Crystal form, pharmaceutical composition, and method of use thereof

Abstract

A crystalline form and pharmaceutical composition of a PRMT5 inhibitor of formula (I), a method for preparing a pharmaceutical composition of a PRMT5 inhibitor of formula (I), and a method for using a PRMT5 inhibitor of formula (I) or a crystalline solid form and a pharmaceutically acceptable composition thereof. JPEG2026508792000023.jpg68165 In some embodiments, a crystalline form of N-(6-amino-5-ethylpyridine-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidine-4-yl)benzo[d]thiazole-5-yl)piperidine-1-yl)-2-oxoacetamide (compound of formula (I)) is provided.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 419,225, filed on October 25, 2022, and U.S. Provisional Application No. 63 / 496,105, filed on April 14, 2023, which are hereby incorporated by reference in their entireties.

Background Art

[0002] To develop a pharmaceutical composition containing one or more novel active ingredients, various considerations are required, such as the route of administration (e.g., enteral, parenteral, topical, etc.), dosage form (e.g., solid: tablets, capsules, etc., liquid: solutions, suspensions, syrups, etc.), strength of the active ingredient(s) (e.g., 1 mg to 1,000 mg), non - therapeutic component(s) (e.g., excipients, etc.), and their respective amounts. Each of these considerations can be accompanied by further considerations (e.g., stability, decomposition, sensitivity to light, solubility, taste when administered enterally, palatability, pH, skin irritation, microbial growth, etc.). To advance a novel active ingredient (e.g., a PRMT5 inhibitor) through strict regulatory authorities, it is required to discover and develop a pharmaceutical composition that addresses these or other considerations.

[0003] Therefore, there is a need for a pharmaceutical composition containing a compound (e.g., a PRMT5 inhibitor) that exhibits desirable properties for treating a disease or disorder (e.g., cancer) in a human patient.

Summary of the Invention

Means for Solving the Problems

[0004] In some embodiments, a crystalline form of N - (6 - amino - 5 - ethylpyridin - 3 - yl) - 2 - ((2R,5S) - 5 - methyl - 2 - (2 - (1 - methylpiperidin - 4 - yl)benzo[d]thiazol - 5 - yl)piperidin - 1 - yl) - 2 - oxoacetamide (a compound of formula (I)) is provided. [ka]

[0005] In some embodiments, the crystalline form of N-(6-amino-5-ethylpyridine-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidine-4-yl)benzo[d]thiazole-5-yl)piperidine-1-yl)-2-oxoacetamide (compound of formula (I)) is, [ka] A crystalline morphology is provided in which the X-ray powder diffraction (XRPD) pattern of the crystalline morphology includes one or more peaks at 2θ angles selected from 9.6±0.2°, 16.8±0.2°, 19.3±0.2°, 19.4±0.2°, 20.9±0.2°, 23.7±0.2°, and 24.5±0.2° (morphology A).

[0006] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0007] In a particular embodiment, the pharmaceutical composition comprises crystalline form A of the compound of formula (I).

[0008] In some embodiments, (a) Compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof (b) Filling material (e.g., microcrystalline cellulose), (c) Fluidizing agent (e.g., colloidal silicon dioxide), (d) Disintegrant (e.g., croscarmellose sodium), and (e) A pharmaceutical composition comprising a lubricant (e.g., magnesium stearate) is provided.

[0009] In some embodiments, the composition comprises a crystalline form (e.g., Form A) of a compound of formula (I) described herein.

[0010] In some embodiments, dosage forms comprising the pharmaceutical compositions described herein are provided.

[0011] In some embodiments, a method for treating MTAP deficiency and / or MTA accumulation diseases in a subject that needs thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form (e.g., Form A of a compound of formula (I)) described herein, is provided.

[0012] In some embodiments, a method for treating MTAP deficiency and / or MTA accumulation diseases in a subject that needs thereof, the method comprising administering to the subject a pharmaceutical composition described herein comprising a therapeutically effective amount of a compound of formula (I), is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] [Figure 1] Exemplary X-ray powder diffraction pattern of crystalline Form A of a compound of formula (I).

[0014] [Figure 2A] Exemplary thermogravimetric analysis (TGA) thermogram of a compound of formula (I) is shown.

[0015] [Figure 2B] Differential scanning calorimetry (DSC) thermogram of crystalline Form A of a compound of formula (I) under a heating-cooling-heating protocol is shown, showing a melting peak at about 145.8 °C.

[0016] [Figure 3A] In an exemplary DVS experiment of a compound of formula (I) (crystalline Form A), changes in the moisture content (solid line curve) and relative humidity (dashed line curve) as a function of time are shown.

[0017] [Figure 3B] In an exemplary DVS experiment with the compound of formula (I) (crystal morphology A), the change in water content as a function of relative humidity is shown.

[0018] [Figure 4A] This shows the antiproliferative activity (survival rate at different concentrations) of the compound of formula (I) in a pair of MTAP isogenic cell lines manipulated by CRISPR-mediated MTAP gene knockout of HAP1 chronic myeloid leukemia cell lines.

[0019] [Figure 4B] This shows the antiproliferative activity (survival rate at different concentrations) of the compound of formula (I) in a pair of MTAP isogenic cell lines manipulated by CRISPR-mediated MTAP gene knockout of the HCT116 colorectal cancer cell line.

[0020] [Figure 4C] This shows the antiproliferative activity (survival rate at different concentrations) of the compound of formula (I) in a pair of MTAP isogenic cell lines manipulated by reconstituting exogenous MTAP in an endogenous MTAP-deficient LU99 non-small cell lung cancer cell line.

[0021] [Figure 4D] This shows the antiproliferative activity (survival rate at different concentrations) of the compound of formula (I) in a pair of MTAP isogenic cell lines manipulated by reconstituting exogenous MTAP in an endogenous MTAP-deficient LN18 glioblastoma cell line.

[0022] [Figure 5A] The pharmacodynamic activity of the compound of formula (I) against PRMT5 is demonstrated by showing graphs of normalized single SDMA-modified protein levels at various concentrations of the PRMT5 inhibitor of formula (I) in HAP 1 MTAP-isogenic cell line pairs. Normalized to the DMSO control for each cell line, the values ​​are expressed as mean ± SD.

[0023] [Figure 5B] The pharmacodynamic activity of compounds of formula (I) against type I PRMT is demonstrated by showing graphs of normalized single ADMA-modified protein levels at various concentrations of PRMT5 inhibitors of formula (I) in HAP 1 MTAP-isogenic cell line pairs. Normalized to the DMSO control for each cell line, the values ​​are expressed as mean ± SD.

[0024] [Figure 5C] The dendrograms of the biochemical selectivity of the compound of formula (I) for PRMT5 in the histone methyltransferase panel are shown.

[0025] [Figure 6] The pharmacokinetic profile of the compound of formula (I) in cynomolgus monkeys is shown, illustrating the free plasma exposure after forced oral administration of 3 mg / kg of the compound of formula (I). The GI50 of wild-type and MTAP null cells is shown by the dotted line.

[0026] [Figure 7] This report shows the results of a 7-day PK / PD trial using a LU99 (lung giant cell carcinoma) MTAP null xenograft model. The compound of formula (I) was administered as shown, and PK and tumor samples were collected at specified time points. SDMA-modified protein levels at each dose are shown as a percentage of the vehicle. N = 4 tumors / group. Data are shown mean ± SEM.

[0027] [Figure 8A] This shows the dose-dependent antitumor activity of the compound of formula (I) against a xenograft model derived from the LN18 MTAP null cell line. Data are shown mean ± SEM.

[0028] [Figure 8B] This shows the dose-dependent antitumor activity of the compound of formula (I) against a xenograft model derived from the OCI-LY19 MTAP null cell line. Data are shown mean ± SEM.

[0029] [Figure 8C] This shows the dose-dependent antitumor activity of the compound of formula (I) against a xenograft model derived from MTAP null mesothelioma patients. Data are shown mean ± SEM.

[0030] [Figure 8D] This shows the dose-dependent antitumor activity of the compound of formula (I) against xenograft models derived from MTAP-null bladder cancer patients. Data are shown mean ± SEM.

[0031] [Figure 8E] This shows the dose-dependent antitumor activity of the compound of formula (I) against xenograft models derived from MTAP-null cholangiocarcinoma patients. Data are shown mean ± SEM.

[0032] [Figure 8F] This shows the dose-dependent antitumor activity of the compound of formula (I) against a xenograft model derived from MTAP-null NSCLC (squamous epithelium) patients. Data are shown mean ± SEM.

[0033] [Figure 8G] This shows the dose-dependent antitumor activity of the compound of formula (I) (40 mg / kg twice daily and 100 mg / kg once daily) in a xenograft model derived from the LU-99 NSCLC MTAP-null cell line. The dotted line is the regression line, defined as the final mean tumor volume which is 30% less than the initial mean tumor volume. Data are shown mean ± SEM.

[0034] [Figure 8H] This shows the dose-dependent antitumor activity of the compound of formula (I) at 30 mg / kg twice daily and 60 mg / kg twice daily in a xenograft model derived from the LU-99 NSCLC MTAP null cell line. The dotted line is the regression line, defined as the final mean tumor volume which is 30% less than the initial mean tumor volume. Data are shown mean ± SEM.

[0035] [Figure 9A] The antitumor activity of the compound of formula (I) in patient-derived xenograft models obtained from bladder cancer, cholangiocarcinoma, mesothelioma, non-small cell lung cancer (e.g., adenocarcinoma and squamous cell carcinoma), and pancreatic cancer (e.g., pancreatic ductal adenocarcinoma) is shown. If the final mean tumor volume of PRMT5 inhibitor-treated mice is greater than the initial mean tumor volume, the data is shown relative to the vehicle-treated tumor (greater than 0). If the final mean tumor volume of PRMT5 inhibitor-treated mice is less than the initial mean tumor volume, the data is shown relative to the mean tumor volume (less than 0).

[0036] [Figure 9B] This shows an updated display of the 9A data with three data points added: xenografts for bile duct cancer (1), bladder cancer (1), and lung cancer (1). Data for lung adenocarcinoma and squamous cell carcinoma have been combined into a single category. The graph shows the final tumor volume as a percentage of the initial tumor volume. The line at 100 represents no change in tumor volume, values ​​between 0% and 100% of the initial tumor volume represent a decrease in tumor volume, and values ​​above 100 represent an increase in tumor volume.

[0037] [Figure 10A] This study demonstrates that the compound of formula (I) can overcome resistance to MTA-cooperative PRMT5 inhibitors in a xenograft model derived from diffuse large B-cell lymphoma cell lines. Data are shown mean ± SEM.

[0038] [Figure 10B] This shows an enlarged portion of Figure 10A, with the y-axis dashed to highlight the region of interest.

[0039] [Figure 11]This waterfall plot shows 180 cancer cell lines representing multiple cancer lineages, including NSCLC, PDAC, bladder, CNS, and heme malignancies, profiled with the PRMT5 inhibitor of formula (I) in a 7-day CellTiter-Glo assay. Maximum efficacy has been reported at a concentration equivalent to 10 times the HAP1 MTAP null GI50, and cell lines are fill-coded according to their MTAP status.

[0040] [Figure 12] This shows the antitumor activity of the compound of formula (I) (30 mg / kg twice daily alone, or in combination with osimertinib at 1 mg / kg once daily) against a xenograft model derived from the NCI-H1650 NSCLC MTAP-null cell line. Data are shown mean ± SEM.

[0041] [Figure 13] The antitumor activity of the compound of formula (I) (30 and 60 mg / kg twice daily alone, and 30 mg / kg twice daily in combination with 10 mg / kg of AGI-41998) against a xenograft model derived from the NCI-H838 NSCLC MTAP-null cell line is shown. Data are shown mean ± SEM. [Modes for carrying out the invention]

[0042] As generally described herein, this disclosure relates to PRMT5 inhibitors (e.g., MTA-noncompetitive PRMT5 inhibitors), e.g., compounds of formula (I): [ka] The invention provides pharmaceutical compositions including the crystalline form thereof, methods for preparing pharmaceutical compositions, and methods for using pharmaceutical compositions to treat medical conditions, diseases, and disorders (e.g., proliferative diseases such as cancer).

[0043] definition When used in this disclosure, the following terms are generally intended to have the meanings set forth below, unless expressly indicated otherwise or the context in which they are used indicates otherwise.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this invention pertains. Abbreviations used herein have their conventional meanings within the fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical valence known in the field of chemistry.

[0045] In the overall modes for carrying out the invention, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is further intended that there exist compositions and kits of the present invention that are essentially composed of or comprise the listed components, and that there exist processes and methods according to the present invention that are essentially composed of or comprise the listed processing steps.

[0046] Where it is stated in this application that an element or component is included in and / or selected from the list of elements or components, it should be understood that the element or component may be any one of the listed elements or components, or that the element or component may be selected from a group consisting of two or more of the listed elements or components.

[0047] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether expressly or implicitly, can be combined in various ways without departing from the spirit and scope of the invention. For example, where a particular compound is mentioned, that compound can be used in various embodiments of the compositions of the invention and / or in the methods of the invention, unless otherwise understood from the context. Where elements are presented as a list, for example in the form of a Markouche group, each subgroup of the elements is also disclosed, and any element(s) may be removed from that group. In other words, while embodiments within this application are described and illustrated in a manner that enables the writing and creation of a clear and concise application, it is intended and to be understood that embodiments can be combined and separated in various ways without departing from the teachings and inventions. For example, it should be understood that all features described and illustrated herein may be applicable to all embodiments of the inventions described and illustrated herein.

[0048] In this disclosure, the articles "a" and "an" are used to refer to one or more (i.e., at least one) grammatical objects of the article, unless the context is inappropriate. For example, in a particular context, "element" means one element and / or multiple elements. As another example, in a particular context, "filler" means one filler and / or multiple fillers (e.g., a mixture of two or more fillers).

[0049] Unless otherwise indicated, the term "and / or" is used in this disclosure to mean either "and" or "or".

[0050] The expression "at least one of ~" should be understood to include each of the items listed after it and any various combinations of two or more of the listed items, unless otherwise understood from the context and usage. The expression "and / or" relating to three or more listed items should be understood to have the same meaning, unless otherwise understood from the context.

[0051] The use of the terms "include / includes / including," "have / has / having," or "contain / contains / containing" (including their grammatical equivalents) should be understood to be generally unrestricted and non-exclusive, unless otherwise specified or understood from the context, and should not exclude, for example, further elements or steps not listed.

[0052] When "approximately" is used before a quantitative value, unless otherwise specified, the present invention also includes the specific quantitative value itself. As used herein, the term "approximately" refers to a variation of ±10% from the nominal value, unless otherwise indicated or inferred from the context.

[0053] In various places in this specification, variables or parameters are disclosed in groups or ranges. In embodiments for carrying out the invention, it is specifically intended to include any partial combination of members of such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to disclose individually 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range of 1 to 20 are specifically intended to disclose individually 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0054] Any use of any example or illustrative term in this specification (e.g., "such as" or "including") is intended merely to better illustrate the invention and does not imply any limitation to the scope of the invention unless otherwise claimed. No term in this specification should be construed as indicating that any unclaimed element is essential for the practice of the invention.

[0055] As a general rule, compositions specifying percentages are based on weight unless otherwise specified. Furthermore, if a variable is not defined, its previous definition prevails.

[0056] As used herein, "XRPD" refers to X-ray powder diffraction. An XRPD pattern is an xy graph in which 2θ (diffraction angle) is plotted on the x-axis and intensity is plotted on the y-axis. These are diffraction peaks used to characterize crystalline materials. Since diffraction peak intensity can be particularly sensitive to sample orientation, diffraction peaks are usually represented and referred to by their position on the x-axis rather than their intensity on the y-axis (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Therefore, typically, those skilled in the art do not use intensity to characterize crystalline materials. As with any data measurement, variability can exist in XRPD data. In addition to variability in diffraction peak intensity, variability can also exist in the position of the diffraction peak on the x-axis. However, this variability is typically taken into consideration when reporting the position of the diffraction peak for characterization purposes. Such variability in the position of the diffraction peak along the x-axis can stem from several causes. One such cause is sample preparation. When samples of the same crystalline material are prepared under different conditions, slightly different diffractograms may be obtained. Factors such as particle size, water content, solvent content, temperature, and orientation can all affect the X-ray diffraction of a sample. Another cause of variability is due to the parameters of the instrument. Different X-ray powder diffractometers operate with different parameters, which can result in slightly different diffraction patterns from the same crystalline material. Similarly, different software packages process XRPD data differently, which can also introduce variability. These and other causes of variability are known to those skilled in the art. Because of these causes of variability, the term "approximately" is sometimes used before the value of each X-ray diffraction peak, or an appropriate range (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.) is used to define the variability of the experiment.

[0057] The crystalline form (e.g., the crystalline form of the compound of formula (I)) can be readily analyzed by XRPD. Data from X-ray powder diffraction can be used in several ways to characterize the crystalline form. For example, the overall X-ray powder diffraction pattern output from the diffractometer can be used to characterize the crystalline form (e.g., the compound of formula (I)). However, smaller subsets of such data may also be suitable and usable for characterizing such crystalline forms. In fact, even a single X-ray powder diffraction peak can be used to characterize such crystalline forms. With respect to the crystalline form of the compound of formula (I), one or more peaks in the X-ray powder diffraction pattern in Figure 1 can be used to characterize the crystalline form of the compound of formula (I) disclosed herein.

[0058] When referring to the peaks in the XRPD pattern of a given chemical entity's crystalline form (e.g., the crystalline form of the compound of formula (I)), the term "characteristic peaks" refers to a specific set of diffraction peaks whose values ​​span a range of 2θ values ​​(e.g., 0° to 40°) and which, as a whole, are characteristic of that particular crystalline form.

[0059] As used herein, "crystalline" refers to the solid phase of a chemical entity in which the three-dimensional structural order is clearly defined. Atoms, ions, and / or molecules are arranged regularly and periodically within a repeating three-dimensional lattice. In various embodiments, the crystalline material may comprise one or more discrete crystalline forms.

[0060] As used herein, “crystalline form,” “crystalline solid form,” “crystalline form,” “solid form,” and related terms herein refer to crystalline modifiers comprising a given substance (e.g., the compound of formula (I)), which include, but are not limited to, single-component crystalline forms and multi-component crystalline forms, as well as polymorphs, solvates, hydrates, and salts.

[0061] The term "substantially crystalline" refers to a solid form that is crystalline to at least a specific weight percentage. A specific weight percentage may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In a particular embodiment, the weight percentage of a particular degree of crystallinity is at least 90%. In a particular other embodiment, the weight percentage of a particular degree of crystallinity is at least 95%. In some embodiments, the compound of formula (I) may be a substantially crystalline sample of any of the crystalline solid forms described herein (e.g., a crystalline form having the XRPD pattern shown in Figure 1).

[0062] The term “substantially pure” relates to the composition of a particular crystalline solid form (e.g., the crystalline form of the compound of formula (I)) that may not contain at least a certain weight percentage of impurities and / or other solid forms. A particular weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In a particular embodiment, the compound of formula (I) may be a substantially pure sample of any of the crystalline solid forms described herein (e.g., the crystalline form having the XRPD pattern shown in Figure 1 (Form A)).

[0063] As used herein, the terms “anhydrous” or “anhydrous” when referring to a crystalline form (e.g., a crystalline form of the compound of formula (I)) mean the absence of water molecules that form part of the unit cell of the crystalline form. An anhydrous crystalline form may still contain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., as residual solvent molecules left over from the production of the crystalline form). In a preferred embodiment, water may constitute about 0.5% by weight of the total composition of the anhydrous form sample. In a more preferred embodiment, water may constitute about 0.2% by weight of the total composition of the anhydrous form sample. In some embodiments, a sample of the anhydrous crystalline form of the compound of formula (I) does not contain water molecules (e.g., does not contain a detectable amount of water).

[0064] As used herein, the terms “desolvated” or “solvated” when referring to a crystalline form (e.g., a crystalline form of the compound of formula (I)) mean that there are no solvent molecules that form part of the unit cells of the crystalline form. A solvated crystalline form may still contain solvent molecules that do not form part of the unit cells of the solvated crystalline form (e.g., as residual solvent molecules left over from the production of the crystalline form). In a preferred embodiment, the solvent may constitute 0.5% by weight of the total composition of the sample in the solvated form. In a more preferred embodiment, the solvent may constitute 0.2% by weight of the total composition of the sample in the solvated form. In some embodiments, a sample of the solvated crystalline form of the compound of formula (I) does not contain solvent molecules (e.g., does not contain a detectable amount of solvent).

[0065] As used herein, “polymorph (singular),” “polymorphic form (singular),” “polymorph (plural),” “polymorphic form (plural),” and related terms refer to two or more crystalline forms that essentially consist of the same molecule (singular or plural) or ion (e.g., the compound of formula (I)). Different polymorphs may exhibit different physicochemical properties, such properties including, but are not limited to, melting temperature, solubility, dissolution rate, and physical stability as a result of differences in the arrangement or stereochemistry of molecules or ions within the crystal lattice.

[0066] When referring to the crystalline form of the compound of formula (I), the term "solvate" means that the solvent molecules (e.g., organic solvents and water) form part of the unit cell of the crystalline form. Solvates containing water as a solvent are also referred to herein as "hydrates."

[0067] As used herein, “dissolution profile” refers to dissolution tests of an active pharmaceutical ingredient (API) or formulation at multiple time points. Dissolution profiles of APIs (e.g., compounds of formula (I)) or formulations (e.g., pharmaceutical compositions described herein) may be performed for characterization and quality control to ensure that the drug is released at a specified rate in at least a well-defined aqueous dissolution medium that is the sink condition for the drug, or in a bio-related medium (e.g., simulated gastric or intestinal fluid corresponding to either fasting or feeding). Dissolution tests may, in certain cases, predict or provide insight into the in vivo bioavailability of an API, but not in other cases. Dissolution tests may be performed using USP test protocols and dissolution equipment.

[0068] As used herein, “granulation” refers to the process of forming granules from a powdered or particulate substance. As used herein, “dry granulation” refers to the process of forming granules without the presence of a solution and may be useful in the preparation of granules of substances sensitive to heat, moisture, or solvents. Roller compression is an example of a dry granulation process. As used herein, wet granulation refers to the formation of granules by binding particles together using a binder or solution. Examples of wet granulation include high-shear granulation and fluidized bed granulation.

[0069] As used herein, “pharmaceutical composition” or “pharmaceutical preparation” means a combination of a therapeutically active agent and an inactive or active pharmaceutically acceptable excipient that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0070] "Medically acceptable" means a compound, molecular entity, composition, substance, and / or dosage form that, when administered to animals or humans as necessary, does not produce adverse reactions, allergic reactions, or other unfavorable reactions, or a means that is approved or eligible for approval by a federal or state regulatory agency or a corresponding agency in a country other than the United States, or a means that is listed in the United States Pharmacopeia or other widely recognized pharmacopoeias for use in animals, more specifically in humans.

[0071] As used herein, “pharmaceutically acceptable salt” means any salt of an acidic or basic group that may be present in the compounds of this disclosure (e.g., the compounds of formula (I)) and is suitable for pharmaceutically acceptable administration.

[0072] As is known to those skilled in the art, “salts” of compounds can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, may be used in the preparation of salts that are useful as intermediate products in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts, even though they themselves are not pharmaceutically acceptable.

[0073] Examples of bases, though not limited to them, include alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+ (where W is C1-C4 alkyl).

[0074] Examples of salts, though not limited to them, include acetate, adipine, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Other examples of salts include anions of the compounds of this disclosure combined with suitable cations (e.g., Na+, K+, Ca2+, NH4+, and NW4+ (wherein W may be a C1-4 alkyl group)).

[0075] With regard to therapeutic use, salts of the compounds of this disclosure are intended to be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0076] As used herein, “pharmaceutically acceptable excipients” means substances that can be included in the compositions of this disclosure without causing serious and harmful toxic effects to the patient, and which assist in the administration and / or absorption of the active agent to the subject. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., brittle diluents or fillers and ductile diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavorings, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxypropyl methylcellulose, polyvinyl pyrrolidine, and colorants. For examples of excipients, see Gennaro, Remington's Pharmaceutical Sciences, 18th Ed., Mack Publ. Co., Easton, PA (1990) or Shesky, Hancock, Moss and Goldfarb, Handbook of Pharmaceutical Excipients, 9th Ed., Pharmaceutical Press, London, UK (2020).

[0077] Examples of diluents or fillers include, but are not limited to, sugars (e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, polydextrose, and combinations thereof), inorganic substances (e.g., dicalcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, starch (e.g., pregelatinized starch), microcrystalline cellulose, silicified microcrystalline cellulose, polysaccharides, cellulose (e.g., hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose), dextrin, maltodextrin, alginic acid, collagen, polyvinylpyrrolidone, polyvinyl acrylate, polyethylene oxide, and polyethylene glycol. In this specification, sugars are defined to include sugar alcohols.

[0078] Examples of disintegrants include, but are not limited to, alginic acid, alginates, Primogel, cellulose (e.g., hydroxypropylcellulose), potassium polaritrin, sodium starch glycolate, croscarmellose sodium, polyplasdone (e.g., crospovidone), and starch (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0079] Examples of binders include, but are not limited to, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (e.g., low viscosity hydroxypropylmethylcellulose), sugars, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polydextrose, chitosan, carrageenan, carbophyll, microcrystalline cellulose, tragacanth gum, guar gum, gellan gum, gelatin, and starch (e.g., corn starch).

[0080] Examples of wetting agents include, but are not limited to, poloxamer (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polydimethylsiloxane, polysorbate (e.g., polyoxyethylene 20 sorbitan monooleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxycholic acid, polyethoxylated castor oil, cetyltrimethylammonium bromide, nonoxynol, α-tocopherol polyethylene glycol 1000 succinate, and sodium doxart.

[0081] Examples of lubricants and fluidizers include, but are not limited to, waxes, glycerides, diesel fuel, polyethylene glycol, sodium stearyl fumarate, magnesium stearate, stearic acid, hydrogenated oils (e.g., hydrogenated vegetable oils), alkyl sulfates, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.

[0082] Examples of fluidizing agents, though not limited to them, include colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0083] Examples of colorants, though not limited to them, include titanium dioxide, aluminum lake, iron oxide, and carbon black.

[0084] Examples of coating agents, though not limited to them, include film-forming polymers (e.g., hypromellose, methylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate succinate, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, Eudragit / acrylate) and plasticizers (e.g., triacetin, polyethylene glycol, propylene glycol).

[0085] Pharmaceutical compositions for oral administration (for example, pharmaceutical compositions of the compound of formula (I) described herein) may be in the form of a bulk liquid solution or suspension or a bulk powder. More generally, however, compositions are presented in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to physically separate units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms for solid compositions include pills, tablets, capsules, etc.

[0086] The "targets" to which administration is intended include, but are not limited to, humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., crab-eating macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the target is human. In certain embodiments, the target is a non-human animal.

[0087] As used herein, “solid dosage form” means a drug dose(s) in solid form, such as tablets, capsules, granules, powders, minitablets, sachets, stick packs, reconstituted powders, dry powder inhalers, lozenges, and chewables.

[0088] As used herein, “administer” means oral administration, pulmonary administration, suppository administration, intramuscular administration, intrathecal administration, intranasal or subcutaneous administration, or implantation of a sustained-release device (e.g., a mini osmotic pump) to a subject. Administration is by any route, including transmucosal (e.g., buccal, sublingual, palate, gingival, nasal cavity, vagina, rectum, or). Parenteral administration includes, for example, intramuscular and subcutaneous administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations. “Concurrent administration” means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents (e.g., anticancer agents, chemotherapeutic agents, or treatments for neurodegenerative diseases). The compounds of formula (I) may be administered to a patient alone or concurrently. Concurrent administration is intended to include administering the compounds individually or in combination (with multiple compounds or drugs) simultaneously or over time. Therefore, the formulation can also be combined with other active substances if desired (for example, to reduce metabolic degradation).

[0089] In this specification, the terms “disease,” “disorder,” and “condition” are used interchangeably.

[0090] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” are intended to describe an action that occurs while a subject is suffering from a particular disease, disorder, or condition, reducing the severity of the disease, disorder, or condition, or delaying or slowing the progression of the disease, disorder, or condition ("therapeutic treatment"), and also to describe an action that occurs before a subject begins to suffer from a particular disease, disorder, or condition ("preventive treatment"). In one embodiment, the compounds provided herein are intended to be used in a method of therapeutic treatment that occurs while a subject is suffering from a particular disease, disorder, or condition, resulting in a reduction of the severity of the disease, disorder, or condition, or delaying or slowing the progression of the disease, disorder, or condition. In alternative embodiments, the compounds provided herein are intended to be used in methods of preventive treatment that act before a subject begins to develop a particular disease, disorder, or condition, thereby preventing the disease, disorder, or condition, or preventing one or more symptoms associated with the disease, disorder, or condition, or preventing the recurrence of the disease, disorder, or condition.

[0091] Generally, the “effective dose” of a compound refers to an amount sufficient to elicit a desired biological response (for example, to treat a disease or disorder described herein). As will be understood by those skilled in the art, the effective dose of a compound in this disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. The effective dose encompasses both therapeutic and prophylactic treatment (i.e., “therapeutic effective dose” and “prophylactic effective dose”).

[0092] As used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to produce a therapeutic benefit in the therapeutic treatment of a disease, disorder, or condition, or sufficient to delay or minimize one or more symptoms associated with the disease, disorder, or condition. “Therapeutic dose” means the amount of a therapeutic agent, either alone or in combination with other therapies, that produces a therapeutic benefit in the therapeutic treatment of a disease, disorder, or condition. The term “therapeutic dose” may encompass amounts that improve the overall therapy, reduce or avoid the symptoms or causes of a disease or condition, or enhance the therapeutic effectiveness of other therapeutic agents.

[0093] As used herein, and unless otherwise specified, the “preventive effective dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition. The preventive effective dose of a compound means the amount of a therapeutic agent that, alone or in combination with other agents, provides a preventive benefit in the prevention of a disease, disorder, or condition. The term “preventive effective dose” may include an amount that improves overall prevention or enhances the preventive effect of another preventive agent.

[0094] compound In some embodiments, the Specified Reference Inhibitor (PRMT5) compound of formula (I), i.e., an MTA-uncompetitive PRMT5 inhibitor, is provided. [ka]

[0095] In a particular embodiment, the compound of formula (I) is the crystalline form of the compound of formula (I). The compound of formula (I) may also be referred to as "compound I".

[0096] In a particular embodiment, the crystalline form of the compound of formula (I) is crystalline form A. In a particular embodiment, form A has an XRPD pattern that includes one or more characteristic peaks (e.g., 1, 2, 3, or 4) between the following 2θ values ​​(degrees): 4.2–4.6 (e.g., 4.4±0.2), 9.4–9.8 (e.g., 9.6±0.2), 16.6–17.0 (e.g., 16.8±0.2), and 24.3–24.7 (e.g., 24.5±0.2) (including the endpoints). In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks between the following 2θ values ​​(degrees): 4.2–4.6 (e.g., 4.4±0.2), 9.4–9.8 (e.g., 9.6±0.2), 16.6–17.0 (e.g., 16.8±0.2), and 24.3–24.7 (e.g., 24.5±0.2) (including both endpoints).

[0097] In a particular embodiment, form A has an XRPD pattern that includes one or more characteristic peaks (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) between the following 2θ values ​​(degrees): 4.2–4.6 (e.g., 4.4±0.2), 9.4–9.8 (e.g., 9.6±0.2), 16.6–17.0 (e.g., 16.8±0.2), 18.4–18.8 (e.g., 18.6±0.2), 19.2–19.6 (e.g., 19.4±0.2), 20.7–21.1 (e.g., 20.9±0.2), 23.5–23.9 (e.g., 23.7±0.2), and 24.3–24.7 (e.g., 24.5±0.2) (including the extreme values). In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks between the following 2θ values ​​(degrees): 4.2–4.6 (e.g., 4.4±0.2), 9.4–9.8 (e.g., 9.6±0.2), 16.6–17.0 (e.g., 16.8±0.2), and 24.3–24.7 (e.g., 24.5±0.2) (including both endpoints), and at least one further characteristic peak selected from the following 2θ values ​​(degrees): 18.4–18.8 (e.g., 18.6±0.2), 19.2–19.6 (e.g., 19.4±0.2), 20.7–21.1 (e.g., 20.9±0.2), and 23.5–23.9 (e.g., 23.7±0.2) (including both endpoints).

[0098] In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks between the following 2θ values ​​(degrees): 4.2–4.6 (e.g., 4.4±0.2), 9.4–9.8 (e.g., 9.6±0.2), 16.6–17.0 (e.g., 16.8±0.2), 18.4–18.8 (e.g., 18.6±0.2), 19.2–19.6 (e.g., 19.4±0.2), 20.7–21.1 (e.g., 20.9±0.2), 23.5–23.9 (e.g., 23.7±0.2), and 24.3–24.7 (e.g., 24.5±0.2) (including the values ​​at both ends).

[0099] In a particular embodiment, form A has the following 2θ values ​​(degrees): 4.2~4.6 (e.g., 4.4±0.2), 9.4~9.8 (e.g., 9.6±0.2), 15.7~16.1 (e.g., 15.9±0.2), 16.6~17.0 (e.g., 16.8±0.2), 18.4~18.8 (e.g., 18.6±0.2), 19.1~19.5 (e.g., 19.3±0.2), 19.2~19.6 (e.g., 19.4±0.2), 20.7~21.1 ( The XRPD pattern has one or more characteristic peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) between 20.9±0.2, 20.8-21.2 (e.g., 21.0±0.2), 23.5-23.9 (e.g., 23.7±0.2), 24.3-24.5 (e.g., 24.5±0.2), 25.5-25.9 (e.g., 25.7±0.2), and 33.8-34.2 (e.g., 34.0±0.2) (including both extreme values).

[0100] In a particular embodiment, the X-ray powder diffraction pattern of form A may include one or more characteristic peaks (e.g., 1, 2, 3, or 4) selected from the peaks at 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A may include at least one characteristic peak selected from the peaks at 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A may include at least two characteristic peaks selected from the peaks at 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A may include at least three characteristic peaks selected from peaks at 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees with respect to 2θ.

[0101] In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks at the following 2θ values ​​(degrees): 4.4±0.2, 9.6±0.2, 16.8±0.2, and 24.5±0.2.

[0102] In a particular embodiment, the X-ray powder diffraction pattern of form A may include one or more characteristic peaks (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ.

[0103] In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least one characteristic peak selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least two characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least three characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least four characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of morphology A includes at least five characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of morphology A includes at least six characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least seven characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2 with respect to 2θ.

[0104] In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks at the following 2θ values ​​(degrees): 4.4±0.2, 9.6±0.2, 16.8±0.2, 19.3±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2, and at least one further characteristic peak at a 2θ value (degree) selected from 19.3±0.2, 19.4±0.2, 20.9±0.2, and 23.7±0.2. In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks at the following 2θ values ​​(degrees): 4.4±0.2, 9.6±0.2, 16.8±0.2, 19.3±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2, and at least two further characteristic peaks at 2θ values ​​(degrees) selected from 19.3±0.2, 19.4±0.2, 20.9±0.2, and 23.7±0.2. In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks at the following 2θ values ​​(degrees): 4.4±0.2, 9.6±0.2, 16.8±0.2, 19.3±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2, and at least three further characteristic peaks at 2θ values ​​(degrees) selected from 19.3±0.2, 19.4±0.2, 20.9±0.2, and 23.7±0.2.

[0105] In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks at the following 2θ values ​​(degrees): 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2, and 24.5±0.2.

[0106] In a particular embodiment, the X-ray powder diffraction pattern of form A may include one or more characteristic peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6±0.2, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ.

[0107] In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least one characteristic peak selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6±0.2, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least two characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least three characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least four characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least five characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ.In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least six characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least seven characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least eight characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least nine characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ. In a particular embodiment, the X-ray powder diffraction pattern of form A includes at least 10 characteristic peaks selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2, and 34.0±0.2 with respect to 2θ.

[0108] In a particular embodiment, form A has an XRPD pattern that includes characteristic peaks at the following 2θ values ​​(degrees): 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, and 25.7±0.2 and 34.0±0.2.

[0109] In some embodiments, form A has an XRPD pattern (obtained using CuKa radiation) that substantially corresponds to the XRPD diffraction pattern shown in Figure 1.

[0110] In some embodiments, form A has an XRPD pattern (obtained using CuKa radiation) that includes characteristic peaks, with respect to the 2θ values ​​(degrees) (±0.2 degrees) shown in Table 1, including characteristic peaks of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. [Table 1-1] [Table 1-2]

[0111] In a particular embodiment, form A is substantially characterized by thermogravimetric analysis (TGA) as shown in Figure 2A.

[0112] In certain embodiments, form A is substantially characterized by the differential scanning calorimetry (DSC) profile shown in Figure 2B. In some embodiments, form A may be characterized by the differential scanning calorimetry (DSC) profile shown in Figure 2B (showing a melting peak at approximately 145.8°C).

[0113] In a particular embodiment, form A is substantially characterized by the DVS profile shown in Figures 3A and 3B.

[0114] Pharmaceutical composition In some embodiments, the crystalline form of the compound of formula (I) [ka] A pharmaceutical composition is provided comprising a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0115] In some embodiments, the crystalline form of the compound of formula (I) [ka] A pharmaceutical composition is provided, comprising (as a free base) and at least one pharmaceutically acceptable excipient.

[0116] In some embodiments, the compound of formula (I) as a pharmaceutically active ingredient [ka] A pharmaceutical composition is provided comprising a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0117] In some embodiments, the pharmaceutically active ingredient is the free base of the compound of formula (I).

[0118] In some embodiments, the composition comprises a crystalline form of the compound of formula (I). In some embodiments, the composition comprises crystalline form A of the compound of formula (I) described herein and at least one pharmaceutically acceptable excipient.

[0119] The amounts and ranges described below with respect to “compound of formula (I)” may refer to compound of formula (I) in general, the crystalline form of compound of formula (I), or crystalline form A of compound of formula (I) as described herein. In compositions and dosage forms containing pharmaceutically acceptable salts of compound of formula (I), the amounts and ranges described below with respect to “compound of formula (I)” refer to the equivalent dose of the free base of the compound contained in the composition or dosage form.

[0120] In some embodiments, the pharmaceutical composition contains about 2% (w / w) to about 20% (w / w) of the compound of formula (I).

[0121] In some embodiments, the pharmaceutical composition contains about 3% (w / w) to about 17% (w / w) of the compound of formula (I).

[0122] In some embodiments, the pharmaceutical composition contains about 5% (w / w) to about 15% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition contains about 8% (w / w) to about 12% (w / w) of the compound of formula (I).

[0123] In some embodiments, the pharmaceutical composition contains about 10% (w / w) of the compound of formula (I).

[0124] In some embodiments, the pharmaceutical composition includes a filler. In certain embodiments, the filler is selected from the group consisting of sugars, inorganic substances, microcrystalline cellulose, starch, polysaccharides, cellulose, polyvinylpyrrolidone, polyvinyl acrylate, and combinations thereof.

[0125] In certain embodiments, the filler is selected from the group consisting of sugars, inorganic substances, and combinations thereof. In certain embodiments, the sugar is selected from the group consisting of mannitol, lactose, sucrose, fructose, glucose, maltose, and combinations thereof. In certain embodiments, the inorganic substance is selected from the group consisting of dicalcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, bentonite, kaolin, and combinations thereof.

[0126] In certain embodiments, the filler is selected from the group consisting of microcrystalline cellulose, starch, polysaccharides, cellulose, polyvinylpyrrolidone, polyvinyl acrylate, and combinations thereof. In certain embodiments, the cellulose is selected from the group consisting of hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof.

[0127] In some embodiments, the filler is microcrystalline cellulose (e.g., Avicel®). The microcrystalline cellulose filler may be of different grades. In some embodiments, the filler is microcrystalline cellulose PH 102, PH 200, or a mixture thereof. In some embodiments, the filler is microcrystalline cellulose PH 102 (e.g., Avicel® PH 102). In some embodiments, the filler is microcrystalline cellulose PH 200 (e.g., Avicel® PH 200). In some embodiments, the filler is a mixture of microcrystalline cellulose PH 102 (e.g., Avicel® PH 102) and microcrystalline cellulose PH 200 (e.g., Avicel® PH 200). In further embodiments, the filler comprises equal amounts of two grades of microcrystalline cellulose.

[0128] In a particular embodiment, the pharmaceutical composition contains approximately 50% (w / w) to approximately 90% (w / w) of filler.

[0129] In certain embodiments, the pharmaceutical composition contains about 75% (w / w) to about 86% (w / w) of filler. In certain embodiments, the pharmaceutical composition contains about 77% (w / w) to about 85% (w / w) of filler. In certain embodiments, the pharmaceutical composition contains about 80% (w / w) to about 85% (w / w) of filler. In certain embodiments, the pharmaceutical composition contains about 82% (w / w) to about 84% (w / w) of filler.

[0130] In a particular embodiment, the pharmaceutical composition contains approximately 75% (w / w), approximately 76% (w / w), approximately 77% (w / w), approximately 78% (w / w), approximately 79% (w / w), approximately 80% (w / w), approximately 81% (w / w), approximately 82% (w / w), approximately 83% (w / w), approximately 83.5% (w / w), approximately 84% (w / w), approximately 85% (w / w), and approximately 86% (w / w) of fillers. In a particular embodiment, the pharmaceutical composition contains approximately 80% (w / w), approximately 81% (w / w), approximately 82% (w / w), approximately 83% (w / w), approximately 83.5% (w / w), approximately 84% (w / w), approximately 85% (w / w), and approximately 86% (w / w) of fillers.

[0131] In a particular embodiment, the pharmaceutical composition contains approximately 83.5% (w / w) of filler.

[0132] In some embodiments, the pharmaceutical composition includes a fluidizing agent. In certain embodiments, the fluidizing agent is selected from the group consisting of colloidal silicon dioxide, talc, kaolin, bentonite, or a combination thereof.

[0133] In further embodiments, the fluidizer is colloidal silicon dioxide. In some embodiments, colloidal silicon dioxide is prepared through a process involving flame hydrolysis of silicon tetrachloride in an oxyhydrogen flame and is referred to as "fumed silica" or "untreated fumed silica" (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0134] In certain embodiments, the pharmaceutical composition contains about 0.5% (w / w) to about 2.5% (w / w) of a fluidizer. In certain embodiments, the pharmaceutical composition contains about 0.75% (w / w) to about 2.25% (w / w) of a fluidizer. In certain embodiments, the pharmaceutical composition contains about 1% (w / w) to about 2% (w / w) of a fluidizer. In certain embodiments, the pharmaceutical composition contains about 1.2% (w / w) to about 1.8% (w / w) of a fluidizer. In certain embodiments, the pharmaceutical composition contains about 1.4% (w / w) to about 1.6% (w / w) of a fluidizer. In certain embodiments, the pharmaceutical composition contains about 1.45% (w / w) to about 1.55% (w / w) of a fluidizer.

[0135] In a particular embodiment, the pharmaceutical composition contains approximately 1.4% (w / w), approximately 1.42% (w / w), approximately 1.44% (w / w), approximately 1.46% (w / w), approximately 1.48% (w / w), approximately 1.5% (w / w), approximately 1.52% (w / w), approximately 1.54% (w / w), approximately 1.56% (w / w), approximately 1.58% (w / w), or approximately 1.6% (w / w) of a fluidizing agent.

[0136] In a particular embodiment, the pharmaceutical composition contains about 1.5% (w / w) of a fluidizing agent.

[0137] In some embodiments, the pharmaceutical composition includes a disintegrant. In certain embodiments, the disintegrant is selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose sodium, and combinations thereof. In further embodiments, the disintegrant is croscarmellose sodium (e.g., Ac-Di-Sol®).

[0138] In certain embodiments, the pharmaceutical composition contains approximately 2% (w / w) to approximately 6% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition contains approximately 3% (w / w) to approximately 5% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition contains approximately 3.6% (w / w) to approximately 4.4% (w / w) of disintegrant. In certain embodiments, the pharmaceutical composition contains approximately 3.8% (w / w) to approximately 4.2% (w / w) of disintegrant.

[0139] In a particular embodiment, the pharmaceutical composition contains approximately 3.2% (w / w), approximately 3.28% (w / w), approximately 3.36% (w / w), approximately 3.44% (w / w), approximately 3.52% (w / w), approximately 3.6% (w / w), approximately 3.68% (w / w), approximately 3.76% (w / w), approximately 3.84% (w / w), and approximately 3.92% (w / w). It contains approximately 4% (w / w), 4.08% (w / w), 4.16% (w / w), 4.24% (w / w), 4.32% (w / w), 4.4% (w / w), 4.48% (w / w), 4.56% (w / w), 4.64% (w / w), 4.72% (w / w), or 4.8% (w / w) of disintegrant. In a particular embodiment, the pharmaceutical composition contains about 3.84% (w / w), about 3.92% (w / w), about 4% (w / w), about 4.08% (w / w), about 4.16% (w / w), about 4.24% (w / w), about 4.32% (w / w), about 4.4% (w / w), about 4.48% (w / w), about 4.56% (w / w), about 4.64% (w / w), about 4.72% (w / w), or about 4.8% (w / w) of a disintegrant. In a particular embodiment, the pharmaceutical composition contains about 3.92% (w / w), about 4.00% (w / w), or about 4.08% (w / w) of a disintegrant.

[0140] In a particular embodiment, the pharmaceutical composition contains about 4% (w / w) of a disintegrant.

[0141] In some embodiments, the pharmaceutical composition includes a lubricant. In certain embodiments, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, and combinations thereof.

[0142] In a further embodiment, the lubricant is magnesium stearate.

[0143] In some embodiments, the pharmaceutical composition contains about 0.5% (w / w) to about 1.5% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition contains about 0.75% (w / w) to about 1.25% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition contains about 0.8% (w / w) to about 1% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition contains about 0.9% (w / w) to about 1.1% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition contains about 0.95% (w / w) to about 1.05% (w / w) of a lubricant.

[0144] In some embodiments, the pharmaceutical composition contains about 0.9% (w / w), about 0.92% (w / w), about 0.94% (w / w), about 0.96% (w / w), about 0.98% (w / w), about 1.0% (w / w), about 1.02% (w / w), about 1.04% (w / w), about 1.06% (w / w), about 1.08% (w / w), or about 1.1% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition contains about 0.98% (w / w), about 1.00% (w / w), or about 1.02% (w / w) of a lubricant.

[0145] In some embodiments, the pharmaceutical composition contains about 1% (w / w) of a lubricant.

[0146] In a particular embodiment, (a) Compound of formula (I), [ka] (b) Filling material (e.g., microcrystalline cellulose), (c) Fluidizing agent (e.g., colloidal silicon dioxide), (d) Disintegrant (e.g., croscarmellose sodium), and (e) A pharmaceutical composition comprising a lubricant (e.g., magnesium stearate) is provided.

[0147] In some embodiments, the composition comprises a crystalline form of the compound of formula (I) described herein (e.g., form A).

[0148] In some embodiments, the composition is (a) Compounds of formula (I) in amounts of approximately 2% (w / w) to approximately 20% (w / w), (b) Filling material of approximately 50% (w / w) to approximately 90% (w / w) (e.g., microcrystalline cellulose), (c) Approximately 0.5% (w / w) to approximately 2.5% (w / w) of a fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 2% (w / w) to approximately 6% (w / w) of a disintegrant (e.g., croscarmellose sodium), (e) Contains approximately 0.5% (w / w) to approximately 1.5% (w / w) of a lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition.

[0149] In some embodiments, the composition is (a) Compounds of formula (I) in amounts of approximately 5% (w / w) to approximately 15% (w / w), (b) Filler of approximately 80% (w / w) to approximately 90% (w / w) (e.g., microcrystalline cellulose), (c) Approximately 1.4% (w / w) to approximately 1.6% (w / w) of a fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 3.6% (w / w) to approximately 4.4% (w / w) of a disintegrant (e.g., croscarmellose sodium), (e) Contains approximately 0.9% (w / w) to approximately 1.1% (w / w) of a lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition.

[0150] In some embodiments, the composition is (a) Compounds of formula (I) at a concentration of approximately 8% (w / w) to approximately 12% (w / w), (b) Filler of approximately 80% (w / w) to approximately 86% (w / w) (e.g., microcrystalline cellulose), (c) Approximately 1.45% (w / w) to approximately 1.55% (w / w) of a fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 3.8% (w / w) to approximately 4.2% (w / w) of a disintegrant (e.g., croscarmellose sodium), (e) Contains approximately 0.95% (w / w) to approximately 1.05% (w / w) of a lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition.

[0151] In some embodiments, the composition is (a) Compound of formula (I) at approximately 10% (w / w), (b) Approximately 83.5% (w / w) of filler (e.g., microcrystalline cellulose), (c) Approximately 1.5% (w / w) of a fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 4% (w / w) of a disintegrant (e.g., croscarmellose sodium), (e) Contains approximately 1% (w / w) of a lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition.

[0152] pharmaceutically acceptable excipients may be present in either the granular or extragranular components of the pharmaceutical composition. In some embodiments, one or more pharmaceutically acceptable excipients are present in both the granular and extragranular components.

[0153] In some embodiments, the pharmaceutical composition comprises an internal granular filler selected from the fillers described herein. In certain embodiments, the internal granular filler is microcrystalline cellulose (e.g., Avicel®). In further embodiments, the internal granular filler is microcrystalline cellulose PH 102 (e.g., Avicel® PH 102).

[0154] In certain embodiments, the pharmaceutical composition contains approximately 50% (w / w) to approximately 90% (w / w) of granular filler. In certain embodiments, the pharmaceutical composition contains approximately 75% (w / w) to approximately 86% (w / w) of granular filler. In certain embodiments, the pharmaceutical composition contains approximately 77% (w / w) to approximately 85% (w / w) of granular filler. In certain embodiments, the pharmaceutical composition contains approximately 80% (w / w) to approximately 85% (w / w) of granular filler. In certain embodiments, the pharmaceutical composition contains approximately 82% (w / w) to approximately 84% (w / w) of granular filler.

[0155] In a particular embodiment, the pharmaceutical composition contains approximately 75% (w / w), approximately 76% (w / w), approximately 77% (w / w), approximately 78% (w / w), approximately 79% (w / w), approximately 80% (w / w), approximately 81% (w / w), approximately 82% (w / w), approximately 83% (w / w), approximately 83.5% (w / w), approximately 84% (w / w), approximately 85% (w / w), and approximately 86% (w / w) of granular filler. In a particular embodiment, the pharmaceutical composition contains approximately 80% (w / w), approximately 81% (w / w), approximately 82% (w / w), approximately 83% (w / w), approximately 83.5% (w / w), approximately 84% (w / w), approximately 85% (w / w), and approximately 86% (w / w) of granular filler.

[0156] In a particular embodiment, the pharmaceutical composition contains approximately 83.5% (w / w) of granular filler.

[0157] In some embodiments, the pharmaceutical composition comprises a granular fluidizer selected from the fluidizers described herein. In some embodiments, the granular fluidizer is colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0158] In some embodiments, the pharmaceutical composition contains about 0.75% (w / w) to about 1.25% (w / w) of the granular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.8% (w / w) to about 1.2% (w / w) of the granular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.85% (w / w) to about 1.15% (w / w) of the granular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.9% (w / w) to about 1.1% (w / w) of the granular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.95% (w / w) to about 1.05% (w / w) of the granular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.97% (w / w) to about 1.3% (w / w) of the granular fluidizing agent.

[0159] In some embodiments, the pharmaceutical composition contains approximately 0.9% (w / w), approximately 0.91% (w / w), approximately 0.92% (w / w), approximately 0.93% (w / w), approximately 0.94% (w / w), approximately 0.95% (w / w), approximately 0.96% (w / w), approximately 0.97% (w / w), approximately 0.98% (w / w), approximately 0.99% (w / w), and approximately Contains 1% (w / w), approximately 1.01% (w / w), approximately 1.02% (w / w), approximately 1.03% (w / w), approximately 1.04% (w / w), approximately 1.05% (w / w), approximately 1.06% (w / w), approximately 1.07% (w / w), approximately 1.08% (w / w), approximately 1.09% (w / w), or approximately 1.1% (w / w) of a granular fluidizing agent.

[0160] In some embodiments, the pharmaceutical composition contains about 1% (w / w) of a granular fluidizing agent.

[0161] In some embodiments, the pharmaceutical composition comprises an extragranular fluidizer selected from the fluidizers described herein. In some embodiments, the extragranular fluidizer is colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0162] In some embodiments, the pharmaceutical composition contains about 0.25% (w / w) to about 0.75% (w / w) of an extragranular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.3% (w / w) to about 0.7% (w / w) of an extragranular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.4% (w / w) to about 0.6% (w / w) of an extragranular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.45% (w / w) to about 0.55% (w / w) of an extragranular fluidizing agent.

[0163] In some embodiments, the pharmaceutical composition contains about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w), or about 0.55% (w / w) of an extragranular fluidizing agent. In some embodiments, the pharmaceutical composition contains about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), or about 0.52% (w / w) of an extragranular fluidizing agent.

[0164] In some embodiments, the pharmaceutical composition contains about 0.5% (w / w) of an extragranular fluidizing agent.

[0165] In some embodiments, the pharmaceutical composition comprises an intragranular disintegrant selected from the disintegrants described herein. In certain embodiments, the intragranular disintegrant is croscarmellose sodium.

[0166] In some embodiments, the pharmaceutical composition contains about 1% (w / w) to about 3% (w / w) of a granular disintegrant. In some embodiments, the pharmaceutical composition contains about 1.5% (w / w) to about 2.5% (w / w) of a granular disintegrant.

[0167] In some embodiments, the pharmaceutical composition contains about 1.8% (w / w) to about 2.2% (w / w) of a granular disintegrant. In some embodiments, the pharmaceutical composition contains about 1.9% (w / w) to about 2.1% (w / w) of a granular disintegrant.

[0168] In some embodiments, the pharmaceutical composition contains about 1.92% (w / w) to about 2.08% (w / w) of a granular disintegrant. In some embodiments, the pharmaceutical composition contains about 1.95% (w / w) to about 2.05% (w / w) of a granular disintegrant.

[0169] In some embodiments, the pharmaceutical composition contains approximately 1.88% (w / w), approximately 1.92% (w / w), approximately 1.96% (w / w), approximately 2% (w / w), approximately 2.04% (w / w), approximately 2.08% (w / w), approximately 2.12% (w / w), approximately 2.16% (w / w), or approximately 2.2% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition contains approximately 1.92% (w / w), approximately 1.93% (w / w), approximately 1.94% (w / w), approximately 1.95% (w / w), approximately 1.96% (w / w), approximately 1.97% (w / w), approximately 1.98% (w / w), approximately 1.99% (w / w), approximately 2% (w / w), approximately 2.01% (w / w), and approximately 2. Contains 0.2% (w / w), approximately 2.03% (w / w), approximately 2.04% (w / w), approximately 2.05% (w / w), approximately 2.06% (w / w), approximately 2.07% (w / w), approximately 2.08% (w / w), approximately 2.09% (w / w), approximately 2.1% (w / w), approximately 2.11% (w / w), or approximately 2.12% (w / w) of granular disintegrant.

[0170] In some embodiments, the pharmaceutical composition contains about 2% (w / w) of a granular disintegrant.

[0171] In some embodiments, the pharmaceutical composition comprises an extragranular disintegrant selected from the disintegrants described herein. In certain embodiments, the extragranular disintegrant is croscarmellose sodium.

[0172] In some embodiments, the pharmaceutical composition contains about 1% (w / w) to about 3% (w / w) of an extragranular disintegrant. In some embodiments, the pharmaceutical composition contains about 1.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant.

[0173] In some embodiments, the pharmaceutical composition contains about 1.8% (w / w) to about 2.2% (w / w) of an extragranular disintegrant. In some embodiments, the pharmaceutical composition contains about 1.9% (w / w) to about 2.1% (w / w) of an extragranular disintegrant.

[0174] In some embodiments, the pharmaceutical composition contains about 1.92% (w / w) to about 2.08% (w / w) of an extragranular disintegrant. In some embodiments, the pharmaceutical composition contains about 1.95% (w / w) to about 2.05% (w / w) of an extragranular disintegrant.

[0175] In some embodiments, the pharmaceutical composition contains about 1.88% (w / w), about 1.92% (w / w), about 1.96% (w / w), about 2% (w / w), about 2.04% (w / w), about 2.08% (w / w), about 2.12% (w / w), about 2.16% (w / w), or about 2.2% (w / w) of an extragranular disintegrant. In some embodiments, the pharmaceutical composition contains about 1.92% (w / w), about 1.93% (w / w), about 1.94% (w / w), about 1.95% (w / w), about 1.96% (w / w), about 1.97% (w / w), about 1.98% (w / w), about 1.99% (w / w), about 2% (w / w), about 2.01% (w / w), about 2. Contains 0.2% (w / w), approximately 2.03% (w / w), approximately 2.04% (w / w), approximately 2.05% (w / w), approximately 2.06% (w / w), approximately 2.07% (w / w), approximately 2.08% (w / w), approximately 2.09% (w / w), approximately 2.1% (w / w), approximately 2.11% (w / w), or approximately 2.12% (w / w) of extragranular disintegrant.

[0176] In some embodiments, the pharmaceutical composition contains about 2% (w / w) of an extragranular disintegrant.

[0177] In some embodiments, the pharmaceutical composition comprises an intragranular lubricant selected from the lubricants described herein. In certain embodiments, the intragranular lubricant is magnesium stearate.

[0178] In some embodiments, the pharmaceutical composition contains about 0.25% (w / w) to about 0.75% (w / w) of an internal lubricant within the granules. In some embodiments, the pharmaceutical composition contains about 0.3% (w / w) to about 0.7% (w / w) of an internal lubricant within the granules. In some embodiments, the pharmaceutical composition contains about 0.35% (w / w) to about 0.65% (w / w) of an internal lubricant within the granules. In some embodiments, the pharmaceutical composition contains about 0.4% (w / w) to about 0.6% (w / w) of an internal lubricant within the granules. In some embodiments, the pharmaceutical composition contains about 0.45% (w / w) to about 0.55% (w / w) of an internal lubricant within the granules. In some embodiments, the pharmaceutical composition contains about 0.47% (w / w) to about 0.53% (w / w) of an internal lubricant within the granules. In some embodiments, the pharmaceutical composition contains about 0.48% (w / w) to about 0.52% (w / w) of an intragranular lubricant.

[0179] In some embodiments, the pharmaceutical composition contains about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w), or about 0.55% (w / w) of an intragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), or about 0.52% (w / w) of an intragranular lubricant.

[0180] In some embodiments, the pharmaceutical composition contains about 0.5% (w / w) of an intragranular lubricant.

[0181] In some embodiments, the pharmaceutical composition comprises an extragranular lubricant selected from the lubricants described herein. In certain embodiments, the extragranular lubricant is magnesium stearate.

[0182] In some embodiments, the pharmaceutical composition contains about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.3% (w / w) to about 0.7% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.35% (w / w) to about 0.65% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.4% (w / w) to about 0.6% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.45% (w / w) to about 0.55% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.47% (w / w) to about 0.53% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.48% (w / w) to about 0.52% (w / w) of an extragranular lubricant.

[0183] In some embodiments, the pharmaceutical composition contains about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w), or about 0.55% (w / w) of an extragranular lubricant. In some embodiments, the pharmaceutical composition contains about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), or about 0.52% (w / w) of an extragranular lubricant.

[0184] In some embodiments, the pharmaceutical composition contains about 0.5% (w / w) of an extragranular lubricant.

[0185] In some embodiments, (a) Compound of formula (I), [ka] (b) Granular filler (e.g., microcrystalline cellulose), (c) Granule fluidizing agent (e.g., colloidal silicon dioxide), (d) Granule disintegrants (e.g., croscarmellose sodium), (e) Granular lubricant (e.g., magnesium stearate), (f) Extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Granule disintegrants (e.g., croscarmellose sodium), and (h) A pharmaceutical composition is provided comprising an extragranular lubricant (e.g., magnesium stearate).

[0186] In some embodiments, (a) Crystallographic form of the compound of formula (I) (for example, crystallographic form A as described herein) [ka] (b) Granular filler (e.g., microcrystalline cellulose), (c) Granule fluidizing agent (e.g., colloidal silicon dioxide), (d) Granule disintegrants (e.g., croscarmellose sodium), (e) Granular lubricant (e.g., magnesium stearate), (f) Extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Granule disintegrants (e.g., croscarmellose sodium), and (h) A pharmaceutical composition is provided comprising an extragranular lubricant (e.g., magnesium stearate).

[0187] In some embodiments, the pharmaceutical composition is (a) Compounds of formula (I) in amounts of approximately 2% (w / w) to approximately 20% (w / w) (e.g., crystalline form A), (b) Granular filler of approximately 50% (w / w) to approximately 90% (w / w) (e.g., microcrystalline cellulose), (c) Approximately 0.75% (w / w) to approximately 1.25% (w / w) of a granular fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 1% (w / w) to approximately 3% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium), (e) Approximately 0.25% (w / w) to approximately 0.75% (w / w) of a granular lubricant (e.g., magnesium stearate), (f) Approximately 0.25% (w / w) to approximately 0.75% (w / w) of an extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Approximately 1% (w / w) to approximately 3% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium), and (h) Contains approximately 0.25% (w / w) to approximately 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition.

[0188] In some embodiments, the pharmaceutical composition is (a) Compounds of formula (I) in amounts of approximately 5% (w / w) to approximately 15% (w / w) (e.g., crystalline form A), (b) Granular filler of approximately 77% (w / w) to approximately 85% (w / w) (e.g., microcrystalline cellulose), (c) Approximately 0.9% (w / w) to approximately 1.1% (w / w) of a granular fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 1.8% (w / w) to approximately 2.2% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium), (e) Approximately 0.9% (w / w) to approximately 1.1% (w / w) of a granular lubricant (e.g., magnesium stearate), (f) Approximately 0.4% (w / w) to approximately 0.6% (w / w) of an extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Approximately 1.8% (w / w) to approximately 2.2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium), and (h) Contains approximately 0.4% (w / w) to approximately 0.6% (w / w) of an extragranular lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition.

[0189] In some embodiments, the pharmaceutical composition is (a) Compounds of formula (I) in approximately 8% (w / w) to 12% (w / w) (e.g., crystalline form A), (b) Granular filler of approximately 80% (w / w) to approximately 85% (w / w) (e.g., microcrystalline cellulose), (c) Approximately 0.95% (w / w) to approximately 1.05% (w / w) of a granular fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 1.9% (w / w) to approximately 2.1% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium), (e) Approximately 0.95% (w / w) to approximately 1.05% (w / w) of a granular lubricant (e.g., magnesium stearate), (f) Approximately 0.45% (w / w) to approximately 0.55% (w / w) of an extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Approximately 1.9% (w / w) to approximately 2.1% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium), and (h) Contains approximately 0.45% (w / w) to approximately 0.55% (w / w) of an extragranular lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition.

[0190] In some embodiments, the pharmaceutical composition is (a) A compound of formula (I) at approximately 10.0% (w / w) (e.g., crystalline form A), (b) Approximately 83.5% (w / w) of granular filler (e.g., microcrystalline cellulose), (c) Approximately 1.0% (w / w) of a granular fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 2% (w / w) of a granular disintegrant (e.g., croscarmellose sodium), (e) Approximately 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate), (f) Approximately 0.5% (w / w) of an extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Approximately 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium), and (h) Contains approximately 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate), As a result, the total is less than 100% (w / w) of the composition. In some embodiments, the total being 100% (w / w) or less of the composition means that "the total is 100% (w / w) of the composition".

[0191] Dosage form In some embodiments, dosage forms comprising the pharmaceutical compositions described herein are provided.

[0192] In some embodiments, dosage forms are provided that are intended for oral administration and comprise the pharmaceutical compositions described herein.

[0193] In a particular embodiment, the dosage form is selected from the group consisting of powders, sachets, stick packs, capsules, mini-tablets, and tablets.

[0194] In a particular embodiment, the dosage form is a tablet.

[0195] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 50 mg to 1000 mg.

[0196] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 100 mg to 750 mg.

[0197] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 50 mg to 150 mg.

[0198] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg.

[0199] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

[0200] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 100 mg.

[0201] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 300 mg to 700 mg. In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 400 mg to 600 mg.

[0202] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg.

[0203] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 450 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, or about 560 mg.

[0204] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 500 mg.

[0205] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 100 mg or approximately 500 mg.

[0206] In some embodiments, the composition contains about 5 mg to about 200 mg of the compound of formula (I). In some embodiments, the dosage form contains about 5 mg to about 100 mg of the compound of formula (I). In some embodiments, the dosage form contains about 10 mg to about 100 mg of the compound of formula (I). In some embodiments, the dosage form contains about 10 mg to about 50 mg of the compound of formula (I).

[0207] In some embodiments, the dosage form contains about 5 mg to about 20 mg, about 20 mg to about 40 mg, about 40 mg to about 60 mg, about 60 mg to about 80 mg, or about 80 to about 100 mg of the compound of formula (I). In some embodiments, the dosage form contains about 5 mg to about 20 mg or about 40 mg to about 60 mg of the compound of formula (I). In some embodiments, the dosage form contains about 5 mg to about 15 mg of the compound of formula (I). In some embodiments, the dosage form contains about 8 mg to about 12 mg of the compound of formula (I). In some embodiments, the dosage form contains about 9 mg to about 11 mg of the compound of formula (I).

[0208] In some embodiments, the dosage form contains about 5 mg, about 6 mg, about 7 mg, 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg of the compound of formula (I).

[0209] In some embodiments, the dosage form contains approximately 10 mg of the compound of formula (I).

[0210] In some embodiments, the dosage form contains approximately 40 mg to approximately 60 mg of the compound of formula (I). In some embodiments, the dosage form contains approximately 45 mg to approximately 55 mg of the compound of formula (I). In some embodiments, the dosage form contains approximately 47 mg to approximately 53 mg of the compound of formula (I).

[0211] In some embodiments, the dosage form contains about 49 mg to about 51 mg of the compound of formula (I). In some embodiments, the dosage form contains about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg of the compound of formula (I).

[0212] In some embodiments, the dosage form contains approximately 50 mg of the compound of formula (I).

[0213] In some embodiments, the dosage form contains about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg of the compound of formula (I).

[0214] In some embodiments, the dosage form contains about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, or about 52 mg of the compound of formula (I).

[0215] In certain embodiments, the dosage form contains approximately 10 mg or approximately 50 mg of the compound of formula (I).

[0216] In some embodiments, the dosage form comprises 10 mg of the compound of formula (I), 83.5 mg of microcrystalline cellulose within granules, 1 mg of colloidal silicon dioxide within granules (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 2 mg of croscarmellose sodium (Ac-Di-Sol®) within granules, 0.5 mg of magnesium stearate within granules, 0.5 mg of colloidal silicon dioxide outside granules (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 2 mg of croscarmellose sodium (Ac-Di-Sol®) outside granules, and 0.5 mg of magnesium stearate outside granules.

[0217] In some embodiments, the dosage form comprises 50 mg of the compound of formula (I), 417.5 mg of microcrystalline cellulose within granules, 5 mg of colloidal silicon dioxide within granules (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 10 mg of croscarmellose sodium (Ac-Di-Sol®) within granules, 2.5 mg of magnesium stearate within granules, 2.5 mg of colloidal silicon dioxide outside granules (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 10 mg of croscarmellose sodium (Ac-Di-Sol®) outside granules, and 2.5 mg of magnesium stearate outside granules.

[0218] In certain embodiments, the tablet further comprises a coating agent. In certain embodiments, the coating agent is selected from the group consisting of film-forming polymers, plasticizers, and combinations thereof. In certain embodiments, the film-forming polymer is selected from the group consisting of hypromellose, ethylcellulose, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylate, and combinations thereof. In certain embodiments, the plasticizer is selected from the group consisting of triacetin, polyethylene glycol, propylene glycol, and combinations thereof. In certain embodiments, the coating agent comprises polyvinyl alcohol.

[0219] In certain embodiments, the coating agent includes a colorant selected from the group consisting of titanium dioxide, aluminum lake, iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.

[0220] Manufacturing method In some embodiments, a method for preparing the pharmaceutical compositions described herein, for example, (a) To obtain a blend, the compound of formula (I) is blended with one or more pharmaceutically acceptable excipients, (b) To obtain granules, the blend is granulated, (c) To obtain the inner phase of the granules, crushing the granules, and (d) To obtain a pharmaceutical composition, blending the inner phase of the granules with one or more excipients for external use in pharmaceuticals, a method is provided.

[0221] In another aspect, a method for preparing the dosage form described herein, for example, (a) To obtain a blend, blending a compound of formula (I) with one or more pharmaceutically acceptable excipients, and (b) To obtain granules, granulating the blend, and (c) To obtain the inner phase of the granules, crushing the granules, and (d) To obtain a pharmaceutical composition (pharmaceutical blend), blending the inner phase of the granules with one or more excipients for external use in pharmaceuticals, and (e) To form tablets, compressing the pharmaceutical blend, a method is provided.

[0222] In certain embodiments, in step (a), the one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, binders, wetting agents, lubricants, fluidizing agents, and combinations thereof.

[0223] In certain embodiments, in step (a), the compound of formula (I) is blended with a filler, a disintegrant, a lubricant, and a fluidizing agent.

[0224] In certain embodiments, in step (a), the filler is microcrystalline cellulose.

[0225] In some embodiments, in step (a), the disintegrant is croscarmellose sodium.

[0226] In certain embodiments, in step (a), the fluidizing agent is colloidal silicon dioxide.

[0227] In a particular embodiment, in step (a), the lubricant is magnesium stearate.

[0228] In a particular embodiment, in step (d), one or more granular excipients are selected from the group consisting of disintegrants, lubricants, fluidizers, and combinations thereof.

[0229] In some embodiments, in step (d), the granular internal phase is blended with a disintegrant, a lubricant, and a fluidizing agent.

[0230] In a particular embodiment, in step (d), the disintegrant is croscarmellose sodium.

[0231] In some embodiments, in step (d), the fluidizing agent is colloidal silicon dioxide.

[0232] In a particular embodiment, in step (d), the lubricant is magnesium stearate.

[0233] In a particular embodiment, granulating a blend to obtain granules includes a dry granulation step. In a particular embodiment, granulating a blend to obtain granules includes a wet granulation step.

[0234] In certain embodiments, the tablet comprises a coating agent. In certain embodiments, the coating agent comprises one or more film-forming polymers selected from the group consisting of hypromellose, ethylcellulose, polyvinylpyrrolidone, polyacrylate, plasticizer, and combinations thereof. In further embodiments, the coating agent comprises polyvinyl alcohol.

[0235] In certain embodiments, the coating agent includes a colorant selected from the group consisting of titanium dioxide, aluminum lake, iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.

[0236] In some embodiments, pharmaceutical compositions prepared by the processes described herein are provided.

[0237] Instructions for use and treatment methods Treatment of MTAP deficiency and / or MTA accumulation and proliferation disorder 5-methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. MTAP deletion is a common genetic event in human cancers. The frequency of MTAP deletions in subsets of human cancers is described in Cerami et al., Cancer Discov. (2012); 2(5): 401-4; Gao et al., Sci Signal. (2013); 6(269): pl1; and Lee et al., Nat. Gen. (2014) 46(11): 1227-32. For example, MTAP deletion is found in over 50% of malignant peripheral nerve sheath tumors (MPNSTs) (Lee et al., Nat. Gen. (2014)). Other cancers with a high frequency of MTAP deletion include glioblastoma (GBM), mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous cell carcinoma of the lung, melanoma, diffuse large B-cell lymphoma (DLBCL), head and neck cancer, cholangiocarcinoma, lung adenoma, sarcoma, gastric cancer, glioma, adrenal cancer, thymoma, breast cancer, liver cancer, ovarian cancer, renal papillary carcinoma, uterine cancer, prostate cancer, and renal clear cell carcinoma. Cellular MTAP deletion is one mechanism that leads to MTAP deficiency and increased intracellular MTA accumulation in cancer cells, enhancing dependence on the protein arginine methyltransferase 5 (PRMT5). Other mechanisms leading to MTAP deficiency include MTAP translocation and MTAP epigenetic silencing, which can also lead to MTAP null and / or MTAP-deficient tumors. Since PRMT5 mediates the formation of symmetric dimethylarginine (SDMA), PRMT5 activity can be evaluated by measuring SDMA levels using antibodies against SDMA or SDMA-modified polypeptides.

[0238] In some embodiments, methods are provided for treating a human or animal subject having or diagnosed with MTAP deficiency-related and / or MTA accumulation proliferative disorder (e.g., cancer), comprising administering a therapeutically effective amount of the compounds of the Disclosure (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I)), a pharmaceutical composition comprising the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a dosage form described herein, to a subject in need thereof.

[0239] In some embodiments, methods are provided for treating MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer) in a subject requiring such treatment, comprising administering an effective amount (e.g., a therapeutically effective amount) of a compound of the Disclosure (e.g., a crystalline form of the compound of formula (I), a crystalline form A of the compound of formula (I)), a pharmaceutical composition comprising the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a dosage form described herein to the subject.

[0240] In some embodiments, a method is provided for treating a human or animal subject having or diagnosed with MTAP deficiency-related and / or MTA accumulation proliferative disorder (e.g., cancer), comprising administering a therapeutically effective dose of the pharmaceutical composition of the Disclosure to a subject in need thereof. In some embodiments, the method comprises administering the dosage form of the Disclosure to the subject. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0241] In some embodiments, a method is provided for treating MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer) in a subject requiring such treatment, comprising administering a therapeutically effective dose of the pharmaceutical composition of the Disclosure to the subject requiring treatment. In some embodiments, the method comprises administering the dosage form of the Disclosure to the subject. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0242] In some embodiments, compounds and compositions for use in the manufacture of a medicament (e.g., a crystalline form of a compound of formula (I), crystalline form A of a compound of formula (I), a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a dosage form described herein) are provided. In some embodiments, compounds and compositions for use in the manufacture of a medicament for treating a human or animal subject having or diagnosed with an MTAP deficiency-related and / or MTA-accumulation proliferative disorder (e.g., cancer) are provided.

[0243] In some embodiments, compounds and compositions for use in the manufacture of a medicament for use in treating an MTAP deficiency-related and / or MTA-accumulation proliferative disorder (e.g., cancer) in a subject that needs it are provided.

[0244] In some embodiments, compounds and compositions for use in the manufacture of a medicament for treating a human or animal subject having or diagnosed with an MTAP deficiency-related and / or MTA-accumulation proliferative disorder (e.g., cancer) are provided. In one embodiment, the medicament is formulated for administration in combination with a second therapeutic agent. In some embodiments, the medicament comprises a therapeutically effective amount of the compound or composition (e.g., a crystalline form of a compound of formula (I), crystalline form A of a compound of formula (I), a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a dosage form described herein).

[0245] In some embodiments, compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a dosage form described herein) are provided for use in methods of treating subjects of human or animal having or diagnosed with MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer).

[0246] In some embodiments, compounds and compositions (e.g., crystalline forms of the compound of formula (I), crystalline form A of the compound of formula (I), pharmaceutical compositions comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or dosage forms as described herein) are provided for use in methods for treating MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer) in subjects requiring such treatment.

[0247] In some embodiments, compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a dosage form described herein) are provided for use in a method of treating a human or animal subject having or diagnosed with MTAP deficiency-related and / or MTA accumulation proliferative disorder (e.g., cancer). In one embodiment, the method comprises administering the compound or composition in combination with a second therapeutic agent. In some embodiments, the method comprises administering a therapeutically effective amount of the compound or composition (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a dosage form described herein) to a patient in need thereof.

[0248] In some embodiments, the use of compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein) is provided for the treatment of human or animal subjects having or diagnosed with MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer).

[0249] In some embodiments, the use of compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein) is provided for treating MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer) in subjects requiring such treatment.

[0250] In some embodiments, the use of compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein) is provided for the treatment of human or animal subjects having or diagnosed with MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer). In one embodiment, this use involves administering the compound or composition in combination with a second therapeutic agent. In some embodiments, this use involves administering a therapeutically effective amount of the compound or composition (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein) to a patient in need thereof.

[0251] In some embodiments, the use of compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein) in the manufacture of a pharmaceutical for the treatment of a human or animal subject having or diagnosed as having an MTAP deficiency-related and / or MTA accumulation proliferative disorder (e.g., cancer).

[0252] In some embodiments, the use of compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein) in the manufacture of a pharmaceutical for treating MTAP deficiency-related and / or MTA accumulation proliferative disorders (e.g., cancer) in subjects requiring such treatment.

[0253] In some embodiments, the use of compounds and compositions (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein) in the manufacture of a pharmacopoeia for the treatment of a human or animal subject having or diagnosed with MTAP deficiency-related and / or MTA accumulation proliferative disorder (e.g., cancer). In one embodiment, the pharmacopoeia is configured for administration in combination with a second therapeutic agent. In some embodiments, the pharmacopoeia comprises a therapeutically effective amount of the compound or composition (e.g., crystalline form of the compound of formula (I), crystalline form A of the compound of formula (I), a pharmaceutical composition comprising the compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a dosage form as described herein).

[0254] In certain embodiments, the disease is MTAP deficiency and / or MTA accumulation cancer.

[0255] In some embodiments, cancers include gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0256] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0257] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0258] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0259] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0260] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0261] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0262] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0263] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0264] In some embodiments, cancers are gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0265] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0266] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0267] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0268] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0269] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0270] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0271] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0272] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0273] In some embodiments, the compounds of formula (I), crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof) and dosage forms thereof described herein can be used in a manner that inhibits the proliferation of MTAP-deficient cells in a subject requiring such inhibition, the manner comprising the step of administering to a subject an amount effective in inhibiting the proliferation of MTAP-deficient cells the compounds of formula (I), crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof) or dosage forms thereof described herein. In one embodiment, the subject requiring it is suffering from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve schwannoma (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colorectal cancer or sarcoma.

[0274] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0275] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0276] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0277] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0278] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0279] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0280] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0281] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0282] In some embodiments, the compounds of formula (I) described herein, crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof) or their dosage forms can be used in a manner that inhibits the proliferation of MTA-accumulating cells in a subject requiring such inhibition, the manner comprising the step of administering the compounds of formula (I) described herein, crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof) or their dosage forms to a subject in an amount effective for inhibiting the proliferation of MTA-accumulating cells. In one embodiment, the subject requiring it is suffering from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve schwannoma (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colorectal cancer or sarcoma.

[0283] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0284] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0285] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0286] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0287] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0288] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0289] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0290] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0291] In some embodiments, the compounds of formula (I) described herein, in crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or a pharmaceutically acceptable salt thereof) or dosage forms can be used in a manner that inhibits the proliferation of MTAP-deficient cells and / or MTA-accumulating cells in a subject requiring such inhibition, the manner comprising the step of administering the compounds of formula (I) described herein, in crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or a pharmaceutically acceptable salt thereof) or dosage forms to a subject in an amount effective for inhibiting the proliferation of MTAP-deficient cells and / or MTA-accumulating cells. In one embodiment, the subject requiring it is suffering from a cancer selected from the group consisting of glioma, glioblastoma, malignant peripheral nerve schwannoma (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colorectal cancer or sarcoma.

[0292] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0293] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0294] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0295] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0296] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0297] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0298] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0299] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0300] Combination therapy In some embodiments, methods are provided for treating MTAP deficiency and / or MTA accumulation proliferative disorders (e.g., cancer) by combining a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof with one or more therapeutic agents.

[0301] In some embodiments, methods are provided for treating MTAP deficiency and / or MTA accumulation proliferative disorders (e.g., cancer) by combining a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof with a second therapeutic agent. In some embodiments, methods are provided for treating MTAP deficiency and / or MTA accumulation proliferative disorders (e.g., cancer) by combining a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof with a second therapeutic agent and a third therapeutic agent. In some embodiments, methods are provided for treating MTAP deficiency and / or MTA accumulation proliferative disorders (e.g., cancer) by using a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof in combination with a second therapeutic agent, a third therapeutic agent, and a fourth therapeutic agent.

[0302] The term “combination” refers to a fixed combination in a single unit dosage form, or a combination of administrations, in which a compound of formula (I), a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form thereof, as described herein, and a combination partner (e.g., another drug described below (also referred to as the “therapeutic agent” or “co-agent”)) can be administered simultaneously or separately and independently within a time interval, particularly in cases where the combination partner can exhibit a cooperative effect (e.g., synergistic effect) due to the time intervals between them. A single component may be packaged in a kit or packaged separately. One or both of the components (e.g., powder or liquid) are reconstituted or diluted to the desired dose before administration. As used herein, terms such as “co-administration” or “combination administration” mean that the selected combination partner is administered to a single subject (e.g., a patient) that requires it, and are intended to encompass therapeutic regimens in which the drugs are not necessarily administered via the same route of administration or simultaneously. As used herein, the term “combination of pharmaceuticals” means the product resulting from the mixing or combination of multiple therapeutic agents, and includes both fixed and unfixed combinations of therapeutic agents. “Fixed combination” means that a therapeutic agent, e.g., the compound of formula (I) described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof), or its dosage form, and a combination partner are administered simultaneously to the patient in the form of a single entity or dosage. “Unfixed combination” means that a therapeutic agent, e.g., the compound of formula (I) described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof), or its dosage form, and a combination partner are administered simultaneously, concurrently, or sequentially without specific time constraints, as separate entities, resulting in therapeutically effective levels of the two compounds in the patient’s body. The latter also applies to cocktail therapy (e.g., administration of three or more therapeutic agents).

[0303] The term “combination therapy” refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described herein. Such administration includes, for example, the co-administration of these therapeutic agents substantially simultaneously in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes the co-administration of each active ingredient in multiple, i.e., separate containers (e.g., tablets, capsules, powders, and liquids). Powders and / or liquids may be reconstituted or diluted to the desired dose before administration. Furthermore, such administration also includes the use of each type of therapeutic agent sequentially, either substantially simultaneously or at different times.

[0304] In certain embodiments, the compounds of formula (I) described herein, their crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof), or their dosage forms are combined with other therapeutic agents (including, but not limited to, other anticancer agents, anti-allergic agents, anti-nausea agents (or antiemetic agents), analgesics, cytoprotective agents, and combinations thereof).

[0305] In some embodiments, a method for treating a disease or disorder (e.g., cancer) comprising a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and a general chemotherapeutic agent (anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busul fex(registered trademark), capecitabine (Xeloda(registered trademark)), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin(registered trademark)), carmustine (BiCNU(registered trademark)), chlorambucil (Leukeran(registered trademark)), cisplatin (Platinol(registered trademark)), cladribine (Leustatin(registered trademark)), cyclophosphamide (Cytoxan(registered trademark) or Neosar(registered trademark)), cytarabine, cytosine arabinoside (Cytosar-U( (Registered Trademark), Cytarabine Liposome Injection (DepoCyt(Registered Trademark)), Dacarbazine (DTIC-Dome(Registered Trademark)), Dactinomycin (Actinomycin D, Cosmegan), Daunorubicin Hydrochloride (Cerubidine(Registered Trademark)), Daunorubicin Tricate Liposome Injection (DaunoXome(Registered Trademark)), Dexamethasone, Docetaxel (Taxotere(Registered Trademark)), Doxorubicin Hydrochloride (Adriamycin(Registered Trademark), Rubex(Registered Trademark)), Etoposide (Vepesid(Registered Trademark) (Registered Trademark), Fludarabine phosphate (Fludara®), 5-Fluorouracil (Adrucil®, Efudex®), Flutamide (Eulexin®), Tezacitibin, Gemcitabine (Difluorodeoxycytidine), Hydroxyurea (Hydrea®), Idamycin (Idamycin®), Ifosfamide (IFEX®), Irinotecan (Camptosar®), L-Asparaginase (ELSPAR®), Leucovorin calcium,Melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), Mirotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), Phoenix (Yttrium90 / MX-DTPA), pentostatin, polyfeprosan 20 (Gliadel®) with carmustine implant, tamoxifen A method is provided comprising administering, in any order or concurrently, a patient requiring the use of fen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinnorelbine (Navelbine®)).

[0306] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering to a patient in need, in any order or concurrently, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition as described herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form thereof, and an EGFR inhibitor (e.g., cetuximab, panitumimab, erlotinib, gefitinib, afatinib, aumeratinib, olmutinib, osimertinib, brigatinib, dacomitinib, lapatinib, vandetanib, pirotinib, mobocertinib, and neratinib) and EGFRi NOS. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or its dosage form, and a MAPK pathway inhibitor (e.g., BRAFi, panRAFi, MEKi, ERKi; PI3K-mTOR pathway inhibitors, e.g., alpha-specific PI3Ki, pan-class I PI3Ki, and mTOR / PI3Ki, particularly everolimus and its analogs) to a patient in need, in any order or concurrently.

[0307] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering to a patient in need, in any order or concurrently, a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a dosage form thereof, and an HDAC inhibitor or a DNA methyltransferase inhibitor. In some embodiments, the HDAC inhibitor is trichostatin A. In some embodiments, the DNA methyltransferase inhibitor is 5-azacitidine.

[0308] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and a MAT2A inhibitor (e.g., AG-270 (S 095033), IDE397, FIDAS-3, FIDAS-5, PF-9366, AGI-24512, AGI-25696, AGI-41998, AGI-43192, AGI-44131, ISM3412 (manufactured by InSilico Medicine), 28 (AZ series), 31 (AZ series), 32 (AZ series), 33 (AZ series), 001 (Simcere series), and 065 (Simcere series)) to a patient in need, in any order or concurrently.

[0309] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering, in any order or concurrently, a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and an inhibitor of a protein that interacts with or is required for the function of PRMT5 (including, but not limited to, pICIN, WDR77, or RIOK1) to a patient in need thereof.

[0310] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering to a patient in need, in any order or concurrently, a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and an HDM2 inhibitor and / or 5-FU or other purine analog (e.g., 6-thioguanine, 6-mercaptopurine).

[0311] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and a CDK4 inhibitor (including, but not limited to, LEE011 or CDK4 / 6 inhibitors (e.g., palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio®))) to a patient in need, in any order or concurrently.

[0312] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering to a patient in need, in any order or concurrently, a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and a targeted therapy (including, but not limited to, HDM2i, PI3K / mTOR-I, MAPKi, RTKi (including inhibitors of EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi) in any order, depending on the dependence of the individual target tumor on the relevant pathway determined by a suitable predictive marker.

[0313] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and immunotherapy, in any order or concurrently, to a patient in need thereof.

[0314] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering cancer immunotherapy (e.g., checkpoint-blocking antibodies) in any order or concurrently to a patient (e.g., a human subject) having (e.g., the disease or disorder described herein (e.g., cancer described herein)) that requires it.

[0315] In some embodiments, the immunotherapy agent is an anti-CTLA-4 antibody (e.g., ipilimumab, tremelimumab).

[0316] In some embodiments, the immunotherapy agent is an anti-PD-1 ligand (e.g., PD-L1 (e.g., B7-HI or CD274) or PD-L2 (e.g., B7-DC or CD273)). In some embodiments, the immunotherapy agent is an anti-PD-1 antibody (e.g., anti-PD-1 or anti-PD-L1, e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538), CT-011, AMP-224, pembrolizumab, pizilizumab, or MK-3475). In some embodiments, the immunotherapy agent is an anti-PD-L1 antibody (e.g., BMS936559 (i.e., MDX-1105), MEDI4736, MSB0010718C (avelumab), or MPDL-3280A).

[0317] In some embodiments, the immunotherapy agent is a checkpoint blocking antibody (e.g., anti-TIM3, anti-LAG3, anti-TIGIT (including IMP321 and MGA271)).

[0318] In some embodiments, the immunotherapy agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0319] In some embodiments, the immunotherapy agent is a co-stimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0320] In some embodiments, the immunotherapy agent is a cancer vaccine (e.g., a neoantigen). These vaccines may be developed using peptides or RNA.

[0321] In some embodiments, the immunotherapy agent is an oncolytic virus.

[0322] In some embodiments, the immunotherapy agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0323] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and a disease-specific huMAB (e.g., an anti-HER3 huMAB) to a patient in need, in any order or concurrently.

[0324] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and ADC / ADCC in any order or concurrently to a patient in need, depending on the expression of relevant surface targets on a target tumor of interest.

[0325] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and one or more DNA damage pathway inhibitors to a patient in need, in any order or concurrently. In some embodiments, the DNA damage pathway inhibitor is selected from the group consisting of bleomycin, ATM inhibitors (e.g., AZD1390), USP1 inhibitors, WEE1 inhibitors (e.g., AZD1775), and Chk1 inhibitors (e.g., AZD7762). In some embodiments, the DNA damage pathway inhibitor is a DNA alkylating agent.

[0326] In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and a PARP inhibitor, in any order or concurrently to a patient in need thereof. In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, E7016, iniparib, and 3-aminobenzamide.

[0327] Some patients may experience allergic reactions to the PRMT5 inhibitors and / or other anticancer agents described herein during or after administration; therefore, anti-allergic agents are often administered to minimize the risk of allergic reactions.In some embodiments, a method for treating a disease or disorder (e.g., cancer) comprising a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and an antiallergic agent (e.g., corticosteroid (but not limited to, dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate; trade names: Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort) Acetate (registered trademark) and Lanacort (registered trademark), prednisolone (marketed under the trade names Delta-Cortel (registered trademark), Orapred (registered trademark), Pediapred (registered trademark), and Prelone (registered trademark)), prednisone (marketed under the trade names Deltasone (registered trademark), Liquid A method is provided comprising administering, in any order or concurrently, to a patient requiring the use of the following: methylprednisolone (sold under the names Red®, Meticorten®, and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone succinate sodium; sold under the trade names Duralone®, Medralone®, Medrol®, M-Prednisol®, and Solu-Medrol®), antihistamines (e.g., diphenhydramine (e.g., Benadryl®), hydroxyzine, and cyproheptadine), and bronchodilators (e.g., beta-adrenergic receptor agonists, albuterol (e.g., Proventil®), and terbutaline (Brethine®))).

[0328] Some patients may experience nausea during or after administration of the PRMT5 inhibitors and / or other anticancer agents described herein; therefore, antiemetics are used to prevent nausea (upper abdomen) and vomiting. In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and an antiemetic (e.g., aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®), dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof) to a patient in need, in any order or concurrently.

[0329] To make patients more comfortable, medicines are often prescribed to alleviate pain experienced during treatment. In some embodiments, methods are provided for treating a disease or disorder (e.g., cancer) that include administering, in any order or concurrently, a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and an analgesic (e.g., an OTC analgesic (e.g., Tylenol®), an opioid analgesic (e.g., hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), fentanyl (e.g., Duragesic®)) to a patient in need thereof.

[0330] In attempts to protect normal cells from therapeutic toxicity and limit organ toxicity, cytoprotective agents (e.g., neuroprotective agents, free radical scavengers, cardioprotective agents, anthracycline extravasation antagonists, nutrients, etc.) may be used as adjunctive therapies. In some embodiments, a method is provided for treating a disease or disorder (e.g., cancer), comprising administering a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form thereof, and a cytoprotective agent (e.g., amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliprodane (Xaprila®), and leucovorin (also known as calcium leucovorin, citroborum factor, and folic acid)) to a patient in need, in any order or concurrently.

[0331] The structure of an active compound, identified by its code number, generic name, or trade name, may be cited from the standard abstract "The Merck Index" or database (e.g., international patents (e.g., IMS World Publications)).

[0332] The compounds described above, which may be used in combination with the PRMT5 inhibitors described herein, can be prepared and administered as described in the Art (including, but not limited to, the literature cited above).

[0333] In one embodiment, a pharmaceutical composition is provided, either alone or in combination with other anticancer agents, comprising at least one compound of the present disclosure (e.g., a crystalline form of the compound of formula (I), e.g., crystalline form A) together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject.

[0334] In detail, the compositions are either formulated together as a combination therapy or administered separately.

[0335] In combination therapy, the PRMT5 inhibitors and other anticancer agents(s) described herein may be administered simultaneously, concurrently, or sequentially without specific time constraints, resulting in therapeutically effective levels of both compounds within the patient's body.

[0336] In preferred embodiments, the compounds of this disclosure (e.g., the compounds of formula (I) described herein, or their crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof) or their dosage forms), and other anticancer agents(s) are generally administered sequentially in any order, either by infusion or orally. The administration regimen may vary depending on the stage of the disease, the patient's physical condition, the safety profiles of the individual drugs, the tolerability of the individual drugs, and other criteria known to the attending physician and healthcare provider(s) administering the concomitant drugs. The PRMT5 inhibitors and other anticancer agents(s) described herein may be administered within minutes, hours, days, or weeks of each other, depending on the specific cycle used in treatment. Furthermore, this cycle may include administering one drug more frequently than the other during the treatment cycle, or administering different doses of the drugs each time.

[0337] In another embodiment, a kit is provided comprising one or more PRMT5 inhibitors (or more) described herein (a compound of formula (I), a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form) and a second therapeutic agent disclosed herein. A typical kit comprises (a) a PRMT5 inhibitor described herein (a compound of formula (I) described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form) and (b) at least one other therapeutic agent (e.g., those shown above), and such a kit may include a package insert or other indications containing instructions for administration.

[0338] The compounds of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof) or their dosage forms described herein may be used in combination with known therapeutic processes (e.g., administration of hormones or, in particular, radiation). The compounds of this disclosure may, in particular, be used as radiosensitizers for the treatment of tumors that are less sensitive to radiation therapy. In some embodiments, methods are provided for treating a disease or disorder (e.g., cancer) comprising administering the compounds of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising the compounds of formula (I) or pharmaceutically acceptable salts thereof) or their dosage forms, and radiation, in any order or concurrently to a patient in need. Patient selection and monitoring

[0339] In some embodiments, a method for determining whether a subject having or diagnosed with cancer (e.g., a cancer patient) will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-noncompetitive PRMT5 inhibitor, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form), the following steps: a) Contacting the test sample obtained from the subject with a reagent capable of detecting human cancer cells having MTAP deficiency and / or MTA accumulation, b) Comparing the test sample to a reference substance (e.g., a reference sample taken from a non-cancer or normal control subject), A method is provided for indicating that the presence of MTAP deficiency and / or MTA accumulation in the test sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or its dosage form).

[0340] In some embodiments, a method for determining whether cancer responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or MTA cooperative binder, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form), the following steps: a) Contacting a test sample obtained from a subject having or diagnosed with the cancer with a reagent capable of detecting human cancer cells having MTAP deficiency and / or MTA accumulation, b) Comparing the test sample to a reference substance (e.g., a reference sample taken from a non-cancer or normal control subject), A method is provided to demonstrate that the presence of MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or its dosage form). In some embodiments, cancers include gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0341] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0342] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0343] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0344] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0345] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0346] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0347] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0348] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0349] In some embodiments, the method further includes a step of quantifying the level of PRMT5 in cancer cells. The expression level of PRMT5 may be taken into consideration when determining the therapeutically effective dose of a PRMT5 inhibitor.

[0350] In one embodiment, a method for quantifying the sensitivity of cancer cells to PRMT5 inhibition (e.g., MTA-uncompetitive PRMT5 inhibitors, e.g., compounds of formula (I) as described herein, crystalline form (e.g., crystalline form A), pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or its dosage form), comprising the following steps: a) Assaying the production, level, activity, expression, or presence of MTAP in the cancer cells, b) Comparing the production, level, activity, expression, or presence of MTAP in cancer cells with the production, level, activity, expression, or presence of MTAP in non-cancerous or normal control cells, A method is provided in which a decrease in the level, activity, or expression of MTAP in cancer cells indicates MTAP deficiency, and that MTAP deficiency indicates sensitivity to a PRMT5 inhibitor in said cancer cells.

[0351] In some embodiments, cancers include gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0352] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0353] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0354] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0355] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0356] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0357] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0358] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0359] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0360] In one embodiment, a method for quantifying the sensitivity of cancer cells to a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or MTA cooperative binder, e.g., a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form) is provided, the following steps: A method is provided which includes a) assaying the level, activity, or expression of the MTAP gene or its gene product in both cancer cells and normal control cells, wherein a decrease in level, activity, or expression in cancer cells indicates MTAP deficiency; b) assaying PRMT5 expression in said cancer cells; and c) comparing PRMT5 expression with PRMT5 expression in cancer cells and normal control cells, wherein the similarity of PRMT5 expression and the presence of said MTAP deficiency in said cancer cells indicate that said cells are sensitive to a PRMT5 inhibitor.

[0361] In some embodiments, cancers include gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0362] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0363] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0364] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0365] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0366] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0367] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0368] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0369] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0370] In one embodiment, a method for treating a subject having or diagnosed with cancer (e.g., cancer associated with MTAP deficiency and / or MTA accumulation), comprising the following steps: a) Evaluating the levels of MTAP and / or MTA in a test sample obtained from the subject (for example, by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells in a test sample obtained from the subject), wherein the MTA level can be evaluated directly (for example, by ELISA or LC-MS / MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC, or by RNA splicing), b) Comparing a test sample to a reference substance (e.g., a reference sample taken from a non-cancer or normal control subject) such that MTAP deficiency and / or MTA accumulation in the test sample indicates that the subject responds to therapeutic treatment with a PRMT5 inhibitor. c) A method is provided which includes administering a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form) to a subject identified in step b).

[0371] In one embodiment, a method for treating cancer (e.g., cancer associated with MTAP deficiency and / or MTA accumulation) in a person in need thereof, comprising the following steps: a) Evaluating the levels of MTAP and / or MTA in a test sample obtained from the subject (for example, by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be evaluated directly (for example, by ELISA or LC-MS / MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC, or by RNA splicing), b) Comparing a test sample to a reference substance (e.g., a reference sample taken from a non-cancer or normal control subject) such that the MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder), c) A method is provided which includes administering a therapeutically effective amount of a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form) to a subject identified in step b).

[0372] In some embodiments, cancers include gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0373] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0374] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0375] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0376] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0377] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0378] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0379] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0380] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0381] In some embodiments, the method further includes the step of quantifying the level of PRMT5 in cancer cells.

[0382] In one embodiment, a method for treating a subject having or diagnosed with cancer associated with MTAP deficiency and / or MTA accumulation, comprising the following steps: a) Evaluating the levels of MTAP and / or MTA in a test sample obtained from the subject (for example, by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be evaluated directly (for example, by ELISA or LC-MS / MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC, or by RNA splicing), b) Comparing a test sample to a reference sample (e.g., a reference sample taken from a non-cancer or normal control subject) such that the MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder), c) A method is provided which includes administering a PRMT5 inhibitor (e.g., an MTA uncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitor, or an MTA cooperative binder, e.g., a compound of formula (I) described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form) to a subject identified in step b).

[0383] In one embodiment, a therapeutic method for treating cancer associated with MTAP deficiency and / or MTA accumulation in a patient in need thereof, comprising the following steps: a) Evaluating the levels of MTAP and / or MTA in a test sample obtained from the subject (for example, by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be evaluated directly (for example, by ELISA or LC-MS / MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC, or by RNA splicing), b) Comparing a test sample to a reference sample (e.g., a reference sample taken from a non-cancer or normal control subject) such that the MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder), c) A method is provided which includes administering a therapeutically effective amount of a composition comprising a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form) to a subject identified in step b).

[0384] In some embodiments, cancers include gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0385] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0386] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0387] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0388] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0389] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0390] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0391] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0392] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0393] In some embodiments, the method further includes the step of quantifying the level of PRMT5 in cancer cells.

[0394] In some embodiments, a method for determining whether a subject having or diagnosed with cancer associated with MTAP deficiency and / or MTA accumulation will respond to treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative binder, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form), the following steps: a) Evaluating the levels of MTAP and / or MTA in a test sample obtained from the subject (for example, by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be evaluated directly (for example, by ELISA or LC-MS / MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC, or by RNA splicing), b) A method is provided which includes comparing a test sample with a reference substance (e.g., a reference sample taken from a non-cancer or normal control subject) to indicate that the MTAP deficiency and / or MTA accumulation in the test sample indicates that the subject responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative conjugate).

[0395] In some embodiments, a method for determining whether cancer associated with MTAP deficiency and / or MTA accumulation responds to treatment with a PRMT5 inhibitor (e.g., an MTA-noncompetitive PRMT5 inhibitor, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form), the following steps: a) Evaluating the levels of MTAP and / or MTA in test samples obtained from subjects having or diagnosed with the cancer (for example, by contacting the sample with a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be evaluated directly (for example, by ELISA or LC-MS / MS) or indirectly (for example, by SDMA-modified protein ELISA or IHC, or by RNA splicing), b) A method is provided which includes comparing a test sample with a reference sample (e.g., a reference sample taken from a non-cancer or normal control subject) to indicate that the MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA non-competitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA conjugate).

[0396] In some embodiments, cancers include gliomas, glioblastomas, malignant peripheral nerve schwannomas (MPNSTs), esophageal cancers (e.g., squamous cell carcinoma or adenocarcinoma of the esophagus), bladder cancers (e.g., urothelial carcinoma of the bladder), pancreatic cancers (e.g., adenocarcinoma of the pancreas, e.g., ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., squamous cell carcinoma or adenocarcinoma of the lung), astrocytomas, undifferentiated pleomorphic sarcomas, diffuse large B-cell lymphoma (DLBCL), leukemias, head and neck cancers, gastric adenocarcinomas, myxofibrosarcomas, cholangiosarcomas, cancers or sarcomas of the brain, stomach, kidneys, breast, endometrium, urinary tract, liver, soft tissues, pleura, and colorectal cancers.

[0397] In some embodiments, the cancer is CNS cancer. In some embodiments, the cancer is not CNS cancer.

[0398] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST), cholangiocarcinoma, NSCLC (e.g., squamous cell and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0399] In some embodiments, the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, cholangiocarcinoma, NSCLC (e.g., squamous cell carcinoma and adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0400] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, colorectal cancer, chronic myeloid leukemia (CML), and diffuse large B-cell lymphoma (DLBCL).

[0401] In some embodiments, the cancer is selected from the group consisting of glioma, glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, bladder cancer, urothelial carcinoma, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and malignant peripheral nerve schwannoma.

[0402] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), NSCLC (adenocarcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0403] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (squamous cell carcinoma), bladder cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), and mesothelioma.

[0404] In some embodiments, the cancer is a glioma. In some embodiments, the cancer is a glioblastoma. In some embodiments, the cancer is a glioblastoma multiforme. In some embodiments, the cancer is urothelial carcinoma, malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (e.g., squamous cell carcinoma and adenocarcinoma of the lung). In some embodiments, the cancer is squamous cell NSCLC. In some embodiments, the cancer is NSCLC adenocarcinoma. In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma of the bladder). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)). In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is chronic myeloid leukemia (CML). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is malignant peripheral nerve schwannoma (MPNST). In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is astrocytoma. In some embodiments, the cancer is undifferentiated pleomorphic sarcoma. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is myxofibrosarcoma. In some embodiments, the cancer is cholangiosarcoma. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is soft tissue cancer. In some embodiments, the cancer is pleural cancer. In some embodiments, the cancer is colorectal cancer.In some embodiments, the cancer is a sarcoma.

[0405] In some embodiments, the method further includes the step of quantifying the level of PRMT5 in cancer cells.

[0406] Sample preparation Furthermore, assays for detecting MTAP deficiency and / or MTA accumulation are also provided. Such assays may include detecting mutations associated with MTAP deficiency and / or MTA accumulation in, for example, body fluids (e.g., blood (e.g., serum or plasma), bone marrow, cerebrospinal fluid, peritoneal / pleural fluid, lymph, ascites, serous fluid, sputum, tears, feces, and urine) or in tissues (e.g., tumor tissue). Tumor tissue may be fresh tissue or preserved tissue (e.g., formalin-fixed tissue, e.g., paraffin-embedded tissue).

[0407] Body fluid samples can be obtained from a subject using any method known in the art. Methods for extracting cellular DNA from body fluid samples are well known in the art. Typically, cells are lysed with a washing agent. After cell lysis, proteins are removed from the DNA using various proteases. The DNA is then extracted with phenol, precipitated in alcohol, and dissolved in an aqueous solution. Methods for extracting cell-free DNA from body fluid samples are also known in the art. Generally, cellular DNA in a body fluid sample is separated from the cells, precipitated in alcohol, and dissolved in an aqueous solution.

[0408] Detection of PRMT5 selectivity Once prepared, a sample can be tested for MTAP deficiency and / or MTA accumulation, and the presence or absence of either or both indicates that the sample is sensitive to treatment with a PRMT5 inhibitor. Cells can be determined to be MTA-accumulating by techniques known in the art, and non-limiting examples of methods for detecting MTA include liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS / MS) (Stevens et al. 2010. J.Chromatogr. A.1217:3282-3288; and Kirovski et al. 2011 Am.J.Pathol.178:1145-1152; and references cited in these publications). Detection of MTAP deficiency can be performed by various methods, such as DNA sequencing, PCR-based methods (including RT-PCR), microarray analysis, Southern blotting, Northern blotting, next-generation sequencing, and dipstick analysis. In some embodiments, MTAP deficiency is assessed by any technique known in the art, for example, by immunohistochemistry and / or genome sequencing using an anti-MTAP antibody or a derivative thereof, or by nucleic acid hybridization, or by amplification using at least one probe or primer (primer is approximately 30 nt or less) containing a sequence of at least 12 consecutive nucleotides (nt) of the MTAP sequence.

[0409] Polymerase chain reaction (PCR) can be used to amplify and identify MTAP deficiencies from genomic DNA or RNA extracted from tumor tissue. PCR is well known in the art and is described in detail in Saiki et al., Science 1988, 239:487.

[0410] A method for detecting MTAP deficiencies by hybridization is provided. This method involves identifying MTAP deficiencies in a sample by determining that they cannot hybridize with MTAP nucleic acids. The nucleic acid probe is detected by labeling with radioisotopes, fluorescent agents, or chromogenic agents. Examples of radioisotopes, but not limited to, include 3H, 32P, 33P, and 35S. Examples of fluorescent agents, but not limited to, include FITC, Texas Red, and Rhodamine.

[0411] The probes used for detection, which can hybridize with MTAP nucleic acids, may be approximately 8 to 100 nucleotides, 10 to 75 nucleotides, 15 to 50 nucleotides, or 20 to 30 nucleotides. The kit may also provide instructions for the analysis of patient cancer samples (indicating whether the presence or absence of MTAP deficiency indicates whether the subject is sensitive or insensitive to treatment with PRMT5 inhibitors).

[0412] Furthermore, single-stranded polymorphisms (SSCPs) can also be used to detect MTAP deficiencies. This technique is described in detail in Orita et al., PNAS 1989, 86:2766-2770.

[0413] Measurement of gene expression The evaluation of MTAP deficiency and the measurement of MTAP gene expression, as well as the measurement of PRMT5 gene expression, can be carried out using any method or reagent known in the art.

[0414] Gene expression can be detected by any suitable method (e.g., detecting the amount of mRNA transcribed from a gene, or the amount of cDNA produced from the reverse transcription of mRNA transcribed from a gene, or the amount of polypeptide or protein encoded by the gene). These methods may be performed on a sample-by-sample basis or modified for high-throughput analysis (e.g., using an Affymetrix® U133 microarray chip).

[0415] In one embodiment, gene expression is detected and quantified by hybridization of a probe appropriate for its biomarker with a probe that specifically hybridizes with that probe. The probe may also be attached to a solid support for use in high-throughput screening assays using methods known in the art.

[0416] In one embodiment, gene expression levels are quantified by exposing a nucleic acid sample to a probe-modified tip. The extracted nucleic acid is preferably labeled, for example, with a fluorescent tag during the amplification step.

[0417] Hybridization of the labeled sample is performed at an appropriate stringency level. The degree of probe-nucleic acid hybridization is quantitatively measured using a detection device.

[0418] Alternatively, one of the following can be quantified using known techniques: gene copy number, transcription, or translation. For example, amplification methods such as PCR may be useful. A general procedure for PCR is taught in MacPherson et al., PCR: A Practical Approach (IRL Press at Oxford University Press (1991)). However, the PCR conditions used for each application reaction are determined empirically. Several parameters affect the success of the reaction. These include annealing temperature and time, extension time, Mg2+ and / or ATP concentration, pH, and the relative concentrations of primers, templates, and deoxyribonucleotides. After amplification, the resulting DNA fragments can be detected by agarose gel electrophoresis and subsequently visualized by ethidium bromide staining and ultraviolet irradiation. In one embodiment, hybridized nucleic acids are detected by detecting one or more labels bound to the sample nucleic acid. The labels can be incorporated by any of several means well known to those skilled in the art. However, in one embodiment, the labels are incorporated simultaneously during the amplification step in the preparation of the sample nucleic acid. Therefore, for example, polymerase chain reaction (PCR) using labeled primers or labeled nucleotides yields a labeled amplification product. In another embodiment, the transcription amplification using labeled nucleotides (e.g., fluorescein-labeled UTP and / or CTP) described above incorporates the label into the transcribed nucleic acid.

[0419] Alternatively, the label may be added directly to the original nucleic acid sample (e.g., mRNA, poly(A), mRNA, cDNA, etc.) or to the amplified product after amplification is complete. Means for attaching the label to the nucleic acid are well known to those skilled in the art, and such means include, for example, nick translation, or terminal labeling (e.g., by labeling RNA) by kinaseating the nucleic acid and then ligating a nucleic acid linker that connects the sample nucleic acid to the label.

[0420] For example, gene expression can be measured through an in-situ hybridization protocol that allows for the detection of RNA molecules on a slide containing tissue sections or cells (e.g., by RNAscope®).

[0421] Suitable detectable labels for use in the methods disclosed herein include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, or chemical means. Useful labels include biotin for staining with labeled streptavidin conjugates, magnetic beads (e.g., Dynabeads®), fluorescent dyes (e.g., fluorescein, Texas Red, rhodamine, green fluorescent protein, etc.), radiolabels (e.g., 3H, 125I, 35S, 14C, or 32P), enzymes (e.g., horseradish peroxidase, alkaline phosphatase, and other enzymes commonly used in ELISA), and calorimetry labels (e.g., colloidal gold or colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads).

[0422] The detection of labels is well known to those skilled in the art. For example, radiolabels can be detected using photographic film or a scintillation counter, and fluorescent markers can be detected using a photodetector that detects emitted light. Enzymatic labels are typically detected by providing a substrate to an enzyme and detecting the reaction product produced by the enzyme's action on the substrate, while colorimetric labels are detected simply by visualizing the colored label. Detectable labels can be added to the target (sample) nucleic acid(s) before or after hybridization, as described in WO97 / 10365, etc. These detectable labels are directly bound to or incorporated into the target (sample) nucleic acid before hybridization. In contrast, “indirect labels” are added to the hybrid duplex after hybridization. Generally, indirect labels are bound to binding sites that are already bound to the target nucleic acid before hybridization. For example, the target nucleic acid may be biotinylated before hybridization. After hybridization, an avidin conjugate fluorophore binds to the biotin-containing hybrid duplex, providing an easily detectable label. For a detailed overview of methods for labeling nucleic acids and detecting labeled hybridized nucleic acids, see Laboratory Techniques in Biochemistry and Molecular Biology, Vol. 24: Hybridization with Nucleic Acid Probes, P. Tijssen, ed. Elsevier, NY (1993).

[0423] Polypeptide detection MTAP protein levels can be quantified by examining protein expression or protein products. Quantification of protein levels involves measuring the amount of any immunospecific binding that occurs between antibodies that selectively recognize and bind to the polypeptide of the biomarker in a sample obtained from the subject, and comparing this to the amount of immunospecific binding to at least one biomarker in a control sample.

[0424] Various techniques are available in the field of protein analysis. These techniques include, but are not limited to, radioimmunoassays, ELISA (enzyme-linked immunosorbent assay), "sandwich" immunoassays, immunoradiometric assays, in situ immunoassays (e.g., using colloidal gold, enzymes, or radioisotopes), Western blotting, immunoprecipitation assays, immunofluorescence assays, flow cytometry, immunohistochemistry, HPLC, mass spectrometry, confocal microscopy, enzyme assays, surface plasmon resonance, and PAGE-SDS.

[0425] adjacent biomarkers Several other biomarkers are present near or adjacent to MTAP on chromosome 9. CDKN2A is often (though not always) deleted along with MTAP. Further genes or pseudogenes within this region include C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0426] In some embodiments of this method, cells that are MTAP-deficient are also deficient in CDKN2A. In some embodiments, cells that are MTAP-deficient are one or more of CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0427] Therefore, in various methods that include the step of evaluating cellular MTAP deficiency or determining whether cells are MTAP deficient, this step may include the step of determining whether cells are deficient in one or more of these markers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG.

[0428] Therefore, in some embodiments, the present disclosure provides a method for determining whether a subject having or diagnosed with cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative conjugate), a) A method comprising evaluating the MTAP deficiency of a test sample obtained from the subject and the MTAP deficiency of a reference sample obtained from a non-cancer or normal control subject, wherein the MTAP deficiency of the test sample compared to the reference sample indicates that the subject responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a crystalline form of the compound of formula (I)), and the MTAP deficiency is evaluated by evaluating the deficiency of one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG, the method further comprising the following steps: b) Quantifying the level of MTAP in the subject, wherein steps a) and b) can be performed in any order. c) Administering a therapeutically effective dose of a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative conjugate, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof) or its dosage form) to the target patient, d) Following step c), the level of PRMT5 activity in the subject may include quantifying whether a decrease in the level of PRMT5 activity correlates with inhibition of cancer growth, and steps c) and d) are performed after steps a) and b).

[0429] In some embodiments, the present disclosure provides a method for determining whether cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA-cooperative conjugate), a) A method comprising evaluating MTAP deficiency in test samples obtained from subjects having or diagnosed with the cancer, and evaluating MTAP deficiency in reference samples obtained from non-cancer or normal control subjects, wherein the MTAP deficiency of the test samples compared to the reference samples indicates that the cancer responds to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA uncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor, or an MTA cooperative binder, e.g., a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a dosage form), and the MTAP deficiency is evaluated by evaluating the deficiency of one or more of the following biomarkers: CDKN2A, C9orf53, ERVFRD-3, TUBB8P1, KHSRPP1, MIR31, and MIR31HG, the method further comprising the following steps: b) Quantifying the level of MTAP in the subject, wherein steps a) and b) can be performed in any order. c) Administering a therapeutically effective dose of a PRMT5 inhibitor (e.g., an MTA-noncompetitive PRMT5 inhibitor, e.g., a compound of formula (I) as described herein, in crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof) or its dosage form) to the target patient, d) Following step c), the level of PRMT5 activity in the subject may include quantifying whether a decrease in the level of PRMT5 activity correlates with inhibition of cancer growth, and steps c) and d) are performed after steps a) and b).

[0430] Biomarker assays and PRMT5 inhibitor therapy Multiple patient stratification strategies (including, but not limited to, testing for MTAP deficiency and / or MTA accumulation) may be used to identify patients who may be susceptible to PRMT5 inhibition with MTA-uncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitors, or MTA-cooperative conjugates (e.g., compounds of formula (I) described herein, crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts thereof) or their dosage forms).

[0431] If a patient's MTAP deficiency and / or MTA accumulation is assayed and they are predicted to be sensitive to treatment with a PRMT5 inhibitor, administration of any PRMT5 inhibitor (e.g., MTA uncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitors, or MTA cooperative binders, e.g., crystalline forms of compounds of formula (I)) to the patient may be a single dose, continuously or intermittently throughout the course of treatment. Methods for determining the most effective means and doses are well known to those skilled in the art and vary depending on the composition used in the therapy, the purpose of the therapy, the target cells being treated, and the subjects being treated. Single or multiple doses may be administered using dose levels and patterns selected by the treating physician. Preferred formulations and methods of administration of the drug may be empirically adjusted.

[0432] Dosage The following dose ranges and enumerations refer to the doses of the compound of formula (I) contained in the dosage forms and pharmaceutical compositions described herein, administered to a subject as part of the method described herein. In some embodiments, the method involves administering to a subject a dose of the compound of formula (I) in amounts ranging from about 5 mg to about 1000 mg once or twice daily.

[0433] In some embodiments, this method is used for doses of approximately 5 mg to approximately 500 mg, approximately 5 mg to approximately 490 mg, approximately 5 mg to approximately 480 mg, approximately 5 mg to approximately 470 mg, approximately 5 mg to approximately 460 mg, approximately 5 mg to approximately 450 mg, approximately 5 mg to approximately 440 mg, approximately 5 mg to approximately 430 mg, approximately 5 mg to approximately 420 mg, approximately 5 mg to approximately 410 mg, approximately 5 mg to approximately 400 mg, approximately 5 mg to approximately 390 mg, approximately 5 mg to approximately 380 mg, approximately 5 mg to approximately 370 mg, approximately 5 mg to approximately 360 mg, approximately 5 mg to approximately 350 mg, approximately 5 mg to approximately 340 mg, approximately 5 mg to approximately 330 mg, approximately 5 mg to approximately 320 mg, and approximately 5 mg ~ 310 mg, 5 mg ~ 300 mg, 5 mg ~ 290 mg, 5 mg ~ 280 mg, 5 mg ~ 270 mg, 5 mg ~ 260 mg, 5 mg ~ 250 mg, 5 mg ~ 240 mg, 5 mg ~ 230 mg, 5 mg ~ 220 mg, 5 mg ~ 2 10mg, about 5mg to about 200mg, about 5mg to about 190mg, about 5mg to about 180mg, about 5mg to about 170mg, about 5mg to about 160mg, about 5mg to about 150mg, about 5mg to about 140mg, about 5mg to about 130mg, about 5mg to about 120mg, about 5mg to about 110mg, Approximately 5 mg to approximately 100 mg, approximately 5 mg to approximately 90 mg, approximately 5 mg to approximately 80 mg, approximately 5 mg to approximately 70 mg, approximately 5 mg to approximately 60 mg, approximately 5 mg to approximately 50 mg, approximately 5 mg to approximately 40 mg, approximately 5 mg to approximately 30 mg, approximately 5 mg to approximately 20 mg, approximately 5 mg to approximately 10 mg, approximately 10 mg to approximately 500 mg, approximately 10mg to about 490mg, about 10mg to about 480mg, about 10mg to about 470mg, about 10mg to about 460mg, about 10mg to about 450mg, about 10mg to about 440mg, about 10mg to about 430mg, about 10mg to about 420mg, about 10mg to about 410mg, about 10mg to about 40 0mg, about 10mg to about 390mg, about 10mg to about 380mg, about 10mg to about 370mg, about 10mg to about 360mg, about 10mg to about 350mg, about 10mg to about 340mg, about 10mg to about 330mg, about 10mg to about 320mg, about 10mg to about 310mg, about 10m g ~ about 300mg, about 10mg - about 290mg, about 10mg - about 280mg, about 10mg - about 270mg, about 10mg - about 260mg, about 10mg - about 250mg, about 10mg - about 240mg, about 10mg - about 230mg, about 10mg - about 220mg, about 10mg - about 210mg,Approximately 10mg to approximately 200mg, approximately 10mg to approximately 190mg, approximately 10mg to approximately 180mg, approximately 10mg to approximately 170mg, approximately 10mg to approximately 160mg, approximately 10mg to approximately 150mg, approximately 10mg to approximately 140mg, approximately 10mg to approximately 130mg, approximately 10mg to approximately 120mg, approximately 10mg to approximately 110mg, approximately 10mg to approximately 100mg, approximately 10mg to approximately 90mg, approximately 10mg to approximately 80mg, approximately 10mg to approximately 70mg, approximately 10mg to approximately 60mg, approximately 10mg to approximately 50mg, approximately 10mg to approximately 40mg, approximately 10mg to approximately 30mg, approximately 10mg to approximately 20mg, approximately 20mg to approximately 500mg mg, approximately 20mg to approximately 490mg, approximately 20mg to approximately 480mg, approximately 20mg to approximately 470mg, approximately 20mg to approximately 460mg, approximately 20mg to approximately 450mg, approximately 20mg to approximately 440mg, approximately 20mg to approximately 430mg, approximately 20mg to approximately 420mg, approximately 20mg to approximately 410mg, approximately 20mg to approximately 400mg, approximately 20mg to approximately 390mg, approximately 20mg to approximately 380mg, approximately 20mg to approximately 370mg, approximately 20mg to approximately 360mg, approximately 20mg to approximately 350mg, approximately 20mg to approximately 340mg, approximately 20mg to approximately 330mg, approximately 20mg to approximately 320mg, approximately 20mg to approximately 310mg, Approximately 20mg to 300mg, approximately 20mg to 290mg, approximately 20mg to 280mg, approximately 20mg to 270mg, approximately 20mg to 260mg, approximately 20mg to 250mg, approximately 20mg to 240mg, approximately 20mg to 230mg, approximately 20mg to 220mg, approximately 20mg to 210mg, approximately 20mg to 200mg, approximately 20mg to 190mg, approximately 20mg to 180mg, approximately 20mg to 170mg, approximately 20mg to 160mg, approximately 20mg to 150mg, approximately 20mg to 140mg, approximately 20mg to 130mg, approximately 20mg to 120mg, approximately 20 mg ~ approx. 110mg, approx. 20mg ~ approx. 100mg, approx. 20mg ~ approx. 90mg, approx. 20mg ~ approx. 80mg, approx. 20mg ~ approx. 70mg, approx. 20mg ~ approx. 60mg, approx. 20mg ~ approx. 50mg, approx. 20mg ~ approx. 40mg, approx. 20mg ~ approx. 30mg, approx. 30mg ~ approx. 500mg, approx. 30mg ~ approx. 490mg, approx. 30mg ~ approx. 480mg, approx. 30mg ~ approx. 470mg, approx. 30mg ~ approx. 460mg, approx. 30mg ~ approx. 450mg, approx. 30mg ~ approx. 440mg, approx. 30mg ~ approx. 430mg, approx. 30mg ~ approx. 420mg, approx. 30mg ~ approx. 410mg, approx. 30mg ~ approx. 400mgApproximately 30mg to approximately 390mg, approximately 30mg to approximately 380mg, approximately 30mg to approximately 370mg, approximately 30mg to approximately 360mg, approximately 30mg to approximately 350mg, approximately 30mg to approximately 340mg, approximately 30mg to approximately 330mg, approximately 30mg to approximately 320mg, approximately 30mg to approximately 310mg, approximately 30mg to approximately 300mg, approximately 30mg to approximately 290mg, approximately 30mg to approximately 280mg, approximately 30mg to approximately 270mg, approximately 30mg to approximately 260mg, approximately 30mg to approximately 250mg, approximately 30mg to approximately 240mg, approximately 30mg to approximately 230mg, approximately 30mg to approximately 220mg, approximately 30mg to approximately 210mg, approximately 30mg~approx. 200mg, approx. 30mg~approx. 190mg, approx. 30mg~approx. 180mg, approx. 30mg~approx. 170mg, approx. 30mg~approx. 160mg, approx. 30mg~approx. 150mg, approx. 30mg~approx. 140mg, approx. 30mg~approx. 130mg, approx. 30mg~approx. 120mg, approx. 30mg~approx. 110mg, approx. 30mg~approx. 100mg, approx. 30mg~approx. 90mg, approx. 30mg~approx. 80mg, approx. 30mg~approx. 70mg, approx. 30mg~approx. 60mg, approx. 30mg~approx. 50mg, approx. 30mg~approx. 40mg, approx. 40mg~approx. 500mg, approx. 40mg~approx. 490mg, approx. 40mg~approx. 48mg 0mg, approximately 40mg~approx. 470mg, approximately 40mg~approx. 460mg, approximately 40mg~approx. 450mg, approximately 40mg~approx. 440mg, approximately 40mg~approx. 430mg, approximately 40mg~approx. 420mg, approximately 40mg~approx. 410mg, approximately 40mg~approx. 400mg, approximately 40mg~approx. 390mg, approximately 40mg~approx. 380mg, approximately 40mg~approx. 370mg, approximately 40mg~approx. 360mg, approximately 40mg~approx. 350mg, approximately 40mg~approx. 340mg, approximately 40mg~approx. 330mg, approximately 40mg~approx. 320mg, approximately 40mg~approx. 310mg, approximately 40mg~approx. 300mg, approximately 40mg~approx. 290mg g, approximately 40mg to approximately 280mg, approximately 40mg to approximately 270mg, approximately 40mg to approximately 260mg, approximately 40mg to approximately 250mg, approximately 40mg to approximately 240mg, approximately 40mg to approximately 230mg, approximately 40mg to approximately 220mg, approximately 40mg to approximately 210mg, approximately 40mg to approximately 200mg, approximately 40mg to approximately 190mg, approximately 40mg to approximately 180mg, approximately 40mg to approximately 170mg, approximately 40mg to approximately 160mg, approximately 40mg to approximately 150mg, approximately 40mg to approximately 140mg, approximately 40mg to approximately 130mg, approximately 40mg to approximately 120mg, approximately 40mg to approximately 110mg, approximately 40mg to approximately 100mg,Approximately 40mg~90mg, approximately 40mg~80mg, approximately 40mg~70mg, approximately 40mg~60mg, approximately 40mg~50mg, approximately 50mg~500mg, approximately 50mg~490mg, approximately 50mg~480mg, approximately 50mg~470mg, approximately 50mg~460mg, approximately 50mg~450mg, approximately 50mg~440mg, approximately 50mg~430mg, approximately 50mg~420mg, approximately 50mg~410mg, approximately 50mg~400mg, approximately 50mg~390mg, approximately 50mg~380mg, approximately 50mg~370mg, approximately 50mg~ Approximately 360mg, approximately 50mg~350mg, approximately 50mg~340mg, approximately 50mg~330mg, approximately 50mg~320mg, approximately 50mg~310mg, approximately 50mg~300mg, approximately 50mg~290mg, approximately 50mg~280mg, approximately 50mg~270mg, approximately 50mg~260mg, approximately 50mg~250mg, approximately 50mg~240mg, approximately 50mg~230mg, approximately 50mg~220mg, approximately 50mg~210mg, approximately 50mg~200mg, approximately 50mg~190mg, approximately 50mg~180mg, approximately 50mg~approximately 170mg, approximately 50mg to 160mg, approximately 50mg to 150mg, approximately 50mg to 140mg, approximately 50mg to 130mg, approximately 50mg to 120mg, approximately 50mg to 110mg, approximately 50mg to 100mg, approximately 50mg to 90mg, approximately 50mg to 80mg, approximately 50mg to 70mg, approximately 50mg to 60mg, approximately 60mg to 500mg, approximately 60mg to 490mg, approximately 60mg to 480mg, approximately 60mg to 470mg, approximately 60mg to 460mg, approximately 60mg to 450mg, approximately 60mg to 440mg, approximately 60mg to 430mg Approximately 60mg to 420mg, approximately 60mg to 410mg, approximately 60mg to 400mg, approximately 60mg to 390mg, approximately 60mg to 380mg, approximately 60mg to 370mg, approximately 60mg to 360mg, approximately 60mg to 350mg, approximately 60mg to 340mg, approximately 60mg to 330mg, approximately 60mg to 320mg, approximately 60mg to 310mg, approximately 60mg to 300mg, approximately 60mg to 290mg, approximately 60mg to 280mg, approximately 60mg to 270mg, approximately 60mg to 260mg, approximately 60mg to 250mg, approximately 60mg to 240mg.Approximately 60mg to 230mg, approximately 60mg to 220mg, approximately 60mg to 210mg, approximately 60mg to 200mg, approximately 60mg to 190mg, approximately 60mg to 180mg, approximately 60mg to 170mg, approximately 60mg to 160mg, approximately 60mg to 150mg, approximately 60mg to 140mg, approximately 60mg to 130mg, approximately 60mg to 120mg, approximately 60mg to 110mg, approximately 60mg to 100mg, approximately 60mg to 90mg, approximately 60mg to 80mg, approximately 60mg to 70mg, approximately 70mg to 500mg, approximately 70mg to 490mg, approximately 70mg to 480mg. Approximately 70mg~470mg, approximately 70mg~460mg, approximately 70mg~450mg, approximately 70mg~440mg, approximately 70mg~430mg, approximately 70mg~420mg, approximately 70mg~410mg, approximately 70mg~400mg, approximately 70mg~390mg, approximately 70mg~380mg, approximately 70mg~370mg, approximately 70mg~360mg, approximately 70mg~350mg, approximately 70mg~340mg, approximately 70mg~330mg, approximately 70mg~320mg, approximately 70mg~310mg, approximately 70mg~300mg, approximately 70mg~290mg, approximately 70mg~280mg g, approximately 70mg to approximately 270mg, approximately 70mg to approximately 260mg, approximately 70mg to approximately 250mg, approximately 70mg to approximately 240mg, approximately 70mg to approximately 230mg, approximately 70mg to approximately 220mg, approximately 70mg to approximately 210mg, approximately 70mg to approximately 200mg, approximately 70mg to approximately 190mg, approximately 70mg to approximately 180mg, approximately 70mg to approximately 170mg, approximately 70mg to approximately 160mg, approximately 70mg to approximately 150mg, approximately 70mg to approximately 140mg, approximately 70mg to approximately 130mg, approximately 70mg to approximately 120mg, approximately 70mg to approximately 110mg, approximately 70mg to approximately 100mg, approximately 70mg to approximately 90mg, approximately 70mg to approximately 80mg mg, approximately 80mg~approx. 500mg, approximately 80mg~approx. 490mg, approximately 80mg~approx. 480mg, approximately 80mg~approx. 470mg, approximately 80mg~approx. 460mg, approximately 80mg~approx. 450mg, approximately 80mg~approx. 440mg, approximately 80mg~approx. 430mg, approximately 80mg~approx. 420mg, approximately 80mg~approx. 410mg, approximately 80mg~approx. 400mg, approximately 80mg~approx. 390mg, approximately 80mg~approx. 380mg, approximately 80mg~approx. 370mg, approximately 80mg~approx. 360mg, approximately 80mg~approx. 350mg, approximately 80mg~approx. 340mg,Approximately 80mg~330mg, approximately 80mg~320mg, approximately 80mg~310mg, approximately 80mg~300mg, approximately 80mg~290mg, approximately 80mg~280mg, approximately 80mg~270mg, approximately 80mg~260mg, approximately 80mg~250mg, approximately 80mg~240mg, approximately 80mg~approximately... 230mg, approximately 80mg~approx. 220mg, approximately 80mg~approx. 210mg, approximately 80mg~approx. 200mg, approximately 80mg~approx. 190mg, approximately 80mg~approx. 180mg, approximately 80mg~approx. 170mg, approximately 80mg~approx. 160mg, approximately 80mg~approx. 150mg, approximately 80mg~approx. 140mg, approximately 80mg~approx. 130mg, approximately 80mg~approx. 120mg, approximately 80mg~approx. 110mg, approximately 80mg~approx. 100mg, approximately 80mg~approx. 90mg, approximately 90mg~approx. 500mg, approximately 90mg~approx. 490mg, approximately 90mg~approx. 480mg, approximately 90mg~approx. 90mg mg ~ approx. 470mg, approx. 90mg ~ approx. 460mg, approx. 90mg ~ approx. 450mg, approx. 90mg ~ approx. 440mg, approx. 90mg ~ approx. 430mg, approx. 90mg ~ approx. 420mg, approx. 90mg ~ approx. 410mg, approx. 90mg ~ approx. 400mg, approx. 90mg ~ approx. 390mg, approx. 90mg ~ approx. 380mg, approx. 90mg ~ approx. 370mg, approx. 90mg ~ approx. 360mg, approx. 90mg ~ approx. 350mg, approx. 90mg ~ approx. 340mg, approx. 90mg ~ approx. 330mg, approx. 90mg ~ approx. 320mg, approx. 90mg ~ approx. 310mg, approx. 90mg ~ approx. 300mg, approx. 90mg ~ approx. 290mg, approx. 90mg ~ approx. 280mg Approximately 90mg~270mg, approximately 90mg~260mg, approximately 90mg~250mg, approximately 90mg~240mg, approximately 90mg~230mg, approximately 90mg~220mg, approximately 90mg~210mg, approximately 90mg~200mg, approximately 90mg~190mg, approximately 90mg~180mg, approximately 90mg~170mg, approximately 90mg~160mg, approximately 90mg~150mg, approximately 90mg~140mg, approximately 90mg~130mg, approximately 90mg~120mg, approximately 90mg~110mg, approximately 90mg~100mg, approximately 100mg~500mg, approximately 100mg~4 90mg, approximately 100mg to approximately 480mg, approximately 100mg to approximately 470mg, approximately 100mg to approximately 460mg, approximately 100mg to approximately 450mg, approximately 100mg to approximately 440mg, approximately 100mg to approximately 430mg, approximately 100mg to approximately 420mg, approximately 100mg to approximately 410mg, approximately 100mg to approximately 400mg, approximately 100mg to approximately 390mg, approximately 100mg to approximately 380mg, approximately 100mg to approximately 370mg, approximately 100mg to approximately 360mg, approximately 100mg to approximately 350mg, approximately 100mg to approximately 340mg, approximately 100mg to approximately 330mg, approximately 100mg to approximately 320mg, approximately 100mg to approximately 310mg,Approximately 100mg to 300mg, approximately 100mg to 290mg, approximately 100mg to 280mg, approximately 100mg to 270mg, approximately 100mg to 260mg, approximately 100mg to 250mg, approximately 100mg to 240mg, approximately 100mg to 230mg, approximately 100mg to 220mg, approximately 100mg to 210mg, approximately 100mg to 200mg, approximately 100mg to 190mg, approximately 100mg to 180mg, approximately 100mg to 170mg, approximately 100mg to 160mg, approximately 100mg to 150mg, approximately 100mg to 140mg, approximately 100mg to 130mg. 0mg, approximately 100mg to approximately 120mg, approximately 100mg to approximately 110mg, approximately 110mg to approximately 500mg, approximately 110mg to approximately 490mg, approximately 110mg to approximately 480mg, approximately 110mg to approximately 470mg, approximately 110mg to approximately 460mg, approximately 110mg to approximately 450mg, approximately 110mg to approximately 440mg, approximately 110mg to approximately 430mg, approximately 110mg to approximately 420mg, approximately 110mg to approximately 410mg, approximately 110mg to approximately 400mg, approximately 110mg to approximately 390mg, approximately 110mg to approximately 380mg, approximately 110mg to approximately 370mg, approximately 110mg to approximately 360mg, approximately 110mg~ Approximately 350mg, approximately 110mg~approximately 340mg, approximately 110mg~approximately 330mg, approximately 110mg~approximately 320mg, approximately 110mg~approximately 310mg, approximately 110mg~approximately 300mg, approximately 110mg~approximately 290mg, approximately 110mg~approximately 280mg, approximately 110mg~approximately 270mg, approximately 110mg~approximately 260mg, approximately 110mg~approximately 250mg, approximately 110mg~approximately 240mg, approximately 110mg~approximately 230mg, approximately 110mg~approximately 220mg, approximately 110mg~approximately 210mg, approximately 110mg~approximately 200mg, approximately 110mg~approximately 190mg, approximately 110mg~approximately 180mg, approximately 11 0mg~approx. 170mg, approx. 110mg~approx. 160mg, approx. 110mg~approx. 150mg, approx. 110mg~approx. 140mg, approx. 110mg~approx. 130mg, approx. 110mg~approx. 120mg, approx. 120mg~approx. 500mg, approx. 120mg~approx. 490mg, approx. 120mg~approx. 480mg, approx. 120mg~approx. 470mg, approx. 120mg~approx. 460mg, approx. 120mg~approx. 450mg, approx. 120mg~approx. 440mg, approx. 120mg~approx. 430mg, approx. 120mg~approx. 420mg, approx. 120mg~approx. 410mg, approx. 120mg~approx. 400mg, approx. 120mg~approx. 390mgApproximately 120mg to approximately 380mg, approximately 120mg to approximately 370mg, approximately 120mg to approximately 360mg, approximately 120mg to approximately 350mg, approximately 120mg to approximately 340mg, approximately 120mg to approximately 330mg, approximately 120mg to approximately 320mg, approximately 120mg to approximately 310mg, approximately 120mg to approximately 300mg, approximately 120mg to approximately 290mg, approximately 120mg to approximately 280mg, approximately 120mg to approximately 270mg, approximately 120mg to approximately 260mg, approximately 120mg to approximately 250mg, approximately 120mg to approximately 240mg, approximately 120mg to approximately 230mg, approximately 120mg to approximately 220mg, approximately 120mg to approximately 21mg 0mg, approximately 120mg to approximately 200mg, approximately 120mg to approximately 190mg, approximately 120mg to approximately 180mg, approximately 120mg to approximately 170mg, approximately 120mg to approximately 160mg, approximately 120mg to approximately 150mg, approximately 120mg to approximately 140mg, approximately 120mg to approximately 130mg, approximately 130mg to approximately 500mg, approximately 130mg to approximately 490mg, approximately 130mg to approximately 480mg, approximately 130mg to approximately 470mg, approximately 130mg to approximately 460mg, approximately 130mg to approximately 450mg, approximately 130mg to approximately 440mg, approximately 130mg to approximately 430mg, approximately 130mg to approximately 420mg, approximately 130mg~ Approximately 410mg, approximately 130mg to approximately 400mg, approximately 130mg to approximately 390mg, approximately 130mg to approximately 380mg, approximately 130mg to approximately 370mg, approximately 130mg to approximately 360mg, approximately 130mg to approximately 350mg, approximately 130mg to approximately 340mg, approximately 130mg to approximately 330mg, approximately 130mg to approximately 320mg, approximately 130mg to approximately 310mg, approximately 130mg to approximately 300mg, approximately 130mg to approximately 290mg, approximately 130mg to approximately 280mg, approximately 130mg to approximately 270mg, approximately 130mg to approximately 260mg, approximately 130mg to approximately 250mg, approximately 130mg to approximately 240mg, approximately 13 0mg~approx. 230mg, approx. 130mg~approx. 220mg, approx. 130mg~approx. 210mg, approx. 130mg~approx. 200mg, approx. 130mg~approx. 190mg, approx. 130mg~approx. 180mg, approx. 130mg~approx. 170mg, approx. 130mg~approx. 160mg, approx. 130mg~approx. 150mg, approx. 130mg~approx. 140mg, approx. 140mg~approx. 500mg, approx. 140mg~approx. 490mg, approx. 140mg~approx. 480mg, approx. 140mg~approx. 470mg, approx. 140mg~approx. 460mg, approx. 140mg~approx. 450mg, approx. 140mg~approx. 440mg, approx. 140mg~approx. 430mgApproximately 140mg to approximately 420mg, approximately 140mg to approximately 410mg, approximately 140mg to approximately 400mg, approximately 140mg to approximately 390mg, approximately 140mg to approximately 380mg, approximately 140mg to approximately 370mg, approximately 140mg to approximately 360mg, approximately 140mg to approximately 350mg, approximately 140mg to approximately 340mg, approximately 140mg to approximately 330mg, approximately 140mg to approximately 320mg, approximately 140mg to approximately 310mg, approximately 140mg to approximately 300mg, approximately 140mg to approximately 290mg, approximately 140mg to approximately 280mg, approximately 140mg to approximately 270mg, approximately 140mg to approximately 260mg, approximately 140mg to approximately 250mg. 0mg, approximately 140mg to approximately 240mg, approximately 140mg to approximately 230mg, approximately 140mg to approximately 220mg, approximately 140mg to approximately 210mg, approximately 140mg to approximately 200mg, approximately 140mg to approximately 190mg, approximately 140mg to approximately 180mg, approximately 140mg to approximately 170mg, approximately 140mg to approximately 160mg, approximately 140mg to approximately 150mg, approximately 150mg to approximately 500mg, approximately 150mg to approximately 490mg, approximately 150mg to approximately 480mg, approximately 150mg to approximately 470mg, approximately 150mg to approximately 460mg, approximately 150mg to approximately 450mg, approximately 150mg to approximately 440mg, approximately 150mg~ Approximately 430mg, approximately 150mg~approximately 420mg, approximately 150mg~approximately 410mg, approximately 150mg~approximately 400mg, approximately 150mg~approximately 390mg, approximately 150mg~approximately 380mg, approximately 150mg~approximately 370mg, approximately 150mg~approximately 360mg, approximately 150mg~approximately 350mg, approximately 150mg~approximately 340mg, approximately 150mg~approximately 330mg, approximately 150mg~approximately 320mg, approximately 150mg~approximately 310mg, approximately 150mg~approximately 300mg, approximately 150mg~approximately 290mg, approximately 150mg~approximately 280mg, approximately 150mg~approximately 270mg, approximately 150mg~approximately 260mg, approximately 15 0mg~approx. 250mg, approx. 150mg~approx. 240mg, approx. 150mg~approx. 230mg, approx. 150mg~approx. 220mg, approx. 150mg~approx. 210mg, approx. 150mg~approx. 200mg, approx. 150mg~approx. 190mg, approx. 150mg~approx. 180mg, approx. 150mg~approx. 170mg, approx. 150mg~approx. 160mg, approx. 160mg~approx. 500mg, approx. 160mg~approx. 490mg, approx. 160mg~approx. 480mg, approx. 160mg~approx. 470mg, approx. 160mg~approx. 460mg, approx. 160mg~approx. 450mg, approx. 160mg~approx. 440mg, approx. 160mg~approx. 430mgApproximately 160mg to approximately 420mg, approximately 160mg to approximately 410mg, approximately 160mg to approximately 400mg, approximately 160mg to approximately 390mg, approximately 160mg to approximately 380mg, approximately 160mg to approximately 370mg, approximately 160mg to approximately 360mg, approximately 160mg to approximately 350mg, approximately 160mg to approximately 340mg, approximately 160mg to approximately 330mg, approximately 160mg to approximately 320mg, approximately 160mg to approximately 310mg, approximately 160mg to approximately 300mg, approximately 160mg to approximately 290mg, approximately 160mg to approximately 280mg, approximately 160mg to approximately 270mg, approximately 160mg to approximately 260mg, approximately 160mg to approximately 25mg. 0mg, approximately 160mg~240mg, approximately 160mg~230mg, approximately 160mg~220mg, approximately 160mg~210mg, approximately 160mg~200mg, approximately 160mg~190mg, approximately 160mg~180mg, approximately 160mg~170mg, approximately 170mg~500mg, approximately 170mg~490mg, approximately 170mg~480mg, approximately 170mg~470mg, approximately 170mg~460mg, approximately 170mg~450mg, approximately 170mg~440mg, approximately 170mg~430mg, approximately 170mg~420mg, approximately 170mg~ Approximately 410mg, approximately 170mg~approximately 400mg, approximately 170mg~approximately 390mg, approximately 170mg~approximately 380mg, approximately 170mg~approximately 370mg, approximately 170mg~approximately 360mg, approximately 170mg~approximately 350mg, approximately 170mg~approximately 340mg, approximately 170mg~approximately 330mg, approximately 170mg~approximately 320mg, approximately 170mg~approximately 310mg, approximately 170mg~approximately 300mg, approximately 170mg~approximately 290mg, approximately 170mg~approximately 280mg, approximately 170mg~approximately 270mg, approximately 170mg~approximately 260mg, approximately 170mg~approximately 250mg, approximately 170mg~approximately 240mg, approximately 17 0mg~approx. 230mg, approx. 170mg~approx. 220mg, approx. 170mg~approx. 210mg, approx. 170mg~approx. 200mg, approx. 170mg~approx. 190mg, approx. 170mg~approx. 180mg, approx. 180mg~approx. 500mg, approx. 180mg~approx. 490mg, approx. 180mg~approx. 480mg, approx. 180mg~approx. 470mg, approx. 180mg~approx. 460mg, approx. 180mg~approx. 450mg, approx. 180mg~approx. 440mg, approx. 180mg~approx. 430mg, approx. 180mg~approx. 420mg, approx. 180mg~approx. 410mg, approx. 180mg~approx. 400mg, approx. 180mg~approx. 390mgApproximately 180mg~380mg, approximately 180mg~370mg, approximately 180mg~360mg, approximately 180mg~350mg, approximately 180mg~340mg, approximately 180mg~330mg, approximately 180mg~320mg, approximately 180mg~310mg, approximately 180mg~300mg, approximately 180mg~290mg, approximately 180mg, g ~ approx. 280mg, approx. 180mg ~ approx. 270mg, approx. 180mg ~ approx. 260mg, approx. 180mg ~ approx. 250mg, approx. 180mg ~ approx. 240mg, approx. 180mg ~ approx. 230mg, approx. 180mg ~ approx. 220mg, approx. 180mg ~ approx. 210mg, approx. 180mg ~ approx. 200mg, approx. 180mg ~ approx. 190mg, approx. 190mg ~ approx. 500mg, approx. 190mg ~ approx. 490mg, approx. 190mg ~ approx. 480mg, approx. 190mg ~ approx. 470mg, approx. 190mg ~ approx. 460mg, approx. 190mg ~ approx. 450mg, approx. 190mg ~ approx. 440mg, approx. 190mg ~ approx. 430mg Approximately 190mg~420mg, approximately 190mg~410mg, approximately 190mg~400mg, approximately 190mg~390mg, approximately 190mg~380mg, approximately 190mg~370mg, approximately 190mg~360mg, approximately 190mg~350mg, approximately 190mg~340mg, approximately 190mg~330mg, approximately 190mg~320mg, approximately 190mg~310mg, approximately 190mg~300mg, approximately 190mg~290mg, approximately 190mg~280mg, approximately 190mg~270mg, approximately 190mg~260mg, approximately 190mg~2 50mg, approximately 190mg~240mg, approximately 190mg~230mg, approximately 190mg~220mg, approximately 190mg~210mg, approximately 190mg~200mg, approximately 200mg~500mg, approximately 200mg~490mg, approximately 200mg~480mg, approximately 200mg~470mg, approximately 200mg~460mg, approximately 200mg~450mg, approximately 200mg~440mg, approximately 200mg~430mg, approximately 200mg~420mg, approximately 200mg~410mg, approximately 200mg~400mg, approximately 200mg~390mg, approximately 200mg~ ... mg ~ approx. 380mg, approx. 200mg ~ approx. 370mg, approx. 200mg ~ approx. 360mg, approx. 200mg ~ approx. 350mg, approx. 200mg ~ approx. 340mg, approx. 200mg ~ approx. 330mg, approx. 200mg ~ approx. 320mg, approx. 200mg ~ approx. 310mg, approx. 200mg ~ approx. 300mg, approx. 200mg ~ approx. 290mg, approx. 200mg ~ approx. 280mg, approx. 200mg ~ approx. 270mg, approx. 200mg ~ approx. 260mg, approx. 200mg ~ approx. 250mg, approx. 200mg ~ approx. 240mg, approx. 200mg ~ approx. 230mg, approx. 200mg ~ approx. 220mg, approx. 200mg ~ approx. 210mgApproximately 210mg~500mg, approximately 210mg~490mg, approximately 210mg~480mg, approximately 210mg~470mg, approximately 210mg~460mg, approximately 210mg~450mg, approximately 210mg~440mg, approximately 210mg~430mg, approximately 210mg~420mg, approximately 210mg~410mg, approximately 210mg~400mg, approximately 210mg~390mg, approximately 210mg~380mg, approximately 210mg~370mg, approximately 210mg~360mg, approximately 210mg~350mg, approximately 210mg~340mg, approximately 210mg~330mg 0mg, approximately 210mg~320mg, approximately 210mg~310mg, approximately 210mg~300mg, approximately 210mg~290mg, approximately 210mg~280mg, approximately 210mg~270mg, approximately 210mg~260mg, approximately 210mg~250mg, approximately 210mg~240mg, approximately 210mg~230mg, approximately 210mg~220mg, approximately 220mg~500mg, approximately 220mg~490mg, approximately 220mg~480mg, approximately 220mg~470mg, approximately 220mg~460mg, approximately 220mg~450mg, approximately 220mg~ Approximately 440mg, approximately 220mg~approximately 430mg, approximately 220mg~approximately 420mg, approximately 220mg~approximately 410mg, approximately 220mg~approximately 400mg, approximately 220mg~approximately 390mg, approximately 220mg~approximately 380mg, approximately 220mg~approximately 370mg, approximately 220mg~approximately 360mg, approximately 220mg~approximately 350mg, approximately 220mg~approximately 340mg, approximately 220mg~approximately 330mg, approximately 220mg~approximately 320mg, approximately 220mg~approximately 310mg, approximately 220mg~approximately 300mg, approximately 220mg~approximately 290mg, approximately 220mg~approximately 280mg, approximately 220mg~approximately 270mg, approximately 22 0mg~approx. 260mg, approx. 220mg~approx. 250mg, approx. 220mg~approx. 240mg, approx. 220mg~approx. 230mg, approx. 230mg~approx. 500mg, approx. 230mg~approx. 490mg, approx. 230mg~approx. 480mg, approx. 230mg~approx. 470mg, approx. 230mg~approx. 460mg, approx. 230mg~approx. 450mg, approx. 230mg~approx. 440mg, approx. 230mg~approx. 430mg, approx. 230mg~approx. 420mg, approx. 230mg~approx. 410mg, approx. 230mg~approx. 400mg, approx. 230mg~approx. 390mg, approx. 230mg~approx. 380mg, approx. 230mg~approx. 370mgApproximately 230mg~360mg, approximately 230mg~350mg, approximately 230mg~340mg, approximately 230mg~330mg, approximately 230mg~320mg, approximately 230mg~310mg, approximately 230mg~300mg, approximately 230mg~290mg, approximately 230mg~280mg, approximately 230mg~270mg, approximately 230mg~260mg, approximately 230mg~250mg, approximately 230mg~240mg, approximately 240mg~500mg, approximately 240mg~490mg, approximately 240mg~480mg, approximately 240mg~470mg, approximately 240mg~460mg 0mg, approximately 240mg~450mg, approximately 240mg~440mg, approximately 240mg~430mg, approximately 240mg~420mg, approximately 240mg~410mg, approximately 240mg~400mg, approximately 240mg~390mg, approximately 240mg~380mg, approximately 240mg~370mg, approximately 240mg~360mg, approximately 240mg~350mg, approximately 240mg~340mg, approximately 240mg~330mg, approximately 240mg~320mg, approximately 240mg~310mg, approximately 240mg~300mg, approximately 240mg~290mg, approximately 240mg~ Approximately 280mg, approximately 240mg~approximately 270mg, approximately 240mg~approximately 260mg, approximately 240mg~approximately 250mg, approximately 250mg~approximately 500mg, approximately 250mg~approximately 490mg, approximately 250mg~approximately 480mg, approximately 250mg~approximately 470mg, approximately 250mg~approximately 460mg, approximately 250mg~approximately 450mg, approximately 250mg~approximately 440mg, approximately 250mg~approximately 430mg, approximately 250mg~approximately 420mg, approximately 250mg~approximately 410mg, approximately 250mg~approximately 400mg, approximately 250mg~approximately 390mg, approximately 250mg~approximately 380mg, approximately 250mg~approximately 370mg, approximately 25 0mg~approx. 360mg, approx. 250mg~approx. 350mg, approx. 250mg~approx. 340mg, approx. 250mg~approx. 330mg, approx. 250mg~approx. 320mg, approx. 250mg~approx. 310mg, approx. 250mg~approx. 300mg, approx. 250mg~approx. 290mg, approx. 250mg~approx. 280mg, approx. 250mg~approx. 270mg, approx. 250mg~approx. 260mg, approx. 260mg~approx. 500mg, approx. 260mg~approx. 490mg, approx. 260mg~approx. 480mg, approx. 260mg~approx. 470mg, approx. 260mg~approx. 460mg, approx. 260mg~approx. 450mg, approx. 260mg~approx. 440mgApproximately 260mg~430mg, approximately 260mg~420mg, approximately 260mg~410mg, approximately 260mg~400mg, approximately 260mg~390mg, approximately 260mg~380mg, approximately 260mg~370mg, approximately 260mg~360mg, approximately 260mg~350mg, approximately 260mg~340mg, approximately 260mg~330mg, approximately 260mg~320mg, approximately 260mg~310mg, approximately 260mg~300mg, approximately 260mg~290mg, approximately 260mg~280mg, approximately 260mg~270mg, approximately 270mg~50mg 0mg, approximately 270mg~490mg, approximately 270mg~480mg, approximately 270mg~470mg, approximately 270mg~460mg, approximately 270mg~450mg, approximately 270mg~440mg, approximately 270mg~430mg, approximately 270mg~420mg, approximately 270mg~410mg, approximately 270mg~400mg, approximately 270mg~390mg, approximately 270mg~380mg, approximately 270mg~370mg, approximately 270mg~360mg, approximately 270mg~350mg, approximately 270mg~340mg, approximately 270mg~330mg, approximately 270mg~ Approximately 320mg, approximately 270mg~310mg, approximately 270mg~300mg, approximately 270mg~290mg, approximately 270mg~280mg, approximately 280mg~500mg, approximately 280mg~490mg, approximately 280mg~480mg, approximately 280mg~470mg, approximately 280mg~460mg, approximately 280mg~450mg, approximately 280mg~440mg, approximately 280mg~430mg, approximately 280mg~420mg, approximately 280mg~410mg, approximately 280mg~400mg, approximately 280mg~390mg, approximately 280mg~380mg, approximately 28 0mg~approx. 370mg, approx. 280mg~approx. 360mg, approx. 280mg~approx. 350mg, approx. 280mg~approx. 340mg, approx. 280mg~approx. 330mg, approx. 280mg~approx. 320mg, approx. 280mg~approx. 310mg, approx. 280mg~approx. 300mg, approx. 280mg~approx. 290mg, approx. 290mg~approx. 500mg, approx. 290mg~approx. 490mg, approx. 290mg~approx. 480mg, approx. 290mg~approx. 470mg, approx. 290mg~approx. 460mg, approx. 290mg~approx. 450mg, approx. 290mg~approx. 440mg, approx. 290mg~approx. 430mg, approx. 290mg~approx. 420mgApproximately 290mg~410mg, approximately 290mg~400mg, approximately 290mg~390mg, approximately 290mg~380mg, approximately 290mg~370mg, approximately 290mg~360mg, approximately 290mg~350mg, approximately 290mg~340mg, approximately 290mg~330mg, approximately 290mg~320mg, approximately 290mg~310mg, approximately 290mg~300mg, approximately 300mg~500mg, approximately 300mg~490mg, approximately 300mg~480mg, approximately 300mg~470mg, approximately 300mg~460mg, approximately 300mg~450mg 0mg, approximately 300mg~440mg, approximately 300mg~430mg, approximately 300mg~420mg, approximately 300mg~410mg, approximately 300mg~400mg, approximately 300mg~390mg, approximately 300mg~380mg, approximately 300mg~370mg, approximately 300mg~360mg, approximately 300mg~350mg, approximately 300mg~340mg, approximately 300mg~330mg, approximately 300mg~320mg, approximately 300mg~310mg, approximately 310mg~500mg, approximately 310mg~490mg, approximately 310mg~480mg, approximately 310mg~ Approximately 470mg, approximately 310mg~approximately 460mg, approximately 310mg~approximately 450mg, approximately 310mg~approximately 440mg, approximately 310mg~approximately 430mg, approximately 310mg~approximately 420mg, approximately 310mg~approximately 410mg, approximately 310mg~approximately 400mg, approximately 310mg~approximately 390mg, approximately 310mg~approximately 380mg, approximately 310mg~approximately 370mg, approximately 310mg~approximately 360mg, approximately 310mg~approximately 350mg, approximately 310mg~approximately 340mg, approximately 310mg~approximately 330mg, approximately 310mg~approximately 320mg, approximately 320mg~approximately 500mg, approximately 320mg~approximately 490mg, approximately 32 0mg~approx. 480mg, approx. 320mg~approx. 470mg, approx. 320mg~approx. 460mg, approx. 320mg~approx. 450mg, approx. 320mg~approx. 440mg, approx. 320mg~approx. 430mg, approx. 320mg~approx. 420mg, approx. 320mg~approx. 410mg, approx. 320mg~approx. 400mg, approx. 320mg~approx. 390mg, approx. 320mg~approx. 380mg, approx. 320mg~approx. 370mg, approx. 320mg~approx. 360mg, approx. 320mg~approx. 350mg, approx. 320mg~approx. 340mg, approx. 320mg~approx. 330mg, approx. 330mg~approx. 500mg, approx. 330mg~approx. 490mgApproximately 330mg to 480mg, approximately 330mg to 470mg, approximately 330mg to 460mg, approximately 330mg to 450mg, approximately 330mg to 440mg, approximately 330mg to 430mg, approximately 330mg to 420mg, approximately 330mg to 410mg, approximately 330mg to 400mg, approximately 330mg to 390mg, approximately 330mg to 380mg, approximately 3, 30mg~approx. 370mg, approx. 330mg~approx. 360mg, approx. 330mg~approx. 350mg, approx. 330mg~approx. 340mg, approx. 340mg~approx. 500mg, approx. 340mg~approx. 490mg, approx. 340mg~approx. 480mg, approx. 340mg~approx. 470mg, approx. 340mg~approx. 460mg, approx. 340mg~approx. 450mg, approx. 340mg~approx. 440mg, approx. 340mg~approx. 430mg, approx. 340mg~approx. 420mg, approx. 340mg~approx. 410mg, approx. 340mg~approx. 400mg, approx. 340mg~approx. 390mg, approx. 340mg~approx. 380mg, approx. 340mg~approx. 370mg g, approximately 340mg~approx. 360mg, approximately 340mg~approx. 350mg, approximately 350mg~approx. 500mg, approximately 350mg~approx. 490mg, approximately 350mg~approx. 480mg, approximately 350mg~approx. 470mg, approximately 350mg~approx. 460mg, approximately 350mg~approx. 450mg, approximately 350mg~approx. 440mg, approximately 350mg~approx. 430mg, approximately 350mg~approx. 420mg, approximately 350mg~approx. 410mg, approximately 350mg~approx. 400mg, approximately 350mg~approx. 390mg, approximately 350mg~approx. 380mg, approximately 350mg~approx. 370mg, approximately 350mg~approx. 360mg, approximately 360mg~approx. 500mg, approximately 360mg~490mg, approximately 360mg~480mg, approximately 360mg~470mg, approximately 360mg~460mg, approximately 360mg~450mg, approximately 360mg~440mg, approximately 360mg~430mg, approximately 360mg~420mg, approximately 360mg~410mg, approximately 360mg~400mg, approximately 360mg~390mg, approximately 360mg~380mg, approximately 360mg~370mg, approximately 370mg~500mg, approximately 370mg~490mg, approximately 370mg~480mg, approximately 370mg~470mg, approximately 370mg mg~approx. 460mg, approx. 370mg~approx. 450mg, approx. 370mg~approx. 440mg, approx. 370mg~approx. 430mg, approx. 370mg~approx. 420mg, approx. 370mg~approx. 410mg, approx. 370mg~approx. 400mg, approx. 370mg~approx. 390mg, approx. 370mg~approx. 380mg, approx. 380mg~approx. 500mg, approx. 380mg~approx. 490mg, approx. 380mg~approx. 480mg, approx. 380mg~approx. 470mg, approx. 380mg~approx. 460mg, approx. 380mg~approx. 450mg, approx. 380mg~approx. 440mg, approx. 380mg~approx. 430mg, approx. 380mg~approx. 420mg,Approx. 380 mg ~ approx. 410 mg, approx. 380 mg ~ approx. 400 mg, approx. 380 mg ~ approx. 390 mg, approx. 390 mg ~ approx. 500 mg, approx. 390 mg ~ approx. 490 mg, approx. 390 mg ~ approx. ~450mg, 390mg~440mg, 390mg~430mg, 390mg~420mg, 390mg~410mg, 390mg~400mg, 400mg~500mg, 400mg~490mg, 400mg~480mg Approximately 400mg to 470mg, approximately 400mg to 460mg, approximately 400mg to 450mg, approximately 400mg to 440mg, approximately 400mg to 430mg, approximately 400mg to 420mg, approximately 400mg to 410mg, approximately 410mg to 500mg, approximately 410mg to 490mg, approximately 410mg to 480mg, approximately 410mg to 470mg, approximately 410mg to 460mg, approximately 410mg to 450mg, approximately 410mg to 440mg, approximately 410mg to 430mg, approximately 410mg to 420mg, approximately 420mg to 500mg g, approx. 420 mg ~ approx. 490 mg, approx. 420 mg ~ approx. 480 mg, approx. 420 mg ~ approx. 470 mg, approx. 420 mg ~ approx. 460 mg, approx. 420 mg ~ approx. 450 mg, approx. mg~490mg, 430mg~480mg, 430mg~470mg, 430mg~460mg, 430mg~450mg, 430mg~440mg, 440mg~500mg, 440mg~490mg, 440mg~480 This includes administering the compound of formula (I) to the subject once or twice daily in doses of mg, approximately 440 mg to 470 mg, approximately 440 mg to 460 mg, approximately 440 mg to 450 mg, approximately 450 mg to 500 mg, approximately 450 mg to 490 mg, approximately 450 mg to 480 mg, approximately 450 mg to 470 mg, approximately 450 mg to 460 mg, approximately 470 mg to 500 mg, approximately 470 mg to 490 mg, approximately 470 mg to 480 mg, approximately 480 mg to 500 mg, approximately 480 mg to 490 mg, or approximately 490 mg to 500 mg.

[0434] In some administrative cases, this method is used for approximately 10mg to 500mg, approximately 10mg to 450mg, approximately 10mg to 400mg, approximately 10mg to 350mg, approximately 10mg to 300mg, approximately 10mg to 250mg, approximately 10mg to 200mg, approximately 10mg to 150mg, approximately 10mg to 120mg, approximately 10mg to 100mg, approximately 10mg to 50mg, approximately 10mg to 20mg, approximately 20mg to 500mg, approximately 20mg to 450mg, approximately 20mg to 400mg, approximately 20mg to 350mg, approximately 20mg to 320mg, and approximately 20mg to 3 00mg, about 20mg to about 250mg, about 20mg to about 200mg, about 20mg to about 150mg, about 20mg to about 120mg, about 20mg to about 100mg, about 20mg to about 50mg, about 40mg to about 500mg, about 40mg to about 450mg, about 40mg to about 400mg, about 40 mg~350mg, 40mg~320mg, 40mg~300mg, 40mg~250mg, 40mg~200mg, 40mg~150mg, 40mg~120mg, 40mg~100mg, 40mg~50mg, 50mg~500m g, approx. 50 mg to approx. 450 mg, approx. 50 mg to approx. 400 mg, approx. 50 mg to approx. 350 mg, approx. 50 mg to approx. 320 mg, approx. 50 mg to approx. 300 mg, approx. ~100mg, 100mg~500mg, 100mg~450mg, 100mg~400mg, 100mg~350mg, 100mg~320mg, 100mg~300mg, 100mg~250mg, 100mg~200mg, approx. mg ~ approx. 150 mg, approx. 100 mg ~ approx. 120 mg, approx. 120 mg ~ approx. 500 mg, approx. 120 mg ~ approx. 450 mg, approx. 20mg to about 200mg, about 120mg to about 150mg, about 150mg to about 500mg, about 150mg to about 450mg, about 150mg to about 400mg, about 150mg to about 350mg, about 150mg to about 320mg, about 150mg to about 300mg, about 150mg to about 250mg,Approximately 150mg to approximately 200mg, approximately 200mg to approximately 500mg, approximately 200mg to approximately 450mg, approximately 200mg to approximately 400mg, approximately 200mg to approximately 350mg, approximately 200mg to approximately 320mg, approximately 200mg to approximately 300mg, approximately 200mg to approximately 250mg , about 250 mg to about 500 mg, about 250 mg to about 450 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, about 250 mg to about 320 mg, about 250 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 450 This includes administering the compound of formula (I) to the subject once or twice daily in doses of approximately 300 mg to 400 mg, 300 mg to 350 mg, 300 mg to 320 mg, 320 mg to 500 mg, 320 mg to 450 mg, 320 mg to 400 mg, 320 mg to 350 mg, 350 mg to 500 mg, 350 mg to 450 mg, 350 mg to 400 mg, 400 mg to 500 mg, 400 mg to 450 mg, or 450 mg to 500 mg.

[0435] In some embodiments, this method is used for approximately 20mg to 400mg, approximately 20mg to 350mg, approximately 20mg to 320mg, approximately 20mg to 300mg, approximately 20mg to 250mg, approximately 20mg to 200mg, approximately 20mg to 150mg, approximately 20mg to 120mg, approximately 20mg to 100mg, approximately 20mg to 50mg, approximately 40mg to 400mg, approximately 40mg to 350mg, approximately 40mg to 320mg, approximately 40mg to 300mg, approximately 40mg to 250mg, and approximately 40mg mg ~ about 200mg, about 40mg - about 150mg, about 40mg - about 120mg, about 40mg - about 100mg, about 50mg - about 400mg, about 50mg - about 350mg, about 50mg - about 320mg, about 50mg - about 300mg, about 50mg - about 250mg, about 50mg to about 200mg, about 50mg to about 150mg, about 50mg to about 120mg, about 50mg to about 100mg, about 100mg to about 400mg, about 100mg to about 350mg, about 100mg to about 320mg, about 100mg to about 3 00mg, about 100mg to about 250mg, about 100mg to about 200mg, about 100mg to about 150mg, about 120mg to about 400mg, about 120mg to about 350mg, about 120mg to about 320mg, about 120mg to about 300mg, about 120m g ~ approx. 250 mg, approx. 120 mg ~ approx. 200 mg, approx. 150 mg ~ approx. 400 mg, approx. 150 mg ~ approx. 350 mg, approx. 150 mg ~ approx. 320 mg, approx. This includes administering a compound of formula (I) to the subject once or twice daily in doses of approximately 00 mg to 400 mg, approximately 200 mg to 350 mg, approximately 200 mg to 320 mg, approximately 200 mg to 300 mg, approximately 200 mg to 250 mg, approximately 250 mg to 400 mg, approximately 250 mg to 350 mg, approximately 250 mg to 320 mg, approximately 250 mg to 300 mg, approximately 300 mg to 400 mg, approximately 300 mg to 350 mg, approximately 320 mg to 400 mg, or approximately 350 mg to 400 mg.

[0436] In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg to about 500 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg to about 400 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg to about 300 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg to about 200 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg to about 100 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 20 mg to about 500 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 20 mg to about 400 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 20 mg to about 300 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 20 mg to about 200 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 20 mg to about 100 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 50 mg to about 500 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 50 mg to about 400 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 50 mg to about 300 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in doses of about 50 mg to about 200 mg once or twice daily to a subject.In some embodiments, the method involves administering a compound of formula (I) in a dose of about 50 mg to about 100 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 100 mg to about 500 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 100 mg to about 400 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 100 mg to about 300 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 100 mg to about 200 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 200 mg to about 500 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 200 mg to about 400 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 200 mg to about 300 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 300 mg to about 500 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 300 mg to about 400 mg once or twice daily to a subject.

[0437] In some embodiments, the method involves administering a compound of formula (I) in a dose of about 15 mg to about 25 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 18 mg to about 22 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 19 mg to about 21 mg once or twice daily to a subject.

[0438] In some embodiments, the method involves administering a compound of formula (I) to a subject once or twice daily in doses of about 15 mg, about 16 mg, about 17 mg, 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg.

[0439] In some embodiments, the method involves administering a compound of formula (I) in a dose of about 40 mg to about 60 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 45 mg to about 55 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 47 mg to about 53 mg once or twice daily to a subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 49 mg to about 51 mg once or twice daily to a subject.

[0440] In some embodiments, the method involves administering a compound of formula (I) to a subject once or twice daily in doses of about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg.

[0441] In some embodiments, the method involves administering to a subject a compound of formula (I) in doses of about 15 mg, about 16 mg, about 17 mg, 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg once or twice daily.

[0442] For some competent purposes, this method is used for approximately 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, and 270mg. This includes administering to the subject a compound of formula (I) in doses of approximately 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg once or twice daily. In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg, about 20 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg to a subject once or twice daily. In some embodiments, the method involves administering a compound of formula (I) in doses of about 20 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg to a subject once or twice daily.

[0443] In some embodiments, the method involves administering a compound of formula (I) to a subject once or twice daily in doses of about 20 mg or about 50 mg.

[0444] In one embodiment, the method comprises administering a dose of about 10 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 20 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 30 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 40 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 50 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 60 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 70 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 80 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 90 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 100 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 110 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 120 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of about 130 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of about 140 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of about 150 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of about 160 mg of the compound of formula (I) once or twice daily to a subject.In one embodiment, the method comprises administering a dose of approximately 170 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method comprises administering a dose of approximately 180 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method comprises administering a dose of approximately 190 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method comprises administering a dose of approximately 200 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method comprises administering a dose of approximately 210 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method comprises administering a dose of approximately 220 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 230 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method involves administering a dose of approximately 240 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method involves administering a dose of approximately 250 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method involves administering a dose of approximately 260 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method involves administering a dose of approximately 270 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method involves administering a dose of approximately 280 mg of the compound of formula (I) to a subject once or twice daily. In one embodiment, the method comprises administering a dose of approximately 290 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of approximately 300 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of approximately 310 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of approximately 320 mg of the compound of formula (I) once or twice daily to a subject.In one embodiment, the method involves administering a dose of approximately 330 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 340 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 350 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 360 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 370 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 380 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 390 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 400 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 410 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 420 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 430 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method involves administering a dose of approximately 440 mg of the compound of formula (I) once or twice daily to the subject. In one embodiment, the method comprises administering a dose of approximately 450 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of approximately 460 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of approximately 470 mg of the compound of formula (I) once or twice daily to a subject. In one embodiment, the method comprises administering a dose of approximately 480 mg of the compound of formula (I) once or twice daily to a subject.In one embodiment, the method comprises administering a compound of formula (I) in a dose of about 490 mg once or twice daily to a subject. In one embodiment, the method comprises administering a compound of formula (I) in a dose of about 500 mg once or twice daily to a subject.

[0445] In some embodiments, this method involves administering a dose of the compound of formula (I) once daily (for example, every 24 hours).

[0446] In some embodiments, the method involves administering a compound of formula (I) in a dose of about 15 mg to about 25 mg once daily (for example, every 24 hours) to the subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 18 mg to about 22 mg once daily (for example, every 24 hours) to the subject.

[0447] In some embodiments, the method involves administering a compound of formula (I) to a subject once daily (for example, every 24 hours) in doses of about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg.

[0448] In a further embodiment, the method involves administering a compound of formula (I) in a dose of about 20 mg once daily (for example, every 24 hours) to the subject.

[0449] In some embodiments, the method involves administering a compound of formula (I) in a dose of about 40 mg to about 60 mg once daily (e.g., every 24 hours) to the subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 45 mg to about 55 mg once daily (e.g., every 24 hours) to the subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 47 mg to about 53 mg once daily (e.g., every 24 hours) to the subject. In some embodiments, the method involves administering a compound of formula (I) in a dose of about 49 mg to about 51 mg once daily (e.g., every 24 hours) to the subject.

[0450] In some embodiments, the method involves administering a compound of formula (I) to a subject once daily (for example, every 24 hours) in doses of about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg.

[0451] In some embodiments, the method involves administering a compound of formula (I) in a dose of about 50 mg once daily (for example, every 24 hours) to a subject.

[0452] In some embodiments, the method involves administering to a subject a compound of formula (I) in doses of about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg once daily (for example, every 24 hours).

[0453] For some competent purposes, this method is suitable for approximately 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, and 28mg. This involves administering a compound of formula (I) in doses of 0 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, or approximately 500 mg to the subject once daily (for example, every 24 hours). In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg, about 20 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg to a subject once daily (for example, every 24 hours).

[0454] In some embodiments, this method involves administering a dose of the compound of formula (I) twice daily.

[0455] In some embodiments, this method involves administering a dose of the compound of formula (I) twice a day (for example, every 12 hours).

[0456] In some embodiments, the method involves administering a compound of formula (I) in doses of about 15 mg to about 25 mg twice daily (e.g., every 12 hours). In some embodiments, the method involves administering a compound of formula (I) in doses of about 18 mg to about 22 mg twice daily (e.g., every 12 hours).

[0457] In some embodiments, the method involves administering a compound of formula (I) in doses of about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg to a subject twice daily (for example, every 12 hours).

[0458] In a further embodiment, the method involves administering a compound of formula (I) in a dose of about 20 mg twice daily (for example, every 12 hours) to the subject.

[0459] In some embodiments, the method involves administering a dose of the compound of formula (I) in a dose of about 40 mg to about 60 mg twice daily (e.g., every 12 hours). In some embodiments, the method involves administering a dose of the compound of formula (I) in a dose of about 45 mg to about 55 mg twice daily (e.g., every 12 hours). In some embodiments, the method involves administering a dose of the compound of formula (I) in a dose of about 47 mg to about 53 mg twice daily (e.g., every 12 hours). In some embodiments, the method involves administering a dose of the compound of formula (I) in a dose of about 49 mg to about 51 mg twice daily (e.g., every 12 hours).

[0460] In some embodiments, the method involves administering a compound of formula (I) in doses of about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg to a subject twice daily (for example, every 12 hours).

[0461] In some embodiments, the method involves administering a compound of formula (I) in a dose of about 50 mg twice daily (for example, every 12 hours) to a subject.

[0462] In some embodiments, the method involves administering a compound of formula (I) in doses of about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, or about 55 mg to a subject twice daily (for example, every 12 hours).

[0463] For some competent purposes, this method is suitable for approximately 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, and 28mg. This involves administering a compound of formula (I) in doses of 0 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, or approximately 500 mg to the subject twice daily (for example, every 12 hours). In some embodiments, the method involves administering a compound of formula (I) in doses of about 10 mg, about 20 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg to a subject twice daily (for example, every 12 hours).

[0464] kit In some embodiments, a kit is provided that describes the method of use described herein.

[0465] In one embodiment, a kit is provided for predicting susceptibility to treatment with a PRMT5 inhibitor for subjects having or diagnosed with MTAP deficiency-related cancer. The kit comprises i) a reagent capable of detecting human MTAP-deficient and / or MTA-accumulating cancer cells, and ii) instructions on how to use the kit. Selected Embodiments Embodiment 1. A crystalline form of N-(6-amino-5-ethylpyridine-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidine-4-yl)benzo[d]thiazole-5-yl)piperidine-1-yl)-2-oxoacetamide (compound of formula (I)), [ka] The crystalline morphology wherein the X-ray powder diffraction (XRPD) pattern of the crystalline morphology includes one or more peaks at 2θ angles selected from 9.6±0.2 degrees, 16.8±0.2 degrees, 19.3±0.2 degrees, 19.4±0.2 degrees, 20.9±0.2 degrees, 23.7±0.2 degrees, and 24.5±0.2 degrees. Embodiment 2. The crystal morphology according to Embodiment 1, wherein the XRPD pattern of the crys...

Claims

1. The crystalline form of N-(6-amino-5-ethylpyridine-3-yl)-2-((2R,5S)-5-methyl-2-(2-(1-methylpiperidine-4-yl)benzo[d]thiazole-5-yl)piperidine-1-yl)-2-oxoacetamide (compound of formula (I)), 【Chemistry 15】 The crystalline morphology wherein the X-ray powder diffraction (XRPD) pattern of the crystalline morphology includes one or more peaks at 2θ angles selected from 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, 18.6±0.2 degrees, 19.4±0.2 degrees, 20.9±0.2 degrees, 23.7±0.2 degrees, and 24.5±0.2 degrees.

2. The crystal morphology according to claim 1, wherein the X-ray powder diffraction (XRPD) pattern of the crystal morphology includes one or more peaks at 2θ angles selected from 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees.

3. The crystal morphology according to claim 1, wherein the X-ray powder diffraction (XRPD) pattern of the crystal morphology includes three or more peaks at 2θ angles selected from 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees.

4. The crystal morphology according to claim 1, wherein the X-ray powder diffraction (XRPD) pattern of the crystal morphology includes peaks at 2θ angles of 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees.

5. The crystal morphology according to claim 1, wherein the X-ray powder diffraction (XRPD) pattern of the crystal morphology includes three or more peaks at 2θ angles selected from 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, 18.6±0.2 degrees, 19.4±0.2 degrees, 20.9±0.2 degrees, 23.7±0.2 degrees, and 24.5±0.2 degrees.

6. The crystal morphology according to claim 1, wherein the X-ray powder diffraction (XRPD) pattern of the crystal morphology includes peaks at 2θ angles of 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, and 24.5±0.2 degrees, and further includes at least one further peak at 2θ angles selected from 18.6±0.2 degrees, 19.4±0.2 degrees, 20.9±0.2 degrees, and 23.7±0.2 degrees.

7. The crystal morphology according to claim 1, wherein the X-ray powder diffraction (XRPD) pattern of the crystal morphology includes peaks at 2θ angles of 4.4±0.2 degrees, 9.6±0.2 degrees, 16.8±0.2 degrees, 18.6±0.2 degrees, 19.4±0.2 degrees, 20.9±0.2 degrees, 23.7±0.2 degrees, and 24.5±0.2 degrees.

8. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant.

9. The pharmaceutical composition according to claim 8, wherein the compound of formula (I) is in the crystalline form described in any one of claims 1 to 7.

10. The pharmaceutical composition according to claim 8 or 9, wherein the composition comprises about 10% (w / w) of the compound of formula (I).

11. (a) Compounds of formula (I) or pharmaceutically acceptable salts thereof 【Chemistry 16】 (b) Filler (e.g., microcrystalline cellulose), (c) Fluidizing agent (e.g., colloidal silicon dioxide), (d) Disintegrant (e.g., croscarmellose sodium), and (e) Lubricant (e.g., magnesium stearate) A pharmaceutical composition containing the following:

12. The pharmaceutical composition according to claim 11, wherein the composition comprises a crystalline form of the compound of formula (I) described in any one of claims 1 to 7.

13. The composition is (a) Approximately 10% (w / w) of the compound of formula (I), (b) Approximately 83.5% (w / w) of filler (e.g., microcrystalline cellulose), (c) Approximately 1.5% (w / w) of a fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 4% (w / w) of a disintegrant (e.g., croscarmellose sodium), and (e) Contains approximately 1% (w / w) of a lubricant (e.g., magnesium stearate), The pharmaceutical composition according to claim 11 or 12, wherein the total is 100% (w / w) or less of the composition.

14. (a) Compound of formula (I), 【Chemistry 17】 (b) Granular filler (e.g., microcrystalline cellulose), (c) Granule fluidizing agent (e.g., colloidal silicon dioxide), (d) Granule disintegrants (e.g., croscarmellose sodium), (e) Granular lubricant (e.g., magnesium stearate), (f) Extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) an extragranular disintegrant (e.g., croscarmellose sodium), and (h) Extragranular lubricant (e.g., magnesium stearate) A pharmaceutical composition containing the following:

15. The pharmaceutical composition according to claim 14, wherein the composition comprises a crystalline form of the compound of formula (I) described in any one of claims 1 to 7.

16. The composition is (a) A compound of formula (I) in an amount of approximately 2% (w / w) to approximately 20% (w / w), (b) Granular filler of approximately 50% (w / w) to approximately 90% (w / w) (e.g., microcrystalline cellulose), (c) Approximately 0.75% (w / w) to approximately 1.25% (w / w) of a granular fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 1% (w / w) to approximately 3% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium), (e) Approximately 0.25% (w / w) to approximately 0.75% (w / w) of an intragranular lubricant (e.g., magnesium stearate), (f) Approximately 0.25% (w / w) to approximately 0.75% (w / w) of an extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Approximately 1% (w / w) to approximately 3% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium), and (h) Contains approximately 0.25% (w / w) to approximately 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate), The pharmaceutical composition according to claim 14 or 15, wherein the total is 100% (w / w) or less of the composition.

17. The composition is (a) Approximately 10% (w / w) of the compound of formula (I), (b) Approximately 83.5% (w / w) of granular filler (e.g., microcrystalline cellulose), (c) Approximately 1% (w / w) of a granular fluidizing agent (e.g., colloidal silicon dioxide), (d) Approximately 2% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium), (e) Approximately 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate), (f) Approximately 0.5% (w / w) of an extragranular fluidizing agent (e.g., colloidal silicon dioxide), (g) Approximately 2% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium), (h) Contains approximately 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate), The pharmaceutical composition according to claim 14 or 15, wherein the total is 100% (w / w) or less of the composition.

18. A dosage form comprising the pharmaceutical composition according to any one of claims 8 to 17.

19. The dosage form according to claim 18, wherein the total weight of the pharmaceutical composition in the dosage form is about 100 mg to about 500 mg.

20. The dosage form according to claim 18 or 19, wherein the composition comprises about 10 mg to about 50 mg of the compound of formula (I).

21. The dosage form according to claim 18 or 19, wherein the composition comprises about 10 mg or about 50 mg of the compound of formula (I).

22. Use of the pharmaceutical composition according to any one of claims 8 to 17, comprising a therapeutically effective amount of the compound of formula (I), in a method for treating MTAP deficiency and / or MTA accumulation disease in a patient in need thereof.

23. The use according to claim 22, wherein the disease is MTAP deficiency and / or MTA accumulation cancer.

24. A method for treating cancer in a person in need thereof, comprising the use of a pharmaceutical composition according to any one of claims 8 to 17, wherein the method is as follows: a) Evaluating the levels of MTAP and / or MTA in a test sample obtained from the subject, wherein the MTA level can be evaluated directly (e.g., by ELISA or LC-MS / MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC, or by RNA splicing), b) Comparing the test sample with a reference substance, wherein the MTAP deficiency and / or MTA accumulation in the test sample compared with the reference substance indicates that the cancer in the subject responds to therapeutic treatment with a PRMT5 inhibitor. c) the use comprising administering to the subject identified in step b) an effective amount (e.g., a therapeutically effective amount) of the compound of formula (I) (formula a (I)) according to any one of claims 8 to 17.

25. The use according to claim 23 or 24, wherein the cancer is glioblastoma, malignant peripheral nerve schwannoma (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, e.g., pancreatic ductal adenocarcinoma (PDAC)), mesothelioma, melanoma, non-small cell lung cancer (NSCLC, e.g., lung squamous cell carcinoma or lung adenocarcinoma), astrocytoma, undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura, and colorectal cancer or sarcoma.

26. The use according to any one of claims 22 to 25, wherein the method further comprises administering a second therapeutic agent.

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