Crystalline form of PI3K inhibitors and their use

Abstract

This specification discloses the crystalline form of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα) inhibitors, as well as their formulations and uses.

Description

[Technical Field]

[0001] (Related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 532,700, filed on 15 August 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] Sequence List This application includes a sequence listing submitted electronically as an XML file named "50006-0100WO1_ST26_SL.XML". The XML file, created on August 12, 2024, is 2,961 bytes in size. The material within the XML file is incorporated herein by reference in its entirety.

[0003] This specification discloses the crystalline form of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα) inhibitors. [Background technology]

[0004] 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is a phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα) inhibitor, disclosed in International Patent Application Publication No. 2022 / 265993, which is incorporated herein by reference in whole. PI3Kα, encoded by the PIK3CA gene, is part of the PI3K / AKT / TOR signaling network and is altered in several human cancers. Several researchers have demonstrated that the role of PI3K / AKT signaling is involved in physiological and pathophysiological functions that drive tumor progression, including metabolism, cell growth, proliferation, angiogenesis, and metastasis. (See Fruman, DACell 2017, 170, 605-635 and Janku, F. et al., Nat. Rev. Clin. Oncol. 2018, 15, 273-291.) Suppression of PI3K / AKT / TOR signaling (e.g., pharmacological or genetic) can induce cancer cell death and regression of tumor growth.

[0005] Crystalline polymorphism, i.e., the occurrence of different crystalline forms, is a characteristic of some molecules and molecular complexes. A given compound has a distinct crystalline structure, as well as a melting point, thermal behavior, X-ray diffraction pattern, IR spectrum, and solid state. 13 Various polymorphs with physical properties such as 13C NMR spectra can be produced. One or more of these techniques can be used to distinguish between different polymorphic forms of a compound.

[0006] Different salts and crystalline forms (including solvated forms) of active pharmaceutical ingredients may have different properties. Such differences in the properties of different salts and crystalline forms and solvates may provide a basis for improving the formulation and / or clinical properties. Different salts and solvates of active pharmaceutical ingredients may also give rise to various polymorphs or crystalline forms. [Overview of the project]

[0007] Some embodiments provide a crystalline form of (R)-1-(2-aminopyrimidine-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.

[0008] Some embodiments provide pharmaceutical compositions comprising a crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0009] Some embodiments provide a method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form disclosed herein, or a pharmaceutically acceptable salt and / or solvate thereof, or a crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0010] Some embodiments provide a method for treating cancer in a subject requiring cancer treatment, the method comprising: (a) determining that the cancer is related to dysregulation of the expression, activity or level of the PIK3CA gene, the PI3Kα protein, or either thereof; and (b) administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the crystalline form disclosed herein, or a pharmaceutically acceptable salt and / or solvate thereof, or the crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0011] Some embodiments provide a method for treating PI3Kα-related cancer in a subject, the method comprising administering to a subject identified or diagnosed with PI3Kα-related cancer a therapeutically effective amount of a pharmaceutical composition comprising the crystalline form disclosed herein or a pharmaceutically acceptable salt and / or solvate thereof, or the crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0012] Some embodiments provide methods for modulating PI3Kα in mammalian cells, the methods comprising contacting mammalian cells with a pharmaceutical composition comprising an effective amount of the crystalline form disclosed herein, or a pharmaceutically acceptable salt and / or solvate thereof, or the crystalline form disclosed herein and a pharmaceutically acceptable carrier.

[0013] Additional definitions To facilitate understanding of the disclosures contained herein, several additional terms are defined below. In general, the nomenclature used herein, as well as the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications referenced throughout this specification and its appendices is incorporated herein by reference in their entirety.

[0014] When referring to a number or numerical range, the term "approximately" means that the number or numerical range referred to is an approximation within, for example, experimental variability and / or statistical experimental error, and therefore the number or numerical range may vary by up to ±10% of the stated number or numerical range.

[0015] When used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not have any lasting adverse effects on the overall health of the subject being treated.

[0016] The terms "inhibit" or "inhibit" mean to reduce by a measurable amount or to completely prevent (e.g., 100% inhibition).

[0017] 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 that share the same molecular formula, but each polymorph can have distinct solid-state physical properties. Thus, a single compound can give rise to various polymorphic forms, each having different distinct solid-state physical properties such as different solubility profiles, dissolution rates, melting points, fluidity, and / or different X-ray diffraction peaks.

[0018] The term "amorphous" refers to a solid in a non-crystalline state. Amorphous solids are characterized by a disordered arrangement of molecules and therefore lack a recognizable crystalline lattice or unit cell, and consequently lack a definable long-range order. The morphology of the solid state can be determined by polarized light microscopy, X-ray powder diffraction ("XRPD"), differential scanning calorimetry ("DSC"), or other standard techniques known to those skilled in the art.

[0019] As used herein, a compound is "substantially pure" if it contains an insignificant amount of other components. Such components may include, for example, starting materials, residual solvents, other polymorphs or crystalline forms, reverse enantiomers, other salt forms, other solvates, or any other impurities that may arise from the preparation, isolation, and / or recrystallization of the compounds provided herein. In some embodiments, other components may include, for example, starting materials, residual solvents, other polymorphs or crystalline forms, reverse enantiomers, other salt forms, or any other impurities that may arise from the preparation, isolation, and / or recrystallization of the compounds provided herein. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is "substantially pure" if its crystalline form consists of at least about 95% by weight of the crystalline form. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is "substantially pure" if the crystalline form constitutes at least about 97% by weight, about 98% by weight, about 99% by weight, or about 99.5% by weight of the crystalline form.

[0020] The term "therapeutic dose" means an amount of the compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Kα protein-related disease or disorder, (ii) reduce, improve or eliminate one or more symptoms of a particular disease, condition or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition or disorder as described herein.

[0021] As used herein, the term “pharmaceutical composition” is intended to encompass any product comprising an active component(s) and an inactive component(s) constituting a carrier, as well as any product directly or indirectly arising from any combination, complex formation, or aggregation of any two or more components, or from the dissociation of one or more components, or from any other type of reaction or interaction of one or more components. Accordingly, the pharmaceutical compositions of the Disclosure encompass any composition prepared by mixing a compound of the Disclosure, or a pharmaceutically acceptable salt and / or solvate thereof, with a pharmaceutically acceptable carrier.

[0022] 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 that it is compatible with other components of a pharmaceutical formulation, suitable for use in contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. For example, 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 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.

[0023] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting the acidic compounds described herein with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, or by other methods previously determined. Pharmacologically acceptable salts are not particularly limited as long as they can be used pharmacopoeia. Examples of salts formed by the compounds described herein with bases include: salts having inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts having organic bases such as methylamine, ethylamine, and ethanolamine; salts having basic amino acids such as lysine and ornithine; and ammonium salts. The salts may also be acid addition salts, which specifically include 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; and acidic amino acids such as aspartic acid and glutamic acid.

[0024] The term "pharmaceutically acceptable solvate" refers to a solvate of a compound that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and properties of the compound. A solvate is a crystalline solid that contains molecules of the solvent within its crystal lattice. In some cases, the solvate form of a compound can 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. If the average number of water molecules present in each repeating unit (i.e., unit cell) of the hydrate's crystal lattice is known, the hydrate is prefixed with 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 a water molecule per unit cell. For more detailed information, see, for example, KRMorris, Polymorphism in Pharmaceutical Solids 1999, pages 125-181; Jeffrey, GAAcc. Chem. Res. 1969:344-352; Rev. Pure Appl. Chem., 1963, 50-90; and Encyclopedia of Pharmaceutical Technology, 1993, 7, pages 393-441 (each of these is incorporated herein by reference in its entirety).

[0025] The term "pharmaceutical composition" refers to a mixture of the compounds described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners (collectively referred to herein as "pharmaceutically acceptable excipients"). Pharmaceutical compositions facilitate the administration of compounds to living organisms. Multiple techniques exist in the art for administering compounds, including but not limited to rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0026] As used herein, the term “Subject” refers to any animal, including primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented.

[0027] As used herein, the terms “to treat” or “treatment” refer to therapeutic or palliative care. Beneficial or desirable clinical outcomes include, but are not limited to, the whole or partial relief of symptoms associated with a disease or disorder or condition, whether detectable or undetectable; a reduction in the severity of the disease; a stable (i.e., non-exacerbating) state of the disease; a delay or slowing of disease progression; improvement or relief of a disease condition (e.g., one or more symptoms of the disease); and remission (whether partial or total), whether detectable or undetectable. “Treatment” may also mean an extended survival compared to the survival expected without treatment.

[0028] Details of one or more embodiments of this disclosure are described in the accompanying drawings and the following description. Other features and advantages of this disclosure will be apparent from the description and drawings, as well as from the claims. [Brief explanation of the drawing]

[0029] [Figure 1] This is a polarized light microscopy (PLM) image of compound A in solid form before the crystallization experiment. [Figure 2] This is an XRPD diffraction diagram of compound A solid before crystallization experiments, which was assigned as morphology 1*. [Figure 3] This is a thermogravimetric analysis / differential scanning calorimetry (TGA / DSC) thermogram of compound A solid before crystallization experiment, assigned as Form 1*. [Figure 4] This is an XRPD diffraction diagram of compound A, hemihydrate form 1, prepared according to the procedure of Example 10. [Figure 5]This is the XRPD diffraction pattern of compound A, form 1*. [Figure 6] This is the XRPD diffraction pattern of compound A, form 2. [Figure 7] This is the XRPD diffraction pattern of compound A, form 3. [Figure 8] This is the XRPD diffraction pattern of compound A, form 4. [Figure 9] This is a polarized light microscopy (PLM) image of Form 1 obtained from the crystallization process of Example 9 after drying and equilibration under ambient conditions (see Example 12). [Figure 10] This is 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). [Figure 11] This is the 1H-NMR spectrum of Form 1 obtained from the crystallization process of Example 9 after drying and equilibration under ambient conditions (see Example 12). [Figure 12] This is the 19F-NMR spectrum of Form 1 obtained from the crystallization process of Example 9 after drying and equilibration under ambient conditions (see Example 12). [Figure 13] Example 2, XRPD diffraction diagram of compound A mesylate formed in procedure A. (A) By-sample of mesylate collected during crystallization, (B) wet mesylate, (C) dried mesylate, (D) see wet mesylate, and (E) see dried mesylate. [Figure 14] Example 2 is a TG / DSC thermogram of compound A mesylate formed in procedure A. [Figure 15] This is an XRPD diffraction diagram of compound A mesylate suspended in different pH buffers for 1 hour in a disproportionation test (Example 2, Procedure B). [Figure 16] This is an XRPD diffraction diagram of amorphous (lyophilized) compound A used as input for primary polymorph screening (Example 5) and other crystallization experiments, shown together with the XRPD of form 1* for reference. [Figure 17]These are XRPD diffraction patterns of the crystalline forms of compound A obtained in the primary polymorph screening (Example 5): 1-butanol (Form 1*), 1-propanol:water 50:50 (Form 1), and 2-propanol:water 80:20 (Form 1). [Figure 18] This is an XRPD diffraction pattern of the crystalline form of compound A obtained in the primary polymorph screening (Example 5). The compounds are 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). [Figure 19] These are XRPD diffraction diagrams of Form 1 of Compound A obtained from MeOH / water in preliminary crystallization experiments (Example 8) before and after grinding, shown together with the XRPD of a known impurity (Impurity 1) in Compound A. [Figure 20] These are XRPD diffraction diagrams of Form 1 of Compound A obtained from EtOH / water in preliminary crystallization experiments (Example 8) before and after grinding, shown together with the XRPD of a known impurity (Impurity 1) in Compound A. [Figure 21] Examples 9 show the XRPD diffraction diagrams of the wet form 1 (before drying) of compound A obtained during the crystallization process optimization in Protocol A, both before and after grinding, along with the XRPD of a known impurity (impurity 1) in compound A. [Figure 22] Examples 9 show the XRPD diffraction diagrams of Form 1 of Compound A obtained during the crystallization process optimization in Protocol B, before and after grinding, along with the XRPD of a known impurity (Impurity 1) in Compound A. [Figure 23] Examples 9 show the XRPD diffraction diagrams of the wet and dry solid forms of compound A in form 1 obtained during the crystallization process optimization in Protocol C, before and after grinding, along with the XRPD of a known impurity (impurity 1) in compound A. [Figure 24] These are XRPD diffraction diagrams of the wet form 1 (before drying) of compound A obtained during the crystallization process optimization in Protocol D, as shown in Example 9 before and after grinding, along with the XRPD of a known impurity (impurity 1) in compound A. [Figure 25] This is an XRPD diffraction pattern of solid compound A in a competitive slurry experiment (Example 11). The upper frame shows Form 1* and a reference to Form 1. (A) 2-propanol:water 20:80, 50°C for 4 days shows Form 1 and trace amounts of Form 1*. (B) 2-propanol:water 20:80, 50°C for 10 days shows only Form 1. [Figure 26] The XRPD diffraction pattern of compound A solid in the competitive slurry experiment (Example 11) is shown. The upper frame shows Form 1* and a reference to Form 1. (A) The solid obtained from 2-propanol::water 20:80 after 4 days at 20°C shows Form 1 and a trace amount of Form 1*. (B) The solid obtained from 2-propanol:water 20:80 after 10 days at 20°C shows Form 1 and a trace amount of Form 1*. [Figure 27] This is an XRPD diffraction diagram of compound A solid in a stability test (Example 12). The top frame shows the reference form 1 and the over-dried solid (form 4). The two bottom frames show that the over-dried solid of compound A (form 4) returns to form 1 when exposed to ambient conditions and 60% relative humidity. [Figure 28] This is a TG / DSC thermogram of the solid obtained after the equilibration protocol (Example 12) (confirmed to be morphology 1 by XRPD, see Figure 27). [Figure 29] This is a DSC thermogram (first thermal cycle) of the solid obtained after the equilibration protocol (Example 12) (confirmed to be morphology 1 by XRPD, see Figure 27). [Figure 30] This is a DSC thermogram (first cooling cycle) of the solid obtained after the equilibration protocol (Example 12) (confirmed to be Form 1 by XRPD, see Figure 27). [Figure 31] This is a DSC thermogram (second thermal cycle) of the solid obtained after the equilibration protocol (Example 12) (confirmed to be morphology 1 by XRPD, see Figure 27). [Figure 32]This is a dynamic vapor adsorption (DVS) plot of the solid obtained after the equilibration protocol (Example 12) (confirmed to be morphology 1 by XRPD, see Figure 27). (A) Kinetic plot, (B) Isotherm plot. [Figure 33] This is an XRPD diffraction diagram of the solid obtained after the equilibration protocol (Example 12) following grinding for 90-540 seconds (confirmed to be morphology 1 by XRPD, see Figure 27). [Figure 34] This is a TG / DSC thermogram of a solid obtained from isopropyl acetate:heptane:acetonitrile:water 68:30:1:1%v / v / v / v by polymorph screening (Example 5, Procedure A) (confirmed to be Form 3 by XRPD). [Modes for carrying out the invention]

[0030] This specification includes 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0031] [ka] It is stated.

[0032] This specification includes (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0033] [ka] (Also known as "Compound A") is described.

[0034] This specification includes (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea

[0035] [ka] It is stated.

[0036] This specification describes the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0037] In some embodiments, the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is racemic, non-racemic (i.e., scalemic), (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is the crystalline form of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0038] In some embodiments, the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is the crystalline form of racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is the crystalline form of racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0039] Also provided herein are amorphous (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, amorphous (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea features an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 16.

[0040] These crystalline forms are useful, for example, for treating conditions, diseases, or disorders in which increased (e.g., excessive) PI3Kα 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). The disclosure also provides compositions containing them, as well as methods for using and preparing them.

[0041] Several embodiments provide the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(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, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a pharmaceutically acceptable solvate. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a hydrate. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a hemihydrate.

[0042] Some embodiments provide (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or pharmaceutically acceptable salts and / or solvates thereof. In some embodiments, (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a pharmaceutically acceptable solvate. In some embodiments, (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a hydrate. In some embodiments, (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a hemihydrate.

[0043] Some embodiments provide the crystalline form of racemic 1-(2-aminopyrimidine-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. In some embodiments, racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a pharmaceutically acceptable solvate. In some embodiments, racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a hydrate. In some embodiments, the racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in hemihydrate form.

[0044] Some embodiments provide a crystalline form of non-racemic 1-(2-aminopyrimidine-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. In some embodiments, non-racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a pharmaceutically acceptable solvate. In some embodiments, non-racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a hydrate. In some embodiments, the non-racemic 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in hemihydrate form.

[0045] Those skilled in the art will recognize that the relative intensity of X-ray powder diffraction pattern peaks can vary depending on the sample preparation technique, crystal size distribution, the various filters used, the sample mounting procedure, and the specific instruments used. Therefore, depending on the type of instrument and settings (including filters) used, new peaks may be observed in subsequently obtained patterns. Alternatively, peaks observed in previously obtained patterns may have negligible relative intensity (and thus not be observed) in subsequently obtained patterns. Thus, the absence of one or more of the aforementioned lower relative intensity peaks is, in itself, a sign of a specific polymorphic form (e.g., form 1, form 1). * It may not be possible to establish that a particular polymorphic form (e.g., form 1, form 3, or form 4) is not present (e.g., in the sample). However, the presence of the lower relative intensity peaks mentioned above generally does not establish that a particular polymorphic form (e.g., form 1, form 1) is not present in the sample. * This can be used to further establish the existence of form 2, form 3, or form 4.

[0046] Form 1 In some embodiments, the crystalline morphology is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 18.3 ± 0.2 degrees 2θ. For ease of explanation, the above-described morphology is referred to herein as “morphology 1”. The X-ray powder diffraction pattern of morphology 1 may also include one or more further characteristic peaks.

[0047] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 6.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.4 ± 0.2 degrees 2θ has the highest relative intensity.

[0048] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 15.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.8 ± 0.2 degrees 2θ has a second relative intensity.

[0049] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 18.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 18.3 ± 0.2 degrees 2θ has the third highest relative intensity.

[0050] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 22.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.3 ± 0.2 degrees 2θ has the fourth highest relative intensity.

[0051] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 20.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.8 ± 0.2 degrees 2θ has the fifth highest relative intensity.

[0052] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 19.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.3 ± 0.2 degrees 2θ has the sixth highest relative intensity.

[0053] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 24.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 24.0 ± 0.2 degrees 2θ has the seventh highest relative intensity.

[0054] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 26.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.9 ± 0.2 degrees 2θ has the eighth highest relative intensity.

[0055] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 14.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.6 ± 0.2 degrees 2θ has the ninth highest relative intensity.

[0056] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 31.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 31.3 ± 0.2 degrees 2θ has the tenth highest relative intensity.

[0057] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 28.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.3 ± 0.2 degrees 2θ has the 11th highest relative intensity.

[0058] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 29.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 29.2 ± 0.2 degrees 2θ has the 12th highest relative intensity.

[0059] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 22.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.8 ± 0.2 degrees 2θ has the 13th highest relative intensity.

[0060] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 28.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.0 ± 0.2 degrees 2θ has the 14th highest relative intensity.

[0061] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.3 ± 0.2 degrees 2θ has the 15th highest relative intensity.

[0062] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 21.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.5 ± 0.2 degrees 2θ has the 16th highest relative intensity.

[0063] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 19.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.9 ± 0.2 degrees 2θ has the 17th highest relative intensity.

[0064] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 27.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 27.6 ± 0.2 degrees 2θ has the 18th highest relative intensity.

[0065] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 20.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.5 ± 0.2 degrees 2θ has the 19th highest relative intensity.

[0066] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 21.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.8 ± 0.2 degrees 2θ has the 20th highest relative intensity.

[0067] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.1 ± 0.2 degrees 2θ has the 21st highest relative intensity.

[0068] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.8 ± 0.2 degrees 2θ has the 22nd highest relative intensity.

[0069] In some embodiments, the crystal morphology is morphology 1, and the XRPD pattern has peaks at 6.4, 15.8, and 18.3 (±0.2 degrees 2θ).

[0070] In some embodiments, the crystal morphology is morphology 1, and the XRPD pattern has peaks 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 (±0.2 degrees 2θ).

[0071] In some embodiments, the crystal morphology is morphology 1, and the XRPD pattern has peaks 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 (±0.2 degrees 2θ).

[0072] In some embodiments, the crystalline morphology is Embodiment 1, characterized by an XRPD pattern substantially identical to the XRPD pattern shown in Figure 4.

[0073] In some embodiments, the crystalline form is approximately 0.5% to 5% (for example, approximately 1% to 5%) at temperatures of approximately 70°C to approximately 140°C (e.g., approximately 90°C to approximately 130°C, approximately 90°C to approximately 120°C, approximately 90°C to approximately 115°C, approximately 100°C to approximately 140°C, approximately 110°C to approximately 140°C, approximately 100°C to approximately 120°C, approximately 105°C to approximately 120°C, approximately 109°C to approximately 115°C, approximately 75°C to approximately 125°C, approximately 85°C to approximately 113°C, approximately 85°C to approximately 105°C, or approximately 112°C. Embodiment 1 has a thermogravimetric analysis (TGA) curve characterized by a weight loss of 3%, approximately 2% to approximately 3%, or approximately 2.3%. In some embodiments, the crystalline form is Embodiment 1 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of approximately 2.3% at approximately 112.5°C. In some embodiments, the crystalline form is Embodiment 1 having a thermogravimetric analysis (TGA) curve characterized by a weight loss of approximately 2.3% at approximately 85°C to approximately 113°C.

[0074] 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 to about 250°C, about 162 to about 248°C, about 230 to about 240°C, about 240 to about 260°C, about 240 to about 250°C, about 242 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, which has a TGA curve characterized by a weight loss of approximately 17.6% between approximately 162°C and approximately 248°C.

[0075] In some embodiments, the crystalline morphology is Embodiment 1, having a TGA curve that is substantially the same as the TGA curve shown in Figure 28. In some embodiments, the crystalline morphology is Embodiment 1, having a thermogravimetric analysis / differential scanning calorimetry (TG / DSC) thermogram that is substantially the same as the thermogram shown in Figure 28.

[0076] In some embodiments, the crystalline morphology is a differential scanning calorimetry (DSC) first thermal cycle thermogram having an endothermic event with a starting temperature of approximately 105°C and a peak at approximately 129°C, an endothermic event with a starting temperature of approximately 158°C and a peak at approximately 162°C, and an endothermic event with a starting temperature of approximately 174°C and a peak at approximately 177°C.

[0077] In some embodiments, the crystalline morphology is Embodiment 1, which has a differential scanning calorimetry (DSC) thermogram that is substantially the same as the thermogram shown in Figure 29.

[0078] In some embodiments, the crystal morphology is Embodiment 1, which has a DSC curve that is substantially the same as the DSC curve shown in Figure 29.

[0079] In some embodiments, the crystalline morphology is a DSC first cooling cycle thermogram having a single exothermic event at a starting temperature of 151°C and a peak temperature of 147°C.

[0080] In some embodiments, the crystalline morphology is Embodiment 1, which has a DSC first cooling cycle thermogram substantially the same as the thermogram shown in Figure 30.

[0081] In some embodiments, form 1 is a hemihydrate.

[0082] In some embodiments, the enantiomer 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%).

[0083] In some embodiments, Embodiment 1 is substantially pure.

[0084] Form 1 * In some embodiments, the crystalline morphology is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.3 ± 0.2 degrees 2θ. For ease of explanation, the above embodiments are referred to herein as "Embodiment 1". * It is called "form 1". * The X-ray powder diffraction pattern may also contain one or more additional characteristic peaks.

[0085] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 6.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.3 ± 0.2 degrees 2θ has the highest relative intensity.

[0086] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 15.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.8 ± 0.2 degrees 2θ has the second highest relative intensity.

[0087] In some embodiments, Form 1 * has an XRPD pattern with a peak at 20.8±0.2 degrees 2θ. In some embodiments, the peak at 20.8±0.2 degrees 2θ has the third highest relative intensity.

[0088] In some embodiments, Form 1 * has an XRPD pattern with a peak at 15.9±0.2 degrees 2θ. In some embodiments, the peak at 15.9±0.2 degrees 2θ has the fourth highest relative intensity.

[0089] In some embodiments, Form 1 * has an XRPD pattern with a peak at 19.8±0.2 degrees 2θ. In some embodiments, the peak at 19.8±0.2 degrees 2θ has the fifth highest relative intensity.

[0090] In some embodiments, Form 1 * has an XRPD pattern with a peak at 19.3±0.2 degrees 2θ. In some embodiments, the peak at 19.3±0.2 degrees 2θ has the sixth highest relative intensity.

[0091] In some embodiments, Form 1 * has an XRPD pattern with a peak at 28.0±0.2 degrees 2θ. In some embodiments, the peak at 28.0±0.2 degrees 2θ has the seventh highest relative intensity.

[0092] In some embodiments, Form 1 * has an XRPD pattern with a peak at 27.6±0.2 degrees 2θ. In some embodiments, the peak at 27.6±0.2 degrees 2θ has the eighth highest relative intensity.

[0093] In some embodiments, Form 1 * has an XRPD pattern with a peak at 24.0±0.2 degrees 2θ. In some embodiments, the peak at 24.0±0.2 degrees 2θ has the ninth highest relative intensity.

[0094] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 22.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.1 ± 0.2 degrees 2θ has the tenth highest relative intensity.

[0095] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 29.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 29.2 ± 0.2 degrees 2θ has the 11th highest relative intensity.

[0096] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 26.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.4 ± 0.2 degrees 2θ has the 12th highest relative intensity.

[0097] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 21.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.6 ± 0.2 degrees 2θ has the 13th highest relative intensity.

[0098] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 14.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.4 ± 0.2 degrees 2θ has the 14th highest relative intensity.

[0099] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 14.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.5 ± 0.2 degrees 2θ has the 15th highest relative intensity.

[0100] In some embodiments, Embodiment 1 *The XRPD pattern has a peak at 26.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.1 ± 0.2 degrees 2θ has the 16th highest relative intensity.

[0101] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 28.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.6 ± 0.2 degrees 2θ has the 17th highest relative intensity.

[0102] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 20.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.3 ± 0.2 degrees 2θ has the 18th highest relative intensity.

[0103] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 31.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 31.2 ± 0.2 degrees 2θ has the 19th highest relative intensity.

[0104] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 26.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.8 ± 0.2 degrees 2θ has the 20th highest relative intensity.

[0105] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 18.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 18.9 ± 0.2 degrees 2θ has the 21st highest relative intensity.

[0106] In some embodiments, Embodiment 1 * The XRPD pattern has a peak at 31.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 31.5 ± 0.2 degrees 2θ has the 22nd highest relative intensity.

[0107] In some embodiments, the crystal morphology is morphology 1 * The XRPD pattern has peaks at 6.3, 15.8, and 20.8 (±0.2 degrees 2θ).

[0108] In some embodiments, the crystal morphology is morphology 1 * The XRPD pattern has peaks at 6.3, 15.8, 20.8, 15.9, 19.8, 19.3, 28.0, 27.6, 24.0, and 22.1 (±0.2 degrees 2θ).

[0109] In some embodiments, the crystal morphology is morphology 1 * The XRPD pattern has peaks (±0.2 degrees 2θ) 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.

[0110] In some embodiments, the crystal morphology is characterized by an XRPD pattern substantially identical to the XRPD pattern shown in Figure 2, as in Embodiment 1. * That is the case.

[0111] In some embodiments, the crystalline morphology has a TG / DSC thermogram characterized by multiple weight loss events before decomposition. * It exhibits a weight loss of approximately 2.5% between approximately 72°C and 114°C (theoretically equivalent to 0.5 moles of water), approximately 2.2% between approximately 147°C and 185°C (theoretically equivalent to 0.5 moles of water), and approximately 12.2% between approximately 185°C and 252°C.

[0112] In some embodiments, the crystalline form 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 2.5%) at temperatures of about 60°C to about 114°C (e.g., about 65°C to about 125°C, about 70°C to about 120°C, or about 72°C to about 140°C). *In some embodiments, the crystalline form has a thermogravimetric analysis (TGA) curve characterized by a weight loss of approximately 2.5% at approximately 72°C and 114°C. * That is the case.

[0113] In some embodiments, the crystalline form has a thermogravimetric analysis (TGA) curve characterized by a weight loss of approximately 0.5% to approximately 5% (e.g., approximately 1% to approximately 23%, approximately 10% to approximately 15%, approximately 12% to approximately 13%, or approximately 12.2%) at approximately 165°C to approximately 275°C (e.g., approximately 175°C to approximately 265°C, approximately 180°C to approximately 260°C, or approximately 185°C to approximately 252°C) at approximately 165°C to approximately 275°C (e.g., approximately 175°C to approximately 265°C, approximately 180°C to approximately 260°C, or approximately 185°C to approximately 252°C). * In some embodiments, the crystalline form has a thermogravimetric analysis (TGA) curve characterized by a weight loss of approximately 12.2% between approximately 185°C and approximately 252°C. * That is the case.

[0114] In some embodiments, the crystal morphology is a form having a TGA curve that is substantially the same as the TGA curve shown in Figure 3. * In some embodiments, the crystalline morphology is substantially the same as that of the thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram shown in Figure 3. * That is the case.

[0115] In some embodiments, the crystal morphology is characterized by an endothermic event with a starting temperature of approximately 86°C and a peak at approximately 102°C, an endothermic event with a starting temperature of approximately 154°C and a peak at approximately 158°C, and an endothermic event with a starting temperature of approximately 172°C and a peak at approximately 176°C, as shown in Embodiment 1 of the TG / DSC thermogram. * In some embodiments, the TG / DSC thermogram curve is characterized by an endothermic event with an onset temperature of approximately 294°C (peak at approximately 301°C) associated with decomposition in some embodiments.

[0116] In some embodiments, the crystal morphology is substantially the same as that of the differential scanning calorimetry (DSC) thermogram shown in Figure 3, as in Embodiment 1. * That is the case.

[0117] In some embodiments, Embodiment 1 * It is a hemihydrate.

[0118] In some embodiments, Embodiment 1 * The enantiomer excess (ee) 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%).

[0119] In some embodiments, Embodiment 1 * It is essentially pure.

[0120] Form 2 In some embodiments, the crystalline morphology is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.2 ± 0.2 degrees 2θ. For ease of explanation, the aforementioned morphology is referred to herein as “morphology 2”. The X-ray powder diffraction pattern of morphology 2 may also include one or more further characteristic peaks.

[0121] In some embodiments, the XRPD pattern of form 2 has a peak at 6.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.2 ± 0.2 degrees 2θ has the highest relative intensity.

[0122] In some embodiments, the XRPD pattern of form 2 has a peak at 15.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.2 ± 0.2 degrees 2θ has the second highest relative intensity.

[0123] In some embodiments, the XRPD pattern of form 2 has a peak at 15.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.3 ± 0.2 degrees 2θ has the third highest relative intensity.

[0124] In some embodiments, the XRPD pattern of form 2 has a peak at 20.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.9 ± 0.2 degrees 2θ has the fourth highest relative intensity.

[0125] In some embodiments, the XRPD pattern of form 2 has a peak at 21.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.9 ± 0.2 degrees 2θ has the fifth highest relative intensity.

[0126] In some embodiments, the XRPD pattern of form 2 has a peak at 22.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.0 ± 0.2 degrees 2θ has the sixth highest relative intensity.

[0127] In some embodiments, the XRPD pattern of form 2 has a peak at 21.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.0 ± 0.2 degrees 2θ has the seventh highest relative intensity.

[0128] In some embodiments, the XRPD pattern of form 2 has a peak at 18.7 ± 0.2 degrees 2θ. In some embodiments, the peak at 18.7 ± 0.2 degrees 2θ has the eighth highest relative intensity.

[0129] In some embodiments, the XRPD pattern of form 2 has a peak at 18.7 ± 0.2 degrees 2θ. In some embodiments, the peak at 18.7 ± 0.2 degrees 2θ has the ninth highest relative intensity.

[0130] In some embodiments, the XRPD pattern of form 2 has a peak at 26.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.9 ± 0.2 degrees 2θ has the tenth highest relative intensity.

[0131] In some embodiments, the XRPD pattern of form 2 has a peak at 24.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 24.0 ± 0.2 degrees 2θ has the 11th highest relative intensity.

[0132] In some embodiments, the XRPD pattern of form 2 has a peak at 21.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.1 ± 0.2 degrees 2θ has the 12th highest relative intensity.

[0133] In some embodiments, the XRPD pattern of form 2 has a peak at 27.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 27.4 ± 0.2 degrees 2θ has the 13th highest relative intensity.

[0134] In some embodiments, the XRPD pattern of form 2 has a peak at 28.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.0 ± 0.2 degrees 2θ has the 14th highest relative intensity.

[0135] In some embodiments, the XRPD pattern of form 2 has a peak at 14.7 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.7 ± 0.2 degrees 2θ has the 15th highest relative intensity.

[0136] In some embodiments, the XRPD pattern of form 2 has a peak at 20.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.6 ± 0.2 degrees 2θ has the 16th highest relative intensity.

[0137] In some embodiments, the XRPD pattern of form 2 has a peak at 19.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.9 ± 0.2 degrees 2θ has the 17th highest relative intensity.

[0138] In some embodiments, the XRPD pattern of form 2 has a peak at 19.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.4 ± 0.2 degrees 2θ has the 18th highest relative intensity.

[0139] In some embodiments, the XRPD pattern of form 2 has a peak at 21.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.5 ± 0.2 degrees 2θ has the 19th highest relative intensity.

[0140] In some embodiments, the XRPD pattern of form 2 has a peak at 17.7 ± 0.2 degrees 2θ. In some embodiments, the peak at 17.7 ± 0.2 degrees 2θ has the 20th highest relative intensity.

[0141] In some embodiments, the XRPD pattern of form 2 has a peak at 26.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.0 ± 0.2 degrees 2θ has the 21st highest relative intensity.

[0142] In some embodiments, the XRPD pattern of form 2 has a peak at 28.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.3 ± 0.2 degrees 2θ has the 22nd highest relative intensity.

[0143] In some embodiments, the crystal morphology is morphology 2, and the XRPD pattern has peaks at 6.2, 15.2, and 15.3 (±0.2 degrees 2θ).

[0144] In some embodiments, the crystal morphology is morphology 2, and the XRPD pattern has peaks at 6.2, 15.2, 15.3, 20.9, 21.9, 22.0, 21.0, 18.7, 18.7, and 26.9 (±0.2 degrees 2θ).

[0145] In some embodiments, the crystalline morphology is morphology 2, and the XRPD pattern has peaks (±0.2 degrees 2θ) 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.

[0146] In some embodiments, the crystalline morphology is morphology 2, which features an XRPD pattern substantially identical to the XRPD pattern shown in Figure 6.

[0147] In some embodiments, form 2 is a hemihydrate.

[0148] In some embodiments, the enantiomer 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%).

[0149] In some embodiments, form 2 is substantially pure.

[0150] Form 3 In some embodiments, the crystalline morphology is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 4.0 ± 0.2 degrees 2θ. For ease of explanation, the aforementioned morphology is referred to herein as “morphology 3”. The X-ray powder diffraction pattern of morphology 3 may also include one or more further characteristic peaks.

[0151] In some embodiments, the XRPD pattern of form 3 has a peak at 4.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 4.0 ± 0.2 degrees 2θ has the highest relative intensity.

[0152] In some embodiments, the XRPD pattern of Embodiment 3 has a peak at 4.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 4.9 ± 0.2 degrees 2θ has the second highest relative intensity.

[0153] In some embodiments, the XRPD pattern of form 3 has a peak at 25.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.8 ± 0.2 degrees 2θ has the third highest relative intensity.

[0154] In some embodiments, the XRPD pattern of form 3 has a peak at 21.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.4 ± 0.2 degrees 2θ has the fourth highest relative intensity.

[0155] In some embodiments, the XRPD pattern of Embodiment 3 has a peak at 9.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 9.1 ± 0.2 degrees 2θ has the fifth highest relative intensity.

[0156] In some embodiments, the XRPD pattern of Embodiment 3 has a peak at 19.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.2 ± 0.2 degrees 2θ has the sixth highest relative intensity.

[0157] In some embodiments, the XRPD pattern of Embodiment 3 has a peak at 6.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.9 ± 0.2 degrees 2θ has the seventh highest relative intensity.

[0158] In some embodiments, the XRPD pattern of form 3 has a peak at 15.7 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.7 ± 0.2 degrees 2θ has the eighth highest relative intensity.

[0159] In some embodiments, the XRPD pattern of form 3 has a peak at 16.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 16.8 ± 0.2 degrees 2θ has the ninth highest relative intensity.

[0160] In some embodiments, the XRPD pattern of Embodiment 3 has a peak at 9.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 9.9 ± 0.2 degrees 2θ has the tenth highest relative intensity.

[0161] In some embodiments, the XRPD pattern of form 3 has a peak at 14.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.3 ± 0.2 degrees 2θ has the 11th highest relative intensity.

[0162] In some embodiments, the XRPD pattern of Embodiment 3 has a peak at 23.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 23.9 ± 0.2 degrees 2θ has the 12th highest relative intensity.

[0163] In some embodiments, the XRPD pattern of form 3 has a peak at 6.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.2 ± 0.2 degrees 2θ has the 13th highest relative intensity.

[0164] In some embodiments, the XRPD pattern of Embodiment 3 has a peak at 7.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 7.5 ± 0.2 degrees 2θ has the 14th highest relative intensity.

[0165] In some embodiments, the XRPD pattern of form 3 has a peak at 31.7 ± 0.2 degrees 2θ. In some embodiments, the peak at 31.7 ± 0.2 degrees 2θ has the 15th highest relative intensity.

[0166] In some embodiments, the crystal morphology is morphology 3, and the XRPD pattern has peaks at 4.0, 4.9, and 25.8 (±0.2 degrees 2θ).

[0167] In some embodiments, the crystal morphology is morphology 3, and the XRPD pattern has peaks at 4.0, 4.9, 25.8, 21.4, 9.1, 19.2, 6.9, 15.7, 16.8, and 9.9 (±0.2 degrees 2θ).

[0168] In some embodiments, the crystal morphology is morphology 3, and the XRPD pattern has peaks 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 (±0.2 degrees 2θ).

[0169] In some embodiments, the crystalline morphology is Embodiment 3, which features an XRPD pattern substantially identical to the XRPD pattern shown in Figure 7.

[0170] In some embodiments, the crystalline form is a 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 155°C, or 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 a 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.

[0171] 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°C (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.

[0172] In some embodiments, the crystal morphology is morphology 3, which has a TGA curve that is substantially the same as the TGA curve shown in Figure 34.

[0173] In some embodiments, the crystal morphology is a DSC curve of morphology 3 characterized by an endothermic event with a starting temperature of approximately 162°C and a peak at approximately 173°C. In some embodiments, the crystal morphology is a DSC curve of morphology 3 characterized by an endothermic event with a starting temperature of approximately 274°C and a peak at approximately 283°C. In some embodiments, the crystal morphology is a DSC curve of morphology 3 characterized by an endothermic event with a starting temperature of approximately 162°C and a peak at approximately 173°C, and an endothermic event with a starting temperature of approximately 274°C and a peak at approximately 283°C.

[0174] In some embodiments, the crystalline morphology is embodiment 3, which has a TG / DSC thermogram that is substantially the same as the thermogram shown in Figure 34.

[0175] In some embodiments, the crystal morphology is morphology 3, which has a TGA curve that is substantially the same as the TGA curve shown in Figure 34.

[0176] In some embodiments, the crystalline morphology is morphology 3, which has a DSC curve that is substantially the same as the DSC curve shown in Figure 34.

[0177] In some embodiments, form 3 is anhydrous.

[0178] In some embodiments, the enantiomer 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%).

[0179] In some embodiments, form 3 is substantially pure.

[0180] Form 4 In some embodiments, the crystalline morphology is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.3 ± 0.2 degrees 2θ (e.g., 6.3 ± 0.2 degrees 2θ and 20.9 ± 0.2 degrees 2θ). For ease of explanation, the aforementioned morphology is referred to herein as “morphology 4”. The X-ray powder diffraction pattern of morphology 4 may also include one or more further characteristic peaks.

[0181] In some embodiments, the XRPD pattern of form 4 has a peak at 6.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.3 ± 0.2 degrees 2θ has the highest relative intensity.

[0182] In some embodiments, the XRPD pattern of form 4 has a peak at 20.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.9 ± 0.2 degrees 2θ has the second highest relative intensity.

[0183] In some embodiments, the XRPD pattern of form 4 has a peak at 15.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.5 ± 0.2 degrees 2θ has the third highest relative intensity.

[0184] In some embodiments, the XRPD pattern of form 4 has a peak at 24.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 24.1 ± 0.2 degrees 2θ has the fourth highest relative intensity.

[0185] In some embodiments, the XRPD pattern of form 4 has a peak at 21.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.5 ± 0.2 degrees 2θ has the fifth highest relative intensity.

[0186] In some embodiments, the XRPD pattern of form 4 has a peak at 27.7 ± 0.2 degrees 2θ. In some embodiments, the peak at 27.7 ± 0.2 degrees 2θ has the sixth highest relative intensity.

[0187] In some embodiments, the XRPD pattern of form 4 has a peak at 15.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.8 ± 0.2 degrees 2θ has the seventh highest relative intensity.

[0188] In some embodiments, the XRPD pattern of form 4 has a peak at 14.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.9 ± 0.2 degrees 2θ has the eighth highest relative intensity.

[0189] In some embodiments, the XRPD pattern of form 4 has a peak at 20.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.5 ± 0.2 degrees 2θ has the ninth highest relative intensity.

[0190] In some embodiments, the XRPD pattern of form 4 has a peak at 26.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.9 ± 0.2 degrees 2θ has the tenth highest relative intensity.

[0191] In some embodiments, the XRPD pattern of form 4 has a peak at 19.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.9 ± 0.2 degrees 2θ has the 11th highest relative intensity.

[0192] In some embodiments, the XRPD pattern of form 4 has a peak at 19.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.3 ± 0.2 degrees 2θ has the 12th highest relative intensity.

[0193] In some embodiments, the XRPD pattern of form 4 has a peak at 28.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.1 ± 0.2 degrees 2θ has the 13th highest relative intensity.

[0194] In some embodiments, the XRPD pattern of form 4 has a peak at 28.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.4 ± 0.2 degrees 2θ has the 14th highest relative intensity.

[0195] In some embodiments, the XRPD pattern of form 4 has a peak at 3.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 3.1 ± 0.2 degrees 2θ has the 15th highest relative intensity.

[0196] In some embodiments, the XRPD pattern of form 4 has a peak at 27.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 27.3 ± 0.2 degrees 2θ has the 16th highest relative intensity.

[0197] In some embodiments, the XRPD pattern of form 4 has a peak at 22.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.1 ± 0.2 degrees 2θ has the 17th highest relative intensity.

[0198] In some embodiments, the XRPD pattern of form 4 has a peak at 25.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.0 ± 0.2 degrees 2θ has the 18th highest relative intensity.

[0199] In some embodiments, the XRPD pattern of form 4 has a peak at 29.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 29.1 ± 0.2 degrees 2θ has the 19th highest relative intensity.

[0200] In some embodiments, the XRPD pattern of form 4 has a peak at 30.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 30.8 ± 0.2 degrees 2θ has the 20th highest relative intensity.

[0201] In some embodiments, the XRPD pattern of form 4 has a peak at 19.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.0 ± 0.2 degrees 2θ has the 21st highest relative intensity.

[0202] In some embodiments, the XRPD pattern of form 4 has a peak at 18.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 18.0 ± 0.2 degrees 2θ has the 22nd highest relative intensity.

[0203] In some embodiments, the crystal morphology is morphology 4, and the XRPD pattern has peaks at 6.3, 20.9, and 15.5 (±0.2 degrees 2θ).

[0204] In some embodiments, the crystal morphology is morphology 4, and the XRPD pattern has peaks at 6.3, 20.9, 15.5, 24.1, 21.5, 27.7, 15.8, 14.9, 20.5, and 26.9 (±0.2 degrees 2θ).

[0205] In some embodiments, the crystalline form is form 4, and the XRPD pattern has peaks (±0.2 degrees 2θ) 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.

[0206] In some embodiments, the crystalline morphology is morphology 4, which features an XRPD pattern substantially identical to the XRPD pattern shown in Figure 8.

[0207] In some embodiments, the enantiomer 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%).

[0208] In some embodiments, form 4 is substantially pure.

[0209] Mesylate In some embodiments, the crystalline morphology is a mesylate having a TG / DSC thermogram that is substantially the same as the thermogram shown in Figure 14. In some embodiments, the crystalline morphology is a mesylate having a TG / DSC thermogram characterized by a single endothermic event with an onset temperature of 200°C and a peak temperature of 207°C.

[0210] Method for preparing Form 1 Methods for preparing (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea can also be found, for example, in PCT Publication Application WO2022 / 265993 filed on 13 June 2022, and Provisional Application No. 63 / 532,695 filed on 15 August 2023, both of which are incorporated herein in their entirety.

[0211] As those skilled in the art will understand, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, its crystalline form, and further methods for synthesizing its crystalline solvates (e.g., hydrates (e.g., hemihydrates)) will be obvious to those skilled in the art. Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful for synthesizing (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea are publicly known in the art, including, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW. Greene and PGMWuts, Protective Groups in Organic Synthesis, 2nd 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.

[0212] Method for preparing Form 1 Form 1 prepared by Method 1 In some embodiments, the crystalline form is (a) Dissolving (R)-1-(2-aminopyrimidine-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, in isopropanol to form a solution, (b) Adding water to the solution to form a mixture, (c) Lowering the temperature of the mixture and then maintaining that temperature over a first period of time, (d) Raising the temperature of the mixture and then maintaining that temperature over a second period, (e) lowering the temperature of the mixture and then maintaining that temperature over a third period, (f) Form 1 prepared by a method comprising isolating Form 1 from the mixture.

[0213] Some embodiments are methods for preparing Embodiment 1, (a) Dissolving (R)-1-(2-aminopyrimidine-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, in isopropanol to form a solution, (b) Adding water to the solution to form a mixture, (c) Lowering the temperature of the mixture and then maintaining that temperature over a first period of time, (d) Raising the temperature of the mixture and then maintaining that temperature over a second period, (e) lowering the temperature of the mixture and then maintaining that temperature over a third period, (f) A method is provided which includes isolating Form 1 from the mixture.

[0214] In some embodiments, Embodiment 1 has one or more features described herein and below.

[0215] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 6.4 ± 0.2 degrees 2θ. In some embodiments, the peak at 6.4 ± 0.2 degrees 2θ has the highest relative intensity.

[0216] In some embodiments, the XRPD pattern of Form 1 has a peak at 15.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 15.8 ± 0.2 degrees 2θ has a second relative intensity.

[0217] In some embodiments, the XRPD pattern of Form 1 has a peak at 18.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 18.3 ± 0.2 degrees 2θ has the third highest relative intensity.

[0218] In some embodiments, the XRPD pattern of Form 1 has a peak at 22.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.3 ± 0.2 degrees 2θ has the fourth highest relative intensity.

[0219] In some embodiments, the XRPD pattern of Form 1 has a peak at 20.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.8 ± 0.2 degrees 2θ has the fifth highest relative intensity.

[0220] In some embodiments, the XRPD pattern of Form 1 has a peak at 19.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.3 ± 0.2 degrees 2θ has the sixth highest relative intensity.

[0221] In some embodiments, the XRPD pattern of Form 1 has a peak at 24.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 24.0 ± 0.2 degrees 2θ has the seventh highest relative intensity.

[0222] In some embodiments, the XRPD pattern of Form 1 has a peak at 26.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 26.9 ± 0.2 degrees 2θ has the eighth highest relative intensity.

[0223] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 14.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 14.6 ± 0.2 degrees 2θ has the ninth highest relative intensity.

[0224] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 31.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 31.3 ± 0.2 degrees 2θ has the tenth highest relative intensity.

[0225] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 28.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.3 ± 0.2 degrees 2θ has the 11th highest relative intensity.

[0226] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 29.2 ± 0.2 degrees 2θ. In some embodiments, the peak at 29.2 ± 0.2 degrees 2θ has the 12th highest relative intensity.

[0227] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 22.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 22.8 ± 0.2 degrees 2θ has the 13th highest relative intensity.

[0228] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 28.0 ± 0.2 degrees 2θ. In some embodiments, the peak at 28.0 ± 0.2 degrees 2θ has the 14th highest relative intensity.

[0229] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.3 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.3 ± 0.2 degrees 2θ has the 15th highest relative intensity.

[0230] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 21.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.5 ± 0.2 degrees 2θ has the 16th highest relative intensity.

[0231] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 19.9 ± 0.2 degrees 2θ. In some embodiments, the peak at 19.9 ± 0.2 degrees 2θ has the 17th highest relative intensity.

[0232] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 27.6 ± 0.2 degrees 2θ. In some embodiments, the peak at 27.6 ± 0.2 degrees 2θ has the 18th highest relative intensity.

[0233] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 20.5 ± 0.2 degrees 2θ. In some embodiments, the peak at 20.5 ± 0.2 degrees 2θ has the 19th highest relative intensity.

[0234] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 21.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 21.8 ± 0.2 degrees 2θ has the 20th highest relative intensity.

[0235] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.1 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.1 ± 0.2 degrees 2θ has the 21st highest relative intensity.

[0236] In some embodiments, the XRPD pattern of Embodiment 1 has a peak at 25.8 ± 0.2 degrees 2θ. In some embodiments, the peak at 25.8 ± 0.2 degrees 2θ has the 22nd highest relative intensity.

[0237] In some embodiments, the XRPD pattern of Embodiment 1 has peaks at 6.4, 15.8, and 18.3 (±0.2 degrees 2θ).

[0238] In some embodiments, the XRPD pattern of Form 1 has peaks (±0.2 degrees 2θ) at 6.4, 15.8, 18.3, 22.3, 20.8, 19.3, 24.0, 26.9, 14.6, and 31.3.

[0239] In some embodiments, the XRPD pattern of Form 1 has peaks (±0.2 degrees 2θ) 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.

[0240] In some embodiments, Form 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 4.

[0241] 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 from about 70°C to about 140°C (e.g., from about 90°C to about 130°C, from about 90°C to about 120°C, from about 90°C to about 115°C, from about 100°C to about 140°C, from about 110°C to about 140°C, from about 100°C to about 120°C, from about 105°C to about 120°C, from about 109°C to about 115°C, from about 75°C to about 125°C, from about 85°C to about 113°C, from about 85°C to about 105°C, or about 112°C). In some embodiments, 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 from about 85°C to about 113°C.

[0242] In some embodiments, Embodiment 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 to about 250°C, about 230 to about 240°C, about 240 to about 260°C, about 240 to about 250°C, about 242 to about 248°C, or about 245°C). In some embodiments, Embodiment 1 has a TGA curve characterized by a weight loss of about 17.6% at about 245°C. In some embodiments, Embodiment 1 has a TGA curve characterized by a weight loss of approximately 17.6% between approximately 162°C and approximately 248°C.

[0243] In some embodiments, Embodiment 1 has a TGA curve that is substantially the same as the TGA curve shown in Figure 28. In some embodiments, Embodiment 1 has a thermogravimetric analysis / differential scanning calorimetry (TG / DSC) thermogram that is substantially the same as the thermogram shown in Figure 28.

[0244] In some embodiments, Embodiment 1 has a differential scanning calorimetry (DSC) first thermal cycle thermogram having an endothermic event with a starting temperature of approximately 105°C and a peak at approximately 129°C, an endothermic event with a starting temperature of approximately 158°C and a peak at approximately 162°C, and an endothermic event with a starting temperature of approximately 174°C and a peak at approximately 177°C.

[0245] In some embodiments, Embodiment 1 has a differential scanning calorimetry (DSC) thermogram which is substantially the same as the thermogram shown in Figure 29.

[0246] In some embodiments, Embodiment 1 has a DSC first cooling cycle thermogram characterized by a single exothermic event at a start temperature of 151°C and a peak temperature of 147°C.

[0247] In some embodiments, Embodiment 1 has a DSC first cooling cycle thermogram substantially the same as the thermogram shown in Figure 30.

[0248] In some embodiments, form 1 is a hemihydrate.

[0249] In some embodiments, the enantiomer 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%).

[0250] In some embodiments, Embodiment 1 is substantially pure.

[0251] In some embodiments, (R)-1-(2-aminopyrimidine-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, comprises (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea as a free base. In some embodiments, (R)-1-(2-aminopyrimidine-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, is (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea of ​​the free base. In some embodiments, (R)-1-(2-aminopyrimidine-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, comprises amorphous (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-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, is amorphous (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.In some embodiments, (R)-1-(2-aminopyrimidine-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, comprises (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in a free base amorphous form. In some embodiments, (R)-1-(2-aminopyrimidine-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, is (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in a free base amorphous form. In some embodiments, (R)-1-(2-aminopyrimidine-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, is Form 1. * Includes. In some embodiments, (R)-1-(2-aminopyrimidine-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, is included in Form 1. * That is the case.

[0252] In some embodiments, the dissolution in step (a) is carried out at approximately 40°C to 60°C (for example, approximately 45°C to 55°C, or approximately 50°C). In some embodiments, the dissolution in step (a) is carried out at approximately 50°C.

[0253] In some embodiments, the solution formed in step (a) has a concentration of about 0.08 g / mL to about 1.65 g / mL (for example, 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.

[0254] In some embodiments, step (a) includes 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) includes cooling the solution to about 40°C. In some embodiments, the cooling is carried out at a rate of about 0.1°C / min to about 5°C / min (e.g., about 0.5°C / min to about 2°C / min, or about 1°C / min). In some embodiments, the cooling is carried out at a rate of about 1°C / min.

[0255] In some embodiments, the volume / volume ratio of water added to the solution in step (b) to isopropanol used for dissolution 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 isopropanol used for dissolution in step (a) is about 4:1.

[0256] In some embodiments, approximately 1 / 8 to 1 / 32 of the water is added to the solution per hour. Alternatively, 1 / 16 of the water is added to the solution per hour. In some embodiments, approximately 1 / 16 of the water is added to the solution per hour.

[0257] 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 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 is about 1 hour. In some embodiments, the first period is about 1 minute.

[0258] In some embodiments, the temperature of the mixture in step (d) is raised 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 raised to about 40°C. In some embodiments, the second period 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 one embodiment, the second period is about 1 hour. In one embodiment, the second period is about 1 minute.

[0259] 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 is approximately 1 minute to approximately 24 hours (for example, approximately 1 minute to approximately 18 hours, approximately 1 minute to approximately 12 hours, approximately 1 minute to approximately 6 hours, approximately 1 minute to approximately 3 hours, approximately 1 minute to approximately 2 hours, approximately 1 minute to approximately 30 minutes, approximately 1 minute to approximately 5 minutes, approximately 30 minutes to approximately 1.5 hours, approximately 45 minutes to approximately 1.25 hours, approximately 6 hours to approximately 18 hours, approximately 6 hours to approximately 24 hours, approximately 9 hours to approximately 15 hours, approximately 9 hours to approximately 14 hours, approximately 10 hours to approximately 12 hours, approximately 10.5 hours to approximately 11.5 hours, approximately 11 hours, approximately 12 hours, approximately 1 hour, or approximately 1 minute). In some embodiments, the third period is approximately 11 hours. In some embodiments, the third period is approximately 11 hours.

[0260] In some embodiments, step (f) includes filtering the mixture to provide form 1. In some embodiments, step (f) includes 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 includes drying the solid after rinsing to provide form 1. In some embodiments, rinsing the solid includes rinsing the solid with a solvent. In some embodiments, the solvent includes an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. In some embodiments, the solvent includes water. In some embodiments, the solvent includes alcohol and water. In some embodiments, the solvent includes methanol and water. In some embodiments, the solvent is methanol and water.

[0261] In some embodiments, step (f) is: To filter a mixture to provide a solid, Rinse the solid with methanol and water, The method includes drying a solid to provide form 1.

[0262] In some embodiments, drying is carried out 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 involves drying the solid at a pressure lower than atmospheric pressure. In some embodiments, drying is carried out 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).

[0263] Form 1 prepared by Method 2 In some embodiments, the crystalline form is Dissolving (R)-1-(2-aminopyrimidine-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, in methanol to form a solution, Adding water to that solution to form the first mixture, Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is added to the first mixture to form the second mixture, Form 1 is prepared by a method comprising isolating a solid from a third mixture to provide Form 1.

[0264] Some embodiments are methods for preparing Embodiment 1, Dissolving (R)-1-(2-aminopyrimidine-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, in methanol to form a solution, Adding water to that solution to form the first mixture, Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is added to the first mixture to form the second mixture, The present invention provides a method comprising isolating a solid from a third mixture to provide form 1.

[0265] In some embodiments, the crystalline form is (a) Dissolving (R)-1-(2-aminopyrimidine-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, in methanol to form a solution, (b) Adding water to the solution to form the first mixture, (c)(R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea form 1 is added to the first mixture to form the second mixture, (d) Stirring the second mixture, (e) Adding water to the second mixture to form a third mixture, (f) Stirring the third mixture, (g) Form 1 prepared by a method comprising isolating Form 1 from a third mixture.

[0266] Some embodiments are methods for preparing Embodiment 1, (a) Dissolving (R)-1-(2-aminopyrimidine-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, in methanol to form a solution, (b) Adding water to the solution to form the first mixture, (c)(R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea form 1 is added to the first mixture to form the second mixture, (d) Stirring the second mixture, (e) Adding water to the second mixture to form a third mixture, (f) Stirring the third mixture, (g) A method is provided which includes isolating Form 1 from a third mixture.

[0267] In some embodiments, the solution formed in step (a) has a concentration of about 0.03 g / mL to about 1 g / mL (for example, 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). In some embodiments, the solution formed in step (a) has a concentration of about 0.16 g / mL.

[0268] In some embodiments, forming a solution by dissolving (R)-1-(2-aminopyrimidine-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, in methanol includes: dissolving (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in a first part of methanol to form an unfiltered solution; filtering the unfiltered solution through a filter to provide a filtrate; and then rinsing the filter with a second part of methanol to provide a rinse solution to be combined with the filtrate. In some embodiments, the filtration is polishing filtration. In some embodiments, the filter has a pore size of about 0.2 micrometers. In some embodiments, the weight of the first part 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 dissolved (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0269] 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 water is added in step (b). In some embodiments, the water added in step (b) is purified water. In some embodiments, adding water in step (b) involves filtering the water through a filter and 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 the weight of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea dissolved in step (a) (e.g., about 0.1 to about 1.5 times, about 0.1 to about 1 time, about 0.3 to about 0.7 times, or about 0.5 times (e.g., about 0.5 times)).

[0270] In some embodiments, form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea added in step (c) is dissolved in step (a) The concentration of (-yl)-2,2,2-trifluoroethyl)urea is approximately 0.1% to 20% by weight (for example, approximately 0.1% to 15% by weight, approximately 0.1% to 10% by weight, approximately 0.1% to 5% by weight, approximately 0.1% to 3% by weight, approximately 0.5% to 3% by weight, approximately 0.7% to 2.5% by weight, approximately 0.7% to 1.3% by weight, or approximately 1% by weight (for example, approximately 1%)).

[0271] In some embodiments, Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea added in step (c) is prepared by Method 1 as described herein. In some embodiments, Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea added in step (c) is prepared by Method 2 as described herein.

[0272] In some embodiments, the stirring in step (d) is carried out at a temperature of approximately 5°C to approximately 35°C (e.g., approximately 10°C to approximately 30°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C, approximately 20°C to approximately 25°C, approximately 17°C to approximately 23°C, approximately 15°C, approximately 20°C, or approximately 25°C (e.g., approximately 15°C to approximately 25°C)). In some embodiments, the stirring in step (d) is carried out at a temperature of approximately 1 minute to approximately 24 hours (e.g., approximately 1 minute to approximately 18 hours, approximately 1 minute to approximately 12 hours, approximately 1 minute to approximately 8 hours, approximately 1 minute to approximately 6 hours, approximately 30 minutes to approximately 6 hours, approximately 1 hour to approximately 5 hours, approximately 2 hours to approximately 4 hours, approximately 2.5 hours to approximately 3.5 hours, or approximately 3 hours (e.g., approximately 3 hours)).

[0273] In some embodiments, the water added in step (e) is purified water. In some embodiments, the addition of water in step (e) involves filtering the water through a filter and then adding water to form a 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 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea dissolved in step (a). In some embodiments, the water added in step (e) is added over a period of time ranging from about 1 second to about 48 hours (for example, 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 (for example, about 8 hours)).

[0274] In some embodiments, the stirring in step (f) is carried out at a temperature of approximately 5°C to approximately 35°C (e.g., approximately 10°C to approximately 30°C, approximately 15°C to approximately 25°C, approximately 15°C to approximately 20°C, approximately 20°C to approximately 25°C, approximately 17°C to approximately 23°C, approximately 15°C, approximately 20°C, or approximately 25°C (e.g., approximately 15°C to approximately 25°C)). In some embodiments, the stirring in step (f) is carried out at a temperature of approximately 1 minute to approximately 48 hours (e.g., approximately 1 minute to approximately 36 hours, approximately 1 minute to approximately 24 hours, approximately 4 hours to approximately 24 hours, approximately 8 hours to approximately 20 hours, approximately 12 hours to approximately 20 hours, approximately 14 hours to approximately 18 hours, approximately 15 hours to approximately 17 hours, or approximately 16 hours (e.g., approximately 16 hours)).

[0275] In some embodiments, step (f) includes filtering the mixture to provide form 1. In some embodiments, step (f) includes 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 includes drying the solid after rinsing to provide form 1. In some embodiments, rinsing the solid includes rinsing the solid with a solvent. In some embodiments, the solvent includes an alcohol. In some embodiments, the alcohol is methanol, ethanol, and / or isopropanol. In some embodiments, the solvent includes water. In some embodiments, the solvent includes alcohol and water. In some embodiments, the solvent includes methanol and water. In some embodiments, the solvent is methanol and water.

[0276] In some embodiments, isolating Form 1 from the third mixture is (i) Filter the third mixture to provide a solid, (ii) Rinse the solid with methanol and water, (iii) drying the solid to provide form 1,

[0277] In some embodiments, the weights of methanol and water are 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 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea 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)).

[0278] In some embodiments, drying a solid includes drying the solid at a temperature of 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 a solid includes drying the solid at a pressure lower than atmospheric pressure. In some embodiments, drying a solid includes drying the solid under an inert gas (e.g., nitrogen or argon (e.g., nitrogen)). In some embodiments, drying a solid includes drying the solid until it contains about 1% to about 4% by weight of water (e.g., about 1.5% to about 3.2% by weight or about 2% to about 2.6% by weight (e.g., about 2% to about 2.6%)). In some embodiments, Form 1 obtained in step (g) contains about 1% to about 4% by weight of water (e.g., about 1.5% to about 3.2% by weight or about 2% to about 2.6% by weight (e.g., about 2% to about 2.6%)).

[0279] Pharmaceutical composition and administration overview In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(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 comprising the chemical substance and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(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, 1-(2-aminopyrimidine-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, is a pharmaceutically acceptable solvate.

[0280] In some embodiments, the chemical may be administered in combination with one or more conventional pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, self-emulsifying drug delivery systems (SEDDS) such as alumina, aluminum stearate, lecithin, d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutically acceptable dosage forms such as Tweens, poloxamers or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering 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, polyvinylpyrrolidone; cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions can be prepared containing the chemicals described herein in an amount ranging from 0.005% to 100%, with the remainder being pharmaceutically acceptable excipients. The compositions to be considered may contain 0.001% to 100%, 0.1% to 95% in one embodiment, 75% to 85% in another embodiment, and 20% to 80% in a further embodiment, of the chemicals provided herein. Practical methods for preparing such dosage forms are known or will become apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK, 2012).

[0281] Route of administration and compositional components In some embodiments, the chemical substances or pharmaceutical compositions thereof described herein may be administered to subjects requiring them by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, cervix, sinuses, trachea, enteral, epidural, interstitial, abdominal, arterial, bronchial, synovial bursa, brain, cisternal, coronary artery, intradermal, intratubular, duodenal, intradural, intraepidermal, esophageal, gastric, gingival, ileum, lymphatic vessel, intramedullary, intrameningeal, intramuscular, ovarian, abdominal, prostate, lung, sac, intramedullary cavity, synovial bursa, testis, intramedullary cavity, intratubular, tumor, uterus, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, percutaneous, transmucosal, tracheal, ureter, urethra, and vagina. In certain embodiments, the route of administration is oral.

[0282] In other embodiments, the compounds or pharmaceutical compositions described herein are suitable for local delivery to the gastrointestinal tract or GI tract by oral administration (e.g., in solid or liquid dosage forms).

[0283] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) hygroscopic agents such as glycerol; d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as 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 glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. Similar types of solid compositions can also be used as fillers for soft and rigid gelatin capsules, using pharmaceutically acceptable excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0284] In one embodiment, the composition may take the form of a unit dosage form such as a pill or tablet, and therefore the composition may contain, along with the chemicals provided herein, diluents such as lactose, sucrose, and dicalcium phosphate; lubricants such as magnesium stearate; and binders such as starch, acacia gum, polyvinylpyrrolidone, gelatin, cellulose, and cellulose derivatives. Another solid dosage form involves encapsulating a powder, malt, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemicals or additional activators provided herein are physically separated, such as capsules (or tablets in capsules) having granules of each drug; two-layer tablets; two-chamber gel capsules, etc. Enteric-coated or sustained-release oral dosage forms are also conceivable.

[0285] 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.

[0286] In some embodiments, the pharmaceutical composition comprises 1-(2-aminopyrimidine-5-yl)-3-(1-(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)-1-(2-aminopyrimidine-5-yl)-3-(1-(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)1-(2-aminopyrimidine-5-yl)-3-(1-(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 a solvate of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea and one or more pharmaceutically acceptable carriers. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is crystalline. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is a solvate. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is a hydrate. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is a hemihydrate. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 1.In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is in form 1. * In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is form 2. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is form 3. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is form 4.

[0287] In some embodiments, the tablet comprises granules. In some embodiments, the tablet comprises granules and extragranular material. In some embodiments, the tablet is surrounded by layers.

[0288] In some embodiments, the pharmaceutical composition contains about 1 mg to about 500 mg (for example, 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 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0289] In some embodiments, the pharmaceutical composition contains about 1 mg to about 500 mg (for example, 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)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0290] In some embodiments, the pharmaceutical composition contains about 1 mg to about 500 mg (for example, 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)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0291] In some embodiments, the pharmaceutical composition contains about 1 mg to about 500 mg (for example, 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)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0292] In some embodiments, the pharmaceutical composition contains about 1 mg to about 500 mg (for example, 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)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate.

[0293] In some embodiments, the pharmaceutical composition contains about 1 mg to about 500 mg (for example, 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)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemihydrate.

[0294] In some embodiments, the pharmaceutical composition contains about 1 mg to about 500 mg (for example, 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 the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 1. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is form 1 * That is the case.

[0295] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately The pharmaceutical composition contains 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of 7 mg, approximately 18 mg to approximately 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg). In some embodiments, the pharmaceutical composition contains approximately 5 mg of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains 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 The pharmaceutical composition contains 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of 7 mg, approximately 18 mg to approximately 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg). In some embodiments, the pharmaceutical composition contains approximately 5 mg of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.In some embodiments, the pharmaceutical composition contains about 20 mg of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0296] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg). The pharmaceutical composition contains (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg. In some embodiments, the pharmaceutical composition contains approximately 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains 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) g contains (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg.In some embodiments, the pharmaceutical composition contains about 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0297] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg). The pharmaceutical composition contains (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg. In some embodiments, the pharmaceutical composition contains approximately 5 mg of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains 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) g contains (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg.In some embodiments, the pharmaceutical composition contains about 5 mg of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0298] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg, The composition contains approximately 18 mg to 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition contains approximately 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition contains 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, It contains a solvate of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 18 mg to 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg).In some embodiments, the pharmaceutical composition contains about 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate.

[0299] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg) The pharmaceutical composition contains (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl) urea hydrate in amounts of approximately 18 mg to 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In some embodiments, the pharmaceutical composition contains approximately 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl) urea hydrate. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition contains 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) It contains (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl) urea hydrate in amounts of approximately 18 mg to 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.In some embodiments, the pharmaceutical composition contains about 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate.

[0300] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg, The pharmaceutical composition contains approximately 18 mg to 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemihydrate. In some embodiments, the pharmaceutical composition contains approximately 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemihydrate. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemihydrate. In some embodiments, the pharmaceutical composition contains about 1 mg to about 100 mg (for example, 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, It contains (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemihydrate in amounts of approximately 18 mg to 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.In some embodiments, the pharmaceutical composition contains about 5 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemihydrate. In some embodiments, the pharmaceutical composition contains about 20 mg of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hemihydrate.

[0301] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg) The pharmaceutical composition contains approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains approximately 5 mg of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains 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) It contains crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 18 mg to 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.In some embodiments, the pharmaceutical composition contains about 5 mg of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0302] In some embodiments, the pharmaceutical composition contains approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately 1 mg to approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg, approximately 18 mg The pharmaceutical composition contains crystalline (R)-Form 1 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In some embodiments, the pharmaceutical composition contains approximately 5 mg of crystalline (R)-Form 1 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of crystalline (R)-Form 1 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains 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 Contains crystalline (R)-Form 1 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in amounts of approximately 22 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.In some embodiments, the pharmaceutical composition contains about 5 mg of crystalline (R)-Form 1 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, the pharmaceutical composition contains about 20 mg of crystalline (R)-Form 1 (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea.

[0303] In some embodiments, the pharmaceutical composition comprises 1 mg of Form 1 as described herein. * Includes. In some embodiments, the pharmaceutical composition includes 5 mg of Form 1 as described herein. In some embodiments, the pharmaceutical composition includes 5 mg of Form 1 as described herein. * Includes. In some embodiments, the pharmaceutical composition includes 10 mg of Form 1 as described herein. In some embodiments, the pharmaceutical composition includes 10 mg of Form 1 as described herein. * Includes. In some embodiments, the pharmaceutical composition includes 20 mg of Form 1 as described herein. In some embodiments, the pharmaceutical composition includes 20 mg of Form 1 as described herein. * Includes. In some embodiments, the pharmaceutical composition includes 25 mg of Form 1 as described herein. In some embodiments, the pharmaceutical composition includes 25 mg of Form 1 as described herein. * Includes.

[0304] In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is crystalline. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is a hydrate. In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is the hemihydrate (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is form 1.

[0305] In some embodiments, the composition comprises microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, stearyl fumarate sodium, 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 stearyl fumarate sodium.

[0306] In some embodiments, the weight of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (e.g., (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea) in the composition The percentages range from approximately 0.1% to approximately 50% (for example, approximately 0.1% to approximately 40%, approximately 0.1% to approximately 30%, approximately 0.1% to approximately 25%, approximately 0.1% to approximately 20%, approximately 0.1% to approximately 15%, approximately 1% to approximately 10%, approximately 1% to approximately 9%, approximately 1% to approximately 5%, approximately 5% to approximately 10%, approximately 3% to approximately 7%, approximately 4% to approximately 6%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, or approximately 10%). In some embodiments, the weight percentage of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (e.g., (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea) in the composition is about 5%.

[0307] In some embodiments, the weight percentage of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(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)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in the composition is about 5%.

[0308] In some embodiments, the weight percentage of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(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)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in the composition is about 5%.

[0309] 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%.

[0310] 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%.

[0311] 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%.

[0312] 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%.

[0313] 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%.

[0314] In some embodiments (for example, when the composition is in the form of a tablet surrounded by layers), the weight percentage of layers 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 layers), the weight percentage of layers in the composition is about 3%.

[0315] In some embodiments, the pharmaceutical composition is in the form of a tablet, and the weight percentage of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(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 35% to about 55%, the weight percentage of mannitol in the composition is about 35% to about 55%, the weight percentage of croscarmellose sodium in the composition is about 1% to about 5%, the weight percentage of colloidal silicon dioxide in the composition is about 0.1% to about 3%, and the weight percentage of stearyl sodium fumarate in the composition is about 0.1% to about 5%.

[0316] In some embodiments, the pharmaceutical composition is in the form of a tablet, and the weight percentage of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(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 stearyl sodium fumarate in the composition is about 1.25%.

[0317] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known, such as phenol and ascorbic acid.

[0318] In certain embodiments, pharmaceutically acceptable excipients are sterile and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage forms, pharmaceutically acceptable excipients such as tablets and capsules do not require sterility. USP / NF standards are usually sufficient.

[0319] In certain embodiments, the solid oral dosage form may further include one or more components that chemically and / or structurally pre-treat the composition to deliver the chemical to the stomach or lower GI, e.g., the ascending colon and / or transverse colon and / or distal colon and / or small intestine. An exemplary formulation technique is described, for example, Filipski, KJ, et al., 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0320] Several embodiments provide a solid dosage form for oral administration, including Embodiment 1 described herein. * The present invention provides a solid dosage form for oral administration, including [specific ingredients / methods]. 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.

[0321] Examples include upper GI targeting technologies, such as Accordion Pill (Intec Pharma), floating capsules, and materials that can adhere to mucosal walls.

[0322] Other examples include lower GI targeting technologies. Several enteric / pH-responsive coatings and pharmaceutically acceptable excipients are available to target various regions of the intestinal tract. These materials are typically polymers designed to dissolve or gradually break down within a specific pH range, selected based on the desired GI region of drug release. These substances also function to protect acid-unstable drugs from gastric juice or to limit exposure when the active ingredient may be irritating to the upper GI (e.g., the hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, the Eudragit series (methacrylate-methyl methacrylate copolymer), and Marcoat). Other technologies include dosage forms that respond to the local flora of the GI tract, pressure-controlled colon delivery capsules, and Pulsincap.

[0323] The composition can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such a composition can be prepared as either a liquid solution or a suspension for injection, and a solid form suitable for use in preparing a solution or suspension when liquid is added before injection can also be prepared, and the preparation can also be emulsified. The preparation of such formulations is known to those skilled in the art in light of this disclosure.

[0324] Suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In all cases, the form must be sterile and fluid enough to be easily injected. It must also be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi.

[0325] The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, in the case of a dispersion, to maintain the required particle size, and by the use of a surfactant. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it is preferable to include an isotonic agent, such as sugar or sodium chloride. Sustained absorption of the injectable composition can be achieved by the use of absorption-delaying agents, such as aluminum monostearate and gelatin in the composition.

[0326] Sterile injection solutions are prepared by incorporating the required amount of active compound, along with various other components listed above as needed, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components listed above. For sterile powders for the preparation of sterile injection solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient + any additional desired components from its previously sterile filtered solution. Intratumoral injection is discussed, for example, in Lammers, et al., Neoplasia. 2006, 10, 788-795.

[0327] pharmaceutically acceptable excipients usable in rectal compositions as gels, creams, enemas, or rectal suppositories include any one or more cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (such as PEG ointment), glycerin, glycerin gelatin, hydrogenated vegetable oil, poloxamer, mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, and anoxide. Examples of ingredients include, but are not limited to, SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopole, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metasulfite, sodium edetate, sodium benzoate, potassium bisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0328] In certain embodiments, suppositories can be prepared by mixing the chemicals described herein with a suitable non-irritating, pharmaceutically acceptable excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0329] The ophthalmic composition may contain, but is not limited to, one or more of the following: biscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0330] Topical compositions may include ointments and creams. Ointments are typically semi-solid preparations based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the “internal” phase, generally consists of petrolatum and fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase is usually not essential but exceeds the volume of the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0331] In any of the embodiments described herein, the pharmaceutical composition may comprise one or more of the following: lipids, interlayer crosslinked multiple lamellar vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0332] Dosage The dosage may be adjusted, for example, depending on the patient's needs and the severity of the condition being treated. Determining the appropriate dosage for a particular situation may be determined by those skilled in the medical field. The total daily dose may be divided and administered in small amounts throughout the day, or by means of providing continuous delivery.

[0333] In some embodiments, the dose of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (for example, 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).

[0334] In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (for example, 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).

[0335] In some embodiments, the dose of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 500 mg (for example, 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).

[0336] In some embodiments, the dose of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(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, crystalline (R)1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is Form 1. In some embodiments, crystalline (R) 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is in form 1 * That is the case.

[0337] In some embodiments, the dose of the (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea solvate is about 1 mg to about 500 mg (for example, 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).

[0338] In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate is about 1 mg to about 500 mg (for example, 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).

[0339] In some embodiments, form 1 of the hemihydrate * The dosage of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 1 mg to approximately 500 mg (for example, approximately 1 mg to approximately 450 mg, approximately 1 mg to approximately 400 mg, approximately 1 mg to approximately 350 mg, approximately 1 mg to approximately 300 mg, approximately 1 mg to approximately 250 mg, approximately 1 mg to approximately 200 mg, approximately 1 mg to approximately 150 mg, approximately 1 mg to approximately 100 mg, or approximately 1 mg to approximately 50 mg).

[0340] In some embodiments, Embodiment 1 * The dosage of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 1 mg to approximately 500 mg (for example, approximately 1 mg to approximately 450 mg, approximately 1 mg to approximately 400 mg, approximately 1 mg to approximately 350 mg, approximately 1 mg to approximately 300 mg, approximately 1 mg to approximately 250 mg, approximately 1 mg to approximately 200 mg, approximately 1 mg to approximately 150 mg, approximately 1 mg to approximately 100 mg, or approximately 1 mg to approximately 50 mg).

[0341] In some embodiments, the dose of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg, approximately The doses are approximately 1 mg to 30 mg, approximately 1 mg to 25 mg, approximately 1 mg to 20 mg, approximately 5 mg to 20 mg, approximately 1 mg to 10 mg, approximately 15 mg to 25 mg, approximately 3 mg to 7 mg, approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg. In some embodiments, the dose of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 5 mg. In some embodiments, the dose of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 20 mg.

[0342] In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg) The amounts are approximately 1 mg to 30 mg, approximately 1 mg to 25 mg, approximately 1 mg to 20 mg, approximately 5 mg to 20 mg, approximately 1 mg to 10 mg, approximately 15 mg to 25 mg, approximately 3 mg to 7 mg, approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg. In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 5 mg. In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 20 mg.

[0343] In some embodiments, the dose of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg) The amounts are approximately 1 mg to 30 mg, approximately 1 mg to 25 mg, approximately 1 mg to 20 mg, approximately 5 mg to 20 mg, approximately 1 mg to 10 mg, approximately 15 mg to 25 mg, approximately 3 mg to 7 mg, approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg. In some embodiments, the dose of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 5 mg. In some embodiments, the dose of (S)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 20 mg.

[0344] In some embodiments, the dose of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg). The amounts are approximately 1 mg to 30 mg, approximately 1 mg to 25 mg, approximately 1 mg to 20 mg, approximately 5 mg to 20 mg, approximately 1 mg to 10 mg, approximately 15 mg to 25 mg, approximately 3 mg to 7 mg, approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg. In some embodiments, the dose of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 5 mg. In some embodiments, the dose of crystalline (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 20 mg.

[0345] In some embodiments, the dose of the solvate of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 1 mg to about 100 mg (for example, 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) The amounts are approximately mg, about 1 mg to 30 mg, about 1 mg to 25 mg, about 1 mg to 20 mg, about 5 mg to 20 mg, about 1 mg to 10 mg, about 15 mg to 25 mg, about 3 mg to 7 mg, about 18 mg to 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, the dose of the solvate of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 5 mg. In some embodiments, the dose of the solvate of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is about 20 mg.

[0346] In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate is approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately 35 mg). The amounts are approximately 1 mg to 30 mg, approximately 1 mg to 25 mg, approximately 1 mg to 20 mg, approximately 5 mg to 20 mg, approximately 1 mg to 10 mg, approximately 15 mg to 25 mg, approximately 3 mg to 7 mg, approximately 18 mg to 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg. In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate is approximately 5 mg. In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea hydrate is about 20 mg.

[0347] In some embodiments, the dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in form 1 of hemihydrate is approximately 1 mg to approximately 100 mg (for example, approximately 1 mg to approximately 90 mg, approximately 1 mg to approximately 80 mg, approximately 1 mg to approximately 70 mg, approximately 1 mg to approximately 60 mg, approximately 1 mg to approximately 40 mg, approximately 1 mg to approximately The dosages are approximately 35 mg, about 1 mg to 30 mg, about 1 mg to 25 mg, about 1 mg to 20 mg, about 5 mg to 20 mg, about 1 mg to 10 mg, about 15 mg to 25 mg, about 3 mg to 7 mg, about 18 mg to 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, the dose of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in form 1 of the hemihydrate is about 5 mg. In some embodiments, the dose of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in form 1 of the hemihydrate is about 20 mg.

[0348] In some embodiments, Embodiment 1 * The dosage of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 1 mg to 100 mg (for example, approximately 1 mg to 90 mg, approximately 1 mg to 80 mg, approximately 1 mg to 70 mg, approximately 1 mg to 60 mg, approximately 1 mg to 40 mg, approximately 1 mg to 35 mg, approximately 1 mg to (Approximately 30 mg, approximately 1 mg to approximately 25 mg, approximately 1 mg to approximately 20 mg, approximately 5 mg to approximately 20 mg, approximately 1 mg to approximately 10 mg, approximately 15 mg to approximately 25 mg, approximately 3 mg to approximately 7 mg, approximately 18 mg to approximately 22 mg, approximately 1 mg, approximately 2 mg, approximately 3 mg, approximately 4 mg, approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, or approximately 50 mg). In some embodiments, Form 1* The dose of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 5 mg. In some embodiments, Form 1 * The dosage of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is approximately 20 mg.

[0349] 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 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 25 mg of Form 1 as described herein. * That is the case.

[0350] regimen The aforementioned doses can be administered daily (for example, as a single dose or as two or more divided doses) or non-daily (for example, every other day, every two days, every three days, once a week, twice a week, once every two weeks, or once a month).

[0351] 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.

[0352] In some embodiments, the duration of administration of the compounds described herein is 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 longer. In further embodiments, the period of administration cessation is 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 longer. In one embodiment, the therapeutic compound is administered to an individual over a certain period, followed by a separate period. In another embodiment, the therapeutic compound is administered in a first period and a second period following the first period, with administration ceasing during the second period, followed by a third period in which administration of the therapeutic compound is initiated, and then a fourth period in which administration is ceasing after the third period. In one aspect of this embodiment, the period of administration of the therapeutic compound and the subsequent period of administration cessation are repeated over a predetermined or unspecified period. In further embodiments, the duration of administration is 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 longer. In further embodiments, the period of discontinuation of administration is 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 longer.

[0353] Treatment method Indications The crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its pharmaceutically acceptable salts and / or solvates, are useful for treating PI3Kα-related diseases and disorders, such as PI3Kα-related overgrowth syndrome (PROS), vascular malformations, and proliferative disorders including hematological malignancies and solid tumors (e.g., progressive or metastatic solid tumors), which can be treated with PI3Kα inhibitors.

[0354] In some embodiments, subjects are identified or diagnosed with cancer (PI3Kα-related cancer) that has dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof (e.g., determined using a regulatory-approved assay or kit, e.g., FDA-approved). In some embodiments, subjects have tumors that are positive for dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof (e.g., determined using a regulatory-approved assay or kit). For example, subjects have tumors that are positive for mutations as listed in Table 1 or Table 2. Subjects may have tumors that are positive for dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof (e.g., identified as positive using a regulatory-approved assay or kit, e.g., FDA-approved). A subject may have a tumor that has dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either thereof (for example, if the tumor is identified as such using a regulatory authority-approved assay or kit, e.g., FDA-approved). In some embodiments, a subject is suspected of having a PI3Kα-associated cancer. In some embodiments, a subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either thereof (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0355] In some embodiments, the subjects are children.

[0356] As used herein, the term “pediatric subjects” refers to subjects under 21 years of age at the time of diagnosis or treatment. The term “pediatric subjects” can be further divided into various subgroups, including: neonates (from birth to 1 month of age), infants (1 month to 2 years of age), children (2 years to 12 years of age), and adolescents (12 to 21 years of age (up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WBSaunders 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, the target age group for children is from birth to 28 days old, from 29 days old to under 2 years old, from 2 years old to under 12 years old, or from 12 years old to 21 years old (up to their 22nd birthday, but excluding their 22nd birthday). In some embodiments, the target age group for children is from birth to 28 days old, from 29 days old to under 1 year old, from 1 month old to under 4 months old, from 3 months old to under 7 months old, from 6 months old to under 1 year old, from 1 year old to under 2 years old, from 2 years old to under 3 years old, from 2 years old to under 7 years old, from 3 years old to under 5 years old, from 5 years old to under 10 years old, from 6 years old to under 13 years old, from 10 years old to under 15 years old, or from 15 years old to under 22 years old.

[0357] In certain embodiments, 1-(2-aminopyrimidine-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, is useful for preventing diseases and disorders as defined herein (e.g., PIK3CA-associated hypergrowth syndrome (PROS) and cancer). As used herein, the term “prevent” means delaying the onset, recurrence, or progression of all or part of the disease or condition or symptoms thereof described herein.

[0358] As used herein, the term “PI3Kα-related disease or disorder” means a disease or disorder that is related to, or has a dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any one of them (e.g., one or more of them) (e.g., any kind of dysregulation of the expression, activity, or level of the PIK3CA gene, or the PI3Kα protein, or any one of them). Non-limiting examples of PI3Kα-related disorders or conditions include, for example, PIK3CA-related hypergrowth syndrome (PROS), brain disorders (e.g., macrocephaly-capillary malformation (MCAP) and hemimegalencephaly), lymphatic malformation (LM), cavernous malformation (CM), congenital lipomas (e.g., overgrowth of vascular malformations), epidermal nevi and skeletal / spinal cord abnormalities (e.g., Cloves syndrome) and fibroadipose hyperplasia (FH), or cancer (e.g., PI3Kα-related cancer).

[0359] Some embodiments provide a method for treating PIK3CA-associated hypergrowth syndrome (PROS) in subjects requiring treatment for PIK3CA-associated hypergrowth syndrome (PROS), comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0360] Some embodiments provide a method for treating a macrocapillary malformation (MCAP) in a subject requiring treatment for the MCAP, comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0361] Some embodiments provide a method for treating hemimegalencephaly in a subject requiring treatment for hemimegalencephaly, comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0362] Some embodiments provide a method for treating lymphatic malformations (LM) in subjects requiring treatment of lymphatic malformations (LM), comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0363] Some embodiments provide a method for treating congenital lipomas in subjects requiring treatment for congenital lipomas, comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0364] Some embodiments provide a method for treating an epidermal nevus in a subject requiring treatment of an epidermal nevus, comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0365] Some embodiments provide a method for treating Cloves syndrome in a subject requiring treatment for Cloves syndrome, comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0366] Some embodiments provide a method for treating fibrolipid hyperplasia (FH) in subjects requiring treatment of FH, comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0367] Some embodiments provide a method for treating cavernous vascular malformations (CM) in subjects requiring treatment of the CM, comprising administering to the subject a therapeutically effective amount of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof.

[0368] As used herein, the term “PI3Kα-related cancer” refers to cancers that are related to, or have, dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them. Non-exclusive examples of PI3Kα-related cancers are described herein.

[0369] The phrase "dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or any of them" refers to increased expression (e.g., increased levels) of wild-type PI3Kα in mammalian cells due to a gene mutation (e.g., a mutation in the PIK3CA gene resulting in the expression of PI3Kα having at least one amino acid deletion compared to wild-type PI3Kα, a mutation in the PIK3CA gene resulting in the expression of PI3Kα having one or more point mutations compared to wild-type PI3Kα, a mutation in the PIK3CA gene resulting in the expression of PI3Kα having at least one inserted amino acid compared to wild-type PI3Kα, a gene duplication resulting in increased levels of PI3Kα in cells, or a mutation in a regulatory sequence (e.g., promoter and / or enhancer) resulting in increased levels of PI3Kα in cells, an alternative splicing version of PI3Kα mRNA resulting in PI3Kα having at least one amino acid deletion compared to wild-type PI3Kα), or increased expression (e.g., increased levels) of wild-type PI3Kα in mammalian cells due to abnormal cellular signaling and / or dysregulation of autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either of them may be due to a mutation in the PIK3CA gene encoding a PI3Kα protein that is constitutively active or has increased activity compared to the protein encoded by the unmutated PIK3CA gene. Non-limiting examples of point mutations / substitutions / insertions / deletions of PI3Kα are listed in Tables 1 and 2.

[0370] The term "activating mutation" with respect to PI3Kα refers to a mutation in the PIK3CA gene that results in the expression of PI3Kα with increased kinase activity, for example, compared to wild-type PI3Kα, when assayed under identical conditions. In another example, an activating mutation may be a mutation in the PIK3CA gene that results in the expression of PI3Kα having one or more amino acid substitutions (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) (e.g., any combination of amino acid substitutions described herein) with increased kinase activity, for example, compared to wild-type PI3Kα, when assayed under identical conditions. In yet another example, an activating mutation may be a mutation in PIK3CA that results in the expression of PI3Kα having one or more amino acid deletions (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10) (e.g., compared to wild-type PI3Kα), when assayed under identical conditions. In another example, an activating mutation could be a mutation in the PIK3CA gene that, when assayed under identical conditions, results in the expression of PI3Kα having 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 insertions compared to wild-type PI3Kα, for example, the exemplary wild-type PI3Kα described herein. Examples of additional activating mutations are known in the art.

[0371] The term "wild type" refers to a nucleic acid (e.g., PIK3CA gene or PI3Kα mRNA) or protein (e.g., PI3Kα) sequence typically found in subjects without disease or disorder related to a reference nucleic acid or protein.

[0372] The term "wild-type PI3Kα" or "wild-type PI3Kα" refers to the normal PI3Kα nucleic acid (e.g., PIK3CA or PI3Kα mRNA) or protein found in subjects that do not have PI3Kα-related diseases, such as PI3Kα-related cancer (and, optionally, subjects that do not have an increased risk of developing PI3Kα-related disease and / or are not suspected of having PI3Kα-related disease), or in cells or tissues from subjects with PI3Kα-related diseases, such as PI3Kα-related cancer (and, optionally, subjects that do not have an increased risk of developing PI3Kα-related disease and / or are not suspected of having PI3Kα-related disease).

[0373] This specification provides a method for treating cancer (e.g., PI3Kα-associated cancer) in subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of 1-(2-aminopyrimidine-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, or a pharmaceutical composition thereof. For example, this specification provides a method for treating PI3Kα-associated cancer in subjects requiring treatment for PI3Kα-associated cancer, the method comprising: a) detecting dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them in a sample from the subject; and b) administering a therapeutically effective amount of 1-(2-aminopyrimidine-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. In some embodiments, dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them includes substitutions / point mutations / insertions of one or more PI3Kα proteins. Non-limiting examples of PI3Kα protein substitutions / insertions / deletions are listed in Tables 1 and 2.

[0374] In some embodiments, the subjects were determined to have one or more mutations in the kinase domain of the PI3Kα protein. In some embodiments, the subjects were determined to have one or more mutations in the helix domain of the PI3Kα protein. In some embodiments, the subjects were determined to have one or more mutations in both the kinase domain and the helix domain of the PI3Kα protein.

[0375] In some embodiments, PI3Kα protein substitution / insertion / deletion is E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, E542L, E545A, E545D, E545G, E545K, E545Q, E545V, E545R, E545T, Q546K, Q546R, Q546P, Q546 The group is selected from E, Q546H, E726K, N1044K, N1044Y, N1044S, N1044I, M1043I, M1043L, M1043T, M1043V, H1047P, H1047I, H1047D, H1047C, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof.

[0376] In some embodiments, the substitution / insertion / deletion of the PI3Kα protein 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, M1043V, H1047P, H1047I, H1047D, H1047C, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof.

[0377] In some embodiments, substitutions / insertions / deletions of the PI3Kα protein 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, G1049R, and combinations thereof. In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is H1047X, where X is any amino acid. In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is H1047R. In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is E542X, where X is any amino acid. In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is E545X, where X is any amino acid. In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is E546X, where X is any amino acid.

[0378] In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is H1047R and E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, E542L, E545A, E545D, E545G, E545K, E545Q, E545V, E545R, E545T, Q546K, Q546R One of the following is selected: Q546P, Q546E, Q546H, E726K, N1044K, N1044Y, N1044S, N1044I, M1043I, M1043L, M1043T, M1043V, H1047P, H1047I, H1047D, H1047C, H1047L, H1047Q, H1047Y, and G1049R.

[0379] In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is selected from E726K, H1047P, H1047I, H1047D, H1047C, H1047L, H1047Q, H1047Y, and G1049R. In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is selected from Q546K, Q546R, Q546P, Q546E, or Q546H, and E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, and E542L.

[0380] In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is selected from E545A, E545D, E545G, E545K, E545Q, E545V, or E545R, and E545T.

[0381] In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is selected from E542A, E542G, E542K, E542Q, E542V, E542S, E542R, E542I, or E542L, and D549N.

[0382] In some embodiments, the substitution / insertion / deletion of the PI3Kα protein is selected from E545A, E545D, E545G, E545K, E545Q, E545V, E545R, or E545T, and D453X.

[0383] In some embodiments, the cancer (e.g., PI3Kα-related cancer) is selected from hematological cancers and solid tumors.

[0384] In some embodiments, the cancer is a locally advanced tumor. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is unresectable. In some embodiments, the subject is administered (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, after surgery to remove the tumor (e.g., adjuvant therapy). In some embodiments, the subject is administered (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, before surgery to remove the tumor (e.g., neoadjuvant therapy).

[0385] In some embodiments, cancer (e.g., PI3Kα-related cancer) is breast cancer (HER2 + and HER2 - Both breast cancers, ER + Breast cancer (including triple-negative breast cancer), endometrial cancer, lung cancer (including non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), esophageal cancer (including esophageal squamous cell carcinoma), ovarian cancer, colorectal cancer, anal cancer, esophageal and gastric adenocarcinoma, stomach cancer, bladder cancer, appendiceal goblet cell carcinoma, head and neck cancer (including head and neck squamous cell carcinoma and oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, glioblastoma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), non-melanoma skin cancer, soft tissue sarcoma, hepatobiliary cancer, prostate cancer, kidney cancer, pancreatic neuroendocrine tumors (pancreatic neuroendocrine tumors) The cancers selected are neoplasms (pNETs), gastric cancer, esophageal cancer, acute myeloid leukemia, myelodysplastic syndromes, B-cell and T-cell lymphomas, multiple myeloma, relapsed and refractory multiple myeloma, sarcomas, pancreatic cancer, and other CNS cancers (including, but not limited to, neuromas, adenomas, schwannomas, astrocytomas, medulloblastomas, and oligodendrogliomas).

[0386] In some embodiments, cancer (e.g., PI3Kα-related cancer) is breast cancer (HER2 + and HER2 - Both breast cancers, ER + The following are selected from breast cancer (including triple-negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell carcinoma (including oropharyngeal squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, and hypopharyngeal squamous cell carcinoma, HNSCC), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocrine tumors (pNETs), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including lung adenocarcinoma and lung squamous cell carcinoma), and endometrial cancer.

[0387] In some embodiments, the cancer (e.g., PI3Kα-related cancer) is selected from breast cancer, lung cancer, endometrial cancer, gastric cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophageal gastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, prostate cancer, and cervical cancer.

[0388] 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.

[0389] In some embodiments, the cancer is a gynecological cancer. In some embodiments, the gynecological cancer is endometrial cancer, ovarian cancer, or cervical cancer.

[0390] 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 dMMR-free.

[0391] In some embodiments of the methods or uses described herein, the PI3Kα-related cancer is breast cancer.

[0392] 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.

[0393] In some embodiments, the cancer is esophageal cancer.

[0394] In some embodiments, the cancer is stomach cancer.

[0395] In some embodiments, the cancer is ovarian cancer.

[0396] In some embodiments, the cancer is colorectal cancer.

[0397] In some embodiments, the cancer is bladder cancer.

[0398] In some embodiments, the cancer is head and neck cancer.

[0399] In some embodiments, the cancer is thyroid cancer.

[0400] In some embodiments, the cancer is prostate cancer.

[0401] In some embodiments, the cancer is a glioma.

[0402] In some embodiments, the cancer is cervical cancer.

[0403] 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 gynecological cancer.

[0404] In some embodiments, the cancer described herein is HER2 + It is cancer. In some embodiments, the cancer described herein is HER2 - It's cancer.

[0405] In some embodiments, the cancer described herein is a HER2-low-expressing cancer. In some embodiments, the cancer has a HER2 score of 0, +1, or +2 (e.g., an IHC score). In some embodiments, the cancer has a HER2 score of 0 or +1 (e.g., an IHC score). 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.

[0406] In some embodiments, the cancer described herein is a HER2-very low-expression cancer (e.g., a cancer with faint, incomplete membrane staining in less than 10% of tumor cells as tested by an IHC assay).

[0407] In some embodiments, the cancer described herein is HER2 + It is breast cancer. In some embodiments, the cancer described herein is HER2 - It is breast cancer. In some embodiments, the cancer described herein is HER2-low-expressing breast cancer.

[0408] In some embodiments, the cancers described herein are hormone receptor-positive (HR + ) is cancer. In some embodiments, the cancer described herein is HER2 - And HR + It is cancer. In some embodiments, the cancer described herein is ER + In some embodiments, the cancer described herein is PR + In some embodiments, cancer is HR + / ER - I have breast cancer.

[0409] 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 of +1.

[0410] 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 of +3.

[0411] In some embodiments, the subjects have been previously identified or determined not to have activating mutations in AKT, RAS, or RAF, or inactivating mutations or loss-of-genomic mutations in PTEN, or a combination thereof. In some embodiments, the subjects have been previously identified or determined not to have activating mutations in AKT and / or PTEN (i.e., inactivating mutations or loss-of-genomic mutations in PTEN). In some embodiments, the subjects have been previously identified or determined not to have the E17K mutation in AKT. In some embodiments, PI3Kα-related cancers are selected from the cancers listed in Tables 1 and 2.

[0412] [Table 1-1]

[0413] [Table 1-2]

[0414] [Table 1-3]

[0415] [Table 1-4]

[0416] Table 1-5

[0417] Table 1-6

[0418] Table 1-7

[0419] Table 1-8

[0420] Table 1-9

[0421] Table 1-10

[0422] Table 1-11

[0423] Table 1-12

[0424] Table 1-13 AUnless otherwise noted, the mutations in Table 1 are found in the cBioPortal database, derived from Cerami et al. The cBio 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,pl1 (2013).

[0425] † 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.PMID:15994075.

[0426] [Table 2-1]

[0427] [Table 2-2] AUnless otherwise noted, the mutations in Table 2 are found in the cBioPortal database, derived from Cerami et al. The cBio 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,pl1 (2013). †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.PMID:15994075.

[0428] In some embodiments, dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them includes splice variations in PI3Kα mRNA, resulting in an expressed protein that is an alternative splicing variant of PI3Kα that has at least one residue deleted (compared to the wild-type PI3Kα protein) and results in constitutive activity of the PI3Kα protein domain.

[0429] In some embodiments, dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or any of them includes at least one point mutation in the PIK3CA gene resulting in the production of a PI3Kα protein having one or more amino acid substitutions, insertions, or deletions in the PIK3CA gene, which results in the production of a PI3Kα protein in which one or more amino acids are inserted or removed compared to the wild-type PI3Kα protein. In some cases, the resulting mutant PI3Kα protein has increased activity compared to the wild-type PI3Kα protein or a PI3Kα protein that does not contain the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Kα protein compared to the wild-type PI3Kα protein or a PI3Kα protein that does not contain the same mutation.

[0430] Exemplary sequence (SEQ ID NO: 1) of human phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA 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 IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN

[0431] In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof, is useful for treating cancers identified as having one or more PI3Kα mutations. Accordingly, the Specified provides a method for treating a subject diagnosed with (or identified as having) cancer, comprising administering to the subject a therapeutically effective amount of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or a pharmaceutically acceptable salt thereof and / or solvate thereof.

[0432] Also provided herein are methods for treating subjects identified or diagnosed with PI3Kα-related cancer, comprising administering to the subject a therapeutically effective amount of 1-(2-aminopyrimidine-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, or a pharmaceutical composition thereof. In some embodiments, subjects are identified or diagnosed with PI3Kα-related cancer by using regulatory authority-approved tests or assays, such as FDA-approved tests, or by performing any non-limiting example of assays described herein, to identify dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either thereof, in the subject or a biopsy sample from the subject. In some embodiments, the tests or assays are provided as kits. In some embodiments, the cancer is PI3Kα-related cancer.

[0433] In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea described herein, or a pharmaceutically acceptable salt and / or solvate thereof, can cross the blood-brain barrier (BBB) ​​after administration to a subject and inhibit mutant PI3Kα in the brain and / or other central nervous system (CNS) structures. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea described herein, or a pharmaceutically acceptable salt and / or solvate thereof, can cross the BBB in therapeutically effective doses after administration to a subject.

[0434] The term "regulatory authority" refers to a national agency that approves the medical use of drugs in a given country. For example, a non-specific example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0435] Furthermore, methods for treating cancer in subjects requiring cancer treatment are also provided, the methods comprising (a) detecting PI3Kα-related cancer in the subject, and (b) administering to the subject a therapeutically effective amount of 1-(2-aminopyrimidine-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, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., immunotherapy). In some embodiments, the subject had previously been treated with another anticancer treatment, such as at least partial resection of the tumor or radiotherapy. In some embodiments, a subject is determined to have PI3Kα-related cancer by using a regulatory authority-approved test or assay, such as an FDA-approved test or assay, or by performing any non-limiting example of an assay described herein, to identify dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof, in the subject or a biopsy sample from the subject. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is PI3Kα-related cancer.

[0436] Also provided are methods for treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either thereof; and administering (e.g., specifically or selectively) a therapeutically effective amount of 1-(2-aminopyrimidine-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, or a pharmaceutical composition thereof to the subject determined to have dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either thereof. Some embodiments of these methods further include administering another anticancer agent (e.g., immunotherapy) to the subject. In some embodiments of these methods, the subject had previously been treated with another anticancer treatment, such as at least partial resection of the tumor or radiotherapy. In some embodiments, the subjects are those suspected of having PI3Kα-related cancer, those exhibiting one or more symptoms of PI3Kα-related cancer, or those at high risk of developing PI3Kα-related 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-approved assay, e.g., an 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.

[0437] Furthermore, to determine whether a subject has dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof, an assay (e.g., an in vitro assay) is performed on a sample obtained from the subject to determine whether the subject has dysregulation of the expression, activity, or level of either of them, 1-(2-aminopyrimidine-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, or a pharmaceutical composition thereof, is provided for use in the treatment of PI3Kα-related cancer in subjects identified or diagnosed with PI3Kα-related cancer, where the presence of dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof identifies the subject as having PI3Kα-related cancer. Furthermore, the use of 1-(2-aminopyrimidine-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, is provided for the manufacture of a pharmaceutical for treating PI3Kα-related cancer in subjects identified or diagnosed with PI3Kα-related cancer through an assay process on a sample obtained from the subject to determine whether the subject has dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof, where the presence of dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof identifies the subject as having PI3Kα-related cancer. Some embodiments described herein further include recording in the subject's clinical record (e.g., on a computer-readable medium) that if the subject is determined, through the performance of an assay, to have dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof, the subject needs to be administered 1-(2-aminopyrimidine-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, 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-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0438] Also provided is 1-(2-aminopyrimidine-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, for use in the treatment of cancer in subjects requiring treatment for cancer or in subjects identified or diagnosed with PI3Kα-related cancer. Also provided is the use of 1-(2-aminopyrimidine-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, for the manufacture of pharmaceuticals for the treatment of cancer in subjects identified or diagnosed with PI3Kα-related cancer. In some embodiments, subjects are identified or diagnosed with PI3Kα-related cancer through the use of regulatory-approved, for example, FDA-approved kits for identifying dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof, in the subject or a biopsy sample from the subject. As provided herein, PI3Kα-related cancers include those described herein and those known in the art.

[0439] In some embodiments, the subject is identified or diagnosed with a cancer involving dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either of them. In some embodiments, the subject has a tumor that is positive for dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either of them. In some embodiments, the subject may have a tumor that is positive for dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either of them. In some embodiments, the subject may have a tumor whose tumor has dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either of them. In some embodiments, the subject is suspected of having a PI3Kα-related cancer. In some embodiments, this specification provides a method for treating PI3Kα-associated cancer in subjects requiring treatment for PI3Kα-associated cancer, the method comprising: a) detecting dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them in a sample from the subject; and b) administering a therapeutically effective amount of 1-(2-aminopyrimidine-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. In some embodiments, dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them includes one or more point mutations / insertions / deletions of the PI3Kα protein. Non-limiting examples of point mutations / insertions / deletions of the PI3Kα protein are listed in Tables 1 and 2. In some embodiments, the point mutation / insertion / deletion of the PI3Kα protein is H1047X, where X is any amino acid.In some embodiments, point mutations / insertions / deletions of the PI3Kα protein 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, cancers with dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof are determined using a regulatory-approved assay or kit, e.g., FDA-approved. In some embodiments, tumors with dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof are determined using a regulatory-approved assay or kit, e.g., FDA-approved.

[0440] In some embodiments, the subject has a clinical record indicating that the subject has a tumor with dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of the thereof. Also provided is a method for treating the subject, comprising administering a therapeutically effective amount of 1-(2-aminopyrimidine-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, to the subject having a clinical record indicating dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of the thereof.

[0441] In some embodiments, the methods described herein include performing an assay on a sample obtained from a subject to determine whether the subject has dysregulation of the expression or level of the PIK3CA gene, the PI3Kα protein, or either thereof. In some such embodiments, the methods also include administering a therapeutically effective amount of 1-(2-aminopyrimidine-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, to a subject determined to have dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either thereof. In some embodiments, the methods include determining whether a subject has dysregulation of the expression or level of the PIK3CA gene, the PI3Kα protein, or either thereof via an assay performed on a sample obtained from the subject. In such embodiments, the method also comprises administering to a subject a therapeutically effective amount of 1-(2-aminopyrimidine-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. In some embodiments, dysregulation in the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or either thereof is one or more point mutations in the PIK3CA gene (e.g., one or more of the point mutations of PI3Kα described herein). One or more point mutations in the PIK3CA gene may result in the translation of the PI3Kα protein having, for example, one or more of the following amino acid substitutions, deletions, and insertions: E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, and G1049R. One or more mutations in the PIK3CA gene may result in the translation of the PI3Kα protein having, for example, one or more of the following amino acids: 542, 545, 1043, and 1047, and 1049.In some embodiments, dysregulation in the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them is due to one or more PI3Kα amino acid substitutions (e.g., any of the PI3Kα amino acid substitutions described herein). Some embodiments of these methods further include administering another anticancer agent (e.g., immunotherapy) to the subject.

[0442] In some embodiments, assays used to determine whether a subject has dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof, using a sample from the subject, may 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 assay is typically carried out using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment. The assay may utilize other detection methods known in the art for detecting dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof (see, for example, the references cited herein). In some embodiments, the sample is a biological or biopsy sample from the subject (e.g., a paraffin-embedded biopsy sample). In some embodiments, the subjects are those suspected of having PI3Kα-related cancer, those having one or more symptoms of PI3Kα-related cancer, and / or those at increased risk of developing PI3Kα-related cancer.

[0443] In some embodiments, dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof can be identified using liquid biopsy (variously referred to as fluid biopsy or fluid-phase biopsy, etc.). See, for example, Karachialiou et al. Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy can be used to detect dysregulation of total tumor volume and / or the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof. Liquid biopsy can be performed on biological samples obtained relatively easily from the subject (e.g., via simple blood sampling) and is generally less invasive than conventional methods used to detect dysregulation of tumor volume and / or the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof. In some embodiments, liquid biopsy can be used to detect the presence of dysregulation of the expression, activity, or level of the PIK3CA gene, PI3Kα protein, or either thereof at an earlier stage than conventional methods. In some embodiments, the biological samples used in liquid biopsy may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cystic fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly sensitive detection techniques such as next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis, etc.) can be used to identify dysregulation of the expression, activity, or levels of PIK3CA, PI3Kα proteins, or either of them.

[0444] In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to the subject as monotherapy in doses of approximately 10 mg to approximately 200 mg per day, for example, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, or approximately 200 mg.

[0445] In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to the subject as monotherapy at doses of approximately 20 mg to approximately 200 mg per day, for example, approximately 20 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 140 mg, approximately 160 mg, approximately 180 mg, or approximately 200 mg.

[0446] In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to the subject as monotherapy at doses of approximately 20 mg to approximately 160 mg per day, for example, approximately 20 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 140 mg, or approximately 160 mg.

[0447] In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to the subject as monotherapy at doses of approximately 60 mg to approximately 160 mg per day, for example, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 140 mg, or approximately 160 mg.

[0448] In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, is administered to the subject once daily. In some embodiments, (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, is administered orally to the subject.

[0449] Furthermore, a method for treating PI3Kα-related cancer in subjects requiring treatment for PI3Kα-related cancer is also provided, which includes administering to the subject a therapeutically effective amount of crystalline form 1 of compound A, or a pharmaceutical composition containing the same.

[0450] Furthermore, a method for treating breast cancer in subjects requiring treatment for breast cancer is also provided, which includes administering to the subject a therapeutically effective amount of crystalline form 1 of compound A, or a pharmaceutical composition containing the same.

[0451] Furthermore, a method for treating gynecological cancers in subjects requiring treatment for gynecological cancers is also provided, which includes administering to the subject a therapeutically effective amount of crystalline form 1 of compound A, or a pharmaceutical composition containing the same.

[0452] Furthermore, a method for treating endometrial cancer in subjects requiring treatment for endometrial cancer is also provided, which includes administering to the subject a therapeutically effective amount of crystalline form 1 of compound A, or a pharmaceutical composition containing the same.

[0453] Other methods Also provided are methods for inhibiting PI3Kα activity in cells, comprising contacting cells with 1-(2-aminopyrimidine-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. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, and the method comprises administering an effective amount of 1-(2-aminopyrimidine-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, to a subject having cells with abnormal PI3Kα activity. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cells are any cancer described herein. In some embodiments, the cancer cells are PI3Kα-associated cancer cells. As used herein, the term “contact” means bringing together the indicated parts in an in vitro or in vivo system. For example, “contact” the PI3Kα protein with the compound provided herein includes administering the compound provided herein to a subject such as a human having the PI3Kα protein, and introducing the compound provided herein into a sample containing a cell preparation or purified preparation containing the PI3Kα protein, for example.

[0454] Furthermore, this specification also provides a method for inhibiting cell proliferation in vitro or in vivo, which comprises contacting cells with an effective amount of 1-(2-aminopyrimidine-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, or a pharmaceutical composition thereof, as defined herein.

[0455] This specification also provides a method for increasing cell death in vitro or in vivo, which involves contacting cells with an effective amount of 1-(2-aminopyrimidine-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, or a pharmaceutical composition thereof, as defined herein. A method for increasing tumor cell death in a subject is also provided herein. This method involves administering to a subject an effective amount of 1-(2-aminopyrimidine-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, in an amount effective to increase tumor cell death.

[0456] When used as a pharmaceutical, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, including its pharmaceutically acceptable salts and / or solvates, may be administered in the form of pharmaceutical compositions described herein.

[0457] combination Some embodiments provide a method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0458] Some embodiments provide a method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject a combination therapy comprising (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0459] In addition to the compositions provided herein, other components of such combination therapy or treatment may include surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signaling inhibitors, and / or monoclonal antibodies. Surgery may be open surgery or minimally invasive surgery and may include partial and total resection of solid tumors. Thus, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its pharmaceutically acceptable salts and / or solvates, may also be useful as adjuvants in cancer treatment, i.e., they may be used in combination with one or more additional therapies or treatment agents, such as chemotherapeutic agents acting by the same or different mechanisms of action. In some embodiments, 1-(2-aminopyrimidine-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, may be used before the administration of additional therapeutic agents or additional therapies. For example, one or more doses of 1-(2-aminopyrimidine-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, may be administered to a subject requiring it for a certain period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of 1-(2-aminopyrimidine-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, reduces the size of the tumor (e.g., tumor volume) before at least partial resection of the tumor. In some embodiments, one or more doses of 1-(2-aminopyrimidine-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, may be administered to patients in need under one or more radiotherapy sessions over a period of time.In some embodiments, treatment with one or more doses of 1-(2-aminopyrimidine-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, reduces tumor size (e.g., tumor volume) prior to one or more radiotherapy sessions.

[0460] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, (a) Testing or having tested subjects to determine whether they have PI3Kα-related cancer, (b) A method is provided comprising administering to a subject (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0461] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, (a) The subject is determined to have PI3Kα-related cancer, (b) A method is provided comprising administering to a subject (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0462] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, (a) The subject is determined to have PI3Kα-related cancer, (b) A method is provided comprising administering to a subject a combination therapy comprising (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0463] Some embodiments provide a method for treating cancer in a subject previously determined to have PI3Kα-related cancer, comprising administering to the subject (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more independently selected additional therapeutic agents.

[0464] Some embodiments provide a method for treating cancer in a subject previously determined to have PI3Kα-associated cancer, comprising administering to the subject a combination therapy comprising (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and one or more additional therapeutic agents.

[0465] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, and the subjects (a)(R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, (b) A method is provided comprising administering 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 agent, 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 any combination thereof. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with one additional therapeutic agent. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with two independently selected additional therapeutic agents.

[0466] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, and the subjects (a)(R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, (b) A method is provided comprising administering a combination therapy comprising one or more independently selected additional therapeutic agents selected from the group consisting of selective estrogen receptor modulators (SERMs) / selective estrogen receptor degraders (SERDs), cytotoxic chemotherapeutic agents, CDK2 inhibitors, cyclin E inhibitors, CDK4 inhibitors, CDK6 inhibitors, CDK4 / 6 inhibitors, HER2 inhibitors, EGFR inhibitors, immune checkpoint inhibitors, MEK inhibitors, RAS inhibitors, and RAF inhibitors, PIM (e.g., PIM1 and PIM3) inhibitors, or any combination thereof. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with one additional therapeutic agent. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with two independently selected additional therapeutic agents.

[0467] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, (a) Testing or having tested subjects to determine whether they have PI3Kα-related cancer, (b) A method is provided comprising administering to a subject (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), cytotoxic chemotherapeutic agent, CDK2 inhibitor, cyclin E inhibitor, CDK4 inhibitor, CDK6 inhibitor, CDK4 / 6 inhibitor, HER2 inhibitor, EGFR inhibitor, immune checkpoint inhibitor, MEK inhibitor, RAS inhibitor, and RAF inhibitor, PIM (e.g., PIM1 and PIM3) inhibitor, or any combination thereof. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with one additional therapeutic agent. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with two independently selected additional therapeutic agents.

[0468] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, (a) The subject is determined to have PI3Kα-related cancer, (b) A method is provided comprising administering to a subject (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), cytotoxic chemotherapeutic agent, CDK2 inhibitor, cyclin E inhibitor, CDK4 inhibitor, CDK6 inhibitor, CDK4 / 6 inhibitor, HER2 inhibitor, EGFR inhibitor, immune checkpoint inhibitor, MEK inhibitor, RAS inhibitor, and RAF inhibitor, PIM (e.g., PIM1 and PIM3) inhibitor, or any combination thereof. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with one additional therapeutic agent. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with two independently selected additional therapeutic agents.

[0469] Some embodiments are methods for treating cancer in subjects requiring cancer treatment, (a) The subject is determined to have PI3Kα-related cancer, (b) A method is provided comprising administering to a subject a combination therapy comprising (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), cytotoxic chemotherapeutic agent, CDK2 inhibitor, cyclin E inhibitor, CDK4 inhibitor, CDK6 inhibitor, CDK4 / 6 inhibitor, HER2 inhibitor, EGFR inhibitor, immune checkpoint inhibitor, MEK inhibitor, RAS inhibitor, and RAF inhibitor, PIM (e.g., PIM1 and PIM3) inhibitor, or any combination thereof. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with one additional therapeutic agent. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with two independently selected additional therapeutic agents.

[0470] Some embodiments are methods for treating cancer in subjects previously determined to have PI3Kα-related cancer, wherein the subjects (a)(R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, (b) A method is provided comprising administering one or more independently selected additional therapeutic agents selected from the group consisting of selective estrogen receptor modulators (SERMs) / selective estrogen receptor degraders (SERDs), cytotoxic chemotherapeutic agents, CDK2 inhibitors, cyclin E inhibitors, CDK4 inhibitors, CDK6 inhibitors, CDK4 / 6 inhibitors, HER2 inhibitors, EGFR inhibitors, immune checkpoint inhibitors, MEK inhibitors, RAS inhibitors, and RAF inhibitors, PIM (e.g., PIM1 and PIM3) inhibitors, or any combination thereof. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with one additional therapeutic agent. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with two independently selected additional therapeutic agents.

[0471] Some embodiments provide a method for treating cancer in a subject previously determined to have PI3Kα-related cancer, comprising administering to the subject a combination therapy comprising (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form or a pharmaceutically acceptable salt and / or solvate thereof, and a selective estrogen receptor modulator (SERM) / selective estrogen receptor degrader (SERD), a cytotoxic chemotherapeutic agent, 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 any combination thereof. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with one additional therapeutic agent. In some embodiments, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered together with two independently selected additional therapeutic agents.

[0472] In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., chemotherapy agents such as multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., chemotherapy agents such as multi-kinase inhibitors, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subject has cancer (e.g., locally advanced or metastatic tumor) for which there is no standard therapy. In some embodiments, the subject is PI3Kα inhibitor naive. For example, the subject is naive to treatment with selective PI3Kα inhibitors. In some embodiments, the subject is not PI3Kα inhibitor naive. In some embodiments, the subject is kinase inhibitor naive. In some embodiments, the subject is not kinase inhibitor naive. In some embodiments, the subject has received prior therapy, for example, treatment with one or a combination of the additional therapeutic agents described herein.In some embodiments, the target is a multi-kinase inhibitor (MKI) or another PI3Kα inhibitor, such as buparlisib (BKM120), alpelisib (BYL719), RLY-2608, WX-037, idelalisib, duvelisib, copanlisib, umbralicib (ALIQOPATM, BAY80-6946), dactricib (NVP-BEZ235, BEZ-235), taselicib (GDC-0032, RG7604), sonolicib (PX-866), fimepinostat (CUDC-907), vimiralisib (PQR309), ZS TK474, SF1126, AZD8835, Inabolici (GDC-0077), ASN003, Pictilicib (GDC-0941), Pilaralicib (XL147, SAR245408), Gedatricib (PF-05212384, PKI-587), Ceravelicib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, Apitricib (GDC-0980), Omiparicib (GSK2126458, GSK458), Boxtalicib (XL756, SAR245409), AMG Previously treated with 511, CH5132799, GSK1059615, paxalisib (GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, Waltmannin, LY294002, PI-103, ligosertib (ON-01910 sodium salt), voxtalisib (XL-765), LY2023414, SAR260301, KIN-193 (AZD-6428), acalisib (GS-9820), AMG319, or GSK2636771.

[0473] In some embodiments, subjects had previously been administered one or more PI3Kα inhibitors. In some embodiments, subjects had previously been administered alpelisib (BYL719), RLY-2608, or both alpelisib (BYL719) and RLY-2608.

[0474] In some embodiments of the methods described herein, the crystalline form of (R)-1-(2-aminopyrimidine-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, is administered in combination with at least one additional therapeutically effective dose of a therapeutic agent selected from one or more additional therapeutic (e.g., chemotherapy) agents. In some embodiments, the therapeutically effective dose of the additional therapeutic agent is a therapeutically effective dose of the agent when administered as monotherapy. In some embodiments, the therapeutically effective dose of the additional therapeutic agent is an amount administered in combination with the crystalline form of 1-(2-aminopyrimidine-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, as described herein.

[0475] In some embodiments, subjects are also instructed to maintain a specific diet and / or exercise regimen to control blood glucose levels.

[0476] Therefore, this specification also relates to a method for treating cancer, comprising, for use simultaneously, separately or sequentially, to a subject requiring treatment for cancer, (a) (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, (b) an additional therapeutic agent, and (c) optionally, simultaneously for the treatment of cancer. A method is also provided comprising administering a pharmaceutical combination for treating cancer, comprising (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and an amount of an additional therapeutic agent, which together is effective in treating cancer, with at least one pharmaceutically acceptable carrier for use separately or sequentially.

[0477] In some embodiments, the additional therapeutic agent comprises one of the therapies or therapeutic agents listed above, which are standard treatments for cancer, and the cancer has dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of them.

[0478] These additional therapeutic agents may be administered, as part of the same or different dosage forms, via the same or different routes of administration, and / or on the same or different schedules, together with one or more doses of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition thereof, as part of the same or different dosage forms, via the same or different routes of administration, and / or on the same or different schedules of administration.

[0479] Furthermore, (i) a pharmaceutical combination for treating cancer in a subject requiring cancer treatment, comprising (a) (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof; (b) at least one additional therapeutic agent (e.g., any exemplary additional therapeutic agent 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. (ii) a pharmaceutically effective combination of nopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and an amount of additional therapeutic agent, is provided herein, as well as (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 commercially available package or product comprising such a combination as a combined preparation for simultaneous, separate, or sequential use, as well as a method for treating cancer in a subject requiring treatment of cancer. In some embodiments, the cancer is PI3Kα-associated cancer.

[0480] As used herein, the term “pharmaceutical combination” refers to a pharmaceutical therapy resulting from a mixture or combination of two or more active ingredients, including both fixed and unfixed combinations of active ingredients. The term “fixed combination” means that 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are administered together to a subject in the form of a single composition or dosage. The term “non-fixed combination” means that 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, along with at least one additional therapeutic agent (e.g., a chemotherapeutic agent), may be administered to a subject in need simultaneously, in parallel, or sequentially, with a limit of sequential time intervals, and such administrations are formulated as separate compositions or dosages such that they result in effective levels of two or more compounds in the subject’s body. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients.

[0481] Accordingly, this specification also describes a method for treating cancer, comprising administering to a subject in need of cancer a pharmaceutical combination for treating cancer comprising (a) 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form or a pharmaceutically acceptable salt and / or solvate thereof, and (b) an additional therapeutic agent. Methods are also provided in which the crystalline form of (5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea and additional therapeutic agents are administered simultaneously, separately, or sequentially, and the amounts of the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its pharmaceutically acceptable salt and / or solvate, and the additional therapeutic agent are effective together in treating cancer. In some embodiments, the crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea, or its pharmaceutically acceptable salt and / or solvate, and the additional therapeutic agent are administered simultaneously in separate doses. In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and an additional therapeutic agent are administered sequentially in any order as separate doses, together in therapeutically effective amounts, for example, in a daily or intermittent dose. In some embodiments, 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, and an additional therapeutic agent are administered simultaneously as a combined dose.

[0482] Non-limiting examples of additional therapeutic agents include other PI3Kα-targeting therapies (i.e., other PI3Kα inhibitors), EGFR inhibitors, VEGFR / VEGF inhibitors, HER2 inhibitors, MEK pathway-targeting therapies (including RAS pathway-targeting therapies, including mTOR modulators / inhibitors as described herein), SHP2 inhibitors, ULK inhibitors, cytotoxic chemotherapeutic agents, 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-targeting therapies (e.g., Trk inhibitors or multi-kinase inhibitors)), KAT6A inhibitors, and farne Examples include siltransferase inhibitors, aromatase inhibitors, selective estrogen receptor modulators or degraders (including SERM / SERD, ERα inhibitors or ERα degraders), vinca alkaloids, signaling pathway inhibitors, antimetabolites, antiandrogens (e.g., androgen receptor (AR) antagonists, AR degraders, AR modulators), alkylating agents, checkpoint inhibitors, apoptotic pathway modulators (e.g., ovatoclax), cytotoxic chemotherapeutic agents (also called antineoplastic chemotherapeutic agents), angiogenesis-targeted therapies (e.g., angiogenesis inhibitors), immunotherapy (including immunotherapy), radiotherapy, glucocorticoids, antidiarrheals (such as loperamide and diphenoxylate-atropine), antihistamines, and retinoic acids.

[0483] As used herein, PIM inhibitors are inhibitors of the provirus integration site for Moloney leukemia virus kinase (sometimes called the proviral insertion site in Murine leukemia virus protein kinase), e.g., PIM1, PIM2, and PIM3, and any of their isoforms (e.g., PIM-1L (molecular weight 44 kDa) and PIM-1S (molecular weight 33 kDa)). PIM kinases regulate cell proliferation, survival, metabolism, cell transport, and signaling, and are overexpressed in several human cancers. Non-exclusive 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 (Belon and Nicot (2023) Mol. Cancer 22(1):18; Mahata S., et al.). 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 Med.206(9):1957-70, Pogacic V., et al., (2007) Cancer Res.67(14):6916-6924).

[0484] Examples of SHP2 inhibitors include JAB-3312, SHP099, SHP099 hydrochloride, SHP504, RMC-3943, AS1949490, SHP394, SHP389, and RMC-4630.

[0485] In some embodiments, the SHP2 inhibitor is RMC-4630.

[0486] Examples of ULK inhibitors include ULK-101, SBP-7455, SBI-0206965, ULK1-IN-2, MRT68921, MRT68921 dihydrochloride, MRT67307, MRT67307 hydrochloride, XST-14, and GW406108X (CW108X).

[0487] Examples of NTRK / ROS inhibitors include entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taretrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005).

[0488] Examples of 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.

[0489] Examples of RET inhibitors include serpercatinib (RETEVMO®, LOXO-292), zeteretinib (BOS-172738, DS-5010), GSK3179106, amvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or prarlcetinib (GAVRETO®, BLU-667).

[0490] Examples of MET inhibitors include capmatinib (TABRECTA®, INC280, INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, vortinib, HMPL-504, AZD-6094), forretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamfetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride).

[0491] Examples of TRK or multitarget kinase inhibitors include altiratinib (DCC-2701), CH7057288, larotrectinib (VITRAKVI®), entrectinib, ANA-12, repotrectinib (TPX-0005), citravatinib (MGCD516, MG-516), restaurtinib (CEP-701, KT-5555), tilhostine AG 879 (AG 879), and ceritrectinib (LOXO-195).

[0492] Examples of tyrosine kinase inhibitors include axitinib (INLYTA®), dasatinib (SPRYCEL®), erlotinib (TARCEVA®), imatinib (GLIVEC), nilotinib (TASIGNA®), pazopanib (VOTRIENT®), sunitinib (SUTENT®), and vemurafenib.

[0493] Similar vinca alkaloids include vinorelbine, vinblastine, vincristine, vindesine, and vinflunine.

[0494] Examples of antimetabolites include methotrexate, 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine (XELODA®), phloxuridine, cytarabine (ARA-C®), fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, pemetrexed (ALIMTA®), phototrexate, decitabine, Vidaza, DFP-11207, and RX-3117 and TAS-114.

[0495] Examples of alkylating agents include cyclophosphamide, lomustine, carmustine, streptozocin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechloretamine, melphalan, chlorambucil, melphalan, busulfan, dacarbazine, temozolomide, altoretamine, thiotepa, carboplatin, cisplatin, lurubinectedin, trabectedin, carmustine, oxaliplatin, and oxaliplatin.

[0496] Examples of checkpoint inhibitors include nivolumab, pembrolizumab, semiprimab, atezolizumab, durvalumab, avelumab, ipilimumab, LAG525 (IMP701), REGN3767 (R3767), BI754091, tevoterimab (MGD013), eftiragimodo alfa (IMP321), FS118, MBG453, Sym023, TSR-022, MGC018, FPA150, EOS100850, AB928, CPI-006, monalizumab, COM701, CM24, and NEO. Examples include -201, defactonib, PF-04136309, MSC-1, Hu5F9-G4(5F9), ALX148, TTI-662, RRx-001, lacunotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), pexidartinib (PLX3397), CAN04, canakinumab (ACZ885), BMS-986253, pepinemab (VX15 / 2503), trevananib, FP-1305, enapotamab vedotin (EnaV), and babituximab.

[0497] Exemplary modulators of the apoptotic pathway include obataclax, oblimersen, ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), Z-VAD-FMK, emricasane, Q-VD-Oph, Z-VAD(OH)-FMK, vernacasane (caspase-1), Z-DEVD-FMK (caspase-3), and Q-VD-OphZ-IETD-FMK (caspase-8). Examples include PAC-1 (Procaspase-3), Nutriin-3, Nutriin-3a, Idasa Nutriin, HDM201, APR-246, CBL0137, Pifisrin-α, Pifisrin-μ, 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).

[0498] Examples of cytotoxic chemotherapeutic agents include 5-fluorouracil, gemcitibin, methotrexate, NB1011, cyclophosphamide, dacarbazine, melphalan, trasectedin, temozolomide, doxorubicin, daunorubicin, mitoxantrone, vinblastine, paclitaxel, docetaxel, irinotecan, etoposide, and platinum-based agents such as carboplatin, cisplatin, and oxaliplatin.

[0499] Examples of topoisomerase inhibitors include etoposide, irinotecan, camptothecin (CPT), topotecan (TPT), irinotecan, berotecan, indenoisoquinoline, phenanthidine, and indolocarbazole. Further examples of topoisomerase inhibitors include aminocamptothecin, CT-2106, cristinator mesylate, DE-310, erinafide, lucanton, MLN576, and mitindomide.

[0500] Examples of angiogenesis-targeted therapies include bevacizumab, itraconazole, carboxamide triazole, TNP-470, CM101, IFN-α, IL-12, platelet factor-4, suramin, SU5416 thrombospongin, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospongin, prolactin, linamide, ramucirumab, tascinimod, ranibizumab, and soraf. Examples include enib, 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.

[0501] In some embodiments, the angiogenesis-targeted therapy is lenalidomide.

[0502] In some embodiments, the angiogenesis-targeted therapy is pomalidomide.

[0503] 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®), rosiletinib (CO-1686). , olmutinib (OLITA®, HM61713, BI-1482694), nacotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelreltinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), abitinib (AC0010), AC0010MA, EAI045, matsuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAbEGFR (registered trademark), saltzumab, MDX447, depatuxizumab (humanized mAb806, ABT-806), depatuxizumab mahodotin (ABT-414), ABT-806, mAb806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkanin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib WZ4002, Brigatinib (AP26113, ALUNBRIG®), Peritinib (EKB-569), Tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, Tesebatinib (KD019, XL647), Lazertinib (YH25448), Epitinib (HMPL-813), Olafertinib (CK-101, RX518), MM-151, Zolifertinib (AZD3759), Vandetanib (ZD6474), PF-064 59988, varlintinib (ASLAN001, ARRY-334543), mobosertinib (AP32788, TAK-788), pimlutamab (HLX07), befotertinib (D-0316), AEE788 (NVP-AEE788), aumorertinib (formerly amonertinib, HS-10296), abitinib, lapatinib (GW572016), pirotinib (SHR1258), SCT200, CPGJ602, Sym004 (futuximab and modoxinib) (In combination with Mab), EMD55900 (MAb-425), Modotuximab (TAB-H49), Futuximab (992DS), Saltumumab, RO5083945, Laprituximab Emtansine (IMGN289), Amivantamab (RYBREVANT® JNJ-61186372), LY3164530, Pan-HER (Sym013), AMG595, Tuxovertinib (BDTX-189), Abatinib, Disulptin, CL-387785 (EKI-785, WAY-EKI 785), EGFR Bi-armed autologous T cells, and EGFRThis is 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), rosiletinib (CO-1686), WZ4002, OMP-305B83, trastuzumab (e.g., TRAZIMERA®, HERCEPTIN®), RG-7597, and amivantanab.

[0504] In some embodiments, the EGFR inhibitor is razertinib. In some embodiments, the EGFR inhibitor is amivantanab. In some embodiments, the EGFR inhibitor is trastuzumab.

[0505] Examples of 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 (TRODELVY®), dacomitinib (e.g., VIZIMPRO®), and Af. Examples include atinib (GILOTRIF®), tucatinib (irbinitinib, ONT-380, ARRY-380, e.g., TUKYSA®), erlotinib (e.g., TARCEVA®), pirotinib, pozotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, dacomitinib (PF299804, PF299), peritinib, margetuximab, AEE-788 (NVP-AEE788), enfortumab vedotin (PADCEV®), and datopotamab deruxtecan.

[0506] 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.

[0507] Examples of VEGFR / VEGF inhibitors include pazopanib, sunitinib, lenvatinib, cabozantinib, sorafenib, regorafenib, ponatinib, lenvatinib axitinib, ziv-aflibercept, vandetanib, tivozanib, batalanib, AZD-2932, aflibercept, vanucizumab, BI836880, double antiangiogenic protein (DAAP), and ramucirumab.

[0508] As used herein, “MEK pathway targeted therapeutic agent” includes any compound that exhibits inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any protein in the MEK pathway, including any protein in the RAS pathway and the RAF pathway. As used herein, “RAS pathway targeted therapeutic agent” includes any compound that exhibits inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any protein in the RAS pathway. Non-limiting examples of proteins in the 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, the RAS pathway modulator may be selective for proteins in the RAS pathway; for example, the RAS pathway modulator may be selective for RAS (also referred to as the RAS modulator). In some embodiments, the RAS modulator is a covalent inhibitor. In some embodiments, the RAS pathway-targeted therapeutic agent is a "KRAS pathway modulator." A KRAS pathway modulator includes any compound that exhibits inactivating activity (e.g., kinase inhibition, allosteric inhibition, dimerization inhibition, and degradation induction) of any protein in the KRAS pathway. Non-limiting examples of proteins in the KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or the PI3K / AKT pathway, e.g., KRAS, RAF, BRAF, MEK, ERK, PI3K (i.e., other PI3K inhibitors described herein), AKT, and mTOR. In some embodiments, the KRAS pathway modulator may be selective for proteins in the RAS pathway; for example, a KRAS pathway modulator may be selective for KRAS (also referred to as the KRAS modulator). In some embodiments, the KRAS modulator is a covalent inhibitor.

[0509] Non-limiting examples of RAS-targeted therapies include sotrasib (AMG 510, Lumakras®), adaglasib (MRTX849), tipifarnib (R115777, Zarnestra), cismethinil, UCM-1336, deltalacin, NHTD, RM007, RM008, gefitib, apatinib, oncrasin-1, bismodegib (GDC-0449), and N-(1-acryloylazetidine-3-yl)-2-(5-bromo-3-(5-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-indole-1-yl)acetate Toamide, 2-((4-((1-(2-(2,4-dichlorophenoxy)acetyl)piperidine-4-yl)amino)-4-oxobutyl)disulfaneil)-N,N-dimethylethane-1-aminium, ARS-1620, ARS-853, Bemcentinib (BGB324), ABT-737, Selumetinib (AZD6244), Dactricib (NVP-BEZ235), PPIN-1, PPIN-2, Pan-RAS inhibitor 3144 (RAS-IN-3144), Deltalacin, SML-8-73-1, SM L-10-70-1, 1-(2-hydroxyethyl)-4-(2-methyl-3,5-diphenylpyrazolo[1,5-a]pyrimidine-7-yl)piperazin-1-ium, (2R,4aR)-3-acryloyl-11-chloro-9-fluoro-10-(6-fluoro-2-hydroxycyclohexa-2,4-dien-1-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-5(6H)-one, NHTD, PD98059 Examples include Waltmannin, Tarniflumate, Gefitib, CPD-0857, KY1022, KYA1797K (ab229170), 0375-0604 (DUN09716), 7773, NSC-658497, JNJ-74699157, PKF115-584 (Carphostine C), Kobe0065, Kobe2602, Salilasib, 3,3'-(ethylazandiyl)bis(N-phenylpropanamide), ML264, GDC-6036, LY3499446, and D-1553.

[0510] Non-exclusive examples of KRAS-targeted therapies (e.g., KRAS inhibitors) include BI 1701963, sotrasib (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.

[0511] A non-limiting example of an HRAS-targeted therapeutic agent (e.g., an HRAS inhibitor) is tipifarnib (ZARNESTRA®). Further non-limiting examples of HRAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments,

[0512] In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), mildametinib (PD0325901), pimacertib (MSC1936369B), SHR7390, TAK-733, RO5126766 (CH5126766), CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

[0513] In some embodiments, the ERK inhibitor is Ameriolex (FRI-20, ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, Temterquib (LY -3214996), lineterquib (LTT-462), KO-947, MK-8353 (SCH900353), SCH772984, urixerutinib (BVD-523), CC-90003, laboxerutinib (GDC-0994, RG-7482), ASN007, 5Z-7-oxozeaenol (FR148083, L783279, LL-Z 1640-2), 5-iodotubercidin (NSC 113939), ONC201 (TIC10), or combinations thereof.

[0514] In some embodiments, the antiandrogens are leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), enzalutamide (MDV3100, XTANDI®), abiraterone (ZYTIGA®), flutamide (EULEXIN®), AR inhibitor EPI-506, apalutamide (ERLEADA®), and darolutamide (NUBEQA®).

[0515] In some embodiments, the other PI3K inhibitor is another PI3Kα inhibitor. In some embodiments, the other PI3K inhibitor is a pan-PI3K inhibitor. In some embodiments, the other PI3K inhibitor is buparlisib (BKM120), alpelisib (BYL719, PIQRAY®), RLY-2608, idelalisib, duvelisib, umbralicib, WX-037, copanlisib (ALIQOPA®, BAY80-6946), dactricib (NVP-BEZ235, BEZ-235), taselicib (GDC-0032, RG7604), sonolicib (PX-866), fimepinostat (CUDC-907), vimiralisib (PQR309), ZSTK474. SF1126, AZD8835, Inaborishi (GDC-0077), ASN003, Pictilisib (GDC-0941), Pilaralisib (XL147, SAR245408), Gedatricib (PF-05212384, PKI-587), Ceravelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, Apitricib (GDC-0980), Omiparisib (GSK2126458, GSK458), Boxtalisib (XL756, SAR245409), AMG Selected from 511, CH5132799, GSK1059615, paxalisib (GDC-0084, RG7666), VS-5584 (SB2343), PKI-402, Waltmannin, LY294002, PI-103, ligosertib (ON-01910 sodium salt), voxtalisib (XL-765), LY2023414, SAR260301, KIN-193 (AZD-6428), acalisib (GS-9820), AMG319, GSK2636771, or a combination thereof.

[0516] In some embodiments, the AKT inhibitor is miltefosine (IMPADIVO®), woltmannin, NL-71-101, H-89, GSK690693, CCT128930, capivacertib (AZD5363), ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib (GSK2141795), afresertib (GSK2110183), DC120, 2-[4-(2-aminopropa-2-yl)phenyl]-3-phenylquinoxa Phosphorus, MK-2206, Edelfosine, Miltefosine, Perifosine (KRX-0401), Elsylphosphocholine, Elfosine, SR13668, OSU-A9, PH-316, PHT-427 (CS-0223), PIT-1, DM-PIT-1, Trisilibine (Tricilibin phosphate monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridine-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl)benzyl)-3-fluorobenzamide, Miransertib (ARQ092), BAY Selected from 1125976, 3-oxo-cylic acid, lactokinomycin, boc-Phe-vinyl ketone, perifosine (D-21266), TCN, TCN-P, ONC201 (TIC10), and TAS117.

[0517] In some embodiments, the AKT inhibitor is capivacertib.

[0518] In some embodiments, the mTOR inhibitor is an analog of rapamycin. Examples of rapamycin analogs include sapanicertib (MLN0128), bisutucertib (AZD-2014), onatacertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaflorimus (AP-23573), sirolimus (rapamycin), ridaflorimus (MK-8669), everolimus (RAD001, e.g., AFINITOR® or ZORTRESS®), umilorumus, zotarolimus, and RMC-5552. In some embodiments, the mTOR inhibitor is an ATP-competitive mTOR kinase inhibitor that competes with ATP at the catalytic site of mTOR. Examples of ATP-competitive mTOR kinase inhibitors include trin-1, trin-2, and vestusertib. Types of ATP-competitive mTOR kinase inhibitors include mTOR / PI3J dual inhibitors and mTORC1 / mTORC2 dual inhibitors (also called TORCdIs). Examples of mTOR / PI3K dual inhibitors include dactricib, voxtalicib, BGT226, SF1126, PKI-587, and NVPBE235. Examples of mTORC1 / mTORC2 dual inhibitors include sapanicertib (codename INK128), AZD8055, and AZD2014.

[0519] Non-exclusive examples of farnesyltransferase inhibitors include ronafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0520] In some embodiments, chemotherapeutic agents include anthracyclines, alkylating agents, taxanes, platinum-based drugs, mitomycin, gemcitabine, pemetrexed, eribulin (HALAVEN®), or combinations thereof.

[0521] Non-exclusive examples of taxanes include paclitaxel, docetaxel, abraxane, and taxotere.

[0522] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, and idarubicin.

[0523] In some embodiments, the platinum-based drug is selected from carboplatin, cisplatin, oxaliplatin, nedoplatin, triplatin tetranitrate, phenantriplatin, picoplatin, satraplatin, and lovaplatin. Any of the platinum-based drugs can be conjugated to a nanocarrier such as gold nanoclusters, gold nanoparticles, or superparamagnetic iron oxide nanoparticles. See, for example, Zhang et al. 2022. Theranostics. 12(5):2115-2132.

[0524] Non-exclusive examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, lucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP-9883, CEP 9722, E7016 (GPI 21016), iniparib, senaparib (IMP4297), benadaparib-Idience (NOV1401, IDX-1197), stenoparib (2X-121), ABT-767, atamparib (RBN-2397), and talazoparib (BMN Examples include 673), olaparib (KU-0059436, AZD2281, e.g., LYNPARZA®), iniparib (BSI-201, SAR240550), lucaparib (AG-014699, PF-01367338), INO-1001, and amerparib (JPI-289).

[0525] Non-exclusive examples of aromatase inhibitors include aminoglutethimide, testactone, anastrozole, letrozole, exemestane, volozol, formestan, and fadrozol.

[0526] Non-exclusive examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include clomiphene, cyclophenyl, anoldrin, propalestrol, napoxidine, olmeroxifene, raloxifene, toremifene, rasofoxifene, bazedoxifene, ospemifene, afimoxifene, enclomifene, cerophene, alzoxifene, tamoxifene, etaxtyl (GW-5638, DPC974), and fulvestrant (FAS Examples include LODEX®, brillanelastrant, elacestrant (ORSERDU®), giledestrant, amsenestrant (SAR439859), camizestrant (AZD9833), lintodestrant, imrunestrant, LSZ102, LY3484356, ZN-c5, taragarestrant (D-0502), AZD9496, clotrimazole, fenticonazole, SHR9549, and parazestrant (OP-1250).

[0527] In some embodiments, SERM / SERD is a parazestrant. In some embodiments, SERM / SERD is an erazestrant. In some embodiments, SERM / SERD is a kamizestrant.

[0528] Non-exclusive examples of glucocorticoids include dexamethasone, beclomethasone, betamethasone, budesonide, cortisone, hydrocortisone, methylprednisolone, prednisolone, prednison, and triamcinolone.

[0529] In some embodiments, the glucocorticoid is dexamethasone.

[0530] In some embodiments, the additional therapeutic agent is retinoic acid.

[0531] Non-exclusive examples of epigenetic agents include EZH2 inhibitors (e.g., TAZVERIK®, tazemetostat such as 3-deazanepranosin A (DZNep or C-c3Ado), EPZ005687, EI1, GSK126, and UNC1999) and HDAC inhibitors (e.g., vorinostat (SAHA) and panobinostat (LBH589)). Non-exclusive examples of HDAC inhibitors include hydroxamic acids (or hydroxamates), e.g., trichostatin A, vorinostat (SAHA), bellinostat (PXD101), LAQ824, and panobinostat (LBH589); cyclic tetrapeptides, e.g., trapoxin B and depsipeptide; benzamides, e.g., entinostat (MS-275), tasejinarin (CI994), and mosetinostat (MGCD0103); electrophilic ketones; and fatty acid compounds, e.g., phenylbutyrate and valproic acid.

[0532] In some embodiments, the epigenetic agent is an EZH2 inhibitor. In some embodiments, the epigenetic agent is tazemettostat. In some embodiments, the EZH2 inhibitor is tazemettostat.

[0533] In some embodiments, the epigenetic agent is an HDAC 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.

[0534] 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.

[0535] Non-exclusive examples of immunotherapy include immune checkpoint therapy, atezolizumab (TECENTRIQ®), and albumin-conjugated paclitaxel. Non-exclusive examples of immune checkpoint therapy include inhibitors targeting CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is nivolumab OPDIVO®, pembrolizumab KEYTRUDA®, semiprimab LIBTAYO®, atezolizumab TECENTRIQ®, durvalumab IMFINZI®, avelumab BAVENCIO®, dostallimab (JEMPERLI®), retifanlimab (ZYNYZ®), voplaterimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), cintilimab (IBI308), tislerizumab (BGB-A317), tripalimab (JS The inhibitor is selected from 001), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680), or acrixolimab (YBL-006). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), semiprimab (LIBTAYO®), or a combination thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or a combination thereof. In some embodiments, the LAG-3 inhibitor is relamirimab (IMP701, LAG525). In some embodiments, the A2AR inhibitor is siforadenanth (CPI-444). In some embodiments, the TIM-3 inhibitor is sabatrimab (MBG453). In some embodiments, the B7-H3 inhibitor is enobrituzumab.In some embodiments, the VISTA inhibitor is ombatirimab (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 herein by reference in its entirety.

[0536] In some embodiments, the CDK2 inhibitor is selected from INX-315, BLU-222, INCB123667, AZD8421, and tagtocyclib (PF-07104091).

[0537] In some embodiments, the CDK4 inhibitor is PF-07220060.

[0538] In some embodiments, the cytotoxic chemotherapeutic agent is Abraxane, Actinomycin, Alitretinoin, All-trans Retinoic Acid, Altretamine, Azacitidine, Azathioprine, Belotecan, Bendamustine, Bexarotene, Bleomycin, Bortezomib, Busulfan, Cabazitaxel, Camptothecin, Carboplatin, Carbocon, Carmustine, Capecitabine, Cisplatin, Chlorambucil, Chlormethine, Chlorozotocin, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dacarbazine, Daunorubicin, Decitabine, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothiron, Erlotinib, Etoposide, Equi Selected from: Satecan, fludarabine, fluorouracil, fotemustine, gefitinib, gemcitabine, dimatecan, idarubicin, ifosfamide, imatinib, irinotecan, ixabepirone, larotaxel, lomustine, melphalan, mercaptopurine, methotrexate, mitobronitol, mitomycin C, mitoxantrone, nelarabine, nimustine, oxaliplatin, paclitaxel, pemetrexed, tafluposide, taxotere, temozolomide, tesetaxel, teniposide, thiotepa, topotecan, tretinoin, arrubicin, vemurafenib, vinblastine, vincristine, vindesine, vinorelbine, bismodegib, and vorinostat.

[0539] In some embodiments, the CDK4 / 6 inhibitor is palbociclib (IBRANCE®, TQB3616, PD-0332991), ribociclib (KISQALI®), abemaciclib (VERZENIO®), boriclib (P1446A-05), trilaciclib, dalpicilib (SHR6390), roniciclib (BAY1000394), dinaciclib, flavopyridol (alvociib, L868275, HMR-1275), roscovitine (R-roscovitine, CYC202, sericiclib), ribiciclib (P276-00, P276), AT7519, TG02 (SB1317), RGB-286638, dinaciclib (SCH Selected from 727965), PHA-793887, ZK-304709, xythosidine, SNS032 (BMS-387032), R547 (R04584820), RGB286147, Pulvaranol A (NG60), Meliolin 3, JNJ7706621, Indirubin, AZD-5438, 10Z-Himennialdisine, AGO24322, PF-06873600, and KIN-8741.

[0540] 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 boriclib. In some embodiments, the CDK4 / 6 inhibitor is roniciclib. In some embodiments, the CDK4 / 6 inhibitor is dinaciclib.

[0541] In some forms, additional therapies or medications include fulvestrant, capecitabine, trastuzumab, ado-trastuzumab emtansine, pertuzumab, paclitaxel, nab-paclitaxel, enzalutamide, olaparib, pegylated liposomal doxorubicin (PLD), trametinib, palbociclib (IBRANCE®), buparlicib, sotrastaurin (AEB071), everolimus, exemestane, cisplatin, letrozole, and ganitumab (AMG). The following are selected from 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 amsenestrant.

[0542] In some embodiments, the additional therapeutic agent is everolimus. In some embodiments, additional therapeutic agents, such as opioids and corticosteroids, may be administered to treat potential side effects of certain anticancer therapies and / or as palliative care. In some embodiments, the additional therapies or therapeutic agents described herein are selected from the group consisting of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, metformin, and combinations thereof.

[0543] Non-exclusive 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.

[0544] Non-exclusive examples of SGLT-2 inhibitors include bexagliflozin, canagliflozin (e.g., INVOKANA®), dapagliflozin (e.g., FARXIGA®), empagliflozin (e.g., JARDIANCE®), erzgliflozin (e.g., STEGLATRO®), ipragliflozin (e.g., SUGLAT®), luseogliflozin (e.g., LUSEFI®), remogliflozin, selfliflozin, lycofliglozin, sotagliflozin (e.g., ZYNQUISTA®), and tofogliflozin.

[0545] Non-exclusive 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®), omaligliptin, evogliptin, and dutogliptin.

[0546] In some embodiments, the additional therapeutic agent is metformin. In some embodiments, the method described herein further comprises administering a therapeutically effective dose of metformin to the subject.

[0547] In some embodiments, the method involves the crystalline form of (R)-1-(2-aminopyrimidine-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 one additional therapeutic agent, e.g., aromatase inhibitors, CDK2 inhibitors, cyclin E inhibitors, CDK4 inhibitors, CDK6 inhibitors, CDK4 / 6 inhibitors, SERM / SERDs, radiotherapy, anti-HER2 antibodies or their antibody-drug conjugates (ADCs), immunotherapy, checkpoint inhibitors (e.g., anti-PD-1 or PD-L1 antibodies, anti-CLTA4 antibodies), VEGFR inhibitors / VEGF inhibitors, KAT6A inhibitors (MOZ inhibitors or...) Therapies include administering an anti-EGFR antibody along with an anti-metabolite (also known as a MYST3 inhibitor), a PI3Kα inhibitor, a MEK pathway targeting agent (including a RAS pathway targeting agent including the mTOR inhibitor described herein), a SHP2 inhibitor, a ULK inhibitor, an NTRK / ROS inhibitor, an ALK inhibitor, a RET inhibitor, a MET inhibitor, a PARP inhibitor, a PIM (e.g., PIM1 and PIM3) inhibitor, another kinase inhibitor (e.g., a Trk inhibitor or a multi-kinase inhibitor), a farnesyltransferase inhibitor, a vinca alkaloid, an antimetabolite, an antiandrogen, an alkylating agent, a checkpoint inhibitor, apoptotic pathway modulator; a cytotoxic chemotherapeutic agent, angiogenesis-targeted therapy, an immunotherapy, or an anti-EGFR antibody.

[0548] In some embodiments, the additional therapeutic agent is an antibody or ADC described herein. In some embodiments, the antibody is daratumumab (e.g., DARZALEX®).

[0549] In some embodiments, the method comprises administering (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt and / or solvate thereof, along with one additional therapeutic agent, such as a HER2 inhibitor, SERM / SERD, cytotoxic chemotherapeutic agent, CDK2 inhibitor, cyclin E inhibitor, CDK4 inhibitor, CDK6 inhibitor, CDK4 / 6 inhibitor, MEK inhibitor, checkpoint inhibitor (e.g., anti-PD-1 or PD-L1 antibody, anti-CLTA4 antibody), multikinase inhibitor, and PI3K inhibitor.

[0550] In some embodiments, the method involves a crystalline form of (R)-1-(2-aminopyrimidine-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 one additional therapeutic agent, such as trastuzumab, pertuzumab, trastuzumab emtansine, fam-trastuzumab deruxtecan, lapatinib, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pirotinib, tanespimycin, dacomitinib, peritinib, margetuximab, clomiphene, cyclophenyl, propalestrol, olmeroxifene, raloxifene, toremifene, rasofoxifene, bazedoxifene This includes administering ospemifene, enclomifene, cerophene, tamoxifen, fulvestrant, elacestrant, camizestrant, lintodestrant, clotrimazole, fenticonazole, nivolumab, pembrolizumab, semiprimab, atezolizumab, durvalumab, avelumab, ipilimumab, palbociclib, ribociclib, abemaciclib, trilaciclib, darpiciclib, trametinib, cobimetinib, binimetinib, selumetinib, mildametinib, pimacertib, alpelicib, RLY-2608, idelalisib, duvelisib, copanlisib, umbralicib, ribociclib, triaciclib, darpiciclib, boriclib, and roniciclib.

[0551] In some embodiments, the additional therapeutic agent is fulvestrant.

[0552] In some embodiments, an additional therapeutic agent is lapatinib.

[0553] In some embodiments, the additional therapeutic agent is abemaciclib.

[0554] In some embodiments, an additional therapeutic agent is trametinib.

[0555] In some embodiments, an additional therapeutic agent is binimetinib.

[0556] In some embodiments, the additional therapeutic agent is alpelisib.

[0557] In some embodiments, the additional therapeutic agent is RLY-2608.

[0558] In some embodiments, the additional therapeutic agent is palbociclib.

[0559] In some embodiments, the additional therapeutic agent is ribociclib.

[0560] In some embodiments, the additional therapeutic agent is trilasiclib.

[0561] In some embodiments, the additional therapeutic agent is darpiciclib.

[0562] In some embodiments, the additional therapeutic agent is borsicrib.

[0563] In some embodiments, the additional therapeutic agent is roniciclib.

[0564] In some embodiments, the additional therapeutic agent is dinaciclib.

[0565] In some embodiments, additional therapeutic agents are palbociclib and clomiphene.

[0566] In some embodiments, additional therapeutic agents are palbociclib and cyclofenil.

[0567] In some embodiments, additional therapeutic agents are palbociclib and anoldrin.

[0568] In some embodiments, additional therapeutic agents are palbociclib and propalestrol.

[0569] In some embodiments, additional therapeutic agents are palbociclib and napoxidine.

[0570] In some embodiments, additional therapeutic agents are palbociclib and olmeroxifen.

[0571] In some embodiments, additional therapeutic agents are palbociclib and raloxifene.

[0572] In some embodiments, additional therapeutic agents are palbociclib and toremifene.

[0573] In some embodiments, additional therapeutic agents are palbociclib and rasofoxifen.

[0574] In some embodiments, additional therapeutic agents are palbociclib and bazedoxifene.

[0575] In some embodiments, additional therapeutic agents are palbociclib and ospemifene.

[0576] In some embodiments, additional therapeutic agents are palbociclib and afimoxifen.

[0577] In some embodiments, additional therapeutic agents are palbociclib and enclomifene.

[0578] In some embodiments, additional therapeutic agents are palbociclib and cerophene.

[0579] In some embodiments, additional therapeutic agents are palbociclib and alzoxifen.

[0580] In some embodiments, additional therapeutic agents are palbociclib and tamoxifen.

[0581] In some embodiments, additional therapeutic agents are palbociclib and etaxtil.

[0582] In some embodiments, additional therapeutic agents are palbociclib and fulvestrant.

[0583] In some embodiments, additional therapeutic agents are palbociclib and brillanestrant.

[0584] In some embodiments, additional therapeutic agents are palbociclib and elacetrant.

[0585] In some embodiments, additional therapeutic agents include palbociclib and guiredetrant.

[0586] In some embodiments, additional therapeutic agents include palbociclib and amsenestrant.

[0587] In some embodiments, additional therapeutic agents are palbociclib and camizestrant.

[0588] In some embodiments, additional therapeutic agents include palbociclib and lintodestrant.

[0589] In some embodiments, additional therapeutic agents are palbociclib and imurunestrant.

[0590] In some embodiments, additional therapeutic agents include palbociclib and LSZ102.

[0591] In some embodiments, additional therapeutic agents include palbociclib and LY3484356.

[0592] In some embodiments, additional therapeutic agents are palbociclib and ZN-c5.

[0593] In some embodiments, additional therapeutic agents include palbociclib and taragarest.

[0594] In some embodiments, additional therapeutic agents are palbociclib and AZD9496.

[0595] In some embodiments, additional therapeutic agents are palbociclib and clotrimazole.

[0596] In some embodiments, additional therapeutic agents are palbociclib and fenticonazole.

[0597] In some embodiments, additional therapeutic agents include palbociclib and SHR9549.

[0598] In some embodiments, additional therapeutic agents are palbociclib and parazestrant.

[0599] In some embodiments, additional therapeutic agents are ribociclib and clomiphene.

[0600] In some embodiments, additional therapeutic agents are ribociclib and cyclofenil.

[0601] In some embodiments, additional therapeutic agents are ribociclib and anoldrin.

[0602] In some embodiments, additional therapeutic agents are ribociclib and propalestrol.

[0603] In some embodiments, additional therapeutic agents are ribociclib and napoxidine.

[0604] In some embodiments, additional therapeutic agents are ribociclib and olmeloxifen.

[0605] In some embodiments, additional therapeutic agents are ribociclib and raloxifene.

[0606] In some embodiments, additional therapeutic agents include ribociclib and toremifene.

[0607] In some embodiments, additional therapeutic agents are ribociclib and rasofoxifen.

[0608] In some embodiments, additional therapeutic agents are ribociclib and bazedoxifene.

[0609] In some embodiments, additional therapeutic agents are ribociclib and ospemifene.

[0610] In some embodiments, additional therapeutic agents are ribociclib and afimoxifen.

[0611] In some embodiments, additional therapeutic agents are ribociclib and enclomifene.

[0612] In some embodiments, additional therapeutic agents are ribociclib and cerophene.

[0613] In some embodiments, additional therapeutic agents include ribociclib and arzoxifen.

[0614] In some embodiments, additional therapeutic agents are ribociclib and tamoxifen.

[0615] In some embodiments, additional therapeutic agents are ribociclib and etaxtil.

[0616] In some embodiments, additional therapeutic agents are ribociclib and fulvestrant.

[0617] In some embodiments, additional therapeutic agents include ribociclib and brillanestrant.

[0618] In some embodiments, additional therapeutic agents are ribociclib and elacestrant.

[0619] In some embodiments, additional therapeutic agents include ribociclib and guiredetrant.

[0620] In some embodiments, additional therapeutic agents include ribociclib and amsenestrant.

[0621] In some embodiments, additional therapeutic agents are ribociclib and camizestrant.

[0622] In some embodiments, additional therapeutic agents are ribociclib and lintodestrant.

[0623] In some embodiments, additional therapeutic agents are ribociclib and imurunestrant.

[0624] In some embodiments, additional therapeutic agents include ribociclib and LSZ102.

[0625] In some embodiments, additional therapeutic agents include ribociclib and LY3484356.

[0626] In some embodiments, additional therapeutic agents are ribociclib and ZN-c5.

[0627] In some embodiments, additional therapeutic agents include ribociclib and taragarest.

[0628] In some embodiments, additional therapeutic agents include ribociclib and AZD9496.

[0629] In some embodiments, additional therapeutic agents are ribociclib and clotrimazole.

[0630] In some embodiments, additional therapeutic agents are ribociclib and fenticonazole.

[0631] In some embodiments, additional therapeutic agents include ribociclib and SHR9549.

[0632] In some embodiments, additional therapeutic agents are ribociclib and parazestrant.

[0633] In some embodiments, additional therapeutic agents are abemaciclib and clomiphene.

[0634] In some embodiments, additional therapeutic agents are abemaciclib and cyclofenil.

[0635] In some embodiments, additional therapeutic agents are abemaciclib and anoldrin.

[0636] In some embodiments, additional therapeutic agents are abemaciclib and proparestrol.

[0637] In some embodiments, additional therapeutic agents are abemaciclib and napoxidine.

[0638] In some embodiments, additional therapeutic agents are abemaciclib and olmeroxifen.

[0639] In some embodiments, additional therapeutic agents are abemaciclib and raloxifene.

[0640] In some embodiments, additional therapeutic agents are abemaciclib and toremifene.

[0641] In some embodiments, additional therapeutic agents are abemaciclib and rasofoxifene.

[0642] In some embodiments, additional therapeutic agents are abemaciclib and bazedoxifene.

[0643] In some embodiments, additional therapeutic agents are abemaciclib and ospemifene.

[0644] In some embodiments, additional therapeutic agents are abemaciclib and afimoxifen.

[0645] In some embodiments, additional therapeutic agents are abemaciclib and enclomifene.

[0646] In some embodiments, additional therapeutic agents are abemaciclib and cerophene.

[0647] In some embodiments, additional therapeutic agents include abemaciclib and alzoxifen.

[0648] In some embodiments, additional therapeutic agents include abemaciclib and tamoxifen.

[0649] In some embodiments, additional therapeutic agents are abemaciclib and etaxtil.

[0650] In some embodiments, additional therapeutic agents are abemaciclib and fulvestrant.

[0651] In some embodiments, additional therapeutic agents are abemaciclib and brillanestrant.

[0652] In some embodiments, additional therapeutic agents are abemaciclib and elacestrant.

[0653] In some embodiments, additional therapeutic agents include abemacicli and guiredetrant.

[0654] In some embodiments, additional therapeutic agents include abemaciclib and amsenestrant.

[0655] In some embodiments, additional therapeutic agents are abemaciclib and camizestrant.

[0656] In some embodiments, additional therapeutic agents are abemaciclib and lintodestrant.

[0657] In some embodiments, additional therapeutic agents are abemaciclib and imurunestrant.

[0658] In some embodiments, additional therapeutic agents include abemaciclib and LSZ102.

[0659] In some embodiments, additional therapeutic agents include abemaciclib and LY3484356.

[0660] In some embodiments, additional therapeutic agents are abemaciclib and ZN-c5.

[0661] In some embodiments, additional therapeutic agents are abemaciclib and taragarestorant.

[0662] In some embodiments, additional therapeutic agents are abemaciclib and AZD9496.

[0663] In some embodiments, additional therapeutic agents are abemaciclib and clotrimazole.

[0664] In some embodiments, additional therapeutic agents are abemaciclib and fenticonazole.

[0665] In some embodiments, additional therapeutic agents include abemaciclib and SHR9549.

[0666] In some embodiments, additional therapeutic agents are abemaciclib and parazestrant.

[0667] In some embodiments, the method comprises administering a crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(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, such as HER2 inhibitors, SERMs / SERDs, cytotoxic chemotherapeutic agents, CDK2 inhibitors, cyclin E inhibitors, CDK4 inhibitors, CDK6 inhibitors, CDK4 / 6 inhibitors, MEK inhibitors, checkpoint inhibitors (e.g., anti-PD-1 or PD-L1 antibodies, anti-CLTA4 antibodies), multikinase inhibitors, and PI3K inhibitors.

[0668] In some embodiments, the method involves a crystalline form of 1-(2-aminopyrimidine-5-yl)-3-(1-(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, such as trastuzumab, pertuzumab, trastuzumab emtansine, fam-trastuzumab deruxtecan, lapatinib, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pirotinib, tanespimycin, dacomitinib, peritinib, margetuximab, clomiphene, cyclophenyl, propalestrol, olmeroxifene, raloxifene, toremifene, rasofoxifene, bazedoxifene, or This includes administering spemifene, enclomifene, cerophene, tamoxifen, fulvestrant, elacestrant, camizestrant, lintodestrant, clotrimazole, fenticonazole, nivolumab, pembrolizumab, semiprimab, atezolizumab, durvalumab, avelumab, ipilimumab, palbociclib, ribociclib, abemaciclib, trilaciclib, darpiciclib, trametinib, cobimetinib, binimetinib, selumetinib, mildametinib, pimacertib, alpelicib, RLY-2608, idelalisib, duvelisib, copanlisib, umbralicib, ribociclib, triaciclib, darpiciclib, boriclib, and roniciclib.

[0669] In some embodiments, additional therapeutic agents are fulvestrant and lapatinib.

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

[0671] In some embodiments, additional therapeutic agents are fulvestrant and trametinib.

[0672] In some embodiments, additional therapeutic agents are fulvestrant and binimetinib.

[0673] In some embodiments, additional therapeutic agents are fulvestrant and alpelicib.

[0674] In some embodiments, additional therapeutic agents are fulvestrant and RLY-2608.

[0675] In some embodiments, additional therapeutic agents are fulvestrant and palbociclib.

[0676] In some embodiments, additional therapeutic agents are fulvestrant and darpiciclib.

[0677] In some embodiments, additional therapeutic agents include fulvestrant and borcilib.

[0678] In some embodiments, additional therapeutic agents include fulvestrant and roniclib.

[0679] In some embodiments, additional therapeutic agents include fulvestrant and dinaciclib.

[0680] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, with an ERα inhibitor or a degrading agent.

[0681] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and a cytotoxic chemotherapeutic agent.

[0682] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and a CDK2 inhibitor.

[0683] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and a cyclin E inhibitor.

[0684] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and a CDK4 inhibitor.

[0685] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and a CDK6 inhibitor.

[0686] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor.

[0687] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and a HER2 inhibitor.

[0688] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and alpelisib.

[0689] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and fulvestrant.

[0690] In some embodiments, the method involves administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or a pharmaceutically acceptable salt thereof, and lapatinib.

[0691] In some embodiments, the method comprises administering 1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or...

Claims

1. (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea in crystalline form, or pharmaceutically acceptable salts and / or solvates thereof.

2. The crystalline form according to claim 1, wherein the (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea exists in the form of a pharmaceutically acceptable solvate.

3. The crystal morphology according to claim 1 or 2, wherein the crystal morphology is characterized by a crystal powder diffraction (XRPD) pattern having a peak at 18.3 ± 0.2 degrees 2θ.

4. The crystal morphology according to claim 3, wherein the XRPD pattern has a peak at 15.8 ± 0.2 degrees 2θ.

5. The crystalline form according to claim 3 or 4, wherein the XRPD pattern has a peak at 6.4 ± 0.2 degrees 2θ.

6. The crystalline form according to any one of claims 3 to 5, wherein the XRPD pattern has a peak at 22.3 ± 0.2 degrees 2θ.

7. The crystalline form according to any one of claims 3 to 6, wherein the XRPD pattern has a peak at 20.8 ± 0.2 degrees 2θ.

8. The crystalline form according to any one of claims 3 to 7, wherein the XRPD pattern has a peak at 19.3 ± 0.2 degrees 2θ.

9. The crystalline form according to any one of claims 3 to 8, wherein the XRPD pattern has a peak at 24.0 ± 0.2 degrees 2θ.

10. The crystalline form according to any one of claims 3 to 9, wherein the XRPD pattern has a peak at 26.9 ± 0.2 degrees 2θ.

11. The crystalline form according to any one of claims 3 to 10, wherein the XRPD pattern has a peak at 14.6 ± 0.2 degrees 2θ.

12. The crystalline form according to any one of claims 3 to 11, wherein the XRPD pattern has a peak at 31.3 ± 0.2 degrees 2θ.

13. The crystalline form according to any one of claims 3 to 12, wherein the XRPD pattern has a peak at 28.3 ± 0.2 degrees 2θ.

14. The crystal morphology according to claim 1 or 2, wherein the crystal morphology is morphology 1, and the XRPD pattern has peaks at 6.4, 15.8, and 18.3 (±0.2 degrees 2θ).

15. The crystal morphology according to claim 1 or 2, wherein the crystal morphology is morphology 1, and the XRPD pattern has peaks (±0.2 degrees 2θ) 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 crystal morphology according to claim 1 or 2, wherein the crystal morphology is morphology 1 and is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 4.

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

19. The crystal form according to any one of claims 1 to 18, wherein the crystal form is form 1 having a TGA curve that is substantially the same as the TGA curve shown in Figure 28.

20. The aforementioned crystal form is (a) Dissolving (R)-1-(2-aminopyrimidine-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, in isopropanol to form a solution, (b) Adding water to the solution to form a mixture, (c) Lowering the temperature of the mixture and then maintaining the temperature over a first period of time, (d) Raising the temperature of the mixture and then maintaining the temperature over a second period of time, (e) Lowering the temperature of the mixture and then maintaining the temperature over a third period, (f) The crystalline form of the form 1 according to any one of claims 1 to 19, which is prepared by a method comprising isolating form 1 from the mixture.

21. The aforementioned crystal form is (a) Dissolving (R)-1-(2-aminopyrimidine-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, in methanol to form a solution, (b) Adding water to the solution to form a first mixture, (c) Form 1 of (R)-1-(2-aminopyrimidine-5-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea is added to the first mixture to form a second mixture, (d) Stirring the second mixture, (e) Adding water to the second mixture to form a third mixture, (f) Stirring the third mixture, (g) The crystalline form of the form according to any one of claims 1 to 4, which is prepared by a method comprising isolating form 1 from the third mixture.

22. Isolating form 1 from the third mixture is (i) Filter the third mixture to provide a solid, (ii) Rinsing the solid with methanol and water, (iii) The crystalline form according to claim 21, comprising drying the solid to provide form 1.

23. The aforementioned crystal morphology is characterized by an X-ray powder diffraction (XRPD) pattern having a peak at 6.3 ± 0.2 degrees 2θ, which is morphology 1. ＊ The crystal form according to claim 1 or 2.

24. The crystal morphology according to claim 23, wherein the XRPD pattern has a peak at 15.8 ± 0.2 degrees 2θ.

25. The crystalline morphology according to claim 23 or 24, wherein the XRPD pattern has a peak at 20.8 ± 0.2 degrees 2θ.

26. The crystalline morphology according to any one of claims 23 to 25, wherein the XRPD pattern has a peak at 15.9 ± 0.2 degrees 2θ.

27. The crystalline form according to any one of claims 23 to 26, wherein the XRPD pattern has a peak at 19.8 ± 0.2 degrees 2θ.

28. The crystal morphology according to claim 1 or 2, wherein the crystal morphology is characterized by an X-ray powder diffraction (XRPD) pattern having peaks (±0.2 degrees 2θ) at 6.2, 15.2, 15.3, 20.9, 21.9, 22.0, 21.0, 18.7, 18.7, and 26.

9.

29. The crystal morphology according to claim 1 or 2, wherein the crystal morphology is characterized by an X-ray powder diffraction (XRPD) pattern having peaks (±0.2 degrees 2θ) at 4.0, 4.9, 25.8, 21.4, 9.1, 19.2, 6.9, 15.7, 16.8, and 9.

9.

30. The crystal morphology according to claim 1 or 2, wherein the crystal morphology is characterized by an X-ray powder diffraction (XRPD) pattern having peaks (±0.2 degrees 2θ) 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 a crystalline form according to any one of claims 1 to 30 and a pharmaceutically acceptable carrier.

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

33. The pharmaceutical composition according to claim 31 or 32, comprising microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, stearyl fumarate sodium, or any combination thereof.

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

35. A method for treating cancer in a subject requiring treatment for cancer, the method comprising: (a) determining that the cancer is related to dysregulation of the expression, activity, or level of the PIK3CA gene, the PI3Kα protein, or any of the thereof; and (b) administering to the subject a therapeutically effective amount of the crystalline form described in any one of claims 1 to 30, or a pharmaceutically acceptable salt and / or solvate thereof, or the pharmaceutical composition described in any one of claims 31 to 33.

36. A method for treating PI3Kα-related cancer in a subject, the method comprising administering to a subject identified or diagnosed with PI3Kα-related cancer a therapeutically effective amount of the crystalline form described in any one of claims 1 to 30, or a pharmaceutically acceptable salt and / or solvate thereof, or the pharmaceutical composition described in any one of claims 31 to 33.

37. A method for modulating PI3Kα in mammalian cells, the method comprising contacting the mammalian cells with an effective amount of the crystalline form described in any one of claims 1 to 30, or a pharmaceutically acceptable salt and / or solvate thereof.

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