Crystalline forms of a pi3k inhibitor and uses of same

Abstract

Disclosed herein are crystalline forms of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα) inhibitors, and formulations and uses of same.

Description

[0001] Crystalline Forms of a PI3K Inhibitor and Uses of Same

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Appl. No. 63 / 532,700, filed on August 15, 2023, which is hereby incorporated by reference in its entirety including any drawings.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named “50006-0100W01_ST26_SL.XML.” The XML file, created on August 12, 2024, is 2,961 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] FIELD

[0007] Disclosed herein are crystalline forms of phosphatidylinositol 4, 5 -bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka) inhibitors.

[0008] BACKGROUND l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea is a phosphatidylinositol 4, 5 -bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka) inhibitor disclosed in WO 2022 / 265993, which is incorporated by reference herein in its entirety. PI3Ka is encoded by the PIK3CA gene is a part of the PI3K / AKT / TOR signaling network and is altered in several human cancers. Several investigators have demonstrated the role of PI3K / AKT signaling is involved in physiological and pathophysiological functions that drive tumor progression such as metabolism, cell growth, proliferation, angiogenesis and metastasis. (See, Fruman, D.A. Cell 2017, 170, 605-635 and Janku, F. et al., Nat. Rev. Clin. Oncol.2018, 15, 273-291.) Suppression (e.g., pharmacological or genetic) of PI3K / AKT / TOR signaling may cause cancer cell death and regression of tumor growth.

[0009] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A given compound may give rise to a variety of polymorphs having distinct crystal structures and physical properties such as melting point, thermal behaviors, X-ray diffraction pattern, IR spectrum, and solid state13C NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0010] Different salts and crystalline forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and crystalline forms and solvates may provide a basis for improving formulation and / or clinical properties. Different salts and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms.

[0011] SUMMARY

[0012] Some embodiments provide a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0013] Some embodiments provide a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0014] Some embodiments provide a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline form disclosed herein, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0015] Some embodiments provide a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of the crystalline form disclosed herein, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0016] Some embodiments provide a method of treating a PI3Ka-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Ka- associated cancer a therapeutically effective amount of the crystalline form disclosed herein, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0017] Some embodiments provide a method for modulating PI3Ka in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of the crystalline form disclosed herein, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0018] Additional Definitions

[0019] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0020] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0021] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0022] The term "inhibit” or “inhibition of’ means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).

[0023] The terms “polymorph” and “polymorphic form” are used interchangeably and refer to different crystalline forms of a single compound. That is, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct solid state physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct solid state physical properties, such as different solubility profiles, dissolution rates, melting point temperatures, flowability, and / or different X-ray diffraction peaks.

[0024] The term “amorphous” means a solid in a non-crystalline state. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state forms can be determined by polarized light microscopy, X-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other standard techniques known to those of skill in the art.

[0025] As used herein, a compound is “substantially pure” if the compound contains an insignificant amount of other components. Such components can include, for example, starting materials, residual solvents, other polymorphic or crystalline forms, the opposite enantiomer, other salt forms, other solvates, or any other impurities that can result from the preparation, isolation, and / or recrystallization of the compounds provided herein. In some embodiments, the other components can include, for example, starting materials, residual solvents, other polymorphic or crystalline forms, the opposite enantiomer, other salt forms, or any other impurities that can result from the preparation, isolation, and / or recrystallization of the compounds provided herein. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is “substantially pure” if the crystalline form consists of at least about 95% by weight of the crystalline form. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea is “substantially pure” if the crystalline form constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the crystalline form.

[0026] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Ka protein- associated disease or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0027] The term “pharmaceutical composition” as used herein is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed , Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe et al. , Eds. ; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.,- Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.,- Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0028] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salts not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0029] The term “pharmaceutically acceptable solvate” refers to a solvate of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. A solvate is a crystalline solid that contains molecules of solvent inside its crystal lattice. Solvate forms of a compound can, in some instances, favorably alter the properties of the compound, such as solubility, stability, dissolution rate, and mechanical behavior. An exemplary solvate is a hydrate, which is a water solvate. When the average number of water molecules present in each repeating unit (i.e., unit cell) of the crystal lattice of a hydrate is known, the hydrate is affixed with a prefix denoting the average number of water molecules in each unit cell. For example, a monohydrate contains an average of one water molecule per unit cell, a dihydrate contains an average of two water molecules per unit cell, and a hemihydrate contains an average of half of a water molecule per unit cell. For more information, see, e.g., K.R. Morris, Polymorphism hi Pharmaceutical Solids 1999, pages 125-181; Jeffrey, G.A. Acc. Chem. Res. 1969, 344-352; Rev. Pure Appl. Chem., 1963, 50-90; Encyclopedia of Pharmaceutical Technology, 1993, 7, pages 393-441, each of which is incorporated herein in its entirety.

[0030] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “pharmaceutically acceptable excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0031] As used herein, the term “subject” refers to any animal, including mammals such as primates (e g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0032] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

[0033] DESCRIPTION OF DRAWINGS

[0034] FIG. 1 Depicts Polarized Light Microscopy (PLM) images of Compound A solids prior to crystallization experiments.

[0035] FIG. 2. Depicts the XRPD diffractogram of Compound A solids prior to crystallization experiments, assigned as Form 1*.

[0036] FIG. 3. Depicts the Thermogravimetric Analysis / Differential Scanning Calorimetry (TGA / DSC) thermogram of Compound A solids prior to crystallization experiments, assigned as Form 1*.

[0037] FIG. 4 Depicts the XRPD diffractogram of Compound A, hemi-hydrate Form 1 prepared by the procedure in Example 10.

[0038] FIG. 5 Depicts the XRPD diffractogram of Compound A, Form 1*.

[0039] FIG. 6 Depicts the XRPD diffractogram of Compound A, Form 2.

[0040] FIG. 7 Depicts the XRPD diffractogram of Compound A, Form 3.

[0041] FIG. 8 Depicts the XRPD diffractogram of Compound A, Form 4.

[0042] FIG. 9 Depicts Polarized Light Microscopy (PLM) images of Form 1 obtained from the crystallization process of Example 9, after drying and equilibration under ambient conditions (see Example 12).

[0043] FIG. 10 Depicts the Infrared (IR) spectrum of Form 1 obtained from the crystallization process of Example 9, after drying and equilibration under ambient conditions (see Example 12). FIG. 11 Depicts the1H-NMR spectrum of Form 1 obtained from the crystallization process of Example 9, after drying and equilibration under ambient conditions (see Example 12).

[0044] FIG. 12 Depicts the19F-NMR spectrum of Form 1 obtained from the crystallization process of Example 9, after drying and equilibration under ambient conditions (see Example 12).

[0045] FIG.13 Depicts XRPD diffractograms of Compound A mesylate salt formed in Example 2, Procedure A: (A) subsample of mesylate salt taken during crystallization, (B) wet mesylate salt, (C) mesylate salt after drying, (D) wet mesylate salt reference, and (E) dry mesylate salt reference.

[0046] FIG.14 Depicts TG / DSC thermogram of Compound A mesylate salt formed in Example 2, Procedure A.

[0047] FIG. 15 Depicts XRPD diffractograms of Compound A mesylate salt suspended in different pH buffers for 1 h in disproportion studies (Example 2, Procedure B).

[0048] FIG. 16 Depicts the XRPD diffractogram of amorphous (lyophilized) Compound A used as input for the primary polymorph screen (Example 5) and other crystallization experiments along with the XRPD of Form 1* as a reference.

[0049] FIG. 17 Depicts the XRPD diffractograms of Compound A crystalline forms obtained in the primary polymorph screen (Example 5): 1-Butanol (Form 1*), 1 -Propanol: water 50:50 (Form 1), and 2-Propanol: water 80:20 (Form 1).

[0050] FIG. 18 Depicts the XRPD diffractograms of Compound A crystalline forms obtained in the primary polymorph screen (Example 5): isopropyl acetate: heptane 70:30 (Form 3), isopropyl acetate:heptane:acetonitrile:water 68:30: 1 : 1 (Form 3), methanol :water 80:20 (Form 1); methyl isopropyl ketone (Form 3), and tetrahydrofuran THF (Form 3).

[0051] FIG. 19 Depicts the XRPD diffractograms of Compound A Form 1 obtained from MeOH / water in the preliminary crystallization experiments (Example 8) before and after grinding along with the XRPD of a known impurity (Impurity 1) in Compound A.

[0052] FIG. 20 Depicts the XRPD diffractograms of Compound A Form 1 obtained from EtOH / water in the preliminary crystallization experiments (Example 8) before and after grinding along with the XRPD of a known impurity (Impurity 1) in Compound A.

[0053] FIG. 21 Depicts the XRPD diffractograms of Compound A wet Form 1 (prior to drying) obtained during the crystallization process optimization in Example 9, Protocol A before and after grinding along with the XRPD of a known impurity (Impurity 1) in Compound A. FIG. 22 Depicts the XRPD diffractograms of Compound A Form 1 obtained during the crystallization process optimization in Example 9, Protocol B before and after grinding along with the XRPD of a known impurity (Impurity 1) in Compound A.

[0054] FIG. 23 Depicts the XRPD diffractograms of Compound A Form 1 wet and dried solid obtained during the crystallization process optimization in Example 9, Protocol C before and after grinding along with the XRPD of a known impurity (Impurity 1) in Compound A.

[0055] FIG. 24 Depicts the XRPD diffractograms of Compound A wet Form 1 (prior to drying) obtained during the crystallization process optimization in Example 9, Protocol D before and after grinding along with the XRPD of a known impurity (Impurity 1) in Compound A.

[0056] FIG. 25 Depicts the XRPD diffractograms of Compound A solids in competitive slurry experiments (Example 11): Top frames show Form 1* and Form 1 references; (A) 2- propanol: water 20:80 4 days at 50°C shows Form 1 and trace of Forml*; (B) 2-propanol: water 20:80 10 days at 50°C shows Form 1 only.

[0057] FIG. 26 Depicts the XRPD diffractograms of Compound A solids in competitive slurry experiments (Example 11): Top frames show Form 1 * and Form 1 references; (A) Solids obtained from 2-propanol: water 20:80 after 4 days at 20°C shows Form 1 and trace of Forml*, (B) solids obtained from 2-propanol :water 20:80 10 days at 20°C shows Form 1 with trace of Form 1*.

[0058] FIG. 27 Depicts the XRPD diffractograms of Compound A solids in the stability study (Example 12): Top frames show Form 1 reference and over-dried solid (Form 4); bottom two frames show that Compound A over-dried solid (Form 4) reverts back to Form 1 when exposed to ambient conditions and 60% relative humidity.

[0059] FIG. 28 Depicts the TG / DSC thermogram of solids (confirmed to be Form 1 by XRPD, see FIG 27) obtained after equilibration protocols (Example 12).

[0060] FIG. 29 Depicts the DSC thermogram (first heat cycle) of solids (confirmed to be Form 1 by XRPD, see FIG 27) obtained after equilibration protocols (Example 12).

[0061] FIG. 30 Depicts the DSC thermogram (first cool cycle) of solids (confirmed to be Form 1 by XRPD, see FIG 27) obtained after equilibration protocols (Example 12).

[0062] FIG. 31 Depicts the DSC thermogram (second heat cycle) of solids (confirmed to be Form 1 by XRPD, see FIG 27) obtained after equilibration protocols (Example 12). FIG. 32 Depicts the dynamic vapor sorption (DVS) plots of solids (confirmed to be Form 1 by XRPD, see FIG 27) obtained after equilibration protocols (Example 12); (A) kinetic plot; (B) isotherm plot.

[0063] FIG. 33 Depicts the XRPD diffractograms of solids (confirmed to be Form 1 by XRPD, see FIG 27) obtained after equilibration protocols (Example 12) after milling from 90 to 540 seconds.

[0064] FIG. 34 Depicts the TG / DSC thermogram of solids (confirmed to be Form 3 by XRPD) obtained from polymorph screen (Example 5, Procedure A) from isopropyl acetate:heptane:acetonitrile:water 68:30: 1 : 1 % v / v / v / v.

[0065] DETAILED DESCRIPTION

[0066] Described herein is l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea

[0067] Described herein is (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (also referred to as “Compound A”). Described herein is (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0068] Described herein are crystalline forms of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0069] In some embodiments, the crystalline forms of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea are crystalline forms of racemic, non- racemic (i.e., scalemic), (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran- 2-yl)-2,2,2-trifluoroethyl)urea, or (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the crystalline forms of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea are crystalline forms of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the crystalline forms of l-(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea are crystalline forms of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.

[0070] In some embodiments, the crystalline forms of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea are crystalline forms of racemic l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the crystalline forms of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea are crystalline forms of scalemic l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0071] Also provided herein is amorphous (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the amorphous (R)-l- (2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is characterized by the XRPD pattern that is substantially the same as that shown in FIG. 16. These crystalline forms are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) PI3Ka activation contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.

[0072] Some embodiments provide a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (also referred to herein as “Compound A”), or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea is present in the form of a pharmaceutically acceptable solvate. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea is present in the form of a hydrate. In some embodiments, the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a hemihydrate.

[0073] Some embodiments provide a crystalline form of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a pharmaceutically acceptable solvate. In some embodiments, the (S)-l -(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a hydrate. In some embodiments, the (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a hemi-hydrate.

[0074] Some embodiments provide a crystalline form of racemic l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the racemic l-(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a pharmaceutically acceptable solvate. In some embodiments, the racemic l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a hydrate. In some embodiments, the racemic l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a hemi-hydrate.

[0075] Some embodiments provide a crystalline form of non-racemic l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the non-racemic l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a pharmaceutically acceptable solvate. In some embodiments, the non- racemic l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea is present in the form of a hydrate. In some embodiments, the non-racemic 1- (2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a hemi-hydrate.

[0076] The skilled artisan will recognize that the relative intensities of X-ray powder diffraction pattern peaks can vary depending on the sample preparation technique, crystal size distribution, various fdters used, sample mounting procedure, and the particular instrument employed. Accordingly, depending on the type of the instrument and settings employed (including filters), new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have a negligible relative intensities (and hence may not be observed) in subsequently obtained patterns. As such, the absence of one or more of the lower relative intensity peaks described above may not, in and of itself, establish that a particular polymorphic form (e.g., Form 1, Form 1 *, Form 2, Form 3, or Form 4) is not present (e g., in a sample). However, the presence of the lower relative intensity peaks described above can, in general, be used to further establish the presence of a particular polymorphic form (e.g., Form 1, Form 1*, Form 2, Form 3, or Form 4) in a sample.

[0077] Form 1

[0078] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 18.3 ± 0.2 degrees 20. For ease of exposition, the aforementioned form is referred to herein as “Form 1.” The X-ray powder diffraction pattern of Form 1 can also include one or more additional characteristic peaks.

[0079] In some embodiments, the XRPD pattern of Form 1 has a peak at 6.4 ± 0.2 degrees 20. In some embodiments, the peak at 6.4 ± 0.2 degrees 20 has the highest relative intensity. In some embodiments, the XRPD pattern of Form 1 has a peak at 15.8 ± 0.2 degrees 20.

[0080] In some embodiments, the peak at 15.8 ± 0.2 degrees 20 has the second relative intensity.

[0081] In some embodiments, the XRPD pattern of Form 1 has a peak at 18.3 ± 0.2 degrees 20.

[0082] In some embodiments, the peak at 18.3 ± 0.2 degrees 20 has the third highest relative intensity.

[0083] In some embodiments, the XRPD pattern of Form 1 has a peak at 22.3 ± 0.2 degrees 20. In some embodiments, the peak at 22.3 ± 0.2 degrees 20 has the fourth highest relative intensity.

[0084] In some embodiments, the XRPD pattern of Form 1 has a peak at 20.8 ± 0.2 degrees 20. In some embodiments, the peak at 20.8 ± 0.2 degrees 20 has the fifth highest relative intensity.

[0085] In some embodiments, the XRPD pattern of Form 1 has a peak at 19.3 ± 0.2 degrees 20. In some embodiments, the peak at 19.3 ± 0.2 degrees 20 has the sixth highest relative intensity.

[0086] In some embodiments, the XRPD pattern of Form 1 has a peak at 24.0 ± 0.2 degrees 20. In some embodiments, the peak at 24.0 ± 0.2 degrees 20 has the seventh highest relative intensity.

[0087] In some embodiments, the XRPD pattern of Form 1 has a peak at 26.9 ± 0.2 degrees 20. In some embodiments, the peak at 26.9 ± 0.2 degrees 20 has the eighth highest relative intensity.

[0088] In some embodiments, the XRPD pattern of Form 1 has a peak at 14.6 ± 0.2 degrees 20. In some embodiments, the peak at 14.6 ± 0.2 degrees 20 has the ninth highest relative intensity.

[0089] In some embodiments, the XRPD pattern of Form 1 has a peak at 31.3 ± 0.2 degrees 20. In some embodiments, the peak at 31.3 ± 0.2 degrees 20 has the tenth highest relative intensity.

[0090] In some embodiments, the XRPD pattern of Form 1 has a peak at 28.3 ± 0.2 degrees 20. In some embodiments, the peak at 28.3 ± 0.2 degrees 20 has the eleventh highest relative intensity.

[0091] In some embodiments, the XRPD pattern of Form 1 has a peak at 29.2 ± 0.2 degrees 20. In some embodiments, the peak at 29.2 ± 0.2 degrees 20 has the twelfth highest relative intensity.

[0092] In some embodiments, the XRPD pattern of Form 1 has a peak at 22.8 ± 0.2 degrees 20. In some embodiments, the peak at 22.8 ± 0.2 degrees 20 has the thirteenth highest relative intensity.

[0093] In some embodiments, the XRPD pattern of Form 1 has a peak at 28.0 ± 0.2 degrees 20. In some embodiments, the peak at 28.0 ± 0.2 degrees 20 has the fourteenth highest relative intensity.

[0094] In some embodiments, the XRPD pattern of Form 1 has a peak at 25.3 ± 0.2 degrees 20. In some embodiments, the peak at 25.3 ± 0.2 degrees 20 has the fifteenth highest relative intensity.

[0095] In some embodiments, the XRPD pattern of Form 1 has a peak at 21.5 ± 0.2 degrees 20. In some embodiments, the peak at 21.5 ± 0.2 degrees 20 has the sixteenth highest relative intensity. In some embodiments, the XRPD pattern of Form 1 has a peak at 19.9 ± 0.2 degrees 20. In some embodiments, the peak at 19.9 ± 0.2 degrees 20 has the seventeenth highest relative intensity.

[0096] In some embodiments, the XRPD pattern of Form 1 has a peak at 27.6 ± 0.2 degrees 20. In some embodiments, the peak at 27.6 ± 0.2 degrees 20 has the eighteenth highest relative intensity.

[0097] In some embodiments, the XRPD pattern of Form 1 has a peak at 20.5 ± 0.2 degrees 20. In some embodiments, the peak at 20.5 ± 0.2 degrees 20 has the nineteenth highest relative intensity.

[0098] In some embodiments, the XRPD pattern of Form 1 has a peak at 21.8 ± 0.2 degrees 20. In some embodiments, the peak at 21.8 ± 0.2 degrees 20 has the twentieth highest relative intensity.

[0099] In some embodiments, the XRPD pattern of Form 1 has a peak at 25.1 ± 0.2 degrees 20. In some embodiments, the peak at 25.1 ± 0.2 degrees 20 has the twenty -first highest relative intensity.

[0100] In some embodiments, the XRPD pattern of Form 1 has a peak at 25.8 ± 0.2 degrees 20. In some embodiments, the peak at 25.8 ± 0.2 degrees 20 has the twenty-second highest relative intensity.

[0101] In some embodiments, the crystalline form is Form 1, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.4, 15.8, and 18.3.

[0102] In some embodiments, the crystalline form is Form I, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.4, 14.6, 15.8, 18.3, 19.3, 20.8, 22.3, 24.0, 26.9, 28.3, 29.2 and 31.3.

[0103] In some embodiments, the crystalline form is Form 1, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.4, 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, 31.3, 28.3, 29.2, 22.8, 28.0, 25.3, 21.5, 19.9, 27.6, 20.5, 21.8, 25.1, and 25.8.

[0104] In some embodiments, the crystalline form is Form 1, characterized by an XRPD pattern substantially the same as that shown in FIG. 4.

[0105] In some embodiments, the crystalline form is Form 1 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 5% (e.g., about 1% to about 3%, about 2% to about 3%, or about 2.3%) at about 70 °C to about 140 °C (e.g., about 90 °C to about 130 °C, about 90 °C to about 120 °C, about 90 °C to about 115 °C, about 100 °C to about 140 °C, about 110 °C to about 140 °C, about 100 °C to about 120 °C, about 105 °C to about 120 °C, about 109 °C to about 115 °C, about 75 °C to about 125 °C, about 85 °C to about 113 °C, about 85 °C to about 105 °C, or about 112 °C. In some embodiments, the crystalline form is Form 1 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 112.5 °C. In some embodiments, the crystalline form is Form 1 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 85 °C to about 1 13 o

[0106] In some embodiments, the crystalline form is Form 1 having a TGA curve characterized by a weight loss of about 5% to about 30% (e.g., about 5% to about 27%, about 5% to about 25%, about 5% to about 22%, about 10% to about 25%, about 20% to about 22%, about 14% to about 20%, or about 17.6%) at about 150 °C to about 250 °C (e.g., about 230 to about 260 °C about 230 °C to about 250 °C, about 162 °C to about 248 °C, about 230 °C to about 240 °C, about 240 °C to about 260 °C, about 240 °C to about 250 °C, about 242 °C to about 248 °C, or about 245 °C). In some embodiments, the crystalline form is Form 1 having a TGA curve characterized by a weight loss of about 17.6% at about 245 °C. In some embodiments, the crystalline form is Form 1 having a TGA curve characterized by a weight loss of about 17.6% at about 162 °C to about 248 °C.

[0107] In some embodiments, the crystalline form is Form 1 having a TGA curve that is substantially the same as that shown in FIG. 28. In some embodiments, the crystalline form is Form 1 having a Thermal Gravimetric / Differential Scanning Calorimetry (TG / DSC) thermogram that is substantially the same as that shown in FIG. 28.

[0108] In some embodiments, the crystalline form is Form 1 having a differential scanning calorimetry (DSC) first heat cycle thermogram having an endothermic event having an onset temperature of about 105 °C and a peak of about 129 °C, an endothermic event having an onset temperature of about 158 °C and a peak of about 162 °C and an endothermic event having an onset temperature of about 174 °C and a peak of about 177 °C.

[0109] In some embodiments, the crystalline form is Form 1 having a Differential Scanning Calorimetry (DSC) thermogram that is substantially the same as that shown in FIG. 29.

[0110] In some embodiments, the crystalline form is Form 1 having a DSC curve that is substantially the same as that shown in FIG. 29.

[0111] In some embodiments, the crystalline form is Form 1 having a DSC first cooling cycle thermogram characterized by a single exothermic event at with an onset temperature of 151 °C and a peak temperature of 147 °C.

[0112] In some embodiments, the crystalline form is Form 1 having a DSC first cooling cycle thermogram substantially the same as that shown in FIG. 30.

[0113] In some embodiments, the Form l is a hemi-hydrate. In some embodiments, the enantiomeric excess (ee) of crystalline Form 1 is at least 90% (e g., at least 92%, at least 94%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%.

[0114] In some embodiments, the Form 1 is substantially pure.

[0115] Form 1*

[0116] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.3 ± 0.2 degrees 20. For ease of exposition, the aforementioned form is referred to herein as “Form 1*.” The X-ray powder diffraction pattern of Form 1* can also include one or more additional characteristic peaks.

[0117] In some embodiments, the XRPD pattern of Form 1* has a peak at 6.3 ± 0.2 degrees 20. In some embodiments, the peak at 6.3 ± 0.2 degrees 29 has the highest relative intensity.

[0118] In some embodiments, the XRPD pattern of Form 1* has a peak at 15.8 ± 0.2 degrees 20. In some embodiments, the peak at 15.8 ± 0.2 degrees 20 has the second highest relative intensity.

[0119] In some embodiments, the XRPD pattern of Form 1* has a peak at 20.8 ± 0.2 degrees 20. In some embodiments, the peak at 20.8 ± 0.2 degrees 20 has the third highest relative intensity.

[0120] In some embodiments, the XRPD pattern of Form 1* has a peak at 15.9 ± 0.2 degrees 20. In some embodiments, the peak at 15.9 ± 0.2 degrees 20 has the fourth highest relative intensity.

[0121] In some embodiments, the XRPD pattern of Form 1* has a peak at 19.8 ± 0.2 degrees 20. In some embodiments, the peak at 19.8 ± 0.2 degrees 20 has the fifth highest relative intensity.

[0122] In some embodiments, the XRPD pattern of Form 1* has a peak at 19.3 ± 0.2 degrees 20. In some embodiments, the peak at 19.3 ± 0.2 degrees 20 has the sixth highest relative intensity.

[0123] In some embodiments, the XRPD pattern of Form 1* has a peak at 28.0 ± 0.2 degrees 20. In some embodiments, the peak at 28.0 ± 0.2 degrees 20 has the seventh highest relative intensity.

[0124] In some embodiments, the XRPD pattern of Form 1* has a peak at 27.6 ± 0.2 degrees 20. In some embodiments, the peak at 27.6 ± 0.2 degrees 20 has the eighth highest relative intensity.

[0125] In some embodiments, the XRPD pattern of Form 1* has a peak at 24.0 ± 0.2 degrees 20. In some embodiments, the peak at 24.0 ± 0.2 degrees 20 has the ninth highest relative intensity.

[0126] In some embodiments, the XRPD pattern of Form 1* has a peak at 22.1 ± 0.2 degrees 20. In some embodiments, the peak at 22.1 ± 0.2 degrees 20 has the tenth highest relative intensity.

[0127] In some embodiments, the XRPD pattern of Form 1* has a peak at 29.2 ± 0.2 degrees 20. In some embodiments, the peak at 29.2 ± 0.2 degrees 20 has the eleventh highest relative intensity. In some embodiments, the XRPD pattern of Form 1 * has a peak at 26.4 ± 0.2 degrees 20. In some embodiments, the peak at 26.4 ± 0.2 degrees 20 has the twelfth highest relative intensity.

[0128] In some embodiments, the XRPD pattern of Form 1* has a peak at 21.6 ± 0.2 degrees 20. In some embodiments, the peak at 21.6 ± 0.2 degrees 20 has the thirteenth highest relative intensity.

[0129] In some embodiments, the XRPD pattern of Form 1* has a peak at 14.4 ± 0.2 degrees 20. In some embodiments, the peak at 14.4 ± 0.2 degrees 20 has the fourteenth highest relative intensity.

[0130] In some embodiments, the XRPD pattern of Form 1* has a peak at 14.5 ± 0.2 degrees 20. In some embodiments, the peak at 14.5 ± 0.2 degrees 20 has the fifteenth highest relative intensity.

[0131] In some embodiments, the XRPD pattern of Form 1* has a peak at 26.1 ± 0.2 degrees 20. In some embodiments, the peak at 26.1 ± 0.2 degrees 20 has the sixteenth highest relative intensity.

[0132] In some embodiments, the XRPD pattern of Form 1* has a peak at 28.6 ± 0.2 degrees 20. In some embodiments, the peak at 28.6 ± 0.2 degrees 20 has the seventeenth highest relative intensity.

[0133] In some embodiments, the XRPD pattern of Form 1* has a peak at 20.3 ± 0.2 degrees 20. In some embodiments, the peak at 20.3 ± 0.2 degrees 20 has the eighteenth highest relative intensity.

[0134] In some embodiments, the XRPD pattern of Form 1* has a peak at 31.2 ± 0.2 degrees 20. In some embodiments, the peak at 31.2 ± 0.2 degrees 20 has the nineteenth highest relative intensity.

[0135] In some embodiments, the XRPD pattern of Form 1* has a peak at 26.8 ± 0.2 degrees 20. In some embodiments, the peak at 26.8 ± 0.2 degrees 20 has the twentieth highest relative intensity.

[0136] In some embodiments, the XRPD pattern of Form 1* has a peak at 18.9 ± 0.2 degrees 20. In some embodiments, the peak at 18.9 ± 0.2 degrees 20 has the twenty -first highest relative intensity.

[0137] In some embodiments, the XRPD pattern of Form 1* has a peak at 31.5 ± 0.2 degrees 20. In some embodiments, the peak at 31.5 ± 0.2 degrees 20 has the twenty-second highest relative intensity.

[0138] In some embodiments, the crystalline form is Form 1*, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.3, 15.8, and 20.8. In some embodiments, the crystalline form is Form 1 *, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.3, 15.8, 20.8, 15.9, 19.8, 19.3, 28.0, 27.6, 24.0, and 22.1.

[0139] In some embodiments, the crystalline form is Form 1*, and wherein the XRPD pattern has peaks (± 0.2 degrees 29) at 6.3, 15.8, 20.8, 15.9, 19.8, 19.3, 28.0, 27.6, 24.0, 22.1, 29.2, 26.4, 21.6, 14.4, 14.5, 26.1, 28.6, 20.3, 31.2, 26.8, 18.9, and 31.5.

[0140] In some embodiments, the crystalline form is Form 1*, characterized by an XRPD pattern substantially the same as that shown in FIG. 2.

[0141] In some embodiments, the crystalline form is Form 1* having a TG / DSC thermogram characterized by multiple weight loss events prior to degradation, with an about 2.5 % weight loss between about 72 °C and about 114 °C (theoretically equivalent to 0.5 moles of water), an about 2.2 % weight loss between about 147 °C and about 185 °C (theoretically equivalent to 0.5 moles of water) and an about 12.2 % weight loss between about 185 °C and about 252 °C.

[0142] In some embodiments, the crystalline form is Form 1 * having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 5% (e.g., about 1% to about 3%, about 2% to about 3%, or about 2.5%) at about 60 °C to about 140 °C (e.g., about 65 °C to about 125 °C, at about 70 °C to about 120 °C, or about 72 °C to about 114 °C. In some embodiments, the crystalline form is Form 1* having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.5% at about 72 °C and 114 °C.

[0143] In some embodiments, the crystalline form is Form 1 * having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 5% (e.g., about 1% to about 23%, about 10% to about 15%, about 12% to about 13%, or about 12.2%) at about 165 °C to about 275 °C (e.g., about 175 °C to about 265 °C, at about 180 °C to about 260 °C, or about 185 °C to about 252 °C). In some embodiments, the crystalline form is Form 1 * having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 12.2% at about 185 °C to about 252 °C.

[0144] In some embodiments, the crystalline form is Form 1* having a TGA curve that is substantially the same as that shown in FIG. 3. In some embodiments, the crystalline form is Form 1* having a Thermal Gravimetric / Differential Scanning Calorimetry (TG / DSC) thermogram that is substantially the same as that shown in FIG. 3.

[0145] In some embodiments, the crystalline form is Form 1* having a TG / DSC thermogram characterized by an endothermic event having an onset temperature of about 86 °C and a peak at about 102 °C, an endothermic event having an onset temperature of about 154 °C and a peak at about 158 °C, and an endothermic event having an onset temperature of about 172 °C and a peak at about 176 °C. In some embodiments, the TG / DSC thermogram curve is characterized by an endothermic event having an onset temperature of about 294 °C (peak at about 301 °C) that is, in some embodiments, associated with degradation.

[0146] In some embodiments, the crystalline form is Form 1* having a Differential Scanning Calorimetry (DSC) thermogram that is substantially the same as that shown in FIG. 3.

[0147] In some embodiments, the Form 1* is a hemi-hydrate.

[0148] In some embodiments, the enantiomeric excess (ee) of Form 1* is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%.

[0149] In some embodiments, the Form 1* is substantially pure.

[0150] Form 2

[0151] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.2 ± 0.2 degrees 20. For ease of exposition, the aforementioned form is referred to herein as “Form 2.” The X-ray powder diffraction pattern of Form 2 can also include one or more additional characteristic peaks.

[0152] In some embodiments, the XRPD pattern of Form 2 has a peak at 6.2 ± 0.2 degrees 20. In some embodiments, the peak at 6.2 ± 0.2 degrees 20 has the highest relative intensity.

[0153] In some embodiments, the XRPD pattern of Form 2 has a peak at 15.2 ± 0.2 degrees 20. In some embodiments, the peak at 15.2 ± 0.2 degrees 20 has the second highest relative intensity.

[0154] In some embodiments, the XRPD pattern of Form 2 has a peak at 15.3 ± 0.2 degrees 20. In some embodiments, the peak at 15.3 ± 0.2 degrees 20 has the third highest relative intensity.

[0155] In some embodiments, the XRPD pattern of Form 2 has a peak at 20.9 ± 0.2 degrees 20. In some embodiments, the peak at 20.9 ± 0.2 degrees 20 has the fourth highest relative intensity.

[0156] In some embodiments, the XRPD pattern of Form 2 has a peak at 21.9 ± 0.2 degrees 20. In some embodiments, the peak at 21.9 ± 0.2 degrees 20 has the fifth highest relative intensity.

[0157] In some embodiments, the XRPD pattern of Form 2 has a peak at 22.0 ± 0.2 degrees 20. In some embodiments, the peak at 22.0 ± 0.2 degrees 20 has the sixth highest relative intensity.

[0158] In some embodiments, the XRPD pattern of Form 2 has a peak at 21.0 ± 0.2 degrees 20. In some embodiments, the peak at 21.0 ± 0.2 degrees 20 has the seventh highest relative intensity. In some embodiments, the XRPD pattern of Form 2 has a peak at 18.7 ± 0.2 degrees 20. In some embodiments, the peak at 18.7 ± 0.2 degrees 20 has the eighth highest relative intensity.

[0159] In some embodiments, the XRPD pattern of Form 2 has a peak at 18.7 ± 0.2 degrees 20. In some embodiments, the peak at 18.7 ± 0.2 degrees 20 has the ninth highest relative intensity.

[0160] In some embodiments, the XRPD pattern of Form 2 has a peak at 26.9 ± 0.2 degrees 20. In some embodiments, the peak at 26.9 ± 0.2 degrees 20 has the tenth highest relative intensity.

[0161] In some embodiments, the XRPD pattern of Form 2 has a peak at 24.0 ± 0.2 degrees 20. In some embodiments, the peak at 24.0 ± 0.2 degrees 20 has the eleventh highest relative intensity.

[0162] In some embodiments, the XRPD pattern of Form 2 has a peak at 21.1 ± 0.2 degrees 20. In some embodiments, the peak at 21.1 ± 0.2 degrees 20 has the twelfth highest relative intensity.

[0163] In some embodiments, the XRPD pattern of Form 2 has a peak at 27.4 ± 0.2 degrees 20. In some embodiments, the peak at 27.4 ± 0.2 degrees 20 has the thirteenth highest relative intensity.

[0164] In some embodiments, the XRPD pattern of Form 2 has a peak at 28.0 ± 0.2 degrees 20. In some embodiments, the peak at 28.0 ± 0.2 degrees 20 has the fourteenth highest relative intensity.

[0165] In some embodiments, the XRPD pattern of Form 2 has a peak at 14.7 ± 0.2 degrees 20. In some embodiments, the peak at 14.7 ± 0.2 degrees 20 has the fifteenth highest relative intensity.

[0166] In some embodiments, the XRPD pattern of Form 2 has a peak at 20.6 ± 0.2 degrees 20. In some embodiments, the peak at 20.6 ± 0.2 degrees 20 has the sixteenth highest relative intensity.

[0167] In some embodiments, the XRPD pattern of Form 2 has a peak at 19.9 ± 0.2 degrees 20. In some embodiments, the peak at 19.9 ± 0.2 degrees 20 has the seventeenth highest relative intensity.

[0168] In some embodiments, the XRPD pattern of Form 2 has a peak at 19.4 ± 0.2 degrees 20. In some embodiments, the peak at 19.4 ± 0.2 degrees 20 has the eighteenth highest relative intensity.

[0169] In some embodiments, the XRPD pattern of Form 2 has a peak at 21.5 ± 0.2 degrees 20. In some embodiments, the peak at 21.5 ± 0.2 degrees 20 has the nineteenth highest relative intensity.

[0170] In some embodiments, the XRPD pattern of Form 2 has a peak at 17.7 ± 0.2 degrees 20. In some embodiments, the peak at 17.7 ± 0.2 degrees 20 has the twentieth highest relative intensity. In some embodiments, the XRPD pattern of Form 2 has a peak at 26.0 ± 0.2 degrees 20. In some embodiments, the peak at 26.0 ± 0.2 degrees 29 has the twenty-first highest relative intensity.

[0171] In some embodiments, the XRPD pattern of Form 2 has a peak at 28.3 ± 0.2 degrees 20. In some embodiments, the peak at 28.3 ± 0.2 degrees 20 has the twenty-second highest relative intensity.

[0172] In some embodiments, the crystalline form is Form 2, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.2, 15.2, and 15.3.

[0173] In some embodiments, the crystalline form is Form 2, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.2, 15.2, 15.3, 20.9, 21.9, 22.0, 21.0, 18.7, 18.7, and 26.9.

[0174] In some embodiments, the crystalline form is Form 2, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.2, 15.2, 15.3, 20.9, 21.9, 22.0, 21.0, 18.7, 18.7, 26.9, 24.0, 21.1, 27.4, 28.0, 14.7, 20.6, 19.9, 19.4, 21.5, 17.7, 26.0, and 28.3.

[0175] In some embodiments, the crystalline form is Form 2, characterized by an XRPD pattern substantially the same as that shown in FIG. 6.

[0176] In some embodiments, Form 2 is a hemi-hydrate.

[0177] In some embodiments, the enantiomeric excess (ee) of Form 2 is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%.

[0178] In some embodiments, Form 2 is substantially pure.

[0179] Form 3

[0180] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 4.0 ± 0.2 degrees 20. For ease of exposition, the aforementioned form is referred to herein as “Form 3.” The X-ray powder diffraction pattern of Form 3 can also include one or more additional characteristic peaks.

[0181] In some embodiments, the XRPD pattern of Form 3 has a peak at 4.0 ± 0.2 degrees 20. In some embodiments, the peak at 4.0 ± 0.2 degrees 29 has the highest relative intensity.

[0182] In some embodiments, the XRPD pattern of Form 3 has a peak at 4.9 ± 0.2 degrees 20. In some embodiments, the peak at 4.9 ± 0.2 degrees 20 has the second highest relative intensity.

[0183] In some embodiments, the XRPD pattern of Form 3 has a peak at 25.8 ± 0.2 degrees 20. In some embodiments, the peak at 25.8 ± 0.2 degrees 20 has the third highest relative intensity. In some embodiments, the XRPD pattern of Form 3 has a peak at 21 .4 ± 0.2 degrees 20. In some embodiments, the peak at 21.4 ± 0.2 degrees 20 has the fourth highest relative intensity.

[0184] In some embodiments, the XRPD pattern of Form 3 has a peak at 9. 1 ± 0.2 degrees 20. In some embodiments, the peak at 9.1 ± 0.2 degrees 20 has the fifth highest relative intensity.

[0185] In some embodiments, the XRPD pattern of Form 3 has a peak at 19.2 ± 0.2 degrees 20. In some embodiments, the peak at 19.2 ± 0.2 degrees 20 has the sixth highest relative intensity.

[0186] In some embodiments, the XRPD pattern of Form 3 has a peak at 6.9 ± 0.2 degrees 20. In some embodiments, the peak at 6.9 ± 0.2 degrees 20 has the seventh highest relative intensity.

[0187] In some embodiments, the XRPD pattern of Form 3 has a peak at 15.7 ± 0.2 degrees 20. In some embodiments, the peak at 15.7 ± 0.2 degrees 20 has the eighth highest relative intensity.

[0188] In some embodiments, the XRPD pattern of Form 3 has a peak at 16.8 ± 0.2 degrees 20. In some embodiments, the peak at 16.8 ± 0.2 degrees 20 has the ninth highest relative intensity.

[0189] In some embodiments, the XRPD pattern of Form 3 has a peak at 9.9 ± 0.2 degrees 20. In some embodiments, the peak at 9.9 ± 0.2 degrees 20 has the tenth highest relative intensity.

[0190] In some embodiments, the XRPD pattern of Form 3 has a peak at 14.3 ± 0.2 degrees 20. In some embodiments, the peak at 14.3 ± 0.2 degrees 20 has the eleventh highest relative intensity.

[0191] In some embodiments, the XRPD pattern of Form 3 has a peak at 23.9 ± 0.2 degrees 20. In some embodiments, the peak at 23.9 ± 0.2 degrees 20 has the twelfth highest relative intensity.

[0192] In some embodiments, the XRPD pattern of Form 3 has a peak at 6.2 ± 0.2 degrees 20. In some embodiments, the peak at 6.2 ± 0.2 degrees 20 has the thirteenth highest relative intensity.

[0193] In some embodiments, the XRPD pattern of Form 3 has a peak at 7.5 ± 0.2 degrees 20. In some embodiments, the peak at 7.5 ± 0.2 degrees 20 has the fourteenth highest relative intensity.

[0194] In some embodiments, the XRPD pattern of Form 3 has a peak at 31.7 ± 0.2 degrees 20. In some embodiments, the peak at 31.7 ± 0.2 degrees 20 has the fifteenth highest relative intensity.

[0195] In some embodiments, the crystalline form is Form 3, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 4.0, 4.9, and 25.8.

[0196] In some embodiments, the crystalline form is Form 3, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 4.0, 4.9, 25.8, 21.4, 9.1, 19.2, 6.9, 15.7, 16.8, and 9.9.

[0197] In some embodiments, the crystalline form is Form 3, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 4.0, 4.9, 25.8, 21.4, 9.1, 19.2, 6.9, 15.7, 16.8, 9.9, 14.3, 23.9, 6.2, 7.5, and 31.7. In some embodiments, the crystalline form is Form 3, characterized by an XRPD pattern substantially the same as that shown in FIG. 7.

[0198] In some embodiments, the crystalline form is Form 3 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 5% (e.g., about 1% to about 3%, about 2% to about 3%, or about 2.4%) at about 20 °C to about 180 °C (e.g., about 20 °C to about 170 °C, about 20 °C to about 160 °C, about 20 °C to about 155 °C, about 20 °C to about 150 °C, about 20 °C to about 140 °C, about 40 °C to about 170 °C, about 50 °C to about 160 °C, about 70 °C to about 155 °C, or about 70 °C to about 155 °C. In some embodiments, the crystalline form is Form 3 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.4% at about 20 °C to about 155 °C.

[0199] In some embodiments, the crystalline form is Form 3 having a TGA curve characterized by a weight loss of about 1% to about 10% (e.g., about 2% to about 8%, about 3% to about 7%, about 4% to about 6%, about 4% to about 5%, about 2% to about 8%, about 2% to about 6%, or about 4.5%) at about 110 to about 230 (e.g., about 120 °C to about 220 °C, about 140 °C to about 210 °C, about 150 °C to about 200 °C, or about 155 °C to about 195 °C). In some embodiments, the crystalline form is Form 3 having a TGA curve characterized by a weight loss of about 4.5% at about 155 °C to about 195 °C.

[0200] In some embodiments, the crystalline form is Form 3 having a TGA curve that is substantially the same as that shown in FIG. 34.

[0201] In some embodiments, the crystalline form is Form 3 having a DSC curve characterized by an endothermic event having an onset temperature of about 162 °C and a peak at about 173 °C. In some embodiments, the crystalline form is Form 3 having a DSC curve characterized by an endothermic event having an onset temperature of about 274 °C and peak at about 283 °C. In some embodiments, the crystalline form is Form 3 having a DSC curve characterized by an endothermic event having an onset temperature of about 162 °C and peak at about 173 °C, and an endothermic event having an onset temperature of about 274 °C and peak at about 283 °C.

[0202] In some embodiments, the crystalline form is Form 3 having a TG / DSC thermogram that is substantially the same as that shown in FIG. 34.

[0203] In some embodiments, the crystalline form is Form 3 having a TGA curve that is substantially the same as that shown in FIG. 34. In some embodiments, the crystalline form is Form 3 having a DSC curve that is substantially the same as that shown in FIG. 34.

[0204] In some embodiments, the Form 3 is anhydrous.

[0205] In some embodiments, the enantiomeric excess (ee) of Form 3 is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%.

[0206] In some embodiments, the Form 3 is substantially pure.

[0207] Form 4

[0208] In some embodiments, the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.3 ± 0.2 degrees 20 (e.g., 6.3 ± 0.2 degrees 20 and 20.9 ± 0.2 degrees 20). For ease of exposition, the aforementioned form is referred to herein as “Form 4.” The X-ray powder diffraction pattern of Form 4 can also include one or more additional characteristic peaks.

[0209] In some embodiments, the XRPD pattern of Form 4 has a peak at 6.3 ± 0.2 degrees 20. In some embodiments, the peak at 6.3 ± 0.2 degrees 20 has the highest relative intensity.

[0210] In some embodiments, the XRPD pattern of Form 4 has a peak at 20.9 ± 0.2 degrees 20. In some embodiments, the peak at 20.9 ± 0.2 degrees 20 has the second highest relative intensity.

[0211] In some embodiments, the XRPD pattern of Form 4 has a peak at 15.5 ± 0.2 degrees 20. In some embodiments, the peak at 15.5 ± 0.2 degrees 20 has the third highest relative intensity.

[0212] In some embodiments, the XRPD pattern of Form 4 has a peak at 24.1 ± 0.2 degrees 20. In some embodiments, the peak at 24.1 ± 0.2 degrees 20 has the fourth highest relative intensity.

[0213] In some embodiments, the XRPD pattern of Form 4 has a peak at 21.5 ± 0.2 degrees 20. In some embodiments, the peak at 21.5 ± 0.2 degrees 20 has the fifth highest relative intensity.

[0214] In some embodiments, the XRPD pattern of Form 4 has a peak at 27.7 ± 0.2 degrees 20. In some embodiments, the peak at 27.7 ± 0.2 degrees 20 has the sixth highest relative intensity.

[0215] In some embodiments, the XRPD pattern of Form 4 has a peak at 15.8 ± 0.2 degrees 20. In some embodiments, the peak at 15.8 ± 0.2 degrees 20 has the seventh highest relative intensity.

[0216] In some embodiments, the XRPD pattern of Form 4 has a peak at 14.9 ± 0.2 degrees 20. In some embodiments, the peak at 14.9 ± 0.2 degrees 20 has the eighth highest relative intensity.

[0217] In some embodiments, the XRPD pattern of Form 4 has a peak at 20.5 ± 0.2 degrees 20. In some embodiments, the peak at 20.5 ± 0.2 degrees 20 has the ninth highest relative intensity. In some embodiments, the XRPD pattern of Form 4 has a peak at 26.9 ± 0.2 degrees 20. In some embodiments, the peak at 26.9 ± 0.2 degrees 20 has the tenth highest relative intensity.

[0218] In some embodiments, the XRPD pattern of Form 4 has a peak at 19.9 ± 0.2 degrees 20. In some embodiments, the peak at 19.9 ± 0.2 degrees 20 has the eleventh highest relative intensity.

[0219] In some embodiments, the XRPD pattern of Form 4 has a peak at 19.3 ± 0.2 degrees 20. In some embodiments, the peak at 19.3 ± 0.2 degrees 20 has the twelfth highest relative intensity.

[0220] In some embodiments, the XRPD pattern of Form 4 has a peak at 28.1 ± 0.2 degrees 20. In some embodiments, the peak at 28.1 ± 0.2 degrees 20 has the thirteenth highest relative intensity.

[0221] In some embodiments, the XRPD pattern of Form 4 has a peak at 28.4 ± 0.2 degrees 20. In some embodiments, the peak at 28.4 ± 0.2 degrees 20 has the fourteenth highest relative intensity.

[0222] In some embodiments, the XRPD pattern of Form 4 has a peak at 3.1 ± 0.2 degrees 20. In some embodiments, the peak at 3.1 ± 0.2 degrees 20 has the fifteenth highest relative intensity.

[0223] In some embodiments, the XRPD pattern of Form 4 has a peak at 27.3 ± 0.2 degrees 20. In some embodiments, the peak at 27.3 ± 0.2 degrees 20 has the sixteenth highest relative intensity.

[0224] In some embodiments, the XRPD pattern of Form 4 has a peak at 22.1 ± 0.2 degrees 20. In some embodiments, the peak at 22.1 ± 0.2 degrees 20 has the seventeenth highest relative intensity.

[0225] In some embodiments, the XRPD pattern of Form 4 has a peak at 25.0 ± 0.2 degrees 20. In some embodiments, the peak at 25.0 ± 0.2 degrees 20 has the eighteenth highest relative intensity.

[0226] In some embodiments, the XRPD pattern of Form 4 has a peak at 29.1 ± 0.2 degrees 20. In some embodiments, the peak at 29.1 ± 0.2 degrees 20 has the nineteenth highest relative intensity.

[0227] In some embodiments, the XRPD pattern of Form 4 has a peak at 30.8 ± 0.2 degrees 20. In some embodiments, the peak at 30.8 ± 0.2 degrees 20 has the twentieth highest relative intensity.

[0228] In some embodiments, the XRPD pattern of Form 4 has a peak at 19.0 ± 0.2 degrees 20. In some embodiments, the peak at 19.0 ± 0.2 degrees 20 has the twenty-first highest relative intensity. In some embodiments, the XRPD pattern of Form 4 has a peak at 18.0 ± 0.2 degrees 20. In some embodiments, the peak at 18.0 ± 0.2 degrees 20 has the twenty-second highest relative intensity.

[0229] In some embodiments, the crystalline form is Form 4, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.3, 20.9, and 15.5.

[0230] In some embodiments, the crystalline form is Form 4, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.3, 20.9, 15.5, 24.1, 21.5, 27.7, 15.8, 14.9, 20.5, and 26.9.

[0231] In some embodiments, the crystalline form is Form 4, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.3, 20.9, 15.5, 24.1, 21.5, 27.7, 15.8, 14.9, 20.5, 26.9, 19.9, 19.3, 28.1, 28.4, 3.1, 27.3, 22.1, 25.0, 29.1, 30.8, 19.0, and 18.0.

[0232] In some embodiments, the crystalline form is Form 4, characterized by an XRPD pattern substantially the same as that shown in FIG. 8.

[0233] In some embodiments, the enantiomeric excess (ee) of Form 4 is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%.

[0234] In some embodiments, the Form 4 is substantially pure.

[0235] Mesylate Salt

[0236] In some embodiments, the crystalline form is a mesylate salt having a TG / DSC thermogram that is substantially the same as that shown in FIG. 14. In some embodiments, the crystalline form is a mesylate salt having a TG / DSC thermogram characterized by one endothermic event with an onset temperature of 200 °C and a peak temperature of 207 °C.

[0237] Methods of Preparing Form 1

[0238] Methods of preparing (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea can also be found in, e.g., PCT Published Application WO 2022 / 265993, filed June 13, 2022; and Provisional Application No. 63 / 532,695, filed on August 15, 2023, both of which are incorporated herein in its entirety.

[0239] As can be appreciated by the skilled artisan, further methods of synthesizing (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, crystalline forms thereof, and crystalline solvates (e.g., hydrates (e.g., hemi-hydrates)) will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0240] Methods of Preparing Form 1

[0241] Form 1 Prepared by Method 1

[0242] In some embodiments, the crystalline form is Form 1 prepared by a method comprising:

[0243] (a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in isopropanol to form a solution;

[0244] (b) adding water to the solution to form a mixture;

[0245] (c) reducing the temperature of the mixture then maintaining the temperature for a first period of time;

[0246] (d) increasing the temperature of the mixture then maintaining the temperature for a second period of time;

[0247] (e) reducing the temperature of the mixture then maintaining the temperature for a third period of time; and

[0248] (f) isolating Form 1 from the mixture.

[0249] Some embodiments provide a method of preparing a Form 1, comprising:

[0250] (a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in isopropanol to form a solution;

[0251] (b) adding water to the solution to form a mixture; (c) reducing the temperature of the mixture then maintaining the temperature for a first period of time;

[0252] (d) increasing the temperature of the mixture then maintaining the temperature for a second period of time;

[0253] (e) reducing the temperature of the mixture then maintaining the temperature for a third period of time; and

[0254] (f) isolating Form 1 from the mixture.

[0255] In some embodiments, Form 1 has one or more characteristics described herein and below.

[0256] In some embodiments, the XRPD pattern of Form 1 has a peak at 6.4 ± 0.2 degrees 29. In some embodiments, the peak at 6.4 ± 0.2 degrees 29 has the highest relative intensity.

[0257] In some embodiments, the XRPD pattern of Form 1 has a peak at 15.8 ± 0.2 degrees 29.

[0258] In some embodiments, the peak at 15.8 ± 0.2 degrees 29 has the second relative intensity.

[0259] In some embodiments, the XRPD pattern of Form 1 has a peak at 18.3 ± 0.2 degrees 29.

[0260] In some embodiments, the peak at 18.3 ± 0.2 degrees 29 has the third highest relative intensity.

[0261] In some embodiments, the XRPD pattern of Form 1 has a peak at 22.3 ± 0.2 degrees 29. In some embodiments, the peak at 22.3 ± 0.2 degrees 29 has the fourth highest relative intensity.

[0262] In some embodiments, the XRPD pattern of Form 1 has a peak at 20.8 ± 0.2 degrees 29. In some embodiments, the peak at 20.8 ± 0.2 degrees 29 has the fifth highest relative intensity.

[0263] In some embodiments, the XRPD pattern of Form 1 has a peak at 19.3 ± 0.2 degrees 29. In some embodiments, the peak at 19.3 ± 0.2 degrees 29 has the sixth highest relative intensity.

[0264] In some embodiments, the XRPD pattern of Form 1 has a peak at 24.0 ± 0.2 degrees 29. In some embodiments, the peak at 24.0 ± 0.2 degrees 29 has the seventh highest relative intensity.

[0265] In some embodiments, the XRPD pattern of Form 1 has a peak at 26.9 ± 0.2 degrees 29. In some embodiments, the peak at 26.9 ± 0.2 degrees 20 has the eighth highest relative intensity.

[0266] In some embodiments, the XRPD pattern of Form 1 has a peak at 14.6 ± 0.2 degrees 29. In some embodiments, the peak at 14.6 ± 0.2 degrees 29 has the ninth highest relative intensity.

[0267] In some embodiments, the XRPD pattern of Form 1 has a peak at 31.3 ± 0.2 degrees 29. In some embodiments, the peak at 31.3 ± 0.2 degrees 29 has the tenth highest relative intensity.

[0268] In some embodiments, the XRPD pattern of Form 1 has a peak at 28.3 ± 0.2 degrees 20. In some embodiments, the peak at 28.3 ± 0.2 degrees 29 has the eleventh highest relative intensity. In some embodiments, the XRPD pattern of Form 1 has a peak at 29.2 ± 0.2 degrees 20. In some embodiments, the peak at 29.2 ± 0.2 degrees 20 has the twelfth highest relative intensity.

[0269] In some embodiments, the XRPD pattern of Form 1 has a peak at 22.8 ± 0.2 degrees 20. In some embodiments, the peak at 22.8 ± 0.2 degrees 20 has the thirteenth highest relative intensity.

[0270] In some embodiments, the XRPD pattern of Form 1 has a peak at 28.0 ± 0.2 degrees 20. In some embodiments, the peak at 28.0 ± 0.2 degrees 20 has the fourteenth highest relative intensity.

[0271] In some embodiments, the XRPD pattern of Form 1 has a peak at 25.3 ± 0.2 degrees 20. In some embodiments, the peak at 25.3 ± 0.2 degrees 20 has the fifteenth highest relative intensity.

[0272] In some embodiments, the XRPD pattern of Form 1 has a peak at 21.5 ± 0.2 degrees 20. In some embodiments, the peak at 21.5 ± 0.2 degrees 20 has the sixteenth highest relative intensity.

[0273] In some embodiments, the XRPD pattern of Form 1 has a peak at 19.9 ± 0.2 degrees 20. In some embodiments, the peak at 19.9 ± 0.2 degrees 20 has the seventeenth highest relative intensity.

[0274] In some embodiments, the XRPD pattern of Form 1 has a peak at 27.6 ± 0.2 degrees 20. In some embodiments, the peak at 27.6 ± 0.2 degrees 20 has the eighteenth highest relative intensity.

[0275] In some embodiments, the XRPD pattern of Form 1 has a peak at 20.5 ± 0.2 degrees 20. In some embodiments, the peak at 20.5 ± 0.2 degrees 20 has the nineteenth highest relative intensity.

[0276] In some embodiments, the XRPD pattern of Form 1 has a peak at 21.8 ± 0.2 degrees 20. In some embodiments, the peak at 21.8 ± 0.2 degrees 20 has the twentieth highest relative intensity.

[0277] In some embodiments, the XRPD pattern of Form 1 has a peak at 25.1 ± 0.2 degrees 20. In some embodiments, the peak at 25.1 ± 0.2 degrees 20 has the twenty -first highest relative intensity.

[0278] In some embodiments, the XRPD pattern of Form 1 has a peak at 25.8 ± 0.2 degrees 20. In some embodiments, the peak at 25.8 ± 0.2 degrees 20 has the twenty-second highest relative intensity.

[0279] In some embodiments, the XRPD pattern of Form 1 has peaks (± 0.2 degrees 20) at 6.4,

[0280] 15.8, and 18.3.

[0281] In some embodiments, the XRPD pattern of Form 1 has peaks (± 0.2 degrees 20) at 6.4,

[0282] 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, and 31.3.

[0283] In some embodiments, the XRPD pattern of Form 1 has peaks (± 0.2 degrees 20) at 6.4,

[0284] 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, 31.3. 28.3, 29.2, 22.8, 28.0, 25.3, 21.5, 19.9, 27.6, 20.5, 21.8, 25.1, and 25.8. In some embodiments, Form 1 is characterized by an XRPD pattern substantially the same as that shown in FIG. 4.

[0285] In some embodiments, Form 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 0.5% to about 5% (e.g., about 1% to about 3%, about 2% to about 3%, or about 2.3%) at about 70 °C to about 140 °C (e g., about 90 °C to about 130 °C, about 90 °C to about 120 °C, about 90 °C to about 115 °C, about 100 °C to about 140 °C, about 110 °C to about 140 °C, about 100 °C to about 120 °C, about 105 °C to about 120 °C, about 109 °C to about 115 °C, about 75 °C to about 125 °C, about 85 °C to about 113 °C, about 85 °C to about 105 °C, or about 112 °C. In some embodiments, the Form 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 112.5 °C. In some embodiments, Form 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 85 °C to about 113 °C.

[0286] In some embodiments, Form 1 has a TGA curve characterized by a weight loss of about 5% to about 30% (e.g., about 5% to about 27%, about 5% to about 25%, about 5% to about 22%, about 10% to about 25%, about 20% to about 22%, about 14% to about 20%, or about 17.6%) at about 150 °C to about 250 °C (e.g., about 230 to about 260 °C about 230 °C to about 250 °C, about 162 °C to about 248 °C, about 230 °C to about 240 °C, about 240 °C to about 260 °C, about 240 °C to about 250 °C, about 242 °C to about 248 °C, or about 245 °C). In some embodiments, Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 245 °C. In some embodiments, the Form 1 has a TGA curve characterized by a weight loss of about 17.6% at about 162 °C to about 248 °C.

[0287] In some embodiments, the Form 1 has a TGA curve that is substantially the same as that shown in FIG. 28. In some embodiments, the crystalline form is Form 1 having a Thermal Gravimetric / Differential Scanning Calorimetry (TG / DSC) thermogram that is substantially the same as that shown in FIG. 28.

[0288] In some embodiments, the Form 1 has a differential scanning calorimetry (DSC) first heat cycle thermogram having an endothermic event having an onset temperature of about 105 °C and a peak of about 129 °C, an endothermic event having an onset temperature of about 158 °C and a peak of about 162 °C and an endothermic event having an onset temperature of about 174 °C and a peak of about 177 °C. In some embodiments, the Form 1 has a Differential Scanning Calorimetry (DSC) thermogram that is substantially the same as that shown in FIG. 29.

[0289] In some embodiments, the Form 1 has a DSC first cooling cycle thermogram characterized by a single exothermic event at with an onset temperature of 151 °C and a peak temperature of 147 °C.

[0290] In some embodiments, the Form 1 has a DSC first cooling cycle thermogram substantially the same as that shown in FIG. 30.

[0291] In some embodiments, the Form l is a hemi-hydrate.

[0292] In some embodiments, the enantiomeric excess (ee) of crystalline Form 1 is at least 90% (e.g., at least 92%, at least 94%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100%.

[0293] In some embodiments, the Form 1 is substantially pure.

[0294] In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof comprises the free base of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof is the free base of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof comprises amorphous (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof is amorphous (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof comprises the free base amorphous form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof is the free base amorphous form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof comprises Form 1 *. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl )urea, or a pharmaceutically acceptable salt and / or solvate thereof is Form 1*.

[0295] In some embodiments, the dissolving in step (a) is performed at about 40 °C to 60 °C (e.g., about 45 °C to about 55 °C, or about 50 °C). In some embodiments, the dissolving in step (a) is performed at about 50 °C.

[0296] In some embodiments, the solution formed in step (a) has a concentration of about 0.08 g / mL to about 1.65 g / mL (e.g., about 0.09 g / mL to about 1.55 g / mL, about 0.1 g / mL to about 0.145 g / mL, about 0.1 g / mL to about 0.135 g / mL, about 0.12 g / mL to about 0.13 g / mL, or about 0.125 g / mL). In some embodiments, the solution formed in step (a) has a concentration of about 0.125 g / mL.

[0297] In some embodiments, step (a) comprises cooling the solution to about 30 °C to 50 °C (e.g., about 35 °C to about 45 °C, or about 40 °C). In some embodiments, step (a) comprises cooling the solution to about 40 °C. In some embodiments, the cooling is performed at about 0.1 °C per minute to about 5 °C per minute (e.g., about 0.5 °C per minute to about 2 °C per minute, or about 1 °C per minute). In some embodiments, the cooling is performed at about 1 °C per minute.

[0298] In some embodiments, the volume / volume ratio of water added to the solution in step (b) to the isopropanol used in the dissolving in step (a) is about 2:1 to about 6:1 (e.g., about 3:1 to about 5: 1, or about 4: 1). In some embodiments, the volume / volume ratio of water added to the solution in step (b) to the isopropanol used in the dissolving in step (a) is about 4: 1.

[0299] In some embodiments, about l / 8thto about l / 32ndof the water is added to the solution per hour. 1 / 16thof the water is added to the solution per hour. In some embodiments, about 1 / 16thof the water is added to the solution per hour.

[0300] In some embodiments, the temperature of the mixture in step (c) is reduced to about 1 °C to about 15 °C (e.g., about 1 °C to about 10 °C, about 2 °C to about 8 °C, about 3 °C to about 7 °C, or about 5 °C). In some embodiments, the temperature of the mixture in step (c) is reduced to about 5 °C. In some embodiments, the first period of time is about 1 minute to about 24 hours (e.g., about 1 minute to about 18 hours, about 1 minute to about 12 hours, about 1 minute to about 6 hours, about 1 minute to about 3 hours, about 1 minute to about 2 hours, about 1 minute to about 30 minutes, about 1 minute to about 5 minutes, about 30 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, about 1 minute, or about 1 hour). In some embodiments, the first period of time is about 1 hour. In some embodiments, the first period of time is about 1 minute.

[0301] In some embodiments, the temperature of the mixture in step (d) is increased to about 25 °C to about 60 °C (e.g., about 25 °C to about 50 °C, about 30 °C to about 60 °C, about 30 °C to about 50 °C, about 35 °C to about 45 °C, or about 5 °C). In some embodiments, the temperature of the mixture in step (c) is increased to about 40 °C. In some embodiments, the second period of time is about 1 minute to about 24 hours (e.g., about 1 minute to about 18 hours, about 1 minute to about 12 hours, about 1 minute to about 6 hours, about 1 minute to about 3 hours, about 1 minute to about 2 hours, about 1 minute to about 30 minutes, about 1 minute to about 5 minutes, about 30 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, about 1 minute, or about 1 hour). In some embodiments, the second period of time is about 1 hour. In some embodiments, the second period of time is about 1 minute.

[0302] In some embodiments, the temperature of the mixture in step (e) is reduced to about 1 °C to about 15 °C (e.g., about 1 °C to about 10 °C, about 2 °C to about 8 °C, about 3 °C to about 7 °C, or about 5 °C). In some embodiments, the temperature of the mixture in step (e) is reduced to about 5 °C. In some embodiments, the third period of time is about 1 minute to about 24 hours (e g., about 1 minute to about 18 hours, about 1 minute to about 12 hours, about 1 minute to about 6 hours, about 1 minute to about 3 hours, about 1 minute to about 2 hours, about 1 minute to about 30 minutes, about 1 minute to about 5 minutes, about 30 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, about 6 hours to about 18 hours, about 6 hours to about 24 hours, about 9 hours to about 15 hours, about 9 hours to about 14 hours, about 10 hours to about 12 hours, about 10.5 hours to about 11.5 hours, about 11 hours, about 12 hours, about 1 hour, or about 1 minute). In some embodiments, the third period of time is about 11 hours. In some embodiments, the third period of time is about 11 hours.

[0303] In some embodiments, step (f) comprises filtering the mixture to provide Form 1. In some embodiments, step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1. In some embodiments, rinsing the solid to provide Form 1 comprises drying the solid after the rinsing to provide Form 1. In some embodiments, the rinsing the solid comprises rinsing the solid with a solvent. In some embodiments, the solvent comprises an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. Tn some embodiments, the solvent comprises water. In some embodiments, the solvent comprises an alcohol and water. In some embodiments, the solvent comprises methanol and water. In some embodiments, the solvent is methanol and water.

[0304] In some embodiments, step (f) comprises: filtering the mixture to provide a solid; rinsing the solid with methanol and water; and drying the solid to provide Form 1.

[0305] In some embodiments, the drying is performed for about 1 minute to about 16 hours (e.g., about 1 minute to about 14 hours, about 1 minute to about 12 hours, about 1 minute to about 8 hours, about 1 minute to about 4 hours, about 1 minute to about 2 hours, about 1 minute to about 1 hour, or about 1 minute to about 30 minutes. In some embodiments, drying the solid comprises drying the solid at a pressure lesser than atmospheric pressure. In some embodiments, the drying is performed at a temperature of about 25 °C to about 100 °C (e.g., about 25 °C to about 80 °C, about 35 °C to about 80 °C, about 45 °C to about 70 °C, about 45 °C to about 60 °C).

[0306] Form 1 Prepared by Method 2

[0307] In some embodiments, the crystalline form is Form 1 prepared by a method comprising: dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0308] 2.2.2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in methanol to form a solution; adding water to the solution to form a first mixture; adding (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0309] 2.2.2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture; and isolating a solid from the third mixture to provide Form 1.

[0310] Some embodiments provide a method of preparing Form 1 comprising: dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0311] 2.2.2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in methanol to form a solution; adding water to the solution to form a first mixture; adding (R)-l -(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0312] 2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture; and isolating a solid from the third mixture to provide Form 1.

[0313] In some embodiments, the crystalline form is Form 1 prepared by a method comprising:

[0314] (a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in methanol to form a solution;

[0315] (b) adding water to the solution to form a first mixture;

[0316] (c) adding (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0317] 2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture;

[0318] (d) agitating the second mixture;

[0319] (e) adding water to the second mixture to form a third mixture;

[0320] (f) agitating the third mixture; and

[0321] (g) isolating Form 1 from the third mixture.

[0322] Some embodiments provide a method of preparing Form 1 comprising:

[0323] (a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in methanol to form a solution;

[0324] (b) adding water to the solution to form a first mixture;

[0325] (c) adding (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0326] 2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture;

[0327] (d) agitating the second mixture;

[0328] (e) adding water to the second mixture to form a third mixture;

[0329] (f) agitating the third mixture; and

[0330] (g) isolating Form 1 from the third mixture.

[0331] In some embodiments, the solution formed in step (a) has a concentration of about 0.03 g / mL to about 1 g / mL (e.g., about 0.03 g / mL to about 0.5 g / mL, about 0.05 g / mL to about 0.3 g / mL, about 0.1 g / mL to about 0.2 g / mL, about 0.13 g / mL to about 0.18 g / mL, or about 0.16 g / mL). Tn some embodiments, the solution formed in step (a) has a concentration of about 0.16 g / mL.

[0332] In some embodiments, dissolving the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in methanol to form a solution comprises dissolving the (R)-l-(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in a first portion of methanol to form an unfiltered solution, filtering the unfiltered solution through a filter to provide a filtrate, then rinsing the filter with a second portion of methanol to provide a rinse that is combined with the filtrate to provide the solution. In some embodiments, the filtering is a polish filtering. In some embodiments, the filter has a pore size of about 0.2 microns. In some embodiments, the weight of the first portion of methanol is about 4 to about 8 times (e.g., about 5 to about 8 times, about 6 to about 7 times, or about 6.3 times (e g., about 6.3 times)) the weight of the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl )urea that is dissolved. In some embodiments, the weight of the first portion of methanol is about 4 to about 8 times (e.g., about 0.5 to about 3 times, about 1 to about 3 times, or about 1.6 times (e.g., about 1.6 times)) the weight of the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved.

[0333] In some embodiments, the solution is cooled to about 5 °C to about 35 °C (e.g., about 10 °C to about 30 °C, about 15 °C to about 25 °C, about 15 °C to about 20 °C, about 20 °C to about 25 °C, about 17 °C to about 23 °C, about 15 °C, about 20 °C, or about 25 °C (e.g., about 15 °C to about 25 °C)) before adding the water in step (b). In some embodiments, the water added in step (b) is purified water. In some embodiments, adding the water in step (b) comprises filtering the water through a filter, then adding the water to form the first mixture. In some embodiments, the water added in step (b) is about 0.1 to about 2 times (e.g., about 0.1 to about 1.5 times, about 0.1 to about 1 times, about 0.3 to about 0.7 times, or about 0.5 times (e.g., about 0.5 times)) the weight of the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea that is dissolved in step (a).

[0334] In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 added in step (c) is about 0.1% to about 20% by weight (e.g., about 0.1% to about 15% by weight, about 0.1% to about 10% by weight, about 0.1% to about 5% by weight, about 0.1% to about 3% by weight, about 0.5% to about 3% by weight, about 0.7% to about 2.5% by weight, about 0.7% to about 1 .3% by weight, or about 1% by weight (e.g., about 1% by weight)) of the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved in step (a).

[0335] In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 added in step (c) is prepared by Method 1 described herein. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea Form 1 added in step (c) is prepared by Method 2 described herein.

[0336] In some embodiments, the agitating in step (d) is performed at about 5 °C to about 35 °C (e.g., about 10 °C to about 30 °C, about 15 °C to about 25 °C, about 15 °C to about 20 °C, about 20 °C to about 25 °C, about 17 °C to about 23 °C, about 15 °C, about 20 °C, or about 25 °C (e.g., about 15 °C to about 25 °C)). In some embodiments, the agitating in step (d) is performed for about 1 minute to about 24 hours (e.g., about 1 minute to about 18 hours, about 1 minute to about 12 hours, about 1 minute to about 8 hours, about 1 minute to about 6 hours, about 30 minutes to about 6 hours, about 1 hour to about 5 hours, about 2 hours to about 4 hours, about 2.5 hours to about 3.5 hours, or about 3 hours (e g., about 3 hours)).

[0337] In some embodiments, the water added in step (e) is purified water. In some embodiments, adding the water in step (e) comprises filtering the water through a filter, then adding the water to form the third mixture. In some embodiments, the water added in step (e) is about 0.1 to about 20 times (e.g., about 0.1 to about 15 times, about 0.1 to about 10 times, about 1 to about 9 times, about 3 to about 7 times, about 4 to about 5 times, or about 4.5 times (e.g., about 4.5 times)) the weight of the (R)- 1 -(2-aminopyrimidin-5 -y 1 )-3 -( 1 -(5, 7-difluoro-3 -methy lbenzofuran-2-yl )-2,2, 2- trifluoroethyl)urea that is dissolved in step (a). In some embodiments, the water added in step (e) is added over a period of about 1 second to about 48 hours (e g., about 1 minute to about 24 hours, about 1 minute to about 18 hours, about 1 hour to about 12 hours, about 4 hours to about 12 hours, about 6 hours to about 10 hours, about 7 hours to about 9 hours, or about 8 hours (e.g., about 8 hours)).

[0338] In some embodiments, the agitating in step (f) is performed at about 5 °C to about 35 °C (e.g., about 10 °C to about 30 °C, about 15 °C to about 25 °C, about 15 °C to about 20 °C, about 20 °C to about 25 °C, about 17 °C to about 23 °C, about 15 °C, about 20 °C, or about 25 °C (e.g., about 15 °C to about 25 °C)). In some embodiments, the agitating in step (f) is performed for about 1 minute to about 48 hours (e.g., about 1 minute to about 36 hours, about 1 minute to about 24 hours, about 4 hours to about 24 hours, about 8 hours to about 20 hours, about 12 hours to about 20 hours, about 14 hours to about 18 hours, about 15 hours to about 17 hours, or about 16 hours (e.g., about 16 hours)).

[0339] In some embodiments, step (f) comprises filtering the mixture to provide Form 1. In some embodiments, step (f) comprises filtering the mixture to provide a solid; and rinsing the solid to provide Form 1. In some embodiments, rinsing the solid to provide Form 1 comprises drying the solid after the rinsing to provide Form 1. In some embodiments, the rinsing the solid comprises rinsing the solid with a solvent. In some embodiments, the solvent comprises an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. In some embodiments, the solvent comprises water. In some embodiments, the solvent comprises an alcohol and water. In some embodiments, the solvent comprises methanol and water. In some embodiments, the solvent is methanol and water.

[0340] In some embodiments, isolating Form 1 from the third mixture comprises:

[0341] (i) filtering the third mixture to provide a solid;

[0342] (ii) rinsing the solid with methanol and water; and

[0343] (iii) drying the solid to provide Form 1.

[0344] In some embodiments, the weight of the methanol and water is about 0.5 to about 5 times (e.g., about 0.5 to about 4 times, about 0.5 to about 3 times, about 1 to about 3 times, about 1.5 to about 2.1 times, or about 1.8 times (e.g, about 1.8 times)) the weight of the (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea that is dissolved in step (a). In some embodiments, the ratio of methanol to water is about 1 : 100 to about 100:1 (e.g., about 20:80 to about 90: 10, about 30:70 to about 90: 10, about 50:50 to about 80:20, about 55:45 to about 65:35, or about 61 :39 (e.g., about 61 :39)).

[0345] In some embodiments, drying the solid comprises drying the solid at about 30 °C to about 60 °C (e.g., about 30 °C to about 50 °C, about 35 °C to about 45 °C, about 35 °C to about 40 °C, about 40 °C to about 45 °C, about 35 °C, about 40 °C, or about 45 °C (e.g., about 35 °C to about 45 °C)). In some embodiments, drying the solid comprises drying the solid at a pressure lesser than atmospheric pressure. In some embodiments, drying the solid comprises drying the solid under an inert gas (e.g., nitrogen or argon (e.g., nitrogen)). In some embodiments, drying the solid comprises drying the solid until the solid includes about 1% to about 4% (e.g., about 1.5% to about 3.2% or about 2% to about 2.6% (e.g., about 2% to about 2.6%) by weight of water. In some embodiments, the Form 1 obtained in step (g) includes about 1% to about 4% (e.g., about 1.5% to about 3.2% or about 2% to about 2.6% (e.g., about 2% to about 2.6%) by weight of water.

[0346] Pharmaceutical Compositions and Administration

[0347] General

[0348] In some embodiments, the l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. In some embodiments, the l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate is a pharmaceutically acceptable salt. In some embodiments, the l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate is a pharmaceutically acceptable solvate. In some embodiments, the l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate is a pharmaceutically acceptable solvate of a salt.

[0349] In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, , and y-cyclodextrin, or chemically modified derivatives such as hydroxy alkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from pharmaceutically acceptable excipients may be prepared. The contemplated compositions may contain 0.001%- 100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).

[0350] Routes of Administration and Composition Components

[0351] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasy novi al, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, the route of administration is oral.

[0352] In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0353] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fdlers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such pharmaceutically acceptable excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0354] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’S, pol oxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0355] In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

[0356] In some embodiments, the pharmaceutical composition comprises l-(2-aminopyrimidin-5- yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises (R)l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition comprises l-(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate, and one or more pharmaceutically acceptable carriers. In some embodiments, the (R)-l -(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is crystalline. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0357] 2,2,2-trifluoroethyl)urea is a solvate. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3- (l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is a hydrate. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0358] 2,2,2-trifluoroethyl)urea is a hemi-hydrate. In some embodiments, the (R)-l-(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 1. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0359] 2,2,2-trifluoroethyl)urea is Form 1*. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 2. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0360] 2,2,2-trifluoroethyl)urea is Form 3. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3- (l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 4.

[0361] In some embodiments, the tablet comprises granules. In some embodiments, the tablet comprises granules and extragranular matter. In some embodiments, the tablet is surrounded by a layer.

[0362] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg (e g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0363] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg (e g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0364] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, of (S)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0365] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, of a pharmaceutically acceptable solvate of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0366] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate.

[0367] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemi-hydrate.

[0368] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg, of a crystalline form of (R)- 1 -(2-aminopyrimidin-5 -yl )-3 -(1 -(5, 7-difluoro-3 -methy lbenzofuran-2-yl )-2,2, 2- trifluoroethyl)urea. In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 1. In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 1*.

[0369] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.

[0370] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0371] 2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- tri fluoroethyl )urea.

[0372] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0373] 2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0374] 2.2.2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.

[0375] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0376] 2.2.2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition comprises about 5 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran- 2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition comprises about 20 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran- 2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition comprises about 5 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition comprises about 20 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate.

[0377] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition comprises about 5 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran- 2-yl)-2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition comprises about 20 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-

[0378] 2-yl)-2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-

[0379] 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition comprises about 5 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition comprises about 20 mg of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of hemi-hydrate (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of hemi-hydrate (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of hemihydrate (R)-l-(2-aminopyrimidin-5- yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about

[0380] 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about

[0381] 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of hemi-hydrate (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of hemi-hydrate (R)- l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of hemi-hydrate (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea.

[0382] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of crystalline (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of crystalline (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of crystalline (R)-l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of crystalline (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of crystalline (R)-l- (2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0383] In some embodiments, the pharmaceutical composition comprises about 20 mg of crystalline (R)- l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea.

[0384] In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of crystalline (R)-Form 1 (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of crystalline (R)-Form 1 (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. Tn some embodiments, the pharmaceutical composition comprises about 20 mg of crystalline (R)-Form 1 (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg) of crystalline (R)-Form 1 (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran- 2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 5 mg of crystalline (R)-Form 1 (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition comprises about 20 mg of crystalline (R)-Form 1 (R)-l-(2-aminopyrimidin-5-yl)-3- (l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0385] In some embodiments, the pharmaceutical composition comprises 1 mg of Form 1, as described herein. In some embodiments, the pharmaceutical composition comprises 1 mg of Form 1*, as described herein. In some embodiments, the pharmaceutical composition comprises 5 mg of Form 1, as described herein. In some embodiments, the pharmaceutical composition comprises 5 mg of Form 1*, as described herein. In some embodiments, the pharmaceutical composition comprises 10 mg of Form 1, as described herein. In some embodiments, the pharmaceutical composition comprises 10 mg of Form 1*, as described herein. In some embodiments, the pharmaceutical composition comprises 20 mg of Form 1, as described herein. In some embodiments, the pharmaceutical composition comprises 20 mg of Form 1*, as described herein. In some embodiments, the pharmaceutical composition comprises 25 mg of Form 1, as described herein. In some embodiments, the pharmaceutical composition comprises 25 mg of Form 1*, as described herein.

[0386] In some embodiments, the l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea. In some embodiments, the (R)- l -(2-aminopyrimidin-5-yl)-3-( l-(5,7-difluoro- 3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is crystalline. In some embodiments, the (R)- l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is a hydrate. In some embodiments, the l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is hemi-hydrate (R)-l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea is Form 1.

[0387] In some embodiments, the composition comprises microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate, or any combination thereof. In some embodiments, the composition comprises microcrystalline cellulose. In some embodiments, the composition comprises mannitol. In some embodiments, the composition comprises croscarmellose sodium. In some embodiments, the composition comprises colloidal silicon dioxide. In some embodiments, the composition comprises sodium stearyl fumarate.

[0388] In some embodiments, the weight percentage of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (e.g., (R)-l-(2-aminopyrimidin-5- yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea) in the composition is about 0.1% to about 50% (e g., about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 1% to about 10%, about 1% to about 9%, about 1% to about 5%, about 5% to about 10%, about 3% to about 7%, about 4% to about 6%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%). In some embodiments, the weight percentage of l-(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (e.g., (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea) in the composition is about 5%.

[0389] In some embodiments, the weight percentage of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in the composition is about 0.1% to about 50% (e.g., about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 1% to about 10%, about 1% to about 9%, about 1% to about 5%, about 5% to about 10%, about 3% to about 7%, about 4% to about 6%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%). In some embodiments, the weight percentage of (R)-l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in the composition is about 5%.

[0390] In some embodiments, the weight percentage of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in the composition is about 0.1% to about 50% (e.g., about 0.1% to about 40%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0.1% to about 15%, about 1% to about 10%, about 1% to about 9%, about 1% to about 5%, about 5% to about 10%, about 3% to about 7%, about 4% to about 6%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%). In some embodiments, the weight percentage of (S)-l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in the composition is about 5%.

[0391] In some embodiments, the weight percentage of microcrystalline cellulose in the composition is about 20% to about 70% (e.g., about 30% to about 60%, about 35% to about 55%, about 40% to about 50%, about 43% to about 47%, about 44%, about 45%, or about 44.6%). In some embodiments, the weight percentage of microcrystalline cellulose in the composition is about 44.6%.

[0392] In some embodiments, the weight percentage of mannitol in the composition is about 20% to about 70% (e.g., about 30% to about 60%, about 35% to about 55%, about 40% to about 50%, about 43% to about 47%, about 44%, about 45%, or about 44.9%). In some embodiments, the weight percentage of mannitol in the composition is about 44.9%.

[0393] In some embodiments, the weight percentage of croscarmellose sodium in the composition is about 0.1% to about 15% (e.g., about 0.1% to about 10%, about 0.1% to about 8%, about 1% to about 6%, about 1% to about 5%, about 2% to about 4%, or about 3%). In some embodiments, the weight percentage of croscarmellose sodium in the composition is about 3%.

[0394] In some embodiments, the weight percentage of colloidal silicon dioxide in the composition is about 0.1% to about 15% (e.g., about 0.1% to about 10%, about 0.1% to about 7%, about 0.1% to about 5%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.5% to about 2%, about 0.75% to about 1.75%, about 1% to about 1.5%, about 1%, about 2%, or about 1.25%). In some embodiments, the weight percentage of colloidal silicon dioxide in the composition is about 1.25%.

[0395] In some embodiments, the weight percentage of sodium stearyl fumarate in the composition is about 0.1% to about 15% (e.g., about 0.1% to about 10%, about 0.1% to about 7%, about 0.1% to about 5%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.5% to about 2%, about 0.75% to about 1.75%, about 1% to about 1.5%, about 1%, about 2%, or about 1.25%). In some embodiments, the weight percentage of sodium stearyl fumarate in the composition is about 1.25%.

[0396] In some embodiments (for example, when the composition is in the form of a tablet surrounded by a layer), the weight percentage of the layer in the composition is about 0.2% to about 6% (e.g., about 1% to about 5%, about 2% to about 4%, or about 3%). In some embodiments (when the composition is in the form of a tablet surrounded by a layer), the weight percentage of the layer in the composition is about 3%.

[0397] In some embodiments, the pharmaceutical composition is in the form of a tablet; the weight percentage of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea in the composition is about 0.1% to about 30%; the weight percentage of microcrystalline cellulose in the composition is about about 35% to about 55%; the weight percentage of mannitol in the composition is about about 35% to about 55%; the weight percentage of croscarmellose sodium in the composition is about about 1% to about 5%; the weight percentage of colloidal silicon dioxide in the composition is about about 0.1% to about 3%; and the weight percentage of sodium stearyl fumarate in the composition is about 0.1% to about 5%.

[0398] In some embodiments, the pharmaceutical composition is in the form of a tablet; the weight percentage of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea in the composition is about 5%; the weight percentage of microcrystalline cellulose in the composition is about 44.6%; the weight percentage of mannitol in the composition is about 44.9%; the weight percentage of croscarmellose sodium in the composition is about 3%; the weight percentage of colloidal silicon dioxide in the composition is about 1.25%; and the weight percentage of sodium stearyl fumarate in the composition is about 1.25%.

[0399] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0400] In certain embodiments, the pharmaceutically acceptable excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well- known sterilization techniques. For various oral dosage forms, pharmaceutically acceptable excipients such as tablets and capsules sterility is not required. The USP / NF standard is usually sufficient.

[0401] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and / or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0402] Some embodiments provide a solid dosage form for oral administration comprising Form 1, as described herein. Some embodiments provide a solid dosage form for oral administration comprising Form 1*, as described herein. In some embodiments, the solid dosage form for oral administration is a tablet. In some embodiments, the solid dosage form for oral administration is a capsule.

[0403] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0404] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and pharmaceutically acceptable excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0405] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0406] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0407] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0408] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof. Intratumoral injections are discussed, e.g., in Lammers, et al., Neoplasia. 2006, 10, 788-795. Pharmaceutically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl capryl ocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0409] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating pharmaceutically acceptable excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0410] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0411] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

[0412] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0413] Dosages

[0414] The dosages may be varied depending on, for example, the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0415] In some embodiments, a dose of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg).

[0416] In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg).

[0417] In some embodiments, a dose of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg).

[0418] In some embodiments, a dose of crystalline (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg). In some embodiments, the crystalline (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea is Form 1. In some embodiments, the crystalline (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 1*.

[0419] In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate is about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg).

[0420] In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate is about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg).

[0421] In some embodiments, a dose of hemi-hydrate Form 1 (R)-l-(2-aminopyrimidin-5-yl)-3- (l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (e g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg).

[0422] In some embodiments, a dose of Form 1* (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difhioro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (e.g., about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg, about 1 mg to about 150 mg, about 1 mg to about 100 mg, or about 1 mg to about 50 mg).

[0423] In some embodiments, a dose of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea is about 5 mg. In some embodiments, a dose of l-(2-aminopyrimidin-5- yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 20 mg.

[0424] In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea is about 5 mg. In some embodiments, a dose of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 20 mg.

[0425] In some embodiments, a dose of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of (S)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea is about 5 mg. In some embodiments, a dose of (S)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 20 mg. In some embodiments, a dose of crystalline (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of crystalline (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 5 mg. In some embodiments, a dose of crystalline (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea is about 20 mg.

[0426] In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate is about 5 mg. In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea solvate is about 20 mg.

[0427] In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate is about 5 mg. In some embodiments, a dose of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea hydrate is about 20 mg.

[0428] In some embodiments, a dose of hemi-hydrateForm 1 (R)-l-(2-aminopyrimidin-5-yl)-3- (l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of hemi-hydrateForm 1 l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 5 mg. In some embodiments, a dose of hemi-hydrate Form 1 l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 20 mg.

[0429] In some embodiments, a dose of Form 1* (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 100 mg (e.g., about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 5 mg to about 20 mg, about 1 mg to about 10 mg, about 15 mg to about 25 mg, about 3 mg to about 7 mg, about 18 mg to about 22 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg). In some embodiments, a dose of Form 1* (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 5 mg. In some embodiments, a dose of Form 1* (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea is about 20 mg.

[0430] In some embodiments, the total daily dose is 1 mg of Form 1, as described herein. In some embodiments, the total daily dose is 1 mg of Form 1*, as described herein. In some embodiments, the total daily dose is 5 mg of Form 1, as described herein. In some embodiments, the total daily dose is 5 mg of Form 1*, as described herein. In some embodiments, the total daily dose is 10 mg of Form 1, as described herein. In some embodiments, the total daily dose is 10 mg of Form 1*, as described herein. In some embodiments, the total daily dose is 20 mg of Form 1, as described herein. In some embodiments, the total daily dose is 20 mg of Form 1*, as described herein. In some embodiments, the total daily dose is 25 mg of Form 1, as described herein. In some embodiments, the total daily dose is 25 mg of Form 1*, as described herein.

[0431] Regimens

[0432] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0433] In some embodiments, the compounds and compositions described herein are administered once daily. In some embodiments, the compounds and compositions described herein are administered twice daily.

[0434] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0435] Methods of Treatment

[0436] Indications

[0437] The crystalline forms of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salts and / or solvates thereof, is useful for treating diseases and disorders which can be treated with a PI3Ka inhibitor, such as PI3Ka-associated diseases and disorders, e.g., PIK3CA-related overgrowth syndromes (PROS), vascular malformation, and proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[0438] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (a PI3Ka-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1 or Table 2. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3Ka -associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PJK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0439] In some embodiments, the subject is a pediatric subject.

[0440] The term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0441] In certain embodiments, l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salts and / or solvates thereof, are useful for preventing diseases and disorders as defined herein (for example, PIK3CA-related overgrowth syndromes (PROS) and cancer). The term "preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0442] The term “PI3Ka-associated disease or disorder” as used herein refers to diseases or disorders associated with or having a dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any (e.g., one or more) of the same (e g., any of the types of dysregulation of a PIK3CA gene, or a PI3Ka protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a PI3Ka-associated disease or disorder include, for example, PIK3CA-related overgrowth syndromes (PROS), brain disorders (e.g., as macrocephaly-capillary malformation (MCAP) and hemimegalencephaly), lymphatic malformations (LMs), cavernous malformations (CMs), congenital lipomatous (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal anomalies (e.g., CLOVES syndrome) and fibroadipose hyperplasia (FH), or cancer (e.g., PI3Ka-associated cancer).

[0443] Some embodiments provide a method of treating PIK3CA-related overgrowth syndromes (PROS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0444] Some embodiments provide a method of treating macrocephaly-capillary malformation (MCAP) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0445] Some embodiments provide a method of treating hemimegalencephaly in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl )urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0446] Some embodiments provide a method of treating lymphatic malformations (LMs) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0447] Some embodiments provide a method of treating congenital lipomatous in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl )urea, or a pharmaceutically acceptable salt and / or solvate thereof. Some embodiments provide a method of treating epidermal nevi in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)- 1 -(2-aminopyrimidin-5 -y 1 )-3 -( 1 -(5, 7-difluoro-3 -methy lbenzofuran-2-yl )-2,2, 2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0448] Some embodiments provide a method of treating CLOVES syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)- 1 -(2-aminopyrimidin-5 -yl)-3 -( 1 -(5, 7-difluoro-3 -methylbenzofuran-2-yl)-2,2, 2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0449] Some embodiments provide a method of treating fibroadipose hyperplasia (FH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0450] Some embodiments provide a method of treating cavernous malformations (CMs) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0451] The term “PI3Ka-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Ku-associated cancers are described herein.

[0452] The phrase “dysregulation QA & PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Kot that includes a deletion of at least one amino acid as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with one or more point mutations as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with at least one inserted amino acid as compared to a wild type PI3Ka, a gene duplication that results in an increased level of PI3Ka in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of PI3Ka in a cell), an alternative spliced version of PI3Kot mRNA that results in PI3Ka having a deletion of at least one amino acid in the PI3Ka as compared to the wild type PI3Ka), or increased expression (e.g., increased levels) of a wild type PI3Ka in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non- cancerous cell). As another example, a dysregulation of a P1K3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same, can be a mutation in &PIK3CA gene that encodes a PI3Ka that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Non-limiting examples of PI3Ka point mutations / substitutions / insertions / deletions are described in Table 1 and Table 2.

[0453] The term “activating mutation” in reference to PI3Ka describes a mutation in a PIK3CA gene that results in the expression of PI3Ka that has an increased kinase activity, e.g., as compared to a wild type PI3Ka, e.g., when assayed under identical conditions. For example, an activating mutation can be a mutation in a PIK3CA gene that results in the expression of a PI3Ka that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type a PI3Ka, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a PIK3CA that results in the expression of a PI3Ka that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wild type PI3Ka, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a PIK3CA gene that results in the expression of a PI3Ka that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wild type PI3Ka, e.g., the exemplary wild type PI3Ka described herein, e.g., when assayed under identical conditions. Additional examples of activating mutations are known in the art.

[0454] The term “wild type” or “wild-type” describes a nucleic acid (e.g., a PIK3CA gene or a PI3Ka mRNA) or protein (e.g., a PI3Ka) sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein.

[0455] The term “wild type PI3Ka” or “wild-type PI3Ka” describes a normal PI3Ka nucleic acid (e.g., &PIK3CA or PI3Ka mRNA) or protein that is found in a subject that does not have a PI3Ka- associated disease, e g., a PI3Ka -associated cancer (and optionally also does not have an increased risk of developing a PI3Ka -associated disease and / or is not suspected of having a PI3Ka- associated disease), or is found in a cell or tissue from a subject that does not have a PI3Ka- associated disease, e.g., a PI3Ka-associated cancer (and optionally also does not have an increased risk of developing a PI3Ka-associated disease and / or is not suspected of having a PI3Ka- associated disease).

[0456] Provided herein is a method of treating cancer (e.g., a PI3Ka-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Ka-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same includes one or more a PI3Ka protein substitutions / point mutations / insertions. Non-limiting examples of PI3Ka protein substitutions / insertions / deletions are described in Table 1 and Table 2.

[0457] In some embodiments, the subject was determined to have one or more mutations in the kinase domain of the PI3Ka protein. In some embodiments, the subject was determined to have one or more mutations in the helical domain of the PI3Ka protein. In some embodiments, the subject was determined to have one or more mutations in each of the kinase domain and the helical domain of the PI3Ka protein.

[0458] In some embodiments, the PI3Ka protein substitution / insertion / deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, E542L, E545A, E545D, E545G, E545K, E545Q, E545V, E545R, E545T, Q546K, Q546R, Q546P, Q546E, Q546H, E726K, N1044K, N1044Y, N1044S, N1044I, M1043I, M1043L, M1043T, M1043V, H1047P, H1047I, H1047D, H1047C, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof.

[0459] In some embodiments, the PI3Ka protein substitution / insertion / deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, E542L, E545A, E545D, E545G, E545K, E545Q, E545V, E545R, E545T, M1043I, M1043L, M1043T, Ml 043V, H1047P, Hl 0471, H1047D, H1047C, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof.

[0460] In some embodiments, the PI3Ka protein substitution / insertion / deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3Ka protein substitution / insertion / deletion is H1047X, where X is any amino acid. In some embodiments, the PI3Ka protein substitution / insertion / deletion is H1047R. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E542X, where X is any amino acid. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E545X, where X is any amino acid. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E546X, where X is any amino acid.

[0461] In some embodiments, the PI3Ka protein substitution / insertion / deletions are selected from H1047R and one of E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, E542L, E545A, E545D, E545G, E545K, E545Q, E545V, E545R, E545T, Q546K, Q546R, Q546P, Q546E, Q546H, E726K, N1044K, N1044Y, N1044S, N1044I, M1043I, M1043L, M1043T, M1043V, H1047P, H1047I, H1047D, H1047C, H1047L, H1047Q, H1047Y, and G1049R.

[0462] In some embodiments, the PI3Ka protein substitution / insertion / deletions are selected from E726K, H1047P, H1047I, H1047D, H1047C, H1047L, H1047Q, H1047Y, and G1049R. In some embodiments, the PI3Ka protein substitution / insertion / deletions are selected from Q546K, Q546R, Q546P, Q546E, or Q546H, and E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, and E542L.

[0463] In some embodiments, the PI3Ka protein substitution / insertion / deletions are selected from E545A, E545D, E545G, E545K, E545Q, E545V, or E545R, and E545T,.

[0464] In some embodiments, the PI3Ka protein substitution / insertion / deletions are selected from E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, or E542L, and D549N.

[0465] In some embodiments, the PI3Ka protein substitution / insertion / deletions are selected from E545A, E545D, E545G, E545K, E545Q, E545V, E545R, or E545T, and D453X.

[0466] In some embodiments, the cancer (e.g., PI3Ka-associated cancer) is selected from a hematological cancer and a solid tumor. In some embodiments, the cancer is a locally advanced tumor. In some embodiments, the cancer is metastatis. In some embodiments, the cancer is unresectable. In some embodiments, the subject is administered a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, after surgery to resect a tumor (e.g., adjuvant therapy). In some embodiments, the subject is administered a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, prior to surgery to resect a tumor (e.g., neoadjuvant therapy).

[0467] In some embodiments, the cancer (e.g., PI3Ka-associated cancer) is selected from breast cancer (including both HER2+and HER2' breast cancer, ER+breast cancer, and triple negative breast cancer), endometrial cancer, lung cancer (including non-small cell lung cancer, small cell lung cancer, adenocarcinoma lung cancer, and squamous cell lung carcinoma), esophageal cancer (including esophageal squamous cell carcinoma), ovarian cancer, colorectal cancer, anal cancer, esophagastric adenocarcinoma, gastric cancer, bladder cancer, goblet cell carcinoma, head and neck cancer (including head and neck squamous cell cancers such as head and neck squamous cell carcinoma and oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, glioblastoma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), nonmelanoma skin cancer, soft tissue sarcoma, hepatobilliary cancer, prostate cancer, kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, myelodysplastic syndrome, B- and T-cell lymphomas, multiple myeloma, relapsed and refractory multiple myeloma, sarcoma, pancreatic cancer, and other CNS cancers (including but not limited to neuromas, adenomas, Schwannomas, astrocytomas, medulloblastomas, and oligodendrogliomas).

[0468] In some embodiments, the cancer (e.g., PI3Ka-associated cancer) is selected from breast cancer (including both HER2+and HER2‘ breast cancer, ER+breast cancer, and triple negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (HNSCC, including oropharyngeal, nasopharyngeal, and hypopharyngeal squamous cell carcinomas), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer.

[0469] In some embodiments, the cancer (e.g., PI3Ka-associated cancer) is selected from breast cancer, lung cancer, endometrial cancer, gastric, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, prostate cancer, and cervical cancer.

[0470] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is lung cancer.

[0471] In some embodiments, the cancer is a gynecologic cancer. In some embodiments, the gynecologic cancer is endometrial cancer, ovarian cancer, or cervical cancer.

[0472] In some embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer is not deficient in DNA mismatch repair (dMMR), i.e., the endometrial cancer is not dMMR.

[0473] In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is breast cancer.

[0474] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer.

[0475] In some embodiments, the cancer is esophageal cancer.

[0476] In some embodiments, the cancer is gastric cancer.

[0477] In some embodiments, the cancer is ovarian cancer.

[0478] In some embodiments, the cancer is colorectal cancer.

[0479] In some embodiments, the cancer is bladder cancer.

[0480] In some embodiments, the cancer is head and neck cancer.

[0481] In some embodiments, the cancer is thyroid cancer.

[0482] In some embodiments, the cancer is prostate cancer.

[0483] In some embodiments, the cancer is glioma.

[0484] In some embodiments, the cancer is cervical cancer.

[0485] In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is locally advanced breast cancer. In some embodiments, the cancer is locally advanced gynecolgic cancer. In some embodiments, the cancer described herein is a HER2+cancer. In some embodiments, the cancer described herein is a HER2' cancer.

[0486] In some embodiments, the cancer described herein is a HER2-low cancer. In some embodiments, the cancer has a HER2 score (e.g., an IHC score) of 0, +1, or +2. In some embodiments, the cancer has a HER2 score (e.g., an IHC score) of 0 or + 1. In some embodiments, the cancer has a HER2 score of 0. In some embodiments, the cancer has a HER2 score of + 1. In some embodiments, the cancer has a HER2 score of +2. In some embodiments, the cancer has a HER2 score of +2 or +3. In some embodiments, the cancer has a HER2 score of +3.

[0487] In some embodiments, the cancer described herein is a HER2 -ultralow cancer (e.g., a cancer with faint, incomplete membrane stained in <=10% tumor cells tested in an IHC assay).

[0488] In some embodiments, the cancer described herein is HER2+breast cancer. In some embodiments, the cancer described herein is HER2‘ breast cancer. In some embodiments, the cancer described herein is HER2-low breast cancer.

[0489] In some embodiments, the cancer described herein is a hormone receptor positive (HR1) cancer. In some embodiments, the cancer described herein is a HER2' and HR+cancer. In some embodiments, the cancer described herein is ER+. In some embodiments, the cancer described herein is PR+. In some embodiments, the cancer is HR+ / ER’ breast cancer.

[0490] In some embodiments, the cancer described herein is HR+ and has a HER2 score of 0 or +1. In some embodiments, the cancer described herein is HR+ and has a HER2 score of 0. In some embodiments, the cancer described herein is HR+ and has a HER2 score +1.

[0491] In some embodiments, the cancer described herein is HR+ and has a HER2 score of +2 or +3. In some embodiments, the cancer described herein is HR+ and has a HER2 score of +2. In some embodiments, the cancer described herein is HR+ and has a HER2 score +3.

[0492] In some embodiments the subject has been previously identified or determined not to have an activating mutation in AKT, RAS, RAF, or an inactivating mutation or genomic loss of PTEN, or a combination thereof. In some embodiments the subject has been previously identified or determined not to have an activating mutation in AKT and / or PTEN (i.e., inactivation or genomic loss of PTEN). In some embodiments the subject has been previously identified or determined not to have an E17K mutation in AKT. In some embodiments, the PI3Ka-associated cancer is selected from the cancers described in Table 1 and Table 2. Table 1. PI3Ka Protein Amino Acid Substitutions / Insertions / Deletions4

[0493]

[0494]

[0495] AUnless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The eBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pH (2013). t Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41( 11): 1649-54. doi: 10.1016 / j.ejca.2005.04.022. PM1D: 15994075. Table 2. Additional PI3Ka Protein Amino Acid Substitutions / Insertions / DeletionsA AUnless noted otherwise, the mutations of Table 2 are found in cBioPortal database derived from Cerami et al. The eBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pH (2013). t Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(l l): 1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[0496] In some embodiments, the dysregulation of &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, includes a splice variation in a PI3Ka mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Ka having at least one residue deleted (as compared to the wild type PI3Ka protein) resulting in a constitutive activity of a PI3Ka protein domain.

[0497] In some embodiments, the dysregulation of &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, includes at least one point mutation in a PIK3CA gene that results in the production of a PI3Ka protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3Ka protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Ka protein. In some cases, the resulting mutant PI3Ka protein has increased activity, as compared to a wild type PI3Ka protein or aPI3Ka protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Ka protein relative to a wild type PI3Ka protein or a PI3Ka protein not including the same mutation.

[0498] Exemplary Sequence of Human Phosphatidylinositol 4, 5 -bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1)

[0499] MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK

[0500] VIEPVGNREE KILNREIGFA 1GMPVCEFDM VKDPEVQDFR RN1LNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLVV LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYK AYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN

[0501] In some embodiments, l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable thereof, is useful for treating a cancer that has been identified as having one or more PI3Ka mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of 1- (2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

[0502] Also provided herein are methods for treating a subject identified or diagnosed as having a PI3Ka-associated cancer that include administering to the subject a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a PI3Ka -associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an PI3Ka- associated cancer.

[0503] In some embodiments, the crystalline forms of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof described herein, are capable of crossing the blood-brain barrier (BBB) and inhibiting mutant PI3Ka in the brain and / or other central nervous system (CNS) structures after administration to a subject. In some embodiments, the crystalline forms of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof described herein, are capable of crossing the BBB in a therapeutically effective amount after administration to a subject.

[0504] The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0505] Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a PI3Ka-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a PI3Ka-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of aPIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an PI3Ka- associated cancer.

[0506] Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments of these methods, the subject was previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a PI3Ka- associated cancer, a subject presenting with one or more symptoms of a PI3Ka-associated cancer, or a subject having an elevated risk of developing a PI3Ka-associated cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art.

[0507] Also provided is l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof, for use in treating a PI3Ka-associated cancer in a subject identified or diagnosed as having a PI3Ka-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, where the presence of a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, identifies that the subject has a PI3Ka-associated cancer. Also provided is the use of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, for the manufacture of a medicament for treating a PI3Ka-associated cancer in a subject identified or diagnosed as having a PI3Ka-associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same where the presence of dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, identifies that the subject has a PI3Ka-associated cancer. Some embodiments described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, through the performance of the assay, should be administered l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency -approved assay, e g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0508] Also provided is l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a PI3Ka-associated cancer. Also provided is the use of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a PI3Ka-associated cancer. In some embodiments, a subject is identified or diagnosed as having a PI3Ka-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a PI3Ka-associated cancer includes those described herein and known in the art.

[0509] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of aPIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same. In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same. In some embodiments, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same. In some embodiments, the subject can be a subject whose tumors have a dysregulation of PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same. In some embodiments, the subject is suspected of having a PI3Koi-associated cancer. In some embodiments, provided herein are methods for treating a PI3Ka-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same includes one or more PI3Ka protein point mutations / insertions / deletions. Non-limiting examples of PI3Ka protein point mutations / insertions / deletions are described in Table 1 and Table 2. In some embodiments, the PI3Ka protein point mutation / insertion / deletion is H1047X, where X is any amino acid. In some embodiments, the PI3Ku. protein point mutations / insertions / deletions are selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. In some embodiments, the cancer with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same is determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.

[0510] In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same.

[0511] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a P1K3CA gene, a PI3Ka protein, or expression or level of any of the same. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same a therapeutically effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the method includes determining that a subject has a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a therapeutically effective amount of l-(2-aminopyrimidin-5- yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the dysregulation in &PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same is one or more point mutation in the PIK3CA gene (e.g., any of the one or more of the PI3Ka point mutations described herein). The one or more point mutations in & PIK3CA gene can result, e.g., in the translation of a PI3Ka protein having one or more of the following amino acid substitutions, deletions, and insertions: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, Ml 0431, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. The one or more mutations in a PIK3CA gene can result, e.g., in the translation of an PI3Ka protein having one or more of the following amino acids: 542, 545, 1043, and 1047 and 1049. In some embodiments, the dysregulation in a PIK3CA gene, a PI3Ka protein protein, or expression or activity or level of any of the same is one or more PI3Ka amino acid substitutions (e.g., any of the PI3Ka amino acid substitution described herein). Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy).

[0512] In some embodiments, an assay used to determine whether the subject has a dysregulation of a PIK3CA gene, or a PI3Ka protein, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a PI3Ka -associated cancer, a subject having one or more symptoms of a PI3Ka-associated cancer, and / or a subject that has an increased risk of developing a PI3Ka-associated cancer).

[0513] In some embodiments, dysregulation of PIK3CA gene, aPI3Ku protein, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., Ann. Transl. Med., 3(3): 36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or the dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same. Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of & PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same.

[0514] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a monotherapy at a dose of about 10 mg to about 200 mg per day, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg.

[0515] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a monotherapy at a dose of about 20 mg to about 200 mg per day, for example, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

[0516] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a monotherapy at a dose of about 20 mg to about 160 mg per day, for example, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, or about 160 mg.

[0517] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a monotherapy at a dose of about 60 mg to about 160 mg per day, for example, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, or about 160 mg.

[0518] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject once per day. In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject orally.

[0519] Also provided are methods of treating a PI3Ka-associated cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline Form 1 of Compound A, or a pharmaceutical composition comprising same.

[0520] Also provided are methods for treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline Form 1 of Compound A, or a pharmaceutical composition comprising same.

[0521] Also provided are methods for treating gynecologic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline Form 1 of Compound A, or a pharmaceutical composition comprising same.

[0522] Also provided are methods for treating endometrial cancer in a subject in need thereof the method comprising administering to the subject a therapeutically effective amount of the crystalline Form 1 of Compound A, or a pharmaceutical composition comprising same. Other Methods

[0523] Also provided is a method for inhibiting PI3Ka activity in a cell, comprising contacting the cell with l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, to a subject having a cell having aberrant PI3Ka activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Ka-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moi eties in an in vitro system or an in vivo system. For example, "contacting" a PI3Ka protein with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having a PI3Ka protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Ka protein.

[0524] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceuticl composition thereof as defined herein.

[0525] Further provided herein is a method of increasing cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective amount of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, in an amount effective to increase tumor cell death.

[0526] When employed as pharmaceuticals, l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, including pharmaceutically acceptable salts and / or solvates thereof, can be administered in the form of pharmaceutical compositions as described herein.

[0527] Combinations

[0528] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0529] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a combination therapy comprising a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0530] The other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies. Surgery can be open surgery or minimally invasive surgery, and includes partial and total resection of a solid tumor. l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or pharmaceutically acceptable salts and / or solvates thereof, therefore may also be useful as an adjuvant to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0531] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising:

[0532] (a) testing or having tested a subject to determine that the subject has a PI3Ka-associated cancer, and

[0533] (b) administering to the subject a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0534] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising:

[0535] (a) determining that the subject has a PI3Ka-associated cancer; and

[0536] (b) administering to the subject a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0537] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising:

[0538] (a) determining that the subject has a PI3Ka-associated cancer; and

[0539] (b) administering to the subject a combination therapy comprising a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents. Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Ka-associated cancer, comprising administering to the subject a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0540] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Ka-associated cancer, comprising administering to the subject of a combination therapy comprising a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more additional therapeutic agents.

[0541] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject

[0542] (a) a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and

[0543] (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with one additional therapeutic agent. In some embodiments, a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with two independently selected additional therapeutic agents.

[0544] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a combination therapy comprising: (a) a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and

[0545] (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with one additional therapeutic agent. In some embodiments, a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with two independently selected additional therapeutic agents.

[0546] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising:

[0547] (a) testing or having tested a subject to determine that the subject has a PI3Ka-associated cancer, and

[0548] (b) administering to the subject a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with one additional therapeutic agent. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with two independently selected additional therapeutic agents.

[0549] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising:

[0550] (a) determining that the subject has a PI3Ka-associated cancer; and

[0551] (b) administering to the subject a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with one additional therapeutic agent. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with two independently selected additional therapeutic agents.

[0552] Some embodiments provide a method of treating cancer in a subject in need thereof, comprising:

[0553] (a) determining that the subject has a PI3Ka-associated cancer; and

[0554] (b) administering to the subject a combination therapy comprising a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with one additional therapeutic agent. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3- (l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with two independently selected additional therapeutic agents.

[0555] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Ka-associated cancer, comprising administering to the subject

[0556] (a) a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and

[0557] (b) one or more independently selected additional therapeutic agents selected from the group consisting of: a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, and a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl )urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with one additional therapeutic agent. In some embodiments, a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with two independently selected additional therapeutic agents.

[0558] Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Ka-associated cancer, comprising administering to the subject of a combination therapy comprising a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, an EGFR inhibitor, an immune checkpoint inhibitor, a MEK inhibitor, a RAS inhibitor, a RAF inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, or a combination of any of the foregoing. In some embodiments, a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyljurea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with one additional therapeutic agent. In some embodiments, a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered with two independently selected additional therapeutic agents.

[0559] In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is PI3Ka inhibitor naive. For example, the subject is naive to treatment with a selective PI3Ka inhibitor. In some embodiments, a subject is not PI3Ka inhibitor naive. In some embodiments, a subject is kinase inhibitor naive. In some embodiments, a subject is not kinase inhibitor naive. In some embodiments, a subject has undergone prior therapy, for example, treatment with any one of the additional therapeutic agents described herein, or a combination thereof. In some embodiments, the subject has undergone prior therapy with a multikinase inhibitor (MKI) or another PI3Ka inhibitor, such as buparlisib (BKM120), alpelisib (BYL719), RLY-2608, WX-037, idelalisib, duvelisib, copanlisib, umbralisib, (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), fimepinostat (CUDC-907), bimiralisib (PQR309), ZSTK474, SF1126, AZD8835, inavolisib (GDC-0077), ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, paxalisib (GDC-0084, RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib (ON-01910 sodium salt), voxtalisib (XL-765), LY2023414, SAR260301, KIN-193 (AZD-6428), acalisib (GS- 9820), AMG319, or GSK2636771. Ill

[0560] In some embodiments, the subject was previously administered one or more PI3Ka inhibitors. In some embodiments, the subject was previously administered alpelisib (BYL719), RLY-2608, or both alpelisib (BYL719) and RLY-2608.

[0561] In some embodiments of any the methods described herein a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents. In some embodiments, the therapeutically effective amount of the additional therapeutic agent(s) is the therapeutically effective amount of the agent(s) when administered as a monotherapy. In some embodiments, the therapeutically effective amount of the additional therapeutic agent(s) is the amount administered in combination with a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, as described herein.

[0562] In some embodiments, the subject is also instructed to maintain a particular diet and / or exercise regimen to control blood sugar levels.

[0563] Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the crystalline form l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea and the additional therapeutic agent are together effective in treating the cancer.

[0564] In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of a PIK3CA gene, a PI3Ku protein, or expression or activity, or level of any of the same.

[0565] These additional therapeutic agents may be administered with one or more doses of a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[0566] Also provided herein is (i) a pharmaceutical combination for treating a cancer in a subject in need thereof, which comprises (a) a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salt and / or solvate thereof, and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a subject in need thereof. In some embodiments, the cancer is a PI3Ka-associated cancer.

[0567] The term “pharmaceutical combination”, as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent), are both administered to a subject simultaneously in the form of a single composition or dosage. The term “non-fixed combination” means that a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients.

[0568] Accordingly, also provided herein is a method of treating a cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salt and / or solvate thereof, and (b) an additional therapeutic agent, wherein a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the amounts of the crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salt and / or solvate thereof, and the additional therapeutic agent are together effective in treating the cancer. In some embodiments, the crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salt and / or solvate thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the crystalline form of l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salt and / or solvate thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e g., in daily or intermittently dosages. In some embodiments, the crystalline form of l-(2-aminopyrimidin-5-yl)- 3-(l-(5,7-difIuoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or pharmaceutically acceptable salt and / or solvate thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage.

[0569] Non-limiting examples of additional therapeutic agents include: other PI3Ka-targeted therapeutic agents (i.e., other PI3Ka inhibitors), EGFR inhibitors, VEGFR inhibitors / VEGF inhibitors, HER2 inhibitors, MEK pathway targeted therapeutic agents (including RAS pathway targeted therapeutic agents, which includes mTOR modulators / inhibitors, as described herein), SHP2 inhibitors, ULK inhibitors, cytotoxic chemotherapeutic, CDK2 inhibitors, Cyclin E inhibitors, CDK4 inhibitors, CDK6 inhibitors, CDK4 / 6 inhibitors, NTRK / ROS inhibitors, ALK inhibitors, RET inhibitors, MET inhibitors, PARP inhibitors, PIM (e.g., PIM1 and PIM3) inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., Trk inhibitors or multi-kinase inhibitors)), KAT6A inhibitors, farnesyl transferase inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (SERMs / SERDs, including ERa inhibitors or ERa degraders), vinca alkaloids, signal transduction pathway inhibitors, anti-metabolites, anti-androgens (e.g., androgen receptor (AR) antagonists, AR degraders, AR modulators), alkylating agents, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax), cytotoxic chemotherapeutics (also called antineoplastic chemotherapeutics), angiogenesis-targeted therapies (e.g., angiogenesis inhibitors), immune- targeted agents (including immunotherapy), radiotherapy, glucocorticoids, antidiarrheal agents (such as loperamide and diphenoxylate-atropine), antihistamines, and retinoic acid.

[0570] As used herein, a PIM inhibitor is any inhib leukemia virus kinase (also sometimes referred to virus protein kinase), e.g., PIM1, PIM2, and PIM3, and any isoforms thereof (e g., PIM-1L (molecular mass of 44 kDa) and PIM-1S (molecular mass of 33 kDa)). PIM kinases regulate cell proliferation, survival, metabolism, cellular trafficking and signaling and are overexpressed in a number of human cancers. Non-limiting examples of PIM1 inhibitors include A47, abemaciclib (Verzenio; NCT03905889), AZD1208 (NCT01588548), AZD1897, ETH-155008, ETP-390101, ETP-45299, ETP-47551, INCB053914 (Uzansertib), JP11646, K00135, K00486, LGB321, LGH447 (PIM447), PIM447, SEL24 / MEN1703 (SEL24-B489), SGI-1776, and TP-3654 (See, Belon and Nicot (2023) Mol. Cancer 22(1): 18; Mahata S., et a;. (2022) Med. Oncol. 39(5): 74; Asasti V., et al. (2019) Eur J Med Chem. 172:95-108; Le X., et al. (2016) Cancer Discov. 6(10): 1134-47; Keeton EK, et al. (2014) Blood 123: 905-13; Garcia P., et al. (2013) ASH 122:1666; Grundler R, et al. (2009) J Exp Afed206(9): 1957-70; Pogacic V., et al., (2007) Cancer Res. 67(14): 6916-6924).

[0571] Exemplary SHP2 inhibitors include JAB-3312, SHP099, SHP099 hydrochloride, SHP504, RMC-3943, AS1949490, SHP394, SHP389, and RMC-4630.

[0572] In some embodiments, the SHP2 inhibitor is RMC-4630.

[0573] Exemplary ULK inhibitors include ULK-101, SBP-7455, SBI-0206965, ULK1-IN-2, MRT68921, MRT68921 dihydrochloride, MRT67307, MRT67307 hydrochloride, XST-14, and GW406108X (CW108X).

[0574] Exemplary NTRK / ROS inhibitors include entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005), Exemplary ALK inhibitors include crizotinib (XALKORI®, PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-011, PF-06463922, ensartinib (X- 396), or CEP-37440.

[0575] Exemplary RET inhibitors include selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS-172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).

[0576] Exemplary MET inhibitors include capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL- 504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS- 115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride).

[0577] Exemplary TRK or multi -targeted kinase inhibitors include altiratinib (DCC-2701), CH7057288, larotrectinib (VITRAKVI®), entrectinib, ANA-12, repotrectinib (TPX-0005), sitravatinib (MGCD516, MG-516), lestaurtinib (CEP-701, KT-5555), tyrphostin AG 879 (AG 879), and selitrectinib (LOXO-195).

[0578] Exemplary tyrosine kinase inhibitors include axitinib (INLYTA®), dasatinib (SPRYCEL®), erlotinib (TARCEVA®), imatinib (GLIVEC), nilotinib (TASIGNA®), pazopanib (VOTRIENT®), sunitinib (SUTENT®), and vemurafenib

[0579] Exemplary vinca alkaloids include vinorelbine, vinblastine, vincristine, vindesine, and vinflunine.

[0580] Exemplary antimetabolites include methotrexate, 5 -fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine (XELODA®), floxuridine, cytarabine (ARA-C®), fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, pemetrexed (ALIMTA®), phototrexate, decitabine, vidaza, DFP- 11207, and RX-3117, TAS-114

[0581] Exemplary alkylating agents include cyclophosphamide, lomustine, carmustine, streptozocin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, melphalan, busulfan, dacarbazine, temozolomide, altretamine, thiotepa, carboplatin, cisplatin, lurbinectedin, trabectedin, carmustine, oxaliplatin, and oxaliplatin. Exemplary checkpoint inhibitors include nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, ipilimumab, LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), FS118, MBG453, Sym023, TSR- 022, MGC018, FPA150, EOS 100850, AB928, CPI-006, monalizumab, COM701, CM24, NEO- 201, defactinib, PF-04136309, MSC-1, Hu5F9-G4 (5F9), ALX148, TTI-662, RRx-001, lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397), CAN04, canakinumab (ACZ885), BMS-986253, pepinemab (VX15 / 2503), trebananib, FP-1305, enapotamab vedotin (EnaV), and bavituximab.

[0582] Exemplary modulators of the apoptosis pathway include obataclax, oblimersen, ABT-737, navitoclax (ABT-263), venetoclax (ABT- 199), Z-VAD-FMK, emricasan, Q-VD-Oph, Z- VAD(OH)-FMK, belnacasan (caspase-1), Z-DEVD-FMK (caspase-3), Q-VD-OphZ-IETD-FMK (caspase-8), PAC-1 (procaspase-3), nutlin-3, nutlin-3a, idasanutlin, HDM201, APR-246, CBL0137, pifithrin-a, pifithrin-p, Z-VAD-FMK, Emricasan, Q-VD-Oph, Z-VAD(OH)-FMK, pomalidomide, lenalidomide, YM155, Venetoclax (Bcl-2), S63845 (MCL-1), and A-1331852 (BCL-XL).

[0583] Exemplary cytotoxic chemotherapeutics include 5-fluorouracil, gemcitibine, methotrexate, NB1011, cyclophosphamide, dacarbazine, melphalan, tracectedin, temozolomide, doxorubicin, daunrorubincin, mitoxantrone, vinblastine, paclitaxel, docetaxel, irinotecan, etoposide, and platinum agents such as carboplatin, cisplatin, and oxaliplatin.

[0584] Exemplary topoisomerase inhibitors include etoposide, irinotecan, camptothecin (CPT), topotecan (TPT), irinotecan, belotecan, indenoisoquinoline, phenanthridines, and indolocarbazoles. Additional examples of topoisomerase inhibitors include aminocamptothecin, CT-2106, crisnatol mesylate, DE-310, elinafide, lucanthone, MLN576, and mitindomide.

[0585] Exemplary angiogenesis-targeted therapies include bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, CM101, IFN-a, IL-12, platelet factor-4, suramin, SU5416 thrombospondin, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, prolactin, linomide, ramucirumab, tasquinimod, ranibizumab, sorafenib, sunitinib, pazopanib, everolimus, lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST® or Imnovid ®), marimistat, 2-methoxyestradiol (PANZEM), SU5415, SU6668, pemaxanib, sunitinib, vandetanib, vitaxin, YM598, ZD6126, and aflibercept.

[0586] In some embodiments, the angiogenesis targeted therapy is lenalidomide. In some embodiments, the angiogenesis targeted therapy is pomalidomide.

[0587] In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSO®), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA®, IMC-11F8), neratinib (HKI-272, NERLYNX®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITA®, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), maverlertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF -299, PF-299804), avitinib (AC0010), AC0010MA, EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT- 414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetyl shikonin, P,P-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), lazertinib (YH25448), epitinib (HMPL-813), olafertinib (CK-101, RX518), MM-151, zorifertinib (AZD3759), vandetanib (ZD6474), PF- 06459988, varlintinib (ASLAN001, ARRY-334543), mobocertinib (AP32788, TAK-788), pimurutamab (HLX07), befotertinib (D-0316), AEE788 (NVP-AEE788), aumolertinib (formerly almonertinib, HS-10296), avitinib, lapatinib (GW572016), pyrotinib (SHR1258), SCT200, CPGJ602, Sym004 (combination of futuximab and modotuximab), EMD 55900 (MAb-425), modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, RO5083945, laprituximab emtansine (IMGN289), amivantamab (RYBREVANT™, JNJ-61186372), LY3164530, Pan-HER (Sym013), AMG 595, tuxobertinib (BDTX-189), avatinib, disruptin, CL-387785 (EKI-785, WAY-EKI 785), EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from gefitinib, erlotinib, afatinib, lapatinib, neratinib, osimertinib (AZD-9291, e.g., TAGRISSO®), CL-387785 (EKI-785, WAY- EKI 785), rociletinib (CO-1686), WZ4002, OMP-305B83, trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), RG-7597, and amivantanab.

[0588] In some embodiments, the EGFR inhibitor is lazertinib. In some embodiments, the EGFR inhibitor is amivantanab. In some embodiments, the EGFR inhibitor is trastuzumab. Exemplary HER2 inhibitors include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), fam-trastuzumab deruxtecan (ENHERTU®), lapatinib, KU004, neratinib (e.g., NERLYNX®), sacituzumab govitecan-hziy (TRODELVY®) dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (irbinitinib, ONT-380, ARRY-380, e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, dacomitinib (PF299804, PF299), pelitinib, margetuximab, AEE-788 (NVP-AEE788), enfortumab vedotin (PADCEV®), and datopotamab deruxtecan.

[0589] In some embodiments, the HER2 inhibitor is fam-trastuzumab deruxtecan. In some embodiments, the HER2 inhibitor is sacituzumab govitecan-hziy. In some embodiments, the HER2 inhibitor is datopotamab deruxtecan.

[0590] Exemplary VEGFR inhibitors / VEGF inhibitors include pazopanib, sunitinib, lenvatinib, cabozantinib, sorafenib, regorafenib, ponatinib, lenvatinib axitinib, ziv-aflibercept, vandetanib, tivozanib, vatalanib, AZD-2932, aflibercept, vanucizumab, BI836880, double anti angiogenic protein (DAAP), and ramucirumab.

[0591] A “MEK pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a MEK pathway including any protein in the RAS pathway and the RAF pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation) A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K / AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K (i.e., other PI3K inhibitors, as described herein), AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor.

[0592] Non-limiting examples of RAS-targeted therapeutic agents include sotorasib (AMG 510, Lumakras®), adagrasib (MRTX849), tipifamib (R115777, zamestra), cysmethynil, UCM-1336, deltarasin, NHTD, RM007, RM008, gefitinib, apatinib, oncrasin-1, vismodegib (GDC-0449), N- (l-Acryloylazetidin-3-yl)-2-(5-bromo-3-(5-methoxy-l,2,3,4-tetrahydroisoquinoline-2-carbonyl)- IH-indol-l-yl) acetamide, 2-((4-((l-(2-(2,4-Dichlorophenoxy) acetyl) piperidin-4-yl) amino)-4- oxobutyl) disulfaneyl)-N,N-dimethylethan-l-aminium, ARS-1620, ARS-853, bemcentinib (BGB324), ABT-737, selumetinib (AZD6244), dactolisib (NVP-BEZ235), PPIN-1, PPIN-2, pan- RAS Inhibitor 3144 (RAS-IN-3144), deltarasin, SML-8-73-1, SML- 10-70-1, l-(2-hydroxyethyl)- 4-(2-methyl-3,5-diphenylpyrazolo[l,5-a] pyrimidin-7-yl) piperazin- 1-ium, (2R,4aR)-3-acryloyl- 1 l-chloro-9-fluoro-10-(6-fluoro-2-hydroxycyclohexa-2,4-dien-l-yl)-2,6-dimethyl-2,3,4,4a- tetrahydro- IH-pyrazino [l’,2’:4,5] pyrazino[2,3-c] quinolin-5(6H)-one, NHTD, PD98059, wortmannin, talniflumate, gefitinib, CPD-0857, KY1022, KYA1797K (ab229170), 0375-0604 (DUN09716), 7773, NSC-658497, JNJ-74699157, PKF115-584 (calphostin C), Kobe0065, Kobe2602, salirasib, 3,3’-(ethylazanediyl)bis(N-phenylpropanamide), ML264, GDC-6036, LY3499446, and D-1553.

[0593] Non-limiting examples of KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include BI 1701963, sotorasib (AMG 510), ARS-3248 (JNJ-74699157), ARS1620, AZD4785 (ION651987), SML-8-73-1, SML-10-70-1, VSA9, AA12, adagrasib (MRTX-849), LY3499446, ARS853, and siG12D LODER.

[0594] Non-limiting examples of HRAS-targeted therapeutic agent (e.g., HRAS inhibitors) include tipifamib (ZARNESTRA®). Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the

[0595] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK 162), selumetinib (AZD6244), mirdametinib (PD0325901), pimasertib (MSC1936369B), SHR7390, TAK-733, RO5126766 (CH5126766), CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

[0596] In some embodiments, the ERK inhibitor is amerliorex (FRI-20, ON-01060), VTX-l le, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS- 136, AZ-13767370, BL-EI-001, temuterkib (LY-3214996), rineterkib (LTT-462), KO-947, MK- 8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, ravoxertinib (GDC-0994, RG-7482), ASN007, 5Z-7-oxozeaenol (FR148083, L783279, LL-Z 1640-2), 5-iodotubercidin (NSC 113939), ONC201 (TIC10), or a combination thereof.

[0597] In some embodiments, the anti-androgen is leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), enzalutamide (MDV3100, XT ANDI®), abiraterone (ZYTIGA®), flutamide (EULEXIN®), AR inhibitor EPI-506, apalutamide (ERLEADA®), and darolutamide (NUBEQ A®).

[0598] In some embodiments, the other PI3K inhibitor is another PI3Ka inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, the other PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719, PIQRAY®), RLY- 2608, idelalisib, duvelisib, umbralisib, WX-037, copanlisib (ALIQOPA®, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), fimepinostat (CUDC-907), bimiralisib (PQR309), ZSTK474, SF1126, AZD8835, inavolisib (GDC-0077), ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF- 05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, paxalisib (GDC-0084, RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib (ON-01910 sodium salt), voxtalisib (XL-765), LY2023414, SAR260301, KIN-193 (AZD-6428), acalisib (GS-9820), AMG319, GSK2636771, or a combination thereof.

[0599] In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, capivasertib (AZD5363), ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib (GSK2141795), afuresertib (GSK2110183), DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK- 2206, edelfosine, miltefosine, perifosine (KRX-0401), erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427 (CS-0223), PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3-yl)benzyl)-3-fluorobenzamide, miransertib (ARQ092), BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, ONC201 (TIC 10), and TAS 117.

[0600] In some embodiments, the AKT inhibitor is capivasertib.

[0601] In some embodiments, the mTOR inhibitor is an analog of rapamycin. Examples of analogs of ramapycin include sapanisertib (MLN0128), vistusertib (AZD-2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), everolimus (RAD001, e g., AFINITOR® or ZORTRESS®), umirolumus, zotarolimus, and RMC-5552. In some embodiments, the mTOR inhibitor is an ATP-competitive mTOR kinase inhibitor, which compete with ATP in the catalytic site of mTOR. Examples of ATP-competitive mTOR kinase inhibitors can include torin-1, torin-2, and vestusertib. Types of ATP-competitive mTOR kinase inhibitors can include mTOR / PI3J dual inhibitors and mTORCl / mTORC2 dual inhibitors (also called TORCdls). Examples of mTORZPI3K dual inhibitors include dactolisib, voxtalisib, BGT226, SF1126, PKI- 587, NVPBE235. Example of mTORCl / mTORC2 dual inhibitors include sapanisertib (codenamed INK128), AZD8055, and AZD2014.

[0602] Non-limiting examples of farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0603] In some embodiments, a chemotherapeutic agent includes an anthracycline, alkylating agents, a taxane, a platinum-based agent, mitomycin, gemcitabine, pemetrexed, eribulin (HALAVEN™), or combinations thereof.

[0604] Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.

[0605] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin.

[0606] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and lobaplatin. Any of the platinum-based agents can be conjugated to a nanocarrier, such as a gold nanocluster, a gold nanoparticle, or a superparamagnetic iron oxide nanoparticles. See, for example, Zhang et al. 2022. Theranostics. 12(5):2115-2132.

[0607] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP-9883, CEP 9722, E7016 (GPI 21016), iniparib, senaparib (IMP4297), venadaparib-idience (NOV1401, IDX-1197), stenoparib (2X-121), ABT-767, atamparib (RBN-2397), talazoparib (BMN 673), olaparib (KU-0059436, AZD2281, e.g. LYNPARZA™), iniparib (BSI-201, SAR240550), rucaparib (A G-014699, PF-01367338), ING-1001, and amelparib (JPI-289).

[0608] Non-limiting examples of aromatase inhibitors include aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, and fadrozole.

[0609] Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include clomifene, cyclofenil, anordrin, broparestrol, nafoxidine, ormeloxifene, raloxifene, toremifene, lasofoxifene, bazedoxifene, ospemifene, afimoxifene, enclomiphene, serophene, arzoxifene, tamoxifen, etacstil (GW-5638, DPC974), fulvestrant (FASLODEX®), brilanestrant, elacestrant (ORSERDU™), giredestrant, amcenestrant (SAR439859), camizestrant (AZD9833), rintodestrant, imlunestrant, LSZ102, LY3484356, ZN-c5, taragarestrant (D-0502), AZD9496, clotrimazole, fenti conazole, SHR9549, and palazestrant (OP-1250).

[0610] In some embodiments, the SERM / SERD is palazestrant. In some embodiments, the SERM / SERD is elacestrant. In some embodiments, the SERM / SERD is camizestrant.

[0611] Non-limiting examples of glucocorticoids include dexamethasone, beclomethasone, betamethasone, budesonide, cortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.

[0612] In some embodiments, the glucocorticoid is dexamethasone.

[0613] In some embodiments, the additional therapeutic agent is retinoic acid.

[0614] Non-limiting examples of epigenetic agents include EZH2 inhibitors (e.g., tazemetostat, such as TAZVERIK ®, 3-deazaneplanocin A (DZNep or C-c3Ado), EPZ005687, Ell, GSK126, and UNC1999) and HD AC inhibitors (e.g., vorinostat (SAHA) and panobinostat (LBH589)). Nonlimiting examples of HDAC inhibitors include hydroxamic acids (or hydroxamates), such as trichostatin A, vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat (LBH589); cyclic tetrapeptides, such as trapoxin B, and depsipeptides; benzamides, such as entinostat (MS- 275), tacedinaline (CI994), and mocetinostat (MGCD0103); electrophilic ketones; and aliphatic acid compounds such as phenylbutyrate and valproic acid.

[0615] In some emodiments, the epigenetic agent is an EZH2 inhibitor. In some embodiments, the epigenetic agent is tazemetostat. In some embodiments, the EZH2 inhibitor is tazemetostat.

[0616] In some emodiments, the epigenetic agent is a HD AC inhibitor. In some embodiments, the epigenetic agent is vorinostat. In some embodiments, the epigenetic agent is panobinostat. In some embodiments, the HDAC inhibitor is vorinostat. In some embodiments, the HDAC inhibitor is panobinostat.

[0617] Non-limiting examples of KAT6A inhibitors include WM-8014, PF-07248144, CTx- 648 (PF-9363), and CTX-0124143. In some embodiments, the KAT6A inhibitor is WM-8014. In some embodiments, the KAT6A inhibitor is PF-07248144. In some embodiments, the KAT6A inhibitor is CTx-648. In some embodiments, the KAT6A inhibitor is CTX-0124143.

[0618] Non-limiting examples of immunotherapy include immune checkpoint therapies, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapies include inhibitors that target CTLA-4, PD-1 , PD-L1 , BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®), atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), avelumab (BAVENCIO®), dostarlimab (JEMPERLI®), retifanlimab (ZYNYZ®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680), orAcrixolimab (YBL- 006). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof. In some embodiments, the LAG-3 inhibitor is leramilimab (IMP701, LAG525). In some embodiments, the A2AR inhibitor is ciforadenant (CPL444). In some embodiments, the TIM-3 inhibitor is sabatolimab (MBG453). In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is onvatilimab (JNJ-61610588). In some embodiments, the IDO inhibitor is indoximod. See, for example, Table 1 of Marin-Acevedo, et al., J Hematol Oncol. 11 : 39 (2018), which is incorporated in its entirety herein.

[0619] In some embodiments, the CDK2 inhibitor is selected from INX-315, BLU-222, INCB123667, AZD8421, and Tagtociclib (PF-07104091).

[0620] In some embodiments, the CDK4 inhibitor is PF-07220060.

[0621] In some embodiments, the cytotoxic chemotherapeutic is selected from abraxane, actinomycin, alitretinoin, all-trans retinoic acid, altretamine, azacitidine, azathioprine, belotecan, bendamustine, bexarotene, bleomycin, bortezomib, busulfan, cabazitaxel, camptothecin, carboplatin, carboquone, carmustine, capecitabine, cisplatin, chlorambucil, chlormethine, chlorozotocin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, decitabine, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, etoposide, exatecan, fludarabine, fluorouracil, fotemustine, gefitinib, gemcitabine, gimatecan, idarubicin, ifosfamide, imatinib, irinotecan, ixabepilone, larotaxel, lomustine, melphalan, mercaptopurine, methotrexate, mitobronitol, mitomycin C, mitoxantrone, nelarabine, nimustine, oxaliplatin, paclitaxel, pemetrexed, tafluposide, taxotere, temozolomide, tesetaxel, teniposide, thiotepa, topotecan, tretinoin, alrubicin, vemurafenib, vinblastine, vincristine, vindesine, vinorelbine, vismodegib, and vorinostat.

[0622] In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (IBRANCE®, TQB3616, PD-0332991), ribociclib (KISQALI®), abemaciclib (VERZENIO®), voruciclib (P1446A-05), trilaciclib, dalpiciclib (SHR6390), roniciclib (BAY1000394), dinaciclib, flavopiridol (alvociib, L868275, HMR-1275), roscovitine (R-roscovitine, CYC202, seliciclib), riviciclib (P276-00, P276), AT7519, TG02 (SB 1317), RGB-286638, dinaciclib (SCH 727965), PHA-793887, ZK-304709, xytocydine, SNS032 (BMS-387032), R547 (Ro 4584820), RGB286147, prvalanol A (NG60), meriolin 3, JNJ7706621, indirubin, AZD-5438, 10Z- hymenialdisine, AGO24322, PF-06873600,and KIN-8741.

[0623] In some embodiments, the CDK4 / 6 inhibitor is KIN-8741. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is dalpiciclib. In some embodiments, the CDK4 / 6 inhibitor is voruciclib. In some embodiments, the CDK4 / 6 inhibitor is roniciclib. In some embodiments, the CDK4 / 6 inhibitor is dinaciclib. In some embodiments, the additional therapy or therapeutic agent is selected from fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab- paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, palbociclib (IBRANCE®), buparlisib, sotrastaurin (AEB071), everolimus, exemestane, cisplatin, letrozole, ganitumab (AMG 479), LSZ102, ribociclib (LEE011), cetuximab, luminespib (NVP- AUY922, AUY922), infigratinib (BGJ398), binimetinib (MEK162, ARRY-162, ARRY-438162), LJM716, PIM447 (LGH447, LGB321), imatinib, gemcitabine, encorafenib (LGX818), and amcenestrant.

[0624] In some embodiments, the additional therapeutic agent is everolimus. In some embodiments, additional therapeutic agents may also be administered to treat potential side-effects for particular anticancer therapies and / or as palliative therapy, for example, opioids and corticosteroids. In some embodiments, the additional therapy or therapeutic agent described herein is selected from the group consisting of a glucagon-like peptide-1 (GLP-1) receptor agonist, a sodium-glucose transport protein 2 (SGLT-2) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, metformin, and combinations thereof.

[0625] Non-limiting examples of GLP-1 receptor agonists include liraglutide (NN2211, e.g., VICTOZA®,), dulaglutide (LY2189265, e.g., TRULICITY®), exenatide (e.g., BYETTA®, BYDUREON®, Exendin-4), taspoglutide, lixisenatide (e.g., LYXUMIA®), albiglutide (e.g., TANZEUM®), semaglutide (e.g, OZEMPIC®, RYBELSUS®), ZP2929, NNC0113-0987 (QBR110395), BPI-3016, and TT401.

[0626] Non-limiting examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (e.g, INVOKANA®), dapagliflozin (e.g, FARXIGA®), empagliflozin (e.g, JARDIANCE®), ertugliflozin (e.g, STEGLATRO™), ipragliflozin (e.g, SUGLAT®), luseogliflozin (e.g, LUSEFI®), remogliflozin, serfliflozin, licofliglozin, sotagliflozin (e.g, ZYNQUISTA™), and tofogliflozin.

[0627] Non-limiting examples of DPP-4 inhibitors include, sitagliptin (e.g, JANUVIA®), vildagliptin, saxagliptin (e g, ONGLYZA®), linagliptin (e.g, TRADJENDA®), gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin (e.g, NESINA®), omarigliptin, evogliptin, and dutogliptin. In some embodiments, the additional therapeutic agent is metformin. In some embodiments, the methods described herein further comprise administering a therapeutically effective amount of metformin to the subject.

[0628] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one additional therapeutic agent, for example, an aromatase inhibitor, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a SERM / SERD, radiation therapy, an anti-HER2 antibody or antibody-drug conjugate (ADC) thereof, an immunotherapy, a checkpoint inhibitor (e.g., an anti-PD-1 or PD-L1 antibody, an anti-CLTA4 antibody), VEGFR inhibitors / VEGF inhibitors, KAT6A inhibitors (also called MOZ inhibitors or MYST3 inhibitors), PI3Ka inhibitors, MEK pathway targeted therapeutic agents (including RAS pathway targeted therapeutic agents, which includes mTOR inhibitors, as described herein), SHP2 inhibitors, ULK inhibitors, NTRK / ROS inhibitors, ALK inhibitors, RET inhibitors, MET inhibitors, PARP inhibitors, PIM (e.g., PIM1 and PIM3) inhibitors, other kinase inhibitors (e.g., Trk inhibitors or multi-kinase inhibitors), farnesyl transferase inhibitors, vinca alkaloids, anti-metabolites, anti-androgens, alkylating agents, checkpoint inhibitors, modulators of the apoptosis pathway; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents including immunotherapy, or an anti- EGFR antibody.

[0629] In some embodiments, the additional therapeutic agent is an antibody or ADC as described herein. In some embodiments, the antibody is daratumumab (e.g., DARZALEX®).

[0630] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difIuoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one additional therapeutic agent, for example, a HER2 inhibitor, a SERM / SERD, a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a MEK inhibitor, a checkpoint inhibitor (e.g., an anti-PD-1 or PD-L1 antibody, an anti-CLTA4 antibody), a multikinase inhibitor, and a PI3K inhibitor.

[0631] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and one additional therapeutic agent, for example, trastuzumab, pertuzumab, trastuzumab emtansine, fam -trastuzumab deruxtecan, lapatinib, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, tanespimycin, dacomitinib, pelitinib, margetuximab, clomifene, cyclofenil, broparestrol, ormeloxifene, raloxifene, toremifene, lasofoxifene, bazedoxifene, ospemifene, enclomiphene, serophene, tamoxifen, fulvestrant, elacestrant, camizestrant, rintodestrant, clotrimazole, fenticonazole, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, ipilimumab, palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, trametinib, cobimetinib, binimetinib, selumetinib, mirdametinib, pimasertib, alpelisib, RLY-2608, idelalisib, duvelisib, copanlisib, umbralisib, ribociclib, triaciclib, dalpiciclib, voruciclib, and roniciclib.

[0632] In some embodiments, the additional therapeutic agent is fulvestrant.

[0633] In some embodiments, the additional therapeutic agent is lapatinib.

[0634] In some embodiments, the additional therapeutic agent is abemaciclib.

[0635] In some embodiments, the additional therapeutic agent is trametinib.

[0636] In some embodiments, the additional therapeutic agent is binimetinib.

[0637] In some embodiments, the additional therapeutic agent is alpelisib.

[0638] In some embodiments, the additional therapeutic agent is RLY-2608.

[0639] In some embodiments, the additional therapeutic agent is palbociclib.

[0640] In some embodiments, the additional therapeutic agent is ribociclib. In some embodiments, the additional therapeutic agent is trilaciclib. In some embodiments, the additional therapeutic agent is dalpiciclib. In some embodiments, the additional therapeutic agent is voruciclib. In some embodiments, the additional therapeutic agent is roniciclib. In some embodiments, the additional therapeutic agent is dinaciclib.

[0641] In some embodiments, the additional therapeutic agents are palbociclib and clomifene. In some embodiments, the additional therapeutic agents are palbociclib and cyclofenil. In some embodiments, the additional therapeutic agents are palbociclib and anordrin. In some embodiments, the additional therapeutic agents are palbociclib and broparestrol. In some embodiments, the additional therapeutic agents are palbociclib and nafoxidine.

[0642] In some embodiments, the additional therapeutic agents are palbociclib and ormeloxifene. In some embodiments, the additional therapeutic agents are palbociclib and raloxifene.

[0643] In some embodiments, the additional therapeutic agents are palbociclib and toremifene. In some embodiments, the additional therapeutic agents are palbociclib and lasofoxifene. In some embodiments, the additional therapeutic agents are palbociclib and bazedoxifene. In some embodiments, the additional therapeutic agents are palbociclib and ospemifene. In some embodiments, the additional therapeutic agents are palbociclib and afimoxifene. In some embodiments, the additional therapeutic agents are palbociclib and enclomiphene. In some embodiments, the additional therapeutic agents are palbociclib and serophene. In some embodiments, the additional therapeutic agents are palbociclib and arzoxifene.

[0644] In some embodiments, the additional therapeutic agents are palbociclib and tamoxifen.

[0645] In some embodiments, the additional therapeutic agents are palbociclib and etacstil.

[0646] In some embodiments, the additional therapeutic agents are palbociclib and fulvestrant.

[0647] In some embodiments, the additional therapeutic agents are palbociclib and brilanestrant.

[0648] In some embodiments, the additional therapeutic agents are palbociclib and elacestrant.

[0649] In some embodiments, the additional therapeutic agents are palbociclib and giredestrant. In some embodiments, the additional therapeutic agents are palbociclib and amcenestrant. In some embodiments, the additional therapeutic agents are palbociclib and camizestrant. In some embodiments, the additional therapeutic agents are palbociclib and rintodestrant. In some embodiments, the additional therapeutic agents are palbociclib and imlunestrant. In some embodiments, the additional therapeutic agents are palbociclib and LSZ102.

[0650] In some embodiments, the additional therapeutic agents are palbociclib and LY3484356.

[0651] In some embodiments, the additional therapeutic agents are palbociclib and ZN-c5.

[0652] In some embodiments, the additional therapeutic agents are palbociclib and taragarestrant. In some embodiments, the additional therapeutic agents are palbociclib and AZD9496. In some embodiments, the additional therapeutic agents are palbociclib and clotrimazole. In some embodiments, the additional therapeutic agents are palbociclib and fenticonazole. In some embodiments, the additional therapeutic agents are palbociclib and SHR9549. In some embodiments, the additional therapeutic agents are palbociclib and palazestrant.

[0653] In some embodiments, the additional therapeutic agents are ribociclib and clomifene.

[0654] In some embodiments, the additional therapeutic agents are ribociclib and cyclofenil.

[0655] In some embodiments, the additional therapeutic agents are ribociclib and anordrin.

[0656] In some embodiments, the additional therapeutic agents are ribociclib and broparestrol.

[0657] In some embodiments, the additional therapeutic agents are ribociclib and nafoxidine. In some embodiments, the additional therapeutic agents are ribociclib and ormeloxifene. In some embodiments, the additional therapeutic agents are ribociclib and raloxifene. In some embodiments, the additional therapeutic agents are ribociclib and toremifene. In some embodiments, the additional therapeutic agents are ribociclib and lasofoxifene. In some embodiments, the additional therapeutic agents are ribociclib and bazedoxifene. In some embodiments, the additional therapeutic agents are ribociclib and ospemifene.

[0658] In some embodiments, the additional therapeutic agents are ribociclib and afimoxifene. In some embodiments, the additional therapeutic agents are ribociclib and enclomiphene. In some embodiments, the additional therapeutic agents are ribociclib and serophene. In some embodiments, the additional therapeutic agents are ribociclib and arzoxifene. In some embodiments, the additional therapeutic agents are ribociclib and tamoxifen.

[0659] In some embodiments, the additional therapeutic agents are ribociclib and etacstil.

[0660] In some embodiments, the additional therapeutic agents are ribociclib and fulvestrant. In some embodiments, the additional therapeutic agents are ribociclib and brilanestrant. In some embodiments, the additional therapeutic agents are ribociclib and elacestrant. In some embodiments, the additional therapeutic agents are ribociclib and giredestrant. In some embodiments, the additional therapeutic agents are ribociclib and amcenestrant. In some embodiments, the additional therapeutic agents are ribociclib and camizestrant.

[0661] In some embodiments, the additional therapeutic agents are ribociclib and rintodestrant. In some embodiments, the additional therapeutic agents are ribociclib and imlunestrant. In some embodiments, the additional therapeutic agents are ribociclib and LSZ102.

[0662] In some embodiments, the additional therapeutic agents are ribociclib and LY3484356.

[0663] In some embodiments, the additional therapeutic agents are ribociclib and ZN-c5.

[0664] In some embodiments, the additional therapeutic agents are ribociclib and taragarestrant. In some embodiments, the additional therapeutic agents are ribociclib and AZD9496.

[0665] In some embodiments, the additional therapeutic agents are ribociclib and clotrimazole. In some embodiments, the additional therapeutic agents are ribociclib and fenticonazole. In some embodiments, the additional therapeutic agents are ribociclib and SHR9549. In some embodiments, the additional therapeutic agents are ribociclib and palazestrant. In some embodiments, the additional therapeutic agents are abemaciclib and clomifene. In some embodiments, the additional therapeutic agents are abemaciclib and cyclofenil. In some embodiments, the additional therapeutic agents are abemaciclib and anordrin.

[0666] In some embodiments, the additional therapeutic agents are abemaciclib and broparestrol. In some embodiments, the additional therapeutic agents are abemaciclib and nafoxidine. In some embodiments, the additional therapeutic agents are abemaciclib and ormeloxifene. In some embodiments, the additional therapeutic agents are abemaciclib and raloxifene.

[0667] In some embodiments, the additional therapeutic agents are abemaciclib and toremifene.

[0668] In some embodiments, the additional therapeutic agents are abemaciclib and lasofoxifene. In some embodiments, the additional therapeutic agents are abemaciclib and bazedoxifene. In some embodiments, the additional therapeutic agents are abemaciclib and ospemifene. In some embodiments, the additional therapeutic agents are abemaciclib and afimoxifene.

[0669] In some embodiments, the additional therapeutic agents are abemaciclib and enclomiphene.

[0670] In some embodiments, the additional therapeutic agents are abemaciclib and serophene.

[0671] In some embodiments, the additional therapeutic agents are abemaciclib and arzoxifene.

[0672] In some embodiments, the additional therapeutic agents are abemaciclib and tamoxifen.

[0673] In some embodiments, the additional therapeutic agents are abemaciclib and etacstil.

[0674] In some embodiments, the additional therapeutic agents are abemaciclib and fulvestrant.

[0675] In some embodiments, the additional therapeutic agents are abemaciclib and brilanestrant.

[0676] In some embodiments, the additional therapeutic agents are abemaciclib and elacestrant.

[0677] In some embodiments, the additional therapeutic agents are abemaciclib and giredestrant.

[0678] In some embodiments, the additional therapeutic agents are abemaciclib and amcenestrant. In some embodiments, the additional therapeutic agents are abemaciclib and camizestrant. In some embodiments, the additional therapeutic agents are abemaciclib and rintodestrant. In some embodiments, the additional therapeutic agents are abemaciclib and imlunestrant. In some embodiments, the additional therapeutic agents are abemaciclib and LSZ102.

[0679] In some embodiments, the additional therapeutic agents are abemaciclib and LY3484356.

[0680] In some embodiments, the additional therapeutic agents are abemaciclib and ZN-c5.

[0681] In some embodiments, the additional therapeutic agents are abemaciclib and taragarestrant.

[0682] In some embodiments, the additional therapeutic agents are abemaciclib and AZD9496.

[0683] In some embodiments, the additional therapeutic agents are abemaciclib and clotrimazole. In some embodiments, the additional therapeutic agents are abemaciclib and fenti conazole. In some embodiments, the additional therapeutic agents are abemaciclib and SHR9549.

[0684] In some embodiments, the additional therapeutic agents are abemaciclib and palazestrant.

[0685] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and two additional independently selected therapeutic agents, for example, a HER2 inhibitor, a SERM / SERD, a cytotoxic chemotherapeutic, a CDK2 inhibitor, a Cyclin E inhibitor, a CDK4 inhibitor, a CDK6 inhibitor, a CDK4 / 6 inhibitor, a MEK inhibitor, a checkpoint inhibitor (e.g., an anti-PD-1 or PD-L1 antibody, an anti-CLTA4 antibody), a multi-kinase inhibitor, and a PI3K inhibitor.

[0686] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and two additional independently selected therapeutic agents, for example, trastuzumab, pertuzumab, trastuzumab emtansine, fam-trastuzumab deruxtecan, lapatinib, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, tanespimycin, dacomitinib, pelitinib, margetuximab, clomifene, cyclofenil, broparestrol, ormeloxifene, raloxifene, toremifene, lasofoxifene, bazedoxifene, ospemifene, enclomiphene, serophene, tamoxifen, fulvestrant, elacestrant, camizestrant, rintodestrant, clotrimazole, fenti conazole, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, ipilimumab, palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, trametinib, cobimetinib, binimetinib, selumetinib, mirdametinib, pimasertib, alpelisib, RLY-2608, idelalisib, duvelisib, copanlisib, umbralisib, ribociclib, triaciclib, dalpiciclib, voruciclib, and roniciclib.

[0687] In some embodiments, the additional therapeutic agents are fulvestrant and lapatinib.

[0688] In some embodiments, the additional therapeutic agents are fulvestrant and abemaciclib.

[0689] In some embodiments, the additional therapeutic agents are fulvestrant and trametinib.

[0690] In some embodiments, the additional therapeutic agents are fulvestrant and binimetinib.

[0691] In some embodiments, the additional therapeutic agents are fulvestrant and alpelisib.

[0692] In some embodiments, the additional therapeutic agents are fulvestrant and RLY-2608.

[0693] In some embodiments, the additional therapeutic agents are fulvestrant and palbociclib.

[0694] In some embodiments, the additional therapeutic agents are fulvestrant and dalpiciclib.

[0695] In some embodiments, the additional therapeutic agents are fulvestrant and voruciclib.

[0696] In some embodiments, the additional therapeutic agents are fulvestrant and roniciclib. In some embodiments, the additional therapeutic agents are fulvestrant and dinaciclib.

[0697] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and an ERa inhibitor or degrader.

[0698] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a cytotoxic chemotherapeutic.

[0699] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a CDK2 inhibitor.

[0700] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difIuoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a Cyclin E inhibitor,

[0701] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a CDK4 inhibitor.

[0702] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a CDK6 inhibitor.

[0703] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor.

[0704] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a HER2 inhibitor.

[0705] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and alpelisib.

[0706] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and fulvestrant. In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and lapatinib.

[0707] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and abemaciclib.

[0708] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and a MEK inhibitor.

[0709] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and trametinib.

[0710] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and binimetinib.

[0711] In some embodiments, the method comprises administering a crystalline form of l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, and palbociclib.

[0712] Dosing of Combinations

[0713] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a combination therapy (such as a double or triple combination) with one or more additional therapeutic agents, wherein the dose of the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is about 10 mg to about 200 mg per day, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg. In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a combination therapy (such as a double or triple combination) with one or more additional therapeutic agents, wherein the dose of the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0714] 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is about 20 mg to about 160 mg per day, for example, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, or about 160 mg.

[0715] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a combination therapy (such as a double or triple combination) with one or more additional therapeutic agents, wherein the dose of the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0716] 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is about 20 mg to about 200 mg per day, for example, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.

[0717] In some embodiments, the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject as a combination therapy (such as a double or triple combination) with one or more additional therapeutic agents, wherein the dose of the crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-

[0718] 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, is about 60 mg to about 160 mg per day, for example, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, or about 160 mg.

[0719] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and fulvestrant. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and fulvestrant, wherein fulvestrant is administered at a dose in a range of about 250 mg to about 500 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l -(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-rnethylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and fulvestrant, wherein fulvestrant is administered at a dose of about 250 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and fulvestrant, wherein fulvestrant is administered at a dose of about 500 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and fulvestrant, wherein fulvestrant is administered as two 5 mb injections on days 1, 15, 29 and once monthly thereafter, where each 5 mb injection includes 250 mg of fulvestrant.

[0720] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and lapatinib. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and lapatinib, wherein lapatinib is administered at a dose in a range of about 1250 mg to about 1500 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and lapatinib, wherein lapatinib is administered at a dose of about 1250 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and lapatinib, wherein lapatinib is administered at a dose of about 1500 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and lapatinib, wherein lapatinib is administered as 5 tablets once daily, where each tablet includes 250 mg of lapatinib. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin- 5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and lapatinib, wherein lapatinib is administered as 6 tablets once daily, where each tablet includes 250 mg of lapatinib.

[0721] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein abemaciclib is administered at a dose in a range of about 150 mg to about 400 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein abemaciclib is administered at a dose of about 150 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein abemaciclib is administered at a dose of about 200 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein abemaciclib is administered at a dose of about 300 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein abemaciclib is administered at a dose of about 400 mg. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein abemaciclib is administered as 50 mg, 100 mg, 150 mg, or 200 mg tablets. In some embodiments, the method comprises administering a crystalline form of (R)- 1 -(2-aminopyrimi din-5 -yl)-3 -( 1 -(5,7-difluoro-3 -methylbenzofuran-2-yl )-2,2, 2- trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein 150 mg of abemaciclib is administered tablets twice daily. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7- difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and abemaciclib, wherein 200 mg of abemaciclib is administered tablets twice daily.

[0722] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and a MEK inhibitor.

[0723] In some embodiments, the method comprises administering a crystalline form of (R)-l-(2- aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof, and trametinib. In some embodiments, the method comprises administering a crystalline form of (R)-l-(2-a...

Claims

WHAT IS CLAIMED IS:

1. A crystalline form of (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3- methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof.

2. The crystalline form of claim 1, wherein the (R)-l-(2-aminopyrimidin-5-yl)-3-(l- (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is present in the form of a pharmaceutically acceptable solvate.

3. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1 characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 18.3 ± 0.2 degrees 26.

4. The crystalline form of claim 3, wherein the XRPD pattern has a peak at 15.8 ± 0.2 degrees 29.

5. The crystalline form of any one of claims 3-4, wherein the XRPD pattern has a peak at 6.4 ± 0.2 degrees 20.

6. The crystalline form of any one of claims 3-5, wherein the XRPD pattern has a peak at 22.3 ± 0.2 degrees 20.

7. The crystalline form of any one of claims 3-6, wherein the XRPD pattern has a peak at 20.8 ± 0.2 degrees 20.

8. The crystalline form of any one of claims 3-7, wherein the XRPD pattern has a peak at 19.3 ± 0.2 degrees 20.

9. The crystalline form of any one of claims 3-8, wherein the XRPD pattern has a peak at 24.0 ± 0.2 degrees 20.

10. The crystalline form of any one of claims 3-9, wherein the XRPD pattern has a peak at 26.9 ± 0.2 degrees 20.

11. The crystalline form of any one of claims 3-10, wherein the XRPD pattern has a peak at 14.6 ± 0.2 degrees 20.

12. The crystalline form of any one of claims 3-11, wherein the XRPD pattern has a peak at 31.3 ± 0.2 degrees 20.

13. The crystalline form of any one of claims 3-12, wherein the XRPD pattern has a peak at 28.3 ± 0.2 degrees 20.

14. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.4, 15.8, and 18.3.

15. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1, and wherein the XRPD pattern has peaks (± 0.2 degrees 20) at 6.4, 14.6, 15.8, 18.3, 19.3, 20.8, 22.3, 24.0, 26.9, 28.3, 29.2 and 31.3.

16. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form 1, characterized by an XRPD pattern substantially the same as that shown in FIG. 4.

17. The crystalline form of any one of claims 1-16, wherein the crystalline form is Form 1 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of about 2.3% at about 112.5 °C.

18. The crystalline form of any one of claims 1-17, wherein the crystalline form is Form 1 having a TGA curve characterized by a weight loss of about 17.6% at about 245 °C.

19. The crystalline form of any one of claims 1-18, wherein the crystalline form is Form 1 having a TGA curve that is substantially the same as that shown in FIG. 28.

20. The crystalline form of any one of claims 1-19, wherein the crystalline form is Form 1 prepared by a method comprising:(a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in isopropanol to form a solution;(b) adding water to the solution to form a mixture;(c) reducing the temperature of the mixture then maintaining the temperature for a first period of time;(d) increasing the temperature of the mixture then maintaining the temperature for a second period of time;(e) reducing the temperature of the mixture then maintaining the temperature for a third period of time; and(f) isolating Form 1 from the mixture.

21. The crystalline form of any one of claims 1-4, wherein the crystalline form is Form 1 prepared by a method comprising:(a) dissolving (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2- yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt and / or solvate thereof in methanol to form a solution;(b) adding water to the solution to form a first mixture;(c) adding (R)-l-(2-aminopyrimidin-5-yl)-3-(l-(5,7-difluoro-3-methylbenzofuran-2-yl)- 2,2,2-trifluoroethyl)urea Form 1 to the first mixture to form a second mixture;(d) agitating the second mixture;(e) adding water to the second mixture to form a third mixture;(f) agitating the third mixture; and(g) isolating Form 1 from the third mixture.

22. The crystalline form of claim 21 , wherein isolating Form 1 from the third mixture comprises:(i) filtering the third mixture to provide a solid;(ii) rinsing the solid with methanol and water; and(iii) drying the solid to provide Form 1.

23. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form1 * characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.3 ± 0.2 degrees 26.

24. The crystalline form of claim 23, wherein the XRPD pattern has a peak at 15.8 ± 0.2 degrees 20.

25. The crystalline form of any one of claims 23-24, wherein the XRPD pattern has a peak at 20.8 ± 0.2 degrees 26.

26. The crystalline form of any one of claims 23-25, wherein the XRPD pattern has a peak at 15.9 ± 0.2 degrees 26.

27. The crystalline form of any one of claims 23-26, wherein the XRPD pattern has a peak at 19.8 ± 0.2 degrees 26.

28. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form2 characterized by an X-ray powder diffraction (XRPD) pattern having peaks (± 0.2 degrees 26) at 6.2, 15.2, 15.3, 20.9, 21.9, 22.0, 21.0, 18.7, 18.7, and 26.9.

29. The crystalline form of any one of claims 1-2, wherein the crystalline form is Form3 characterized by an X-ray powder diffraction (XRPD) pattern having peaks (± 0.2 degrees 26) at 4.0, 4.9, 25.8, 21.4, 9.1, 19.2, 6.9, 15.7, 16.8, and 9.9.

30. The crystalline form of any one of claims 1 -2, wherein the crystalline form is Form 4 characterized by an X-ray powder diffraction (XRPD) pattern having peaks (± 0.2 degrees 20) at 6.3, 20.9, 15.5, 24.1, 21.5, 27.7, 15.8, 14.9, 20.5, and 26.9.

31. A pharmaceutical composition comprising the crystalline form of any one of claims 1-30 and a pharmaceutically acceptable carrier.

32. The pharmaceutical composition of claim 31, wherein the composition is in the form of a tablet.

33. The pharmaceutical composition of any one of claims 31-32, wherein the composition comprises microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate, or any combination thereof.

34. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1-30, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition of any one of claims 31-33.

35. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1-30, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition of any one of claims 31-33.

36. A method of treating a PI3Ka-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of the crystalline form of any one of claims 1-30 or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition of any one of claims 31-33.

37. A method for modulating PI3Ka in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of the crystalline form of any one of claims 1-30, or a pharmaceutically acceptable salt and / or solvate thereof.

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