provides a method comprising:

[0012] In another aspect, the disclosure provides a method for preparing crystalline Form III of Compound 1 or a composition thereof, comprising: (1) providing a solution of Compound 1 in one or more solvents; (2) precipitating crystalline Form III of Compound 1 from a solution of Compound 1; and (3) isolating crystalline form III of compound 1 The present invention provides a method comprising:

[0013] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof.

[0014] In another aspect, the present disclosure provides a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof for use in treating cancer in a subject in need thereof.

[0015] In another aspect, the present disclosure provides a use of a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof for the treatment of cancer in a subject in need thereof.

[0016] In another aspect, the present disclosure provides use of a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of basal cell carcinoma, a solid tumor, or acute myeloid leukemia in a subject in need thereof.

[0017] In another aspect, the present disclosure provides a kit comprising a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof, and instructions for using the crystalline form, composition, or pharmaceutical composition.

[0018] Details of certain embodiments of the present invention are set forth in the detailed description of specific embodiments, as set forth below. Other features, objects, and advantages of the present invention will be apparent from the definition, examples, drawings, and claims. It is to be understood that the aspects disclosed herein are not limited to specific embodiments, methods, or configurations, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting unless specifically defined herein. [Brief explanation of the drawings]

[0019] [Figure 1] 1 shows the X-ray powder diffraction (XPRD) pattern of Form II of Compound 1. [Figure 2] 1 shows a differential scanning calorimetry (DSC) thermogram of Form II of Compound 1. [Figure 3] 1 shows a thermogravimetric analysis (TGA) thermogram of Form II of Compound 1. [Figure 4] 1 shows the XPRD pattern of Form III of Compound 1. [Figure 5] 1 shows a DSC thermogram of Form III of Compound 1. [Figure 6] 1 shows a TGA thermogram of Form III of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition Compound 1: [ka] is also referred to herein as "CRT0329868" and "4-(5-cyclopropyl-4-piperazin-1-yl-pyrido[3,4-d]pyrimidin-2-yl)-9H-pyrido[2,3-b]indole."

[0021] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts. Salts include ionic compounds resulting from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) such that it is electrically neutral (has no net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, and hydroxybenzoates. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0022] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1~4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0023] The term "solvate" refers to a compound or a salt form thereof that is associated with a solvent, typically via solvolysis. In some embodiments, this physical association involves hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. In some embodiments, the compounds described herein are prepared, for example, in crystalline form, and are solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, solvates are capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0024] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, in some embodiments, a hydrate of a compound can be represented by the general formula R·xH2O, where R is the compound and x is a number greater than 0. In some embodiments, a given compound can form more than one hydrate, such as a monohydrate (x is 1), a hypohydrate (x is greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0025] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers." Stereoisomers that are not mirror images of each other are referred to as "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. In some embodiments, an enantiomer is characterized by the absolute configuration of its asymmetric center and described by the R and S configuration rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomer, respectively). In some embodiments, a chiral compound exists as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture."

[0026] The terms "tautomer" or "tautomeric" refer to two or more interconverting compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valency (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, tautomerization (i.e., the reaction giving rise to a tautomeric pair) is acid- or base-catalyzed. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(different enamine) tautomerization.

[0027] The term "amorphous" or "amorphous form" refers to a solid form ("solid form") that substantially lacks three-dimensional order. In certain embodiments, a solid amorphous form is a solid form that is substantially non-crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the amorphous form is CuK αFor example, the XRPD pattern of the amorphous form has a broad scattering band with peaks at 2θ between, inclusive, 20° and 70°. In certain embodiments, the XRPD pattern of the amorphous form further comprises one or more peaks attributable to a crystalline structure. In certain embodiments, the maximum intensity of any one of the one or more peaks attributable to a crystalline structure observed at 2θ between, inclusive, 20° and 70° is 300 times or less, 100 times or less, 30 times or less, 10 times or less, or 3 times or less than the maximum intensity of the broad scattering band. In certain embodiments, the XRPD pattern of the amorphous form does not comprise any peaks attributable to a crystalline structure.

[0028] The term "crystalline" refers to a solid phase in which a material has a regularly ordered internal structure at the molecular level and gives a characteristic X-ray diffraction pattern with well-defined peaks. Such materials, when heated sufficiently, will also exhibit the properties of a liquid, although the change from solid to liquid is typically characterized by a first-order (melting point) phase change. The term "crystalline" or "crystalline form" refers to a solid form that exhibits substantial three-dimensional order. In certain embodiments, a solid crystalline form is a solid form that is not substantially amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more well-defined peaks.

[0029] The term "cocrystal" refers to a crystal structure comprising at least two different components (e.g., a compound disclosed herein and an acid), each of which is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A cocrystal of a compound disclosed herein and an acid differs from a salt formed from a compound disclosed herein and an acid. In a salt, the compound disclosed herein is complexed with the acid such that proton transfer (e.g., complete proton transfer) from the acid to the compound disclosed herein occurs readily at room temperature. However, in a cocrystal, the compound disclosed herein is complexed with the acid such that proton transfer from the acid to the compound disclosed herein does not occur readily at room temperature. In certain embodiments, in a cocrystal, there is no proton transfer from the acid to the compound disclosed herein. In certain embodiments, there is partial proton transfer from the acid to the compound disclosed herein. In some embodiments, cocrystals are useful for improving the properties (e.g., solubility, stability, and ease of formulation) of the compounds disclosed herein.

[0030] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. In some embodiments, the recrystallization solvent, rate of crystallization, storage temperature, and other factors cause one crystalline form to predominate. In some embodiments, various polymorphs of a compound are prepared by crystallization under different conditions.

[0031] When a characteristic peak in an X-ray powder diffraction pattern is expressed as "degrees 2-theta (±0.2)" at Z (where Z is a number), the characteristic peak lies between and including Z+0.2 degrees 2-theta and Z-0.2 degrees 2-theta.

[0032] The term "impurity" refers to a contaminant contained in a desired substance (e.g., a compound (e.g., Compound 1), or a salt, solvate, hydrate, co-crystal, amorphous form, or crystalline form thereof). Contaminants include one or more substances that differ from the desired substance. In certain embodiments, contaminants are undesirable contaminants. For example, if the desired substance is a crystalline compound, an amorphous form of the compound contained in or with the crystalline compound is an impurity. For example, if the desired substance is a crystalline compound, a different crystalline form of the compound contained in or with the crystalline compound is an impurity.

[0033] The term "substantially Y" where Y is a property (e.g., anhydrous) refers to a property that is at least 99.5%, at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 92%, or at least 90% the same as Y, unless expressly specified otherwise.

[0034] The term "substantially free of impurities" means that the desired substance does not contain significant amounts of contaminants (e.g., undesired contaminants). What constitutes a significant amount of contaminants depends on the subject matter and is understood in the art. In certain embodiments, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 20%, or at least 30% of the contaminants by weight in the desired substance is a significant amount of contaminants. In some embodiments, the amount of impurities is measured using high performance liquid chromatography (HPLC), e.g., at about 214 or about 220 nm, e.g., with an ultraviolet (UV) detector. In some embodiments, under suitable conditions, the desired substance and each impurity are separated after HPLC, and the areas of the peaks in the resulting HPLC chromatogram are determined. In certain embodiments, the weight ratio of the amount of impurity to the amount of desired substance is the ratio of the peak area of ​​the impurity to the peak area of ​​the desired substance.

[0035] In some embodiments, when polymorphic forms are described, "substantially free" refers to the specified polymorph described herein being substantially free of other polymorphs. "Substantially free" of another polymorph refers to at least a 70 / 30 molar ratio of the two polymorphs, more preferably 80 / 20, 90 / 10, 95 / 5, 97 / 3, 98 / 2, 99 / 1, or greater. In some embodiments, one of the polymorphs will be present in an amount of at least 99 / 1.

[0036] The term "polar solvent" refers to a solvent with a large dipole moment or a high dielectric constant. In some embodiments, the term "polar solvent" refers to an aprotic polar solvent, a polar protic solvent, or a combination thereof. In some embodiments, in polar solvents, the positive and negative charges are permanently separated, or the positive and negative charge centers are not coincident within the molecule. Polar solvents include, but are not limited to, chloromethane, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, acetonitrile, nitromethane, propylene carbonate, formic acid, butanol, isopropanol, methyltetrahydrofuran, trifluoromethylbenzene, ethyl acetate, ethyl ether, acetone, dimethyl sulfoxide, alcohols, acetic acid, and esters.

[0037] The term "nonpolar solvent" refers to a solvent with a low dipole moment or a small dielectric constant. In some embodiments, the solvent lacks significant partial charges on the atoms (e.g., hydrocarbons). In some embodiments, the solvent contains polar bonds arranged such that the effects of those partial charges are negated (e.g., chloroform). Nonpolar solvents include, but are not limited to, hydrocarbons, benzene, toluene, xylene, pentane, cyclohexane, n-hexane, n-heptane, octane, isooctane, chloroform, ether, dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, and neutral or nonionic surfactants.

[0038] The term "aprotic solvent" refers to a solvent that cannot accept or donate a proton. Aprotic solvents include, but are not limited to, acetone, acetonitrile, benzene, butanone, butyronitrile, carbon tetrachloride, chlorobenzene, chloroform, 1,2-dichloroethane, dichloromethane, diethyl ether, dimethylacetamide, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethyl acetate, ethylene glycol dimethyl ether, hexane, N-methyl-2-pyrrolidone, pyridine, tetrahydrofuran (THF), and toluene. Certain aprotic solvents are polar solvents. Examples of polar aprotic solvents include, but are not limited to, acetone, acetonitrile, butanone, N,N-dimethylformamide, and dimethyl sulfoxide. Certain aprotic solvents are nonpolar solvents. Examples of non-polar aprotic solvents include, but are not limited to, diethyl ether, aliphatic hydrocarbons such as hexane, aromatic hydrocarbons such as benzene and toluene, and symmetrical halogenated hydrocarbons such as carbon tetrachloride.

[0039] The term "protic solvent" refers to a solvent containing a hydrogen atom bonded to an electronegative atom such as an oxygen atom or a nitrogen atom. Protic solvents include, but are not limited to, carboxylic acids such as acetic acid, alcohols (e.g., methanol, ethanol, isopropanol), amines, amides, and water.

[0040] The terms "pharmaceutical composition" and "formulation" are used interchangeably.

[0041] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, or adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially important mammal (e.g., a cow, pig, horse, sheep, goat, cat, or dog), or a bird (e.g., a commercially important bird such as a chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. In some embodiments, the non-human animal is male or female at any stage of development. In some embodiments, the non-human animal is a transgenic or genetically engineered animal.

[0042] The term "patient" refers to a human subject in need of treatment for a disease.

[0043] The term "biological sample" refers to any sample, including tissue samples (such as tissue sections and needle biopsies of tissue); cell samples (e.g., cytological smears (such as Pap smears or blood smears) or samples of cells obtained by microdissection); whole organism samples (such as yeast or bacterial samples); or cell fractions, fragments, or organelles (such as those obtained by lysing cells and centrifuging or otherwise separating their components). Other examples of biological samples include blood, serum, urine, semen, stool, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by incisional or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (such as oral swabs), or any material containing biomolecules derived from an initial biological sample.

[0044] The term "target tissue" refers to any biological tissue (including a group of cells, a body part, or an organ) or portion thereof of a subject, including blood vessels and / or lymphatic vessels, to which a compound, particle, and / or composition of the present disclosure is delivered. In some embodiments, the target tissue is an abnormal or unhealthy tissue. In some embodiments, the target tissue is an abnormal or unhealthy tissue that needs to be treated. In some embodiments, the target tissue is a normal or healthy tissue that is at higher than normal risk of becoming abnormal or unhealthy, and that needs to be prevented. In certain embodiments, the target tissue is skin. "Non-target tissue" refers to any biological tissue (including a group of cells, a body part, or an organ) or portion thereof of a subject, including blood vessels and / or lymphatic vessels that are not target tissues.

[0045] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound disclosed herein or a composition thereof into or to a subject.

[0046] The terms "condition," "disease," and "disorder" are used interchangeably.

[0047] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease disclosed herein. In some embodiments, treatment is administered after one or more signs or symptoms of disease have occurred or are observed. In other embodiments, treatment is administered in the absence of signs or symptoms of disease. For example, in some embodiments, treatment is administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a pathogen). In some embodiments, treatment is continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0048] The terms "prevent," "preventing," or "prevention" refer to the prophylactic treatment of a subject who does not currently or previously have the disease but is at risk of developing the disease, or who has had the disease and does not currently have the disease but is at risk of disease relapse. In certain embodiments, the subject is at higher risk of developing the disease or disease relapse than the average healthy member of the population.

[0049] An "effective amount" of a compound disclosed herein refers to an amount sufficient to elicit a desired biological response. In some embodiments, the effective amount of a compound disclosed herein varies depending on factors such as the desired biological endpoint, side effects, severity of the disease or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age, and health or general condition of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic treatment. In certain embodiments, the effective amount is the amount of a compound disclosed herein in a single administration. In certain embodiments, the effective amount is the combined amount of a compound disclosed herein in multiple administrations. In certain embodiments, the desired dose is delivered three times a day, twice a day, once a day, every other day, every three days, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose is administered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0050] In certain embodiments, an effective amount of a compound for one or more administrations per day to a 70 kg adult human comprises from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound per unit dosage form.

[0051] It will be appreciated that the dosage ranges disclosed herein provide guidance for administration of the provided pharmaceutical compositions to adults. In some embodiments, for example, the amount to be administered to a child or adolescent is determined by a practitioner or skilled artisan. In some embodiments, for example, the amount to be administered to a child or adolescent is determined by a practitioner or skilled artisan and is lower than or the same as the amount administered to an adult.

[0052] A "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. In some embodiments, the term "therapeutically effective amount" encompasses an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a condition, and / or increases the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit atypical protein kinase C. In certain embodiments, a therapeutically effective amount is an amount sufficient to treat basal cell carcinoma. In certain embodiments, a therapeutically effective amount is an amount sufficient to inhibit atypical protein kinase C and treat basal cell carcinoma.

[0053] A "prophylactically effective amount" of a compound disclosed herein is an amount sufficient to prevent a condition or one or more symptoms associated with a condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a condition. In some embodiments, the term "prophylactically effective amount" encompasses an amount that improves overall prevention or increases the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient to inhibit atypical protein kinase C. In certain embodiments, a prophylactically effective amount is an amount sufficient to prevent basal cell carcinoma. In certain embodiments, a prophylactically effective amount is an amount sufficient to inhibit atypical protein kinase C and prevent basal cell carcinoma.

[0054] As used herein, the term "inhibit" or "inhibition," in the context of a kinase, for example, atypical protein kinase C, refers to a reduction in the activity of the kinase. In some embodiments, the term refers to a reduction in activity, e.g., the level of atypical protein kinase C activity, to a level that is statistically significantly lower than an initial level. In some embodiments, the term refers to a reduction in activity, e.g., the level of atypical protein kinase C activity, to a level that is statistically significantly lower than an initial level, which is the baseline level of activity. In some embodiments, the term refers to a reduction in activity, e.g., the level of atypical protein kinase C activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the initial level. In some embodiments, the term refers to a reduction in activity, e.g., the level of atypical protein kinase C activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of the initial level, which is the baseline level of activity.

[0055] "Proliferative disorder" refers to a disorder caused by abnormal growth or expansion of cells through proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). In some embodiments, a proliferative disorder is associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., neoplastic cell metastasis); 3) the pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as that seen in proliferative retinopathies and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory disorders, and autoimmune disorders.

[0056] The term "angiogenesis" refers to the physiological process by which new blood vessels form from pre-existing vessels. Angiogenesis differs from vasculogenesis, which is the de novo formation of endothelial cells from mesodermal cell precursors. The first blood vessels in the developing embryo form by vasculogenesis, and thereafter, angiogenesis is responsible for most blood vessel growth during normal and abnormal development. Angiogenesis is a crucial process in growth and development, as well as in wound healing and the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transformation of tumors from a benign to a malignant state, leading to the use of angiogenesis inhibitors in the treatment of cancer. In some embodiments, angiogenesis is chemically stimulated by angiogenic proteins such as growth factors (e.g., VEGF). "Pathological angiogenesis" refers to aberrant (e.g., excessive or insufficient) angiogenesis that results in and / or is associated with disease.

[0057] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue whose growth exceeds and is out of step with normal tissue growth. In some embodiments, a neoplasm or tumor is "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), rate of growth, local invasion, and metastasis. "Benign neoplasms" are generally well-differentiated, have a characteristically slower growth rate than malignant neoplasms, and remain localized at the primary site. Furthermore, benign neoplasms lack the ability to invade, infiltrate, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, soft fibromas, senile hemangiomas, seborrheic keratoses, moles, and sebaceous hyperplasia. In some cases, certain "benign" tumors later give rise to malignant neoplasms, such as those resulting from additional genetic alterations in a subpopulation of neoplastic cells in the tumor; these tumors are referred to as "premalignant neoplasms." An exemplary premalignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and have characteristically rapid growth accompanied by progressive invasion, infiltration, and destruction of surrounding tissue. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites. The terms "metastasis," "metastatic," or "metastasize" refer to the spread or migration of cancer cells from a primary or original tumor to another organ or tissue, and are typically identifiable by the presence of a "secondary tumor" or "secondary cell population" of the histological type of the primary or original tumor, rather than the histological type of the organ or tissue in which the secondary (metastatic) tumor is located. For example, prostate cancer that has migrated to bone is referred to as metastatic prostate cancer and includes cancerous prostate cancer cells growing within bone tissue.

[0058] The term "cancer" refers to a group of diseases characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissue. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma ... esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic cancer (e.g., leukemia, e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));Lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary Mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer lymphoma, and leukemia. leukemia / lymphoma; mixed leukemia / lymphoma of one or more of the above; and multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)). SCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle carcinoma; myelodysplastic syndromes (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown etiology (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis type 1 or type 2 (NF), schwannoma);Neuroendocrine cancers (e.g., gastroenteropancreatic neuroendoctrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancers (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasms (IPMN), pancreatic islet cell tumors); penile cancers (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumors (PNT); plasma cell neoplasms; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancers (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine Cancers include, but are not limited to, cancer (e.g., appendiceal cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva);

[0059] Except in the examples or where otherwise specified, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." "About" and "approximately" are intended to generally refer to an acceptable degree of error for the measured amount given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, or more typically within 5%, 4%, 3%, 2%, or 1% of a given value or range of values. In some embodiments, the term "about X," where X is a number or percentage, refers to a number or percentage that is 99.5% to 100.5%, 99% to 101%, 98% to 102%, 97% to 103%, 96% to 104%, 95% to 105%, 92% to 108%, or 90% to 110% of X, inclusive. For example, the term "about 100" refers to 99.5 to 100.5, 99 to 101, 98 to 102, 97 to 103, 96 to 104, 95 to 105, 92 to 108, or 90 to 110, inclusive.

[0060] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0061] Detailed Description of Some Embodiments Compound 1 has been found to exist in the crystalline forms described herein. Different crystalline forms of a compound (e.g., Compound 1) typically differ in their physical and / or chemical properties due to the arrangement of molecules in the solid form (e.g., the arrangement of molecules in a crystal lattice). In some embodiments, the different crystalline forms result in different pharmacokinetic and / or pharmacodynamic properties. In some embodiments, the different crystalline forms exhibit one or more of increased solubility, increased permeability, increased stability, increased ease of formulation, storage, transportation, and / or administration, reduced costs of formation, transportation, storage, and / or administration, increased adsorption, modified distribution, increased bioavailability, increased or decreased metabolism, increased or decreased excretion, increased potency, increased efficacy, decreased toxicity, reduced frequency and / or severity of side effects, and / or increased patient compliance relative to Compound 1, an amorphous form of Compound 1, an amorphous form of a salt of Compound 1, a different crystalline form of Compound 1, a different crystalline form of a salt of Compound 1, and / or a different cocrystal comprising Compound 1.

[0062] Different solid forms of a compound (e.g., Compound 1) are typically distinguished by X-ray diffraction, particularly X-ray powder diffraction (e.g., XRPD obtained by the methods described herein), as well as by other methods such as differential scanning calorimetry (e.g., DSC obtained by the methods described herein), thermogravimetric analysis (e.g., TGA obtained by the methods described herein), and / or solubility (e.g., thermodynamic solubility).

[0063] Crystal form II In one aspect, the present disclosure provides crystalline Form II of Compound 1: [ka]

[0064] In some embodiments, crystalline Form II of Compound 1 is CuK αThe crystalline Form II of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern, as measured using X-rays, substantially similar to that shown in Figure 1. In some embodiments, crystalline Form II of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially similar to that summarized in Table 3.

[0065] In some embodiments, crystalline Form II of Compound 1 is CuK α In some embodiments, crystalline Form II of Compound 1 is characterized by an XRPD pattern comprising characteristic peaks expressed at 8.1, 9.6, and 10.9 degrees two-theta (±0.2) when measured using a CuK α In some embodiments, crystalline Form II of Compound 1 is further characterized by an XRPD pattern comprising one or more additional characteristic peaks expressed in degrees 2-theta (±0.2) selected from 10.2 and 13.2 when measured using CuK α It is characterized by an XRPD pattern containing only four peaks at about 7 to about 12 degrees 2-theta when measured using radiation.

[0066] In some embodiments, crystalline Form II of Compound 1 is CuK α In some embodiments, crystalline Form II of Compound 1 is characterized by an XRPD pattern that does not exhibit a peak at 4.3 degrees 2-theta (±0.2) when measured using CuK α It is characterized by an XRPD pattern that does not show a peak at 5.6 degrees 2-theta (±0.2) when measured using a line.

[0067] In some embodiments, crystalline Form II of Compound 1 is CuK α In some embodiments, crystalline Form II of Compound 1 is characterized by an XRPD pattern that is free of peaks between about 3 and about 4.8 expressed in degrees 2-theta when measured using CuK αIn some embodiments, crystalline Form II of Compound 1 is characterized by an XRPD pattern that is free of peaks between about 4.8 and about 6 expressed in degrees 2-theta when measured using CuK α In some embodiments, crystalline Form II of Compound 1 is characterized by an XRPD pattern that is free of peaks at about 3 to about 7 degrees 2-theta when measured using CuK α In some embodiments, crystalline Form II of Compound 1 is characterized by an XRPD pattern that is free of peaks between about 3 and about 7.5 expressed in degrees 2-theta when measured using CuK α It is characterized by an XRPD pattern that is free of peaks between about 11.2 and about 12.5 expressed in degrees 2-theta when measured using a line.

[0068] In some embodiments, crystalline Form II of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 2. In some embodiments, crystalline Form II of Compound 1 has an onset temperature (T m In some embodiments, crystalline Form II of Compound 1 is characterized by a DSC thermogram comprising an endotherm including a peak temperature (T) of about 120.41° C. max In some embodiments, crystalline Form II of Compound 1 is characterized by a DSC thermogram comprising an enthalpy of endothermic transition (ΔH) of about 0.584±0.03 J / g.

[0069] In some embodiments, crystalline Form II of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 3. In some embodiments, crystalline Form II of Compound 1 is characterized by a TGA thermogram comprising a weight loss of about (0.262±0.013)% by 120°C. In some embodiments, crystalline Form II of Compound 1 is characterized by a TGA thermogram comprising a weight loss of about (0.360±0.018)% by 220°C.

[0070] In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 25±5° C. or about 50±5° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 20° C. to about 55° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 20° C. to about 50° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 20° C. to about 45° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 25° C. to about 55° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 25° C. to about 50° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 25° C. to about 45° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 30° C. to about 55° C.In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutylacetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 30° C. to about 50° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in methyl isobutylacetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 30° C. to about 45° C.

[0071] In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 50±5°C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 50±2°C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 50°C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 45°C to about 55°C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 45°C to about 50°C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 50°C to about 55°C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 48°C to about 52°C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 48° C. to about 50° C. In some embodiments, crystalline Form II of Compound 1 is obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 50° C. to about 52° C.

[0072] In some embodiments, crystalline Form II of Compound 1 is substantially free of impurities. In some embodiments, crystalline Form II of Compound 1 is substantially free of other salts of Compound 1. In some embodiments, crystalline Form II of Compound 1 is substantially free of solvent.

[0073] In some embodiments, crystalline Form II of Compound 1 is substantially free of amorphous forms of Compound 1. In some embodiments, crystalline Form II of Compound 1 is substantially free of amorphous forms of salts of Compound 1. In some embodiments, crystalline Form II of Compound 1 is substantially free of amorphous forms of solvates of Compound 1. In some embodiments, crystalline Form II of Compound 1 is substantially free of other crystalline forms of Compound 1.

[0074] In another aspect, the present disclosure provides a composition comprising crystalline Form II of Compound 1, wherein the composition comprises 90% or more by weight of crystalline Form II of Compound 1.

[0075] In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 90% or more crystalline Form II of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 95% or more crystalline Form II of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 96% or more crystalline Form II of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 97% or more crystalline Form II of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 98% or more crystalline Form II of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 99% or more crystalline Form II of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 99.5% or more crystalline Form II of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form II of Compound 1 comprises 99.9% or more crystalline Form II of Compound 1 by weight.

[0076] In another aspect, the disclosure provides a composition comprising crystalline Form II of Compound 1, wherein the molar ratio of the amount of Form II to the sum of the amounts of other forms of Compound 1 in the composition is 90:10 or greater.

[0077] In some embodiments, in a composition comprising crystalline Form II of Compound 1, the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 95:5 or greater. In some embodiments, in a composition comprising crystalline Form II of Compound 1, the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 96:4 or greater. In some embodiments, in a composition comprising crystalline Form II of Compound 1, the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 97:3 or greater. In some embodiments, in a composition comprising crystalline Form II of Compound 1, the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 98:2 or greater. In some embodiments, in a composition comprising crystalline Form II of Compound 1, the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 99:1 or greater. In some embodiments, in a composition comprising crystalline Form II of Compound 1, the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 99.5:0.5 or greater. In some embodiments, in a composition comprising crystalline Form II of Compound 1, the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 99.9:0.1 or greater.

[0078] Crystalline Form III of Compound 1 In another embodiment, the present disclosure provides crystalline Form III of Compound 1: [ka]

[0079] In some embodiments, crystalline Form III of Compound 1 is CuK αThe crystalline Form III of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern, as measured using X-rays, substantially similar to that shown in Figure 4. In some embodiments, crystalline Form III of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially similar to that summarized in Table 4.

[0080] In some embodiments, crystalline Form III of Compound 1 is CuK α In some embodiments, crystalline Form III of Compound 1 is characterized by an XRPD pattern comprising three or more characteristic peaks expressed at 4.3, 5.6, and 11.8 degrees two-theta (±0.2) when measured using a CuK α It is characterized by an XRPD pattern which contains an additional characteristic peak expressed at 6.7 degrees 2-theta (±0.2) when measured using a line.

[0081] In some embodiments, crystalline Form III of Compound 1 is characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 5. In some embodiments, crystalline Form III of Compound 1 has an onset temperature (T m In some embodiments, crystalline Form III of Compound 1 is characterized by a DSC thermogram comprising an endotherm including a peak temperature (T max In some embodiments, crystalline Form III of Compound 1 is characterized by a DSC thermogram comprising an enthalpy of endothermic transition (ΔH) of about 80.80±4.0 J / g.

[0082] In some embodiments, crystalline Form III of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 6. In some embodiments, crystalline Form III of Compound 1 is characterized by a TGA thermogram comprising a weight loss of about (4.255±0.2)% by 75°C. In some embodiments, crystalline Form III of Compound 1 is characterized by a TGA thermogram comprising a weight loss of about (1.240±0.060)% from 75°C to 175°C.

[0083] In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 50±5°C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 50±2°C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 50°C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 45°C to about 55°C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 45°C to about 50°C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 50°C to about 55°C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 48°C to about 52°C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 48° C. to about 50° C. In some embodiments, crystalline Form III of Compound 1 is obtained by phase equilibration in 1,4-dioxane at about 50° C. to about 52° C.

[0084] In some embodiments, crystalline Form III of Compound 1 is substantially free of impurities. In some embodiments, crystalline Form III of Compound 1 is substantially free of other salts of Compound 1. In some embodiments, crystalline Form III of Compound 1 is substantially free of solvent.

[0085] In some embodiments, crystalline Form III of Compound 1 is substantially free of amorphous forms of Compound 1. In some embodiments, crystalline Form III of Compound 1 is substantially free of amorphous forms of salts of Compound 1. In some embodiments, crystalline Form III of Compound 1 is substantially free of amorphous forms of solvates of Compound 1. In some embodiments, crystalline Form III of Compound 1 is substantially free of other crystalline forms of Compound 1.

[0086] In another aspect, the present disclosure provides a composition comprising crystalline Form III of Compound 1, wherein the composition comprises 90% or more by weight of crystalline Form III of Compound 1.

[0087] In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 90% or more crystalline Form III of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 95% or more crystalline Form III of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 96% or more crystalline Form III of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 97% or more crystalline Form III of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 98% or more crystalline Form III of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 99% or more crystalline Form III of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 99.5% or more crystalline Form III of Compound 1 by weight. In some embodiments, a composition comprising crystalline Form III of Compound 1 comprises 99.9% or more crystalline Form III of Compound 1 by weight.

[0088] In another aspect, the disclosure provides a composition comprising crystalline Form III of Compound 1, wherein the molar ratio of the amount of Form III to the sum of the amounts of other forms of Compound 1 in the composition is 90:10 or greater.

[0089] In some embodiments, in a composition comprising crystalline Form III of Compound 1, the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 95:5 or greater. In some embodiments, in a composition comprising crystalline Form III of Compound 1, the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 96:4 or greater. In some embodiments, in a composition comprising crystalline Form III of Compound 1, the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 97:3 or greater. In some embodiments, in a composition comprising crystalline Form III of Compound 1, the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 98:2 or greater. In some embodiments, in a composition comprising crystalline Form III of Compound 1, the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 99:1 or greater. In some embodiments, in a composition comprising crystalline Form III of Compound 1, the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 99.5:0.5 or greater. In some embodiments, in a composition comprising crystalline Form III of Compound 1, the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 99.9:0.1 or greater.

[0090] Pharmaceutical Compositions, Kits, and Administration In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form provided herein, or a composition provided herein, and a pharmaceutically acceptable excipient.

[0091] In another aspect, the present disclosure provides a kit comprising a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof, and instructions for using the crystalline form, composition, or pharmaceutical composition.

[0092] Pharmaceutical compositions disclosed herein can be prepared by any of the methods known in the art of pharmacy. In general, such methods of preparation include bringing into association a compound disclosed herein (i.e., the "active ingredient") with the carrier or excipient and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product in the desired single or multi-dosage unit.

[0093] In some embodiments, a pharmaceutical composition is prepared, packaged, and / or sold in bulk, as a single dosage unit, and / or as a plurality of single dosage units. A "dosage unit" is a discrete amount of a pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dose, such as one-half or one-third of such a dose.

[0094] The relative amounts of active ingredient, pharmaceutically acceptable excipient, and / or additional ingredients in the pharmaceutical compositions disclosed herein will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. In some embodiments, the composition comprises 0.1% to 100% (w / w) active ingredient.

[0095] Pharmaceutically acceptable excipients used in preparing the disclosed pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. In some embodiments, excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and flavoring agents are present in the composition.

[0096] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0097] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0098] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl stearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), colorants, and the like. Geenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0099] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Chorizoides extract, panwar gum, ghatti gum, mucilage of psyllium husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0100] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0101] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0102] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0103] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0104] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoic acid esters, and phenylethyl alcohol.

[0105] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0106] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0107] Exemplary buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, calcium hydrogen phosphate, phosphoric acid, tricalcium phosphate, hydroxyapatite, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0108] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0109] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver oil, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grapeseed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, lily of the valley, and macadamia. Exemplary synthetic oils include, but are not limited to, citric acid, citric acid, citric acid (citric acid), ...

[0110] In some embodiments, dosage forms for topical and / or transdermal administration of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers. Furthermore, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of the active ingredient to the body. In some embodiments, such dosage forms are prepared, for example, by dissolving and / or dispensing the active ingredient in a suitable medium. In some embodiments, the rate is alternatively or additionally controlled by either providing a rate-controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel. In some embodiments, the pharmaceutical composition is in the form of a topical formulation.

[0111] Suitable devices for use in delivering the intradermal pharmaceutical compositions disclosed herein include short-needle devices. In some embodiments, the intradermal composition is administered by a device that controls the effective penetration length of the needle into the skin. In some embodiments, alternatively or additionally, a conventional syringe is used in the classical Mantoux method of intradermal administration. Jet injection devices are suitable, delivering liquid formulations to the dermis via a liquid jet injector and / or a needle that pierces the stratum corneum and creates a jet that reaches the dermis. Ballistic powder / particle delivery devices are suitable, using compressed gas to accelerate a compound in powder form through the outer layer of the skin to the dermis.

[0112] Suitable formulations for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as liniments and lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. In some embodiments, topically administrable formulations contain, for example, about 1% to about 10% (w / w) active ingredient. In some embodiments, the concentration of the active ingredient is as high as the solubility limit of the active ingredient in the solvent. In some embodiments, formulations for topical administration further comprise one or more of the additional ingredients disclosed herein.

[0113] Although the description of pharmaceutical compositions disclosed herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or implement such modifications with routine experimentation.

[0114] The compounds disclosed herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage.However, it will be understood that the total daily amount of the compositions disclosed herein will be determined by a physician within the scope of sound medical judgment.The specific therapeutically effective dose level for a specific subject or organism will depend on various factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient being used; the specific composition being used; the age, weight, general health, sex and diet of the subject; the administration time, administration route and excretion rate of the specific active ingredient being used; the duration of treatment; the drugs used in combination with or simultaneously with the specific active ingredient being used; and similar factors well known in the medical field.

[0115] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the species, age, and general condition of the subject, the severity of any side effects or disorders, the identity of the particular compound, the mode of administration, etc. In some embodiments, an effective amount is contained in a single administration (e.g., a single oral dose) or multiple administrations (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses in the multiple doses contain different or substantially the same amounts of a compound disclosed herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency with which the multiple doses are administered to a subject or applied to a tissue or cell is 3 doses per day, 2 doses per day, 1 dose per day, 1 dose every other day, 1 dose every 3 days, 1 dose per week, 1 dose every 2 weeks, 1 dose every 3 weeks, or 1 dose every 4 weeks. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is one dose per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is two doses per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the period between the first and last administration of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the period between the first and last administration of the multiple doses is three months, six months, or one year. In certain embodiments, the period between the first and last administration of the multiple doses is the lifetime of the subject, tissue, or cell.

[0116] The dosage ranges disclosed herein provide guidance for administration of the disclosed pharmaceutical compositions to adults. In some embodiments, for example, the amount to be administered to a child or adolescent may be determined by a medical practitioner or skilled artisan and may be lower than or the same as the amount administered to an adult.

[0117] In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 1,500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 1,000 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 150 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 2 mg to about 8 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 4 mg to about 6 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the pharmaceutical composition comprises about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,250 mg, or 1,500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 2 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 3 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 4 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 6 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 7 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 8 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 9 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 12.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof.In some embodiments, the pharmaceutical composition comprises about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 110 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof.In some embodiments, the pharmaceutical composition comprises about 140 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 160 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 180 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 220 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 240 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 260 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 280 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 400 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 600 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 700 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 800 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 900 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1,000 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1,250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 1,500 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, a compound or composition disclosed herein is administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). In some embodiments, the compound or composition is administered in combination with an additional pharmaceutical agent that improves its activity (e.g., activity (e.g., efficacy and / or potency) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk of developing a disease in a subject in need thereof, and / or in inhibiting the activity of atypical protein kinase C in a subject or cell), improves bioavailability, improves safety, reduces drug resistance, reduces and / or modulates metabolism, inhibits excretion, and / or modulates distribution in a subject or cell. It will also be appreciated that in some embodiments, the therapies utilized achieve desired effects and / or different effects for the same disorder. In certain embodiments, a pharmaceutical composition disclosed herein comprising a compound disclosed herein and an additional pharmaceutical agent exhibits a synergistic effect that is present in both cases but not in a pharmaceutical composition comprising one of the compound and the additional pharmaceutical agent. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves a different effect.

[0120] In some embodiments, the compound or composition is administered simultaneously with, before, or after one or more additional pharmaceutical agents. In some embodiments, the one or more additional pharmaceutical agents are useful, for example, as a combination therapy. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as defined in the Code of Federal Regulations (CFR) for human or veterinary use), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. Additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, steroidal or nonsteroidal anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol-lowering agents, antidiabetic agents, antiallergic agents, contraceptives, analgesics, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroidal or antihistamines, antigens, vaccines, antibodies, decongestants, analgesics, opiates, pain relievers, antipyretics, hormones, and prostaglandins.

[0121] In some embodiments, each additional pharmaceutical agent is administered at a dosage and / or on a time schedule determined for that pharmaceutical agent. In some embodiments, the additional pharmaceutical agents are administered together with each other and / or with the compounds or compositions disclosed herein in a single dosage or composition, or separately in different dosages or compositions. The particular combination utilized in a regimen will take into account the compatibility of the compounds disclosed herein with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in the combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than the levels utilized individually.

[0122] Kits (e.g., pharmaceutical packs) are also encompassed by the present disclosure. In some embodiments, the kits disclosed herein include a pharmaceutical composition or compound disclosed herein and a container (e.g., a vial, ampoule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the disclosed kits optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound disclosed herein. In some embodiments, the pharmaceutical composition or compound disclosed herein provided in the first container and the second container combine to form a single unit dosage form.

[0123] Thus, in one aspect, disclosed herein is a kit comprising a first container comprising a compound or pharmaceutical composition disclosed herein. In certain embodiments, the kit is useful for treating BCC in a subject in need thereof. In certain embodiments, the kit is useful for preventing BCC in a subject in need thereof. In certain embodiments, the kit is useful for reducing the risk of BCC in a subject in need thereof. In certain embodiments, the kit is useful for inhibiting atypical protein kinase C in a subject or cell.

[0124] In certain embodiments, the kits disclosed herein further comprise instructions for using the kit. In some embodiments, the kits disclosed herein also comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kit and instructions provide for the treatment of BCC in a subject in need thereof. In certain embodiments, the kit and instructions provide for the prevention of BCC in a subject in need thereof. In certain embodiments, the kit and instructions provide for the reduction of the risk of developing BCC in a subject in need thereof. In certain embodiments, the kit and instructions provide for the inhibition of atypical protein kinase C in a subject or cell. In some embodiments, the kits disclosed herein comprise one or more additional pharmaceutical agents disclosed herein as separate compositions.

[0125] Method of preparation In another aspect, the disclosure provides a method for preparing crystalline Form II of Compound 1 or a composition thereof, comprising: (1) providing a solution of Compound 1 in one or more solvents; (2) precipitating crystalline Form II of Compound 1 from a solution of Compound 1; and (3) isolating crystalline form II of compound 1 The present invention provides a method comprising:

[0126] In some embodiments, a solution of Compound 1 is provided by heating a mixture of solid Compound 1 and one or more solvents. In some embodiments, at least one of the one or more solvents is a non-polar solvent. In some embodiments, at least one of the one or more solvents is a polar solvent. In some embodiments, at least one of the one or more solvents is an aprotic solvent. In some embodiments, at least one of the one or more solvents is a protic solvent. In some embodiments, at least one of the one or more solvents is acetonitrile, dichloromethane, dimethylformamide, 2-methoxyethanol, methyl isobutyl ketone, acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, heptane, isobutyl acetate, isopropyl acetate, methyl ethyl ketone, tetrahydrofuran, or dimethyl sulfoxide.

[0127] In some embodiments, the solution of Compound 1 is saturated or supersaturated. In some embodiments, the solution of Compound 1 is saturated. In some embodiments, the solution of Compound 1 is supersaturated.

[0128] In some embodiments, the precipitation step comprises the addition of one or more seed crystals of crystalline Form II of Compound 1. In some embodiments, the precipitation step comprises one or more of phase equilibration, evaporation, anti-solvent addition, reverse addition, and cooling of a saturated solution. In some embodiments, the precipitation step comprises evaporation. In some embodiments, the precipitation step comprises anti-solvent addition. In some embodiments, the precipitation step comprises reverse addition. In some embodiments, the precipitation step comprises cooling of a saturated solution. In some embodiments, the precipitation step comprises phase equilibration.

[0129] In some embodiments, the precipitation step comprises phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF. In some embodiments, the precipitation step comprises phase equilibration in methyl isobutyl acetone. In some embodiments, the precipitation step comprises phase equilibration in n-butyl alcohol. In some embodiments, the precipitation step comprises phase equilibration in methyl tert-butyl ether. In some embodiments, the precipitation step comprises phase equilibration in ethyl acetate. In some embodiments, the precipitation step comprises phase equilibration in isobutyl acetate. In some embodiments, the precipitation step comprises phase equilibration in isopropyl acetate. In some embodiments, the precipitation step comprises phase equilibration in THF.

[0130] In some embodiments, phase equilibration is carried out at about 25±5°C to about 50±5°C. In some embodiments, phase equilibration is carried out at about 20°C to about 55°C. In some embodiments, phase equilibration is carried out at about 20°C to about 50°C. In some embodiments, phase equilibration is carried out at about 20°C to about 45°C. In some embodiments, phase equilibration is carried out at about 25°C to about 55°C. In some embodiments, phase equilibration is carried out at about 25°C to about 50°C. In some embodiments, phase equilibration is carried out at about 25°C to about 45°C. In some embodiments, phase equilibration is carried out at about 30°C to about 55°C. In some embodiments, phase equilibration is carried out at about 30°C to about 50°C. In some embodiments, phase equilibration is carried out at about 30°C to about 45°C.

[0131] In some embodiments, the precipitation step comprises phase equilibration in dichloromethane or methyl ethyl ketone. In some embodiments, the precipitation step comprises phase equilibration in dichloromethane. In some embodiments, the precipitation step comprises phase equilibration in methyl ethyl ketone.

[0132] In some embodiments, phase equilibration is carried out at about 50±5°C. In some embodiments, phase equilibration is carried out at about 50±2°C. In some embodiments, phase equilibration is carried out at about 45°C to about 55°C. In some embodiments, phase equilibration is carried out at about 45°C to about 50°C. In some embodiments, phase equilibration is carried out at about 50°C to about 55°C. In some embodiments, phase equilibration is carried out at about 48°C to about 52°C. In some embodiments, phase equilibration is carried out at about 48°C to about 50°C. In some embodiments, phase equilibration is carried out at about 50°C to about 52°C. In some embodiments, phase equilibration is carried out at about 50°C.

[0133] In some embodiments, the precipitation step comprises adding an anti-solvent to a solution of compound 1 in dimethylformamide, 2-methoxy-ethanol, or dimethyl sulfoxide. In some embodiments, the precipitation step comprises adding an anti-solvent to a solution of compound 1 in dimethylformamide or 2-methoxy-ethanol. In some embodiments, the precipitation step comprises adding an anti-solvent to a solution of compound 1 in dimethylformamide or dimethyl sulfoxide. In some embodiments, the precipitation step comprises adding an anti-solvent to a solution of compound 1 in dimethylformamide or dimethyl sulfoxide. In some embodiments, the precipitation step comprises adding an anti-solvent to a solution of compound 1 in dimethylformamide. In some embodiments, the precipitation step comprises adding an anti-solvent to a solution of compound 1 in 2-methoxy-ethanol. In some embodiments, the precipitation step comprises adding an anti-solvent to a solution of compound 1 in dimethyl sulfoxide. In some embodiments, the anti-solvent is methyl tert-butyl ether or acetonitrile. In some embodiments, the anti-solvent is methyl tert-butyl ether. In some embodiments, the anti-solvent is acetonitrile.

[0134] In some embodiments, the precipitation step comprises the inverse addition of an anti-solvent to a solution of compound 1 in dimethylformamide, 2-methoxy-ethanol, or dimethyl sulfoxide. In some embodiments, the precipitation step comprises the inverse addition of an anti-solvent to a solution of compound 1 in dimethylformamide or 2-methoxy-ethanol. In some embodiments, the precipitation step comprises the inverse addition of an anti-solvent to a solution of compound 1 in dimethylformamide or dimethyl sulfoxide. In some embodiments, the precipitation step comprises the inverse addition of an anti-solvent to a solution of compound 1 in 2-methoxy-ethanol or dimethyl sulfoxide. In some embodiments, the precipitation step comprises the inverse addition of an anti-solvent to a solution of compound 1 in dimethylformamide. In some embodiments, the precipitation step comprises the inverse addition of an anti-solvent to a solution of compound 1 in 2-methoxy-ethanol. In some embodiments, the precipitation step comprises the inverse addition of an anti-solvent to a solution of compound 1 in dimethyl sulfoxide. In some embodiments, the anti-solvent is methyl tert-butyl ether or acetonitrile. In some embodiments, the anti-solvent is methyl tert-butyl ether. In some embodiments, the anti-solvent is acetonitrile.

[0135] In another aspect, the disclosure provides a method for preparing crystalline Form III of Compound 1 or a composition thereof, comprising: (1) providing a solution of Compound 1 in one or more solvents; (2) precipitating crystalline Form III of Compound 1 from a solution of Compound 1; and (3) isolating crystalline form III of compound 1 The present invention provides a method comprising:

[0136] In some embodiments, a solution of Compound 1 is provided by heating a mixture of solid Compound 1 and one or more solvents. In some embodiments, at least one of the one or more solvents is a non-polar solvent. In some embodiments, at least one of the one or more solvents is a polar solvent. In some embodiments, at least one of the one or more solvents is an aprotic solvent. In some embodiments, at least one of the one or more solvents is a protic solvent. In some embodiments, at least one of the one or more solvents is acetonitrile, dichloromethane, dimethylformamide, 2-methoxyethanol, methyl isobutyl ketone, acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, heptane, isobutyl acetate, isopropyl acetate, methyl ethyl ketone, tetrahydrofuran, or dimethyl sulfoxide.

[0137] In some embodiments, at least one of the one or more solvents is 1,4-dioxane or n-propanol. In some embodiments, at least one of the one or more solvents is 1,4-dioxane. In some embodiments, at least one of the one or more solvents is n-propanol.

[0138] In some embodiments, the solution of Compound 1 is saturated or supersaturated. In some embodiments, the solution of Compound 1 is saturated. In some embodiments, the solution of Compound 1 is supersaturated.

[0139] In some embodiments, the precipitation step comprises adding one or more seed crystals to crystalline Form III of Compound 1. In some embodiments, the precipitation step comprises one or more of phase equilibration, evaporation, anti-solvent addition, reverse addition, and cooling of a saturated solution. In some embodiments, the precipitation step comprises evaporation. In some embodiments, the precipitation step comprises anti-solvent addition. In some embodiments, the precipitation step comprises reverse addition. In some embodiments, the precipitation step comprises cooling of a saturated solution. In some embodiments, the precipitation step comprises phase equilibration.

[0140] In some embodiments, the precipitation step comprises phase equilibration in 1,4-dioxane.

[0141] In some embodiments, phase equilibration is carried out at about 50±5°C. In some embodiments, phase equilibration is carried out at about 50±2°C. In some embodiments, phase equilibration is carried out at about 45°C to about 55°C. In some embodiments, phase equilibration is carried out at about 45°C to about 50°C. In some embodiments, phase equilibration is carried out at about 50°C to about 55°C. In some embodiments, phase equilibration is carried out at about 48°C to about 52°C. In some embodiments, phase equilibration is carried out at about 48°C to about 50°C. In some embodiments, phase equilibration is carried out at about 50°C to about 52°C. In some embodiments, phase equilibration is carried out at about 50°C.

[0142] Treatment methods and uses In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof.

[0143] In another aspect, the present disclosure provides a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof for use in treating cancer in a subject in need thereof.

[0144] In another aspect, the present disclosure provides a use of a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof for the treatment of cancer in a subject in need thereof.

[0145] In another aspect, the present disclosure provides use of a crystalline form provided herein, a composition thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of basal cell carcinoma, a solid tumor, or acute myeloid leukemia in a subject in need thereof.

[0146] In some embodiments, the cancer is basal cell carcinoma, a solid tumor, or acute myeloid leukemia. In some embodiments, the cancer is basal cell carcinoma or a solid tumor. In some embodiments, the cancer is basal cell carcinoma or acute myeloid leukemia. In some embodiments, the cancer is a solid tumor or acute myeloid leukemia. In some embodiments, the cancer is basal cell carcinoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is acute myeloid leukemia.

[0147] In some embodiments, the topical formulation comprises a therapeutically effective amount of Compound 1. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 1,500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 1,000 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 150 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg to about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 1 mg to about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 2 mg to about 8 mg of Compound 1 or a pharmaceutically acceptable salt thereof.In some embodiments, the therapeutically effective amount is about 4 mg to about 6 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the therapeutically effective amount is about 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 110 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,250 mg, or 1,500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 1 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 2 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 3 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 4 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 6 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 7 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 8 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 9 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 12.5 mg of Compound 1 or a pharmaceutically acceptable salt thereof.In some embodiments, the therapeutically effective amount is about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 110 mg of Compound 1 or a pharmaceutically acceptable salt thereof.In some embodiments, the therapeutically effective amount is about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 140 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 160 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 180 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 220 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 240 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 260 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 280 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 300 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 400 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 600 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 700 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 800 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 900 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 1,000 mg of Compound 1 or a pharmaceutically acceptable salt thereof.In some embodiments, the therapeutically effective amount is about 1,250 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount is about 1,500 mg of Compound 1 or a pharmaceutically acceptable salt thereof. [Example]

[0149] In order that the present disclosure may be more fully understood, the following examples are set forth: The examples disclosed herein are given to illustrate the methods disclosed herein and should not be construed as limiting in any way their scope. [Example]

[0150] Example 1. Phase equilibria at 25±1°C and 50±1°C Forms II and III of Compound 1 were prepared by phase equilibration from various solvents at 50±1°C and 25±1°C. Compound 1 (20-100 mg) was added to the solvent until a cloudy solution was obtained, and then approximately 20 mg of Compound 1 was added to the cloudy solution. The mixture was stirred at 50±1°C for 24 hours or at 25±1°C for 48 hours. The solids were filtered and analyzed by XRPD.

[0151] Form II of Compound 1 was prepared by phase equilibration in methyl isobutyl acetone, n-BuOH, MTBE, EtOAc, isobutyl acetate, isopropyl acetate, and THF at both 25° C. and 50° C. Form II of Compound 1 was also prepared by phase equilibration in dichloromethane and methyl ethyl ketone at 50° C.

[0152] Form III of Compound 1 was prepared by phase equilibration in 1,4-dioxane at 50°C.

[0153] Example 2. Antisolvent addition Form II of Compound 1 was prepared by anti-solvent addition. Saturated and nearly saturated solutions of Compound 1 (250 mg) were prepared in 2.5 mL of room temperature DMF, MOEtOH, or DMSO. 15 mL of anti-solvent (MTBE or MeCN) was added dropwise to induce precipitation of Form II of Compound 1, as shown in Table 1. [Table 1]

[0154] Example 3. Reverse addition Form II of Compound 1 was prepared by inverse addition: saturated and nearly saturated solutions of Compound 1 (250 mg) in 2.5 mL of DMF, MeOEtOH, DMSO, or ethyl formate were prepared at 25° C. and then added dropwise to a larger volume (15 mL) of a miscible antisolvent (MeCN or MTBE) to form Form II of Compound 1, as shown in Table 2. [Table 2]

[0155] Example 4. Crystalline morphology characterization Forms II and III of Compound 1 were characterized by XRPD (Figures 1 and 4, respectively), DSC (Figures 2 and 5, respectively), and TGA (Figures 3 and 6, respectively). X-ray powder diffraction analysis was performed on a Rigaku MiniFlex 6G X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1)K b (1) X-ray emission from copper with a filter at 1.054056 Å; (2) X-ray output at 30 KV and 15 mA; and (3) sample powder dispersed on a zero-background sample holder. The general measurement conditions for XRPD were a start angle of 3 degrees, a stop angle of 45 degrees, a sampling of 0.02 degrees, and a scan rate of 2 degrees / min.

[0156] Differential scanning calorimetry (DSC) was performed on a TA Instruments Model Q200 calorimetry equipped with an autosampler. DSC instrument conditions were as follows: 45°C to 300°C at 10°C / min; Tzero aluminum sample pan and lid; and 50 mL / min nitrogen gas flow. For Compound 1 Form II, a 1.2000 mg sample was analyzed. For Compound 1 Form III, a 2.8000 mg sample was analyzed.

[0157] TGA thermograms were collected on a TA Instruments thermogravimetric analyzer, TGA Q500, equipped with an autosampler. Typical experimental conditions for the TGA were: ramp from 25°C to 600°C at 20°C / min; nitrogen purge, 25 mL / min gas flow; platinum sample pan. For Compound 1 Form II, 6.5020 mg was analyzed. For Compound 1 Form III, 6.5020 mg was analyzed.

[0158] Example 5. Summary XRPD Data for Form II Table 3 provides a list of peaks corresponding to those labeled in FIG. 1 of the XPRD pattern of Compound 1 Form II. [Table 3]

[0159] Example 6. List of XRPD Data for Form III of Compound 1 Table 4 provides a list of peaks corresponding to the labeled peaks in Figure 4 of the XPRD pattern of Compound 1 Form III. [Table 4]

[0160] Equivalents and Scope In the claims, articles such as "a," "an," and "the" can mean one or more, unless indicated otherwise or clear from context. A claim or description including "or" between one or more members of a group is considered to be satisfied when one, more than one, or all of the group members are present in, utilized in, or otherwise relevant to a given product or process, unless indicated otherwise or clear from context. The invention includes embodiments in which exactly one member of a group is present in, utilized in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, utilized in, or otherwise relevant to a given product or process.

[0161] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. In general, when the invention, or aspects of the invention, are referred to as comprising particular elements and / or features, it is to be understood that particular embodiments of the invention or aspects of the invention consist of, or consist essentially of, such elements and / or features. For the sake of brevity, those embodiments have not been specifically recited in those exact terms herein. It is also noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise specified or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume, in different embodiments of the invention, every specific value or subrange within the stated range, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0162] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments disclosed herein. The scope of the embodiments disclosed herein is not intended to be limited to the above specification, but rather is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications herein can be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

1. Crystalline Form II of Compound 1: 【Chemistry 1】

2. CuK α 2. Crystalline Form II of Compound 1 according to claim 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 1, when measured using X-rays.

3. CuK α 3. Crystalline Form II of Compound 1 according to claim 1 or 2, characterized by an XRPD pattern comprising characteristic peaks expressed at 8.1, 9.6, and 10.9 degrees two-theta (±0.2), as measured using a ray.

4. CuK α 4. Crystalline Form II of Compound 1 according to claim 3, further characterized by an XRPD pattern comprising one or more additional characteristic peaks expressed in degrees 2-theta (±0.2) selected from 10.2 and 13.2, when measured using a line.

5. CuK α 5. Crystalline Form II of Compound 1 according to any one of claims 1 to 4, characterized by an XRPD pattern that does not exhibit a peak at 4.3 degrees 2-theta (±0.2) when measured using a ray.

6. CuK α 6. Crystalline Form II of Compound 1 according to any one of claims 1 to 5, characterized by an XRPD pattern that does not exhibit a peak at 5.6 degrees 2-theta (±0.2) when measured using a ray.

7. CuK α 7. Crystalline Form II of Compound 1 according to any one of claims 1 to 6, characterized by an XRPD pattern having an absence of peaks between about 3 and about 4.8 expressed in degrees two-theta, when measured using a ray.

8. CuK α 8. Crystalline Form II of Compound 1 according to any one of claims 1 to 7, characterized by an XRPD pattern having an absence of peaks between about 4.8 and about 6 expressed in degrees 2-theta, when measured using a ray.

9. CuK α 9. Crystalline Form II of Compound 1 according to any one of claims 1 to 8, characterized by an XRPD pattern having an absence of peaks at about 3 to about 7 expressed in degrees 2-theta, when measured using a ray.

10. CuK α 10. Crystalline Form II of Compound 1 according to any one of claims 1 to 9, characterized by an XRPD pattern having an absence of peaks between about 3 and about 7.5 expressed in degrees 2-theta, when measured using a ray.

11. CuK α 11. Crystalline Form II of Compound 1 according to any one of claims 1 to 10, characterized by an XRPD pattern having an absence of a peak at about 11.2 to about 12.5 expressed in degrees two-theta, when measured using a ray.

12. CuK α 12. Crystalline Form II of Compound 1 according to any one of claims 1 to 11, characterized by an XRPD pattern comprising only four peaks at about 7 to about 12 expressed in degrees 2-theta, when measured using a ray.

13. 13. Crystalline Form II of Compound 1 according to any one of claims 1 to 12, characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 2.

14. Onset temperature (T ｍ 14. The crystalline form II of compound 1 according to any one of claims 1 to 13, characterized by a DSC thermogram comprising an endotherm comprising:

15. Peak temperature (T ｍａｘ 15. The crystalline Form II of Compound 1 according to any one of claims 1 to 14, characterized by a DSC thermogram comprising:

16. 16. Crystalline Form II of Compound 1 according to any one of claims 1 to 15, characterized by a DSC thermogram comprising an enthalpy of endothermic transition (ΔH) of about 0.584±0.03 J / g.

17. 17. Crystalline Form II of Compound 1 according to any one of claims 1 to 16, characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 3.

18. 18. The crystalline form II of compound 1 of any one of claims 1 to 17, characterized by a TGA thermogram comprising a weight loss of about (0.262±0.013)% up to 120°C.

19. 19. The crystalline Form II of Compound 1 of any one of claims 1 to 18, characterized by a TGA thermogram comprising a weight loss of about (0.360±0.018)% up to 220°C.

20. 20. Crystalline Form II of Compound 1 according to any one of claims 1 to 19, obtained by phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF at about 25±5°C or about 50±5°C.

21. Crystalline Form II of Compound 1 according to any one of claims 1 to 20, obtained by phase equilibration in dichloromethane and methyl ethyl ketone at about 50°C.

22. 22. Crystalline Form II of Compound 1 according to any one of claims 1 to 21, which is substantially free of impurities.

23. 23. The crystalline Form II of Compound 1 of any one of claims 1 to 22, wherein the crystalline Form II is substantially free of amorphous forms of Compound 1.

24. 24. A composition comprising crystalline Form II of Compound 1 according to claim 22 or 23, wherein the composition comprises 90% by weight or more of said crystalline Form II of Compound 1.

25. 25. The composition of claim 24, comprising 95% by weight or more of the crystalline Form II of Compound 1.

26. 26. The composition of claim 24 or 25, comprising 99% by weight or more of the crystalline Form II of Compound 1.

27. 24. A composition comprising crystalline Form II of Compound 1 according to claim 22 or 23, wherein the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 90:10 or greater.

28. 28. The composition of claim 27, wherein the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 95:5 or greater.

29. 29. The composition of claim 27 or 28, wherein the molar ratio of the amount of Form II of Compound 1 to the sum of the amounts of other forms in the composition is 99:1 or greater.

30. Crystalline Form III of Compound 1: 【Chemistry 2】

31. CuK α 31. The crystalline Form III of Compound 1 of claim 30, characterized by an X-ray powder diffraction (XRPD) pattern substantially similar to that shown in Figure 4, when measured using X-rays.

32. CuK α 32. The crystalline Form III of Compound 1 of claim 30 or 31, characterized by an XRPD pattern comprising three or more characteristic peaks expressed at 4.3, 5.6, and 11.8 degrees two-theta (±0.2), as measured using a ray.

33. CuK α 33. The crystalline Form III of Compound 1 of any one of claims 30 to 32, characterized by an XRPD pattern including an additional characteristic peak expressed at 6.7 degrees two-theta (±0.2) when measured using a ray.

34. 34. Crystalline Form III of Compound 1 according to any one of claims 30 to 33, characterized by a differential scanning calorimetry (DSC) thermogram substantially similar to that shown in Figure 5.

35. Onset temperature (T ｍ 35. The crystalline Form III of Compound 1 of any one of claims 30 to 34, characterized by a DSC thermogram comprising an endotherm comprising:

36. Peak temperature (T ｍａｘ 36. The crystalline Form III of Compound 1 of any one of claims 30 to 35, characterized by a DSC thermogram comprising:

37. 37. The crystalline Form III of Compound 1 of any one of claims 30-36, characterized by a DSC thermogram comprising an enthalpy of endothermic transition (ΔH) of about 80.80±4.0 J / g.

38. 38. Crystalline Form III of Compound 1 according to any one of claims 30 to 37, characterized by a thermogravimetric analysis (TGA) thermogram substantially similar to that shown in Figure 6.

39. 39. The crystalline Form III of Compound 1 of any one of claims 30-38, characterized by a TGA thermogram comprising a weight loss of about (4.255±0.2)% up to 75°C.

40. 40. The crystalline Form III of Compound 1 of any one of claims 30-39, characterized by a TGA thermogram comprising a weight loss of about (1.240±0.060)% from 75°C to 175°C.

41. 41. The crystalline form III of compound 1 according to any one of claims 30 to 40, obtained by phase equilibration in 1,4-dioxane at about 50±5°C.

42. 42. The crystalline Form III of Compound 1 of any one of claims 30 to 41, which is substantially free of impurities.

43. 43. The crystalline Form III of Compound 1 of any one of claims 30 to 42, wherein the crystalline Form III is substantially free of amorphous forms of Compound 1.

44. 44. A composition comprising crystalline Form III of Compound 1 according to claim 42 or 43, wherein the composition comprises 90% by weight or more of said crystalline Form III of Compound 1.

45. 45. The composition of claim 44, comprising 95% or more by weight of the crystalline Form III of Compound 1.

46. 46. ​​The composition of claim 44 or 45, comprising 99% by weight or more of the crystalline Form III of Compound 1.

47. 44. A composition comprising crystalline Form III of Compound 1 according to claim 42 or 43, wherein the molar ratio of the amount of Form III to the sum of the amounts of other forms of Compound 1 in the composition is 90:10 or greater.

48. 48. The composition of claim 47, wherein the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 95:5 or greater.

49. 49. The composition of claim 47 or 48, wherein the molar ratio of the amount of Form III of Compound 1 to the sum of the amounts of other forms in the composition is 99:1 or greater.

50. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 23 or 30 to 43 or the composition of any one of claims 24 to 29 or 44 to 49, and a pharmaceutically acceptable excipient.

51. 51. The pharmaceutical composition of claim 50, in the form of an external preparation.

52. A method for preparing crystalline form II of compound 1 according to any one of claims 1 to 23 or a composition according to any one of claims 24 to 29, comprising: (1) providing a solution of Compound 1 in one or more solvents; (2) precipitating the crystalline Form II of Compound 1 from the solution of Compound 1; and (3) isolating the crystalline form II of Compound 1 A method comprising:

53. 53. The method of claim 52, wherein the solution of Compound 1 is provided by heating a mixture of solid Compound 1 and one or more solvents.

54. 54. The method of claim 52 or 53, wherein at least one of the one or more solvents is a non-polar solvent.

55. 54. The method of claim 52 or 53, wherein at least one of the one or more solvents is a polar solvent.

56. 56. The method of any one of claims 52 to 55, wherein at least one of the one or more solvents is an aprotic solvent.

57. 56. The method of any one of claims 52 to 55, wherein at least one of the one or more solvents is a protic solvent.

58. 54. The method of claim 52 or 53, wherein at least one of the one or more solvents is acetonitrile, dichloromethane, dimethylformamide, 2-methoxy-ethanol, methyl isobutyl ketone, acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, heptane, isobutyl acetate, isopropyl acetate, methyl ethyl ketone, tetrahydrofuran, or dimethyl sulfoxide.

59. 59. The method of any one of claims 52 to 58, wherein the solution of Compound 1 is saturated or supersaturated.

60. 60. The method of any one of claims 52 to 59, wherein the precipitation step comprises one or more of phase equilibration, evaporation, anti-solvent addition, reverse addition, and cooling of a saturated solution.

61. 61. The method of any one of claims 52-60, wherein the precipitating step comprises adding one or more seed crystals to crystalline Form II of Compound 1.

62. 61. The method of claim 60, wherein the precipitation step comprises phase equilibration in methyl isobutyl acetone, n-butyl alcohol, methyl tert-butyl ether, ethyl acetate, isobutyl acetate, isopropyl acetate, or THF.

63. 63. The method of claim 62, wherein the phase equilibration is carried out at about 25±5°C to about 50±5°C.

64. 61. The method of claim 60, wherein the precipitation step comprises phase equilibration in dichloromethane or methyl ethyl ketone.

65. 65. The method of claim 64, wherein the phase equilibration is carried out at about 50±5°C.

66. 61. The method of claim 60, wherein the precipitation step comprises adding an anti-solvent to a solution of Compound 1 in dimethylformamide, 2-methoxy-ethanol, or dimethylsulfoxide.

67. 67. The method of claim 66, wherein the anti-solvent is methyl tert-butyl ether or acetonitrile.

68. 61. The method of claim 60, wherein the precipitating step comprises the inverse addition of an anti-solvent to a solution of Compound 1 in dimethylformamide, 2-methoxy-ethanol, or dimethylsulfoxide.

69. 69. The method of claim 68, wherein the anti-solvent is methyl tert-butyl ether or acetonitrile.

70. A method for preparing crystalline Form III of Compound 1 according to any one of claims 30 to 43, or a composition according to any one of claims 44 to 49, comprising the steps of: (1) providing a solution of Compound 1 in one or more solvents; (2) precipitating said crystalline Form III of Compound 1 from said solution of Compound 1; and (3) isolating the crystalline form III of Compound 1. A method comprising:

71. 71. The method of claim 70, wherein the solution of compound 1 is provided by heating a mixture of solid compound 1 and one or more solvents.

72. 72. The method of claim 70 or 71, wherein at least one of the one or more solvents is a non-polar solvent.

73. 72. The method of claim 70 or 71, wherein at least one of the one or more solvents is a polar solvent.

74. 74. The method of any one of claims 70 to 73, wherein at least one of the one or more solvents is an aprotic solvent.

75. 74. The method of any one of claims 70 to 73, wherein at least one of the one or more solvents is a protic solvent.

76. 72. The method of claim 70 or 71, wherein at least one of the one or more solvents is 1,4-dioxane or n-propanol.

77. 77. The method of any one of claims 70 to 76, wherein the solution of Compound 1 is saturated or supersaturated.

78. 71. The method of claim 70, wherein the precipitation step comprises one or more of phase equilibration, evaporation, antisolvent addition, reverse addition, and cooling of a saturated solution.

79. 79. The method of any one of claims 70-78, wherein the precipitating step comprises adding one or more seed crystals to crystalline Form III of Compound 1.

80. 79. The method of claim 78, wherein the precipitation step comprises phase equilibration in 1,4-dioxane.

81. 81. The method of claim 80, wherein the phase equilibration is carried out at about 50±5°C.

82. 52. A method of treating cancer in a subject in need thereof, comprising administering to the subject a crystalline form of any one of claims 1-23 or 30-43, a composition of claims 24-29 or 44-49, or a pharmaceutical composition of claim 50 or 51.

83. 83. The method of claim 82, wherein the cancer is basal cell carcinoma, a solid tumor, or acute myeloid leukemia.

84. 52. The crystalline form of any one of claims 1 to 23 or 30 to 43, the composition of claims 24 to 29 or 44 to 49, or the pharmaceutical composition of claim 50 or 51, for use in treating cancer in a subject in need thereof.

85. 85. The crystalline form of claim 84, wherein the cancer is basal cell carcinoma, a solid tumor, or acute myeloid leukemia.

86. 52. Use of the crystalline form of any one of claims 1 to 23 or 30 to 43, the composition of claims 24 to 29 or 44 to 49, or the pharmaceutical composition of claim 50 or 51 for the treatment of cancer in a subject in need thereof.

87. 52. Use of the crystalline form of any one of claims 1 to 23 or 30 to 43, the composition of claims 24 to 29 or 44 to 49, or the pharmaceutical composition of claim 50 or 51 in the manufacture of a medicament for the treatment of basal cell carcinoma, solid tumors, or acute myeloid leukemia in a subject in need thereof.

88. 88. The use of claim 86 or 87, wherein the cancer is basal cell carcinoma, a solid tumor, or acute myeloid leukemia.

89. 52. A kit comprising the crystalline form of any one of claims 1 to 23 or 30 to 43, the composition of claims 24 to 29 or 44 to 49, or the pharmaceutical composition of claim 50 or 51, and instructions for using said crystalline form, composition, or pharmaceutical composition.

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